Who-Guide Intens Tbcase Ipticf PDF

Guidelines for intensified
tuberculosis case-finding
and isoniazid preventive
therapy for people
living with HIV
in resourceconstrained
settings
Annexes
(for web posting and CD-Rom distribution in tandem

with the guidelines document)
Guidelines for intensified

tuberculosis case-finding
and isoniazid preventive
therapy for people
living with HIV
in resourceconstrained
settings
Annexes
(for web posting and CD-Rom distribution in tandem

with the guidelines document)
Department of HIV/AIDS
Stop TB Department
World Health Organization, Geneva, Switzerland
WHO Library Cataloguing-in-Publication Data

Guidelines for intensified tuberculosis case-finding and isoniazid preventive therapy for people living with HIV in
resource-constrained settings.
1.Tuberculosis - prevention and control. 2.Tuberculosis - diagnosis. 3.HIV infections - complications. 4.Isoniazid therapeutic use. 5.Predictive value of tests. 6.Developing countries. 7.Guidelines. I.World Health Organization. Stop TB
Dept. II.World Health Organization. Dept of HIV/AIDS.
ISBN 978 92 4 150070 8
(NLM classification: WF 220)
World Health Organization 2011
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Summary of declarations of interest

All members of the Guidelines Group were asked to complete a World Health Organization (WHO) declaration of interest
form and only two declared a conflict of interest. These were discussed within the WHO steering group and then with the
Guidelines Group before the deliberations. Alison Grant declared receiving financial support of GB 200 from Roche to
attend the International AIDS Conference, Sydney, 2007 when the aeroplane she was flying in broke down and the GB
200 was paid for a flight deviation. Helen Ayles declared receiving financial support amounting to US$ 15 000 from the Bill
and Melinda Gates Foundation, US$ 50 000 from Senter Novum and 150 000 from Delft Imaging Systems to conduct
research on intensified TB case-finding and isoniazid preventive therapy for TB, and the development of computer-aided
diagnostics for TB/HIV. The Guidelines Group discussed these and concluded that there was no conflict of interest.
Declarations of interest were collected from all non-WHO peer reviewers. No peer reviewer declared a conflict of interest.
All declarations of interest are on electronic file with the Department of HIV/AIDS of WHO.
Acknowledgements
The development of these guidelines was financially supported by the Joint United Nations Programme on HIV/AIDS
Unified Budget and Workplan (UNAIDS UBW) and the US Presidents Emergency Plan for AIDS Relief (PEPFAR) through
the Centers for Disease Control and Prevention (CDC) and United States Agency for International Development (USAID).
Contents
Annex 1: WHO guidelines meeting on preventive therapy and case-finding for TB in people living with HIV: list

of participants
Annex 2: WHO guidelines group
Annex 3: WHO meeting on preventive therapy and case-finding for TB among people living with HIV: meeting

agenda
Annex 4: Report on the consultation for the revision of the WHO/UNAIDS policy statement on preventive therapy

against TB for people living with HIV
Annex 5: Summary of findings and quality of evidence evaluation: intensified TB case-finding for adults and

adolescents living with HIV
24
Annex 6: Summary of findings and quality of evidence evaluation: preventive therapy for adults and adolescents

living with HIV
32
Annex 7: Summary of findings and quality of evidence evaluation: secondary prophylaxis
80
Annex 8: Summary of findings and quality of evidence: tuberculin skin test (TST)
86
Annex 9: Summary of findings and quality of evidence evaluation: interferon gamma release assays (IGRA)
92
Annex 10: Summary of findings and quality of evidence: INH resistance
99
Annex 11: Summary of finding and quality of evidence: adherence to preventive therapy
107
Annex 12: Summary of findings and quality of evidence: cost effectiveness
113
Annex 13: Summary of findings and quality of evidence evaluation: intensive TB case-finding for children living

with HIV
120
Annex 14: Summary of findings and quality of evidence: preventive therapy for children living with HIV
128
Annex 15: Research gaps
135
ii
Annex 1: WHO guidelines meeting on preventive therapy
and case-finding for TB in people living with HIV: list of participants

2527 January 2010
Helen Ayles
Department of Medicine
P.O. Box 50697
Ridgeway Campus, Nationalist Road
Lusaka
Zambia
Mean Chhivun
National Center for HIV/AIDS Dermatology and STD
Ministry of Health
No 266, St 1019, SK Phnom Penh Thmey Khan
Roesseykeo
Phnom Penh
Cambodia
Draurio Barreira
Programa Nacional de Controle da Tuberculose
DEVEP/SVS/MS
SCS Quadra 4 Bloco A
Edif. Principal 3 andar
70.304-000 Braslia - DF
Anupong Chitwarakorn
HIV/STI/TB) Bureau of AIDS/TB/STI
Department of Disease Control
Ministry of Public Health
1100 Nonthaburi
Thailand
Franois-Xavier Blanc
Agence Nationale de Recherche sur le SIDA et les
Hpatites virales
101 rue de Tolbiac, 75013 Paris
France
Gavin Churchyard
Aurum Institute for Health Research
P.O. Box 61587, 2107, Marshalltown
Republic of South Africa
Charlene Brown
Technical Leadership & Research Division
Office of HIV/AIDS
US Agency for International Development
United States of America
Mark Cotton
Stellenbosch University
Department of Paediatrics and Child Health
Faculty of Health Sciences
P.O. Box 19063, 7505 Tygerberg
Kevin Cain
International Research and Programs Branch
Division of Tuberculosis Elimination
Centers for Disease Control and Prevention
1600 Clifton Rd., MS-E-10 Atlanta, GA 30333
Anand Date
Global AIDS Program, TB/HIV Team, HIV Care and
Treatment Branch
1600 Clifton Road, N.E.
Mailstop E-04
Atlanta, GA 30333
Rolando A. Cedillos
Proyecto Regional VIH SIDA Centroamricamerica
Av. El Espino 65 Urbanizacion Madre Selva
Antiguo Cuscatlan, La Libertad
El Salvador
Richard Chaisson
Consortium to Respond Effectively to the AIDS and
TB Epidemic
Johns Hopkins University
Center for Tuberculosis Research
1503 E. Jefferson Street
21231-1003, Baltimore
Kevin De Cock (Co-chair)

P.O. Box 54840-00200
Kenya
Dmytro Donchuk
State Medical University
Ukraine
Annex 1
Wafaa El-Sadr
Michael Kimerling
International Center for AIDS Care and Treatment Bill and Melinda Gates Foundation
Programs
PO Box 23350
Mailman School of Public Health
Seattle, WA 98102
Columbia University
USA
722 West 168th Street, Room 715
New York, NY 10032
Steve Lawn
Institute of Infectious Diseases and Molecular

Medicine, Faculty of Health
Peter Godfrey-Faussett
Desmond Tutu HIV Centre
Department of Infection & Tropical Diseases
Anzio Road
London School of Hygiene & Tropical Medicine
Observatory 7925
Keppel Street, WC1E 7HT, London
Cape Town
United Kingdom of Great Britain and Northern
Ireland
Gary Maartens
Olga Petrovna Frolova
University of Cape Town, Faculty of Health Sciences
TB/HIV Health Care Centre of Ministry of Health and Division of Clinical Pharmacology Department of

Social Development
Medicine
107014, Moscow,
Observatory 7925
3, Barbolina Street
Russian Federation
Barbara Jean Marston
Paula Fujiwara
Global AIDS Program, Care and Treatment Branch
International Union Against Tuberculosis & Lung Centers for Disease Control and Prevention
Disease
1600 Clifton Road, N.E. Mailstop E04
68 boulevard Saint-Michel, 75006
Atlanta, GA 30333
Paris
France
Thombile Mbengashe
Alison Grant
National AIDS Programme Cluster
Clinical Research Unit
National Department of Health
London School of Hygiene & Tropical Medicine
Private Bag X828
Keppel Street
Pretoria 0001
London WC1E 7HT
Ireland
Zenebe Melaku
International Center for AIDS Care and Treatment
Mark Harrington
Programs
Treatment Action Group
Addis Ababa
611 Broadway, Suite 612
Ethiopia
New York, NY 10012
Peter Mgosha
Ministry of Health and Social Welfare
Catherine Hewison
National AIDS Control Programme
Mdecins Sans Frontires
P.O. Box 11578
8 Rue Saint-Sabin
Tanzania
75011, Paris
France
Muhamed Mulongo
Tropical Medical and Maternity Center District
Maureen Kamene Kimenye
P.O. Box 17, Sironko
Uganda
P.O. Box 10016
Nairobi
Kenya
Annex 1: WHO guidelines meeting on preventive therapy and case-finding for TB in people living with HIV: list of participants
Sharon Nachman
Health Science Center State University New York
Stony Brook
NY 11794-8111
Alasdair Reid
HIV/TB Adviser
UNAIDS
20 Avenue Appia
CH -1211 Geneva 27
Switzerland
Stewart Reid
Centre for Infectious Disease Research in Zambia
P.O. Box 34681
Plot 2374 , Counting House Square
Thabo Mbeki Road
Lusaka
Zambia
Taraz Samandari
1600 Clifton Road
MS-E-10 Atlanta, GA 30333
Paula Isabel Samo Gudo
National Tuberculosis Program
Mozambique
Mauro Schechter
Hospital Universitario Clementino Fraga Filho
Universidade Federal do Rio de Janeiro
Rua Professor Rodolpho Paulo Rocco, n 255 Ilha
do Fundo Rio de Janeiro RJ
Brazil 21941.590
Holger Schnemann
Department of Clinical Epidemiology & Biostatistics
McMaster University of Health Sciences Centre
Room 2C10B, 1200 Main Street West
Hamilton, ON, L8N 3Z5
Canada
Wim Vandevelde
European Community Advisory Board
European AIDS Treatment Group
Place Raymond Blyckaerts 13
B-1050 Brussels
Belgium
Eric van Praag
Family Health International
Off Haile Selassie Road
Plot No. 8/10, Oysterbay
PO Box 78735 Dar es Salaam
Tanzania
Jay K. Varma
U.S. CDC International Emerging Infections Program
CDC-GAP China Office
23 Dongzhimenwai Dajie
Beijing 100600
Peoples Republic of China
Fujie Zhang
Fujie Zhang National Center for AIDS/STD
Control and Prevention
Chinese CDC
No. 27 Nanwei Road
Beijing, P.R. China 100050
Annex 1
WHO REGIONAL OFFICES

AFRO
Frank Lule
WPRO
Massimo Ghidinelli
AMRO
Rafael Lopez Olarte
SEARO
Puneet Dewan
WHO SECRETARIAT, HEADQUARTERS

Lopold Blanc
STOP TB Department
Suzanne Hill (Co-chair)

Policy, Access and Rational Use
Siobhan Crowley
HIV/AIDS Department
Ying-Ru Lo
HIV/AIDS Department
Colleen Daniels
STOP TB Department
Lulu Muhe
Child and Adolescent Health
Andrew Doupe
HIV/AIDS Department
Eyerusalem Negussie
HIV/AIDS Department
Haileyesus Getahun (Guidelines Coordinator)

STOP TB Department
Rose Pray
STOP TB Department
Sandy Gove
HIV/AIDS Department
Mario Raviglione
STOP TB Department
Reuben Granich (Guidelines Coordinator)

HIV/AIDS Department
Delphine Sculier
STOP TB Department
Teguest Guerma
HIV/AIDS Department
Yves Souteyrand
HIV/AIDS Department
Malgorzata Grzemska
STOP TB Department
Diana Weil
STOP TB Department
Christian Gunneberg
STOP TB Department
WHO CONSULTANTS
Christopher Akolo
9040 I Steinberg Way
Laurel
MD 29723
Martina Penazzato
Via E. Forcellini 43
35128 Padova
Italy
Georgina Russell
16 Oliphant Street, London W10 4EG
Ireland
Caoimhe Smyth
WHO HIV/AIDS Department
Annex 2: WHO guidelines group

The following group represents experts from the fields of HIV, TB, HIV/TB, sexually transmitted
infections, child health, infectious and tropical diseases, clinical research, maternal health,
infectious disease research, clinical epidemiology and biostatistics.
Helen Ayles (ZAMBART Project, Zambia), Draurio Barreira (National TB Program, Brazil), Franois-Xavier Blanc
(Agence Nationale de Recherche sur le SIDA et les Hpatites virales, France), Charlene Brown (US Agency
for International Development [USAID], United States of America [USA]), Kevin Cain (Centers for Disease
Control and Prevention [CDC], USA), Rolando Cedillos (Proyecto Regional VIH SIDA para Centroamrica, El
Salvador), Richard Chaisson (Johns Hopkins University, USA), Mean Chhivun (National AIDS Programme,
Cambodia), Anupong Chitwarakorn (Ministry of Public Health, Thailand), Gavin Churchyard (Aurum Institute for
Health Research, Republic of South Africa), Mark Cotton (Stellenbosch University, Republic of South Africa),
Anand Date (CDC, USA), Dmytro Donchuk (State Medical University, Ukraine), Wafaa El-Sadr (International
Center for AIDS Programs, Columbia University, USA), Peter Godfrey-Faussett (London School of Hygiene
and Tropical Medicine, UK), Olga Petrovna Frolova (Ministry of Health and Social Development, Russian
Federation), Paula Fujiwara (International Union Against Tuberculosis and Lung Disease [The Union], France),
Alison Grant (London School of Hygiene and Tropical Medicine, UK), Mark Harrington (Treatment Action Group,
USA), Catherine Hewison (Medecins sans Frontieres [MSF], France), Maureen Kamene Kimenye (Ministry
of Public Health, Kenya), Michael Kimerling (Bill and Melinda Gates Foundation, USA), Stephen D. Lawn,
(University of Cape Town, South Africa), Gary Maartens (University of Cape Town, South Africa), Barbara Jean
Marston (CDC, USA), Thombile Mbengashe (National Department of Health, Republic of South Africa), Zenebe
Melaku (International Center for AIDS Care and Treatment Programs [ICAP], Ethiopia), Peter Mgosha (Ministry
of Health and Social Welfare, Tanzania), Muhamed Mulongo (Tropical Medical and Maternity Centre, Uganda),
Sharon Nachman (Stony Brook University Medical Center, USA), Alasdair Reid (Joint United Nations Programme
on HIV/AIDS [UNAIDS], Geneva), Stewart Reid (Centre for Infectious Disease Research in Zambia [CIDRZ],
Zambia), Taraz Samandari (CDC, USA), Paula Isabel Samo Gudo (Ministry of Public Health, Mozambique),
Mauro Schechter (AIDS Research Laboratory, Brazil), Wim Vandevelde (European Community Advisory Board,
European AIDS Treatment Group, Belgium), Eric van Praag (Family Health International, Tanzania), Jay K.
Varma (CDC, USA), Fujie Zhang (National Center for AIDS/STD Control and Prevention, Peoples Republic of
China)
Peer reviewers
Jesus Maria Garcia Calleja (HIV/AIDS Department, WHO), Jacob Creswell (Stop TB Department, WHO),
Irina Eramova (WHO EURO), Robert Gie (University of Stellenbosch, South Africa), Steve Graham (The
Union, Australia), Prakash Kudur Hanumaiah (Karnataka Health Promotion Trust, India), Cathy Hewisson
(MSF, France), Charles Mwansambo (Kamuzu Central Hospital, Malawi), Nguyen Viet Nhung (National TB
programme, Viet Nam), Carla Obermeyer (HIV/AIDS Department, WHO), Ikushi Onozaki (Stop TB Department,
WHO), Cyril Pervilhac (HIV/AIDS Department, WHO), Renee Ridzon (Bill and Melinda Gates Foundation, USA),
Matji Rifiloe (Ministry of Health, South Africa), Quaid Saeed (WHO EMRO), Fabio Scano (WHO WPRO), Sahu
Suvanand (Stop TB Partnership), Risard Zaleskis (WHO EURO)
WHO Headquarters and Regional offices
Lopold Blanc (Stop TB Department, WHO), Colleen Daniels (Stop TB Department, WHO), Puneet Dewan
(WHO SEARO), Massimo Ghidinelli (WHO WPRO), Sandra Gove (HIV/AIDS Department, WHO), Malgorzata
Grzemska (Stop TB Department, WHO), Teguest Guerma (HIV/AIDS Department, WHO), Christian Gunneberg
(Stop TB Department, WHO), Rafael Lopez Olarte (WHO AMRO), Frank Lule (WHO AFRO), Eyerusalem
Negussie (HIV/AIDS Department, WHO), Rose Pray (Stop TB Department, WHO), Mario Raviglione (Stop TB
Department, WHO)
Coordinated by
Haileyesus Getahun and Reuben Granich
Annex 3: WHO guidelines meeting on preventive therapy
and case-finding for TB in people living with HIV: meeting agenda

2527 January 2010, Geneva, Switzerland
Day 1: 25 January 2010
08:3009:00
Registration
09:1509:30
Meeting overview and introductions
09:3009:50
Rationale and review process of guidelines
09:5010:00
Overview of GRADE methodology and review of PICOT questions for

systematic reviews of scientific evidence
09:0009:15
10:0010:30
10:3011:30
Welcome remarks
T. Guerma
M. Raviglione
K. De Cock
(Co-chair)
H. Shnemann
(Co-chair)
R. Granich
H. Getahun
M. Penazzato
Coffee break
GRADE profiles, systematic reviews and draft recommendations for

M. Penazzato
PICOT Question 1: Define the optimal duration and drug regimen (e.g. INH,
rifampicin, etc.) for treatment of LTBI to reduce the risk of developing TB
Community commentary:
W. Vandevelde, Belgium
Country/national programme commentary:
A. Chitwarakorn, Thailand
11:3012:30
Discussion: Open to the floor

M. Penazzato
PICOT Question 2: Define the optimal time to start considering IPT (i.e.
should immune status be considered and should IPT be started with ART).
N. Muraguri, Kenya
12:3014:00
14:0015:00

Lunch

A. Sharma
PICOT Question 3: Determine whether people living with HIV who had
received TB treatment in the past should be provided secondary treatment
for LTBI to prevent reinfection or recurrence of tuberculosis.
M. Harrington, United States of America
T. Mbengashe, Republic of South Africa
Annex 3: WHO meeting on preventive therapy and case-finding for TB in people living with HIV: meeting agenda
15:0016:30
16:3017:30
18:00
Working group session

Group A/PICOT 1 Optimal duration/drug regimen
Group B/PICOT 2 Optimal time to start
Group C/PICOT 3 Secondary treatment of LTBI
Report back from Groups A, B, C:

Group A/PICOT 1 (15) Optimal duration/drug regimen
Group B/PICOT 2 (15) Optimal time to start
Group C/PICOT 3 (15) Secondary treatment of LTBI
Reception:
Cafeteria, WHO/UNAIDS D Building
Day 2: 26 January
09:0009:10
Overview of Day 2
09:1010:00

PICOT Question 8: Determine the best combination of signs, symptoms
and diagnostic procedures (e.g. radiography, serum-based tests such as
IGRA, etc.) that can be used as screening tools to determine eligibility
for LTBI treatment and to diagnose TB among people living with HIV
(feasibility considerations included).
K. De Cock
(Co-chair)
H. Shnemann
(Co-chair)
K. De Cock
(Co-chair)
H. Shnemann
(Co-chair)
A. Date
Z. Melaku, Ethiopia
10:0010:30
10:3012:30

Coffee break
GRADE profiles, systematic reviews and draft recommendations

A. Sharma
for PICOT Question 4: Determine whether treatment for LTBI among
people living with HIV leads to significant development of mono-resistance
against the drugs used for LTBI treatment.
R. Cedillos, El Salvador
12:0012:30

PICOT Question 7: TST in resource-limited settings
D. Barreria, Brazil
12:3013:30
15:3015:45

Lunch
Working coffee
C. Akolo
Annex 3
15:4517:00
17:0018:30
Working group session (contd)

Group A/PICOT 4+5
Group B/PICOT 6+7
Group C/PICOT 8
Report back from Groups A, B, C:

Group A/PICOT 4 +5 (20) Resistance
Group B/PICOT 6+7 (20) TST
Group C/PICOT 8 (20) Signs, symptoms/diagnostics
Day 3: 27 January
09:0009:15
Overview of Day 3
09:1510:00
Paediatrics and IPT
10:0010:15
Coffee break
11:1512:00
Research priorities:
Report back from each group of research issues that emerged from
working group discussions
10:1511:15
12:0012:15
12:1512:30
Review of recommendations
Group A (5)
Group B (5)
Group C (5)
Wrap-up of major conclusions, recommendations

Closing and Next steps
K. De Cock
(Co-chair)
S. Hill
(Co-chair)
K. De Cock
(Co-chair)
S. Hill
(Co-chair)
S. Nachman
M. Cotton
K. De Cock
(Co-chair)
K. De Cock (Co-chair)
S. Hill (Co-chair)
R. Granich
H. Getahun
T. Guerma
M. Raviglione
Consultation for the

Revision of the WHO/UNAIDS
Policy Statement
on Preventive
Therapy against
TB for People
Living with HIV
Annex 4:
Report on the consultation for the revision of the

WHO/UNAIDS policy statement on preventive therapy
against TB for people living with HIV
16 November11 December 2009
Consultation for the

Revision of the WHO/UNAIDS
Policy Statement
on Preventive
Therapy against
TB for People
Living with HIV
Global Network of People Living with HIV

December 2009
Contents
Contents
Acknowledgments
13
Executive Summary
13
Introduction
14
Methodology
14
Results and findings
14
Survey
15
Introduction
15
Design
15
Implementation
16
16
Conclusions and Recommendations
17
Annexes
18
12
Annex 4. Report on the consultation for the revision of the WHO/UNAIDS policy statement on preventive therapy against TB for people living with HIV
Acknowledgements
he Global Network of People living with HIV

(GNP+) would like to thank and acknowledge
the following people for their assistance in
and contributions to making this e-consultation a
success: Rose Bradbury; Georgina Caswell; Chris
Mallouris; Thomas Paterson; all of the people
living with HIV who donated their time and made

valuable contributions to this consultation; and the
World Health Organization (WHO) for its support.
The e-consultation and report was coordinated and
written by Jason Farrell, CEO, Harm Reduction
Consulting Services, Inc.
Executive summary
his report represents the key findings and

recommendations that emerged during an online
e-consultation to revise the WHO/UNAIDS policy
statement on preventive therapy against TB for people
living with HIV. GNP+ organized an e-consultation
(three weeks) as well as an online survey to solicit
comments and recommendations from people living
with HIV on the WHO/UNAIDS policy statement.
The online e-consultation organized by GNP+ and
hosted by NAM was held between 16 November
and 6 December 2009. The GNP+ e-consultations
were designed to gather the perspectives and
recommendations from people living with HIV.
Each week, the consultation focused on a different
topic with several questions that covered various
aspects of the guidelines:
Week 1: (1622 November) Treatment initiation
and adherence
Week 2: (2329 November) Access to treatment
for people living with HIV
Week 3: (30 November6 December) Resolving
barriers and building support for expanded
treatment
GNP+ invited 306 advocates among people living
with HIV to participate in the consultation via e-mail.
Approximately 53 registered, representing 52
countries. Of those who registered, four were male,
30 female and 19 others chose not to identify their
gender.
Based on the numerous responses we received, a
few critical key points stood out. What was strongly
agreed to by a significant number of PLHIV advocates
was that WHOs overall goal should be to eliminate
TB infection worldwide; deal more efficiently with poor
outcomes of treatment; and make all efforts to provide
TB diagnosis and treatment as early as possible.
More importantly, we found that responses to our
consultation reflected many of the prerequisites for
13
preventive therapy as indicated in the 1998 Policy

statement on preventive therapy against TB for people
living with HIV.
As suggested in 1998, today we find that the provision
of co-located and integrated TB/HIV care should be
made available where and when possible, and there
should be an appropriate number of skilled and
efficient medical providers knowledgeable in current
diagnostics, treatment and care.
Many of the GNP+ contributors felt that the quality
of care tends to vary between doctors, nurses
and counsellors. It was suggested that all medical
providers working with people living with HIV should
have a standardized level of current knowledge on TB
prevention and treatment.
In addition to the e-consultation, GNP+ also developed
a survey to capture information on how being
diagnosed with TB, participating in medical treatment
and maintaining TB treatment impacts the daily
living situation of someone with TB. The survey was
designed to provide us with a better understanding
of the quality of care being provided and how the
relationship between the medical provider and patient
can impact treatment outcomes.
The GNP+ survey was posted during the last week of
the e-consultation (30 November7 December 2009)
using the survey monkey program. Forty HIV-positive
advocates filled out the survey. The findings showed
that having a supportive relationship with the medical
provider as well as with a family member, friend or
spouse is critical to successful TB treatment including
treatment adherence. Many of those who participated
in the survey reported being HIV-positive for an
average of 1015 years and were in a good medical
condition, indicating that they had undetectable viral
loads and did not have significant side-effects from
medications for TB prevention and/or treatment.
Annex 4
Introduction
he online e-consultation organized by GNP+

and hosted by NAM was conducted from
16 November to 6 December 2009. GNP+
e-consultations were designed to gather perspectives
and recommendations from people living with HIV.
Each week, the e-consultation focused on a different

topic, with several questions that covered various
aspects of the guidelines:
GNP+ invited 306 HIV-positive advocates

to participate in the consultation via e-mail.
Approximately 53 registered, representing 52
countries. Of those who registered, four were male,
30 female and 19 others chose not to identify their
gender.
Week 1: (1622 November) Treatment initiation

and adherence
Week 2: (2329 November) Access to treatment

for people living with HIV
Week 3: (30 November6 December) Resolving
barriers and building support for expanded
treatment
Methodology
uilding on the experience of undertaking

e-consultations, GNP+ employed a userfriendly, accessible and interactive webbased tool to gain the views and experiences of
people living with HIV globally on TB. The GNP+
e-consultation included a range of questions and
issues requested by WHO. All questions were
open-ended and aimed at gathering qualitative
information on the experiences and perspectives of
people living with HIV.
During a three-week period, a series of questions

were made available to HIV-positive advocates
through the use of a password and user name for an
online access system. Each week, a different set of
questions was posted to obtain responses from those
who had registered. To ensure timely responses to
questions and concerns regarding the consultation,
GNP+ engaged a consultant to moderate the site and
discussions, and respond to any problem or question
pertaining to TB policy and the consultation process.
hile responding to each weeks questions,

participants shared similar opinions and/or
beliefs as to what constitutes acceptable and
appropriate treatment. Keeping in mind that all those
who responded came from different geographical
locations/regions and varied types of settings and/or
delivery systems for medical care, it is the quality and
provision of care that is a cause for concern among
many of the participants. In addition to the quality and
provision of care, stigma due to their having TB and
lack of acceptance by others remain barriers for many
who are interested in seeking screening diagnosis,
treatment and maintaining ongoing medical care.
Not only were concerns regarding the quality of care
and stigma consistently noted among our participants,
but it was also strongly suggested that TB screening
be co-located within HIV testing sites. Combination
treatment should be client-centred, and tailored to
the patients specific needs such as living conditions
as well as the potential adverse effects of combining
TB medications with other prescribed medications

and/or any illicit drugs taken.
One of our participants reported that I would prefer
to receive treatment at a hospital as this creates
the way to incorporate other services while being
treated and this would also prevent some amount
of stigma and discrimination... in my country, this
exists a lot so the hospital setting would be perfect
for me. As stigma can deter many from accessing
care even in facilities with integrated care systems,
anonymity of service provision needs to be taken into
consideration. Therefore, medical centres or facilities
need to be inconspicuous and not identifiable as HIV
or TB clinics.
As stigma was mentioned throughout the consultation,
we want to draw attention to the provision of
comprehensive care. When we asked what are the
most essential outcomes sought from TB preventive
therapy, not only did we receive many responses
14
that TB should be eradicated worldwide, but we also

received a number of responses identifying the need
to assess and treat mental health conditions. I know
many people living with HIV in my country and other
countries in the xxx region who have suffered from
TB, and have been treated very badly by the healthcare providers and some of them died after few days.
I think, as people living with HIV, when they got TB,
they faced a double stigma from their surroundings
which forced them into a depressive period and really
affected their status.
Therefore, as we focus on the provision of
comprehensive care and treatment adherence, there
is clearly an identified need for attention to be devoted

to mental health support and establishing social
support systems for patients. Without appropriate
support systems, recently diagnosed individuals and
patients currently engaged in preventive therapy
are at high risk for developing depression and
terminating treatment and/or making any contact with
medical providers as well as family and friends. This
is especially the case when treating adolescents.
As reported in our consultation, adolescents are
subjected to peer pressure and stigma. These as well
as economic status can adversely affect treatment or
outcomes of preventive therapy.
Survey
Introduction
n addition to the e-consultation, GNP+ developed

a survey to capture information on how being
diagnosed with TB participating in preventive
therapy, continuing with ongoing medical treatment
and treatment adherence impacts the daily living
situation of people living with HIV. Additionally, the
goal of our survey was to gain a better understanding
of the provision of care, specifically the quality of
care, and how the relationship between the patient
and medical provider impacts treatment outcomes.
Our survey was posted during the last week of the
e-consultation (30 November7 December 2009)
using the survey monkey program. Forty HIVpositive advocates joined us in filling out the survey
questionnaires. Based on the survey findings,
having a supportive relationship with the medical
provider as well as with a family member, friend
or spouse is critical to successful TB treatment,
including treatment adherence. Many of those
who participated in the survey reported being
HIV-positive for an average of 1015 years, and
were in a good medical condition, indicating that
they had undetectable viral loads and did not have
significant side-effects from TB prevention and/or
treatment medications.
Design
he concept of conducting a survey was based

on the desire to gain a better understanding
of how TB affects or impacts the lifestyle of
people living with HIV. The e-consultation questions
were primarily based on WHO interests, focused
more on clinical issues such as preventive therapy
and treatment adherence. Therefore, we felt that
offering an alternative, less clinical approach would
be successful in garnering a broad range of pertinent
viewpoints and opinions from the community of
people living with HIV.
15
Many of the questions included in the survey were

designed to elicit information on how the doctor
patient relationship can effect treatment; what
support systems are needed or are beneficial for
maintaining treatment adherence, and who becomes
the primary source of support for and information on
TB.
The survey consisted of five sections: demographic
information; risk information; medical provider
information; TB treatment and care information; and
social support information.
Annex 4
Implementation
he survey prepared by GNP+ was made

available during the last week of our
e-consultation (30 November7 December).
HIV-positive advocates were invited to participate
in the survey by using the same password and user
name provided for the e-consultation questions. The

survey was conducted by using the survey monkey
program to rank the critical outcomes that people
living with HIV seek from TB preventive therapy.
ur survey provided interesting results.

Basic demographic information of the
survey respondents showed that:
Those taking part in the survey were mostly
from Africa, Asia, Europe and Eastern Europe.
Of them, 54% were male and 46% female.
Many reported being HIV-positive for 1015
years and were predominately between 40 and
50 years of age.
Of those who completed the survey, 54%
indentified as being men who have sex with
men (MSM), 29% as drug users and 17% had a
history of incarceration.
Individuals who reported drug use did not
mention if they had notified their medical
provider about this due to fear of the treatment
being terminated or a change in the relationship
between them.
Regarding the quality of medical care, 54% of
survey participants reported receiving medical
care regularly on a monthly basis and were
happy with their medical provider.
Surprisingly, 55% reported having a mutually
respectful relationship with their medical
provider and, of those individuals, eightyfive per cent took HIV medications and had
undetectable viral loads.
Fifty per cent of survey respondents said that
the relationship with the medical provider was
helpful for treatment adherence and, because of
this relationship, they felt comfortable disclosing
when medication doses were missed.
Of those who reported taking TB medications,
none reported any side-effects that required
discontinuation or switching of medications.
The survey findings showed that having a respectful

and/or good relationship with the medical provider
is critical for successful treatment outcomes.
Individuals who disclosed taking TB medications
also reported having undetectable viral loads and
were clinically in a good medical condition. They
self-reported that this increased the benefits they
obtained from preventive therapy. Additionally,

all survey participants reported having a family
member, spouse or friend to provide support, and
all were stably housed.
These four elements of having (1) a good relationship
with the medical provider, (2) responding well to
HIV treatment, (3) having support systems, and
(4) stable housing are key factors for successful
treatment outcomes.
However, as substantiated by the findings of the
survey, it is apparent that the individuals who
participated were well connected to medical care
and all of them indicated that they had support
either from the family, spouse or friends. Because
of these key factors, many responded well to HIV
treatment and preventive therapy for TB. Further
consultations and additional funding are required
to obtain information from individuals who are not
connected to care and support systems.
The population of people living with HIV which does
not have internet access or computers need to be
reached. This target group consists of individuals
who are at high risk for and vulnerable to resistant
strains of TB, poor care, unstable housing and
substance use. Therefore, we need to obtain
information from the population that we could not
connect with.
The information obtained clearly shows that if
there is a good relationship with the doctor, and a
supportive family environment, people will respond
well to any medical treatment. It would thus be
worthwhile for WHO consider providing additional
funding to conduct specific outreach efforts
targeting the unreached community of people
living with HIV at risk for TB, and to conduct focus
groups designed to obtain the information required
to develop appropriate interventions to successfully
connect this group with comprehensive preventive
therapy.
16
GNP+ recommends that future consultations with

people living with HIV be designed and implemented
such that they draw on the experiences of HIVpositive people at the community level, people who
may not have been reached through the GNP+
e-consultation referred to in this document.
Networks of people living with HIV and/or TB-related

organizations at country and/or regional level
may have to be supported to develop appropriate
methodologies to collect, analyse and present the
recommendations from people living with HIV at the
community level.
Conclusions and Recommendations
e provide WHO with the following

recommendations and highlight key issues
for further discussion.
The provision of preventive therapy for TB needs to

be offered in a safe, stigma-free environment that
is not identified as a TB/HIV clinic. The anonymity of
the patient needs to be taken into consideration at all
times.
HIV testing locations must have on-site screening and
preventive therapy for TB available. Opportunities
for early TB screening must be sought whenever
possible.
The quantity of medication provided to each patient
should be based solely upon the doctors prescription,
and the distance from medical provider/clinic. Those
who live near a clinic should receive a one-month
supply and those who live at a greater distance
should receive a three-month supply.
Regional and/or local HIV treatment adherence rates
should not be used to determine if TB preventive
services should be made available. They should be
used to examine why adherence rates are low and
this information should be used to improve adherence
to TB treatment.
An individuals state of health should be taken into
consideration to determine the best time and health
condition to start treatment for better results and
fewer problems from side-effects.
17
Personal perceptions regarding treatment efficacy and

its benefits can impact adherence and overall treatment
outcomes. Therefore, mental health screening should
be conducted to determine if depression and/or
personal perception could affect treatment outcome
and overall well-being.
In addition to standard testing to determine if the
prescribed TB prevention medication is working
efficiently, additional testing such as polymerase chain
reaction (PCR) HIV viral load tests should be provided
to determine if TB has been eradicated entirely from
the patient.
Treatment outcomes for adolescents can be affected
by peer support/pressure as well as stigma and
economic status.
When treating injecting drug users and those who use
other drugs, drug interactions need to be discussed
and monitored. Bioavailability and safety issues
pertaining to interactions between TB medications and
illicit drugs were noted as a concern.
The number of pills required for TB prevention and/or
treatment can present significant barriers to successful
treatment.
Substance use among individuals who have been
prescribed TB preventive therapy has not been
reported as a barrier to successful treatment. However,
each persons substance use situation can vary and
should be assessed based on the individuals stability.
Annexes
Annex 1: e-Consultation questions
Week 1: Treatment initiation and adherence
1. What do you think are the most essential outcome
or outcomes from TB preventive therapy?
2. In your opinion what do you think the best TB
preventive treatments would be: isoniazid (INH),
rifampicin (RIF), or pyrazinamide (PZA)?
3. How long do you think would be the best number
of days/months needed to take it?
4. Are there benefits of shorter treatment time
periods versus potential risks of developing
drug-resistant TB?
5. Would providing a three-month supply of
medication as opposed to a one-month supply
each month improve treatment adherence?
6. What are the acceptable and unacceptable
uncertainties relating to TB preventive therapy?
(e.g. starting too early; not having long-term
safety data on drug contraindications with
antiretroviral drugs; hepatitis coinfection and
liver toxicity)
7. What have been some of your fears and
uncertainties about TB drug resistance, both
of being (re)infected with resistant TB and
developing drug resistance while taking TB
preventive therapy?
Week 2: Access to treatment for people living
with HIV
1. What issues or problems, if any, do you think
affect people living with HIV who may be
diagnosed with TB or are taking TB preventive
therapy?
2. Should people living with HIV who received
TB treatment in the past be given secondary
treatment for latent TB infection to prevent
reinfection or recurrence of TB?
3. What would be the best time to start considering
preventive
therapy
(isoniazid
preventive
treatment; IPT)?
4. Should the condition of a persons immune status

be considered as a factor for when to start? (e.g.
T4/T8 cell count, HIV viral load)
5. Should preventive therapy (IPT) be started at
the same time as ART? What would you see as
personal and medical treatment benefits and
trade-offs between earlier and later start of IPT?
6. Do you think low adherence rates to TB preventive
therapy should be a barrier to implementation of
TB prevention programmes among people living
with HIV?
7. What is the level and quality of TB-related health
care you receive from your HIV-related healthcare provider? (e.g. doctors, nurses, counsellors,
home-based care providers, community and peer
outreach workers, etc.)
8. Where would you prefer to receive TB preventive
treatment services? (e.g. home, TB clinic, HIV
clinic, general services clinic)
Week 3: Resolving barriers and building support
for expanded treatment
1. Do you think peoples perceptions regarding
screening for and diagnosis of TB will have any
impact regarding interest of people living with
HIV in receiving TB screening? (e.g. healthcare workers, family, work colleagues, friends,
community perceptions, etc.) What are those
perceptions? And what is their impact?
2. Do you think peoples perceptions regarding
adherence to TB preventive therapy will have any
impact on adherence rates among people living
with HIV? What are those perceptions? And what
impact?
affect children who may be taking TB preventive
therapy?
4. What issues or problems, if any, do you think affect
adolescents in taking TB preventive therapy?
affect injection drug users and other drug users
including those who may use stimulants (yaba,
crystal, etc.) in taking TB preventive therapy?
18
6. What can be or have been barriers to you or

someone you know to successfully taking TB
preventive therapy? (e.g. number of pills, pill
burden, important drug interactions, side-effects,
need for toxicity monitoring, etc.)
Annex 2: TB patient survey 2009

Recommendations for preventive therapy against tuberculosis for people living with HIV
1. Demographic information:
Gender:
O Male
O Female
O Lesbian
Race:
O White
O Asian
O African
Country of residence:
O Africa
O North America
O Latin
O South America
In the past six months where did you live most of the time?
O Your house or apartment
O Parents house or apartment
O Relatives house or apartment
O Someone elses house or apartment
O Hotel, rooming house or shelter
O In a squat
O On the streets
O In jail
How would you consider your housing situation?
O Permanent
O Temporary
O Transitional
O Homeless
2. Risk information:
What TB risk group do you identify with?
Check all that apply.
O Drug user
O MSM
O Prison/jail history
Past and current drug use:
O Never
O Less than six times
O 3x or more daily O Monthly
O All
O Weekly
O 23 times per month
O 23 times per week
In past 30 days what drugs were used?

In past six months what drugs were used?
Do you live in a country that has a high rate of TB and HIV? Please indicate country.
Do you know how you contracted TB?
19
Annexes
3. Medical provider information

When was the last time you received any medical services?
O Past 30 days
O 6 months to a year ago
Where did your medical visit take place?

O Clinic/doctors office
O Walk-in clinic
O 12 years ago
O 2+ years ago
O Other
O Emergency room O Other
How would you rate your last medical visit?

O Excellent O Good
O Fair
O Poor
Do you see a health professional (doctor, nurse, etc.) for regular check-ups?
O Yes
O No
O Dont know
If no, why dont you see a health professional for regular check-ups?
O They are disrespectful
O They assume any/all health problems are due to drug use
O They always tell me to get drug treatment O No health insurance
O Dont know of a doctor
O Other
If you use illicit drugs does your doctor know?
O Yes
O No
O Dont know
If your health professional knows about your drug use has it affected you treatment?
O Yes
O No
In what way has it affected your treatment?
O Provider became hostile
O Presumed all symptoms caused by drug use
O No difference/no impact on treatment
O Stopped treatment/referred to other provider

O Always talked about stop using
O Other
When did you find out you were HIV-positive?

Where were you tested?
O HIV testing site
O Doctors office/clinic/jail
O Other
How many years have you been living with HIV infection?
O Less than one year
O 15 years
O 510 years
O 1015 years
O 15+ years
What is your current viral load?
What is your current T-cell count?
Are you taking any HIV medications?
O Yes
O No
If taking HIV medication, what medications are you taking?
Has your doctor informed you about new treatments?
O Yes
O No
Would you recommend your doctor to a friend?
O Yes
O No
20
4. TB treatment and care information

Upon noticing TB-related symptoms how long did you wait until you went to a doctor?
O 1 week
O 30 days
O 2 months
O 36 months
O 69 months
O 912 months
O 1 year +
During the doctors visit did he or she offer any information or explanation about TB diagnosis and
treatments?
O Yes
O No
What type of testing was provided to determine TB infection?
O Blood tests
O Chest X-ray
O Both
O Other
How much information did the doctor provide?
O As much as I asked for O Just enough
O Very little
O None
If the doctor did not offer information, where did you find TB treatment information?
O Friends
O Family
O Partner/boyfriend/girlfriend
O Husband/wife
O Educational pamphlets O Outreach workers
O Other
How was the relationship with your medical provider?
O Very good
O Good
O Acceptable
Was your medical provider respectful?
O Very respectful
O Somewhat respectful
O Tolerable
O Disrespectful
O Not acceptable
O Reasonable
Did your relationship with medical provider affect treatment adherence?

O Yes
O No
Were you comfortable telling the medical provider when you missed taking medication?
O Yes
O No
Did the number of pills required to be taken make it difficult to manage treatment?
O Yes
O No
What TB medications where you taking? For treatment or prevention? Please list.
Did you develop any side-effects from TB medications? Describe.

Did the side-effects at any time cause you to discontinue or miss treatment?
O Yes
O No
If side-effects caused missing medication how long was it before you started again?
O 13 days
O 37 days
O 12 weeks
O 1 month
O 12 months
Did you take any drugs aside from those prescribed to help with side-effects?
O Yes
O No
21
O Internet
O Poor
Annexes
If yes, what illicit drugs did you take for relief from side-effects?
Did you ever switch TB medications to reduce side-effects?
O Yes
O No
If yes, what medication did you stop taking and switch to with less side-effects?
Stopped taking
Switched to
5. Social support information
Did you inform others about your TB diagnosis?
O Yes
O No
How long after being diagnosed with TB did you feel comfortable telling others?
O 13 days O 37 days O 12 weeks O 1 month
O 12 months
Who were the first people or first person you disclosed your TB infection?
O Boyfriend O Girlfriend O Mother
O Husband O Wife
O All listed

Why were these people the first you disclosed?
O Trusted them
O Would receive support O Offered information
O All
How supportive was your family?
O Very supportive O Supportive
O Barely supportive O Not supportive
O Somewhat supportive
Was your husband, wife, boyfriend, girlfriend, best friend or employer supportive?
O Yes
O No
If not how did they react to your TB diagnosis and treatment period?
O Avoided you due to fear of exposure
O Stopped talking to you
O Embarrassed/ashamed to know you
O Disclosed diagnosis without consent
O Used different plates and utensils
O Cleaned/wiped everything you touched
O Discontinued/ended relationship
O Other
Did friends, family, spouse, and/or employer support help with treatment adherence?
O Yes
O No
How would or does support from friends family, spouse, and/or employer help with treatment adherence?
Please describe.
When you meet people, do you feel comfortable disclosing that you have/had TB?
O Yes
O No
If not, why, did people discriminate or make you uncomfortable?
O Yes
O No
Did the people who knew you had/have TB treat you differently? If yes, please describe.
O Yes
O No
22
Please describe. It is important for us to document all discrimination and mistreatment.
23
Annex 5: Summary of findings and quality of evidence evaluation:

intensified TB case-finding for adults and adolescents living with HIV
PICOT Question: What is the best combination of
symptoms (with or without abnormal chest radiograph
findings) that can be used as a screening tool to identify
Population: Adults and adolescents living with HIV
Intervention: Combination of signs and symptoms
and diagnostic tools that can be used as a
screening tool to identify adults and adolescents
living with HIV who are eligible for treatment of
LTBI and diagnosis of active TB
adults living with HIV who are eligible for treatment of

latent TB infection (LTBI) and for diagnostic work-up of
active TB?
Comparison: TB prevalence without intervention
Outcomes: Negative predictive value, sensitivity,
specificity, positive predictive value
Timeline: 12 months during work-up for TB
1. Outcomes of interest
Outcomes
Negative predictive value (to identify
those eligible for treatment of LTBI)
Relative importance
(rank 1 9 most critical)
9
Comment
Critical
Sensitivity (to identify patients for further 9

diagnostic work-up)
Critical
Positive predictive value
Important
Specificity
Important
2. Literature search strategy and information retrieval

Search criteria
PubMed
Search
(Tuberculosis[Mesh])
AND
HIV[Mesh]) AND (Diagnosis[Mesh]) OR (TB
screening, intensified case-finding, active case-finding,
HIV, tuberculosis)
Leading researchers in the area were also contacted

to provide any unpublished data fulfilling the search
criteria.
2119
articles
Limits
Clinical trial, meta-analysis, randomized controlled
trial, review, clinical trial, phase I, clinical trial,
phase II, clinical trial, phase III, clinical trial, phase
IV, comparative study, controlled clinical trial,
multicentre study, adolescent: 1318 years, adult:

1944 years, middle-aged: 4564 years, middleaged + aged: 45+ years, aged: 65+ years, 80 and
over: 80+ years
24
Annex 5. Summary of findings and quality of evidence: Intensified TB case finding for adults and adolescents living with HIV
258
By title
53
By
abstract
26
Of
interest
21
primary
data
meta-analysis
entitled
Development of a standardized screening
rule for tuberculosis in people living with HIV in
resource constrained settings: individual participant
data meta-analysis of observational studies was
used to identify the best symptoms to screen a
person living with HIV for treatment of LTBI. The
meta-analysis was conducted in collaboration with
WHO, CDC and principal investigators of 12 studies
that met the inclusion criteria [112]. The inclusion
criteria for the meta-analysis included: systematic
collection of sputum specimens regardless of signs
or symptoms, at least one mycobacterial culture,
clinical symptoms, and HIV and TB disease status.
Studies which looked at the performance of individual
or a combination of symptoms with or without chest
X-ray as a screening tool were also examined but
they were not considered for evidence retrieval as
their participants were limited to TB suspects (cough
>2 weeks) or only smear-negative TB patients or
they did not use culture as the gold standard [1320].
Twelve studies [112] were included in the primary
data meta-analysis [20]. In addition to these studies,
other studies were found, which examined the role
of symptoms, individually or in combination with or
25
without chest radiology, as a screening tool for TB

[14, 1519]. Of these, two studies [14,15] collected
information on signs and symptoms only among
TB suspects, defined as patients with cough >2/3
weeks duration. Many studies have demonstrated
that cough alone is not a sensitive screening tool
and would miss a large number of potential TB
cases. Hence, these studies would have missed a
large number of TB cases even before assessing the
utility of other symptoms and would not have allowed
proper assessment of the role of symptoms or their
combination. Three studies [14, 16, 18] did not use
culture as a gold standard for the entire or a part of
their study population. One study [18] focused only
on smear-negative TB, thus limiting their findings
to patients with smear-negative disease only.
Findings from one study [13] were presented at the
16th Conference on Retroviruses and Opportunistic
Infections (CROI) as a poster and had not yet been
published in a peer-reviewed journal at the time
the guidelines were developed. The poster did not
provide details of the symptoms used other than
cough. The findings of the study for combination of
symptoms with abnormal findings on chest X-ray
were similar to the results of the primary patient
meta-analysis.
Annex 5
3. Findings and GRADE profile
he primary patient meta-analysis and other

studies were examined using GRADE criteria.
Although all the studies included in the metaanalysis were observational; all the studies except two
[6,9] met the criteria (population of interest, uncertain
diagnosis, consecutive enrolment and comparison
with a gold standard), and therefore qualified as
being of the highest quality before other factors for
determining the final strength of the evidence were
considered [21].
The primary patient meta-analysis showed that at a
TB prevalence of 5%, which is commonly found in
many heavily impacted settings, absence of all of
current cough, night sweats, fever and weight loss
could identify a subset of people living with HIV who
have a very low probability of having TB disease
(negative predictive value 0.97 [95% CI: 0.97, 0.98])
and could be considered for treatment of LTBI based
on their eligibility. Using this screening tool, more than
half of the patients would screen negative and could

be considered for treatment of LTBI. Of these 4375
individuals, 107 (2.4%) TB patients might be wrongly
put on treatment for LTBI as the negative predictive
value is not 1.
This screening rule had a sensitivity of 0.79 (95% CI:
0.58, 0.91) with a specificity of 0.49 (95% CI: 0.29,
0.70). Using the combination of symptoms proposed
in a population of people living with HIV with a 5% TB
prevalence requires the investigation of 11 extra cases
for every TB case detected; a ratio of TB suspects to a
TB case identified that is not much different from what
national TB control programmes target in the general
population. The meta-analysis also showed that the
addition of chest radiography with abnormal findings to
the combination increased the sensitivity substantially
from 0.79 to 0.90; however, the specificity reduced
by 11% (from 50% to 39%). There was no significant
gain in the negative predictive value.
GRADE profile table 1: TB screening for adults and adolescents:

What is the best combination of symptoms with or without radiology that can be used as a screening tool to
identify people living with HIV who are eligible for treatment of LTBI and diagnostic work-up for active TB?
Any one of current cough, fever, night sweats, weight loss as the best combination of
symptoms for screening
Values and uncertainty around these
Number of participants (studies)
Quality of evidence Importance
0.97 (95% CI: 0.97, 0.98)
8148 (9 studies)
Moderate
Critical
0.79 (95% CI: 0.75, 0.82)
8148 (9 studies)
Moderate
Critical
0.49 (95% CI: 0.29, 0.70)
8148 (9 studies)
Moderate
Important
Negative predictive value

Sensitivity
Specificity
Any one of current cough, fever, night sweats, weight loss and abnormal chest X-ray
findings as the best combination of symptoms for screening
Quality of evidence Importance
0.98 (95% CI: 0.97, 0.99)
2805 (4 studies)
Moderate
Critical
0.90 (95% CI: 0.66, 0.97)
2805 (4 studies)
Moderate
Critical
0.38 (95% CI: 0.12, 0.73)
2805 (4 studies)
Moderate
Important

Sensitivity
Specificity
26
4. Risk and benefit assessment

Adults and adolescents living with HIV who do not have current cough, fever, weight loss or night
sweats are unlikely to have active TB and should be offered isoniazid preventive therapy (IPT)
Intervention: Symptom screening using a combination of symptoms comprising current cough, fever, night sweats
or weight loss as a screening tool
Factor
Quality of evidence
Decision
Moderate
Benefits or desired effects
Explanation
The GRADE assessment of the evidence relies on a primary

patient meta-analysis of 12 studies including over 8000 patients.
The meta-analysis assessed a combination of different symptoms
(with or without abnormal X-ray findings). The four-symptom rule
has a negative predictive value of 98% and the probability of
disease among those who screen negative is very low.

Risks or undesired effects
Strong (Benefits
outweigh risks)
Values and preferences
Identifies people living with HIV eligible for treatment of

LTBI (and potential for reduced TB-related morbidity/
transmission).
Identifies people living with HIV not in need of treatment for
active TB.
Identifies people living with HIV not in need of further
evaluation with diagnostic tests for active TB disease.
Increases health-care worker focus on screening.
Some patients with active TB may not be given treatment
for TB.
Some patients with active TB may be given treatment for
LTBI (see discussion on scientific evidence of low risk for
developing drug resistance).
Improved quality of HIV care

Access to treatment for LTBI
Prevention of life-threatening disease and transmission to
family, friends and the larger community
Costs
Strong
Feasibility
Moderate
Overall ranking of
recommendation
Strength of recommendation
Strong
27
Increased by:
Additional staff time required for screening
Cost of supplying isoniazid and pyridoxine
Reduced by:
Limited resources needed for symptom screening among
persons who regularly attend clinical services for HIV
Avoiding costs of additional diagnostic tests including chest
X-ray
Avoiding costs that would have been associated with
treatment of TB
Implementation of symptom screening would be feasible as
Screening tool includes common TB-associated symptoms
and health-care workers are familiar with these
Avoids the need for repeat follow up and/or additional
diagnostic tests
But
Would need improved coordination between TB and HIV
programmes
Would need operational aspects of implementing IPT to be
worked out.
Annex 5
Adults and adolescents living with HIV who have any one symptom of current cough, fever, weight
loss or night sweats may have active TB and should be evaluated for TB and other diseases.
Intervention: Symptom screening using a combination of symptoms comprising current cough, fever, night sweats
or weight loss as a screening tool
Factor
Quality of evidence
Decision
Moderate
Explanation

patient meta-analysis of 12 studies including over 8000 patients.
The meta-analysis assessed a combination of different symptoms
(with or without abnormal X-ray findings). The four-symptom rule
has a negative predictive value of 98% and the probability of
disease among those who screen negative is very low.

Conditional
Early identification of TB suspects followed by treatment of

identified TB cases reduces TB-associated morbidity and
mortality among people living with HIV.
Identification and treatment of non-tuberculous pulmonary
infections
Increase in demand for availability of clinical and diagnostic
services
Increased volume and attention to importance of TB may
result in improved quality of TB diagnostic services.
Because about half of all HIV-infected patients in high HIV/
TB prevalence settings will have symptoms, there could be
a substantial burden on clinical and diagnostic services.
If total diagnostic capacity is compromised, then increased
demand could result in the displacement of patients in
greatest need of diagnostics.
Volume may negatively influence the quality of laboratory
diagnostic services, which might lead to missed diagnoses.
Not all patients with a positive screen will have TB so, for
some patients, there will be inconvenience/cost of tests
without benefit.
Strong
Costs
Conditional
Increased by:
Routine screening will require increased staff time.
Additional diagnostic evaluations (staff, reagents, transport,
laboratory capacity)
Increased quality assurance of diagnostic services
Reduced by:
Using a relatively low-cost screen to identify persons in
need for further diagnostic evaluation avoids the costs of
using more expensive tests more broadly
Feasibility
Overall ranking of
recommendation
Patients generally desire an accurate diagnosis of disease

and may be willing to undergo diagnostic evaluation or
treatment in an effort to prevent morbidity/mortality and
transmission.
An additional burden of diagnostic tests will be placed on

already overburdened laboratories.
It requires an increased need for referral and a better system
for tracking of referrals, which is already compromised.
Diagnostic services for those identified as TB suspects might
not be available.
Quality of diagnostic services needs to be improved.
Although conducting a symptom screen may be more feasible
than some other diagnostic interventions, it still requires time
from already overburdened health-care workers.
Strong
28
In resource-limited settings where chest radiology is easily available and affordable,

chest X-ray should be added to the screening tool to improve the sensitivity of screening
for TB among adults and adolescents living with HIV.
Intervention: Screening using a combination of symptoms comprising current cough, fever, night sweats, weight
loss or abnormal chest X-ray as a screening tool
Factor
Quality of evidence
Decision
Moderate
Explanation

patient meta-analysis of 12 studies including over 8000
patients. The meta-analysis assessed a combination of different
symptoms (with or without abnormal X-ray findings). The
GRADE assessment of the evidence showed that the addition of
abnormal chest radiograph findings to the four symptom-based
rule increases the sensitivity from 79% to 91% with a drop in
specificity from 50% to 39%.

Conditional
Costs
Weak (very costly)
Feasibility
Conditional
Overall ranking of
recommendation
29
Increase in the number of patients identified and evaluated

as being likely to have TB disease who might have been
missed by symptom screening alone
Early identification of TB suspects among HIV-infected
people followed by appropriate treatment of identified TB
cases which, in turn, can reduce TB-associated morbidity
and mortality among people living with HIV.
Identification and treatment of non-tuberculous pulmonary
infections
Substantial burden on the radiology technicians and
radiologists reading the X-rays
Issues with reading of X-rays and inter-reader variability
In an effort to identify all patients with TB, screening could
result in the displacement of patients in greatest need of
diagnostics if the total diagnostic capacity is limited.
Not all patients who screen positive will have TB so, for
some patients, there will be inconvenience, unnecessary
exposure to radiation, and cost of tests without benefit.
Patients generally desire an accurate diagnosis of disease

and may be willing to undergo diagnostic evaluation or
treatment in an effort to prevent morbidity/mortality and TB
transmission to family, friends and the community.
Increased by:
Routine screening will require staff time.
Chest X-ray for every patient will require additional
resources.
Identification of additional persons requiring diagnostic
evaluation will require resources (staff, reagents, transport,
laboratory capacity).
Reduced by:
Treatment benefits patients and the society.

Feasible only if enough financial and human resources
Strong
Annex 5
Figure 1. Algorithm for TB screening in adults and adolescents living with HIV
in HIV-prevalent and resource-constrained settings
Adults and adolescents living with HIV*
Positive screen for TB with any one of the following:
Current cough
Fever
Weight loss
Night sweats
No
Assess for contraindications to IPT
No
Yes
Give IPT
Defer IPT
Yes
Investigate for TB and other diseases
Other diagnosis
Not TB
TB
Give
appropriate
treatment and
consider IPT
Follow up
and
consider IPT
Treat
for TB
Screen for TB regularly at each encounter with a health worker or visit to a health facility
FOOTNOTES TO ADULT ALGORITHM

* Every adult and adolescent needs to be evaluated for eligibility to receive antiretroviral therapy (ART) and infection control measures
should be prioritized to reduce M. tuberculosis transmission in all settings that provide care.
Chest radiography can be done if available, but it is not required to classify patients into TB and non-TB groups. In high HIVprevalence settings with a high TB prevalence among people living with HIV, strong consideration must be given to performing
additional sensitive investigations.
Contraindications include: active hepatitis (acute or chronic) or regular and heavy alcohol consumption or symptoms of peripheral
neuropathy. Past history of TB and current pregnancy should not be contraindications for starting IPT. Although not a requirement for
initiating IPT, tuberculin skin testing (TST) may be done as part of eligibility screening in some settings.
Investigations for TB should be done in accordance with existing national guidelines.
30
References
1. Ayles H et al. Prevalence of tuberculosis, HIV and respiratory symptoms in two Zambian communities: implications
for tuberculosis control in the era of HIV. PLoS One, 2009, 4(5):e5602.
2. Cain KP et al. An algorithm for tuberculosis screening and diagnosis in people with HIV. New England Journal of
Medicine, 2010, 362(8):707716.
3. Chheng P et al. Pulmonary tuberculosis among patients visiting a voluntary confidential counseling and testing
center, Cambodia. International Journal of Tuberculosis and Lung Disease, 2008, 12(3 Suppl 1):5462.
4. Corbett EL et al. Epidemiology of tuberculosis in a high HIV prevalence population provided with enhanced diagnosis
of symptomatic disease. PLoS Medicine, 2007, 4(1):e22.
5. Corbett EL et al. Provider-initiated symptom screening for tuberculosis: diagnostic value, and the impact of HIV.
Bulletin of the World Health Organization, 2010, 88:1321.
6. Day JH et al. Screening for tuberculosis prior to isoniazid preventive therapy among HIV-infected gold miners in
South Africa. International Journal of Tuberculosis and Lung Disease, 2006, 10(5):523529.
7. Kimerling ME et al. Prevalence of pulmonary tuberculosis among HIV-infected persons in a home care program in
Phnom Penh, Cambodia. International Journal of Tuberculosis and Lung Disease, 2002, 6(11):988994.
8. Lawn SD et al. Urine lipoarabinomannan assay for tuberculosis screening before antiretroviral therapy diagnostic
yield and association with immune reconstitution disease. AIDS, 2009, 23(14):18751880.
9. Lewis JJ et al. HIV infection does not affect active case finding of tuberculosis in South African gold miners. American
Journal of Respiratory and Critical Care Medicine, 2009, 180(12):12711278.
10. Mohammed A et al. Screening for tuberculosis in adults with advanced HIV infection prior to preventive therapy.
International Journal of Tuberculosis and Lung Disease, 2004, 8(6):792795.
11. Shah S et al. Intensified tuberculosis case finding among HIV-Infected persons from a voluntary counseling and
testing center in Addis Ababa, Ethiopia. Journal of Acquired Immune Deficiency Syndromes, 2009, 50(5):537545.
12. Wood R et al. Undiagnosed tuberculosis in a community with high HIV prevalence: implications for tuberculosis
control. American Journal of Respiratory and Critical Care Medicine, 2007, 175(1):8793.
13. Bassett IV et al. Intensive tuberculosis screening for HIV-infected patients starting antiretroviral therapy in Durban,
South Africa: limitations of WHO guidelines. In: Proceedings of the 16th Conference on Retroviruses and Opportunistic
infections; Montreal, Canada, February 2009 [Abstract #779].
14. Burgess AL et al. Integration of tuberculosis screening at an HIV voluntary counselling and testing centre in Haiti.
AIDS, 2001, 15(14):18751879.
15. Espinal MA et al. Screening for active tuberculosis in HIV testing centre. Lancet, 1995, 345(8954):890893.
16. Samb B et al. Methods for diagnosing tuberculosis among in-patients in eastern Africa whose sputum smears are
negative. International Journal of Tuberculosis and Lung Disease, 1997, 1(1):2530.
17. Tamhane A et al. Predictors of smear-negative pulmonary tuberculosis in HIV-infected patients, Battambang,
Cambodia. International Journal of Tuberculosis and Lung Disease, 2009, 13(3):347354.
18. Were W et al. A simple screening tool for active tuberculosis in HIV-infected adults receiving antiretroviral treatment
in Uganda. International Journal of Tuberculosis and Lung Disease, 2009, 13(1):4753.
19. Wilson D et al. Diagnosing smear-negative tuberculosis using case definitions and treatment response in HIVinfected adults. International Journal of Tuberculosis and Lung Disease, 2006, 10(1):3138.
20. Getahun H et al. Development of a standardized screening rule for tuberculosis in people living with HIV in resource
constrained settings: individual participant data meta-analysis of observational studies. PLoS Medicine, 2010, 8(1):
e1000391. doi:10.1371/journal.pmed.1000391.
21. Schunemann HJ et al. Grading quality of evidence and strength of recommendations for diagnostic tests and
strategies. British Medical Journal, 2008, 336(7653):11061110.
31

preventive therapy for adults and adolescents living with HIV
6.1 Optimal duration of and drug regimen for the treatment of latent TB
infection (LTBI)
PICOT Question: What is the optimal duration of and
drug regimen (e.g. INH, rifampicin [RIF], pyrazinamide
[PZA], etc.) for the treatment of LTBI to reduce the risk

of developing TB among people living with HIV/AIDS?
Efficacy
Q6.1.4
Population: Adults and children living with HIV

Intervention: IPT (any regimen)
Comparison: No IPT
Outcomes: Active TB incidence, mortality,
progression of HIV disease, adverse effects (AEs),
adherence, TB drug resistance, interval to active
TB (Atb), interval to death
Timeline: Lifetime
Q6.1.1
Population: Adults living with HIV
Intervention: IPT (6 months INH)
Comparison: No IPT
progression of HIV disease, AEs, adherence, TB
drug resistance, interval to Atb, interval to death
Timeline: Lifetime
Q6.1.2
Intervention: IPT (INH+RIF)
Comparison: No IPT
Timeline: Lifetime
Q.6.1.3
Intervention: IPT (RIF+pyrazinamide [PZA])
Comparison: No IPT
Timeline: Lifetime

Intervention: IPT (INH+RIF+PZA)
Comparison: No IPT
progression of HIV disease, AEs, adherence,
TB drug resistance, interval to Atb, interval to
death
Timeline: Lifetime
Q6.2 Optimal duration (a)
Comparison: IPT (12 months INH)
Timeline: Lifetime
Q6.2 Optimal duration (b)
Intervention: IPT (continuous INH)
Comparison: IPT (6 months INH)
Timeline: Lifetime
Q6.3 Optimal regimen
Comparison: Any other regimen
Timeline: Lifetime
32
Annex 6: Summary of findings and quality of evidence evaluation: preventive therapy for adults and adolescents living with HIV
Q6.3.1
Q6.3.4

Comparison: RIF+PZA
Timeline: Lifetime

Intervention: INH+RIF
Comparison: INH+RIF+PZA
Timeline: Lifetime
Q6.3.2
Q6.3.5

Comparison: INH+RIF
Timeline: Lifetime

Intervention: INH+RIF
Comparison: RIF+PZA
Timeline: Lifetime
Q6.3.6
Q6.3.3

Intervention: INH+RPT
Comparison: INH
Timeline: Lifetime

Comparison: INH+RIF+PZA
Timeline: Lifetime
Outcomes
Active TB incidence (suspected, probable, confirmed)
Confirmed TB
Mortality
Progression of HIV disease

Adverse events
Adherence
TB drug resistance
Cost-effectiveness
Interval to active TB
Interval to death
33
Relative importance
Comment
Critical
9
9
8
8
7
7
7
6
6
Critical
Critical
Critical
Critical
Critical (addressed by Annex 11)

Less critical
Less critical
Annex 6

2.1 Pubmed Search (Tuberculosis[Mesh] AND HIV Infections[Mesh]) AND
Therapeutics[Mesh]
1375
articles
Limits
trial, review, phase I, clinical trial, phase II, clinical
trial, phase III, clinical trial, phase IV, comparative
study, controlled clinical trial, multicentre study,
adolescent: 1318 years, adult: 1944 years,

middle-aged: 4564 years, middle-aged + aged:
45+ years, aged: 65+ years, 80 and over: 80+
years
219
By title
30
By
abstract
19
Of
interest
16
International conferences (CROI [Conference on Retroviruses and Opportunistic Infections], International

AIDS Society [IAS], Interscience Conference on Antimicrobial Agents and Chemotherapy [ICAAC], World AIDS
conference), excluding published papers:
ICAAC 2009 and previous 0
IAS conferences 9
CROI 2009 and previous 4
34
he WHO Guidelines Group reviewed the

evidence on a wide range of regimens and
their duration for TB prevention among
people living with HIV, including results from three
unpublished trials. The evidence reviewed studies of
drug combinations used for prevention including INH,
rifampicin, pyrazinamide and rifapentine. A total of
seven studies [17] compared INH alone with other
regimens, and found that regimens which included
pyrazinamide, rifampicin and rifapentine were as
efficacious as INH alone, but were associated with

higher rates of toxicity (Table 1). The WHO Guidelines
Group concluded that INH at a dose of 300 mg/day
remains the drug of choice for chemotherapy to
prevent TB in adults living with HIV.
The WHO Guidelines Group reviewed and graded
the evidence on the duration and durability of effect
of IPT in people living with HIV. The critical outcome
of interest considered was the efficacy of IPT in
preventing active TB, relapse, reinfection and toxicity.
Table 1: Comparison of the efficacy of different drug regimens

Intervention
Comparator
RR (95% Cl)
Quality of evidence
INH
INH and rifampicin
0.97 (0.521.83)
Moderate
INH
INH
INH and rifampicin
INH and rifapentine
Rifampicin and pyrazinamide
INH, rifampicin and pyrazinamide 0.69 (0.231.57)

INH, rifampicin and pyrazinamide 0.75 (0.211.82)
INH
he WHO Guidelines Group considered the

existing evidence on the optimal duration of IPT
(6, 9, 12 and 36 months). Although nine months
of IPT is supported by evidence and recommended
in some guidelines, there are no studies that have
directly compared six and nine months of IPT.
Therefore, the discussion focused on the choice
between a six- versus 12-month duration of IPT, which
showed no significant difference in efficacy. This led
the Guidelines Group to strongly recommend the sixmonth duration. The durability of effect of IPT ranges
from six months to five years. The Guidelines Group
also reviewed unpublished evidence from two studies
that suggest increased benefit with a 36-month or
longer duration of IPT, particularly in people who are
TST positive.[8,9] The Guidelines Group considered
at least 36 months duration as a surrogate for lifelong
treatment and emphasized the potential benefit of this
regimen for people living with HIV in settings with a
background of high TB prevalence and transmission.
Given the preliminary nature of the evidence,
feasibility concerns and potential adverse events,
the Guidelines Group conditionally recommends 36
months duration of IPT for people living with HIV in
settings with high TB prevalence and transmission.
The Guidelines Group reviewed available data on
the initiation of IPT and immune status, including
concomitant use with ART. Six studies were
examined [4,913] and showed contrasting results
regarding the reduction of TB risk by immune status.
35
1.03 (0.751.4)
1.05 (0.561.97)
Moderate
Low
Moderate
Moderate
Additional protective benefits of concomitant use of

IPT with ART were demonstrated in two observational
studies from Brazil and South Africa [12,13], other
studies from South Africa [4,12,14,15], and a subanalysis of data from an unpublished randomized
clinical trial from Botswana. Based on this evidence
and the potential benefit of concomitant use of IPT
with ART, the Guidelines Group strongly recommend
that IPT be given irrespective of immune status and
whether or not the person is on ART. IPT initiation
or completion should not delay commencement of
ART in eligible people living with HIV. However, the
Guidelines Group recognizes the absence of evidence
on whether concomitant initiation of IPT with ART or
delayed initiation of IPT is better in terms of efficacy
and reduction in toxicity.
Pregnant women living with HIV are at risk for
TB, which can impact on maternal and perinatal
outcomes, ranging from death of the mother and
the newborn, to prematurity and low birth weight.
The Guidelines Group stressed the importance of
screening pregnant women living with HIV for active
TB using the standard clinical algorithm for adults
and adolescents as listed in Annex 5. The Group
concluded that existing evidence and experience in
the pre-HIV and HIV era suggest that IPT is safe in
pregnant women. Therefore, the Guidelines Group
strongly recommends that pregnancy should not
exclude women living with HIV from symptom-based
screening for TB and receiving IPT.
Annex 6
The Guidelines Group reviewed the evidence and

discussed the use of IPT as secondary prophylaxis
for people who have previously been successfully
treated for TB. The evidence was analysed using
the GRADE process. Evidence from four studies
including three randomized controlled trials and one
observational study showed the value of providing
IPT immediately after successful completion of TB
treatment. The WHO Guidelines Group strongly
recommends that adults and adolescents living with
HIV who have successfully completed TB treatment

should continue to receive INH for six months and
should conditionally receive it for 36 months based on
the local situation and existing national guidelines. As
there was no evidence on the potential role of IPT for
a patient who had successfully completed treatment
for multidrug-resistant (MDR) or extensively drugresistant (XDR) TB, the Guidelines Group has not
made any recommendation on the use of IPT after
successful treatment for MDR or XDR TB.
2. Pubmed Search ((Child[Mesh] OR Child, Preschool[Mesh]) OR

Infant[Mesh]) AND Tuberculosis[Mesh] AND HIV Infections[Mesh] AND
Therapeutics[Mesh])
187
articles
Limits
trial, review, phase I, clinical trial, phase II, clinical
trial, phase III, clinical trial, phase IV, comparative
study, controlled clinical trial, evaluation studies,
multicentre study, Medline, PubMed Central, all

infants: birth23 months, newborn: birth1 month,
infant: 123 months, preschool child: 25 years,
child: 612 years
54
By title
By
abstract
Of
interest
International conferences (CROI, IAS, ICAAC, World AIDS conference) excluding published papers:
ICAAC 2009 and previous 1
IAS conferences 2
CROI 2009 and previous 1
36
wo studies [14,16] were considered for the

GRADE analysis. One study suggested
significant benefits for children receiving INH
for six months, in particular, with regard to significant
reductions in mortality. However, findings from a
randomized controlled trial [14] conducted in South
Africa showed that when HIV-infected infants with no
known exposure to a TB source case are identified
in the first three to four months of life, given rapid
access to ART and carefully monitored for new TB
exposure or disease on a monthly basis, there is no
benefit from IPT.
Therefore, based on this, the Guidelines Group
recommends that all children more than 12 months
of age who are living with HIV and who are unlikely
to have active TB should receive six months of IPT
as part of a comprehensive package of HIV care.
For children less than 12 months of age, only those

with a history of contact with a TB case should
receive six months of IPT. In contrast to adults and
adolescents, there is no evidence to support the
use of INH for longer than six months in children.
Therefore, the Guidelines Group concludes that until
more data are available, INH for children could not
be recommended for more than six months. Similarly,
there is no evidence on whether repeating a course
of IPT is beneficial for children.
INH should be given at a dose of 10 mg/kg of body
weight/per day and it is desirable that 25 mg of vitamin
B6 be supplied daily with INH. All available data to
date suggest that INH is not toxic for children, even
in those receiving ART. The following table shows a
simplified dosing schedule for INH at a dose of 10
mg/kg/day.
Table 2: Dosing schedule for INH in children

Weight range (kg)
<5
5.19.9
1013.9
1419.9
2024.9
>25
Number of 100 mg tablets of INH

to be administered per dose
Dose given (mg)
1 tablet
100
2 tablets
200
tablet
1 tablet
2 tablets
37
150
3 tablets or one adult tablet
he Guidelines Group noted that there is no

evidence on the use of IPT in children after
successful completion of TB treatment.
However, like adults, children living with HIV are
exposed to reinfection and recurrence of TB. Therefore,
the Group recommends that children who have been
successfully treated for TB and are living in settings
with high TB transmission should receive IPT for an
additional six months. IPT can be started immediately
following the last doses of antituberculosis therapy. TB
screening should be carried out regardless of a history
of TB treatment during each contact of the child with a
health-care worker.
50
250
300
The Guidelines Group also concluded that there are

no data regarding the efficacy of IPT for children
stratified by the degree of immunosuppression.
However, the Group noted that there is biological
plausibility in extrapolating what is known for adults
and adolescents to children. Therefore, it conditionally
recommends the combined use of IPT with ART for
all children. The Group emphasizes that ART should
not be delayed while starting or completing a course
of IPT.
Design
Limitations
Inconsistency
Indirectness
Imprecision
Other
considerations
Randomized trials
Serious1
Randomized trials
No serious
limitations1
Randomized trials
Serious1
Randomized trials
No serious
limitations
No serious
inconsistency
No serious
indirectness
No serious
indirectness2
No serious
indirectness2
No serious
indirectness2
Randomized trials
No serious
limitations
No serious
inconsistency
No serious
indirectness
No serious
imprecision
No serious
imprecision
No serious
imprecision
No serious
imprecision
No serious
imprecision
None
None
None
None
None
140/3602 (3.9%)
41/184 (22.3%)
633/3728 (17%)
50/1547 (3.2%)
142/3728 (3.8%)
Preventive therapy
(any TB drug)
0%
33/1923 (1.7%)
RR 2.55 (1.73.85)
0 more per 1000

(from 0 more to 0
more)
27 more per 1000

(from 12 more to 49
more)
60 fewer per 1000

(from 200 fewer to
140 more)
50%
19 fewer per 1000

(from 63 fewer to 44
more)
1 fewer per 1000
(from 4 fewer to 3
more)
RR 0.88 (0.61.28)
1%
43/272 (15.8%)
30 fewer per 1000

more)
50%
13 fewer per 1000

more)
1 fewer per 1000
(from 3 fewer to 1
more)
RR 0.94 (0.851.05)
2%
427/2034 (21%)
108 fewer per 1000

(from 204 fewer to
32 more)
40%
12 fewer per 1000

(from 23 fewer to 4
more)
5 fewer per 1000
(from 10 fewer to 2
more)
RR 0.73 (0.491.08)
2%
47/1026 (4.6%)
160 fewer per 1000

fewer)
50%
20 fewer per 1000

fewer)
Absolute
6 fewer per 1000

(from 3 fewer to 9
fewer)
RR 0.68 (0.540.85)
Relative risk
(95% CI)
Summary of findings
Effect
2%
129/2034 (6.3%)
Control
No. of patients
HIGH
HIGH
LOW
HIGH
MODERATE
Quality
CRITICAL
CRITICAL
CRITICAL
CRITICAL
CRITICAL
Importance
Concealment of allocation was adequate in five studies and unclear in the remaining seven; in seven trials both providers and participants were blinded; the inclusion of randomized
participants was adequate in all the included trials; intention-to-treat (ITT) analysis has been performed in 10 trials; participants loss to follow up ranged from 0 to 31%. Mohammed
et al. 2007 was not powered to assess the effectiveness of IPT.
2
A different TST status was considered across the studies; however, TST -negative patients were considered only in settings with >30% of LTBI.
3
Four out of nine studies provided an opposite direction of the effect.
Adverse drug reaction leading to treatment interruption (follow up 13 years; clinical and laboratory monitoring)
HIV disease progression (follow up 13 years; clinical and immunological criteria)
Serious3
No serious
inconsistency
No serious
inconsistency
Mortality (any cause) (follow up 13 years; review of hospital records)
Confirmed TB (follow up 13 years; culture-proven)
12
Active TB incidence (possible, probable, confirmed) (follow up 13 years; clinical examination, chest X-ray, sputum for acid-fast bacilli [AFB])
No. of
studies
Quality assessment
Q 1.1 Efficacy
Q 1.1.1 ANY TB DRUG
A. Question: Should preventive therapy (any TB drug) be used in people living with HIV with any PPD status?
Settings: Any TB/HIV prevalence
Bibliography: Pape et al. 1993; Whalen et al. 1997; Hawken et al. 1997; Mwinga et al. 1998; Fitzgerald et al. 2001; Gordin et al. 1997; Mohammed et al.
2007; Rivero et al. 2003; Gordin et al. 2000; Hasley et al. 1998; Martinez et al. 2000; Rivero 2007
Annex 6
3. Findings and GRADE profiles
38
39
Design
Limitations
Inconsistency
Indirectness
Imprecision
Randomized trials
No serious
limitations
Randomized trial
No serious
limitations
Randomized trials
No serious
limitations
Serious3
Randomized trial
No serious
limitations
No serious
inconsistency
No serious
indirectness
No serious
indirectness
No serious
indirectness
No serious
indirectness
Only one study is available to address this outcome.

Small sample size and wide confidence interval
3
One of the four studies showed an opposite direction of the effect.
Serious1
No serious
inconsistency
No serious
imprecision
No serious
imprecision
Serious2
No serious
imprecision
Active TB incidence (possible, probable or confirmed) (follow up 13 years; clinical examination, chest X-ray, sputum for AFB)
No. of
studies
Quality assessment
None
None
None
None
Other
considerations
6/38 (15.8%)
195/1760 (11.1%)
2/101 (2%)
39/1760 (2.2%)
Preventive therapy
(any TB drug)
320 fewer per 1000

fewer)
50%
282 fewer per 1000

fewer)
32 fewer per 1000
(from 7 fewer to 43
fewer)
RR 0.36 (0.150.85)
5%
11/25 (44%)
100 fewer per 1000

more)
50%
27 fewer per 1000

(from 50 fewer to 3
more)
10 fewer per 1000
(from 19 fewer to 1
more)
RR 0.80 (0.631.02)
5%
84/618 (13.6%)
350 fewer per 1000

(from 470 fewer to
285 more)
50%
47 fewer per 1000

more)
14 fewer per 1000
more)
RR 0.30 (0.061.57)
2%
4/60 (6.7%)
310 fewer per 1000

(from 215 fewer to
375 fewer)
50%
46 fewer per 1000

fewer)
Absolute
12 fewer per 1000

(from 9 fewer to 15
fewer)
RR 0.38 (0.250.57)
Relative risk
(95% CI)
Summary of findings
Effect
2%
46/618 (7.4%)
Control
No. of patients
B. Question: Should preventive therapy (any TB drug) be used in TST-positive people living with HIV?
Settings: Different TB/HIV prevalences
Bibliography: Pape et al. 1993; Whalen et al. 1997; Hawken et al. 1997; Mwinga et al. 1998
HIGH
MODERATE
LOW
HIGH
Quality
CRITICAL
CRITICAL
CRITICAL
CRITICAL
Importance
Design
Limitations
Inconsistency
Indirectness
Imprecision
Randomized trials
No serious
limitations
Randomized trials
Randomized trials
No serious
limitations
No serious
limitations
Serious3
Serious2
Serious1
Randomized trials
No serious
limitations
Serious4
No serious
indirectness
No serious
indirectness
No serious
indirectness
No serious
indirectness
No serious
imprecision
No serious
imprecision
No serious
imprecision
No serious
imprecision
Three studies out of eight showed a different direction of the effect.

One of the three studies available presented an opposite direction of the effect.
3
The direction of effect was different across the studies.
4
Opposite direction of the effect
Mortality (any cause) (follow up 13 years)
Active TB incidence (follow up 13 years; clinical presentation, chest X-ray, sputum for AFB, response to TB treatment)
No. of
studies
Quality assessment
None
None
None
None
Other
considerations
35/146 (24%)
387/1677 (23.1%)
22/853 (2.6%)
75/1677 (4.5%)
Preventive therapy
(any TB drug)
50 more per 1000

more)
50%
22 more per 1000

more)
2 more per 1000
(from 6 fewer to 2
more)
RR 1.10 (0.721.1)
2%
32/146 (21.9%)
5 more per 1000

more)
50%
3 more per 1000

more)
0 more per 1000
(from 2 fewer to 3
more)
RR 1.01 (0.891.14)
2%
316/1243 (25.4%)
104 fewer per 1000

(from 248 fewer to
180 more)
40%
8 fewer per 1000

more)
5 fewer per 1000
(from 12 fewer to 9
more)
RR 0.74 (0.381.45)
2%
15/500 (3%)
55 fewer per 1000

(from 180 fewer to
120 more)
50%
5 fewer per 1000

more)
Absolute
2 fewer per 1000

(from 7 fewer to 5
more)
RR 0.89 (0.641.24)
Relative risk
(95% CI)
Summary of findings
Effect
2%
60/1243 (4.8%)
Control
No. of patients
MODERATE
MODERATE
MODERATE
MODERATE
Quality
CRITICAL
CRITICAL
CRITICAL
CRITICAL
Importance
C. Question: Should preventive therapy (any TB drug) be used in TST-negative people living with HIV?
Settings: High TB prevalence settings (>30% LTBI)
Bibliography: Fitzgerald et al. 2001; Gordin et al. 1997; Hawken et al. 1997; Mohammed et al. 2007; Mwinga et al. 1998; Pape et al. 1993; Rivero et al. 2003; Whalen
et al.1997 anergy
Annex 6
40
41
Design
Limitations
Inconsistency
Indirectness
Imprecision
Randomized trials
No serious
limitations
Randomized trials
No serious
limitations
Randomized trials
No serious
limitations
Serious
No serious
inconsistency
No serious
inconsistency
No serious
indirectness
No serious
indirectness
No serious
indirectness
No serious
imprecision
No serious
imprecision
Serious1
Active TB incidence (follow up 13 years; clinical presentation, chest X-ray, sputum for AFB, response to TB treatment)
No. of
studies
Quality assessment
None
None
None
Other
considerations
51/291 (17.5%)
26/593 (4.4%)
28/291 (9.6%)
Preventive therapy
(any TB drug)
80 fewer per 1000

(from 210 fewer to
120 more)
50%
34 fewer per 1000

more)
3 fewer per 1000
(from 8 fewer to 5
more)
RR 0.84 (0.581.24)
2%
37/173 (21.4%)
84 fewer per 1000

(from 212 fewer to
128 more)
40%
13 fewer per 1000

more)
4 fewer per 1000
(from 11 fewer to 6
more)
RR 0.79 (0.471.32)
2%
28/466 (6%)
95 fewer per 1000

(from 255 fewer to
170 more)
50%
25 fewer per 1000

more)
Absolute
4 fewer per 1000

(from 10 fewer to 7
more)
RR 0.81 (0.491.34)
Relative risk
(95% CI)
Summary of findings
Effect
2%
23/173 (13.3%)
Control
No. of patients
D. Question: Should preventive therapy (any TB drug) be used in people living with HIV with unknown TST status?
Bibliography: Mwinga et al. 1998; Hawken et al. 1997
HIGH
HIGH
LOW
Quality
CRITICAL
CRITICAL
CRITICAL
Importance
Design
Limitations
Inconsistency
Indirectness
Imprecision
Randomized trials
No serious
limitations
Randomized trials
No serious
limitations
Randomized trials
No serious
limitations
Randomized trials
No serious
limitations
Serious2
No serious
indirectness
No serious
indirectness
No serious
indirectness
No serious
indirectness
Randomized trials
No serious
limitations
No serious
inconsistency
No serious
indirectness
Three out of eight showed an opposite direction of the effect.

Different direction of the effect across the studies
Serious2
No serious
inconsistency
No serious
inconsistency1
No serious
imprecision
No serious
imprecision
No serious
imprecision
No serious
imprecision
No serious
imprecision
Active TB incidence ( probable, possible, confirmed) (follow up 13 years; clinical examination, chest X-ray, sputum for AFB)
No. of
studies
Quality assessment
None
None
None
None
None
Other
considerations
56/2026 (2.8%)
41/184 (22.3%)
427/2152 (19.8%)
34/1037 (3.3%)
85/2152 (3.9%)
INH
prophylaxis
132 more per 1000

(from 18 more to 302
more)
20%
12 more per 1000

(from 2 more to 27
more)
0 more per 1000
(from 0 more to 0
more)
RR 1.66 (1.092.51)
0%
33/1873 (1.8%)
60 fewer per 1000

(from 200 fewer to
140 more)
50%
30 fewer per 1000

more)
12 fewer per 1000
more)
RR 0.88 (0.61.28)
10%
43/272 (15.8%)
25 fewer per 1000

more)
50%
11 fewer per 1000

more)
3 fewer per 1000
(from 7 fewer to 3
more)
RR 0.95 (0.851.06)
5%
419/1984 (21.1%)
140 fewer per 1000

more)
50%
13 fewer per 1000

(from 24 fewer to 5
more)
6 fewer per 1000
(from 11 fewer to 2
more)
RR 0.72 (0.471.11)
2%
47/1026 (4.6%)
165 fewer per 1000

fewer)
50%
20 fewer per 1000

(from 8 fewer to 30
fewer)
Absolute
7 fewer per 1000

(from 3 fewer to 10
fewer)
RR 0.67 (0.510.87)
Relative risk
(95% CI)
Summary of findings
Effect
2%
123/1984 (6.2%)
Control
No. of patients
HIGH
MODERATE
MODERATE
HIGH
HIGH
Quality
CRITICAL
CRITICAL
CRITICAL
CRITICAL
CRITICAL
Importance
Q 1.1.2 INH vs PLACEBO

A. Question: Should INH prophylaxis be used in people living with HIV with any TST status?
Bibliography: Pape et al. 1993; Whalen et al. 1997; Hawken et al. 1997; Mwinga et al. 1998; Fitzgerald et al. 2001; Gordin et al. 1997; Rivero et al. 2003; Whalen et
al.1997 anergy
Annex 6
42
43
Design
Limitations
Inconsistency
Indirectness
Imprecision
Randomized trials
No serious
limitations
Randomized trial
No serious
limitations
Randomized trials
No serious
limitations
No serious
inconsistency3
Randomized trial
No serious
limitations
Serious1
No serious
indirectness
No serious
indirectness
No serious
indirectness
No serious
indirectness
Only one study was available to address this outcome.

Small sample size and wide CI
3
Mwinga et al. reported an opposite direction of the effect.
Serious1
No serious
inconsistency
No serious
imprecision
No serious
imprecision
Serious2
No serious
imprecision
Active TB incidence (possible, probable, confirmed) (follow up 13 years; clinical examination, chest X-ray, sputum for AFB)
No. of
studies
Quality assessment
None
None
None
None
Other
considerations
6/11 (54.5%)
71/693 (10.2%)
0/52 (0%)
18/693 (2.6%)
INH
prophylaxis
Control
320 fewer per 1000

fewer)
50%
973 fewer per 1000

(from 228 fewer to
1292 fewer)
64 fewer per 1000
fewer)
RR 0.36 (0.150.85)
10%
38/25 (152%)
130 fewer per 1000

(from 225 fewer to
0 more)
50%
35 fewer per 1000

(from 61 fewer to 0
more)
5 fewer per 1000
(from 9 fewer to 0
more)
RR 0.74 (0.551)
2%
84/618 (13.6%)
435 fewer per 1000

(from 495 fewer to
660 more)
50%
58 fewer per 1000

more)
17 fewer per 1000
more)
RR 0.13 (0.012.32)
2%
4/60 (6.7%)
320 fewer per 1000

(from 195 fewer to
390 fewer)
50%
48 fewer per 1000

fewer)
Absolute
13 fewer per 1000

(from 8 fewer to 16
fewer)
RR 0.36 (0.220.61)
Relative risk
(95% CI)
Summary of findings
Effect
2%
46/618 (7.4%)
No. of patients
B. Question: Should INH prophylaxis be used in TST-positive people living with HIV?
MODERATE
HIGH
LOW
HIGH
Quality
CRITICAL
CRITICAL
CRITICAL
CRITICAL
Importance
Design
Limitations
Inconsistency
Indirectness
Randomized trials
No serious
limitations
Randomized trials
No serious
limitations
Randomized trials
No serious
limitations
No serious
inconsistency
Randomized trials
No serious
limitations
Serious3
No serious
indirectness
No serious
indirectness
No serious
indirectness
No serious
indirectness
No serious
imprecision
No serious
imprecision
No serious
imprecision
Fitzgerald et al. and Hawken et al. showed an opposite direction of the effect.
3
Serious2
No serious
inconsistency1
No serious
imprecision
Imprecision
Active TB (possible, probable, confirmed) (follow up 13 years; clinical examination, chest X-ray, sputum for AFB)
No. of
studies
Quality assessment
None
None
None
None
Other
considerations
35/146 (24%)
328/1297 (25.3%)
12/521 (2.3%)
49/1297 (3.8%)
INH
prophylaxis
50 more per 1000

(from 140 fewer to
345 more)
50%
22 more per 1000

more)
10 more per 1000
more)
RR 1.10 (0.721.69)
10%
32/146 (21.9%)
10 more per 1000

more)
50%
5 more per 1000

more)
0 more per 1000
(from 2 fewer to 3
more)
RR 1.02 (0.91.16)
2%
298/1193 (25%)
120 fewer per 1000

(from 320 fewer to
305 more)
50%
7 fewer per 1000

more)
5 fewer per 1000
more)
RR 0.76 (0.361.61)
2%
15/500 (3%)
70 fewer per 1000

(from 205 fewer to
130 more)
50%
6 fewer per 1000

more)
Absolute
3 fewer per 1000

(from 8 fewer to 5
more)
RR 0.86 (0.591.26)
Relative risk
(95% CI)
Summary of findings
Effect
2%
54/1193 (4.5%)
Control
No. of patients
MODERATE
HIGH
MODERATE
HIGH
Quality
CRITICAL
CRITICAL
CRITICAL
CRITICAL
Importance
C. Question: Should INH prophylaxis be used in people living with HIV who are TST -negative?
Bibliography: Fitzgerald et al. 2001; Gordin et al. 1997; Hawken et al. 1997; Mwinga et al. 1998; Pape et al. 1993; Rivero et al. 2003; Whalen et al.1997 anergy
Annex 6
44
45
Design
Limitations
Inconsistency
Indirectness
Randomized trials
No serious
limitations
Randomized trials
No serious
limitations
Randomized trials
No serious
limitations
No serious
inconsistency
No evidence
available
Serious1
No serious
inconsistency
No serious
indirectness
No serious
indirectness
No serious
indirectness
No serious
imprecision
No serious
imprecision
No serious
imprecision
Imprecision
No. of
studies
Quality assessment
None
None
None
None
Other
considerations
0/0 (0%)
28/162 (17.3%)
22/464 (4.7%)
18/162 (11.1%)
INH
prophylaxis
Control
0%
0/0 (0%)
RR 0 (00)
0 fewer per 1000

(from 0 fewer to 0
fewer)
0 fewer per 1000

(from 0 fewer to 0
fewer)
95 fewer per 1000

(from 240 fewer to
135 more)
50%
41 fewer per 1000

more)
4 fewer per 1000
(from 10 fewer to 5
more)
RR 0.81 (0.521.27)
2%
37/173 (21.4%)
105 fewer per 1000

(from 270 fewer to
180 more)
50%
13 fewer per 1000

more)
4 fewer per 1000
(from 11 fewer to 7
more)
RR 0.79 (0.461.36)
2%
28/466 (6%)
70 fewer per 1000

(from 260 fewer to
260 more)
50%
19 fewer per 1000

more)
Absolute
3 fewer per 1000

more)
RR 0.86 (0.481.52)
Relative risk
(95% CI)
Summary of findings
Effect
2%
23/173 (13.3%)
No. of patients
D. Question: Should INH prophylaxis be used in people living with HIV with unknown TST status?
Bibliography: Mwinga et al. 1998; Hawken et al. 1997
HIGH
HIGH
MODERATE
Quality
CRITICAL
CRITICAL
CRITICAL
CRITICAL
Importance
Design
Limitations
Inconsistency
Indirectness
Randomized trials
No serious
limitations
Randomized trial
No serious
limitations
Randomized trials
No serious
limitations
No serious
inconsistency
No evidence
available
No serious
indirectness
No serious
indirectness
No serious
indirectness
Randomized trials
No serious
limitations
No serious
inconsistency
Only one study is available for this outcome.

No serious
indirectness
Serious1
No serious
inconsistency
No serious
imprecision
No serious
imprecision
Serious2
No serious
imprecision
Imprecision
No. of
studies
Quality assessment
None
None
None
None
None
Other
considerations
28/638 (4.4%)
0/0 (0%)
61/638 (9.6%)
3/82 (3.7%)
12/638 (1.9%)
0%
1/541 (0.2%)
0%
0/0 (0%)
RR 16.72 (3.2984.89)
RR 0 (00)
0 more per 1000

(from 0 more to 0
more)
29 more per 1000

(from 4 more to 155
more)
0 fewer per 1000

(from 0 fewer to 0
fewer)
0 fewer per 1000

(from 0 fewer to 0
fewer)
155 fewer per 1000

fewer)
50%
43 fewer per 1000

(from 7 fewer to 69
fewer)
31 fewer per 1000
(from 5 fewer to 50
fewer)
RR 0.69 (0.50.95)
10%
75/541 (13.9%)
150 fewer per 1000

(from 420 fewer to
1025 more)
50%
16 fewer per 1000

more)
0 fewer per 1000
(from 0 fewer to 0
more)
RR 0.70 (0.163.05)
0%
4/77 (5.2%)
295 fewer per 1000

fewer)
50%
27 fewer per 1000

(from 9 fewer to 37
fewer)
Absolute
12 fewer per 1000

(from 4 fewer to 16
fewer)
RR 0.41 (0.210.81)
Relative risk
(95% CI)
Summary of findings
Effect
2%
25/541 (4.6%)
Control
No. of patients
INH+RIF
prophylaxis
Q 1.1.3 INH+RIF vs PLACEBO

A. Question: Should INH+RIF prophylaxis be used in people living with any TST status?
Bibliography: Whalen et al. 1997; Rivero et al. 2003
HIGH
HIGH
LOW
HIGH
Quality
CRITICAL
CRITICAL
CRITICAL
CRITICAL
CRITICAL
Importance
Annex 6
46
47
Design
Limitations
Inconsistency
Indirectness
Imprecision
Randomized trial
No serious
limitations
No evidence
available
Randomized trial
No serious
limitations
Serious2
Serious1
No evidence
available
Only one study addressed this outcome.

No explanation was provided.
No serious
indirectness
No serious
indirectness
No serious
imprecision
No serious
imprecision
Active TB disease (possible, probable, confirmed) (follow up 13 years; clinical examination, chest X-ray, sputum for AFB)
No. of
studies
Quality assessment
None
None
None
None
Other
considerations
0/0 (0%)
57/556 (10.3%)
0/0 (0%)
9/556 (1.6%)
INH+RIF
prophylaxis
Control
0%
0/0 (0%)
RR 0 (00)
0 fewer per 1000

(from 0 fewer to 0
fewer)
0 fewer per 1000

(from 0 fewer to 0
fewer)
130 fewer per 1000

more)
50%
36 fewer per 1000

(from 65 fewer to 6
more)
0 fewer per 1000

(from 0 fewer to 0
fewer)
0 fewer per 1000

(from 0 fewer to 0
fewer)
26 fewer per 1000

(from 47 fewer to 4
more)
RR 0.74 (0.531.04)
RR 0 (00)
10%
64/464 (13.8%)
0%
0/0 (0%)
320 fewer per 1000

(from 115 fewer to
415 fewer)
50%
29 fewer per 1000

fewer)
Absolute
13 fewer per 1000

(from 5 fewer to 17
fewer)
RR 0.36 (0.170.77)
Relative risk
(95% CI)
Summary of findings
Effect
2%
21/464 (4.5%)
No. of patients
B. Question: Should INH+RIF prophylaxis be used in people living with HIV who are TST-positive?
Bibliography: Whalen et al. 1997
MODERATE
MODERATE
Quality
CRITICAL
CRITICAL
CRITICAL
CRITICAL
Importance
Design
Limitations
Randomized trial
No serious
limitations
Randomized trial
No serious
limitations
Randomized trial
No serious
limitations
Serious3
Serious1
Serious1
No evidence
available
Only one study addressed this outcome.

3
Indirectness
No serious
indirectness
No serious
indirectness
No serious
indirectness
Serious2
Serious2
Serious2
Imprecision
None
None
None
None
Other
considerations
0/0 (0%)
4/82 (4.9%)
3/82 (3.7%)
3/82 (3.7%)
INH+RIF
prophylaxis
0%
0/0 (0%)
RR 0 (00)
0 fewer per 1000

(from 0 fewer to 0
fewer)
0 fewer per 1000

(from 0 fewer to 0
fewer)
330 fewer per 1000

more)
50%
94 fewer per 1000

(from 127 fewer to
4 more)
66 fewer per 1000
(from 89 fewer to 3
more)
RR 0.34 (0.111.03)
10%
11/77 (14.3%)
150 fewer per 1000

(from 420 fewer to
1025 more)
50%
16 fewer per 1000

more)
6 fewer per 1000
more)
RR 0.70 (0.163.05)
2%
4/77 (5.2%)
150 fewer per 1000

(from 420 fewer to
1025 more)
50%
16 fewer per 1000

more)
Absolute
6 fewer per 1000

more)
RR 0.70 (0.163.05)
Relative risk
(95% CI)
Summary of findings
Effect
2%
4/77 (5.2%)
Control
No. of patients
D. Question: Should INH+RIF prophylaxis be used in people living with HIV with unknown TST status?
Bibliography: No studies available
Inconsistency
No. of
studies
Quality assessment
C. Question: Should INH+RIF prophylaxis be used in people living with HIV who are TST -negative?
Bibliography: Rivero et al. 2003
LOW
LOW
Quality
CRITICAL
CRITICAL
CRITICAL
CRITICAL
Importance
Annex 6
48
49
Design
Limitations
Inconsistency
Indirectness
Randomized trial
No serious
limitations
Randomized trial
No serious
limitations
Randomized trial
No serious
limitations
Serious2
Serious2
Serious2
No evidence
available
Serious4
Serious3
Serious3
Randomized trial
No serious
limitations
Serious2
No serious
indirectness
Mortality (any cause) (follow up 13 years1; review of hospital records)
Johnson et al. 2001 provided data on long-term follow up.

Only one study is available to assess this outcome.
3
Only TST-positive subjects were considered.
4
Imprecision
No serious
imprecision
No serious
imprecision
No serious
imprecision
No serious
imprecision
Active TB (possible, probable, confirmed) (follow up 13 years1; clinical examination, chest X-ray, sputum for AFB)
No. of
studies
Quality assessment
None
None
None
None
None
Other
considerations
26/462 (5.6%)
0/0 (0%)
58/462 (12.6%)
58/462 (12.6%)
10/462 (2.2%)
INH+RIF+PZA
prophylaxis
0%
1/464 (0.2%)
0%
0/0 (0%)
13.8%
64/464 (13.8%)
RR 26.11 (3.56191.63)
RR 0 (00)
RR 0.69 (0.50.95)
0 more per 1000

(from 0 more to 0
more)
54 more per 1000

(from 6 more to 411
more)
0 fewer per 1000

(from 0 fewer to 0
fewer)
0 fewer per 1000

(from 0 fewer to 0
fewer)
12 fewer per 1000

more)
12 fewer per 1000

more)
45 fewer per 1000

(from 175 fewer to
135 more)
50%
12 fewer per 1000

more)
2 fewer per 1000
(from 7 fewer to 5
more)
RR 0.91 (0.651.27)
2%
64/464 (13.8%)
260 fewer per 1000

(from 385 fewer to
0 more)
50%
24 fewer per 1000

(from 35 fewer to 0
more)
Absolute
10 fewer per 1000

(from 15 fewer to 0
more)
RR 0.48 (0.231)
Relative risk
(95% CI)
Summary of findings
Effect
2%
21/464 (4.5%)
Control
No. of patients
Q 1.1.4 INH+RIF+PZA vs placebo

A. Question: Should INH+RIF+PZA prophylaxis be used in people living with HIV with any TST status?
MODERATE
OO
LOW
LOW
LOW
Quality
CRITICAL
CRITICAL
CRITICAL
CRITICAL
CRITICAL
Importance
Limitations
Inconsistency
Indirectness
Randomized trial
No serious
limitations
Randomized trial
No serious
limitations
Randomized trial
No serious
limitations
Serious1
Serious1
Serious1
No evidence
available
No serious
indirectness
No serious
indirectness
No serious
indirectness
No serious
imprecision
No serious
imprecision
No serious
imprecision
Imprecision
None
None
None
None
Other
considerations
0/0 (0%)
0/0 (0%)
58/462 (12.6%)
10/462 (2.2%)
INH+RIF+PZA
prophylaxis
0%
0/0 (0%)
0%
0/0 (0%)
D. Question: Should INH+RIF+PZA prophylaxis be used in people living with HIV with unknown TST status?
RR 0 (00)
RR 0 (00)
0 fewer per 1000

(from 0 fewer to 0
fewer)
0 fewer per 1000

(from 0 fewer to 0
fewer)
0 fewer per 1000

(from 0 fewer to 0
fewer)
0 fewer per 1000

(from 0 fewer to 0
fewer)
45 fewer per 1000

(from 175 fewer to
135 more)
50%
12 fewer per 1000

more)
2 fewer per 1000
(from 7 fewer to 5
more)
RR 0.91 (0.651.27)
2%
64/464 (13.8%)
260 fewer per 1000

(from 385 fewer to
0 more)
50%
24 fewer per 1000

(from 35 fewer to 0
more)
Absolute
10 fewer per 1000

(from 15 fewer to 0
more)
RR 0.48 (0.231)
Relative risk
(95% CI)
Summary of findings
Effect
2%
21/464 (4.5%)
Control
No. of patients
C. Question: Should INH+RIF+PZA prophylaxis be used in people living with HIV who are TST-negative?
Design
No. of
studies
Quality assessment
B. Question: Should INH+RIF+PZA prophylaxis be used in people living with HIV who are TST-positive?
Bibliography: Whalen et el. 1997
MODERATE
MODERATE
MODERATE
Quality
CRITICAL
CRITICAL
CRITICAL
CRITICAL
Importance
Annex 6
50
51
Design
Limitations
Inconsistency
Indirectness
Randomized trials
No serious
limitations
Randomized trials
No serious
limitations
Randomized trials
No serious
limitations
No evidence
available
No serious
indirectness
No serious
indirectness
No serious
indirectness
Randomized trials
No serious
limitations
No serious
inconsistency
No serious
indirectness
Serious1
No serious
inconsistency
No serious
inconsistency
No serious
imprecision
No serious
imprecision
No serious
imprecision
No serious
imprecision
Imprecision
No. of
studies
Quality assessment
None
None
None
None
None
Other
considerations
27/428 (6.3%)
0/0 (0%)
73/428 (17.1%)
13/428 (3%)
26/428 (6.1%)
RIF+PZA
prophylaxis
Control
0%
3/427 (0.7%)
0%
0/0 (0%)
RR 7.84 (2.623.67)
RR 0 (00)
0 more per 1000

(from 0 more to 0
more)
48 more per 1000

more)
0 fewer per 1000

(from 0 fewer to 0
fewer)
0 fewer per 1000

(from 0 fewer to 0
fewer)
20 more per 1000

(from 115 fewer to
205 more)
50%
6 more per 1000

more)
4 more per 1000
more)
RR 1.04 (0.771.41)
10%
69/427 (16.2%)
155 fewer per 1000

(from 330 fewer to
190 more)
50%
14 fewer per 1000

more)
0 fewer per 1000
(from 0 fewer to 0
more)
RR 0.69 (0.341.38)
0%
19/427 (4.4%)
230 fewer per 1000

fewer)
50%
52 fewer per 1000

fewer)
Absolute
9 fewer per 1000

(from 3 fewer to 13
fewer)
RR 0.54 (0.340.86)
Relative risk
(95% CI)
Summary of findings
Effect
2%
48/427 (11.2%)
No. of patients
Q 1.1.5 RIF+PZA vs placebo

A. Question: Should RIF+PZA prophylaxis be used in people living with HIV with any TST status?
Bibliography: Mwinga et al. 1998; Rivero et al. 2003
HIGH
MODERATE
HIGH
HIGH
Quality
CRITICAL
CRITICAL
CRITICAL
CRITICAL
CRITICAL
Importance
Design
Limitations
Inconsistency
Indirectness
Randomized trial
No serious
limitations
Randomized trial
No serious
limitations
Randomized trial
No serious
limitations
Serious1
Serious1
Serious1
No evidence
available
Only one study available to address this outcome

No serious
indirectness
No serious
indirectness
No serious
indirectness
Serious2
Serious2
No serious
imprecision
Imprecision
No. of
studies
Quality assessment
None
None
None
None
Other
considerations
0/0 (0%)
9/49 (18.4%)
2/49 (4.1%)
2/49 (4.1%)
RIF+PZA
prophylaxis
Control
0%
0/0 (0%)
RR 0 (00)
0 fewer per 1000

(from 0 fewer to 0
fewer)
0 fewer per 1000

(from 0 fewer to 0
fewer)
880 more per 1000

(from 50 fewer to
3705 more)
50%
117 more per 1000

more)
176 more per 1000
more)
RR 2.76 (0.98.41)
10%
4/60 (6.7%)
195 fewer per 1000

(from 440 fewer to
1100 more)
50%
26 fewer per 1000

more)
8 fewer per 1000
more)
RR 0.61 (0.123.2)
2%
4/60 (6.7%)
390 fewer per 1000

fewer)
50%
143 fewer per 1000

fewer)
Absolute
16 fewer per 1000

(from 1 fewer to 19
fewer)
RR 0.22 (0.050.96)
Relative risk
(95% CI)
Summary of findings
Effect
2%
11/60 (18.3%)
No. of patients
B. Question: Should RIF+PZA prophylaxis be used in TST-positive people living with HIV?
Bibliography: Mwinga et al. 1998
LOW
LOW
MODERATE
Quality
CRITICAL
CRITICAL
CRITICAL
CRITICAL
Importance
Annex 6
52
53
Design
Limitations
Inconsistency
Indirectness
Randomized trials
No serious
limitations
Randomized trials
No serious
limitations
Randomized trials
No serious
limitations
Serious1
No evidence
available
Serious1
No serious
inconsistency
No serious
indirectness
No serious
indirectness
No serious
indirectness
No serious
imprecision
No serious
imprecision
No serious
imprecision
Imprecision
No. of
studies
Quality assessment
None
None
None
None
Other
considerations
0/0 (0%)
41/250 (16.4%)
7/250 (2.8%)
14/250 (5.6%)
RIF+PZA
prophylaxis
Control
0%
0/0 (0%)
RR 0 (00)
0 fewer per 1000

(from 0 fewer to 0
fewer)
0 fewer per 1000

(from 0 fewer to 0
fewer)
10 more per 1000

(from 160 fewer to
260 more)
50%
3 more per 1000

more)
2 more per 1000
more)
RR 1.02 (0.681.52)
10%
39/243 (16%)
120 fewer per 1000

(from 360 fewer to
505 more)
50%
9 fewer per 1000

more)
5 fewer per 1000
more)
RR 0.76 (0.282.01)
2%
9/243 (3.7%)
180 fewer per 1000

(from 330 fewer to
115 more)
50%
31 fewer per 1000

more)
Absolute
7 fewer per 1000

(from 13 fewer to 5
more)
RR 0.64 (0.341.23)
Relative risk
(95% CI)
Summary of findings
Effect
2%
21/243 (8.6%)
No. of patients
C. Question: Should RIF+PZA prophylaxis be used in people living with HIV who are TST-negative?
MODERATE
MODERATE
HIGH
Quality
CRITICAL
CRITICAL
CRITICAL
CRITICAL
Importance
Design
Limitations
Inconsistency
Indirectness
Randomized trial
No serious
limitations
Randomized trial
No serious
limitations
Randomized trial
No serious
limitations
Serious1
Serious1
Serious1
No evidence
available
No serious
indirectness
No serious
indirectness
No serious
indirectness
No serious
imprecision
No serious
imprecision
No serious
imprecision
Imprecision
No. of
studies
Quality assessment
None
None
None
None
Other
considerations
0/0 (0%)
23/129 (17.8%)
4/129 (3.1%)
10/129 (7.8%)
RIF+PZA
prophylaxis
0%
0/0 (0%)
RR 0 (00)
0 fewer per 1000

(from 0 fewer to 0
fewer)
0 fewer per 1000

(from 0 fewer to 0
fewer)
75 fewer per 1000

(from 245 fewer to
205 more)
50%
31 fewer per 1000

more)
15 fewer per 1000
more)
RR 0.85 (0.511.41)
10%
26/124 (21%)
180 fewer per 1000

(from 405 fewer to
610 more)
50%
17 fewer per 1000

more)
7 fewer per 1000
more)
RR 0.64 (0.192.22)
2%
6/124 (4.8%)
200 fewer per 1000

(from 360 fewer to
135 more)
50%
52 fewer per 1000

more)
Absolute
8 fewer per 1000

(from 14 fewer to 5
more)
RR 0.60 (0.281.27)
Relative risk
(95% CI)
Summary of findings
Effect
2%
16/124 (12.9%)
Control
No. of patients
D. Question: Should RIF+PZA prophylaxis be used in people living with HIV with unknown TST status?
MODERATE
MODERATE
MODERATE
Quality
CRITICAL
CRITICAL
CRITICAL
CRITICAL
Importance
Annex 6
54
55
Design
Limitations
Inconsistency
Indirectness
Randomized trials
No serious
limitations
Randomized trials
No serious
limitations
Randomized trials
No serious
limitations
No serious
inconsistency2
Serious2
Serious1
No evidence
available
No serious
indirectness
No serious
indirectness
No serious
indirectness
Randomized trials
No serious
limitations
No serious
inconsistency
No serious
indirectness

Gordin et al. 2000 showed an opposite direction of the effect.
Adverse drug reactions leading to treatment interruption (follow up 13 years; clinical and laboratory monitoring)
No serious
imprecision
No serious
imprecision
No serious
imprecision
No serious
imprecision
Imprecision
No. of
studies
Quality assessment
None
None
None
None
None
Other
considerations
73/1705 (4.3%)
0/0 (0%)
299/1597 (18.7%)
43/1597 (2.7%)
77/1705 (4.5%)
INH
prophylaxis
Relative risk
(95% CI)
0%
114/1704 (6.7%)
0%
0/0 (0%)
RR 0.63 (0.480.84)
RR 0 (00)
0 fewer per 1000

(from 0 fewer to 0
fewer)
25 fewer per 1000

fewer)
0 fewer per 1000

(from 0 fewer to 0
fewer)
0 fewer per 1000

(from 0 fewer to 0
fewer)
15 more per 1000

more)
50%
6 more per 1000

more)
3 more per 1000
more)
RR 1.03 (0.891.19)
10%
283/1540 (18.4%)
10 more per 1000

(from 165 fewer to
275 more)
50%
1 more per 1000

(from 9 fewer to 14
more)
0 more per 1000
(from 7 fewer to 11
more)
RR 1.02 (0.671.55)
2%
42/1599 (2.6%)
15 more per 1000

(from 125 fewer to
200 more)
50%
1 more per 1000

more)
Absolute
1 more per 1000

(from 5 fewer to 8
more)
RR 1.03 (0.751.4)
Summary of findings
Effect
2%
75/1704 (4.4%)
RIF+PZA
prophylaxis
No. of patients
Q 1.2 OPTIMAL REGIMEN

Q.1.2.1 INH vs RIF+PZA
A. Question: Should INH vs RIF+PZA prophylaxis be used in people living with HIV with any TST status?
Bibliography: Gordin et al. 2000; Halsey et al. 1998; Mwinga et al. 1998; Rivero et al. 2007; Rivero et al. 2003
HIGH
HIGH
MODERATE
MODERATE
Quality
CRITICAL
CRITICAL
CRITICAL
CRITICAL
CRITICAL
Importance
Design
Limitations
Inconsistency
Indirectness
Randomized trials
No serious
limitations
Randomized trials
Randomized trials
No serious
limitations
No serious
limitations
Serious2
Serious2
Serious1
No evidence
available

One out of the three studies showed an opposite effect.
Mortality (any cause) (follow up 13 years)
No serious
indirectness
No serious
indirectness
No serious
indirectness
No serious
imprecision
No serious
imprecision
No serious
imprecision
Imprecision
No. of
studies
Quality assessment
None
None
None
None
Other
considerations
0/0 (0%)
238/1214 (19.6%)
31/1214 (2.6%)
51/1322 (3.9%)
INH
prophylaxis
0%
0/0 (0%)
RR 0 (00)
0 fewer per 1000

(from 0 fewer to 0
fewer)
0 fewer per 1000

(from 0 fewer to 0
fewer)
45 more per 1000

more)
50%
16 more per 1000

more)
2 more per 1000
(from 1 fewer to 6
more)
RR 1.09 (0.931.29)
10%
219/1220 (18%)
0 fewer per 1000

(from 190 fewer to
315 more)
50%
0 fewer per 1000

more)
0 fewer per 1000
(from 8 fewer to 13
more)
RR 1 (0.621.63)
2%
31/1220 (2.5%)
0 fewer per 1000

(from 160 fewer to
235 more)
50%
0 fewer per 1000

more)
Absolute
0 fewer per 1000

(from 6 fewer to 9
more)
RR 1 (0.681.47)
Relative risk
(95% CI)
Summary of findings
Effect
2%
51/1325 (3.8%)
RIF+PZA
prophylaxis
No. of patients
B. Question: Should INH vs RIF+PZA prophylaxis be used in TST-positive people living with HIV?
Bibliography: Gordin et al. 2000; Halsey et al. 1998; Mwinga et al. 1998; Rivero et al. 2007
MODERATE
MODERATE
MODERATE
Quality
CRITICAL
CRITICAL
CRITICAL
CRITICAL
Importance
Annex 6
56
57
Design
Limitations
Inconsistency
Indirectness
Randomized trials
No serious
limitations
Randomized trials
No serious
limitations
No serious
inconsistency
No serious
inconsistency
Randomized trials
No serious
limitations
No serious
inconsistency
No evidence
available
No serious
indirectness
No serious
indirectness
No serious
indirectness
No serious
imprecision
No serious
imprecision
No serious
imprecision
Imprecision
No. of
studies
Quality assessment
None
None
None
None
Other
considerations
0/0 (0%)
42/261 (16.1%)
9/261 (3.4%)
17/261 (6.5%)
INH
prophylaxis
0%
0/0 (0%)
RR 0 (00)
0 fewer per 1000

(from 0 fewer to 0
fewer)
0 fewer per 1000

(from 0 fewer to 0
fewer)
100 fewer per 1000

more)
50%
43 fewer per 1000

more)
4 fewer per 1000
(from 9 fewer to 3
more)
RR 0.80 (0.541.17)
2%
41/191 (21.5%)
120 more per 1000

(from 265 fewer to
1140 more)
50%
7 more per 1000

more)
5 more per 1000
more)
RR 1.24 (0.473.28)
2%
7/250 (2.8%)
85 more per 1000

(from 205 fewer to
660 more)
50%
10 more per 1000

more)
Absolute
3 more per 1000

(from 8 fewer to 26
more)
RR 1.17 (0.592.32)
Relative risk
(95% CI)
Summary of findings
Effect
2%
14/250 (5.6%)
RIF+PZA
prophylaxis
No. of patients
C. Question: Should INH vs RIF+PZA prophylaxis be used in TST-negative people living with HIV?
HIGH
HIGH
HIGH
Quality
CRITICAL
CRITICAL
CRITICAL
CRITICAL
Importance
Design
Limitations
Inconsistency
Indirectness
Randomized trial
No serious
limitations
Randomized trial
No serious
limitations
Randomized trial
No serious
limitations
Serious1
Serious1
Serious1
No evidence
available
No serious
indirectness
No serious
indirectness
No serious
indirectness
Active TB (possible, probable, confirmed) (follow up 1-3 years; clinical examination, chest X-ray, sputum for AFB)
No. of
studies
Quality assessment
No serious
imprecision
No serious
imprecision
No serious
imprecision
Imprecision
None
None
None
None
Other
considerations
0/0 (0%)
19/122 (15.6%)
3/122 (2.5%)
9/122 (7.4%)
INH
prophylaxis
0%
0/0 (0%)
RR 0 (00)
0 fewer per 1000

(from 0 fewer to 0
fewer)
0 fewer per 1000

(from 0 fewer to 0
fewer)
65 fewer per 1000

(from 250 fewer to
260 more)
50%
23 fewer per 1000

more)
0 fewer per 1000

(from 0 fewer to 0
more)
7 fewer per 1000

more)
13 fewer per 1000

more)
RR 0.87 (0.51.52)
RR 0.79 (0.183.47)
10%
23/129 (17.8%)
0%
4/129 (3.1%)
25 fewer per 1000

(from 300 fewer to
630 more)
50%
4 fewer per 1000

more)
Absolute
1 fewer per 1000

more)
RR 0.95 (0.42.26)
Relative risk
(95% CI)
Summary of findings
Effect
2%
10/129 (7.8%)
RIF+PZA
prophylaxis
No. of patients
D. Question: Should INH vs RIF+PZA prophylaxis be used in people living with HIV with unknown TST status?
MODERATE
MODERATE
MODERATE
Quality
CRITICAL
CRITICAL
CRITICAL
CRITICAL
Importance
Annex 6
58
59
Design
Limitations
Inconsistency
Indirectness
Randomized trials
No serious
limitations
Randomized trials
No serious
limitations
Randomized trials
Serious4
Serious5
Serious2
Serious1
No serious
indirectness
No serious
indirectness
No serious
indirectness
Randomized trials
No serious
limitations
No serious
inconsistency6
No serious
indirectness
No serious
imprecision
No serious
imprecision
Serious3
Martinez et al. 2000 showed an opposite direction of the effect.

One out of the three studies showed an opposite direction of the effect.
3
4
In Martinez et al. 2000 RR was not estimable for lack of events.
5
Different direction and size of the effect across studies
6
Martinez et al. 2000 found an opposite direction of the effect.
No serious
imprecision
Imprecision
No. of
studies
Quality assessment
None
None
None
None
Other
considerations
31/0 (0%)
71/683 (10.4%)
7/147 (4.8%)
18/791 (2.3%)
INH
prophylaxis
0%
40/0 (0%)
RR 0.79 (0.51.23)
0 fewer per 1000

(from 0 fewer to 0
fewer)
0 fewer per 1000

(from 0 fewer to 0
fewer)
45 more per 1000

(from 100 fewer to
250 more)
50%
9 more per 1000

more)
9 more per 1000
more)
RR 1.09 (0.81.5)
10%
67/702 (9.5%)
245 more per 1000

(from 255 fewer to
1750 more)
50%
16 more per 1000

more)
10 more per 1000
more)
RR 1.49 (0.494.5)
2%
5/151 (3.3%)
15 fewer per 1000

(from 240 fewer to
415 more)
50%
1 fewer per 1000

more)
Absolute
1 fewer per 1000

more)
RR 0.97 (0.521.83)
Relative risk
(95% CI)
Summary of findings
Effect
2%
19/810 (2.3%)
RIF+INH
prophylaxis
No. of patients
Q 1.2.2 INH vs INH+RIF

A. Question: Should INH vs RIF+INH prophylaxis be used in people living with HIV with any TST status?
Bibliography: Martinez et al. 2000; Rivero et al. 2007; Rivero et al. 2003; Whalen et al. 1997
HIGH
LOW
LOW
MODERATE
Quality
CRITICAL
CRITICAL
CRITICAL
CRITICAL
Importance
Design
Limitations
Inconsistency
Indirectness
Randomized trials
No serious
limitations
Randomized trials
No serious
limitations
Randomized trials
No serious
limitations
Serious4
Serious2
Serious1
No evidence
available
No serious
indirectness
No serious
indirectness
No serious
indirectness
Martinez et al. 2000 showed an opposite direction of the effect.

3
4
In Martinez et al. 2000 the RR was not estimable.
No serious
imprecision
Serious3
No serious
imprecision
Imprecision
No. of
studies
Quality assessment
None
None
None
None
Other
considerations
0/0 (0%)
58/557 (10.4%)
3/21 (14.3%)
14/665 (2.1%)
INH
prophylaxis
0%
0/0 (0%)
50%
10%
57/577 (9.9%)
RR 0 (00)
RR 1.06 (0.751.49)
0 fewer per 1000

(from 0 fewer to 0
fewer)
0 fewer per 1000

(from 0 fewer to 0
fewer)
30 more per 1000

(from 125 fewer to
245 more)
6 more per 1000

more)
6 more per 1000

more)
1355 more per 1000

(from 290 fewer to
16075 more)
50%
104 more per 1000

(from 22 fewer to
1237 more)
54 more per 1000
more)
RR 3.71 (0.4233.15)
2%
1/26 (3.8%)
15 fewer per 1000

(from 265 fewer to
485 more)
50%
1 fewer per 1000

more)
Absolute
1 fewer per 1000

more)
RR 0.97 (0.521.83)
Relative risk
(95% CI)
Summary of findings
Effect
2%
15/685 (2.2%)
RIF+INH
prophylaxis
No. of patients
B. Question: Should INH vs RIF+INH prophylaxis be used in TST-positive people living with HIV?
Bibliography: Martinez et al. 2000; Rivero et al. 2007; Whalen et al. 1997
MODERATE
LOW
MODERATE
Quality
CRITICAL
CRITICAL
CRITICAL
CRITICAL
Importance
Annex 6
60
61
Limitations
Inconsistency
Indirectness
Randomized trials
No serious
limitations
Randomized trials
No serious
limitations
Randomized trials
No serious
limitations
No evidence
available

Serious2
No serious
inconsistency
No serious
inconsistency
No serious
indirectness
No serious
indirectness
No serious
indirectness
Serious1
Serious1
Serious1
Imprecision
None
None
None
None
Other
considerations
0/0 (0%)
13/126 (10.3%)
4/126 (3.2%)
4/126 (3.2%)
INH
prophylaxis
0%
0/0 (0%)
50%
2%
10/125 (8%)
RR 0 (00)
RR 1.29 (0.592.84)
0 fewer per 1000

(from 0 fewer to 0
fewer)
0 fewer per 1000

(from 0 fewer to 0
fewer)
145 more per 1000

(from 205 fewer to
920 more)
6 more per 1000

(from 8 fewer to 37
more)
23 more per 1000

more)
5 fewer per 1000

(from 375 fewer to
1435 more)
50%
0 fewer per 1000

more)
0 fewer per 1000
more)
RR 0.99 (0.253.87)
2%
4/125 (3.2%)
5 fewer per 1000

(from 375 fewer to
1435 more)
50%
0 fewer per 1000

more)
Absolute
0 fewer per 1000

more)
RR 0.99 (0.253.87)
Relative risk
(95% CI)
Summary of findings
Effect
2%
4/125 (3.2%)
RIF+INH
prophylaxis
No. of patients
D. Question: Should INH vs RIF+INH prophylaxis be used in people living with HIV with unknown TST status?
Design
No. of
studies
Quality assessment
C. Question: Should INH vs RIF+INH prophylaxis be used in TST-negative people living with HIV?
Bibliography: Martinez et al. 2000; Rivero et al. 2007
LOW
MODERATE
MODERATE
Quality
CRITICAL
CRITICAL
CRITICAL
CRITICAL
Importance
Design
Limitations
Inconsistency
Indirectness
Randomized trial
No serious
limitations
Randomized trial
No serious
limitations
Randomized trial
No serious
limitations
Serious1
Serious1
Serious1
No evidence
available
Serious2
No serious
indirectness
Serious2
Randomized trial
No serious
limitations
Only one study assessed this outcome.

Only TST-positive patients
Serious1
No serious
indirectness
No serious
imprecision
No serious
imprecision
No serious
imprecision
No serious
imprecision
Imprecision
No. of
studies
Quality assessment
None
None
None
None
None
Other
considerations
3/536 (0.6%)
0/0 (0%)
58/536 (10.8%)
58/536 (10.8%)
7/536 (1.3%)
INH
prophylaxis
450 fewer per 1000

(from 335 fewer to
485 fewer)
50%
51 fewer per 1000

fewer)
0 fewer per 1000

(from 0 fewer to 0
fewer)
0 fewer per 1000

(from 0 fewer to 0
fewer)
18 fewer per 1000

fewer)
RR 0.10 (0.030.33)
RR 0 (00)
2%
26/462 (5.6%)
0%
0/0 (0%)
70 fewer per 1000

(from 195 fewer to
105 more)
50%
18 fewer per 1000

more)
14 fewer per 1000
more)
RR 0.86 (0.611.21)
10%
58/462 (12.6%)
70 fewer per 1000

(from 195 fewer to
105 more)
50%
18 fewer per 1000

more)
3 fewer per 1000
(from 8 fewer to 4
more)
RR 0.86 (0.611.21)
2%
58/462 (12.6%)
200 fewer per 1000

(from 385 fewer to
285 more)
50%
9 fewer per 1000

more)
Absolute
8 fewer per 1000

more)
RR 0.60 (0.231.57)
Relative risk
(95% CI)
Summary of findings
Effect
2%
10/462 (2.2%)
INH+RIF+PZA
prophylaxis
No. of patients
Q 1.2.3 INH vs INH+RIF+PZA

A. Question: Should INH vs INH+RIF+PZA prophylaxis be used in people living with HIV with any TST status?
MODERATE
LOW
MODERATE
LOW
Quality
CRITICAL
CRITICAL
CRITICAL
CRITICAL
CRITICAL
Importance
Annex 6
62
63
Limitations
Inconsistency
Indirectness
Randomized trial
No serious
limitations
Randomized trial
No serious
limitations
Randomized trial
No serious
limitations
No evidence
available
Only one study assessed this outcome.
HIV disease progression (clinical and immunological criteria)
Mortality (any cause) (review of hospital records)
Serious1
Serious1
Serious1
No serious
indirectness
No serious
indirectness
No serious
indirectness
No serious
imprecision
No serious
imprecision
No serious
imprecision
Imprecision
None
None
None
None
Other
considerations
0/0 (0%)
0/0 (0%)
58/536 (10.8%)
7/536 (1.3%)
INH
prophylaxis
0%
0/0 (0%)
0%
0/0 (0%)
D. Question: Should INH vs INH+RIF+PZA prophylaxis be used in people living with HIV with unknown TST status?
RR 0 (00)
RR 0 (00)
0 fewer per 1000

(from 0 fewer to 0
fewer)
0 fewer per 1000

(from 0 fewer to 0
fewer)
0 fewer per 1000

(from 0 fewer to 0
fewer)
0 fewer per 1000

(from 0 fewer to 0
fewer)
70 fewer per 1000

(from 195 fewer to
105 more)
50%
18 fewer per 1000

more)
3 fewer per 1000
(from 8 fewer to 4
more)
RR 0.86 (0.611.21)
2%
58/462 (12.6%)
200 fewer per 1000

(from 385 fewer to
285 more)
50%
9 fewer per 1000

more)
Absolute
8 fewer per 1000

more)
RR 0.60 (0.231.57)
Relative risk
(95% CI)
Summary of findings
Effect
2%
10/462 (2.2%)
INH+RIF+PZA
prophylaxis
No. of patients
C. Question: Should INH vs INH+RIF+PZA prophylaxis be used in TST-negative people living with HIV?
Design
No. of
studies
Quality assessment
B. Question: Should INH vs INH+RIF+PZA prophylaxis be used in TST-positive people living with HIV?
MODERATE
MODERATE
MODERATE
Quality
CRITICAL
CRITICAL
CRITICAL
CRITICAL
Importance
Design
Limitations
Inconsistency
Indirectness
Randomized trial
No serious
limitations
No evidence
available
Randomized trial
No serious
limitations
Serious1
Serious1
No evidence
available
Serious2
Serious2
Randomized trial
No serious
limitations
Serious

Only TST-positive patients
No serious
indirectness
No serious
imprecision
No serious
imprecision
No serious
imprecision
Imprecision
No. of
studies
Quality assessment
None
None
None
None
None
Other
considerations
13/556 (2.3%)
0/0 (0%)
57/556 (10.3%)
0/0 (0%)
9/556 (1.6%)
INH+RIF
prophylaxis
0%
26/462 (5.6%)
0%
0/0 (0%)
RR 0.42 (0.220.8)
RR 0 (00)
0 fewer per 1000

(from 0 fewer to 0
fewer)
33 fewer per 1000

fewer)
0 fewer per 1000

(from 0 fewer to 0
fewer)
0 fewer per 1000

(from 0 fewer to 0
fewer)
90 fewer per 1000

more)
50%
23 fewer per 1000

more)
0 fewer per 1000

(from 0 fewer to 0
fewer)
0 fewer per 1000

(from 0 fewer to 0
fewer)
18 fewer per 1000

more)
RR 0.82 (0.581.15)
RR 0 (00)
10%
58/462 (12.6%)
0%
0/0 (0%)
125 fewer per 1000

(from 345 fewer to
410 more)
50%
5 fewer per 1000

more)
Absolute
5 fewer per 1000

more)
RR 0.75 (0.311.82)
Relative risk
(95% CI)
Summary of findings
Effect
2%
10/462 (2.2%)
INH+RIF+PZA
prophylaxis
No. of patients
Q 1.2.4 INH+RIF vs INH+RIF+PZA

A. Question: Should INH+RIF vs INH+RIF+PZA prophylaxis be used in people living with HIV with any TST status?
MODERATE
LOW
LOW
Quality
CRITICAL
CRITICAL
CRITICAL
CRITICAL
CRITICAL
Importance
Annex 6
64
65
Limitations
Inconsistency
Indirectness
Randomized trial
No serious
limitations
No evidence
available
Randomized trial
No serious
limitations
Serious1
Serious1
No evidence
available
No serious
indirectness
No serious
indirectness
No serious
imprecision
No serious
imprecision
Imprecision
None
None
None
None
Other
considerations
0/0 (0%)
57/556 (10.3%)
0/0 (0%)
9/556 (1.6%)
INH+RIF
prophylaxis
Relative risk
(95% CI)
0%
0/0 (0%)
D. Question: Should INH+RIF vs RIF+PZA+INH prophylaxis be used in people living with HIV with unknown TST
status?
RR 0 (00)
0 fewer per 1000

(from 0 fewer to 0
fewer)
0 fewer per 1000

(from 0 fewer to 0
fewer)
90 fewer per 1000

more)
50%
23 fewer per 1000

more)
0 fewer per 1000

(from 0 fewer to 0
fewer)
0 fewer per 1000

(from 0 fewer to 0
fewer)
18 fewer per 1000

more)
RR 0.82 (0.581.15)
RR 0 (00)
10%
58/462 (12.6%)
0%
0/0 (0%)
125 fewer per 1000

(from 345 fewer to
410 more)
50%
5 fewer per 1000

more)
Absolute
5 fewer per 1000

more)
RR 0.75 (0.311.82)
Summary of findings
Effect
2%
10/462 (2.2%)
INH+RIF+PZA
prophylaxis
No. of patients
C. Question: Should INH+RIF vs INH+RIF+PZA prophylaxis be used in TST-negative people living with HIV?
Design
No. of
studies
Quality assessment
B. Question: Should INH+RIF vs INH+RIF+PZA prophylaxis be used in TST-positive people living with HIV?
Bibliography: Rivero et al. 2007
MODERATE
MODERATE
Quality
CRITICAL
CRITICAL
CRITICAL
CRITICAL
Importance
Design
Limitations
Inconsistency
Randomized trial
No serious
limitations
Randomized trial
No serious
limitations
Serious1
Serious1
No serious
indirectness
No serious
indirectness
Indirectness
Randomized trial
No evidence
available
No serious
limitations
Serious1
No serious
indirectness
Randomized trial
No serious
limitations
Serious1
No serious
indirectness
Only one trial is available to address this outcome and comparison.

Calculated on the basis of TB incidence (per 100 person-years)
3
Calculated on crude numbers
4
Calculated on the basis of death incidence (per 100 person-years)
No serious
imprecision
No serious
imprecision
No serious
imprecision
Imprecision
No serious
imprecision
Adverse drug reaction leading to treatment interruption (follow up median 3.91 years; clinical and laboratory monitoring)
HIV disease progression (follow up 3.91 years)
Mortality (any cause) (follow up median 3.91 years; review of hospital records and patients files)
Confirmed TB (follow up median 3.91 years; culture-proven)
Active TB (follow up median 3.91 years; clinical examination, chest X-ray, sputum for AFB)
No. of
studies
Quality assessment
None
None
None
None
None
Other
considerations
4/240 (1.7%)
0/0 (0%)
17/250 (6.8%)
20/329 (6.1%)
24/329 (7.3%)
INH+RPT
prophylaxis
0%
4/208 (1.9%)
0%
0/0 (0%)
RR 0.87 (0.223.42)3
RR 0 (00)
0 fewer per 1000

(from 0 fewer to 0
more)
2 fewer per 1000

more)
0 fewer per 1000

(from 0 fewer to 0
fewer)
0 fewer per 1000

(from 0 fewer to 0
fewer)
170 fewer per 1000

(from 335 fewer to
130 more)
50%
35 fewer per 1000

more)
34 fewer per 1000
more)
RR 0.66 (0.331.26)4
10%
25/241 (10.4%)
75 fewer per 1000

(from 275 fewer to
295 more)
50%
8 fewer per 1000

more)
3 fewer per 1000
more)
RR 0.85 (0.451.59)3
2%
17/328 (5.2%)
25 more per 1000

(from 220 fewer to
485 more)
50%
3 more per 1000

more)
Absolute
1 more per 1000

(from 9 fewer to 19
more)
RR 1.05 (0.561.97)2
Relative risk
(95% CI)
Summary of findings
Effect
2%
22/328 (6.7%)
INH
prophylaxis
No. of patients
Q 1.2.5 INH vs rifapentine (RPT)+INH

A. Question: Should INH+RPT vs INH prophylaxis be used in TST-positive people living with HIV?
Bibliography: Martinson et al. 2009
MODERATE
MODERATE
MODERATE
MODERATE
Quality
CRITICAL
CRITICAL
CRITICAL
CRITICAL
CRITICAL
Importance
Annex 6
66
67
Design
Limitations
Inconsistency
Indirectness
Imprecision
Randomized trials
No serious
limitations1
Randomized trial
No serious
limitations
No serious
inconsistency
No serious
inconsistency
Randomized trials
No evidence
available
No serious
limitations1
No serious
inconsistency
Serious2,3,4
Serious
Serious2,3,4
No serious
imprecision
No serious
imprecision
No serious
imprecision
Randomized trials
No serious
limitations
Serious6
No serious
indirectness
No serious
imprecision
None
None
None
None
None
Other
considerations
70/983 (7.1%)
0/0 (0%)
15/997 (1.5%)
14/997 (1.4%)
20/997 (2%)
Continuous INH
prophylaxis
1%
12/846 (1.4%)
0%
0/0 (0%)
RR 5.02 (2.749.198)
RR 0 (00)
40 more per 1000

(from 17 more to 82
more)
57 more per 1000

more)
0 fewer per 1000

(from 0 fewer to 0
fewer)
0 fewer per 1000

(from 0 fewer to 0
fewer)
285 fewer per 1000

(from 110 fewer to
380 fewer)
50%
20 fewer per 1000

(from 8 fewer to 26
fewer)
57 fewer per 1000
fewer)
RR 0.43 (0.240.78)
10%
40/1150 (3.5%)
260 fewer per 1000

fewer)
50%
15 fewer per 1000

(from 3 fewer to 21
fewer)
10 fewer per 1000
(from 2 fewer to 15
fewer)
RR 0.48 (0.260.9)
2%
33/1150 (2.9%)
250 fewer per 1000

fewer)
50%
20 fewer per 1000

(from 6 fewer to 28
fewer)
Absolute
10 fewer per 1000

(from 3 fewer to 14
fewer)
RR 0.50 (0.290.84)
Relative risk
(95% CI)
Summary of findings
Effect
2%
46/1150 (4%)
6 months INH
prophylaxis
No. of patients
The Soweto trial was not a head-to-head comparison but a four-arm study designed to compare the efficacy of different regimens as well.
The Soweto trial considered TST-positive patients while the BOTUSA trial enrolled those with TST+/3
Mean CD4 count at baseline was >500 cells/mm3 in the Soweto trial and around 200 cells/mm3 in the BOTUSA trial.
4
The Soweto trial enrolled patients who were not eligible for ART, while in the BOTUSA trial about 40% of the patients had started ART.
5
Sub-anaylsis on this outcome is expected to be performed soon.
6
The difference in the size of the effect is large.
Adverse drug reactions leading to treatment interruption (follow up 36 months; laboratory monitoring and clinical assessment)
05
HIV disease progression
Mortality (any cause) (follow up 36 months; review of hospital records and patients files)
Confirmed TB (follow up mean 36 months; culture-proven)
Active TB ( possible, probable, confirmed) (follow up mean 36 months; clinical assessment, chest X-ray, sputum for AFB)
No. of
studies
Quality assessment
Q 1.3 Duration
Q1.3.1 6 months INH vs 36 months INH
A. Question: Should continuous INH vs 6 months INH prophylaxis be used in people living with HIV with any TST status?
Settings: High TB/HIV prevalence settings
Bibliography: Martinson et al. 2009; Samandari et al. 2009
MODERATE
MODERATE
MODERATE
MODERATE
Quality
CRITICAL
CRITICAL
CRITICAL
CRITICAL
CRITICAL
Importance
Design
Limitations
Inconsistency
Indirectness
Randomized trials
Very serious
No evidence
available
No serious
inconsistency
Randomized trials
No evidence
available
Very serious
No serious
inconsistency
No serious
indirectness
No serious
indirectness
No serious
imprecision
Randomized trials
Very serious
No serious
inconsistency
No serious
indirectness
Not estimable due to the lack of events in the 12 months group
No serious
imprecision
Adverse drug reactions leading to treatment interruption (follow up 13 years; laboratory monitoring and clinical assessment)
Mortality (any cause) (follow up 13 years; review of hospital records and patients files)
No serious
imprecision
Imprecision
Active TB ( possible, probable, confirmed) (follow up 13 years; clinical assessment, chest X-ray, sputum for AFB)
No. of
studies
Quality assessment
None
None
None
None
None
Other
considerations
56/1968 (2.8%)
0/0 (0%)
375/1806 (20.8%)
0/0 (0%)
57/1806 (3.2%)
6 months of
INH prophylaxis
0%
0/58 (0%)
0%
0/0 (0%)
RR 0 (0 to 0)1
RR 0 (00)
0 fewer per 1000

(from 0 fewer to 0
fewer)
0 fewer per 1000

(from 0 fewer to 0
fewer)
0 fewer per 1000

(from 0 fewer to 0
fewer)
0 fewer per 1000

(from 0 fewer to 0
fewer)
295 more per 1000

more)
50%
77 more per 1000

more)
59 more per 1000
(from 9 more to 134
more)
RR 1.59 (1.0852.34)
10%
24/184 (13%)
0 fewer per 1000

(from 0 fewer to 0
fewer)
0%
0 fewer per 1000

(from 0 fewer to 0
fewer)
0 fewer per 1000
(from 0 fewer to 0
fewer)
RR 0 (00)
0%
0/0 (0%)
210 fewer per 1000

more)
50%
23 fewer per 1000

(from 38 fewer to 7
more)
Absolute
8 fewer per 1000

(from 14 fewer to 2
more)
RR 0.58 (0.31.12)
Relative risk
(95% CI)
Summary of findings
Effect
2%
10/184 (5.4%)
12 months of
INH prophylaxis
No. of patients
LOW
LOW
LOW
Quality
CRITICAL
CRITICAL
CRITICAL
CRITICAL
CRITICAL
Importance
Q 1.3.2 INH 6 months vs 12 months

A. Question: Should 6 months of INH vs 12 months of INH prophylaxis be used in people living with HIV with any TST status?
Bibliography: Pape et al. 1993; Whalen et al. 1997; Hawken et al. 1997; Mwinga et al. 1998; Fitzgerald et al. 2001; Gordin et al. 1997; Rivero et al. 2003; Gordin et al.
2000; Martinez et al. 2000; Halsey et al. 1998; Rivero et al. 2007
Annex 6
68
69
Design
Limitations
Inconsistency
Indirectness
Randomized trials
Very serious
No evidence
available
No serious
inconsistency
Randomized trials
No evidence
available
Very serious
No serious
inconsistency
Very small sample size in the 12 months group
No serious
indirectness
No serious
indirectness
Serious1
Serious1
Imprecision
No. of
studies
Quality assessment
None
None
None
None
Other
considerations
0/0 (0%)
68/655 (10.4%)
0/0 (0%)
16/655 (2.4%)
6 months of
INH prophylaxis
0%
0/0 (0%)
RR 0 (00)
0 fewer per 1000

(from 0 fewer to 0
fewer)
0 fewer per 1000

(from 0 fewer to 0
fewer)
155 more per 1000

(from 285 fewer to
1490 more)
50%
24 more per 1000

more)
31 more per 1000
more)
RR 1.31 (0.433.98)
10%
3/38 (7.9%)
0 fewer per 1000

(from 0 fewer to 0
fewer)
0%
0 fewer per 1000

(from 0 fewer to 0
fewer)
0 fewer per 1000
(from 0 fewer to 0
fewer)
RR 0 (00)
0%
0/0 (0%)
270 fewer per 1000

(from 445 fewer to
475 more)
50%
28 fewer per 1000

more)
Absolute
11 fewer per 1000

more)
RR 0.46 (0.111.95)
Relative risk
(95% CI)
Summary of findings
Effect
2%
2/38 (5.3%)
12 months of
INH prophylaxis
No. of patients
B. Question: Should 6 months of INH vs 12 months of INH prophylaxis be used in people living with HIV with a positive TST status?
VERY LOW
VERY LOW
Quality
CRITICAL
CRITICAL
CRITICAL
CRITICAL
Importance
Design
Limitations
Inconsistency
Indirectness
Randomized trials
No evidence
available
Very serious
No serious
inconsistency
Randomized trials
No evidence
available
Very serious
No serious
inconsistency
No serious
indirectness
No serious
indirectness
Serious1
None
None
None
None
Other
considerations
Sample size in the 12 months-group was much smaller than that in the 6 months group
Confirmed TB (culture-proven)
Serious1
Imprecision
No. of
studies
Quality assessment
0/0 (0%)
307/1151 (26.7%)
0/0 (0%)
41/1151 (3.6%)
6 months of
INH prophylaxis
0%
0/0 (0%)
RR 0 (00)
0 fewer per 1000

(from 0 fewer to 0
fewer)
0 fewer per 1000

(from 0 fewer to 0
fewer)
310 more per 1000

more)
50%
102 more per 1000

more)
0 fewer per 1000

(from 0 fewer to 0
fewer)
62 more per 1000

more)
RR 1.62 (1.112.37)
RR 0 (00)
10%
24/146 (16.4%)
0/0 (0%)
175 fewer per 1000

(from 345 fewer to
180 more)
50%
19 fewer per 1000

more)
Absolute
7 fewer per 1000

(from 14 fewer to 7
more)
RR 0.65 (0.311.36)
Relative risk
(95% CI)
Summary of findings
Effect
2%
8/146 (5.5%)
12 months of
INH prophylaxis
No. of patients
VERY LOW
VERY LOW
Quality
CRITICAL
CRITICAL
CRITICAL
CRITICAL
Importance
C. Question: Should 6 months of INH vs 12 months of INH prophylaxis be used in TST -negative people living with HIV?
Bibliography: Whalen et al. 1997; Hawken et al. 1997; Mwinga et al. 1998; Fitzgerald et al. 2001; Gordin et al. 1997; Rivero et al. 2003; Whallen et al. 1997 anergy
Annex 6
70

Adults and adolescents living with HIV, who have an unknown or positive TST status
and are unlikely to have active TB, should receive at least six months of IPT as part of a
comprehensive package of HIV care. This includes individuals irrespective of degree of
immunosuppression, those on ART, those who have previously been treated for TB and
pregnant women.
TST is not a requirement for initiating IPT among people living with HIV.
Where feasible, TST can be used as people with a positive test benefit more from IPT than
those with a negative test.
Intervention: At least six months of IPT (300 mg plus vitamin B6 25 mg daily)

Factor
Quality of evidence
Decision
High
Explanation
Provision of IPT reduces active TB incidence by:

33% regardless of TST status (GRADE high)
64% in TST-positive persons (GRADE high)
14% in TST-negative persons (GRADE high)
14% in those with unknown TST status (GRADE moderate)
IPT has been shown to be equally efficacious but less toxic
than multidrug regimens in preventing active TB disease
(GRADE low/moderate)

Strong
71
Reduction in TB morbidity
Reduction in TB transmission
Reduction in mortality (even if there is no evidence of a
direct effect in terms of death GRADE moderate)
Potential reduction in generation of MDR and XDR TB by
reducing TB incidence
Reduction in prevalence of non-INH mono/drug-resistant
strains in the community (e.g. mono-RIF)
Avoidance of side-effects of TB treatment
Reduction in drugdrug interaction in patients on ART and
TB treatment
Improved TB infection control in health-care and community
settings (particularly in HIV clinics)
Fewer side-effects than with a preventive combination
regimen (GRADE high)
Less drugdrug interaction caused by alternative preventive
regimens containing RIF
Potential increase in adherence to other treatment (ART,
co-trimoxazole, etc.)
Longer regimen compared to a combination preventive

regimen
Potential for development of greater resistance compared to
a combination prevention regimen
Increase in number of persons receiving unnecessary
treatment (especially when TST is not performed or in case
of false-positive TST where TST is performed)
Potential INH toxicity
Potential development and transmission of INH-resistant
strains by treating undiagnosed active TB
Potential reduction in adherence to other treatment (ART,
co-trimoxazole, etc.)
Annex 6
Strong
Less pill burden than in other preventive combination

regimens
Fewer side-effects than in other preventive combination
regimens
Easier to take treatment
Avoids active TB disease, deaths and transmission to other
family members
Health-care workers would be less exposed to active TB
cases and would feel more protected
Infection control benefits for patients, family and the
community both in terms of preventing TB and also in
preventing infection and/or reinfection
Avoids potential need for long TB treatment with a high pill
burden and significant side-effects
Patients would feel protected against TB, adding value to HIV
care services
BUT
Longer regimen
RIF would make it easier to monitor adherence
May be concerns regarding the side-effects of INH
Pill burden
Stigma
Increase in number of people attending clinics
Adds burden to supply chain
Costs
Weak
Increased by:
Longer provision as compared to other shorter preventive
regimens
Costs of INH (including storage, supply and transportation)
Potential laboratory monitoring (in case of toxicity)
Additional staff time in overburdened HIV care settings
Second-line TB treatment needed in case INH resistance
occurs and is transmitted
Treatment of rare INH-related toxicity (blood tests,
hospitalization, patients loss of earning)
Additional costs of providing vitamin B6
Decreased by:
Less expensive regimen as compared to other preventive
regimens
Avoids treatment costs of active TB
Less hospitalization costs
Reduction in social costs and loss of earnings
Reduction in costs due to treatment of secondary cases
including in health-care workers, which may improve staff
retention
Reduction in costs related to TBART co-treatment which
often includes more expensive regimens
Reduction in drugdrug interaction from TB treatment in
patients on ART
Potential reduction in generation of MDR and XDR TB by
reducing the incidence of TB
72
Feasibility
Strong
Overall ranking of
recommendation
Strong
Clear clinical and public health benefit with strong evidence

base
Less monitoring needed as compared to other preventive
regimens
Drug easily available and inexpensive
Administration of IPT fits well with the schedule of HIV
programmes
Does not require laboratory monitoring
Health-care workers are already familiar with the drug
BUT
Longer-term intervention when compared to other
preventive regimens
Would mean adding an intervention to an overburdened
system
May increase clinic visits and require more staff time
Space required for storage and difficulties in procurement
INH as a single formulation less commonly available
compared to fixed-dose combination (FDC) TB medicines
Opinion leaders are reluctant to use IPT in the face of
scientific evidence
Requires additional training of health-care workers on
benefits of IPT and TB screening
Adults and adolescents living with HIV who have successfully completed their TB
treatment should be provided secondary INH prophylaxis for at least six months (strong
recommendation) or at least 36 months (conditional recommendation)
Population: People living with HIV who have successfully completed TB treatment
Intervention: Secondary INH prophylaxis
Factor
Quality of evidence
Decision
Moderate
Explanation

Strong

Costs

Weak
Strong
Feasibility
Overall ranking
of recommendation
73
Strong
Evidence is available from three randomized trials and one

observational study. One randomized trial compared INH with
rifampicin after successful TB treatment.
Adverse events and mortality were not addressed (critical
outcome)
(moderate grade of evidence for recurrent TB outcome)
Reduction in incidence of recurrent TB
Reduction in TB transmission
Potential reduction in generation of MDR strains by reducing
TB incidence
Improved TB infection control in health-care settings by
reducing active TB and also preventing new infections or
reinfection (particularly in HIV clinics)
Pill burden
Reduction in compliance with other treatments (ART, cotrimoxazole, etc.)
Lack of motivation in patients as they have already been
treated for TB
Lack of confidence in efficacy of TB drugs
Costs are unlikely to increase as it can easily be

incorporated into routine care for people living with HIV
Cost-saving implications through preventing development of
recurrent TB
It will be part of routine care for people living with HIV
Strong (at least 6 months)
Conditional (at least 36 months)
Annex 6
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16. Zar HJ t al. Effect of isoniazid prophylaxis on mortality and incidence of tuberculosis in children with HIV: randomized
controlled trial. British Medical Journal, 2007, 334:136.
17. Mohammed A et al. Randomised controlled trial of isoniazid preventive therapy in South African adults with advanced
HIV disease. International Journal of Tuberculosis and Lung Disease, 2007, 11:11141120.
18. Johnson JL et al.; for the UgandaCase Western Reserve University Research Collaboration. Duration of efficacy
of treatment of latent tuberculosis infection in HIV-infected adults. AIDS, 2001, 15:21372147.
19. Gordin F et al. Rifampin and pyrazinamide vs isoniazid for prevention of tuberculosis in HIV-Infected persons. An
international randomized trial. Journal of the American Medical Association, 2000, 283:14451450.
20. Halsey NA et al. Randomised trial of isoniazid versus rifampicin and pyrazinamide for prevention of tuberculosis in
HIV-1 infection. Lancet, 1998, 351:786792.
21. Rivero A et al. A randomized clinical trial investigating three chemoprophylaxis regimens for latent tuberculosis
infection in HIV-infected patients. Enfermedades infecciosas y microbiologia clinica, 2007, 25:305310.
74
6.2. Timing of initiation: Define the optimal time to start considering IPT (i.e.
should immune status be considered and should IPT be started with ART?).
PICOT Question: What is the optimal time to
start considering IPT (i.e. should immune status
be considered and should IPT be started with

ART)?
6.2.1 Immune status
Q6.2.2 (b) ART
Population: People living with HIV

Intervention: Starting IPT if immune suppression not
severe (CD4 count >200 cells/mm3)
Comparison: Starting IPT if immune suppression
severe (CD4 count <200 cells/mm3)
Outcomes: Active TB incidence, mortality, AEs,
progression of HIV disease, adherence, TB drug
resistance, interval to active TB (Atb), interval to death
Timeline: Lifetime

Intervention: Starting IPT and ART at the same
time
Comparison: Starting ART first followed by IPT
progression of HIV disease, adherence, TB
Timeline: Lifetime
Q6.2.2 (a) ART

Intervention: Starting IPT and ART at the same
time
Comparison: Starting IPT first followed by ART
progression of HIV disease, adherence, TB
Timeline: Lifetime
Outcomes
Relative importance
Active TB incidence (suspected, probable, confirmed) 9

Confirmed TB
Mortality
Adverse events
Adherence
TB drug resistance
Cost-effectiveness
Interval to death
75
9
8
7
7
7
6
6
Critical
Critical
Critical
Critical
Critical

Less critical
Less critical
Annex 6
2. Literature search and information retrieval

1. Pubmed Search (Tuberculosis[Mesh] AND HIV Infections[Mesh]) AND Therapeutics[Mesh]
1375
articles
Limits
phase II, clinical trial, phase III, clinical trial,
phase IV, comparative study, controlled clinical
trial, multicentre study, adolescent: 1318 years,

adult: 1944 years, middle-aged: 4564 years,
middle-aged + aged: 45+ years, aged: 65+ years,
80 and over: 80+ years
219
By title
30
By
abstract
19
Of
interest
Evidence retrieval findings

The Guidelines Group reviewed the available data
regarding the initiation of IPT and immune status,
including concomitant use with ART. Six studies [16]
were examined and showed contrasting results on
the reduction of TB risk by immune status. Additional
protective benefits of concomitant use of IPT with ART
were demonstrated in two [3,4] observational studies
from Brazil and South Africa, and a sub-analysis of
data from an unpublished randomized clinical trial
from Botswana. Based on this evidence and the
potential benefit of concomitant use of IPT with ART,
the Guidelines Group strongly recommends that IPT
be given irrespective of immune status and whether or
not the person is on ART. IPT initiation or completion
should not delay commencement of ART in eligible

people living with HIV. However, the Guidelines Group
recognizes the absence of evidence as to whether
concomitant initiation of IPT with ART or delayed
initiation of IPT is better in terms of efficacy and toxicity.
A large, randomized controlled study (TEMPRANO
study) is currently ongoing in Ivory Coast and will
provide data on patients randomized to IPT before
ART versus simultaneous initiation of IPT and ART.
However, relevant studies providing stratifications/
sub-analysis or some kind of guidance in terms of
optimal time of initiation have been selected as
follows:
76
STUDIES
BRIEF DESCRIPTION OF RELEVANT FINDINGS
Churchyard et al. 2003

[2]
No significant difference in the efficacy of IPT by CD4 stratum (above or below 200
cells/mm3) though absolute TB recurrence rates were substantially higher in the group
with CD4 count <200 cells/mm3 as one would expect.
Mwinga et al. 1998 [5]
Golub et al. 2007 [4]

Brazil
Samandari et al. 2009 [6]

Botswana
Akolo et al. 2010 [1]

Cochrane Review
Churchyard et al. 2010
[2]
77
Protection against TB was limited to those with total lymphocyte count of 2x109/l or
higher
RRs for TB stratified by TST and lymphocyte count are most marked in those with a
lymphocyte count of 2x109/l or more, and TST reading of 5 mm or more. The rate of TB
was 6/56 = 10.71 per 100 person-years in the placebo group and 2/95 = 2.10 per 100
person-years in the INH and RIF+PZA groups combined (RR = 0.19, 95%CI: 0.04
0.94, P = 0.026)
The subjects included 11 026 HIV-infected patients receiving medical care at 29 public
clinics in Rio de Janeiro, Brazil, between 1 September 2003 and 1 September 2005
Data were collected through a retrospective medical records review.
The combination of IPT and ART was associated with significant reduction in incidence
of TB for patients with both advanced and early HIV disease.
In the population of patients with advanced HIV disease (CD4 cell count <350 cells/
mm3), over a period of two years, ART alone was associated with a significantly
reduced incidence of TB, whereas IPT alone was not.
In patients with a CD4 cell count >350 cells/mm3 at baseline, ART significantly
reduced the risk of TB, IPT reduced the risk but not at a statistically significant level,
whereas the combination reduced the risk substantially.
The overall incidence of TB was 2.28 cases/100 person-years (95%CI: 2.062.52).
Among patients who received neither ART nor IPT, the incidence was 4.01/100 personyears. Patients who received ART had a TB incidence of 1.90/100 person-years (95%
CI: 1.662.17) and those treated with IPT had a rate of 1.27/100 person-years (95%CI:
0.412.95). The incidence among patients who received ART and IPT was 0.80/100
person-years (95% CI: 0.381.47). Multivariate Cox proportional hazards modelling
revealed a 76% reduction in TB risk among patients receiving both ART and IPT
(adjusted relative hazard 0.24; P<0.001) after adjusting for age, previous diagnosis of
TB, and CD4 cell counts at baseline.
Cox regression model that included IPT, baseline CD4 count, baseline TST and ART as
a continuous time-dependent variable was performed. For each extra day of ART, the
risk of TB decreased by 0.3% (P = 0.018). If provided for 300 days, the risk of TB was
reduced by 56%.
Overall mortality 1.4% per annum with 2% in the first year
Mortality if starting ART:
First year: 2.3%
Second year: 0.6%
Third year: 1.1%
From sub-analysis of TST result:
Only ART benefits TST-negative persons with a 56% reduction in TB incidence.
While ART is important for many reasons, it added only slightly to TB reduction in TSTpositive persons receiving continuous IPT.
Among the papers reviewed, the single placebo-controlled trial that assessed the effect
of INH by stage of HIV/AIDS at baseline found no difference (with AIDS [RR 0.96,
95% CI: 0.79 to 1.17] and without AIDS [RR 1.07, 95% CI: 0.84 to 1.35]). (Gordin et al.
1997)
(Personal communication)
Observational study: IPT started within three months of starting ART substantially
reduces the risk of death within the first year compared to ART alone, adding further
support to the benefits of combining IPT with ART.
Annex 6

The GRADE profile was not done since none of the available studies directly assessed the question of interest.

HIV-infected adults and children, who are unlikely to have active TB, should receive IPT as
soon as possible irrespective of their degree of immunosuppression.
Population: Adults, adolescents and children living with HIV who are on or not on ART
Intervention: IPT (1020 mg/kg for children, 300 mg for adults, plus vitamin B6 25 mg daily)
Factor
Quality of evidence
Decision
Moderate
Explanation

Benefits or desired
effects
Risks or undesired
effects

Weak
No direct evidence available (likely to be available soon from

ongoing randomized controlled trials)
Indirect evidence supports the concomitant use of IPT and
ART as a more effective intervention than the two alone
(Golub et al. 2007; Samandari et al. 2010)
Reduction in early mortality (first three months)
Patients with advanced disease present additional

challenges for diagnosis and potential onset of immune
reconstitution inflammatory syndrome (IRIS).
The Botswana trial reported a statistically non-significant
1.6-fold increase in hepatitis due to INH in people who
concomitantly received ART.
Strong
Feasibility
Strong
Overall ranking
of recommendation
Strong
Costs
Strong
Increased pill burden at ART initiation
Not likely to increase cost unless poorer adherence

compromises the efficacy of first-line regimen inducing
failure
Additional costs of toxicity
Administration fits well with the schedule of HIV
programmes.
78
Figure 1. Algorithm for TB screening in adults and adolescents living with HIV
in HIV-prevalent and resource-constrained settings
Adults and adolescents living with HIV*
Screen for TB with any one of the following:
Current cough
Fever
Weight loss
Night sweats
No
No
Give IPT
Yes
Defer IPT
Yes
Other diagnosis
Not TB
TB
Give
appropriate
treatment and
consider IPT
Follow up
and
consider IPT
Treat
for TB
Screen for TB regularly at each encounter with a health worker or visit to a health facility
FOOTNOTES TO ADULT ALGORITHM

* Every adult and adolescent needs to be evaluated for eligibility for ART. Infection control measures should be prioritized to reduce
M. tuberculosis transmission in all settings providing care.
Chest radiography can be done if available, but is not required to classify patients into TB and non-TB groups. In high HIVprevalence settings with a high TB prevalence among people living with HIV (e.g. greater than 10%), strong consideration must be
given to conducting additional sensitive investigations.
Contraindications include: active hepatitis (acute or chronic) or regular and heavy alcohol consumption or symptoms of peripheral
neuropathy. Past history of TB and current pregnancy should not be contraindications for starting IPT. Although not a requirement for
initiating IPT, TST may be done as a part of eligibility screening in some settings.
Investigations for TB should be done in accordance with existing national guidelines.
References
Reviews, 2010, (1):CD000171.
3. Golub JE et al. Isoniazid preventive therapy, HAART and tuberculosis risk in HIV-infected adults in South Africa: a
prospective cohort. AIDS, 2009, 23:631636.
4. Golub JE et al. The impact of antiretroviral therapy and isoniazid preventive therapy on tuberculosis incidence in
HIV-infected patients in Rio de Janeiro, Brazil. AIDS, 2007, 21:14411448.
2457.
6. Samandari T et al.; on behalf of BOTUSA IPT study. Preliminary results of the Botswana IPT Trial: 36 months vs. 6
months isoniazid for TB prevention in HIV-infected adults. 40th Union World Lung Conference, Cancun, 2009.
79

secondary prophylaxis
PICOT Question: Should secondary treatment of

LTBI be provided to prevent recurrence of TB among
Population: Adults living with HIV who have received
TB treatment
Intervention: IPT (612 months INH) or any regimen
Comparison:
No IPT or any other regimen
immediately after TB treatment
people living with HIV who had received TB treatment

in the past?
Outcomes: Recurrent TB incidence, mortality,
progression of HIV disease, AEs, adherence, interval
to recurrent TB, interval to death
Timeline: Lifetime
Following the GRADE approach, the key
outcomes that needed to be considered in making
recommendations were chosen and ranked in order
Outcomes
to identify the data that had to be sought from the

process of evidence retrieval.
Relative importance
Comment
Recurrent confirmed TB
Critical
Critical
Recurrent TB
(suspected, probable, confirmed)
Mortality
Adverse events
Interval to death
9
8
6
6
Critical
Critical
Critical
Less critical
Less critical
80

2.1 Google Scholar and PubMed were used with
the following search strategy (Tuberculosis[Mesh]
AND HIV Infections[Mesh]) AND ([TB treatment
in the past{Mesh}] or ([Recurrence{Mesh}]

([Relapse{Mesh}]
or
([Reinfection{Mesh}]
([secondary treatment{Mesh}])
or
or
1456
articles
Limits
multicentre study, adolescent: 1318 years, adult:

1944 years, middle-aged: 4564 years, middle
aged + aged: 45+ years, aged: 65+ years, 80 and
over: 80+ years
72
By title
57
By
abstract
Of
interest
he studies of interest include those that compared

people living with HIV who had undergone
previous treatment for TB and were put on IPT
for a duration of six to 12 months with those who did
not receive IPT. The Guidelines Group reviewed the
evidence and discussed IPT as secondary prophylaxis
for people who had previously been successfully
treated for TB. GRADE evidence from four studies
[14] including three randomized controlled trials
and one observational study showed the value of
providing IPT immediately after successful completion
81
of TB treatment. The WHO Guidelines Group strongly

recommends that adults and adolescents living with HIV
who have successfully completed their TB treatment
should continue receiving INH for six months and
should conditionally receive it for 36 months based on
the local situation and existing national guidelines. No
evidence was available on the potential role of IPT for
a patient who had successfully completed treatment
for MDR or XDR TB. Therefore, the Guidelines Group
did not make any recommendation on the use of IPT
after successful treatment for MDR or XDR TB.
Annex 7

Perriens et al. 1995
Haller et al. 1999
Methods/design
Randomized trial
Randomized trial
Population
Kinshasa, Zaire.
335 HIV-positive
persons with TB =>
260 completed TB
treatment => 240
enrolled in further
prophylaxis study
280 HIV-positive
persons, >15 years
old, completed TB
treatment, two years
follow up (192 person
years treatment vs
142 person-years
Intervention
Of 260 who
263 eligible HIVcompleted TB
positive persons
treatment => 121 RIF => 134 INH + co+ INH prophylaxis
trimoxazole
Comparison
Of 260 who
completed TB
treatment => 119
were given placebo
Treatment regimen
Six months, twice

weekly RIF 600
mg/450 mg, INH 15
mg/kg
Placebo
Of 263=> 129
patients
INH, 300 mg
once daily plus
sulphadoxine
pyrimethamine (S,
500 mg/P, 25 mg
once weekly), up to
24 months
Fitzgerald et al.
2000
Churchyard et al.
2003
Port au Prince, Haiti,

>18 years old, HIVpositive, diagnosed
and treated for first
TB episode, given
prophylaxis or
placebo after that.
Mean follow up 25
months
South Africa, HIVpositive gold miners

with documented
successful
completion of TB
treatment
Randomized trial
Observational study
Of 354 with TB
=> 274 completed
treatment => 233
randomized.
Of 142 HIV-positive
persons => 68
assigned IPT
338 had received

secondary preventive
therapy
Of 142 => 74 were

given placebo
221 had no
therapy
12-month INH 300

mg + vitamin B6 40
mg
INH 300 mg/daily
Vitamin B6 40 mg
No treatment
Co-trimoxazole
prophylaxis if their
CD4 T cell count
was <250x106 cells/l
and if symptomatic
or <200x106 cells/l
regardless of
symptoms
Outcome
Recurrent TB
Recurrent TB
Recurrent TB
Recurrent TB
Information
on recurrence
1/73 had relapse in

prophylaxis group (48
lost to follow up) vs
9/83 who relapsed
in placebo group (36
lost to follow up)
4/134 in prophylaxis
group vs 10/129
in control group.
The incidence of
TB was 2.1 (0.63)
observations/100
person-years in the
prophylaxis group
and 7.0 (3.412.6)
observations/100
person-years in the
control group (relative
risk 0.30 [0.090.94]).
IPT patients 1.4/100

person-years vs
placebo 7.8/100
person-years (relative
risk 0.18 [0.040.83],
P=0.010)
Incidence rates 8.6

(INH group) and 19.1
(no treatment group)
per 100 personyears; incidence
rate ratio, 0.45; 95%
confidence interval
0.260.78
55% reduction in
prophylaxis group
82
Perriens et al. 1995

Comment
83
HIV-seropositive
patients followed for
relapse; there was no
difference in survival
between those
assigned to RIF
plus INH and those
assigned to placebo
(P = 0.95).
The life-table
estimate of relapse
rate 18 months after
completion of sixmonth treatment was
1.9% for HIV-positive
prophylaxis patients
lower than the rate
of 9% in HIV-positive
placebo patients
(P<0.01).
At 24 months, the
HIV-seropositive
patients who received
extended treatment
had a relapse rate of
1.9%, as compared
with 9% among the
HIV-seropositive
patients who received
placebo for the
second six months
(P<0.01). Extended
treatment did not
improve survival,
however.
Haller et al. 1999
Fitzgerald et al.
2000
Churchyard et al.
2003
The TB recurrence
Limited population
rate was significantly miners
lower among the HIV1-positive patients
receiving INH than
among the HIV-1positive patients
receiving placebo.
Design
Limitations
Inconsistency
Indirectness
Observational
study
Randomized trials
No serious
limitations
Serious
No serious
inconsistency
No serious
inconsistency
No serious
indirectness1
Serious
Serious2
No serious
imprecision
Imprecision
None
Strong association
Other
considerations
The study by Perriens et al. 1995 provided INH+ RIF for six months instead of INH
Small numbers
TB recurrence (randomized)
TB recurrence (observational) (follow up 0.91 versus 0.41 patient-years; isoniazid vs co-trimoxazole)
No. of
studies
Quality assessment
7/275 (2.5%)
28/338 (8.3%)
Secondary
treatment of LTBI
31/286 (10.8%)
23/221 (10.4%)
Control
No. of patients
RR 0.23 (0.110.52)
RR 0.45 (0.260.78)
Relative risk
(95% CI)
Absolute
83 fewer per 1000

fewer)
57 fewer per 1000

fewer)
Summary of findings
Effect
MODERATE
VERY LOW
Quality
Importance
Question 5: Should secondary treatment for LTBI be used for people living with HIV who had received TB treatment in the past to prevent recurrence of TB?
Settings: High HIV/TB burden
Bibliography: Churchyard et al. (observational) 2003; Perriens et al. 1995; Haller et al. 1999; Fitzgerald et al. 2000
Annex 7
84

People living with HIV who have successfully completed their TB treatment should be
provided secondary INH prophylaxis.
Population: People living with HIV who have successfully completed TB treatment
Intervention: Secondary INH prophylaxis
Factor
Quality of evidence
Decision
Moderate
Explanation

Benefits or desired
effects
Strong
Risks or undesired
effects
Costs

Weak
Strong
Feasibility
Overall ranking
of recommendation
Strong
Only three randomized trials and one observational study.

One randomized trial compared provision of INH with
rifampicin after successful TB treatment.
Adverse events and mortality were not addressed (critical
outcome).
Moderate grade of evidence for recurrent TB outcome
Reduced recurrent TB incidence

Reduced TB transmission and improved TB infection control
in health-care settings (particularly in HIV clinics)
Reduced chances of reinfection
Potential reduction in generation of MDR strains by reducing
TB incidence
Pill burden
Reduced adherence to other treatment (ART, cotrimoxazole, etc.)
Lack of motivation among patients as they had just been

treated for TB
Lack of familiarity with and confidence in efficacy of IPT
Costs are unlikely to increase as INH can easily be
incorporated into routine care for people living with HIV.
Cost-saving implications through prevention of new
infections and development of recurrent TB
It will be part of routine care for people living with HIV.
Strong
References
2. Fitzgerald DW et al. Effect of post-treatment isoniazid on prevention of recurrent tuberculosis in HIV-1-infected
individuals: a randomised trial. Lancet, 2000, 356:14701474.
3. Haller L et al. Isoniazid plus sulphadoxinepyrimethamine can reduce morbidity of HIV-positive patients treated for
tuberculosis in Africa: a controlled clinical trial. Chemotherapy, 1999, 45:452465.
4. Perriens JH et al. Pulmonary tuberculosis in HIV-infected patients in Zaire. A controlled trial of treatment for either 6
or 12 months. New England Journal of Medicine, 1995, 332:779784.
85
Annex 8: Summary of findings and quality of evidence: tuberculin

skin test (TST)
PICOT Question: Is it feasible to perform TST for all people living with HIV before treatment of LTBI in
resource-poor settings?
Intervention: Feasibility of using TST in resourceconstrained settings
Comparison: Using IPT without TST

Outcomes: Access to IPT vs minimal or no access
Timeline: 540 years
tudies to date indicate that people living

with HIV who are TST-positive are most
likely to benefit from preventive therapy.
[1] However, TST implementation poses some
Outcomes
Cost associated with TST
Failure to return for results
Stability of purified protein derivative

(PPD) and need for cold chain
Measurement issues and interpersonal

variability
Access to TST
challenges for programmes in resource-poor

settings. We evaluated the evidence regarding the
feasibility of using TST testing before providing IPT
for LTBI in resource-constrained settings.
Relative importance
Comment
Critical
Critical
Critical
Critical
Critical
he key feasibility issues assessed were the

following:
Cold chain/stability of tuberculin

Production quality of tuberculin
Price/costs associated with TST
Measurement issues/inter-reader variability
Loss to follow up/failure to return for TST result
Anergy
PubMed and Embase were considered as the

principal databases. Additional studies were
identified by searching reference lists of primary
studies and review articles. Web sites and package
inserts were also checked for relevant information.
Additionally, experts in the field of HIV/TB were
consulted for relevant articles. Although each of
above issues was not separately searched for,
each one was included in the overall review of
each possible study/article included.
86
3. Findings
3.1 Search terms
(((Tuberculin[MeSH terms] OR Tuberculin[all
fields]) OR TST (all fields) OR PPD[all fields]) AND
(hiv[MeSH terms] OR HIV[all fields]) AND (TB[all
fields] AND (prevention and control[subheading]
OR (prevention[all fields] AND control[all
fields]) OR prevention and control[all fields] OR

(preventive[all fields] AND therapy[all fields]) OR
preventive therapy[all fields])) PPD and cold
chain, PPD and cost OR price, tuberculin
and stability.
Reports were
identified:
184
references
By reading
titles:
85
references
By reading
abstract:
45
references
By reading
paper:
29
references
Articles/
reports of
interest:
23
references
87
tudies/articles/reports included were those

that evaluated the technical aspects of TST
in the general population and HIV-infected
individuals, and were conducted either in highincome or low-income countries.
Annex 8
3.2 Stability of PPD and need for cold chain
ne of the important conditions for maintaining

the potency of tuberculin is the need for it to
be transported and stored at the appropriate
temperature. Preparations of PPD are stable until the
indicated date of expiry, if they are kept continuously
cold between +2C and +8C and protected from
light.[2,3] PPD solution can be adversely affected by
exposure to light; therefore, the product should be
stored in the dark except when doses are actually
being withdrawn from the vial.[2,3] Failure to store and
handle PPD as recommended will result in a loss of
potency and inaccurate test results.[4] Some studies
suggest the possibility of PPD remaining stable even
at temperatures outside those recommended.[57]
Another report from India showed that on comparing

the mean values of PPD test results obtained by using
vials at room temperature with those of refrigerated
vials, the differences were not significant although
the data from this study pertain to non-refrigeration
up to 96 hours only and require further validation
under rigorous control conditions.[5] Magnus et al.
reported that PPD dilutions can be stored at 20C
for some months without significant loss of potency.
[7] Although it is possible that PPD solutions can
remain stable for at least one year even at 37C,
[5,6] performance may still be jeopardized and the
recommended temperatures for storage should still
be used.
3.3 Costs associated with TST

Company
Dose
TST/PPD cost
Cost/dose (US$)
Cost/100 000 doses (US$)*
4.7
470 000
8.9
890 000
6.1
610 000
49
490 000
8.7
870 000
5.8
580 000
Price range/100 000 doses: US$ 470 000890 000

*Excluding shipping
Example: Cost of shipment to Kenya
Type of shipment
(shipping takes 510 days)
Cost/1000 doses (US$)
Cost/100 000 doses (US$)
Courier
85
8 500
Air freight
177
17 700
Air freight
125
12 500
Company
G
NB: Refrigerated item incurs additional shipping charge based on shipping zone.
uberculin testing costs less than US$ 10 per

person,[8,9] but the prevalence of true positive
results is relatively low, and screening may
cost up to US$ 4500 per person eligible for treatment
with isoniazid, and US$ 350 000 per case of TB
prevented,[8,9] given the added cost associated
with the investigation of false-positive reactions,
as well as the costs of treatment and follow up.[10]

Though most studies did not state clearly how much
cost is associated with TST, the test may also add
more costs in terms of the increased workload on
personnel, need for patients to return for results to be
read and cost of consumables.
88
3.4 Failure to return
he use of TST in identifying patients who

might benefit from ITP adds further time and
expense, and is an additional step where
patients are lost to follow up.[11] Most of the included
studies showed that about 1121% of patients who
had TST did not return for their results to be read.
[1214] The burden of having to return to the healthcare facility after 4872 hours of undergoing TST is
particularly a great challenge in many resource-poor
settings. However, the study by Aisu et al. suggested
that the rate of return for TST to be read increased
after HIV counsellors were retrained in HIV and
TB.[12] This finding may support the suggestion that
field experience in the care of HIV-infected patients

may be the best predictor of physician adherence
with a recommended TST procedure.[15] However,
the feasibility of having to retrain a large population
of health-care providers in resource-poor settings on
the use of TST also needs to be considered. It has
been reported that the need for subjects to be seen a
second time so that test results can be read limit the
usefulness of TST.[16] Therefore, while useful, there
are considerable feasibility challenges around the
need for follow up. In addition, accurate interpretation
of the results is occasionally not possible, particularly
among people with HIV and low CD4 counts.[17]
3.5 Measurement issues and interpersonal variability
actors such as variability between and

within readers, need for trained personnel to
administer and read the test, and the need
for the subjects to be seen a second time so that
test results can be read all impact the usefulness
of TST.[16] With regard to interpersonal variability
in reading the TST, the available evidence shows
that groups of health-care workers can be trained
to accurately interpret TSTs with a minimum of
variability.[1821] Evidence that supports other

modes of measuring the response is also available,
such as the use of flexible calipers.[20] However,
measurement methods are imprecise and a
number of factors including the time that the results
are read after placement of the test may affect the
results. The feasibility of training large numbers of
health-care workers to place and accurately read
TSTs on a large scale is unknown.
3.6 Access to TST
efore TST can be used to screen for LTBI, it

must first be made available to programmes
providing HIV prevention, care and treatment
services. The global supply may not be sufficient to
meet the demand. According to a report from India,
good-quality tuberculin in various strengths is seldom
available.[16] Reports from South Africa also found

difficulty in keeping tuberculin for the test in stock.
[22] However, it is possible that manufacturers could
scale up production to meet the demand but that
would largely depend on market forces.
3.7 Anergy
ST has been used for decades to detect LTBI,

but is not entirely reliable due to its low specificity
and sensitivity.[23] This is particularly important
in persons with LTBI and immunosuppression.
Because of their depressed cell-mediated immunity,
people living with HIV may not be able to mount a
response to TST. Thus, a negative TST in a person
living with HIV may be due to true absence of infection
with Mycobacterium tuberculosis or an inability to
mount a response due to immunosuppression.[24]
Anergy is defined as absence of induration in response
to three antigens (PPD, Candida albicans and parotiditis
antigen) applied by the Mantoux method.[25] It has
89
been recommended that other cutaneous allergens

be used to differentiate between the presence of nonreactivity to tuberculin due to an absence of infection
or due to anergy.[26] However, anergy testing is not an
ideal field test as it requires a repeat visit 4872 hours
after placement of the test and handling injectable
materials (syringe, cold chain, etc.), as well as a cadre
of trained personnel.[27] A study by Garcia et al.
reported that the use of tetanus toxoid and Candida
antigen were not useful in differentiating between the
absence of reactivity to tuberculin caused by HIVassociated immunodeficiency and that due to absence
of latent M. tuberculosis infection.[28] Tuberculin
and anergy skin testing have a low predictive value
Annex 8
in detecting M. tuberculosis infection in HIV-infected

persons, and therefore such testing has a limited role
in identifying HIV-infected persons who may benefit
from preventive therapy programmes for TB.[29] The
usefulness of anergy testing has been questioned and
its use to guide administration of TB chemoprophylaxis

has been discontinued in the United States.[30] Until
well-designed studies of anergy testing as an adjunct
to tuberculin testing are conducted, it is safest to
discourage anergy testing.

TST is not a requirement for initiating IPT for people living with HIV. Where feasible, TST can be used
as people with a positive test result benefit more from IPT than those with a negative test result.
Intervention: TST
Factor
Quality of evidence
Decision
High
Benefits or desired
effects
Risks or undesired
effects
Weak
Strong
Costs
Strong
Feasibility
Strong
Explanation

Benefits:
Early identification of LTBI
Increase in numbers of people diagnosed with LTBI
Minimizes number to be exposed to INH
Correctly identifies people who will benefit from IPT

Strong
Risk of adverse reaction to PPD

Risk of false-negative results (HIV anergy, reader error, poor
product), false-positive results, interaction with BCG)
Patients may not want to have TST
Concerns regarding returning for results
TST not a form of treatment
Risk of adverse effects
Reduced by:
Increased demand for TST may lower cost of PPD
Reduction in the number of patients on INH (related toxicity
management and follow up)
Increased by:
Procurement of PPD/need for storage
Training of workers
Time spent by health-care worker for test
Travel cost for follow-up visits by the patient
Cost associated with further screening for TB

Overall ranking
of recommendation
Provision of IPT reduces active TB incidence by:

33% (GRADE high) regardless of TST status
64% in TST-positive persons (GRADE high)
14% in TST-negative persons (GRADE high)
14% in those with unknown TST results (GRADE moderate)
Therefore, TST is useful in identifying the population who
would benefit most from IPT.
Not many studies in resource-poor settings examined the

major issues
Need for refrigeration and cold chain maintenance
Considerable loss to follow up
Need for training of health-care workers
Increased workload of health-care workers
Need for more training on the use of TST in clinical and
public health practice
But:
Cost of PPD could be offset by the TB cases prevented
PPD could remain stable at room temperature
90
References
Reviews, 2010, (1):CD000171.
2. Landi S, Held HR. Effect of light on tuberculin purified protein derivative solutions. American Review of Respiratory
Disease, 1975, 111:5261.
3. Medsafe. Tuberculin purified protein derivative (Mantoux) diagnostic antigen. 2007. Available from: http://www.
medsafe.govt.nz/profs/datasheet/t/Tubersolinj.htm (accessed on 12 November 2010).
4. Landi S, Held HR. Stability of a dilute solution of tuberculin purified protein derivative at extreme temperatures.
Journal of Biological Standardization, 1981, 9:195199.
5. Ladha A. Effect of refrigeration on Mantoux test result. Indian Pediatrics, 1995, 32:1036.
6. Landi S, Held HR. Stability of dilute solutions of tuberculin purified protein derivative. Tubercle, 1978, 59:121133.
7. Magnus K et al. Stability of purified tuberculin in high dilution. Bulletin of the World Health Organization, 1958,
19:765782.
8. Price LE, Rutala WA, Samsa GP. Tuberculosis in hospital personnel. Infection Control, 1987, 8:97101.
9. Raad I et al. Annual tuberculin skin testing of employees at a university hospital: a costbenefit analysis. Infection
Control and Hospital Epidemiology, 1989, 10:465469.
10. Menzies D et al. Tuberculosis among health care workers. New England Journal of Medicine, 1995, 332:9298.
11. Hawken MP, Muhindi DW. Tuberculosis preventive therapy in HIV-infected persons: feasibility issues in developing
countries. International Journal of Tuberculosis and Lung Disease, 1999, 3:646650.
12. Aisu T et al. Preventive chemotherapy for HIV-associated tuberculosis in Uganda: an operational assessment at a
voluntary counselling and testing centre. AIDS, 1995, 9:267273.
13. Antonucci G et al. Guidelines of tuberculosis preventive therapy for HIV-infected persons: a prospective, multicentre
study. GISTA (Gruppo Italiano di Studio Tubercolosi e AIDS). European Respiratory Journal, 2001, 18:369375.
14. Sackoff JE et alB. Purified protein derivative testing and tuberculosis preventive therapy for HIV-infected patients in
New York City. AIDS, 1998, 12:20172023.
15. DeRiemer K, Daley CL, Reingold AL. Preventing tuberculosis among HIV-infected persons: a survey of physicians
knowledge and practices. Preventive Medicine, 1999, 28:437444.
16. Mohan A, Sharma SK. In search of a diagnostic test for tuberculosis infection: where do we stand? Indian Journal
of Chest Disease and Allied Sciences, 2006, 48:56.
17. Syed J. TB diagnostics: a crisis for people living with HIV/AIDS worldwide. 2006. Available from: http://www.thebody.
com/content/art1760.html (accessed on 12 November 2010).
18. Carter ER, Lee CM. Interpretation of the tuberculin skin test reaction by pediatric providers. Pediatric Infectious
Disease Journal, 2002, 21:200203.
19. Ozuah PO et al. Assessing the validity of tuberculin skin test readings by trained professionals and patients. Chest,
1999, 116:104106.
20. Perez-Stable EJ, Slutkin G. A demonstration of lack of variability among six tuberculin skin test readers. American
Journal of Public Health, 1985, 75:13411343.
21. Villarino ME et al. Comparable specificity of 2 commercial tuberculin reagents in persons at low risk for tuberculous
infection. Journal of the American Medical Association, 1999, 281:169171.
22. Smart T. Continuous isoniazid preventive therapy (IPT) superior to short course in TST-positive HIV patients but
only in those with a positive tuberculin skin test (TST). HIV & AIDS Treatment in Practice (HATIP), 2009, 151.
Available from: http://www.stoptb.org/wg/tb_hiv/assets/documents/hatip151.pdf (accessed on 13 November 2010).
23. Farhat M, Greenaway C, Pai M, Menzies D. False-positive tuberculin skin tests: what is the absolute effect of BCG
and non-tuberculous mycobacteria? International Journal of Tuberculosis and Lung Disease, 2006, 10:11921204.
24. Markowitz N et al. Tuberculin and anergy testing in HIV-seropositive and HIV-seronegative persons. Pulmonary
Complications of HIV Infection Study Group. Annals of Internal Medicine, 1993, 119:185193.
Enfermedades Infecciosas y Microbiologa Clnica, 2003, 21:287292.
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Lung Disease, 1996, 77 (Suppl 1):119.
27. Jones-Lopez EC et al. Delayed-type hypersensitivity skin test reactivity and survival in HIV-infected patients in
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Tropical Medicine and Hygiene, 2006, 74:154161.
28. Garcia-Garcia ML et al. Underestimation of Mycobacterium tuberculosis infection in HIV-infected subjects using
reactivity to tuberculin and anergy panel. International Journal of Epidemiology, 2000, 29:369375.
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Report, 1998, 47(RR-20):3641.
91

interferon gamma release assays (IGRA)
PICOT Question: What is the role of IGRA in identifying adults and children who would benefit from treatment
for LTBI or active TB?
Population: Adults and children living with HIV
Intervention: Use of IGRA in identifying adults and
children who would benefit from treatment for LTBI
or active TB
Comparison: No identification of LTBI; TST

Timeline: One week during work-up to exclude TB
before starting IPT
Outcomes
Predictive value for identification of
persons at risk for developing TB
Relative importance
9
Comment
Critical
Specificity for identification of persons at 9

risk for developing TB
Critical
Important
Specificity for identification of persons at 4

low risk for TB
Important
Sensitivity for identification of persons

with active TB
Degree of agreement between results of 5

IGRA and results of TST
Important

Search criteria
PubMed Search (Tuberculosis[Mesh]) AND
HIV[Mesh]) AND Diagnosis[Mesh]) OR (IGRA,
interferon gamma release assay, Quantiferon
gamma Gold In-Tube, T-SPOT, ELISPOT, T-cell
based assay, whole blood Quantiferon gamma
release assay, TB, HIV).

Leading researchers in the area were also contacted
to provide any unpublished data fulfilling the search
criteria.
92
684
articles
Limits

multicentre study.
225
By title
68
By
abstract
58
Of
interest
28
Studies of interest
Twenty-six abstracts/articles [126] provided
information about sensitivity/specificity of IGRA
among the HIV-infected population or performance
of IGRA in comparison to TST. Two articles [27,28]
specifically provided information on the cost and
feasibility of IGRA.
Studies evaluating IGRA that are commercially
available (T-SPOT, Quantiferon Gold In Tube [QFN
G IT]) and their pre-commercial predecessors
(ELISPOT based on antigens included in T-SPOT)
were included but assays based on alternate
antigens were eliminated.
Information was specifically abstracted on:

predictive value of IGRA among persons who
developed TB (incident TB) and persons with HIV
and prevalent active TB (including information about
the performance of IGRA in persons with active TB
disaggregated by category of CD4 cell count, if
available). We also extracted results of IGRA and
TST among persons with HIV and no evidence of
active TB, including information on the numbers
of patients with positive, negative or indeterminate
results of each test, and reported kappa values for
the degree of agreement between TST and IGRA.
hree studies [2,6,8] considered the ability of

IGRA to predict development of TB over time
(IGRA Table 1.1). The results of one of these
studies [8] were disregarded because only a CD4
cell count-corrected measure of interferon-gamma
(IFN-) release was reported. One study [2] reported
that among 822 HIV-positive persons in Austria
without active TB who were tested with QFN G IT
(results: 37 positive, 738 negative, 47 indeterminate),
three developed active TB during follow up, all three
93
of whom had a positive QFN G IT test at baseline.

The other study [6] followed 20 people living with
HIV with no respiratory symptoms, but with positive
ELISPOT; two developed active TB at three and 10
months of follow up.
Eight studies [13,13,17,23,25,26] evaluated the
performance of QFN G IT assay among adults with
HIV in whom prevalent active TB was confirmed by
a combination of signs, symptoms, AFB smear and
Annex 9
mycobacterial culture (IGRA Table 2.1). All studies

were in settings with high TB and HIV prevalence.
The reported sensitivity of QFN G IT ranged from
30% to 83% with a pooled sensitivity of 0.63 (95% CI:
0.570.68). The number of persons included in most
studies was small (range 8105), and the total number
of persons evaluated was 339.
One study [22] evaluated the sensitivity of QFN G IT
among HIV-infected children with active TB. Among 36
children with HIV and active TB, 17 had positive QFN
G IT tests; the reported sensitivity for QFN G IT was
0.47 (0.310.64).
Five studies [5,6,9,13,18] reported the sensitivity of a
T-SPOT assay among HIV-infected adults in whom
active TB was confirmed by a combination of signs,
symptoms, AFB smear and mycobacterial culture
(IGRA Table 2.2), although one of these [9] reported
only disaggregated sensitivity for subgroups with lower
and higher CD4 cell counts and was not included in
the pooled estimate. In the remaining four studies
[5,6,13,18] reported sensitivity ranged from 0.89 to
0.90 and the pooled sensitivity was 0.90 (0.840.96).
The total number of persons included in these studies
was 109.
Two studies [7,14] reported the sensitivity of T-SPOT
among HIV-infected children with active TB, confirmed
by a combination of signs, symptoms, AFB smear
and mycobacterial culture (IGRA Table 2.2). The
pooled sensitivity was 0.69 (95% CI: 0.570.82). The
total number of children studied was 52. One study
[13] reported on rates of positive IGRA among 10
individuals considered to be at low risk for TB (IGRA
Table 3). The number of persons with positive tests
were 0 (QFN G IT) and one (with T-SPOT). Ten
studies [4,10,12,13,15,16,19,20,22,24] compared the
results of QFN G IT with those of TST in HIV-infected
persons without evidence of active TB (IGRA Table 4).
In five studies [4,9,12,16,22], the number of persons

with positive QFN G IT tests was greater than the
number with positive TST and, in the remaining five
[10,15,19,20,22], the number of persons with positive
TST was greater than the number with positive QFN
G IT. Eight studies (IGRA Table 4) compared the
results of T-SPOT or ELISPOT with those of TST
[9,11,13,16,19,20,22,24]; in six, a larger proportion of
patients had positive T-SPOTs [9,11,13,16,19,22], in
two, a larger proportion of patients had positive TST.
[20,24]
In addition to comparing the proportions of persons
positive based on each type of test, many studies
reported kappa values for correlation between tests
(IGRA Table 4). Reported kappa values varied widely;
from 0.02 to 0.43 for agreement between T-SPOT
and TST, and between 0.23 and 0.59 for agreement
between QFN G IT and TST. These values would be
considered by some to be consistent with a range
between no and moderate agreement.
The performance of QFN G IT was compromised
among HIV-infected people compared with HIVnegative persons. Rates of indeterminate test results
for QFN G IT were significantly higher in persons with
HIV compared with persons without HIV, and in persons
with low CD4 cell counts compared with persons with
higher CD4 cell counts. QFN G IT sensitivity was
significantly reduced among patients with low CD4
counts. While most studies found no impact of low
CD4 count on T-SPOT sensitivity, at least one study
[24] found that low CD4 count was associated with an
increased risk of indeterminate test results.
Importantly, because there are few longitudinal
studies [2,6,8] and no accurate gold standard for LTBI,
it is difficult to assess the trade-offs that would occur
between sensitivity and specificity using different levels
of IFN- gamma release to define positive tests.
IGRA Table 1.1: Predictive value of IGRA among persons with HIV who
developed TB during follow up (incident TB)
GRADE table
Reference
Test
Design
Limitations
Consistency
Directness
Precision
Overall
quality
Total no.
with
positive
results
followed up
Predictive
value
No. of persons with active

TB in whom test was
+ ve
- ve
indeterminate
1 study
QFN G IT
Observational
Very
low
36
0.8
(0.020.21)
1 study
T-SPOT
Observational
Very
low
20
0.1
(0.010.31)
94
Summary table
Reference
Test
Design
Limitations
Aichelburg
et al.
QFN G IT
Observational
Clark et al.
T-SPOT
Observational
Consistency
Directness
Precision
Total no. with

positive results
followed up
Predictive
value
No. of persons with active TB

in whom test was
+ ve
- ve
indeterminate
10 unclear
36
0.8
(0.020.21)
10 unclear
20
0.1
(0.010.31)
Aichelburg et al.: 18 months of follow up (radiology, culture for TB confirmation)

Clark et al.: median follow up of 12 months
IGRA Table 2.1: Sensitivity of IGRA among persons with HIV

and active TB at baseline (prevalent TB)
GRADE table for QFN G IT
Reference
Test
Design
Limitations
Consistency
Directness
Precision
Overall
quality
N (with
active TB)
Sensitivity
(CI)
+ ve
- ve
indeterminate
8 studies
(adults)
QFN G IT
Observational
OK
Very
low
339
0.63
(0.570.68)
212
65
62
1 study
(children)
QFN G IT
Observational
Very
low
36
0.47
(0.310.64)
17
10

TB in whom test was
Summary table for QFN G IT

Reference
Test
Design
Limitations
(QUADAS)
Consistency
Directness
Precision
N (with
active TB)
Sensitivity
(CI)
No. of persons with active TB

in whom test was
+ ve
- ve
indeterminate
Aabye et al.
QFN G IT
Observational
4 and 10
OK
OK
68
0.65
(0.530.76)
44
9
(13%)
15 (22%)
Aichelburg
et al.
QFN G IT
Observational
10 not clear
0.88
(0.641)
1
(12%)
Baba et al.
(confirmed)
QFN G IT
Observational
10 not clear
OK pleural
12
0.58
(0.30.9)
1
(6%)
4 (33%)
Baba et al.
(probable)
QFN G IT
Observational
10 not clear
OK pleural
12
0.83
(0.621)
10
2 (17%)
Kabeer et al.
QFN G IT
Observational
10 not clear
OK
OK
105
0.65
(0.560.74)
68
19
(18%)
18 (17%)
Leidl et al.
QFN G IT
Observational
10 not clear
OK
19
0.68
(0.470.89)
13
Raby et al.
QFN G IT
Observational
10 not clear
OK
OK
59
0.63
(0.50.78)
37
10
(17%)
12 (20%)
Tsiouris et al.
QFN G IT
Observational
10 not clear
OK
26
0.65
(0.460.81)
17
Veldsman et al.
QFN G IT
Observational
None
OK
30
0.30
(0.140.46)
15
Stavri et al.
(children)
QFN G IT
Observational
4,10 not clear
36
0.47
(0.310.64)
17
10
QUADAS Quality Assessment of Diagnostic Accuracy Studies
IGRA Table 2.2: Sensitivity of IGRA among persons with HIV

with active TB at baseline (prevalent TB)
GRADE table for T-SPOT
Reference
Test
Design
Limitations
Consistency
Directness
Precision
Overall
quality
N (with
active TB)
Sensitivity
(CI)

TB in whom test was
+ ve
- ve
indeterminate
4 (adults) *
T-SPOT
Observational
OK
Very
low
109
0.9
(0.840.96)
98
2 (children)
T-SPOT
Observational
OK
OK
Very
low
52
0.69
(0.570.82)
36
15
95
Annex 9
Summary table for T-SPOT

Directness
Precision
N (with
active TB)
Sensitivity (CI)
+ ve
- ve
indeterminate
10 not
clear
30
0.90 (0.791)
27
10 No
OK
39
0.9 (0.800.99)
35
OK
18*
66.7 (CD4 <200)
Reference
Test
Design
Limitations
Clark et al.
T-SPOT
Observational
Chapman et al.
T-SPOT
Observational
Jiang et al.*
T-SPOT
Consistency

TB in whom test was
85.7 (CD4 200)

Leidl et al.
T-SPOT
Rangaka et al.
T-SPOT
Davies et al.
(children)
T-SPOT
Liebeschuetz et
al.(children)
T-SPOT
Observational
10 not
clear
OK
19
0.89 (0.751)
17
None
OK
21
0.9 (0.781)
19
Observational
OK
OK
22
0.67 (0.430.85)
14
Observational
OK
OK
30
0.73 (0.540.88)
22
*Overall sensitivity/raw numbers not available for one study (Jiang et al.)
IGRA Table 3: Specificity of IGRA in HIV-positive persons at low risk for TB

Summary GRADE table
Reference
Test
Design
Limitations
Leidl et al.
QFN G IT
Observational
Leidl et al.
T-SPOT
Observational
Consistency
Directness
Precision
Overall
quality
No. with
no risk for
TB
Sensitivity

TB in whom test was
+ ve
- ve
indeterminate
1?
Very
low
10
10
1?
Very
low
10
0.9
IGRA Table 4: Agreement between results of IGRA and TST

Study
Setting
HIV/TB
burden
TSPOT
+ve (N)
TSPOT
+ve
(%)
TSPOT
indeter
(N)
TSPOT
indeter
(%)
TST
+ve
(N)
TST
+ve
(%)
Jiang et al.
68
High
46
67.6
0.0
28
41.2
Karam et al.
247
High
125
50.6
53
21.5
Leidl et al.
109
High
59
54.1
3.7
42
47.2
74
67.9
3.7
Mandalakas et
al. (adults)
20
High
13
65.0
10.0
10
50.0
11
55.0
Rangaka et al.
74
High
38
52
35
52
32
43.2
Richeldi et al.
116
Low
3.4
5.1
Stephan et al.
275
Low
66
24.0
2.9
33
12.0
Talati et al.
336
Low
14
4.2
1.5
Balcells
109
Low
Jones et al.
201
Kimura et al.
Kappa
QFN G
IT vs
TST
Kappa
T-SPOT
QFN
G IT
0.37
0.34
0.17
15.0
0.43
0.46
0.6
0.58
4.3
0.16
0.52
0.19
52
18.9
0.2
0.33
0.15
9.3
2.7
1.5
0.16
0.23
11
10.1
17
15.6
0.0
0.59
Low
13
6.5
11
5.5
10
5.0
0.38
167
Low
16
9.6
32
19.2
0.0
0.28
Luetkemeyer
et al.
296
Low
19
9.3
25
8.4
15
5.1
0.37
Mandalakas et
al. (children)
23
High
26.1
16.7
0.0
12
52.2
0.0
QFN G
IT +ve
(N)
QFN G
IT +ve
(%)
QFT
N IT
indeter
(N)
QFN
G IT
indeter
(%)
Kappa
TSPOT
vs TST
0.23
-0.02
0.44
96

Recommendation: There is currently insufficient evidence to support the use of IGRA to identify persons living with
HIV (adults and children) who are eligible for IPT.
Population: HIV-infected adults and children
Intervention: Use of IGRA to identify people eligible for treatment of LTBI

Factor
Quality of evidence
Decision
High
Benefits or desired
effects
Risks or undesired
effects
Explanation
The quality of evidence on the role of IGRA in correctly identifying

people eligible for treatment of LTBI is very high. While there is
some information about test performance in persons with active
TB or at low risk for TB, longitudinal data are very limited. Overall,
the evidence does not support the use of IGRA at this time.

Strong

Costs
Strong
Feasibility
Strong
Overall ranking
of recommendation
97
Sensitivity of T-SPOT may be higher than that of TST

IGRA may require fewer return visits than TST
Risk of adverse events with IGRA may be less than that of
TST
Potential for boosting (with TST) eliminated with IGRA
Insufficient information to determine whether IGRA can

differentiate between LTBI and active TB disease
Insufficient information to determine whether IGRA can
identify persons likely to benefit from LTBI treatment
IGRA performance is affected by immunosuppression
(increased rate of indeterminate results in persons with low
CD4 counts).
IGRA requires a blood draw.
There is a chance of failed phlebotomy, especially in
children.
Patients may prefer to avoid visible reaction to TST.
Patients may prefer to avoid blood draw.
Increased by:
Need to establish well-equipped laboratory
Need to procure equipment and supplies for IGRA
performance and quality assurance
Need for staff training

Need for well-established laboratories

Need for careful handling and processing of blood samples
to ensure accuracy of tests
Availability of well-trained staff or staff that can be trained
Strong
Annex 9
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assay in patients with pulmonary tuberculosis. PLoS One, 2009, 4:e4220.
2. Aichelburg MC et al. Detection and prediction of active tuberculosis disease by a whole-blood interferon-gamma
release assay in HIV-1-infected individuals. Clinical Infectious Diseases, 2009, 48:954962.
3. Baba K et al. Evaluation of immune responses in HIV infected patients with pleural tuberculosis by the QuantiFERON
TB-Gold interferon-gamma assay. BMC Infectious Diseases, 2008, 8:35.
4. Balcells ME et al. A comparative study of two different methods for the detection of latent tuberculosis in HIV-positive
individuals in Chile. International Journal of Infectious Diseases, 2008, 12:645652.
5. Chapman AL et al. Rapid detection of active and latent tuberculosis infection in HIV-positive individuals by
enumeration of Mycobacterium tuberculosis-specific T cells. AIDS, 2002, 16:22852293.
6. Clark SA et al. Tuberculosis antigen-specific immune responses can be detected using enzyme-linked immunospot
technology in human immunodeficiency virus (HIV)-1 patients with advanced disease. Clinical and Experimental
Immunology, 2007, 150:238244.
7. Davies MA et al. Detection of tuberculosis in HIV-infected children using an enzyme-linked immunospot assay.
AIDS, 2009, 23:961969.
8. Elliott JH et al. Immunopathogenesis and diagnosis of tuberculosis and tuberculosis-associated immune reconstitution
inflammatory syndrome during early antiretroviral therapy. Journal of Infectious Diseases, 2009, 200:17361745.
9. Jiang W et al. High-sensitive and rapid detection of Mycobacterium tuberculosis infection by IFN-gamma release
assay among HIV-infected individuals in BCG-vaccinated area. BMC Immunology, 2009, 10:31.
10. Jones S et al. Utility of QuantiFERON-TB Gold in-tube testing for latent TB infection in HIV-infected individuals.
International Journal of Tuberculosis and Lung Disease, 2007, 11:11901195.
11. Karam F et al. Sensitivity of IFN-gamma release assay to detect latent tuberculosis infection is retained in HIVinfected patients but dependent on HIV/AIDS progression. PLoS One, 2008, 3:e1441.
12. Kimura M et al. Comparison between a whole blood interferon-gamma release assay and tuberculin skin testing
for the detection of tuberculosis infection among patients at risk for tuberculosis exposure. Journal of Infectious
Diseases, 1999, 179:12971300.
13. Leidl L et al. Relationship of immunodiagnostic assays for tuberculosis and numbers of circulating CD4+ T-cells in
HIV infection. European Respiratory Journal, 2009, 35:619626.
14. Liebeschuetz S et al. Diagnosis of tuberculosis in South African children with a T-cell-based assay: a prospective
cohort study. Lancet, 2004, 364:21962203.
15. Luetkemeyer AF et al. Comparison of an interferon-gamma release assay with tuberculin skin testing in HIV-infected
individuals. American Journal of Respiratory and Critical Care Medicine, 2007, 175:737742.
16. Mandalakas AM et al. High level of discordant IGRA results in HIV-infected adults and children. International Journal
of Tuberculosis and Lung Disease, 2008, 12:417423.
17. Raby E et al. The effects of HIV on the sensitivity of a whole blood IFN-gamma release assay in Zambian adults with
active tuberculosis. PLoS One, 2008, 3:e2489.
18. Rangaka MX et al. Clinical, immunological, and epidemiological importance of antituberculosis T cell responses in
HIV-infected Africans. Clinical and Infectious Diseases, 2007, 44:16391646.
19. Rangaka MX et al. Effect of HIV-1 infection on T-cell-based and skin test detection of tuberculosis infection. American
Journal of Respiratory and Critical Care Medicine, 2007, 175:514520.
20. Richeldi L et al. Performance of tests for latent tuberculosis in different groups of immunocompromised patients.
Chest, 2009, 136:198204.
21. Stavri H et al. Comparison of tuberculin skin test with a whole-blood interferon gamma assay and ELISA, in HIV
positive children and adolescents with TB. Roumanian Archives of Microbiology and Immunology, 2009, 68:1419.
22. Stephan C et al. Comparing QuantiFERON-tuberculosis gold, T-SPOT tuberculosis and tuberculin skin test in HIVinfected individuals from a low prevalence tuberculosis country. AIDS, 2008, 22:24712479.
23. Kabeer BSA et al. Role of interferon gamma release assay in active TB diagnosis among HIV infected individuals.
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BMC Infectious Diseases, 2006, 6:47.
98
Annex 10: Summary of findings and quality of evidence:

INH resistance
PICOT Question: Does treatment for LTBI among people living with HIV lead to significant development of
mono-resistance against the drugs used for LTBI?
oncerns regarding the development of

isoniazid resistance during IPT in people
who develop and/or have active TB while
on preventive treatment is the dominant reason
offered for not implementing IPT. Although the
study design of this issue is difficult, a review of the

existing data suggests that there is little scientific
evidence to support concerns regarding the
development of mono-isoniazid resistance and/or
multidrug resistance.
Population: Adults living with HIV who received

treatment for LTBI
Intervention: IPT (612 months INH) or any
rifampicin-containing preventive treatment regimen
Comparison: No IPT or any other regimen
Outcomes: Occurrence of mono-isoniazid resistance

in TB isolates from people who have received the
intervention compared with those who did not receive
the intervention
Timeline: Lifetime
ollowing the GRADE approach, the key

outcomes that needed to be considered in
making recommendations have been chosen
Outcomes
Mono-resistance to IPT
(IPT versus no treatment/placebo)
Mono-resistance to IPT vs rifampicin

(IPT intervention vs rifampicin as
control)
and accordingly ranked in order to identify the data

that had to be sought from the process of evidence
retrieval.
Relative importance
Comment
Less critical
Critical

2.1 PubMed Search
(HIV[MeSH Terms]) AND (Tuberculosis[MeSH Terms]) AND (Antitubercular Agents[MeSH Terms]) OR
(latent[Title/Abstract]) OR (isoniazid[Title/Abstract]) OR (prevent*[Title/Abstract]) OR (resist*[Title/
Abstract])
99
Annex 10
eading researchers in the field and WHO staff

were contacted and provided with the articles
reviewed in this study. They were requested
to advise on any other unpublished data or further
articles that were not identified by the search strategy.
The major HIV/AIDS and TB conference web sites

were also reviewed for abstracts that satisfied the
above search criteria.
220
articles
Limits activated
Humans, clinical trial, meta-analysis, randomized
controlled trial, review, clinical trial, phase I, clinical
trial, phase II, clinical trial, phase III, clinical trial,
phase IV, comparative study, controlled clinical

trial, evaluation studies, technical report, validation
studies
95
studies
(including 36
reviews)
Of interest
17
studies
Studies of interest:
Seventeen articles of original research including
abstracts from conferences [117] provided some
information about the incidence of resistance among
abstracts
from
conferences
people living with HIV who had latent TB and were

provided preventive therapy.
2.2 Inclusion and exclusion criteria
he patients in the studies had to meet specific

criteria for being diagnosed with HIV and not
suffering from active TB at the time of the
study, or being on antitubercular medication prior
to the study. Latent TB or no previous history of TB

was noted by the studies. Observational studies
and trials were analysed separately for GRADE
purposes.
Net studies reviewed for grading of evidence:

14 studies
7 IPT versus placebo, randomized trials
3 IPT versus rifampicin, randomized trials
4 IPT versus placebo, observational
Mwinga et al. 1998 randomized trial excluded of 96 TB cases, only 12 tested for sensitivities
Kawai et al. 2006 observational, no numerical data
Mugisha et al. 2006 observational, no placebo group comparison
100
he studies of interest include those that

compared people living with HIV who had
undergone previous treatment for TB and were
put on IPT, with no IPT, or a rifampicin-containing

regimen for a duration of six to 12 months and/or a
shorter duration of the rifampicin regimen.
Study
Campos et al.
Churchyard et al.
Golub et al.
Gordin et al.
Halsey et al.
Hawken et al.
Publication year
2003
2003
2008
2000
1998
1997
Methods/design
Casecontrol
retrospective
observational
Observational study
Cohort retrospective
Randomized
controlled trial
Randomized
prospective
unmasked trial
Randomized doubleblind placebocontrolled trial
Data collection
Feb 1999Jan 2000
From 1998 to July

2001
Mar 1990Mar 1998
Sept 1991May 1996
Apr 1990July 1992
Apr 1992Mar 1994
Population
Lima and Callao,

Peru
Adults >18 years,
80/81 male
South Africa, gold

miners, HIV-positive,
documented
successful
completion of TB
treatment1
Injecting drug users

Baltimore, US,
adults, TST-positive
with active TB- (by
symptom review and
chest X-ray)
Outpatients in clinics,
US/Mexico/Haiti/
Brazil, age >13 years
Haiti, age 1677

years, HIV-1-positive,
TST-positive >5 mm,
normal chest X-ray,
median follow up 2.5
years
Kenya, HIV-positive,
1465 years, no
past/current TB,
clinic or voluntary
counselling and
testing (VCT)
attendees
Sample size
415 HIV-positive
with new TB -> 258
reviewed -> 135 TB
culture positive -> TB
Drug susceptibility
tested on 81 => 35
MDR TB-positive
338 had received

therapy
800 HIV-positive
=> 649 TST => 102
TST-positive => 60
IPT started => 36
completed IPT (35%
of TST-positives
completed IPT), 26week course
1583 HIV-positive,
TST-positive (>5 mm,
non-active TB), no
past treatment for TB
>2 months 35.8% vs
36.8% on ART in the
2 treatment groups
750 HIV-positive =>

332 on IPT
342 INH
Comparison group
Vs 46 MDR TBnegative HIV-positive

patients vs 38 MDR
TB-positive of 965
HIV-negative patients
221 had no
therapy
1576 HIV-negative
=> 1104 TST =>
434 TST-positive
=> 239 IPT started
=> 129/434 IPT
completed (30%)
636 completed RIF/

PZA vs 544 INH
therapy, 36 months
follow up
333 on RIF
prophylactic therapy
342 controls
TB latent/nil
New TB
History of TB
Latent
Latent
Latent
No TB history
Treatment regimen
TB prophylaxis
MDR TB-positive
6.75 months vs
MDR TB-negative
4.43.3 months of
prophylaxis (P=0.27)
INH 300 mg/daily
IPT
INH 300 mg/day +

pyridoxine HCl 12
months (N=792)
IPT 24 weeks INH

800 mg/pyridoxine
25 mg bi-weekly
6 months INH 300

mg daily
No treatment
RIF 600 mg/day +

PZA 20 mg/kg/day
for 2 months (N=791)
RIF 450 mg/day +

PZA 2000 mg for 2
months, bi-weekly
Placebo
Culture-confirmed
TB, adverse events
Resistant TB
Culture-confirmed TB
IPT group 24/26 TB

cases susceptibility
tested 2 with INH
monoresistance,
1 MDR; RIF/PZA
group 19/19 TB
cases tested 0 RIF
monoresistance, 2
MDR
14 (3.8%) IPT and

19 (5.0%) RIF
preventive therapy
patients developed
TB. Seven had
suspectibility testing,
2 resistant to INH,
not signficantly
different from the 180
other MTB isolates
from TB patients
without preventive
therapy.
19 INH culturepositive patients

vs 22 culturepositive controls,
2 resistant/17
tested (INH) vs 0
resistant/21 tested
(control) risk for
resistant TB/1000
10.05 vs 1.46 (RR
6.88 [0.013882.85])
Control
Outcomes
MDR TB
Resistant TB
Resistance
information
MDR TB in HIVinfected patients was

not associated with
previous TB therapy
or prophylaxis.
51 cases of TB
were diagnosed, 28
(8.3%) among the
IPT cohort and 23
(10.4%) among the
control cohort.
There was no
significant difference
in the prevalence of
isoniazid resistance
between the IPT
and control cohorts
(20% [2/10] and 23%
[3/13], respectively,
(P=1.0).
101
No INH resistance
detected among
TB cases who
had received any
duration of IPT
No IPT 20 TB
cases/24 585
person-years
(incidence ratio 0.81
[0.501.26]/1000
person-years) vs
all starting IPT 2 TB
cases/4185 personyears (IR 0.48
[0.061.72]/1000
person-years), IPT
30 days 1 TB/3358
person-years (IR
0.29 [0.011.66]),
completing IPT
0/2385 person-years
(IR 0 [01.55])
Annex 10
Study
Johnson et al.
Kawai et al.
Mosimaneotsile
et al.
Moreno et al.
Mugisha et al.
Mwinga et al.
Publication year
2001
2006
2009
1997
2006
1998
Methods/design
Randomized
placebo-controlled
trial
Retrospective
review of MDR TB
in a prospective TB
treatment trial
Cohort prospective
no placebo group,
part of ongoing trial
Historical cohort, not

blinded
Retrospective IPT
review feasibility
of service provision
study
Randomized doubleblind placebocontrolled trial
Data collection
Mar 1993Apr 1995
Feb 1999July 2000
20042006
19851994
Sep 2001Sep 2003

(25-month period)
Aug 1992Jul 1994
Population
Uganda, HIVpositive, 1850

years, TST, no
history of TB
Peru, TB patients
identified and
treated. Risk
factors for MDR
TB retrospectively
reviewed
Botswana, HIVpositive
Spain, 121 HIVpositive and PPDpositive
Uganda
Zambia, HIV-positive,
no TB treatment
history, both
TST-positive and
-negative patients;
1.8 years median
follow up
Sample size
2736 TST-positive
and -negative HIVpositive adults, 2018
TST-positive => 536
INH prophylaxis =>
459 completed and
evaluated
224 patients
diagnosed with TB,
commenced on TB
directly observed
treatment, shortcourse (DOTS)
1995 (72% female,

age 1870 years, no
TST criteria
29 INH (median
follow up 89 months)
6305 HIV-positive
=> 3366 TST =>
894 TST-positive
=> 506 IPT => 335
completed
Of 2063 HIV-positive
=> 1053 subjects =>
350 INH
Comparison group
Of 2018 TST-positive
=> 464 placebo =>
318 completed and
evaluated
No control, part of
ongoing trial
92 no treatment
(median follow up 60
months)
TB latent/nil
Latent
No/latent TB
(not treated in past)
Latent
Latent
No TB and latent TB
Treatment regimen
INH 6 months,
INF+RIF 3 months,
INH+RIF+ PZA 3
months, or placebo 6
months
INH 6 months +
pyridoxine 25 mg
912 months of INH
9 months in a
12-month period
INH 300 mg/25 mg
pyridoxine
6 months INH twice

a week
??
No placebo/no
review
No treatment
Outcomes
3 definite, 2 possible
incident, 3 possible
deaths
Current TB
351 on RIF/352 on
placebo
RIF + PZA twice/

week, OR placebo
Resistance
information
TB cases INH vs
control = 36 vs 46,
resistant/total tested
5/20 vs 1/24
MDR TB is
associated with
previous TB
treatment; found
an association with
previous IPT
0 out of 3 cultureconfirmed TB cases

were resistant to INH
3 TB cases INH vs
39/43 tested in no
treatment group.
Resistance 2 out
of 2 tested INH
vs 0/12 tested no
treatment. Risk for
resistance 118.64 vs
5.41 (21.95 [0.0411
582.31])
5/533 on IPT
developed TB; 4 had
been on treatment
for many months
Findings/comments
Risk for resistant

TB/1000 13.69
vs 3.39 (RR 4.04
[0.5032.80]) INH vs
placebo
At the infectious
diseases unit where
all patients were
HIV-positive, 30
(47%) of them had
MDR TB. Multiple
regression analysis
revealed that MDR
TB was associated
with previous TB
preventive therapy
(hazard ratio [HR]
16, 95% CI: 2.885,
P < 0.002)
Eighty-six per cent

(1710/1995) were
adherent to the entire
6-month course of
IPT
Median survival
was more than 111
months in patients
who received
isoniazid compared
with 75 months
in patients who
did not receive
isoniazid
(P < 0.001).
The prevalence of
INH resistance in
Uganda was 6.7% in
previously untreated
cases in surveillance
from 1996 to 1997,
--portion of IPT
patients will develop
disease IPT would
not be expected to
be effective.
96 TB cases in
all three groups,
culture results 26 =>
sensitivity results for
12 only. One placebo
patient resistant to
INH
102
Study
Pape et al.
Rivero et al.
Saenghirunvatta
et al.
Zar et al.
le Roux et al.
Publication year
1993
2003
1996
2007
2009
Methods/design
Randomized clinical
trial
Randomized clinical
trial
Prospective trial
Prospective doubleblind placebocontrolled trial
Prospective trial
Data collection
19861989
Jun 1994Dec 1998
19941995
Jan 2003May 2004
December 2002March 2008
Population
Haiti, asymptomatic
HIV-positive 1865
years, no TB history,
118 enrolled (77%
female)
Madrid and
Andalusia, Spain,
HIV-positive patients
1865 years with
TST anergy, no TB
history/treatment
Thailand, HIVpositive
South Africa, HIVpositive children

>8 weeks (median
age 24.7 months),
average 5.7 months
follow up
South Africa, children >8 weeks, median age

25.9 months, average 25 months follow up
Sample size
58 on INH+B6
Of 319 HIV-positive
=> 83 on 6 months
INH
46 HIV-positive =>
10 IPT
263 HIV-positive =>

132 IPT
276 patients
placebo
Comparison group
60 vitamin B6 alone
82 3 months RIF/
77 in 2 months
RIF+PZA / 77 in
no treatment group
(follow up 88 personyears INH for six
months group / 96
person-years RIF
3 months / 81 RIF
plus PZA 2 months /
126 person-years no
treatment group)
36 controls no
therapy
131 placebo
105 placebo
TB latent/nil
No TB history
No TB history
If previous TB,
placed on therapy,
and once completed,
placed on trial
No TB history
Treatment regimen
12 months daily INH

300 mg+ pyridoxine
(50 mg)
INH 6 months
12 months 300 mg
INH daily
INH three times/

week
INH daily 43%, 3x per week 57%
Comparison
12 months
pyridoxine only
RIF + INH 3 months

/ RIF 2 months / no
treatment
No treatment
Placebo three times/

week
Placebo daily 49%, 3x per week 51%
11/60 vit B6 and

4/58 INH patients
had TB; 0 out of 15
TB patients had any
drug resistance (all
responsive to TB
therapy)
11 cases TB overall,
2/3 in INH group
resistant to INH, 0/3
in RIF 3 months,
1/1 resistant to
INH PZA+RIF in
2-month RIF group,
4/4 resistant to
INH+Strep in no
treatment group
0/10 AND 1/36 cases

TB, no resistance
TB incidence INH
5/132 vs placebo
13/131. Incidence
of resistant M.
tuberculosis infection
did not increase
in children on
prophylaxis.
22/41 children who were diagnosed with TB

were taking daily prophylaxis (P = 0.53). Two
diagnosed with MDR TB; both were on daily
prophylaxis and had mean adherence below
90%.
171 prophylaxis, 105
Outcomes
Resistance
information
Comments
Small numbers
103
Small sample size2
At enrolment, 9% on
HAART, by end 31%
Design
Limitations
Randomized trials
Serious3
No serious
inconsistency
Inconsistency
Randomized trials
Serious3
No serious
inconsistency
Recruitment bias Churchyard gold miners

Few patients, few resistance measurements
3
Incomplete accounting of patients and outcomes
4
Small number of cases and patients
Mono-resistance to IPT vs rifampicin (IPT intervention vs rifampicin as control)
Mono-resistance to IPT vs placebo (IPT vs placebo)
No. of
studies
No serious
indirectness
No serious
indirectness
Indirectness
Quality assessment
Very serious
Serious4
Imprecision
None
None
Other
considerations
3/1469 (0.2%)
11/1255(0.9%)
Anti-TB
medications
1/1469 (0.1%)
5/1069 (0.5%)
No medications
No. of patients
RR 2 (0.1822.03)
RR 1.87 (0.65 5.38)
Relative risk
(95% CI)
Absolute
1 more per 1000

(from 1 fewer to 14
fewer)
4 more per 1000

(from 2 fewer to 20
more)
Summary of findings
Effect
VERY LOW
MODERATE
Quality
Less critical
Critical
Importance
Annex 10
104

Providing IPT for people living with HIV who are unlikely to have active TB does not significantly
increase the risk of developing INH-resistant TB. Therefore, concerns regarding the development of
isoniazid resistance should not be a barrier to implementing IPT programmes.
Intervention: Programmatic implementation of IPT for people living with HIV in resource-constrained settings
Action: Concerns regarding the development of isoniazid resistance should not be a barrier to implementing IPT
programmes.
Factor
Quality of evidence
Decision
Moderate
Benefits or desired
effects
Explanation

Direct evidence from a number of studies and meta-analyses

Comparison of those on IPT with those receiving placebo
shows no significantly increased risk.
IPT prevents active TB in people living with HIV.

IPT can be given with no significant risk of developing INHresistant TB.
The rare patients who do develop INH mono-resistance can
be treated successfully with routine TB treatment.
Treating mono-RIF resistant LTBI with IPT can prevent
future MDR (INH- and RIF-resistant) TB

Risks or undesired
effects
Strong
Strong
Costs
Strong
Feasibility
Overall ranking
of recommendation
105
Minimal risk that patients will develop TB while on IPT

Minimal risk that those who develop TB will develop INHresistant TB
Minimal risk that those who develop INH resistance will be
untreatable
Minimal risk of transmission of INH resistance
Minimal risk of development of MDR TB due to using IPT in
the face of pre-existing mono-RIF resistant TB
High INH resistance may reduce efficacy of IPT
IPT is a valuable TB prevention intervention with

considerable potential to prevent morbidity, mortality and TB
transmission.
Minimal risk of INH resistance not likely to increase cost as
the majority of patients will not develop TB and those who
do will likely be successfully treated with routine treatment
MDR rare but potentially costly event (e.g. laboratory
testing, second-line treatment, extended duration)
May be difficult to overcome health-care workers concerns

regarding development of TB drug resistance
Evidence and experience strongly supports implementation.
Strong
Annex 10
References
1. Campos PE et al. Multidrug-resistant Mycobacterium tuberculosis in HIV-infected persons, Peru. Emerging Infectious
Diseases, 2003, 9:15711578.
3. Golub JE et al. Long-term effectiveness of diagnosing and treating latent tuberculosis infection in a cohort of HIVinfected and at-risk injection drug users. Journal of Acquired Immune Deficciency Syndromes, 2008, 49:532537.
4. Gordin F et al. Rifampin and pyrazinamide vs isoniazid for prevention of tuberculosis in HIV-infected persons: an
international randomized trial. Terry Beirn Community Programs for Clinical Research on AIDS, the Adult AIDS
Clinical Trials Group, the Pan American Health Organization, and the Centers for Disease Control and Prevention
Study Group. Journal of the American Medical Association, 2000, 283:14451450.
7. Johnson JL et al. Duration of efficacy of treatment of latent tuberculosis infection in HIV-infected adults. AIDS, 2001,
15:21372147.
8. Kawai V et al. Tuberculosis mortality, drug resistance, and infectiousness in patients with and without HIV infection
in Peru. American Journal of Tropical Medicine and Hygiene, 2006, 75:10271033.
9. le Roux SM et al. Adherence to isoniazid prophylaxis among HIV-infected children: a randomized controlled trial
comparing two dosing schedules. BMC Medicine, 2009, 7:67.
10. Moreno S, et al. Isoniazid preventive therapy in human immunodeficiency virus-infected persons. Long-term effect
on development of tuberculosis and survival. Archives of Internal Medicine, 1997, 157:17291734.
11. Mosimaneotsile B et al. Isoniazid tuberculosis preventive therapy in HIV-infected adults accessing antiretroviral
therapy: a Botswana experience, 20042006. Journal of Acquired Immune Deficiency Syndromes, 2009, 54:7177.
12. Mugisha B et al. Tuberculosis case finding and preventive therapy in an HIV voluntary counseling and testing center
in Uganda. International Journal of Tuberculosis and Lung Disease, 2006, 10:761767.
2457.
Lancet, 1993, 342:268272.
Enfermedades Infecciosas y Microbiologa Clnica, 2003, 21:287292.
16. Saenghirunvattana S. Effect of isoniazid prophylaxis on incidence of active tuberculosis among Thai HIV-infected
individuals. Journal of the Medical Association of Thailand, 1996, 79:285287.
17. Zar HJ et al. Effect of isoniazid prophylaxis on mortality and incidence of tuberculosis in children with HIV: randomised
106

adherence to preventive therapy
PICOT Question: Will low adherence rates to treatment for LTBI be a barrier to the implementation of LTBI
treatment among people living with HIV?
Adults
Population: Adults living with HIV/AIDS in areas where TB prevalence is >30%
Intervention: Good adherence to LTBI treatment (>80% medication taken)
Comparison: Poor adherence, i.e. <80%
Outcomes: Consider only outcomes graded critical in the table below
Timeline: Lifetime (although no study has lifetime follow up)
Children
Population: Children (<15 years) living with HIV/AIDS in areas where TB prevalence is >30%
Intervention: Good adherence to LTBI treatment (>80%)
Comparison: Poor adherence, i.e. <80%
Outcomes: Consider only outcomes graded critical in the table below
Timeline: Lifetime (although no study has lifetime follow up)
Outcomes for individuals
Relative score
Severity index
Prevention of TB transmission
Critical
Prevention of deaths from TB

Reduction in incidence of TB
Acceptably low rate of adverse effects
Outcomes for programmes
8
9
7
Critical
Critical
Critical
Service uptake justifies staff allocation
Critical
Time allocation
Less critical
Resource allocation
Critical

Medline and Embase were used to locate appropriate articles.
Keywords: latent TB infection treatment, adherence, HIV PLWHA, isonazid prophylaxis
Inclusion criteria
Trials (randomized controlled trials/observational
studies) that involved LTBI treatment in an unselected
HIV population (adult or child) and commented on
adherence with reference to how it was monitored,
107
outcome with regard to adherence (if possible), and

made qualitative and quantitative statements with
regard to achieving good adherence.
Annex 11
Search strategy
Articles identified:
63
Selected by title:
47
Selected by abstract:
24
After reading:
Additional material:
Reviewed:
15
nlike treatment for TB which, if unsuccessful,

could result in severe morbidity, death and
further TB transmission, IPT is a preventive
measure, and whether an individual is adherent
and the degree to which they are adherent primarily
only directly impacts their personal risk for TB.
There are a variety of perspectives on adherence
including how many people are lost to follow up, or
how many complete treatment, and how many take

most of their tablets. It has been suggested that
taking >80% of a course of IPT can be considered
successful completion of treatment.[1] This has been
interpreted in a number of ways: taking six months
treatment within nine months, collecting more than
80% of tablets, taking >80% of the regimen. We
have specified how adherence has been measured
108
Annex 11: Summary of findings and quality of evidence: adherence to preventive therapy
in the studies reviewed for the guidelines. Studies

examining the effect of individual adherence at a
population level have not been performed; this is
not surprising as any study designed to evaluate the
effect of poor adherence on community levels of TB
or latent TB would involve very large numbers with
long-term follow up and, as yet, there are few places
implementing IPT on such a large scale to allow this
to be accurately and meaningfully studied.
There are few studies that look at the effect of
individual adherence on individual outcome. One
study [2] attempts to link adherence with outcome
(note, though, that the study [probably due to
inadequate power] does not show the overall
benefit of IPT over placebo in preventing TB, see
GRADE proforma attached). If the definition of poor
adherence is not finishing the course of treatment
then those patients lost to follow up in the studies
represent poor adherence; and the outcomes of
patients who default would answer the question
of the effect of adherence on individual outcomes
there are no studies on this issue for patients
with HIV. It is sometimes assumed that those who
default are equivalent to those untreated, that the
non-adherer returns to baseline TB risk and that
the question of poor adherence affecting individual
outcome is the same as asking whether treatment
for LTBI is efficacious. However, this is by no means
certain as it may depend on the amount of IPT
takenit is biologically plausible that even some
IPT may be better than none.
There are no studies that show the graded response
of adherence to individual outcome, e.g. outcome
by adherent patient months, which would be
interesting. For example, is adherence to five months

of IPT equivalent to not taking the medication and/
or what is the difference between adherence to six
months or nine months of treatment? If there is a
graded response on an individual basis to varying
levels of adherence, this may have a knock-on effect
on population transmission, but again, this has not
been studied.
There has been some discussion in the literature
suggesting that if adherence to an LTBI prevention
programme is low it may reduce the enthusiasm of
staff to run one and will potentially raise unit costs.
However, this is not reported by the studies as an
outcome measure and is often written from a TB
programmes perspective where the traditional
focus has been treatment of active TB. HIV services,
having experience with long-term prophylaxis such
as co-trimoxazole, may have a different chronic or
preventive care perspective. The issue of adherence
and drug resistance is often raised. Despite a
thorough review, no study has been identified that
assesses this theoretical risk.
Although data are not available, the assumption is
that good adherence will lead to better outcomes
and the search brought up a number of studies that
examined factors that affect adherence including
social, personal, clinical and programmatic
interventions. If IPT is offered as part of chronic
care for people living with HIV then it may benefit
from other efforts to improve adherence. The table
below provides a summary of adherence and an
approximation of how it has been measured by
both the randomized controlled trials (RCTs) and
observational studies (OS) that looked at adherence.
Study/author and year
Population
Location
Regimen
Method of adherence
measurement (good
adherence)
Adherence rates
Randomized controlled
trial (RCT)/observational
study (OS); Halsey et al.
Lancet 1998 [3]
784
Haiti
INH twice weekly 6/12 or

PZA+RIF twice weekly
2/12
Clinic visit attended

(>80%)
74% patients taking

RIF+PZA
RCT/OS; Hawken et al.

AIDS 1997 [2]
1053
Uganda
INH twice weekly 6/12 or

RIF+PZA twice weekly
for 2/12
Pill collection/self-report/
return within one month
of last dose (collect 80
100% tablets, self-report
taking >80% tablets)
74%
OS; Lugada et al. Int J

Tuberc Lung Dis 2002
[15]
98
Uganda
INH daily 6/12
Self-report/pill collection/
urine (collect pills within
2 weeks of end of last
prescription or positive
urine)
88% by urine, 76% by pill

collection
OS; Munseri et al. Int J

Tuberc Lung Dis 2008 [8]
565
Tanzania
INH daily 6/12
Not documented
87% (NB: 4% physician

terminated)
OS; Mohammed et al.

Int J Tuberc Lung Dis
2007 [6]
118
Cape Town
INH daily 12/12 if TSTpositive or randomized

to INH despite TSTnegative or placebo if
randomized to that and
TST-negative
Pill counts, supervisor

tick sheet (not given)
Median percentage of
doses taken per subject
81.291.7% (placebo
open label INH)
109
Annex 11
Study/author and year
Population
Location
Regimen
Method of adherence
measurement (good
adherence)
Adherence rates
Data review; Rowe et

al. Int J Tuberc Lung Dis
2005 [10]
87
South Africa
INH daily 6/12
Collection of pills (collect

6 months medicines in
9/12 period)
47%
OS; Szakacs et al. BMC

Infect Dis 2006 [12]
301
South Africa
INH daily long term
Urine dipstick one-off
72%
OS; Ngamvithaypong et
al. AIDS 1997 [9]
412
Thailand
9/12 daily INH
Monthly pill count
67.5%
OS: Mosimaneotsile et
al. JAIDS 2009 [7]
1995
Botswana
6/12 INH
2-monthly pill count and

clinic attendance
86%
OS: De Souza et al.

MIOC 2009 [16]
138
Brazil
6/12 INH
Pill count
87.7%
RCT; Whalen et al. N

Engl J Med 1997 [17]
2018
Uganda
INH+RIF 3/12 or
INH+RIF+PZA 3/12 or
INH 6/12
Self-report and clinic

attendance
Antonnucci et al. Eur

Respir J 2001 [18]
40
Italy
INH 6/12
Self-report
34.5%
100% compliant
RCT; le Roux et al. BMC

Med 2009 [5]
324 children
South Africa
INH daily or 3 x week

6/12
Pill count and self-report
94.7%
Summary
here is no evidence available to accurately

answer whether low adherence rates to
treatment for LTBI should be a barrier to
implementation of treatment for LTBI among people
living with HIV. However, some useful information
can be derived from the published studies that
include adherence information. Firstly, adherence
data vary between studies (4794%). However, the
studies that achieved higher adherence rates are
not always feasible models for scaling up service;
they may provide transportation fees to attend
clinic appointments [4,6] or incentives on arrival.
There is also mention of ineligibility for IPT due
to the possibility of poor adherence, which would
mean adherence rates are higher than would
be achieved in routine programme conditions.
It is noticeable that adherence in observational
studies that reviewed retrospective adherence in
a non-trial setting have lower rates of adherence.
[10,12,18] The only published data [2] that linked
adherence to LTBI treatment in an HIV-infected
population to risk of TB found no increased risk
of TB in poor adherers compared with those who
adhered well.[2] This supports the proposal that

even if adherence is less than desirable, individual
outcomes are not affected. There are no published
data suggesting a link between poor adherence and
the development of mono-isoniazid resistance. The
factors addressed in the research setting, however,
are not those that subjects comment on as reasons
for poor adherence in the qualitative assessments
reported. Side-effects or toxicity are also not
mentioned as a risk factor for poor adherence. These
conclusions compare favourably with the community
consultation document [see Annex 4] and represent
opportunities for programme implementation to
improve adherence in the design and running of an
LTBI programme. Additional research is needed on
operationalizing IPT in a patient-centred manner
which can improve adherence; however, it must
also be recognized that IPT is a preventive measure
and non-adherence impacts the individuals future
risk of developing TB. The Guidelines Group made
a strong recommendation that concerns regarding
adherence should not be a barrier to implementing
treatment for LTBI.
110
Annex 11: Summary of findings and quality of evidence: adherence to preventive therapy

Concerns regarding adherence should not be considered a barrier to implementing
treatment for LTBI.
Intervention: Implementation of IPT regardless of adherence concerns

Action: HIV programmes should implement IPT
Factor
Quality of evidence
Decision
Low
Explanation

Benefits or desired
effects
Risks or undesired
effects
Strong
Strong
Studies where adherence is not a measured outcome

Observational studies with limited patient numbers
Qualitative assessments by interviews with small numbers
of patients (adherent and non-adherent)
Wide variety of adherence-related factors suggesting that
local context is important
Adherence will:
Reduce TB transmission
Reduce morbidity and mortality secondary to TB
Improve overall impact of the programme

Extra work for clinic staff

Extra cost in terms of patient information materials
People living with HIV will appreciate a complete package

of HIV/TB care.
People living with HIV will benefit from lack of active TB
disease as a result of IPT.
Costs
Strong
Feasibility
Strong
Overall ranking
of recommendation
Strong
111
Increased by:
Initiation of a programme that is not currently running
will entail extra costs in terms of staff, equipment, drugs,
storage space, clinic time, patient time
Decreased by:
Overall costs decrease by efficacy of LTBI treatment
programme
Community involvement in programme
Less spending on treatment of active TB (initial or
secondary cases)

Fits well within HIV care structure

Drug staff are familiar with its use
ART programmes are familiar with focusing on adherence
issues
Annex 11
References
1. De Cock KM, Grant A, Porter JD. Preventive therapy for tuberculosis in HIV-infected persons: international
recommendations, research, and practice. Lancet, 1995, 345:833836.
4. Hiransuthikul N et al. INH preventive therapy among adult HIV-infected patients in Thailand. International Journal of
Tuberculosis and Lung Disease, 2005, 9:270275.
5. le Roux SM et al. Adherence to isoniazid prophylaxis among HIV-infected children: a randomized controlled trial
comparing two dosing schedules. BMC Medicine, 2009, 7:67.
7. Mosimaneotsile B et al. Isoniazid tuberculosis preventive therapy in HIV-infected adults accessing antiretroviral
therapy: a Botswana experience, 20042006. Journal of Acquired Immune Deficiency Syndromes, 2009, 54:7177.
8. Munseri PJ et al. Completion of isoniazid preventive therapy among HIV-infected patients in Tanzania. International
Journal of Tuberculosis and Lung Disease, 2008, 12:10371041.
9. Ngamvithayapong J et al. Adherence to tuberculosis preventive therapy among HIV-infected persons in Chiang Rai,
Thailand. AIDS, 1997, 11:107112.
10. Rowe KA et al. Adherence to TB preventive therapy for HIV-positive patients in rural South Africa: implications for
antiretroviral delivery in resource-poor settings? International Journal of Tuberculosis and Lung Disease, 2005,
9:263269.
11. Scardigli A et al. Responding to the challenge of patients adherence to IPT: experience of an urban ART facility in
Mozambique. PEPFAR Implementing Meeting, Namibia, 11 June 2009.
12. Szakacs TA et al. Adherence with isoniazid for prevention of tuberculosis among HIV-infected adults in South Africa.
BMC Infectious Diseases, 2006, 6:97.
13. WHO, UNAIDS. Consultation for the revision of WHO/UNAIDS policy statement on Preventive Therapy against TB
for PLWHIV. 2010. [Annex 4]
2457.
15. Lugada ES et al. Operational assessment of isoniazid prophylaxis in a community AIDS service organisation in
Uganda. International Journal of Tuberculosis and Lung Disease, 2002, 6:326331.
16. Souza CT et al. Effectiveness and safety of isoniazid chemoprophylaxis for HIV-1 infected patients from Rio de
Janeiro. Memrias do Instituto Oswaldo Cruz, 2009, 104:462467.
of Medicine, 1997, 337:801808.
18. Antonucci G et al. Guidelines of tuberculosis preventive therapy for HIV-infected persons: a prospective, multicentre
study. GISTA (Gruppo Italiano di Studio Tubercolosi e AIDS). European Respiratory Journal, 2001, 18:369375.
112

cost effectiveness
PICOT Question: Is the treatment of LTBI in people living with HIV cost effective?
revious PICOT discussions have shown

LTBI treatment to be efficacious, safe and an
important tool for preventing TB in people living
Population: Adults living with HIV in areas where the

prevalence of LTBI is >30%
Intervention: Treatment for LTBI
with HIV. However, there are significant demands on

limited funds within HIV programmes, which raise the
issue of the cost effectiveness of treatment for LTBI.
Comparator: No treatment for LTBI
Outcome: See below
Timeline: Lifetime
Outcomes
Relative score
Severity status
Cost of treatment of LTBI related to the

cost of treating active TB, i.e. does not
take screening costs into account
Critical
Cost of screening for and treating LTBI

related to the cost of treating active
TB that would occur in the absence of
treatment for LTBI
Critical

The Medline and Embase databases were used.
Keywords:
IPT, latent TB infection treatment, PLWHA, HIV, latent TB treatment, preventive TB treatment, cost-efficacy,
cost-effectiveness, cost analysis
Inclusion criteria:
LTBI programme in HIV-positive individuals, clearly defined cost inclusive of screening for eligibility for
preventive therapy, and estimate made of savings, again clearly defining where costings estimated from and
documenting assumptions with regard to TB and programme implementation
113
Annex 12
Articles identified:
113
Selected by title:
50
Selected by abstract:
14
After reading:
13
Additional articles supplied by Guidelines

Committee or sourced from references in other articles
13
Reviewed:
There were no studies on cost efficacy specifically related to children. There were also no studies on cost
efficacy in a population with HIV living in an area with low TB prevalence.
114
he GRADE system is designed to review

interventions scored on a number of outcomes.
Cost efficacy can be an outcome; however,
the articles that deal directly with cost-efficacy do
not specifically have an outcome or control group
and are therefore difficult to assess within the

GRADE approach. Therefore, GRADE software
and methodology has not been used to answer this
particular question.[1]
Published literature on cost-efficacy of IPT in HIV-infected populations
lthough the GRADE software has not been

used to review the published literature, the
principles encompassed within GRADE
(transparent assessment looking at directness,
consistency, precision) can be applied. This allows
for an assessment of the quality of evidence
available and a strength of recommendation that is
possible to make from the available studies. Cost
considerations are very situation specific cost of
human resources, transportation, training, inpatient
care and investigations varies widely between
locations; this means that any comparison has to
be based on cost relative to an outcome. However,
the limited literature does not use a standardized
measure to assess cost. Some studies chose to

measure cost per quality-adjusted life year (QALY),
some cost per TB case averted, some cost of TB
in the person receiving IPT, some cost per averted
TB case and averted secondary cases. There is
also the issue of economic perspective: cost to
the health-care system, cost to the patient, cost
inclusive of screening for TB prior to treatment
(by a variety of means), and cost of screening for
HIV (see tables below). This variability renders
direct comparison between studies difficult. Each
study is best assessed on its individual merits and
the results accumulated in order to formulate a
recommendation.
Trial
Setting and set-up
Assumptions
Outcomes
Directness
Precision
Comment
Foster et al.
AIDS, 1997,
11:919925
Zambia district
hospital, 6 months
IPT after initial
HIV test, clinical
examination,
smear, chest X-ray,
confirmatory HIV
test.
Cost of IPT vs cost
of treating TB (2/12
in hospital, drugs,
diagnostics, lost
earnings, health
service costs)
1000 patients,
spreadsheet model
Efficacy of IPT
4575%
Adherence 5080%
Likelihood of
developing TB
2540%
Secondary cases
25
Costs taken from
1997 programmatic
costs, no data on
where assumptions
come from, TB and
HIV incidence from
local data
Measured in benefit
cost ratio 0.383.86
or including patients
lost wages
0.866.12
(greatest being most
efficacious with
maximal infectivity)
Relevant setting
BUT a model, i.e.
not based on reality,
and in terms of
population assumed
around 30% HIV
seropositivity with
costs inclusive of 2
HIV tests
Wide variability
given assumptions.
Note benefitcost
ratio significantly >1
only when patient
earnings taken into
account
Initial population not

all HIV-positive
Shrestha et al. Int

J Tuberc Lung Dis,
2007, 11:747754
Urban Uganda (VCT

centre). No HAART.
Cost of IPT includes
screening with
questionnaire, smear,
chest X-ray, physical
examination, TST or
treat all, i.e. no TST.
Also included staff,
training, equipment,
space costs with
decline over years
of programme, no
start-up cost. IPT
means either 6 or 9
months of INH. Cost
discount rate of 3%
per year. Markov
cohort simulation
Costs supplied from

programmatic costs
with a range.
TST sensitivity
0.20.9
TST specificity
0.650.98
Adherence
0.4450.99
Risk of developing
TB in controls
0.0340.1
All-cause mortality
per year 0.0470.141
Adverse events
0.0140.041
Protection provided
by IPT 15 years
For QALY, survival
of HIV-infected
individual estimated
Expected QALY with

no intervention 498,
with targeted TST
testing 509 and with
a treat-all strategy
539. Cost per QALY
of targeted testing
averaged $102, cost
per QALY gained for
treat all $106 (NB:
if TST sensitivity is
less than 0.52 as
might be expected
in advanced HIV,
then target testing
becomes more
expensive at $115
per QALY)
Modelled so
by necessity
not completely
transferable
Wide range
of results,
given variable
assumptions.
Consistent
Authors comment
on non-HAART
population.
115
Annex 12
Trial
Setting and set-up
Assumptions
Outcomes
Directness
Precision
Comment
Hausler et al.
Bull WHO, 2006,
84:528536
Part of ProTEST,
Cape Town PHC,
STI, CHC clinics.
Costs from clinic
data note cost of
ICF/IPT included
screening for active
TB with smear, TST,
chest X-ray, physical
examination, also
included personnel
time and start-up,
building, vehicle
and coordination
costs. Rated against
number of cases of
TB prevented.
Each case of TB
infects 114 cases
per year.
ICF decreases
infectious period
from 9.6 months by
30%, so for every
100 cases picked up
by ICF, 25 cases of
TB are prevented.
For IPT, the assumed
incidence of TB
decreases by 60%
for 2 years if TSTpositive (if adherence
6080%)1, annual
incidence of TB in
TST-positive HIVpositive individuals
is 8% and each
case causes one
other. Therefore, for
every 100 people
completing IPT using
TST, 19 cases of TB
are averted.
Cost per case of TB

prevented by IPT
$486962 (PHCCHC) but a 36%
reduction if chest
X-ray removed from
screening equation.
Removing TST
reduces cost by 60%
but cost per case
prevented by only
4% as IPT is less
efficacious.
The assumptions
made are from
generally well
accepted data.
The population
studied is relevant.
Specific costs are
of course site- and
country-specific (note
significant variation
from PHC to CHC in
same location)
Consistent and
plausible variation in
cost due to different
site.
Note: authors argue

cost-effective with
TST, and could be
more so without
chest X-ray.
Bell et al. AIDS,

1999, 13:15491556
Model based on
reported costings
in the literature and
using assumptions
for the literature.
Modelled the effect of
3 preventive therapy
strategies: INH 6/12,
INH + RIF 3/12, twice
weekly RIF+PZA
for 2/12. Used a
Markov model with
3% discount rate and
costs inclusive of
indirect social costs
and well as cost of
secondary cases of
infection.2 Cost of
preventive therapy
included screening
costs (with chest
X-ray, smear, TST,
drug cost, personnel
in case of RIF+PZA
includes cost of
DOT and nutrition
supplementation).
Measured cost per
case prevented and
cost per QALY
TB rate if TSTpositive 3.410% per

annum
Secondary cases
210
Efficacy of preventive
therapy duration 1.5
years to lifetime
Efficacy of INH
2386%, efficacy for
INH +RIF 1482%,
efficacy for RIF+PZA
3090%, adverse
events mild/severe
0.25 per month0.99
per day
Taking all extremes

of assumptions
and varying costs
(halving or doubling)
does little to change
overall outcome.
Compared with
cost of treating TB,
preventive therapy
is cost saving only
if social costs are
included. However,
all regimens are cost
reducing in terms
of cost of treating
TB if incidence of
secondary infection
is >2.4
Translatable to
answer the question
Wide variability in
costings and efficacy
data exists and are
used; however, does
not alter overall
outcomes.
In a sense, a metaanalysis of costefficacy data
Masobe et al. S
Afr Med J, 1995,
85:7581
South Africa
predominantly high
TB prevalence area.
Costs included
TST in those from
low-prevalence
background, cost of
drug (INH), clinical
services, treatment
of INH hepatitis,
transportation and
breakthrough TB
compared with cost
of treating TB and
secondary TB cases.
Costs estimated
in 1993 SA Rand
with 4% discount
rate taken from
consensus view
of functional TB
programme. Estimate
8-year follow up
Assumed 97.2% of
patients from highrisk TB background,
2.8% from low risk.
TST-positive in
5%. Assume risk
of 4.68 adult and
3.2 child secondary
cases per active
TB case and 6% of
contacts develop TB.
Annual rate of TB in
HIV-positive 58%,
INH efficacy 90%,
compliance 68.5%
and INH hepatitis
rate 0.48%.
Over 8 years cost

saving of
R 40 551 952
(assumed prevent
21 800 cases of
active TB)
If compliance only
41% then saving only
R10.5 million
Translatable to
answer the question
Direct in terms of
applicable setting
Some sensitivity
analysis commented
on in terms of
compliance, 4168%
and sensitivity
analysis in terms of
discount rate. Still
cost-saving
Bucher et al. Isonazid prophylaxis for TB in HIV infection: a meta-analysis of randomized controlled trials. AIDS, 1999, 13:501-507.
Cost taken from Saunderson. Social Science and Medicine, 1995, 40:1203-1212, Foster et al., AIDS, 1997,11:919-925, Aisu et al., AIDS,
1995, 9:267-273.
1
2
116
Annex
Annex12
12: Summary of findings and quality of evidence: cost effectiveness
Trial
Setting and set-up
Assumptions
Outcomes
Directness
Precision
Comment
Observational studies of cost (not always compared with outcomes)

Sutton et al.
Int J Tuberc
Lung Dis,, 2009,
13:713718.
Cambodia analysis
of figures from 2003
to 2006 of running
programme. Cost of
IPT includes drugs
(INH 9/12) and
transportation of
drugs, cost of patient
transportation, cost
of screening X-ray
and clinical time,
capital cost, human
resource costs
including training and
education. Number
of patients from their
centre, cost from the
centre. Compliance
(completion rate)
86%
Assume annual TB
incidence in HIVpositive population
(where TST result
not known) is
8%, assume that
IPT reduces TB
incidence by 60%
for 2 years. Assume
17/100 patients
taking IPT are the
number of TB cases
prevented. Estimate
that there is 1
secondary case in an
HIV-positive person
per active case.
Cost per TB case

prevented $955
(if 13/100 cases
prevented), cost
per case prevented
$1274 but if 25/100
then falls to $764
Study direct, relative
Costs similar to
those reported in
other studies
Note 88% of patients

without active
TB were deemed
ineligible for IPT
(pregnant,alcoholic
liver disease, poor
adherence likely)
Terris-Prestholt et al.
Cost Effectiveness
and Resource
Allocation, 2008, 6:2
Zambia ProTEST
initiative facilitating
care programme.
Cost of running
programme (not
clear exactly what
included) from 3
sites, cost of IPT
does not specify if
includes screening.
Costs from 2007
converted to USD.
All real-time costs,

i.e. no estimate of
efficacy or protection
but sensitivity
analysis performed
to look at variation of
compliance
Cost per person

completing IPT
$2938 (NB: cost per
person starting IPT
$718)overall though
altering compliance
has less than 10%
effect on unit costs
Real-time costings
Similar in terms of
cost to other studies
No attempt to
analyse in terms of
efficacy
he Guidelines Group made a strong

recommendation that, while there is significant
variation between the studies assessed, the
literature suggests that treatment for LTBI is likely to
be cost effective. In some studies, there are a number
of factors that must be taken into consideration
to justify this conclusion. For example, one study
[2] argues that the intervention is cost efficacious
only if the social cost of having TB and treating TB
are taken into consideration, and another study
[3] discovered that the intervention becomes cost
effective only if each TB case creates five secondary
cases, all of which need treatment. In some studies,
there are interesting programmatic alterations that
dramatically affect cost. A study [4] found that the
inclusion of chest X-ray in screening reduced cost
efficacy; another study [5] found that the use of
117
TST reduced the cost of IPT. Yet another study [6]

showed that reduction in patient compliance reduced
the overall cost savings. None of the studies have
been conducted in a population that was also on
ART, and this would potentially change costs as well
as the additional efficacy of IPT, and the number of
secondary active TB cases among people living
with HIV. There is considerable room for further
research in this area, particularly given the recent
improvements in HIV services and the emphasis on
an integrated approach to TB and HIV prevention,
care and treatment. The strong recommendation
supports the overall recommendation for the wide
use of IPT within comprehensive HIV prevention,
care and treatment services, both as a measure of
good clinical practice and as a likely cost-effective
measure.
Annex 12

Treatment of LTBI should be considered cost effective in people living with HIV.
Intervention: Implementation of IPT programme
Action: HIV programmes should not avoid the addition of LTBI treatment to their service on cost grounds
Factor
Quality of evidence
Decision
Low
Explanation

Benefits or desired
effects
Risks or undesired
effects
Strong
Strong
Limited number of studies with inconsistent outcomes

means that cumulative evidence is weak.
Studies are hypothetical with variable assumptions made
with regard to TB incidence, transmission and efficacy of
IPT.
All studies report IPT to be cost effective.
Will allow programmes to start LTBI treatment programmes

as part of a package of HIV care
Will save money within HIV and TB programmes which can
be re-allocated to other parts of the programme
Considering LTBI treatment cost effective and therefore
initiating IPT programmes will reduce TB transmission,
active TB in the individual and potentially realize the
benefits listed for recommendation of IPT
Initial costs will be higher since all studies show cost
efficacy over >2-year period and not in the first year of a
programme.
Given the limited data from studies, it is possible that a
universal roll-out of IPT may have unforeseen costs (not
accounted for on a smaller scale).
For the individual, it is likely that cost efficacy is

unimportant.
For programmes, being able to justify IPT provision as cost
effective will satisfy donors and financial backers.
Costs
Strong
Increased by:
Use of chest X-ray
Poor adherence
Longer regimen
Use of RIF+PZA
Decreased by:
Use of TST
Good adherence
Symptom screening
Feasibility
Strong
Overall ranking
of recommendation
Strong
The incremental cost in excess of HIV programme would

be limited and feasibility improved as it would be an add-on
to existing programmes and no capital investment would
be needed.
118
References
1. GRADE Working Group. Grading quality of evidence and strength of recommendations. British Medical Journal,
2004, 328:14901499.
2. Aisu T et al. Preventive chemotherapy for HIV-associated tuberculosis in Uganda: an operational assessment at a
voluntary counselling and testing centre. AIDS, 1995, 9:267273.
3. Foster S, Godfrey-Faussett P, Porter J. Modelling the economic benefits of tuberculosis preventive therapy for
people with HIV: the example of Zambia. AIDS, 1997, 11:919925.
4. Shrestha RK et al. Cost-utility of tuberculosis prevention among HIV-infected adults in Kampala, Uganda. International
Journal of Tuberculosis and Lung Disease, 2007, 11:747754.
5. Shrestha RK et al. Cost-effectiveness of including tuberculin skin testing in an IPT program for HIV-infected persons
in Uganda. International Journal of Tuberculosis and Lung Disease, 2006, 10:656662.
6. Masobe P, Lee T, Price M. Isoniazid prophylactic therapy for tuberculosis in HIV-seropositive patientsa least-cost
analysis. South African Medical Journal, 1995, 85:7581.
7. Hausler HP et al. Costs of measures to control tuberculosis/HIV in public primary care facilities in Cape Town, South
Africa. Bulletin of the World Health Organization, 2006, 84:528536.
8. Bell JC, Rose DN, Sacks HS. Tuberculosis preventive therapy for HIV-infected people in sub-Saharan Africa is costeffective. AIDS, 1999, 13:15491556.
9. Bucher HC GLGGS. Isoniazid prophylaxis for tuberculosis in HIV infection: a meta-analysis of randomized controlled
trials. AIDS, 1999, 13:501507.
10. Saunderson P. An economic evaluation of alternative programme designs for tuberculosis control in rural Uganda.
Social Science and Medicine, 1995, 40:12031212.
11. Sutton BS et al. The cost of intensified case finding and isoniazid preventive therapy for HIV-infected patients in
Battambang, Cambodia. International Journal of Tuberculosis and Lung Disease, 2009, 13:713718.
12. Terris-Prestholt F et al. Integrating tuberculosis and HIV services for people living with HIV: costs of the Zambian
ProTEST Initiative. Cost Effectiveness and Resource Allocation, 2008, 6:2; doi:10.1186/1478-7547-6-2.
119

intensive TB case-finding for children living with HIV
PICOT Question: What is the best combination of signs and symptoms and diagnostic tools that can be used
as a screening tool to identify children living with HIV who are eligible for treatment of LTBI and diagnosis of
active TB?
Population: People living with HIV, children living
with HIV
Intervention: Combination of signs and symptoms
and diagnostic tools that can be used as a screening
tool to identify children living with HIV who are eligible
for treatment of LTBI and diagnosis of active TB

Comparison: TB prevalence without intervention
Timeline: 12 months during work-up for TB
Outcomes
Negative predictive value (to identify
children eligible for treatment of LTBI)
Relative score
(rank 1
9 most critical)
9
Severity status
Critical
Sensitivity (to identify children for further 9

diagnostic work-up)
Critical
Important
Specificity
6
6
Important
120
Annex 13: Summary of findings and quality of evidence evaluation: intensive TB case-finding for children living with HIV

Search criteria:
PubMed Search (Child[Mesh] OR Child, Preschool[Mesh]) OR Infant[Mesh]) AND Tuberculosis[Mesh])
AND HIV Infections[Mesh]) AND Diagnosis[Mesh]) OR (TB screening, Children, HIV)
546
articles
Limits:
Clinical trial, meta-analysis, randomized controlled trial, review, clinical trial, phase I, clinical trial, phase II,
clinical trial, phase III, clinical trial, phase IV, comparative study, controlled clinical trial, evaluation studies,
multicentre study, Medline, PubMed Central, all infant: birth23 months, newborn: birth1 month, infant: 123
months, preschool child: 25 years, child: 612 years
161
By title
57
(+ 17 added)
By
abstract
20
(+10 added from

references)
Of
interest
15
International conferences: CROI, IAS, International AIDS conference

CROI 2008, 2009: 0
IAS 2009: 2
IAC 2008: 2
Abstracts of interest: 1
121
Annex 13
Studies of interest:
A total of 16 articles/abstracts provided information
on the clinical presentation of TB among HIVinfected children, or the utility of the TB scoring
system in HIV-infected children, or a combination
of signs and symptoms or diagnostic tests among
HIV-infected children.[116]
Information available:
There was only one study by Song et al.

that looked at the combination of signs,
symptoms and diagnostic tests among HIVinfected children.[1] Most of the identified
studies presented information on the clinical
presentation of TB among HIV-infected children
and gave the frequency of various symptoms or
the results of tests such as TST and chest X-ray
among HIV-infected children with TB.[214]
Two other studies evaluated the potential role of
scoring systems for identification of TB in HIVinfected children.[15,16] Some review articles
have summarized the difficulty in diagnosing
TB among HIV-infected children.[17,18] The

WHOCDC meta-analysis focused only on
adults and adolescents and did not address
children.[19]
An important challenge was the identification of
an appropriate gold standard for the confirmation
of TB among HIV-infected children. Among
children with active TB, both sample collection
and the yield of positive culture are generally
thought to be low. Reviewed studies [216] used
bacteriological confirmation of Mycobacterium
tuberculosis by culture alone or in combination
with radiological findings, TST reaction or
response to antituberculosis therapy as the
standard for comparison of the yield of various
tests or symptom combinations. However, the
difficulties encountered in confirming TB, even
with the best available tests and technologies,
severely limit the ability to identify practical
approaches to the identification of TB in children.
ost of the studies [214] identified reported

on the clinical presentation of TB among HIVinfected children or positivity of different tests
(such as TST or chest X-ray). However, they did not
report on the best combination of symptoms or tests
that could be used as a screening tool to identify TB
among HIV-infected children.
Some studies [15,16] assessed the utility of scoring
systems or consistency of different scoring systems
in HIV-infected children. These scoring systems
are limited by the absence of standard symptom
definitions and adequate validation. Therefore, in their
current form, their utility among HIV-infected children
is limited. The scoring system used in Brazil worked
equally well as the clinical algorithm for diagnosis of
TB among HIV-infected children; however, its utility in
high HIV- and TB-prevalence settings has not been
tested and is uncertain.
A study by Marais et al.[7] suggested that an
algorithm based only on signs and symptoms was
a poor predictor of a diagnosis of TB among HIVinfected children. The presence any one symptom
of persistent, non-remittent cough for more than two
weeks, objective weight loss in the preceding three
months, or reported fatigue reached a sensitivity
of only 0.56 and thus would fail to identify a large

proportion of HIV-infected children with TB if used as
a screening tool for diagnosis of TB in this population.
This combination of symptoms had a specificity of
0.62.
A study by Song et al.[1] reported on the evaluation
of TB screening among 303 HIV-infected children in
Rwanda using a combination of signs and symptoms
and diagnostic tests. The results of screening tests
were compared to a gold standard of microbiological
confirmation or chest radiograph findings characteristic
of TB. Absence of cough for two weeks or more,
failure to thrive and fever had a negative predictive
value of 0.99. Half the children were found to have a
negative symptom screen and would not need further
evaluation. Only two children were found to have a
false-negative test result when compared with the
gold standard. The combination had a sensitivity of
0.90 and specificity of 0.65 for identifying children for
further diagnostic evaluation of active TB. Addition
of a positive TST to the combination increased the
sensitivity to 0.95 with a slight reduction in specificity
to 0.59. Thus, 95% of children likely to have TB would
be identified by this combination and sent for further
evaluation. However, 5% of children likely to have the
disease would still be missed.
122
GRADE profile and summary of findings

What is the best combination of symptoms and diagnostic tools that can be used as a screening tool to
identify HIV-infected children who are eligible for treatment of LTBI?
Quality assessment
No. of
studies
Design/no. of
participants
Limitations
Inconsistency
Indirectness
Imprecision
Other
considerations
Quality
Any one of cough 2 weeks, fever, or failure to thrive

Negative predictive value 0.99
1
Observational
study/303
Serious
limitation*
No serious
inconsistency
No serious
indirectness
No serious
imprecision#
Low
Observational
study/303
Serious
limitation*
No serious
inconsistency
No serious
indirectness
No serious
imprecision#
Low
Observational
study/303
Serious
limitation*
No serious
inconsistency
No serious
indirectness
No serious
imprecision#
Low
Serious
limitation*
No serious
inconsistency
No serious
indirectness
No serious
imprecision#
Low
Sensitivity 0.90
1
Specificity 0.65
1
Positive predictive value 0.14

1
Observational
study/303
Culture and radiological appearance were used as a gold standard, which is not a perfect gold standard. Being an observational study and
not having a well-defined gold standard, the study did not qualify for the highest quality of evidence.
* The reference standard used is unlikely to correctly classify all the children with disease as having the disease. Moreover, sputum was
collected only from children with signs and symptoms suggestive of TB or abnormal chest X-rays.
# Confidence intervals for the sensitivity and specificity were not reported.
What is the best combination of symptoms and diagnostic tools that can be used as a screening tool to identify children for further diagnostic evaluation
of active TB?
Cough 2 weeks failure to thrive fever positive TST
Quality of evidence
0.99
303 (1 study)
Low
0.95
303 (1 study)
Low
0.59
303 (1 study)
Low
0.14
303 (1 study)
Low

Sensitivity
Specificity
123
Annex 13

Children living with HIV without poor weight gain,* fever and current cough are unlikely to
have active TB and should be offered IPT.
Children living with HIV who are more than 12 months of age and who are unlikely to have
active TB should receive six months of INH preventive therapy (10 mg/kg/day) as part of a
comprehensive package of HIV care services.
After successful completion of treatment for TB disease, all children living with HIV who
are more than 12 months of age should receive INH for an additional six months.
All children with a history of contact with a TB case should receive six months of IPT.
* Poor weight gain is defined as reported weight loss, or very low weight (weight-for-age less than 3 z-score), or underweight
(weight-for-age less than 2 z-score), or confirmed weight loss (>5%) since the last visit, or growth curve flattening.
Population: Children living with HIV
Intervention: Careful history-taking and clinical assessment

Factor
Quality of evidence
Decision
Moderate
Benefits or desired
effects
Risks or undesired
effects
Explanation
The quality of evidence is low and comes from one study by Song
et al.

Strong
Simplifies screening and limits the number of radiological

and laboratory investigations
Identifies children who can benefit from IPT (and thus
reduces morbidity/mortality due to TB)
A small number of children with active TB might be given

monotherapy
Increase in time spent by health-care workers in screening
for TB
Strong
Costs
Weak/conditional
Feasibility
Weak
Increased by:
Training of clinicians and nurses to perform clinical
assessment and correctly determine poor weight gain
Additional staff required due to increase in time spent by
existing staff for screening
Reduced by:
Limited resources needed for symptom screening among
children already regularly attending clinical services for HIV
Avoiding costs of additional diagnostic tests including chest
X-ray
Avoiding costs that would have been associated with
treatment of TB (if LTBI is effectively treated)
Overall ranking
of recommendation
Parents would like their children to be protected from TB

by provision of IPT, especially in settings with a high TB
burden.
History-taking and clinical assessment would be feasible

but would require additional training and time from already
overburdened staff.
Strong (initial IPT for six months)

Conditional (post TB treatment)
124
Children living with HIV with any one of the following: poor weight gain, fever or current cough may
have active TB and should be evaluated for TB and other diseases.
Intervention: Careful history-taking and clinical assessment

Factor
Quality of evidence
Decision
Low
Benefits or desired
effects
Risks or undesired
effects
Explanation
The quality of evidence is low and comes from one study by Song
et al.

Weak
Early identification of TB suspects followed by appropriate

treatment of identified TB cases can reduce TB-associated
morbidity and mortality among children living with HIV.
Increased demand for clinical and laboratory investigations

This approach would result in a larger number of children
undergoing diagnostic testing, including possible risks
(generally not high) associated with sample collection (e.g.
from lymph nodes or gastric aspirates)
Patients/parents generally desire accurate diagnosis of

disease and may be willing to undergo diagnostic evaluation
or treatment in an effort to prevent morbidity/mortality.
Costs
Weak
Feasibility
Weak
Overall ranking
of recommendation
Strong
125
Increased by:
Increase in number of children requiring diagnostic
evaluation for TB will require resources (staff, reagents,
transport, laboratory capacity)
Increased need for quality assurance of diagnostic services
Need for additional drugs due to increase in number of
cases
Decreased by:
Decreased costs of managing severely ill or dying children if
TB is recognized

May require some additional training and time from

overburdened health-care workers, laboratory workers and
families of affected children
Annex 13
Figure 2. Algorithm for TB screening in children more than one year of age and
living with HIV
Child more than 12 months of age and living with HIV*
Poor weight gain
Fever
Current cough
Contact with a TB case
Yes
No

No
Give IPT
Yes
Defer IPT
Other diagnosis
Not TB
TB
Give
appropriate
treatment and
consider IPT
Follow up
and
consider IPT
Treat
for TB
Screen regularly for TB
FOOTNOTES TO ALGORITHM FOR CHILDREN

* All children and infants less than one year of age should be provided with IPT if they have a household contact history with a TB
case.
Poor weight gain is defined as reported weight loss, or very low weight (weight-for-age less than 3 z-score), or underweight
(weight-for-age less than 2 z-score), or confirmed weight loss (>5%) since the last visit, or growth curve flattening.
Contraindications include: active hepatitis (acute or chronic) and symptoms of peripheral neuropathy. Past history of TB should not
be a contraindication for starting IPT. Although not a requirement for initiating IPT, TST may be done as part of eligibility screening in
some settings.
Investigations for TB must be done in accordance with existing national guidelines.
126
References
1. Song R et al. Evaluation of TB screening approaches among HIV-infected children Rwanda, 2008. 5th IAS
conference on HIV pathogenesis and treatment, 1922 July 2009 [Abstract no TUPEB132].
2. Hesseling AC et al. Outcome of HIV infected children with culture confirmed tuberculosis. Archives of Disease in
Childhood, 2005, 90:11711174.
3. Iriso R et al. The diagnosis of childhood tuberculosis in an HIV-endemic setting and the use of induced sputum.
International Journal of Tuberculosis and Lung Disease, 2005, 9:716726.
4. Jeena PM et al. Impact of HIV-1 co-infection on presentation and hospital-related mortality in children with culture
proven pulmonary tuberculosis in Durban, South Africa. International Journal of Tuberculosis and Lung Disease,
2002, 6:672678.
5. Kiwanuka J et al. Diagnosis of pulmonary tuberculosis in children in an HIV-endemic area, Malawi. Annals of Tropical
Paediatrics, 2001, 21:514.
6. Madhi SA et al. HIV-1 co-infection in children hospitalised with tuberculosis in South Africa. International Journal of
Tuberculosis and Lung Disease, 2000, 4:448454.
7. Marais BJ et al. A refined symptom-based approach to diagnose pulmonary tuberculosis in children. Pediatrics,
2006, 118:e13501359.
8. Mukadi YD et al. Impact of HIV infection on the development, clinical presentation, and outcome of tuberculosis
among children in Abidjan, Cote dIvoire. AIDS, 1997, 11:11511158.
9. Palme IB et al. Impact of human immunodeficiency virus 1 infection on clinical presentation, treatment outcome and
survival in a cohort of Ethiopian children with tuberculosis. Pediatric Infectious Disease Journal, 2002, 21:1053
1061.
10. Ramirez-Cardich ME et al. Clinical correlates of tuberculosis co-infection in HIV-infected children hospitalized in
Peru. International Journal of Infectious Diseases, 2006, 10:278281.
11. Sassan-Morokro M et al. Tuberculosis and HIV infection in children in Abidjan, Cote dIvoire. Transactions of the
Royal Society of Tropical Medicine and Hygiene, 1994, 88:178181.
12. Schaaf HS et al. Culture-confirmed childhood tuberculosis in Cape Town, South Africa: a review of 596 cases. BMC
Infectious Diseases, 2007,7:140.
13. Van Rheenen P. The use of the paediatric tuberculosis score chart in an HIV-endemic area. Tropical Medicine and
International Health, 2002, 7:435441.
14. Walters E et al. Clinical presentation and outcome of tuberculosis in human immunodeficiency virus infected children
on anti-retroviral therapy. BMC Pediatrics, 2008, 8:1.
15. Edwards DJ, Kitetele F, Van Rie A. Agreement between clinical scoring systems used for the diagnosis of pediatric
tuberculosis in the HIV era. International Journal of Tuberculosis and Lung Disease, 2007, 11:263269.
16. Pedrozo C et al. Clinical scoring system for paediatric tuberculosis in HIV-infected and non-infected children in Rio
de Janeiro. International Journal of Tuberculosis and Lung Disease, 2009, 13:413415.
17. Marais BJ et al. Diagnostic and management challenges for childhood tuberculosis in the era of HIV. Journal of
Infectious Diseases, 2007, 196 (Suppl 1):S76S85.
18. WHO. Guidance for national tuberculosis programmes on the management of tuberculosis in children. Geneva,
World Health Organization, 2006 [WHO/HTM/TB/2006.37; WHO/FCH/CAH/2006.7].
19. Getahun H et al. Development of a standardized screening rule for tuberculosis in people living with HIV in resource
constrained settings: individual participant data meta-analysis of observational studies. PLoS Medicine, 2011, 8(1):
e1000391. doi:10.1371/journal.pmed.1000391.
127

preventive therapy for children living with HIV
PICOT Question: What is the optimal duration and drug regimen (e.g. INH, RIF, etc.) for treatment of LTBI to
reduce the risk of TB developing among children living with HIV/AIDS?
Comparison: No IPT
Outcomes: Active TB incidence,
mortality,
progression of HIV disease, adverse events,

adherence, TB drug resistance, interval to active TB,
interval to death
Timeline: Lifetime
Outcomes
Relative score
(rank 1
9 most critical)
Comment
Confirmed TB
Critical
Critical
Active TB incidence (suspected,

probable, confirmed)
Mortality
Adherence
8
7
TB drug resistance
Cost effectiveness
6
6
Adverse events
Interval to death
Critical
Critical
Critical
Critical (addressed by
Annex 11)
Annex 10)
Annex 12)
Less critical
Less critical
128

Pubmed Search (Child[Mesh] OR Child, Preschool[Mesh]) OR Infant[Mesh]) AND Tuberculosis[Mesh])
AND HIV Infections[Mesh]) AND Therapeutics[Mesh]
187
articles
Limits:
Clinical trial, meta-analysis, randomized controlled trial, review, clinical trial, phase I, clinical trial, phase II,
clinical trial, phase III, clinical trial, phase IV, comparative study, controlled clinical trial, evaluation studies,
multicentre study, Medline, PubMed Central, all infant: birth23 months, newborn: birth1 month, infant: 123
months, preschool child: 25 years, child: 612 years
54
By title
By
abstract
Of
interest
International conferences: (CROI, IAS, ICAAC, World AIDS conference) excluding published papers:
ICAAC 2009 and previous: 1
IAS conferences: 2
CROI 2009 and previous: 1
verall, two studies were considered for the

grade analysis.[1,12] One study suggested
significant benefits for children receiving INH
for six months, in particular, with regard to significant
reductions in mortality.[12] However, findings from a
randomized controlled trial conducted in South Africa
showed that when HIV-infected infants with no known
exposure to a TB source case are identified in the
first three to four months of life, given rapid access to
ART and carefully monitored for new TB exposure or
disease on a monthly basis, there is no benefit from
IPT.[1]
129
Therefore, based on this, the Guidelines Group

recommends that all children more than 12 months
of age who are living with HIV and who are unlikely
to have active TB should receive six months of IPT
as part of a comprehensive package of HIV care.
For those children less than 12 months of age, only
those with a history of contact with a TB case should
receive six months of IPT. In contrast to adults and
adolescents, there is no evidence to support the
use of INH for longer than six months in children.
Therefore, the Guidelines Group concludes that until
more data are available, INH for children could not
Annex 14
be recommended for more than six months. Similarly,

there is no evidence on whether repeating a course
of IPT is beneficial for children.
INH should be given at a dose of 10 mg/kg body weight
daily and it is desirable that vitamin B6 be supplied
Weight range (kg)

<5
5.19.9
1013.9
1419.9
2024.9
>25
with INH at a dose of 25 mg daily. All available data

to date suggest that INH is not toxic for children, even
in those receiving ART. The following table shows a
simplified dosing schedule for INH 10 mg/kg/day.
Number of 100 mg tablets of INH

to be administered per dose
Dose given (mg)
1 tablet
100
2 tablets
200
tablet
1 tablet
2 tablets
150
3 tablets or one adult tablet
he Guidelines Group noted that there is no

evidence on the use of IPT in children after
successful completion of TB treatment.
However, like adults, children living with HIV are
exposed to reinfection and recurrence of TB.
Therefore, the Group conditionally recommends that
children who have been successfully treated for TB
and are living in settings with high TB transmission
should receive IPT for an additional six months. IPT
can be started immediately following the last dose
of antituberculosis therapy. Regardless of a history
of TB treatment, TB screening should be carried out
50
250
300
during each contact of the child with a health-care

worker.
The Guidelines Group also concludes that there are no
data regarding the efficacy of IPT for children stratified
by degree of immunosuppression. However, it noted
that there is biological plausibility in extrapolating
what is known for adults and adolescents to children.
Therefore, the Group conditionally recommends the
combined use of IPT with ART for all children. The
Group emphasizes that ART should not be delayed
while starting or completing a course of IPT.
130
131
Design
Limitations
Inconsistency
Indirectness
Randomized trials
No serious
limitations
Randomized trial
No serious
limitations
Serious3
Serious1
Randomized trials
No serious
limitations
Serious1
No serious
indirectness2
No serious
indirectness
No serious
indirectness2
Randomized trials
No evidence
available
No serious
limitations
No serious
inconsistency
No serious
indirectness5
No serious
imprecision
No serious
imprecision
Serious4
No serious
imprecision
Imprecision
None
None
None
None
None
Other
considerations
0/0 (0%)
5/132 (3.8%)
26/358 (7.3%)
3/226 (1.3%)
44/358 (12.3%)
INH prophylaxis
(6 months)
0%
0/0 (0%)
0%
8/131 (6.1%)
10%
31/357 (8.7%)
0.9%
3/226 (1.3%)
5%
45/357 (12.6%)
Placebo
No. of patients
RR 0 (00)
RR 0.62 (0.211.85)
RR 0.84 (0.511.37)
RR 1.5 (0.258.89)
RR 0.97
(0.66091.4384)
Relative risk
(95% CI)
Absolute
0 fewer per 1000

(from 0 fewer to 0
fewer)
0 fewer per 1000

(from 0 fewer to 0
fewer)
0 fewer per 1000

(from 0 fewer to 0
more)
23 fewer per 1000

more)
16 fewer per 1000

more)
14 fewer per 1000

more)
4 more per 1000

(from 7 fewer to 71
more)
7 more per 1000

more)
1 fewer per 1000

more)
4 fewer per 1000

more)
Summary of findings
Effect
Opposite direction of the effect.

P1041 (Madhi et al.) represents an optimal HIV care setting, with capacity to diagnose infectious diseases and good facilities to rule out
active TB: children were younger, healthier and presented in a less advanced stage of the disease. The study by Zar et al. represents the
most common condition in rural areas with a later diagnosis, children presenting in a more advanced stage of the disease and challenging
TB diagnosis.
3
One trial available
4
Wide confidence intervals
5
Raw data are missing for P1041 (but no significant difference was reported between the two groups).
Adverse reactions (grade 3 or 4 toxicity) (follow up 5.79 months; clinical and laboratory monitoring)
Mortality (all causes) (follow up 5.79 months; review of hospital records and patients files)
Confirmed TB (follow up 5.79 months; culture-proven)
Active TB (follow up 5.79 months; clinical algorithm criteria, chest X-ray, bacteriological isolates from any site)
No. of
studies
Quality assessment
Q3.1 Efficacy in children

Question: Should INH prophylaxis (six months) vs placebo be used in HIV-infected children (PPD-positive or TB-exposed)?
Settings: High HIV/TB prevalence country
Bibliography: Zar et al. 2007; Madhi et al. 2008
HIGH
MODERATE
LOW
MODERATE
Quality
CRITICAL
CRITICAL
CRITICAL
CRITICAL
CRITICAL
Importance
3. GRADE profiles and summary of findings
Annex 14

HIV-infected children who are unlikely to have active TB should receive six months of IPT.
Population: HIV-infected children
Intervention: 69 months of IPT (1020 mg/kg plus vitamin B6 25 mg daily)
Action: Concerns regarding the development of isoniazid resistance should not be a barrier to implementing IPT
programmes.
Factor
Quality of evidence
Decision
Moderate
Explanation

Benefits or desired
effects
Risks or undesired
effects
Strong

Strong
The evidence for provision of IPT in children is still

inconclusive (GRADE moderate)
69 months of INH prophylaxis is the only regimen that has
been investigated so far in this specific population.
No specific biological reasons to think that IPT in children
would be less effective than in adults
Reduction in TB incidence
Reduction in TB transmission (even if children are less likely
to transmit)
Reduction in mortality (Zar et al. GRADE moderate)
especially in children with advanced disease in whom TB
may remain undiagnosed
Avoids side-effects of TB treatment
Reduction in drugdrug interactions between drugs for TB
treatment and ARVs in children on ART
Improved TB infection control in health-care and community
settings (particularly in HIV clinics)
Increase in unnecessary treatment (especially when TST is
not performed or in case of false-positive TST where TST is
performed)
Potential INH toxicity (even if both randomized controlled
trials are reassuring on this)
Potential development and transmission of INH-resistant
strains by treating undiagnosed TB (especially in children
with more advanced disease where ruling out TB might be
even more challenging)
Reduction in compliance with other treatment (ART, cotrimoxazole, etc.)
Avoids active TB disease as well as deaths and disease

transmission to other family members
Health-care workers would be less exposed to active TB
cases and would feel more protected (less of a problem in
children as they are considered to be less contagious)
Infection control for patient (less of a problem in children as
they are considered to be less contagious)
Avoids all the daily implications of long TB treatment with
high pill burden and significant side-effects
Parents would feel their children were protected against TB,
adding value to HIV programmes
BUT
May be worried about side-effects of INH
Pill burden
Stigma
132
Factor
Decision
Explanation
Feasibility
Strong
Overall ranking
of recommendation
Strong
Costs
133
Weak
Increased by:
Costs of diagnosing LTBI (TST)
Costs of INH (including storage, supply and transportation)
Monitoring liver function tests (if standard monitoring or in
case of toxicity)
Additional staff in ART settings are already overloaded by
routine activities
Need for second-line TB treatment in case INH resistance
occurs and is transmitted
Costs for INH-related toxicity (blood tests, hospitalizations,
parents loss of earning)
Additional costs of providing vitamin B6
Decreased by:
Avoiding active TB treatment costs
Less cost of hospitalizations
Reduction in social costs and loss of parents earnings
Reduction in costs due to treatment of secondary cases
including in health-care workers, improving staff retention
Reduction in costs achieved by preventing TBART cotreatment including potential need for a more expensive
regimen and possible ART failure
Dose adjustment would require more frequent follow up
Drug easily available and cheap

Administration fits well with the schedule of HIV
programmes
Does not require strict monitoring (laboratory)
Health-care workers would already be familiar with the drug
BUT
Lack of child-friendly formulation for infants and very small
children
Would mean adding an intervention to an overburdened
system
May increase clinic visits and require more staff
Space required for storage and difficulties in procurement
INH single formulation less easily available compared to
fixed-dose combinations (FDCs)
Difficult to overcome health-care workers reluctance to use
IPT
Health-care workers need to be trained in conducting and
reading TST or IGRA
Dose adjustment would require more frequent follow up
Annex 14
Figure 2. Algorithm for TB screening in children more than one year of age and
living with HIV
Child more than 12 months of age and living with HIV*
Poor weight gain
Fever
Current cough
Contact with a TB case
Yes
No

No
Give IPT
Yes
Defer IPT
Other diagnosis
Not TB
TB
Give
appropriate
treatment and
consider IPT
Follow up
and
consider IPT
Treat
for TB
Screen for TB regularly
FOOTNOTES TO ALGORITHM FOR CHILDREN

* All children and infants less than one year of age should be provided with IPT if they have a household contact history with a TB case.
Poor weight gain is defined as reported weight loss, or very low weight (weight-for-age less than 3 z-score), or underweight
(weight-for-age less than 2 z-score), or confirmed weight loss (>5%) since the last visit, or growth curve flattening
Contraindications include: active hepatitis (acute or chronic) and symptoms of peripheral neuropathy. Past history of TB should not
be a contraindication for starting IPT. Although not a requirement for initiating IPT, TST may be done as part of eligibility screening in
some settings.
Investigations for TB must be done in accordance with existing national guidelines.
References
1. Madhi SA et al.; and the P1041 Team. Lack of efficacy of primary isoniazid (INH) prophylaxis in increasing tuberculosis
(TB) free survival in HIV-infected (HIV+) South African children. 48th ICAAC/IDSA 46th annual meeting, 2008 [G21346a].
2. Martinez Alfaro EM, et al. [Evaluation of 2 tuberculosis chemoprophylaxis regimens in patients infected with human
immunodeficiency virus. The GECMEI Group]. Medicina Clinica (Barc), 2000, 115:161165.
3. Martinson NB et al. Novel regimens for treating latent TB in HIV-infected adults in South Africa: a randomized clinical
trial. 16th Conference on Retroviruses and Opportunistic Infections, Montreal, 811 February 2009 [Paper 36bLB].
2457.
Lancet, 1993, 342:26872.
7. Quigley MA et al. Long-term effect of preventive therapy for tuberculosis in a cohort of HIV-infected Zambian adults.
AIDS, 2001, 15:215222.
8. Rivero A et al. [A randomized trial of three regimens to prevent tuberculosis in HIV-infected patients with anergy].
Enfermedades Infecciosas y Microbiologia Clinica, 2003, 21:287292.
9. Rivero A et al. [Randomized clinical trial investigating three chemoprophylaxis regimens for latent tuberculosis
infection in HIV-infected patients]. Enfermedades Infecciosas y Microbiologia Clinica, 2007, 25:305310.
10. Samandari T et al.; on behalf of BOTUSA IPT study. Preliminary results of the Botswana IPT Trial: 36 months vs. 6
months isoniazid for TB prevention in HIV-infected adults. 40th Union World Lung Conference, Cancun, 2009.
of Medicine, 1997, 337:801808.
12. Zar HJ et al. Effect of isoniazid prophylaxis on mortality and incidence of tuberculosis in children with HIV: randomised
134
Annex 15: Summary of findings and quality of evidence

evaluation: selected research gaps

The optimal timing for starting IPT and whether/

when to combine it with ART should be further
investigated, with particular attention to the
possible benefits and risks for patients already on
ART. In addition, the possibility of discontinuing
INH once immunological recovery has been
achieved would be of great interest.
The efficacy, safety and tolerability of a longer
regimen of INH prophylaxis should be addressed
in the paediatric population.
Potential co-formulation of INH with cotrimoxazole should be made available and
longitudinal data on its effectiveness collected.
The potential impact of INH monoresistance
on IPT and possible efficacy of subsequent TB
treatment should be assessed.
Operational research should be conducted on
scaling up the implementation of IPT.
Programmes implementing IPT as part of HIV
prevention and care should be monitored and
evaluated.
Mathematical modelling to evaluate the
effectiveness of IPT should be planned,
including examination of the risks and benefits
with particular attention to benefits stratified by
TST status.
A proper cost-effectiveness analysis addressing
different strategies for provision of IPT and TST
should be performed.
The optimal frequency of screening people with
HIV for active TB with a symptom questionnaire
and the timing of repeat TST in HIV-positive
individuals receiving ART should be addressed.
The algorithm for intensive case-finding in
children should be validated.
Limited studies have evaluated the clinical
utility of IGRA in persons with HIV and, to
date, no evidence is available to warrant its
programmatic use in resource-limited settings
as a screening test before IPT. There is a clear
need for longitudinal studies that assess the
ability of IGRA to identify people at high risk for
135
developing active TB or those who would benefit

from treatment of LTBI. Because of concerns
about the impact of immunosuppression on the
performance of IGRA, it would be most useful
if such studies included persons with both high
and low CD4 cell counts and provided results
stratified by CD4 cell count. Longitudinal
assessment with serial measures is required to
elucidate the clinical significance of discordant
IGRA and TST, and the predictive value of IGRA
for M. tuberculosis infection among HIV-infected
persons.
Better diagnostics for children should be
identified. Prospective studies using cases of
bacteriologically confirmed TB and appropriate
controls including children not suspected of
having TB would be needed to evaluate the
diagnostic value of TB symptoms.
Although some studies have evaluated different
aspects of the TST in the general population and
among HIV-infected persons, very few studies
have provided information on the feasibility of
using TST in resource-poor settings. No studies
have evaluated the actual costs involved in largescale TST screening among people with HIV
infection, and the overall burden of performing
TST on already overstretched health systems in
resource-poor settings.
The stability of tuberculin from the point of
manufacture to the point of use should be
assessed, especially under natural environmental
conditions in developing countries where facilities
for refrigeration are not readily available.
The reliability of other categories of health-care
professionals in reading TST results, particularly
in the HIV-infected population, needs to be
evaluated. Efforts are currently being made in
the area of task-shifting with the overall goal of
scaling up HIV prevention, care and treatment
activities. Different strategies are also needed
to reduce the proportion of patients who fail to
return for the TST results to be read.

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Guidelines for intensified

(for web posting and CD-Rom distribution in tandem

Guidelines for intensified

(for web posting and CD-Rom distribution in tandem

WHO Library Cataloguing-in-Publication Data

(NLM classification: WF 220)

World Health Organization 2011

Summary of declarations of interest

Annex 2: WHO guidelines group

Annex 7: Summary of findings and quality of evidence evaluation: secondary prophylaxis

Annex 10: Summary of findings and quality of evidence: INH resistance

Annex 12: Summary of findings and quality of evidence: cost effectiveness

Annex 15: Research gaps

Annex 1: WHO guidelines meeting on preventive therapy

and case-finding for TB in people living with HIV: list of participants

Kevin De Cock (Co-chair)

WHO REGIONAL OFFICES

WHO SECRETARIAT, HEADQUARTERS

Suzanne Hill (Co-chair)

Haileyesus Getahun (Guidelines Coordinator)

Reuben Granich (Guidelines Coordinator)

Annex 2: WHO guidelines group

Annex 3: WHO guidelines meeting on preventive therapy

and case-finding for TB in people living with HIV: meeting agenda

Meeting overview and introductions

Rationale and review process of guidelines

Overview of GRADE methodology and review of PICOT questions for

GRADE profiles, systematic reviews and draft recommendations for

Discussion: Open to the floor

GRADE profiles, systematic reviews and draft recommendations for

Discussion: Open to the floor

GRADE profiles, systematic reviews and draft recommendations for

Working group session

Report back from Groups A, B, C:

GRADE profiles, systematic reviews and draft recommendations for

Discussion: Open to the floor

GRADE profiles, systematic reviews and draft recommendations

Discussion: Open to the floor

GRADE profiles, systematic reviews and draft recommendations for

Discussion: Open to the floor

Working group session (contd)

Report back from Groups A, B, C:

Paediatrics and IPT

Wrap-up of major conclusions, recommendations

Consultation for the

Report on the consultation for the revision of the

16 November11 December 2009

Consultation for the

Global Network of People Living with HIV

Results and findings

Results and findings

Conclusions and Recommendations

he Global Network of People living with HIV

living with HIV who donated their time and made

his report represents the key findings and

preventive therapy as indicated in the 1998 Policy

he online e-consultation organized by GNP+

Each week, the e-consultation focused on a different

GNP+ invited 306 HIV-positive advocates

Week 1: (1622 November) Treatment initiation

Week 2: (2329 November) Access to treatment

uilding on the experience of undertaking