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Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators

APPENDIX 1

HIV Drug Resistance Early


Warning Indicators: Summary
from 50 countries 2004-2009

Diane Bennett, MD MPH

Epidemiology and Strategic Information


Branch
DGHA
CDC, Atlanta, GA

Background: HIV Drug Resistance


(HIVDR) Early Warning Indicators (EWI)
50 countries monitored HIVDR EWI in cohorts starting
ART between 2004-2009
Most countries monitoring EWI in multiple years did
not monitor in the same clinics, so trends cannot be
analyzed

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Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011

50 Countries monitored HIVDR EWI


as of January 2010 and reported results to WHO

Countries monitoring <3 EWI Countries monitoring 4-5 EWI

Countries monitoring >6 EWI

EXAMPLE of COUNTRY ADULT EWI RESULTS

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Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators

EWIs 1-4 by region 2004-2009


N= number of sites monitored

EWIs 5,6,8 by region 2004-2009


N= number of sites monitored

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Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011

Pediatric EWI were only monitored by a


few countries
Country Regio Number EWI EWI 1: EWI 2: EWI 3: EWI 4: EWI 5: EWI 6: EWI 8:
n of Cohort % % % % % % %
Clinics Year or Clinics Clinics Clinics Clinics Clinics Clinics Clinics
Monitor Years Meeting Meeting Meeting Meeting Meeting Meeting Meeting
ed Target Target Target Target Target Target Target
Botswana AFR 19 2008-20 100 78.9 93.75
09
Cambodia WPR 9 2007 100 100 86 57 89.00
(N=7) (N=7) (N=7)
Cambodia WPR 25 2008-20 100 100 92 76 88.00
09
Dominican LAC 4 2009 75 100
Republic
Thailand SEAR 296 2008 90.5 73.6 68.5 67.4

Viet Nam WPR 4 2006- 75 100 100 75 75.00


2007
Zimbabwe AFR 2 2006 50 100 50

Results summary
EWIs 1-3 (prescribing practices, loss to follow-up and
retention on first-line ART at 12 months,
respectively) were monitored at 93%-99% of clinics.
EWI 5 (on-time appointment-keeping) was monitored
in 65% of clinics
EWIs 4 and 6 (on-time ARV pickup and ARV supply
continuity, respectively) at a minority of clinics (17%
and 34%, respectively).
EWI 8 (viral load at 12 months) was monitored in 2%
of clinics.
EWI 7 (pill count) was monitored by only two
countries (<1% of sites) and data were not included
in our analyses.

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Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators

Results summary 2
Among participating clinics, most in Africa and Asia met
the target for EWI 1, prescribing practices (all >73%). In
Latin America and the Caribbean (LAC), 46% of clinics
met the EWI 1 target.
Overall, 69% of clinics met the target for EWI 2 (loss to
follow-up), and 67% met the EWI 3 target (retention on
first-line ART).
17% of 352 clinics met the EWI 4 target (on-time drug
pickup). In Africa, 15% of 321 clinics met the target; in
Asia, 0% of 10 clinics met the target; in LAC 57% of 21
clinics met the target.
58% of clinics met the target for EWI 5 (on-time
appointment keeping).
65% of clinics met the EWI 6 target (ARV supply
continuity). Of the 100 clinics in Asia that monitored EWI
6, 89% met the target.

Results summary 3:
Pediatric EWI
Six countries monitored pediatric EWIs 2006-2009
Thailand contributed 296 (89%) of 331 sites
monitored.
High percentages of clinics in all countries met
targets for EWIs 1 and 2.
Lower percentages were reported by some countries
for EWI 3 and EWI 5.
No countries monitored EWI 4; only two countries
monitored EWI 6.

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Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011

Discussion
Regional and global results were heavily influenced
by country-specific data. For example, Thailands
EWI monitoring contributed 902 (43%) of 2,107 adult
clinics in this analysis, and 296 (89%) of 331
pediatric clinics.
Few countries monitored EWI 7: standardized
adherence
Few countries had the capacity to monitor EWI 8:
viral load, because most countries do not perform
viral loads routinely.

Discussion
Only 21/50 countries (42%) had records enabling
abstraction of on-time antiretroviral drug (ARV)
pickups (EWI 4).
Many countries could not monitor all their selected
EWIs in all sites because of medical and pharmacy
record limitations.
Many countries took action to improve records and
clinic/program functioning following EWI monitoring.
Examples follow.

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Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators

Quality of Records

In Malawi, all the EWI could not be monitored


in 2006-2007.
Since that time, record systems and supervision
have been revised to ensure that all EWI (with the
exception of EWI 8) can be monitored.
In China, staff had difficulty abstracting EWI.
Based on the new definitions of EWI, China
has improved its web-based ART
information system. An extension of EWI
monitoring in 46 sites in 4 provinces is
currently being implemented.

Losses to follow-up

In Kenya, none of the 18 clinics monitored met the


target for on-time appointment attendance for
patients starting ART in 2007.
A community health worker system to trace defaulters was
implemented.
The Ministry of Health and Social Services in Namibia
identified migrant workers as being at risk of being
lost to follow-up.
The MOH planned an intensification of existing defaulter
tracking systems through improvements in its electronic
record keeping system and the establishment of a national
patient database with unique identifiers, and increased
mobilization and redistribution of human resources

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Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011

Conclusions
As pediatric ART is scaled up, monitoring of
pediatric EWI will become increasingly
important.
EWI have been monitored in 50 countries,
generating results that supported public
health actions at a clinic and program level.
Our task here is to prioritize and simplify the
EWI to make them and the process of
abstraction.
Representative sampling of sites should also
be a priority.

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Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators

APPENDIX 2

Routine data collection and use of


HIV DR Early Warning Indicators
as an integral strategy to optimize
HIV Care and Treatment in Viet Nam

Masaya Kato, WHO Viet Nam


WHO HIV DR Early Warning Indicator Advisory Meeting
Geneva, 11-12 August 2011

HIV epidemic and response in Viet Nam

Statistics Number of people


Estimated HIV population (2010) 254,400
receiving ART in Viet Nam
Estimated adult ART needs (2010) 102,000
Reported HIV cases (2010) 183,938
People receiving ART (2010) 49,492
HIV prevalence in IDUs (2009) 18.4%

Viet Nam Authority of HIV/AIDS Control


(VAAC)
National AIDS Program (MoH)

Concentrated epidemic
Injection drug use - major driver.
Harm reduction interventions expanded.

Successful ART scale-up


18 times increase, 315 ART sites
But coverage still at 46%

Treatment 2.0 pilot


Decentralization, Integration, POC diagnosis

2|

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Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011

Challenges for HIV care and treatment in Viet Nam

Late treatment initiation common (average baseline CD4


count<100).
Late diagnosis; Lost-to-follow-up between diagnosis and care.
Mortality high in early phase of ART

Limited access and retention


Limited access in closed settings and remote mountainous provinces
Stigma, discrimination, punitive laws against MARPs - barriers for access

Burden of TB, viral hepatitis and drug dependence high


Highly verticalized HIV, TB, MCH programs limited collaboration and
linkages.
Limited availability and complex procedures of drug dependence
treatment.

Sustainability challenges
90% of HIV treatment and care budget funded by external donors.
3 | HIV services delivered through donor projects.

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Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators

HIV DR in Viet Nam

HIV DR country plan 2008-2012

Survey of transmitted HIV DR


Hanoi (2006) low prevalence (< 5%) Hanoi
HCMC (2008) moderate prevalence (5-15%)

Survey of acquired HIV DR


Survey completed at 4 sites
Genotyping not yet conducted

HIV DR early warning indicators (EWIs)


3 annual rounds completed Ho Chi Minh City
(HCMC)
National HIV DR laboratory
Preparation for WHO accreditation underway

5|

HIV DR EWI monitoring - Premises

EWIs can be an integral element of


broader HIV treatment and care
monitoring framework

Involvement of local team critical


to translate data into public health
action

6|

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Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011

Indicators, Indicators, Indicators


Government report
Quality Improvement Project report
VAAC VAAC
program report ARV drug report
PEPFAR
HIVQUAL (Decision 26) (Decision 2051)
project report
500+ indicators !
TQM GFATM
other QI initiative project report
ART site
HIV DR Pharmacovigilance

Cohort Event
HIV DR EWIs
Monitoring

HIV DR UNGASS Spontaneous


monitoring survey Universal Access Reporting

TB/HIV PMTCT

Sometimes different definitions. Efforts to harmonize. Need for core national indicators.

Annual HIV care and treatment


data collection exercise
Set of core indicators across
continuum of care Number of sites
Including EWIs
Year of Adult Pediatric Total
Involvement of regional and local abstraction
teams site site
Capacity building Late
Data use for public health action 17 4 21
2007
3 annual rounds completed
4th round in preparation 2009 27 4 31
Diverse sites included
Funders 2010 38 4 42
Geographical regions
Administration levels
2011 56 6 62
Large scale
Selected sites represented 47% of
national adult ART cohorts (2009)
8|

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Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators

Indicators

Pre-ART ART cohort (at 12 months)


Clinical stage at care ART retention **
enrolment Lost-to-follow-up (LTFU) *
Pre-ART attrition On appropriate 1st line *
Duration from eligibility
diagnosis to ART initiation ART cross sectional
Baseline CD4
TB/HIV
Prescribing practice *
HIV+ incident TB cases
Appointment keeping *
receiving TB and HIV
Treatment ** Supply continuity *

* HIV DR early warning indicators, ** UNGASS indicators

9|

Analysis of National Status


ART retention / attrition (2007 cohort)

ART retention Causes of attrition

(VAAC 2009, 2010) Net cohort = 4531 adults and 313 children at month 12

10 |

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Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011

Analysis of Site Performance


HIV DR EWIs (2010 Round)

Number of sites meeting


HIV DR EWIs WHO Targets
the targets
% Appropriate initial ART regimen
100% 39/42 (93%)
prescriptions

% Lost to follow-up 12 month after


20% 41/42 (98%)
ART initiation
% Persons on appropriate 1st line
70% 35/42 (83%)
ART at 12 months
% ART patients keeping clinic
appointments on time 80% 35/42 (83%)

% Months with no ARV stock outs 12 months 42/42 (100%)

11 |

% Appropriate initial ART regimen prescriptions - 2010

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Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators

% Lost to follow-up 12 month after ART initiation - 2010

28.3%

% persons on appropriate 1st line ART at 12 months - 2010

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Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011

% ART patients keeping clinic appointments on time - 2010

Using data to guide public health action

Data review meeting


Every round
Involving local teams

Guide public health action at sites


Defensive reactions at beginning
Productive discussion emerging
Role of facilitator critical

Analysis of correlates of site


performance
to inform policy and resource
allocation

16 |

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Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators

Summary

EWIs should be an integral element of HIV and health


monitoring framework
Harmonization of indicators, their definition and collection modality
important

EWI data have to be used to inform policy and action

Involvement of local teams in data collection and use critical


Role of facilitators with non-judgemental attitude

Mechanism to ensure data quality


Phased approach to decentralization while building regional/local
capacity

21 |

Additional slides

22 |

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Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011

Multivariate Analysis of Selected Factors


Associated with Dose Non-Adherence (VAS)
11

10

8
Adjusted Odd Ratio

5 5.04
4

3.26
3

2.17
2

1.52
1

No Drug + Alcohol Drug + No alcohol Drug + Alcohol Major Depression (vs


(vs. No Drug + No Alcohol) no/mild)
23 |

Multivariate Analysis of Selected Factors


associated with Dose Non-Adherence (VAS) (cont.)
1.20
Model: -2 Log likelihood=543; R2=0.314
1.15

1.10
Adjusted Odds Ratio

1.06
1.05
1.03
1.00

0.95
0.94 0.94
0.93
0.90

0.85

0.80
Side-effect Chance HLC Information Quality Satisfaction w Social
24 | from HCPs Support Connectedness

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Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators

Using data to guide public health action

Thanh Chau District (An Giang) Ba Dinh District (Hanoi)


- Eligibility diagnosis to ART initiation -

Strengthening of community support Simplification of ART preparation process

17 |

Associations of site characteristics and performance at adult ART sites


Site Patient ART retention at 12 months Lost to follow-up at 12 months

(N) (N) % OR (95% CI) % OR (95% CI)

Regions
Hanoi City 4 406 90.1% 1 3.0% 1
Northern 8 932 79.1% 0.41 (0.21-0.81)* 5.4% 1.86 (0.73-4.73)
Provinces
Ho Chi Minh City 7 2665 82.4% 0.51 (0.25-1.03) 6.0% 2.11 (0.95-4.71)
Southern 8 528 72.2% 0.28 (0.13-0.60)** 6.1% 2.12 (0.64-7.04)
Provinces

Number of patients
>500 7 2829 82.3% 1 5.9% 1
201-500 7 909 82.2% 0.99 (0.62-1.60) 5.5% 0.93 (0.47-1.85)
101-200 6 564 79.6% 0.84(0.53-1.34) 1.6% 0.26 (0.15-0.44)***
<100 7 229 68.6% 0.47 (0.28-0.79)** 12.7% 2.31 (1.26-4.24)**

Sites in Northern and Southern provinces


lower ART retention (vs. sites in the urban center)
Sites with the small number of patients (<100)
lower ART retention / higher LTFU
Sites with the modest number of patients (101-200)
lower LTFU

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Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011

Tools used in Viet Nam

Developed for the first round (2007) based on:


WHO HIV DR EWI draft guidelines (2007)
WHO patient monitoring guidelines (2006)

Some differences vs WHO EWI 2010 guidelines


Sampling
Definition

In 2010 round, Viet Nam tool and WHO electronic


tool were compared at 11 sites.

19 |

Comparison of
Viet Nam tool and WHO electronic tool

Appointment keeping Lost-to-follow-up

R2 = 0.9451 (p<0.0001) R2 = 0.4769 (p=0.0187)

20 |

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Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators

APPENDIX 3

Map of Namibia

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Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011

Background on HIV/AIDS
First 4 cases of HIV were reported in 1986
Strong political will and MoHSS commitment to HIV/
AIDS
Global Fund HIV/AIDS funding since 2004
PEPFAR funding since 2004
Prevalence in general population (15+): 13.3%
(2008/09)
By March 2011, over 92,000 PLHIV and among
whom approximately ten percent (10%) on life
saving treatment
45 main sites providing ART services
Namibia

Eort to prevent HIVDR


Proactive in optimizing patient care and minimizing
HIVDR:
National M+E cohort reporting
Centralized pharmacy distribution system
Implementation of standard paper and electronic
medical records
Strong support from partners

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Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators

Chosen Early Warning Indicators


in Namibia
1. ART prescribing practices; target 100 %
2. Patients lost to follow-up at 12 months; target < 20%
3. Patients on appropriate rst-line ART at 12 months;
target = 0% - assessment of inappropriate switching
4. On-time ARV drug pick-up: target; 90%
6. ARV drug-supply continuity; target 100%

Namibia ART delivery structure


Outreach
DH
site
Outreach
Region HC
site
Outreach
MoHSS Clinic
site
Outreach
Region DH
site

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Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011

ART Clinic selecGon


EWIs are designed to be collected routinely from all
ART clinics within a country, or a large number of
representative clinics
In 2009, clinic selection was balanced with feasibility to
facilitate the learning of critically important lessons
and to facilitate training of the HIVDR TWG in the
methodology.
In 2010 all main ART delivery clinics were chosen for
EWI abstraction in 2010 including clinics that
participated in EWI abstraction in 2009.

2010 EWI AbstracGon


For EWI 1, 2, and 3, data were abstracted centrally
from all sites for ART starters beginning on 1 July, 2008
until the appropriate sample size was reached for each
site; regardless of how many months it took to reach
the appropriate sample size.
For EWI 4, the baseline month of 1 January, 2010 was
selected. Data were abstracted centrally on all patients
consecutively picking up ARV drugs during that month
until the appropriate sample size was reached.
For EWI 6, data were abstracted centrally on stock-
outs of each ARV drug in routine use for 12 calendar
months in 2009

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Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators

EWI AbstracGon process


Use electronic systems available
Generate queries
Validate with paper records and between electronic
systems clean data
Validate queries with WHO team and update queries
accordingly
Abstract data using queries and import into WHO tool
Analyze data
Send to sites for verication (using paper records)
Write report

LTFU with and without ePMS


Clinic % starting first-
line ART lost to
% starting first-line
ART lost to follow-
follow-up at 12 up at 12 months
months (2008-2009)
(2008-2009) Target 20%
Target 20%

1 31/100 (31) 25/100 (25)

2 44/120 (37) 25/120 (21)

3 41/75 (55) 29/75 (39)

4 50/135 (37) 43/135 (32)

5 63/110 (57) 40/110 (36)

6 8/20 (40) 8/20 (40)

7 0/155 (0) 0/155 (0)

8 61/175 (35) 61/175 (35)

9 NA NA

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Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011

Summary of EWI Results


EWI Target Preliminary results
EWI 1: ART prescribing practices 100% 8/29 reached target
(28%)
EWI 2: Patients lost to follow-up at 12 < 20% 15/33 reached target
months (45%)

EWI 3b: Patients on appropriate rst- 0% 0/33 reached target (0%)


line ART at 12 months- assessment of
inappropriate switching

EWI 4a: On-time ARV drug pick-up 90% Limitations on EDT data

EWI 6: ARV drug-supply continuity 100% 0/33 reached targets


using electronic data

Challenges with EWI abstracGon


Data quality issues reliability, completeness,
accuracy
Non-standardized dispensing practices among
pharmacies
Stock-out data not recorded on the EDT
Data validation by the facilities
Denominators dier from EWI to EWI making mega
cohort analysis challenging

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Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators

Challenges with EWI abstracGon


cont
Denitions may not be realistic-
EWI 3 not clear whether measuring adherence or
prescribing practices
Diculty in dening appropriate for EWI 1
Not enough time and resources for central level to
collect data physically annually: decentralized data
abstraction required for sustainability

Plans to strengthen EWI


abstracGon and monitoring
Support routine data validation at facility level
between all available systems
Support communication between stas at the
registration and pharmacy
Provide clear denition of rst line and second line
therapy
Support data validation exercise from central level
when needed

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Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011

RecommendaGons for EWIs 1


After validation process is complete, provide training
where indicated to improve
Prescribing practices
Data quality
Stock maintenance and availability
Handling ARV drug toxicities and switching
Eorts should be made to strengthen existing
standardized defaulter tracking mechanisms

RecommendaGons for EWIs 2


Standardize dispensing practices and recording in
all pharmacies
Use more accurate adherence monitoring
methods
Eorts should be made to strengthen existing
standardized defaulter tracking mechanisms

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Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators

Lessons Learnt
Collecting data annually by central level is dicult
and not sustainable
EWIs must be integrated into routine program
monitoring
EWI exercise helped identify gaps in health
information systems

Future EWI Monitoring in


Namibia (1)
EWI from all sites may be able to be abstracted
centrally in future years utilizing EDT and ePMS
from all sites
Data from all sites will need to be validated by the
sites
EWI abstraction should be expanded to include
outreach sites

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Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011

Future EWI Monitoring in


Namibia (2)
Paediatric EWI: EWI abstraction in 2010 focused on
adults only. Future plans include extraction of
paediatric EWIs from sites providing paediatric ART
using the WHO Paediatric EWI Brieng
Private sites: Engage private sector in developing
national HIVDR evidence base. Consider expanding
EWI data abstraction to existing insurance company
claims data to assess overall private practitioner
function in regards to following national standard
treatment guidelines and assess patient adherence
using on time drug pick-up/MPR

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Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators

APPENDIX 4

Indicators, norm-referencing, criterion-


referencing, mixed methods, and score-carding
Some ways of thinking about indicators that may be useful

Indicators : Naming of parts


Simply a clinical audit indicator has two components :
Criteria : What is being measured
Standard : Level that defines good and bad performance
Indicators tend to be about classification of performance as above or
below a satisfactory level
Both classification and estimation are useful
Where are we? : Classification
Where are we going? : Estimation
How far are we from our goal? : Estimation

Note : Don't confuse criteria and criterion (later)

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Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011

Standards : Norm-referencing
Standards are defined by examination of the performance of existing
programs
Example :
Poor : central value
Good : > central value
May use different summary measures (e.g. above / below Q3)
Problems :
Thresholds my reflect poor existing practice
Failure of aspiration
More about ranking than good or best practice

Standards : Criterion-referencing
Standards are defined by desirable levels of performance :
Usually evidence-based for example
Measles vaccine coverage : 80% highly desirable
Problems :
Need for evidence
sometimes only expert opinion available
or sometimes only expert opinion available

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Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators

Mixed methods
Possible to use mixed methods
Three class indicators :
Poor : central value (mean or median)
Good : from central to criteria-reference
Excellent : criteria-reference
Three class indicators frequently used in private-sector monitoring
and evaluation (corporate metrics) activities and known as
SCORE-CARDING
Sometimes called balanced score-carding balance is a
reference to a mix of indicators addressing a full set of business
processes (i.e. a comprehensive indicator set)

No endorsement of this particular product is intended

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Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011

Score-carding
In brief :
Indicator-set created
Triage system (i.e. standards for poor and excellent) established
Routine data collection
Analysis / presentation by traffic-light method (aim for all green)
Advantages :
Allows mixed method thresholds
Politically clever does not fail everyone at start
Clear presentation of results preferred by managers due to
simplicity of reading / interpretation

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Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators

APPENDIX 5
Systematic Review HIVDR EWI Targets Version 25 July, 2011

Review of published findings relevant to

World Health Organization HIV Drug Resistance

Early Warning Indicator targets

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Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011

Systematic Review HIVDR EWI Targets Version 25 July, 2011

INTRODUCTION

General considerations when setting targets

To monitor and evaluate the effectiveness of HIV programs, routinely collected data is organized

into programmatic indicators. These indicators can guide funders and government agencies on how best

to identify problems and allocate resources within programs. Over 200 indicators have been generated by

different funding agencies for HIV programs, resulting in UNAIDS developing an online registry to

document these indicators at a single source [1]. Many of these indicators are ascribed targets which act

as a yardstick to measure results. The targets aim to provide clarity for all stakeholders (funders,

implementers, beneficiaries) on what is considered achievable within a program.

Within the field of HIV care and prevention multiple United Nations (UN) based agencies have

provided guidance on how to set targets [2-5]. Targets need to be ambitious so as to mobilize increased

resources and effort to improve outcomes, but also be realistic on what can be achieved if specific barriers

are overcome. This advice also supports the development of targets at a national level, helping countries

to: define and prioritize their efforts, promote accountability, reflect priority areas of the national program

and facilitate efforts to mobilize resources. However, there are also global targets in the field of HIV care

such as targets within the UN General Assembly declaration of commitment on HIV/AIDS [6], and the

Millennium Development Goal specific to HIV/AIDS [7].

Early Warning Indicator (EWI) targets

The World Health Organization (WHO) has developed a Global Strategy for HIV Drug

Resistance Prevention and Assessment using a public health approach [8]. The foundation of WHO's

prevention and assessment strategy is the routine monitoring at all ART sites, or a large number of

representative ART sites within a country of HIV drug resistance (HIVDR) early warning indicators

(EWIs). HIVDR EWIs assess factors at antiretroviral therapy (ART) sites which are known to create

situations, which favour the emergence of drug resistant HIV. EWI results may be used to optimize

patient care and make ART clinic- and national program-level adjustments to minimize the emergence of

preventable HIVDR.

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Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators

Systematic Review HIVDR EWI Targets Version 25 July, 2011

The WHO recommends a target for each EWI that facilities should reach to prevent emergence of

drug resistance in ART patients. Current EWI targets are based on a review of the published medical

literature and consensus of international experts. Additionally, it is not recommended that individual

countries set more lenient targets but if countries choose they may set more stringent targets. [9]

Therefore, while EWI targets provide global guidance, their ability to be tailored to national requirements

also renders them national targets.

Current targets were developed in 2004-5 at a time when the provision of free ART in low- and

middle-income countries (LMICs) using a public healthy model of care had only recently commenced.

Since that time there has been rapid scale up of antiretroviral therapy (ART) provision in LMIC treatment

programs [10], and increasing amounts of published research relevant to EWIs in these settings.

This review aims to summarize currently available evidence relevant to HIVDR EWI targets and

whether the evidence supports use of the current targets, or adjustment of the targets.

METHODS

Methods relevant to all EWIs are considered in this section as general methods. Methods specific

to individual EWIs will be detailed under the section for the relevant EWI.

Search strategy

Searches were performed on the online database Ovid MEDLINE for the following EWIs: EWI 2

and 3 (lost to follow up [LTFU] and retention on first line ART), EWI 4 (on time ARV pick-up), EWI 5

(on time appointment keeping), EWI 6 (ART stock-outs) and EWI 8 (virological suppression). We

limited the searches to studies published: in English, from January 2003 to May 2011, and excluded

studies on children (< 13 years old). Our search strategy combined all sets of terms under the following

Medical Subject Headings (MeSH) to identify HIV infected participants receiving ART: HIV or HIV

Infections or Antiretroviral Therapy, Highly Active or Anti-Retroviral Agents. To identify studies

from LMICs we combined all sets of terms under the following MeSH: Africa or Asia or Caribbean

region or central America or Latin America or south America, in addition to the following terms:

resource limited or resource constrained or developing countries or low income countries or low

and middle income countries or africa or afrika or "sub saharan" or southern africa or asia or

latin america or south america.

3
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Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011

Systematic Review HIVDR EWI Targets Version 25 July, 2011

Using search terms specific to the relevant EWI we searched the online conference abstract

databases for the International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention

and the International AIDS Conference (2009-2010) and the Conference on Retroviruses and

Opportunistic Infections (2009-2011).

Reference lists from recent reviews on patient outcomes in resource limited settings consistent

with relevant EWIs were also searched. [11-16]

When more than one study reported on the same EWI in the same cohort of patients we included

the study containing the most detailed information on the EWI of interest. If two studies were considered

complimentary for findings in the one cohort this was noted.

Study selection

We included original research studies or abstracts that reported on HIV infected individuals

receiving combination ART in LMICs. Studies were included if they were specifically designed to report

on the EWI of interest or where it was a secondary finding. Studies could be cross-sectional or cohort

studies, and may be prospective or retrospective. Clinical trials were included for EWIs pertaining to viral

suppression, appointment keeping or adherence (EWIs 4, 5, and 8). Clinical trials were excluded for:

LTFU, retention on first line ART and stock-outs (EWIs 2, 3 and 6) due to the importance of these EWIs

in service delivery, or non-research settings

We excluded studies where most patients were children (defined as < 13 years old), patients

received mono- or dual-therapy, or that were not performed in LMICs

Selected studies could be excluded at one of 3 steps. All titles of identified studies were reviewed

and certain studies excluded, abstracts of remaining studies were then reviewed and further studies

excluded. The final potential point of exclusion was after retrieving and reviewing original research

papers for abstracts not already excluded.

Data extraction and management

For each EWI the following data was extracted to a Microsoft Excel spreadsheet: first author,

year of publication, country or countries, healthcare facility, healthcare setting (public, private, non-

governmental organization), healthcare provider, whether patient pays for ART, dates observed, number

of sites, number receiving ART, baseline demographics (age, gender, CD4 count, clinical stage), ART

regimen, whether ART nave at baseline, study definition of the EWI, proportion meeting study definition

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of EWI, and whether the study definition will likely lead to a lower or higher estimate of the EWI of

interest than the WHO definition of the EWI.

Data analysis

Proportions of patients meeting the study definition of the EWI of interest were derived from text,

and tables within studies. Proportions derived from graphs used the exact value when available, if the

exact value was not available and the proportion was estimated from the graph axes this was noted.

Where appropriate, summary estimates of the proportions obtained from studies were determined by

reporting the median estimate, range of estimates and calculating weighted means, with weighting by

cohort size. Data presented as incidence density (e.g. person years) was converted to cumulative

incidence using standard formulae [17].

EWI 1 - ART PRESCRIBING PRACTICES

EWI Definitions

A summarized definition for EWI 1 and current target are as follows:

Percentage of adult patients initiating ART at the site who are initially prescribed, or who initially

pick up from the pharmacy, an appropriate first-line ART regimen

Suggested target: 100%

Key Questions

Is there data that does not support the initial prescribing of an appropriate first-line regimen?

o A WHO recommended first line regimen [18] would be an example relevant to LMICs

which are:

Triple antiretroviral (ARV) non-nucleoside reverse transcriptase inhibitor

(NNRTI) based regimens

The alternatives are triple nucleoside reverse transcriptase inhibitor (NRTI)

regimens and are only recommended when NNRTIs cannot be tolerated or are

contraindicated in conditions such as pregnancy or HIV-2 infection.

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Discussion

ARV monotherapy has led to reductions in levels of circulating HIV since the first clinical

trials with the NRTI zidovudine in the late 1980s [19] and subsequently protease inhibitors (PIs) in the

mid 1990s [20]. Despite these initial advances, subsequent elevations in HIV viral load and the

development of ARV resistance [21] while receiving monotherapy lead to increasing investigation of

combination ARV therapy. Clinical trials of different ARV combinations reported the superiority of

double NRTIs over NRTI monotherapy [22], and subsequently the combination of 3 ARVs, including

either a protease inhibitor or non-nucleoside reverse transcriptase inhibitor, over double NRTI

regimens [23-25]. In addition, concerns about inferior virological efficacy of triple NRTI containing

regimens versus NNRTI containing regimens [26] has led to recommendations that initial ARV

regimens should contain a minimum of 3 active drugs made up of a double NRTI backbone and a third

non-NRTI ARV, typically a NNRTI or protease inhibitor [PI] [18, 27]. These recommendations are

also consistent with data from an LMIC, Cote dIvoire, where double-NRTI regimens were initiated in

some patients due to the increased cost of triple ARV regimens, with the double-NRTI regimens

having inferior virological efficacy [28].

Justification for current targets or a change in targets

Data is not available to support not prescribing an appropriate first line regimen (e.g. triple

ARV NNRTI based regimen). There is no justification to change the current prescribing practices

target from 100%

EWI 2 - LOST TO FOLLOW UP 12 MONTHS AFTER ART INITIATION, AND

EWI 3 - RETENTION ON APPROPRIATE FIRST LINE ART AT 12 MONTHS

In this review the areas of loss to follow up (LTFU) and retention on first line ART will be

considered in one section. Important findings will be discussed separately for the 2 EWIs. Current

summarized EWI definitions, and key questions this review attempts to answer for these EWIs are as

follows.

EWI Definitions

Summarized definitions for EWI 2 and 3, and current targets:

EWI 2 - Patients lost to follow-up during the first 12 months of ART


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o Percentage of patients initiating ART at the site who are lost to follow-up 12 months after

ART initiation. (Excludes deaths, transfers out)

Suggested target: 20%

EWI 3a - Patients retention on appropriate first-line ART at 12 months

o Percentage of adult patients initiating ART at the site who are taking an appropriate first-

line ART regimen 12 months later (Excludes transfers out)

Suggested target: 70%

EWI 3b - Patients retention on appropriate first-line ART at 12 months

o Percentage of patients initiating ART at the site whose initial ART regimen was changed

during the first 12 months to a regimen that includes a different drug class

Suggested target: 0%

Key Questions:

What is the current reported range and summary estimates of LTFU and retention on first line

when defined in a manner similar to EWIs?

Do these estimates support the currently published targets, or a change to the targets?

Methods specific to EWI 2 and 3

Search strategy In addition to search terms outlined within the general methods section, search

terms used specifically for EWIs 2 and 3 were: attrition or retention or lost to follow up or

all terms under the MeSH patient dropouts. (Appendix 1)

Study selection Studies were included if they report the proportion of individuals LTFU and / or

retained after 12 months of ART. Any definition of LTFU or retention was accepted. Where

cohorts did not report 12 month outcomes but a median duration of follow up, studies were

included if the median duration of follow up was 9 to 15 months. Studies were included if they

reported on ART programs providing service delivery (i.e. non-research settings). The search

strategy and study selection is summarized in Figure 1.

Data extraction and management Definitions used for LTFU and retention were sought from

reviewed studies. Proportions of subjects meeting these definitions were obtained, and if

available; the proportion of subjects who died, transferred out of the ART program, stopped ART

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and switched to second line ART. If this data (death, transfer out, stop, or switch to second line)

was not available this was noted. Due to limitations of available data and to provide consistency

across all studies the denominator in estimates of LTFU and retention obtained from studies

include subjects who died or were transferred out. (i.e. different from EWI 2 and 3 definitions)

Data analysis Median estimate, range of estimates and weighted mean (the summary estimates)

were determined for papers and / or abstracts with any definition of LTFU. The summary

estimates were also determined for papers that defined LTFU most similar to EWI 2; where

median period of follow up was 12 to 15 months, and patients were defined as LTFU when lost

from care 3 or 4 months. Additionally the summary estimates were determined for papers that

defined LTFU in a way that would likely generate lower estimates of LTFU (i.e. classify less

people as LTFU); where median period of follow up was < 12 months,, and / or defined as LTFU

when lost from care 6 months. Lastly, the summary estimates were determined for papers that

reported patient tracing, and for papers where tracing did not occur or was not reported. Estimates

of retention were documented in 3 possible ways: 1) as reported in the study; 2) calculated from

data in the study and including patients transferred out in the numerator (i.e. Retained on ART);

and 3) calculated from data in the study excluding patients transferred out from the numerator

(i.e. Retained on ART at the original site/s). For an estimate of retention to be calculated the

study had to report at least the number of patients who were LTFU and died. If data on transfer

out, ART stop or switch to second line ART was available this data was also incorporated into the

retention estimate. In situations where there was concern with overlap of patient cohorts (multi-

country studies by Medecines Sans Frontieres [MSF], the International Epidemiologic Databases

to Evaluate AIDS [IeDEA], and the WHO) implicated studies were excluded from calculations of

summary estimates. Summary estimates were also calculated for death, ART stop, transfer out

and switch to second line ART.

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Identified studies Identified studies


261 papers 616 conference abstracts

Excluded after Excluded after


reviewing titles reviewing titles
51 papers 312 conference
abstracts
Excluded after
reviewing abstracts
98 papers

Full text review Full text review


112 papers 282 conference abstracts

Included in the review Included in the review


43 papers 22 conference abstracts

43 papers and 22 conference


abstracts included in the review

Figure 1: Search strategy and study selection EWI 2 and 3. Reasons for exclusion were: duplicate, not

on ART, not HIV infected, research setting (not service delivery), not a study of patient outcomes, not

LMIC, insufficient information, study of children

Results

In total 65 studies were identified that met inclusion criteria, 43 papers (Table 1) [29-71] and 22

conference abstracts. (Table 2) [72-93] Studies reported on 21 countries from sub-Saharan Africa, 4

multi-country cohorts from sub-Saharan Africa, 4 countries from South East Asia, 1 from South America,

1 from Eastern Europe and 1 worldwide multi-country cohorts.

In regard EWI 2, LTFU ranged from 0.3 - 34.8% across all studies (n=213,821), and in 8 cohorts

where the definition of LTFU was most similar to EWI 2 the range was 0.3 - 31.9% (n=43,871) [30, 35,

39, 43, 45, 48, 53, 56, 59, 61, 65, 67]. (Table 3) In 9 papers where the definition of LTFU would most

likely lead to lower estimates of patients lost, the range was 1.7 34.8% (n=58,810) [41, 44, 46, 47, 50,

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52, 57, 66, 71]. Weighted means of LTFU across these 3 categories were similar: 14.7% across all

studies, 12.1% when defined similarly to EWI 2 and 14.7% in studies that would likely lead to lower

estimates of LTFU than EWI 2. Studies that reported patient tracing had a lower weighted mean LTFU of

8.1% and a range of 0.3 18.5% (n=21,265), while studies without patient tracing or those not

mentioning whether patient tracing occurred had a weighted mean LTFU of 15.4% and a range of 0.8

34.8% (n=192,556).

In addition to the numbers who died and were LTFU, critical to interpreting estimates of retention

on first line ART is understanding the number of patients who transferred out, stopped ART, or switched

to second line therapy. (Table 3) 14 studies reported the proportion of patients transferred out with

retention ranging from 60.6 91.6% (n=17,908) when including patients transferred out, and a range of

49.7 89.1% when excluding patients transferred out. Weighted mean estimates of retention for these 2

categories are 81.0% and 73.3% respectively. When considering all studies that either reported a

proportion retained or where retention could be calculated from study data 61 studies, made up of 83

cohorts (n=535,438), were identified. In this large group of patients the range of estimates for retention is

49.7 91.0% with a weighted mean of 77.1% patients retained (retention estimates calculated from study

data excluded transfer out, stop or switch if reported). Performing the same analysis less 1 study that

accounted for the majority of subjects [87] (n=253,134), did not change the range of estimates and

resulted in a similar weighted mean of 75.4%.

Of the reviewed studies, only a small number reported on switch to second line ART or ART

stop. 5 studies reported on patients switching ARV class or to second line treatment; 3 studies with 1%

switch [39, 54, 56], 1 study with 2% switch [61] and 1 study with 7% switch [47]. With a weighted mean

of 2.0% switched (Range 0.2 7.0%). 9 studies (29 cohorts) reporting ART stop resulted in weighted

mean of 2.7% stopped ART (Range 0.3 8.5%). 49 studies, made up of 71 cohorts and 511,608subjects,

provided estimates of the proportion of subjects who died, and ranged from 0.5 29.7% with a weighted

mean of 6.4%. However, excluding 1 study that accounted for the majority of subjects [87] (n=253,134)

the weighted mean for death from the remaining 36 studies increased to 7.7%.

Discussion

Weighted means for LTFU are consistently 12 - 15% when any definition of LTFU is accepted or

when studies are separated into groups that have more lenient or stringent definitions of LTFU. It is not

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clear why estimates of LTFU are similar among groups with different durations of follow up and periods

lost to care, and whether studies with short duration of follow up (< 12 months) and longer periods lost (

6 months) would have different summary estimates for LTFU if definitions similar to EWI 2 were used.

Further, studies that reported patient tracing programs had the interesting but not unexpected finding of a

lower weighted mean LTFU (8.1%), compared to programs without, or not reporting tracing (15.4%). An

understanding of whether patient tracing is present within an ART program or at a site may therefore be

important when accurately interpreting LTFU data.

A critical difference between the presentation of this data, and EWIs 2 and 3 is how the

proportion LTFU or retained is calculated. In the data presented, the denominator of the proportion is all

individuals who started ART, unlike EWI 2 where patients who have died or transferred out are excluded

and EWI 3a where patients transferred out are excluded. How this reflects on targets for these EWIs can

be demonstrated by using the following weighted means derived from this review: LTFU 15%, died 8%,

transfer out 8%, switch 2% and stop ART 3%. By excluding death and transfer out in EWI 2 these

categories have to be excluded from both numerator and denominator, hence the proportion LTFU using

EWI 2 changes from 15% , to 15 / (100 8 8) = 18%. A similar discussion about retention is more

complicated due to the different ways summary estimates for retention can be determined. Summary

estimates for retention calculated in this review include many studies where only LTFU and death were

excluded from the total number of ART starters which could lead to increased estimates of retention

compared to calculating retention by subtracting the summary estimates for the different sub-groups of

those not retained (i.e. LTFU, died, transfer out, switch and stop). Additionally, in many other included

studies the study definition of retention is accepted and the method for calculating retention is not

reported, also potentially leading to increased estimates of retention if the study definition did not

incorporate the different sub-groups for those not retained. If we take the approach where we consider all

the sub-groups relevant to EWI 3a we will likely gain the most stringent definition of retention. Therefore

based on these summary estimates (LTFU 15%, died 8%, transfer out 8%, switch 2% and stop ART 3%)

and the fact that EWI 3a excludes transfer out from the analysis we derive the following for retention;

(100 15 8 8 2 3) / (100-8) = 70%. Importantly only 2 of the 83 studies actually report all these

relevant sub-groups [39, 54] suggesting caution when interpreting this most stringent definition of

retention based on the weighted means of LTFU, transfer out, switch and ART stop derived from

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different groups of studies. An alternate approach would be to consider the proportion retained in the 14

studies that reported the proportion transferred out, importantly only 3 of these studies report on ART

switch [39, 47, 54] and 5 on ART stop [35, 39, 50, 54, 58]. Therefore, if we take the weighted mean for

those retained on ART at the original site (73%), and adjust this proportion to also exclude transfer out

from the denominator; 73 / (100 8) = 79% could also act as a new adjusted figure for retention on ART

at the original site. Lastly, overall retention rates reported from all studies, weighted mean 77%

(n=535,408), without further adjustment may provide the most powerful representation of average levels

of retention in LMICs.

Justification for current targets or a change in targets

EWI 2 the current target of 20% is below average rates of LTFU from available data even

when this data is manipulated to account for the EWI definition excluding death and transfer out.

Lowering this target to 15% using the same EWI definition (excluding death and transfer out)

would be consistent with current average rates of LTFU in the reviewed data. As EWI targets act

as guidance for countries to not set more lenient targets but can set more stringent targets if they

choose, a new EWI 2 target of 15% would guide countries to achieve no worse than the average

rate of LTFU based on the current literature.

EWI 3a the current target of 70% retention using the EWI definition is consistent with average

rates of retention even when using the most conservative method to calculate retention

(subtracting all subgroups not retained [LTFU, died, transfer out, switch, stop] from 100%).

However, very few studies report using this stringent definition and alternative methods for

considering average numbers of individuals retained suggest levels of retention of 75-80%.

Increasing this target to 75% would more accurately reflect average retention using the EWI

definition, and would act as a target under which more lenient retention targets would not be

recommended.

EWI 3b Only 5 studies reported on patients switching ARV class or to second line treatment

and all reported small numbers of patients switching. Despite only a small number of studies

being available the current target of 0% may be too stringent based on this data. Increasing this

target from 0% to 2% would make the new target consistent with the average switch to second

line ART from the reviewed literature.

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EWI 4 ON TIME ARV PICK UP

Current summarized EWI definitions, and key questions this review attempts to answer for this

EWI are as follows.

EWI Definitions

Summarized definitions for EWI 4, and current targets:

EWI 4a - Percentage of patients picking up prescribed ARV drugs on time (3 consecutive pick-

ups [baseline + 2 further pick-ups])

Suggested target: 90%

EWI 4b - Percentage of patients initiating ART at the site who picked up all prescribed ARV

drugs on time during their first 12 months of ART

Suggested target: 90%

Key Questions:

What is the current reported range of estimates for picking up all prescribed ARVs on time when

defined in a manner similar to the EWI?

Do these estimates support the currently published targets, or a change to the targets?

Methods specific to EWI 4

Search strategy In addition to search terms outlined within the general methods section, search

terms used specifically for EWI 4 were: compliance or adherence or all terms under the

MeSH Medication Adherence or Patient Compliance, AND the terms pill count or pick

up or on time or MPR or medication possession or drug possession or all terms under

the MeSH Pharmacy or Prescriptions. (Appendix 2)

Study selection Studies were included if they reported Pharmacy Adherence Measures

(Medication Possession Ratio, Pill Count or Pill Pick-up) where the duration of adherence

assessment was from 3 12 months. Where the duration of adherence assessment was the first 12

months of ART these studies were considered comparable to EWI 4b with other studies

comparable to EWI 4a (3 consecutive ARV pick-ups). As EWI 4 measures the proportion of

patients who have picked up all their ARVs on time (either over 3 pickups or 12 months), only

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studies where the proportion of patients 100% adherent by a Pharmacy Adherence Measure

(PAM) were included. This prerequisite was imposed because a patient <100% adherent by a

PAM will not have picked up all their ARVs on time. The search strategy and study selection is

summarized in Figure 2.

Data extraction and management Definitions for the PAM and the proportion of patients

meeting that definition were obtained from selected studies. While the proportion of subjects who

died or were LTFU was reported in some studies adherence estimates were not reported for these

patients, hence all adherence data retrieved was for patients that were alive and actively enrolled

in ART programs. One study did collect adherence data on some patients who were subsequently

LTFU, died or transferred out, but importantly the duration of adherence assessment for these

patients only included the period from ART start until the last visit in the clinic [67].

Data analysis The list and range of estimates for included studies was determined. Due to the

small number of heterogeneous studies fitting inclusion criteria weighted means were not

calculated.

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Identified studies Identified studies


55 papers 116 conference abstracts

Excluded after Excluded after


reviewing titles reviewing titles
10 papers 66 conference
abstracts
Excluded after
reviewing abstracts
10 papers

Full text review Full text review


35 papers 50 conference abstracts

Included in the review Included in the review


6 papers 1 conference abstracts

6 papers and 1 conference


abstracts included in the review

Figure 2: Search strategy and study selection EWI 4. Reasons for exclusion were: duplicate, not on ART,

not HIV infected, not a study of patient outcomes, not LMIC, insufficient information, study of children,

inappropriate study type

Results

In total 7 studies were identified that met inclusion criteria, 6 papers [37, 67, 94-97] and 1

conference abstract [98] (Table 4) Studies included 2 single country cohorts from sub-Saharan Africa, 3

multi-country cohorts from sub-Saharan Africa, 1 from Asia and 1 from South America.

Four studies were included for EWI 4a and all had a duration, or median duration, of adherence

assessment of approximately 6 months. The range of estimates for 100% adherence ranged from 43

64% in these 4 studies (n=11,714). (Table 5) The 3 studies reporting the proportion 100% adherent for

patients receiving their first 12 months of ART, had estimates ranging from 12 28% (n=30,603). Study

definitions were all deemed to potentially create higher estimates of on time ARV pick-up than the EWI

definition. Reasons included the selection of a population who had already achieved virological

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suppression and were likely more adherent [96], or exclusion of individuals that subsequently died or

became LTFU who would likely be less adherent [37, 94, 95]. One study that included subjects who

became LTFU was also different from the EWI definition in that the assessment of adherence concluded

at the last time the patient visited the clinic, compared to the EWI definition where patients who become

LTFU after a baseline ARV pick-up are classified as not picking up their pills on time [67].

In the process of reviewing studies for inclusion it became apparent that many studies reported

the proportion of study subjects who were > 90 or 95% adherent but did not report the proportion of

subjects who were 100% adherent. While the literature search did not focus on identifying studies

reporting the proportion of patients with > 90 or 95% adherence, a number of papers were identified

where this was the case. Therefore, summary estimates for those > 95% adherent have been presented

from a group of papers to help interpret current EWI 4 targets and definitions. A systematic review of the

abstracts and any remaining papers may identify more studies reporting the proportion for subjects with >

95% adherence. Therefore, 8 studies (11 cohorts) were identified that fitted the original inclusion criteria

for studies comparable to EWI 4a, [67, 94, 99-104] and 5 studies for EWI 4b, [37, 95, 102, 105, 106] but

differed by reporting a proportion of patients > 95% adherent. The range of estimates were appreciably

higher, 49 89% for EWI 4a (n=14,723), and 37 87% (n=31,340) for EWI 4b using this new adherence

threshold. An alternative presentation of this data is stating that; 7 of the 11 estimates for the > 95%

threshold for EWI 4a were higher than all the estimates for the 100% threshold, and all the estimates with

the > 95% threshold for EWI 4b were higher than all the estimates for EWI 4b with the 100% threshold.

Discussion

Conclusions regarding targets for EWI 4 are limited by the number of studies available reporting

the proportion of subjects that are 100% adherent. Despite the small of number of studies, the target of

90% of patients being 100% adherent over a period of 3 pick-ups (EWI 4a) or the first 12 months of ART

(EWI 4b) appears too high, but the limited data does not provide clear guidance on how to revise this

target downwards. An alternative approach to adjusting the current target based on picking up all ARVs

on time would be to review studies looking at an altered definition of the EWI where the threshold of

adherence is lowered to 90 or 95%. Estimates of adherence in LMICs in general are higher than high

income countries (HICs), so there is the potential for considerable variability in the proportions meeting

these different high adherence thresholds (i.e. > 90%, 95%, or 100% adherence) [107]. In addition,

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studies are more likely to report the proportion of subjects 100% adherent when adherence is measured by

self report compared to PAMs where thresholds < 100% are more commonly used [14, 107], adding

further weight to a literature review which focuses on adherence data reporting on thresholds < 100%.The

data presented in this review for a 95% adherence threshold reveals considerably higher proportions of

patients meeting this threshold, and a larger number of available studies to guide the setting of targets

even though all available data (e.g. conference abstracts) were not systematically reviewed for this altered

definition of EWI 4.

Justification for current targets or a change in targets

Based on available data the current target for EWI 4a and 4b appears too high but it is unclear to

what extent the current target should be revised downwards due to limitations of available data.

Alternative approaches to reviewing literature for on time ARV pick-up have been discussed

EWI 5 CLINIC APPOINTMENT KEEPING

Current summarized EWI definitions, and key questions this review attempts to answer for this

EWI are as follows.

EWI Definitions

Summarized definitions for EWI 5, and current targets:

EWI 5 - ART clinic appointment-keeping

o EWI 5a - Percentage of ART patients who attend clinical consultations within 7 days of

the scheduled or expected appointment (3 consecutive consultations)

Suggested target: 80%

o EWI 5b - Percentage of patients initiating ART at the site who attended all clinical

consultations within 7 days of the scheduled or expected appointment during the first 12

months of ART

Suggested target: 80%

Key Questions:

What is the current reported range of rates for attending ART clinic appointment on time when

defined in a manner similar to EWIs?

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Do these estimates support the currently published targets, or a change to the targets?

Methods specific to EWI 5

Search strategy In addition to search terms outlined within the general methods section, search

terms used specifically for EWI 5 were: appointment or attendance or all terms under the

MeSH Appointments and Schedules or Referral and Consultation, AND the terms on time

or date or all terms under the MeSH Time Factors or Chronology as Topic.(Appendix 3).

Study selection Studies were included if they reported on patients attending clinical consultations

(not pharmacy appointments) over as few as 3 months and up to a maximum of 12 months.

Where patients were assessed over the first 12 months of ART these studies were considered

comparable to EWI 5b with other studies comparable to EWI 5a (3 consecutive clinical

consultations). Studies were only included if they reported on patients attending a consultation

within 7 days of the scheduled or expected consultation to be consistent with the EWI definition

of On Time clinic appointment keeping. The search strategy and study selection is summarized

in Figure 3.

Data extraction and management Definitions for clinical appointment keeping and the

proportion of patients meeting that definition were obtained from selected studies. Whether

studies included patients who were subsequently LTFU after their baseline clinical appointment

was sought, as the EWI definition includes these patients and could be a source of variability

between reviewed studies and the EWI.

Data analysis The list and range of estimates for included studies was determined. Median

estimate and weighted mean was calculated for the group of studies most comparable to EWI 5a.

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Identified studies Identified studies


58 papers 233 conference abstracts

Excluded after Excluded after


reviewing titles reviewing titles
26 papers 115 conference
abstracts
Excluded after
reviewing abstracts
21 papers

Full text review Full text review


11 papers 118 conference abstracts

Included in the review Included in the review


2 papers 5 conference abstracts

2 papers and 5 conference


abstracts included in the review

Figure 3: Search strategy and study selection EWI 5. Reasons for exclusion were: duplicate, not on

ART, not HIV infected, not a study of patient outcomes, not LMIC, insufficient information, study of

children, inappropriate study type

Results

In total 7 studies were identified that met inclusion criteria, 2 papers [100, 108] and 5 conference

abstracts [72, 83, 109-111]. (Table 6) Studies included 4 single country cohorts from sub-Saharan Africa,

2 multi-country studies from sub-Saharan Africa, and 1 from Asia.

Five studies were comparable to EWI 5a and 2 studies comparable to EWI 5b. Two papers from

sub-Saharan Africa reported the proportion keeping appointments using different definitions of attending

on time. [100, 108] For both papers the more lenient definition of on time attendance was utilized when

calculating summary estimates (Table 6). The remaining studies reporting on clinical appointment

keeping were all conference abstracts, 1 of which reported a range of estimates in Vietnam using the EWI

definition without reporting one proportion for a single group of patients, hence this study is not included

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as part of the summary estimates [83]. (Table 7) The 7 cohorts contributing to the summary estimates for

EWI 5a all define on time appointment keeping over 3 or 4 months. The proportion on time ranges from

53 93% with a weighted mean of 84.0% (n=13,137), and when the large cohort of Neethling et al

[110](n=9,603) is excluded from this calculation the weighted mean is revised down to 75.8% (n=3,534).

The 2 studies reporting on time appointment keeping over the first 12 months of ART, include one

abstract of a large South African population (n=11,397) where 63% of patients were on time and a

smaller multi-country cohort (n=566) where 70% of patients consistently attended within 8 days of the

scheduled appointment.

Discussion

The selected studies all had similar definitions for on time clinic appointment keeping as both

EWI 5a and 5b. Interestingly all studies relevant to EWI 5a assessed on time appointment keeping over 3

or 4 months with 3 of 5 studies providing estimates where patients could be up to 7 days late to the

scheduled consultation [100, 110, 111]. Only one study definitely included patients who became LTFU

after their baseline clinical appointment [111], as does the EWI definition, but it is unclear how the

inclusion or exclusion of these patients would affect estimates of on time clinic appointment keeping.

Weighted means were calculated using the more lenient definition of on time (up to 3 days late) in the

study by Chalker et al [100] for EWI 5a and by Blacher et al for EWI 5b meaning that the cohorts

contributing to the weighted means included only one cohort (Kenya cohort of Chalker et al[n=373]) that

definitely used the most stringent definition of on time (attending on or before the scheduled

appointment). Therefore, the weighted means provide the most lenient summary estimates available from

the selected studies. For EWI 5a the weighted means happen to straddle the current target for EWI 5a

depending on whether the one study with a disproportionate number of patients [110] is included (84.0%)

or excluded (75.8%) . Both the studies found relevant to EWI 5b provide estimates of on-time

appointment keeping (63 and 70%) below the current recommended target of 80%.

Justification for current targets or a change in targets

EWI 5a Despite the small number of studies available all are defined in a manner similar to

EWI 5a. The current target of 80% is consistent with current average rates of on time clinic

appointment keeping in the reviewed data. Based on this review, maintaining the current target

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would guide countries to achieve no worse than the average rate of on time appointment keeping,

while allowing the setting of more stringent targets if countries so choose.

EWI 5b Due to the lack of data, guidance on this target is unclear. Based on the 2 studies found

the current target appears too high but it is uncertain to what extent the current target should be

revised downwards due to limitations of available data

EWI 6 ARV DRUG SUPPLY CONTINUITY (STOCK-OUTS)

Current summarized EWI definitions, and key questions this review attempts to answer for this

EWI are as follows.

EWI Definitions

Summarized definitions for EWI 6, and current targets:

EWI 6a and 6b - Percentage of months in a designated year in which there were no ARV drug

stock-outs

o Suggested target: 100%

EWI 6c1 Percentage of patients whose regimen was stopped, switched, substituted or

incompletely dispensed due to ARV stock-out in a 12-month period

o Suggested target: 0%

EWI 6c2 Percentage of patients whose regimen was stopped, switched, substituted or

incompletely dispensed due to ARV stock-out during the first 12-monts of ART

o Suggested target: 0%

Key Questions:

Are ARV stock-outs reported at the level of the site or affecting patient populations in LMICs?

Is there data to support the safety of treatment interruptions or switching of ARVs, or ART

regimens, due to a lack of the continuous supply of ARV stock?

Methods specific to EWI 6

Search strategy In addition to search terms outlined within the general methods section, search

terms used specifically for EWI 5 were: stock out or drug supply or stock shortage or out

of stock. (Appendix 4)

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Study selection Studies were included if they reported on stock-outs of ARVs at a site, or

reported on patients whose regimen was stopped, switched, substituted or incompletely dispensed

over a period of 9 15 months. This range was used as all variants of EWI 6, whether they be site

or patient based, assess outcomes over a 12 month period. If patients were assessed over the first

12 months of ART then these studies were considered comparable to EWI 6c2, with other patient

based studies considered comparable to EWI 6c1. Studies using data obtained from pharmacy

records or from patient surveys were included. Due to the potential for recall bias from survey

data to underestimate outcomes, studies were still included where patients were on ART for > 15

months and stock-outs were assessed by patient survey. The search strategy and study selection is

summarized in Figure 4.

Data extraction and management Definitions for ARV stock-outs and the proportion of patients

meeting that definition were obtained from selected studies. If studies also reported associations

of ARV stock-outs with virological or clinical outcomes this was obtained.

Data analysis The list and range of estimates for included studies was determined.

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Identified studies Identified studies


27 papers 178 conference abstracts

Excluded after Excluded after


reviewing titles reviewing titles
1 papers 139 conference
abstracts
Excluded after
reviewing abstracts
11 papers

Full text review Full text review


15 papers 39 conference abstracts

Included in the review Included in the review


7 papers 3 conference abstracts

7 papers and 3 conference


abstracts included in the review

Figure 4: Search strategy and study selection. EWI 6. Reasons for exclusion were: duplicate, not on

ART, not HIV infected, not a study of patient outcomes, not LMIC, insufficient information, study of

children, inappropriate study type

Results

In total 10 studies were identified that met inclusion criteria, 7 papers [112-118] and 3 conference

abstracts [119-121]. (Table 8) Studies included 9 single country cohorts from sub-Saharan Africa and 1

multi-country study from the Caribbean. 2 studies used the EWI definition and both reported on the

number of sites with ARV stock-outs [115, 121]. The remaining 8 studies all reported on the proportion

of patients affected by stock-outs, with 5 of these 8 studies using surveys to question patients about stock-

outs [112-114, 116, 117] and the remaining 3 studies using clinic and pharmacy records to establish

whether stock-outs occurred for individual patients [118-120].

Only one study, that documented a range of outcomes using EWI definitions, reported no ARV

stock-outs [115]. The other study using EWI definition in Caribbean countries reported 64% of sites

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having ARV stock-outs [121]. The remaining 8 studies report a range of 1-28% of patients experiencing

stock-outs, with the list of estimates (%) as follows: 1, 1.5, 7, 10, 11, 17, 26 and 28. In addition 2 of the

studies report associations between ARV stock-outs and other outcomes; Marcellin et al [114] report

association between ARV shortages and treatment interruptions > 48 hrs, and Pasquet et al [118] report

ARV discontinuations > 1 month in length due to a stock-out being associated with death and patient

LTFU.

Discussion

In both LMICs and HICs clinical trials reporting on structured interruptions of ART have

reported higher rates of opportunistic disease, severe morbidity and death [122, 123]. In addition,

unplanned treatment interruptions of more than 48 hrs for patients receiving NNRTI based regimens has

been reported to predict virological rebound and the development of HIV drug resistance in both LMICs

and HICs [124, 125].

The studies reporting on stock-outs presented in this review are particularly heterogeneous. For

example, the different methods used to assess for stock-outs such as questioning patients a method

affected by recall bias, versus using clinic and pharmacy records. Also, the variable periods of time

individuals had been receiving ART, and the fact that some studies reported on stock-outs at the site or

pharmacy level while others reported on stock-outs directly impacting patients. Despite this

heterogeneity, the observation that ARV stock-outs occur in LMICs and lead to alterations and

interruptions in ART regimens is critically important in the setting of previous studies reporting negative

clinical outcomes due to both structured and unplanned treatment interruptions. Further, no data was

available from LMICs to support the safety of an interrupted supply of ARVs.

Justification for current targets or a change in targets

There are no data to support the changing of regimens (switch or substitution) or the interruption

of treatment due to ARV stock-outs. Maintaining the current targets (0% for EWI 6a and b, 100% for

EWI 6c1 and 6c2) would guide countries to always have the necessary ARVs to prevent unnecessary

changes in ART regimens due to stock-outs.

EWI 8 VIRAL LOAD SUPPRESSION

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Current summarized EWI definitions, and key questions this review attempts to answer for this

EWI are as follows.

EWI Definitions

Summarized definitions for EWI 8, and current targets:

Viral load suppression 12 months after ART initiation

o Percentage of patients initiating ART at the site whose viral load is <1000 copies/ml after

12 months of ART (Excludes transfers out)

Suggested target: 70%

Key Questions:

What is the current reported range and summary estimates of virological suppression after 12

months ART when defined in a manner similar to EWIs?

Do these estimates support the currently published targets, or a change to the targets?

Methods specific to EWI 8

Search strategy In addition to search terms outlined within the general methods section, search

terms used specifically for EWI 8 were: virologic or hiv rna or resistance or genotype or

all terms under the MeSH Viral Load AND the terms one year or twelve months or first

year or all terms under the MeSH Time Factors:. (Appendix 5)

Study selection Studies were included if they report the proportion of individuals with a

virological outcome after 12 months of ART. Any definition of virological suppression (or

failure) was accepted that reported a proportion of patients below (or above) a threshold of HIV

viral load measured in copies/mL from plasma after 12 months of ART. Studies were excluded if

they only reported a change in HIV viral load from baseline. Where cohorts did not report 12

month outcomes but a median duration of follow up, studies were included if the median duration

of follow up was 9 to 15 months. Both clinical trials and studies that reported on ART programs

providing service delivery (i.e. non-research settings) were included. The search strategy and

study selection is summarized in Figure 5.

Data extraction and management Definitions used for virological suppression were sought

from reviewed studies. Proportions of subjects meeting these definitions were obtained, and if

available; the proportion of subjects who died, transferred out of the ART program, stopped ART

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and switched to second line ART. If this data (death, transfer out, stop, or switch to second line)

was not available this was noted. Whether the proportion with virological outcome was an on-

treatment analysis (denominator includes only patients tested for HIV viral load at 12 months) or

intention-to-treat (denominator includes the number of starters for whom viral load testing was

intended) was noted. In addition to reported intention-to-treat (ITT) analyses, ITT analyses were

also calculated from raw data when available and sample sizes for these ITT calculations was

noted. Additionally, and consistent with the EWI definition, the proportion that stopped ART

were included, and the proportion transferred out excluded from the denominator when reported.

Studies only reporting the proportion with virological failure were converted into a proportion

with virological suppression so it could be more easily compared to the EWI target. If studies also

reported outcomes for the emergence of HIV drug resistance this was data was also extracted.

Data analysis Median estimate, range of estimates and weighted means were determined for

studies categorized into on-treatment (OT) and ITT analyses. The median estimate, range of

estimates and weighted mean were also determined for OT and ITT analyses where the threshold

for virological suppression was 1,000 copies/mL and for studies where the thresholds were 500

copies/mL (i.e. included thresholds ranging from 50 500 copies/mL).

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Identified studies Identified studies


279 papers 410 conference abstracts

Excluded after Excluded after


reviewing titles reviewing titles
59 papers 156 conference
abstracts
Excluded after
reviewing abstracts
115 papers

Full text review Full text review


105 papers 254 conference abstracts

Included in the review Included in the review


36 papers 17 conference abstracts

36 papers and 17 conference


abstracts included in the review

Figure 5: Search strategy and study selection EWI 8. Reasons for exclusion were: duplicate, not on

ART, not HIV infected, research setting (not service delivery), not a study of patient outcomes, not

LMIC, insufficient information, study of children

Results

In total 53 studies were identified that met inclusion criteria, 36 papers [28, 31, 45, 58, 59, 103,

108, 126-154] and 17 conference abstracts [76, 78, 155-169]. (Tables 9 and 10) Studies included 38

single country cohorts from sub-Saharan Africa, 6 multi-country cohorts (5/6 from sub-Saharan Africa), 4

cohorts from Asia and 4 LMIC cohorts from the Caribbean and Americas. 8 studies each reported 2 or

more results for the proportion with virological suppression by using different thresholds of plasma HIV

RNA [31, 127, 141, 142, 145, 149, 151, 158]. Only 1 study required more than one viral load below a

threshold of HIV RNA for an individual to be classified as having virological suppression. [158] 2

different studies reported on the same sub-Saharan cohort of patients but each study used different

thresholds for virological suppression so both studies were included [129, 148].When including all patient

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cohorts regardless of the virological threshold used, 53 cohorts reported the proportion with virological

suppression in OT analyses and 29 cohorts for ITT analyses. (Table 11) The weighted mean of virological

suppression at 12 months for the 53 OT analyses was 90.6% (n=69,115, median estimate 87%, range 49 -

97%). Thirteen cohorts reported OT analyses with virological thresholds 1,000 copies/mL with a

weighted mean 94.3% suppressed (n=42,804), and for the 11 cohorts where the threshold was 1,000

copies/mL , 94.4% were suppressed (n=38,161, median estimate 87%, range 74 96%). The majority of

cohorts (n=41) reported OT outcomes using thresholds of detectable HIV in plasma 500 copies/mL, of

which 28 used the threshold of 400 copies/mL. For 61,383patients in 41 cohorts using thresholds 500

copies/mL, 89.2% were virologically suppressed (median estimate 83%, range 49 97%). Importantly,

with all the weighted means for OT analyses the abstract by Fox et al [158] accounts for 32,603 subjects.

Additionally this is the only study that requires subjects to record 2 viral loads between 6 and 12 months

of treatment below an HIV RNA threshold. This definition of virological suppression potentially

classifies more individuals as virologically suppressed compared to all other studies in this review that

define virological suppression based on one viral load test at 12 months. Weighted means for OT analyses

excluding the study by Fox et al are noted as part of Table 11, and are 5-9% lower than when the Fox et al

study is included.

Twenty nine cohorts reported ITT analyses for 19,527patients and the weighted mean of

virological suppression was 69.8% (median estimate 70%, range 50 92%). 26 of 29 cohorts use

thresholds to define suppression that are 500 copies/mL, with 19 of the cohorts using the threshold 400

copies/mL. For the 13,032patients in the 26 studies with thresholds 500 copies/mL 68.9% were

virologically suppressed (median estimate 70%, range 50-92%). Only 4 ITT analyses reported the

proportion with virological suppression using a threshold of 1,000 copies/mL. For the 1201 patients in

these 4 studies a weighted mean 77.1% were suppressed (list of estimates: 69, 69, 83 and 87%). Notably,

no ITT analyses were identified using a threshold for virological suppression > 1,000 copies/mL.

Discussion

Summary estimates for virological suppression at 12 months are higher in OT compared to ITT

analyses, and also as the threshold of plasma HIV RNA below which patients are defined as being

suppressed increases. This is not unexpected, as individuals who have died or become LTFU in ITT

analyses are considered unsuppressed, and definitions of virological suppression using higher thresholds

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(e.g. 1,000 copies/mL) will also allow patients with low level viraemia to be considered suppressed as

compared to lower thresholds (e.g. 50 copies/mL).

The current EWI target, 70% virologically suppressed at 12 months, is consistent with the

weighted mean of the most stringent definition of virological suppression in this review (i.e. thresholds

500 copies/mL in ITT analyses). Importantly the EWI definition differs from this stringent definition in

2 ways; it uses a more lenient threshold for virological suppression (1,000 copies/mL), and also excludes

individuals from the analysis who have transferred out.

In this review, only 5 studies reported transfer out data which was excluded from the estimate of

virological suppression as per the EWI definition [58, 126, 135, 144, 146], and only one of these studies

used a threshold of 1000 copies/mL to define suppression [126]. Interestingly, in this single study from

Uganda with definitions most similar to the EWI definition, 69% of patients were suppressed at 12

months. Apart from these 5 studies, it is unclear how patients who may have transferred out have been

accounted for in other studies. Possibilities include; these patients have been incorporated into the

denominator of ITT analyses and this detail has not been reported, or OT analyses have been reported

which do not require the inclusion of those transferred out. On the assumption that there is a degree of

transfer out in all cohorts which has not been reported in ITT analyses we could adjust the estimates of

virological suppression using an approximation of the proportion transferred out from care after 12

months of ART in LMICs. Previous analysis in this review around EWIs 2 and 3 yielded a weighted

mean of 7.7% transferred out after 12 months ART (n=17,908) in a different population but as this figure

was derived from programs in LMICs providing ART it could serve as a useful approximation of the

proportion transferred out. Adjusting the summary estimates for virological suppression to exclude

transfer out would lead to an overall small rise in the summary estimate for virological suppression at 12

months. For example adjusting the ITT weighted mean to remove those transferred out from the

denominator, would result in a new estimate; 70 / (100-8) = 76%.

In addition to how transfer out may affect how we consider this data we also need to consider the

threshold for defining virological suppression. Within ITT analyses which are more similar to the EWI

definition than OT analyses, there are only 4 studies that use the same threshold as EWI 8 to define

virological suppression, 1,000 copies/mL . The weighted mean of these 1,201 patients is 77.1%,

considerably higher than the mean of 68.9% for studies with lower thresholds. Ultimately, conclusions

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from this review about ITT analyses using a threshold of 1,000 copies/mL are limited as there are only 4

studies with this definition. Nevertheless, average rates of virological suppression for the 1,000 copies/mL

threshold in ITT analyses are likely higher than the proportion suppressed in studies with thresholds 500

copies/mL, a finding which is also seen in OT analyses where there is data for increased numbers of

patients with thresholds of 1,000 copies/mL.

Justification for current targets or a change in targets

The current target is consistent with the average proportion of patients meeting a more stringent

definition of virological suppression than EWI 8. In the setting of the potential for upward adjustment of

current ITT weighted means to cater for: patients who may have transferred out, and to accommodate the

EWI threshold of 1,000 copies/mL the current target of 70% represents guidance that may be too lenient.

Raising the target to 75% would serve as more accurate guidance for countries to aim for rates of

virological suppression consistent with average rates of virological suppression using the current EWI

definition.

CONCLUSIONS

This review strives to place current targets for HIVDR EWIs in the context of currently available

literature. Revision of the targets aims to provide guidance for countries to achieve levels of program

function that are at least consistent with average rates of these outcomes based on the available literature.

Additionally, countries are able to set more stringent targets than the revised targets presented here.

Recommendations for current targets based on the review are as follows:

EWI 1 (Prescribing practices) maintain at 100%

EWI 2 (LTFU) decrease from 20% to 15%

EWI 3a (Retention on first line) increase from 70% to 75%

EWI 3b (Switch to second line) increase from 0% to 2%

EWI 4a and 4b (On time ARV pick-up) current target of 90% patients picking up all ARVs

on time is too high but unclear to what extent to lower target. Consider review of data with

alternative definition of on time ARV pick-up

EWI 5a (On time appointment keeping) maintain at 80%. EWI 5b limited data but current

target likely too high

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EWI 6a and 6b (Stock-outs) maintain at 100%. EWI 6c1 and 6c2 - maintain at 0%.

EWI 8 (Virological suppression) - increase from 70% to 75%

ACKNOW LEDGEMENTS

James H. McMahon MBBS MPH (Infectious Diseases Unit, The Alfred Hospital, Melbourne, Australia

and Department of Public Health and Community Medicine, Tufts University, Boston, USA)

Michael Jordan MD MPH (World Health Organization, Geneva, Switzerland and Tufts University
School of Medicine, Boston, USA)

Rachel Kubiak MPH (Tufts University School of Medicine, Boston, USA)

Elizabeth Richardson MLS MEd (Hirsh Health Sciences Library, Boston, USA)

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Table 1. EWI 2 and 3 (LTFU and Retention on First line) - Papers

% retained
Study
Baseline on ART at
Study definition of %
features ART original
definition retention on meeting
(median regimens % site/s
LTFU will first line (if study
Country Pay age, % (all ART Time Study % retained (excludes TF Patient
Study HC HC Dates Site Starting % likely lead not defined definition % TF
(cohort or Provider s for male, nave at since ART definition % Died ART on ART out / stop / Tracing
(year) facility setting observed s (n) ART (n) LTFU to lower or then % of out
data source) ART median baseline start LTFU stop (include switch from
higher retained on retention
CD4, WHO unless TF out) numerator if
estimates ART on first
clinical stated) reported,
than EWI 2 columns are line
stage) most similar
calculated)
to EWI 3a)
May et Cote Clinics NGO NGO No Initiated Mul 2117 35, 26%, Regime Mean Not attend 11.5 Lower 8.7% NR Not defined NR NR 79.7% Yes
al [57] d'Ivoire (CEPRE ART Jan tipl 129, 82% n NR 10.6 clinic for > 6 % (shorter (also no
(2010) (Abidjan - F) 2004 - e advanced months months (Max duration of data on 2nd
CEPREF) Mar 2007 (Max 1 F/U 1 yr) F/U and lost line switch )
yr) for 6
months)
As Malawi Hospita Public MOH No Initiated 1 3028 36, 41%, Regime Mean Not attend 12.4 Lower 8.9% NR Not defined 79.1% 14% 65.1% Yes
above (Lilongwe l and ART Jan 127, 96% n NR 9.84 clinic for > 6 % (shorter (also no
Lighthouse) partner 2004 - advanced months months (Max duration of data on 2nd
s Mar 2007 (Max 1 F/U 1 yr) F/U and lost line switch )
(Lighth yr) for 6
ouse) months)
Tassie 61 LMICs Mixed Mixed Mixed Mix Started Mul 297048 NR Regime 12 Variable for Mea Unclear NR NR Proportion Mean of NR NR Mean of NR
et al (WHO / ed ART 2007 tipl ns NR months different n of of ART 79.9% 79.9%
[64] UNICEF / e sites (period 20.1 starters
(2010) UNAIDS) defining % alive and
LTFU ranges on ART at
from - 12 months
missing last (also no
appointment data on 2nd
Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011

to several line switch )


months)
Geng Uganda Region Public MOH No Initiated 1 3628 35,39%, Regime 12 Not 16% Lower (lost 1.7% NR Not defined NR NR 82.3% (no Yes
et al (Mbarara) al clinic ART Jan 95, NR ns NR months attended (no for 6 (7.5 (also no tracing) (as
[46] 2004 - clinic for > 6 traci months) % data on 2nd sub-
(2010) Sept 2007 months ng) post line switch ) study)
traci
ng
stud
y)
Thai et Cambodia Hospita Privat MOH No Mar 2003 1 1667 35, 99.7% 12 Not 3.9% Lower (lost 7.6% NR Not defined NR NR 88.5% Yes
al [66] (Phnom l e (not and - Dec 49.4%, NNRTI months attended for 6 (also no
(2009) Penh) for partner 2007 61, Stage regimen clinic for 6 months) data on 2nd
profit) s (ITM, I 4% s consecutive line switch )
Antwer Stage II months
p) 11%,
Stage III
39%
Stage IV
46%

32
Lowran Rwanda Clinics Public MOH No Initiated 30 3194 37, 35%, NNRTI 12 Not 4.9% Similar to
4.6% 0.3 Alive and 86.9% 91.2% 4.3% 86.7% No
ce et al (National ART Jan 141, regimen months attended EWI % on ART at (86.9%
[54] sample) 2004 - s clinic for > clinic 0.2%
(2009) Dec 2005 90 days where ART switch to
initiated. 2nd line)
Also < 1%
switched to
2nd line
(7/3192)
Bisson Botswana Region Public MOH No Initiated 1 410 37, 40%, 97% Median Last contact 16.6 Lower 7.1% NR in care and 76.3% NR NR 76.3% Yes
et al (Gaborone - al ART Feb 81 NNRTI duration with clinic or % (shorter had refilled
[34] IDCC) Hospita 2003 - regimen F/U 44 pharmacy > duration of script for
(2008) l August s, 12% weeks 30 days after F/U) HAART in
2003 prior (10 last Higher (lost prior 30
ARV mths) scheduled for 1 month) days (also
exposur visit no data on
e 2nd line
switch )
Bedelu South Africa Hospita Public NGO No Initiated 1 430 NR Regime median Not defined 19.3 Unclear 13.5 NR Not defined 67.2% 4.0% 63.2% NR
et al (Lusikisiki) l (MSF) Jan 2005 ns NR 12 % % (also no
[32] and - June months data on 2nd
(2007) MOH 2005. line switch )
Followed
to July
2006
As As above Clinic Public NGO No Initiated 12 595 NR Regime median Not defined 2.2% Unclear 16.8 NR Not defined NR NR 81.0% Yes
above (MSF) Jan 2005 ns NR 12 % (also no
and - June months data on 2nd
MOH 2005. line switch )
Followed
to July
2006
Etard Senegal Clinic Public MOH Part Initiated Unc 404 37, 45%, 42% PI 12 6 months 1.7% Lower (lost 11.6 NR Not defined NR NR 86.6% Yes
et al ial Aug 1998 lear 128 regimen months with no for 6 % (also no
[44] - April ( , 95% contact, or months) data on 2nd
(2006) 2002. 3) ART willingness line switch )
Observed nave at to resume
to Sep baseline ART (after
2005 phone calls
and home
visits)
Ferradi Malawi District Public MOH No 2001 (no 1 1308 35, 36%, 98% 12 Not 5% Similar to 19% NR "On 76% NR NR 76% Yes
ni et al (Chiradzulu) Hospita and month) - 112, NNRTI months attended EWI HAART"
[45] l NGO April 2004 Stage I regimen clinic > 2 (not died,
(2006) (MSF) and II s (3 pts months after LTFU, stop.
18% PI last Also no
Stage III regimen scheduled data on 2nd
55% ), 97% visit (tracing line switch)
Stage IV ART attempted)
27% nave

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68
Wools- Kenya 1 Public AMPAT So Nov 2001 8 2059 37, 40%, 95.1% Median Not 24.5 Lower 5.4% NR Not defined NR NR 70.1% NR
Kalous (Western) Region H me - Feb 86, Stage NNRTI duration attended % (shorter (also no
tian et al, 1 progra pai 2005 I 33% regimen F/U 40 clinic > 3 (12 duration of data on 2nd
al [71] district m d Stage II s weeks months mont F/U) line switch)
(2006) Hospita 12% (9.2 h
l, 6 Stage III mths) LTFU
clinics 38% 22.4
Stage IV %)
17%
Kabug Uganda Tertiary Public MOH Part Aug 1998 1 321 38, 51%, HAART Median Not defined NR NR NR Alive and in 56.0% NR NR 56.0% NR
o et al care and ial - Dec 79 44%, duration care at 1
[51] Hospita partner 2002 2NRTI F/U 16.8 year = not
(2005) l s 37%, months Died or
none/un LTFU (also
known no data on
for 59 2nd line
(18%) switch)
Wester Botswana Region Public MOH No April 2001 1 153 36, 41%, 100% 12 Miss 2 8.4% ? Higher (? 15.3 NR Not defined 76.3% 5.2% 71.1% NR
et al (Gaborone - al - Nov 96, Stage NNRTI months( consecutive Lost for 2 % (also no
[70] IDCC) Hospita 2003 I 2% regimen visits (i.e. months) data on 2nd
(2005) (Different l (Different Stage 2 s likely miss line switch)
patients to patients 21% for 2
Bisson PloS to Bisson Stage III months) and
One) PloS One) 30% not
Stage IV contacted
47% on 2
attempts
Macha Kenya Clinics Privat Private Yes Oct 1996 5 300 NR , 72% on 12 Not defined NR NR NR Remaining 78% 78% No
ria et al (Nairobi) e clinicia - June 60%, 80 HAART months on ART
[55] ns 2001 (3NRTI, (also no
(2003) NNRTI data on 2nd
or PI line switch)
regimen
)
Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011

Charal Sth. Africa Hospita Privat Compa No Oct 2002 69 2262 41, 95%, NNRTI 12 "Stopped 8.3% Unclear 4.2% See Not defined 82.6% 5.5% 77.1% NR
ambou ls and e ny - Dec 158, regimen months treatment" = LTF (also no
s et al Clinics (Work (Anglo 2005 Stage III s due to U data on 2nd
[36] place) Americ 45% patient line switch)
(2007) an) Stage IV request, not
27% returning to
clinic or for
ART, or non-
adherence
Bisson Botswana Clinic Privat Private Yes Initiated 1 346 37, 42%, Regime 12 No viral load 12.4 Unclear 5.2% NR Not defined 82.4% 12.1 70.2% NR
et al (Gaborone) e clinicia ART Dec between ns NR months tests after % (also no %
[33] (Different to ns 1999 - 80 and ART start, data on 2nd
(2006) other 2 Jan 2004 113, then not line switch)
Gaborone contactable
studies as by phone
private) and no
record of
ART pick up

34
Lauren Cameroon Hospita Public Public Yes Oct 2000 19 788 39, 48%, cART Median Did not 25.1 Similar to 6.6% NR Not defined NR NR 68.3% NR
t et al (Douala) ls and and and - Dec 123, CDC for all duration attend in 3 % EWI (also no
[53] Clinics Privat Private 2003 stage B but one, of F/U months prior data on 2nd
(2005) (10 e clinicia 57% 85.5% 13 to the chart line switch)
private ns CDC nave at months review
9 stage C baseline
public) 33%
Marsto Kenya Clinic NGO AMREF No Feb 2003 1 283 Mean 36, 99% 12 No clinic 13.0 Similar to 7.0% NR alive and 81% NR NR 80% (81% Yes
n et al (Kibera) , MOH - Feb 30%, 157, NNRTI months visit in 3 % EWI on ART at (Paper -1%
[56] 2005 Stage I/II regimen months prior 12 months says changed
(2007) 29% s, 1% to censor 81% ARV class)
Stage III PI date even
23% regimen though
Stage IV s 100-13-
48% 7=80)
Karche Kenya District Public MOH No Apr 2004 1 124 31, 29%, NNRTI Median
Not 15.3 Lower 12.1 NR Not defined NR NR 72.6% No
r et al (Migori) Hospita and - Sept 189, CDC regimen duration
attended % (Shorter % (also no
[52] l partner 2005 Stage C s F/U 9
within 4 duration of data on 2nd
(2007) (GTZ) 46% months
months after F/U) line switch)
a scheduled
appointment
Hawkin Kenya Hospita NGO Local No Initiated 1 1286 36, 99% Median missed clinic 34.8 Lower 1.1% NR Not 64.1% 4.9% 52.2% No
s et al (Nairobi l clinicia ART Sept 40.9%, NNRTI duration visits and % (shorter defined. (64.1% -
[47] Saint ns 2004 - 121 regimen 11.6 failure to duration of 7% TF out -
(2007) Marys) Aug 2006 s months collect ART F/U) patients 7% switch
refills for 3 switched ARV class)
months ARV class

Coetze Sth Africa Clinics Public MOH, No Initiated 3 287 31, 30%, 99% Median not attended 0.3% Similar to 13.2 3.1 Not 83.3% 1.0% 81.3% Yes
e et al (Khayelitsha NGO May 2001 43, NNRTI duration services EWI % % defined. (83.3 - TF
[39] - NB: earlier (MSF) - Dec regimen 13.9 (clinic + 1% out 1%
(2004) than Lancet 2002, s months other switched to switch 2nd
data 2010) Censored services not second line line)
July 2003 defined) for regimen
3 months
after last
scheduled
appointment
Vella et Sth Afrcia Clinics Public MOH No Initiated 32 2835 34, 33% NR 11 Not defined NR NR NR retained 81% NR NR 81% Yes
al [69] (Kwa Zulu Mar 2004 months on
(2010) Natal) - May treatment
2006. = attended
Followed in 3 months
to July 1 prior to
2007 censor.
(also no
data on 2nd
line switch)
Palom Mozambiqu Clinics Public DREAM No Initiated 5 3749 34, 38%, 97% Median Not 2.8% Similar to 10.5 NR Not 86.7% NR 84.7% Yes
bi et al e, Malawi. progra Feb 2002 192, NNRTI duration attending EWI % defined. (86.7% -
[61] Guinea- m - Jan Stage III regimen 14.5 clinic for > 3 2% 2% switch
(2009) Conkary 2006. or IV 37% s, 3% months months switched to to 2nd line)
Followed 3NRTI a second
to June regimen line at 1
2007 s year
35
Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators

69
70
Unge Kenya Clinic NGO AMREF No Jan 2005 1 830 Mean 35, 97% 12 No 12 month NR NR NR On care 74.0% NR NR 74.0% Yes
et al (Kibera) NB: , MOH - Sept 35%, NNRTI, months outcome and in
[68] Recruited 2007 Mean 2% treatment
(2009) after CD4 203 NRTI (LTFU =
Marston only, not
2007 study 1% PI attended >
regimen 90 days
s post ART
run out
date. Also
no data on
2nd line
switch)
Chung Kenya Clinic NGO Coptic No Initiated 1 1231 NR (All > No data 12 Not 10.0 Higher (Lost NR NR Not being 90.0% NR NR 90.0% NR
et al (Nairobi - Hope Mar 2006 15 y.o.) on months attending % for 1 month) LTFU (i.e.
[38] Coptic Center - Dec regimen clinic > 30 no mention
(2010) Center) 2007 s days after of death,
last TF out,
scheduled Also no
pharmacy data on 2nd
appointment line switch)
or 120 days
after last
clinic visit if
no
pharmacy
data
Toure Cote Clinics Public Public Part Initiated 18 Less 36, 30%, 94% 12 last contact 18% Similar to NR NR Not defined NR NR NR
et al d'Ivoire and and ial ART May than 123, NNRTI month with care EWI (also no
[67] (Abidjan) Privat Private 2004 - 10211 Stage I regimen center > 3 data on 2nd
(2008) NB: May e clinicia Feb 2007 and II s (NB: months and line switch)
Lancet 2010 ns, 19% for not known
is only Stage III 10211 to be dead
CEPREF 69% persons or TF out
clinic data. Stage IV )
Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011

Here, non- 12% (NB:


CEPREF for 10211
clinic in persons)
Aconda
program
Shumb Rwanda Clinics Public MOH No Initiated 4 435 39, 37%, 100% 12 Not NR NR NR Proportion 91.6% 91.6% 2.5% 89.1% NR
usho et (FHI ART Sept 184, NNRTI month attending at 12 at 12 alive and
al [63] supported 2005 - Stage I regimen clinic > 3 mont mont on ART at
(2009) rural sites) March 24% s mo since hs hs 12 months
2008 Stage II last visit, (i.e.
39% without excludes
Stage III alternative death,
35% explanation LTFU)
Stage IV (e.g. death,
2% TF out)
Collini Ghana Teachin Public MOH Part Jan 2004 1 237 Mean 40, NNRTI 12 Not defined 20.3 Unclear NR NR Not NR NR NR No
et al (Kumasi) g ial - Jan 41%, regimen months % defined.
[40] Hospita 2007 Mean s (also no
(2009) l CD4 120, data on 2nd
Stage line switch)
III/IV 78%

36
DeSilv Nigeria (Jos) Clinic NGO Faith No Initiated 1 1552 34, 29%, 99% Mean No clinic 8.8% Similar to 6.7% NR Not defined NR NR 84.5% NR
a et al Alive Dec 2004 112 NNRTI duration records for > EWI (also no
[43] Progra - Apr regimen of F/U 3 months data on 2nd
(2009) m 2006. s, 1% 14.6 line switch)
Followed PI months
to Dec regimen
2006 s
Jansse Cambodia Clinic Public MOH No initiated 2 2497 median NNRTI 12 to 18 Not defined 6.5% Unclear 16.8 NR Still alive 76.7% 17.9 58.8% NR
ns et al (Siem Reap, and ART Mar CD4 53 regimen months % and in %
[49] Takeo) NGO 2002 - s (assume active F/U.
(2007) (MSF) Dec 2005 'almost median (also no
all 15 data on 2nd
patients months) line switch)
'
Barth Sth Africa Clinic NGO Local No Initiated 1 609 35, 29%, 100% 12 Not defined 15.0 Unclear 19.0 NR Alive and in 66% NR NR 66% Yes
et al (Ndlovu) NGO Sept 2003 67, Stage NNRTI months % % care. (also
[31] - Apr I 10% regimen no data on
(2008) 2006 Stage II s 2nd line
10% switch)
Stage III
62%
Stage IV
17%
Assefa Ethiopia Mixed Public MOH No Initiated 353 60476 NR 100% 12 Not on ART 18.4 Higher 8.6% NR Alive and 73.0% NR NR 73.0% No
et al Sept 2003 NNRTI months and not % (potentially on ART
[29] - Oct regimen known to only miss
(2010) 2007 s have died at one appt to
12 months be lost)
Bacha India Hospita Public MOH No Initiated 3 927 35. 66%, 16% 12 missed clinic 11.0 Lower (not 11.2 NR Alive and 77.9% NR NR 77.9% Yes
ni et al (Mumbai, ls Oct 2004 119, receive months visits for 3 % followed to % on ART
[30] Tambaram - Jan d prior months 15 months)
(2010) Chennai, 2005 ART,
Hyderabad) 100%
NNRTI
regimen
s
Cornell South Africa Mixed Public MOH No Initiated 8 44177 35, 32%, NR 12 > 6 months 14.4 Lower 6.6% NR Enrolled in 80.0% NR NR 78.40% Yes
et al (IeDEA-Sth ART from 103, months without % (longer ART
[41] Africa) Jan 2002 Stage I patient period LTFU programme
(2010) - Dec 9% Stage contact and shorter and not
2007 II 12% duration of dead or
Stage III F/U) LTFU
48%
Stage IV
32%
Hong Namibia NR Public MOH No Initiated 9 1620 NR 100% 12 EWI 17.5 Same as NR NR EWI 0.2% for Yes
et al ART after NNRTI months definition % EWI definition EWI 3b
[48] Jan 2007 regimen (not returned (Proportion translate
(2010) s to pharmacy of patients s into
or clinic < 90 switching 99.8%
days after to second
last ART line ART at
run-out date 12 months)
and who
were not TF
out, stopped
37
Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators

71
72
ART, or
died)
Moore Malawi Region Public MOH No Initiated 1 300 mean 36, 100% 12 Failure to 2.7% Higher 14.3 5.3 Alive and 72.3% 77.6% 5.3% 72.3% Yes.
et al (Blantyre) al 2005 39%, NNRTI months attend clinic (shorter % % on ART in
[58] Hospita mean regimen 4 weeks period LTFU) the study
(2010) l 157, s after Lower (not clinic
Stage IV scheduled followed to
29% appointment 15 months)
Muteve Sth Africa Hospita Public MOH No Initiated 16 3010 34-37, 100% 12 No clinic 3.7% Lower (not 10.9 NR Alive and 84% 85.4% 1.4% 84.0% Yes
dzi et (Kwa-Zulu l and ART Oct 22%, 91- NNRTI months visit for 90 followed to % on ART in
al [59] Natal) Clinics 2004 - 128, NR regimen days 15 months) the study
(2010) Sept 2007 s clinic
Sharm India (Delhi - Referral Public MOH No Initiated 1 631 Mean 36, 100% 12 NR 18.5 Unclear 13.0 NR NR Being 68.5% NR 68.5% Yes
a et al AIIMS) Hospita ART May 80%, 110, NNRTI months % % followed
[62] l 2005 - Stage I regimen in clinic
(2010) Oct 2006 13% s
Stage II
5% Stage
III 51%
Stage IV
31%
Tassie Cambodia NR NGO NGO No Initiated 1 606 NR NR 12 no recorded 4.4% Lower (not 9.6% 4.8 Alive on 81.1% NR NR 81.1% NR
et al (Kampong (MSF) ART Jan - months visit for 90 followed to % ART at the
[65] Cham) Dec 2005 days from 15 months) original site
(2010) the last visit
As Cambodia NR NGO NGO No Initiated 1 610 NR NR 12 no recorded 0.8% Lower (not 3.3% 8.5 Alive on 87.4% NR NR 87.4% NR
above (Phnom (MSF) ART Jan - months visit for 90 followed to % ART at the
Penh) Dec 2005 days from 15 months) original site
the last visit
As Burkina NR NGO NGO No Initiated 1 899 NR NR 12 no recorded 15.9 Lower (not 6.0% 5.8 Alive on 72.3% NR NR 72.3% NR
above Faso (Pissy) (MSF) ART Jan - months visit for 90 % followed to % ART at the
Dec 2005 days from 15 months) original site
the last visit
As DRC NR NGO NGO No Initiated 1 1065 NR NR 12 no recorded 8.1% Lower (not 16.7 1.3 Alive on 73.9% NR NR 73.9% NR
Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011

above (Kinshasa) (MSF) ART Jan - months visit for 90 followed to % % ART at the
Dec 2005 days from 15 months) original site
the last visit
As Kenya NR NGO NGO No Initiated 1 860 NR NR 12 no recorded 8.5% Lower (not 6.4% 3.0 Alive on 82.1% NR NR 82.1% NR
above (Busia) (MSF) ART Jan - months visit for 90 followed to % ART at the
Dec 2005 days from 15 months) original site
the last visit
As Kenya NR NGO NGO No Initiated 1 954 NR NR 12 no recorded 10.9 Lower (not 10.6 1.6 Alive on 76.9% NR NR 76.9% NR
above (Hornabay) (MSF) ART Jan - months visit for 90 % followed to % % ART at the
Dec 2005 days from 15 months) original site
the last visit
As Kenya NR NGO NGO No Initiated 1 435 NR NR 12 no recorded 11.3 Lower (not 5.3% 5.7 Alive on 77.7% NR NR 77.7% NR
above (Kibera) (MSF) ART Jan - months visit for 90 % followed to % ART at the
Dec 2005 days from 15 months) original site
the last visit
As Kenya NR NGO NGO No Initiated 1 549 NR NR 12 no recorded 13.5 Lower (not 4.2% 5.8 Alive on 76.5% NR NR 76.5% NR
above (Mathare) (MSF) ART Jan - months visit for 90 % followed to % ART at the
Dec 2005 days from 15 months) original site
the last visit
As Malawi NR NGO NGO No Initiated 1 1599 NR NR 12 no recorded 11.6 Lower (not 9.4% 1.4 Alive on 77.6% NR NR 77.6% NR
above (Chiradzulu) (MSF) ART Jan - months visit for 90 % followed to % ART at the
Dec 2005 days from 15 months) original site
38
the last visit

As Malawi NR NGO NGO No Initiated 1 1359 NR NR 12 no recorded 8.9% Lower (not 12.7 2.4 Alive on 76.0% NR NR 76.0% NR
above (Thyolo) (MSF) ART Jan - months visit for 90 followed to % % ART at the
Dec 2005 days from 15 months) original site
the last visit
As Mozambiqu NR NGO NGO No Initiated 1 1208 NR NR 12 no recorded 20.3 Lower (not 1.9% 1.8 Alive on 76.0% NR NR 76.0% NR
above e (AltoMae) (MSF) ART Jan - months visit for 90 % followed to % ART at the
Dec 2005 days from 15 months) original site
the last visit
As Mozambiqu NR NGO NGO No Initiated 1 1294 NR NR 12 no recorded 10.2 Lower (not 5.0% 3.8 Alive on 81.0% NR NR 81.0% NR
above e (Mavalan) (MSF) ART Jan - months visit for 90 % followed to % ART at the
Dec 2005 days from 15 months) original site
the last visit
As Mozambiqu NR NGO NGO No Initiated 1 278 NR NR 12 no recorded 4.3% Lower (not 5.4% 5.0 Alive on 85.2% NR NR 85.2% NR
above e (Moatize) (MSF) ART Jan - months visit for 90 followed to % ART at the
Dec 2005 days from 15 months) original site
the last visit
As Nigeria NR NGO NGO No Initiated 1 713 NR NR 12 no recorded 9.7% Lower (not 5.7% 1.7 Alive on 82.9% NR NR 82.9% NR
above (Lagos) (MSF) ART Jan - months visit for 90 followed to % ART at the
Dec 2005 days from 15 months) original site
the last visit
As Uganda NR NGO NGO No Initiated 1 1137 NR NR 12 no recorded 13.4 Lower (not 3.9% 2.9 Alive on 79.8% NR NR 79.8% NR
above (Arua) (MSF) ART Jan - months visit for 90 % followed to % ART at the
Dec 2005 days from 15 months) original site
the last visit
As Zambia NR NGO NGO No Initiated 1 559 NR NR 12 no recorded 3.4% Lower (not 12.0 0.9 Alive on 83.7% NR NR 83.7% NR
above (Kapiri (MSF) ART Jan - months visit for 90 followed to % % ART at the
Kawama) Dec 2005 days from 15 months) original site
the last visit
As Zimbabwe NR NGO NGO No Initiated 1 222 NR NR 12 no recorded 13.5 Lower (not 11.5 0.5 Alive on 74.4% NR NR 74.4% NR
above (Bulawayo) (MSF) ART Jan - months visit for 90 % followed to % % ART at the
Dec 2005 days from 15 months) original site
the last visit
As Zimbabwe NR NGO NGO No Initiated 1 173 NR NR 12 no recorded 3.3% Lower (not 15.9 0.5 Alive on 80.4% NR NR 80.4% NR
above (Murrambin (MSF) ART Jan - months visit for 90 followed to % % ART at the
da) Dec 2005 days from 15 months) original site
the last visit
As India (YRG) NR Public MOH No Initiated 1 767 NR NR 12 no recorded 31.9 Lower (not 3.6% 6.0 Alive on 58.9% NR NR 58.9% NR
above and and ART Jan - months visit for 90 % followed to % ART at the
Privat clinicia Dec 2005 days from 15 months) original site
e ns the last visit
As Kenya NR Public MOH No Initiated 1 4111 NR NR 12 no recorded 15.0 Lower (not 6.7% 3.8 Alive on 74.6% NR NR 74.6% NR
above (AMPATH) ART Jan - months visit for 90 % followed to % ART at the
Dec 2005 days from 15 months) original site
the last visit
As Zimbabwe NR Public MOH No Initiated 1 378 NR NR 12 no recorded 4.0% Lower (not 6.3% 1.6 Alive on 88.6% NR NR 88.6% NR
above (Connaught) ART Jan - months visit for 90 followed to % ART at the
Dec 2005 days from 15 months) original site
the last visit
O'Brie Congo Rural NGO NGO No During 2 236 37, 31%, NNRTI Mean NR 8.5% Unclear 12.3 NR NR NR NR 79.2% NR
n et al (Pool) Hospita (MSF) 2007 104, and PI duration %
[60] l Stage I regimen of F/U 9
(2009) and II 3% s months
Stage III
53%
39
Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators

73
74
Stage IV
44%
Culbert Congo Rural NGO NGO No Initiated 1 494 37, 34%, 100% 12 NR 5.4% Unclear 7.9% NR NR NR NR 86.7% NR
et al (Bukavu) Hospita (MSF) ART May 123, NNRTI months
[42] l 2002 - Stage I regimen
(2007) Jan 2006 3% Stage s
II 12%
Stage III
49%
Stage IV
34%
Johann Tanzania Clinic NGO NGO No Initiated 1 320 35, 30%, 100% Mean missed 9.7% Lower (, 29.7 2.2 NR 60.6% 10.9 49.7% Yes
essen (Manyara) (Luther ART Oct NR, Stage NNRTI duration appointment shorter % % %
et al an 2003 - I and II regimen of F/U s for 3 duration of
[50] Church) Nov 2006 3% Stage s 10.9 months F/U, not
(2008) III 31% months followed to
Stage IV 15 months)
66%
Chang Uganda Clinic NGO NGO No Initiated 1 360 38, 66%, 100% 12 Did not visit 8.0% Lower (not 18.0 2.0 Alive and 72.0% 72.0% 1.0% 71.0% NR
et al (Kampala) (Reach ART Oct 81-107, NNRTI months the clinic in followed to % % active on
[35] Out - 2003 - Jul Stage I regimen 90 days 15 months) ART at one
(2009) Faith 2004 and II s year
based) 26%
Stage III
49%
Stage IV
24%
Chi et Zambia Clinics Public MOH No Initiated 18 37039 35, 39%, 100% 12 NR 13.8 Unclear 9.9% 3.1 Alive and 73.2% NR NR 73.2% NR
al [37] (Lusaka) ART Apr 110-132, NNRTI months % % active in
(2009) 2004 - Stage I regimen the
Sept 2007 and II s program
30%
Stage III
59%
Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011

Stage IV
10%
Notes: HC, healthcare; ART, antiretroviral therapy; WHO, World Health Organization; LTFU, lost to follow up; EWI, early warning indicator; TF, transfer; NR,
not reported; F/U, follow up; MOH, ministry of health; NGO, non-governmental organization; MSF, medecines sans frontiers; NNRTI. Non-nucleoside reverse
transcriptase inhibitors; PI, protease inhibitors; NRTI, nucleoside reverse transcriptase inhibitors;

40
Table 2. EWI 2 and 3 (LTFU and Retention on First line) Abstracts

%
retained
on ART
at
Baseline Study
original
features definition %
ART % site/s
(median LTFU will Study meeting
regimens retaine (excludes
Author Star age, % Time likely definition study
Pati (all ART Study % % d on % TF out / Patient
and HC HC Dates Site ting male, since lead to % of definitio
Country Provider ent nave at definition LTF ART ART TF stop / Tracing
meeting facility setting observed s (n) ART median ART lower or Died retention n of
pays baseline LTFU U stop (includ out switch
(n) CD4, start higher on first retentio
unless e TF from
WHO estimates line n on
stated) out) numerato
clinical than first line
r if
stage) WHO EWI
reported,
most
similar to
EWI 3a)
Chinh Vietnam Hospita Public MOH No Initiated 1 889 30, 77%, NR (all Median NR 4.0% Unclear 5.0% NR still in 88.6% 88.6% 1.2 87.6% NR
et al (Ho Chi l Sep 2005 - 143,Stage first line duratio follow-up %
[79] Minh City) Dec 2007 III / IV regimens) n F/U on first-
CROI 51% All 'ART 10 line ART
(2010) nave' but months (excludes
76% prior LTFU,
ARV death,
exposure switch for
treatment
failure)
Cortes Chile NR Public MOH No Oct 2001 - 29 3045 36.9, 100% 12 NR 2.3% Unclear 7.1% NR Maintena 66.2% NR NR 66.2% NR
et al (Chilean Sept 2008 84.7%, HAART months nce on
[81] AIDS NR, NR (63% first ART
CROI cohort) NNRTI, regimen
(2010) 15% PI) (?
Excluded
changes
due to
toxicity,
'administr
ative
causes',
viral
failure,
'simplifica
tion')
Serenat South Mixed Public MOH, No June 2005 NR 840, NR, 33%, NR 12 NR NR Unclear NR NR for NR NR NR NR 77.0% NR
a et al Africa (91%), PEPFA - Sept 673 NR, NR months for for 12
[91] (PEPFAR NGO / R 2009 (? 12 12 month
CROI sites) Private no mont mont s
(2010) (9%) for hs hs
12
mon
th
anal

41
Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators

75
76
ysis)

Okello Uganda Hospita Public, NGO No 2005-2009 NR 1869 26, 39%, 100% 12 NR NR Unclear NR NR for Not NR for NR NR 92.0% NR
et al (Mildmay) l NGO (Mildm (?1) NR, NR initiating months for for 12 defined 12 for
[90] IAS ay) HAART 12 12 month months 12
(2010) mont mont s mo
hs hs nth
s
Eramov 12 Mixed Mixed mixed No 2007-2008 NR 3181 NR NR 12 NR 6.8% Unclear 8.0% 6.3% NR NR NR NR 79% NR
a et al European months
[85] IAS countries
(2010) (former
USSR, but
not
Estonia,
Russia,
Turkmenist
an)
Duong Vietnam Mixed Public MOH No 2008 27 1222 NR NR 12 EWI LTFU 5.6% EWI NR NR EWI 81.2% NR NR 81.2% NR
et al 1 months definition definition retention
[83] IAS (114 definition
(2010) 32
adul
ts)
Geng et Uganda Region Public MOH No 2004-2007 1 3,62 NR NR 12 no visit 3 NR NR NR NR Attended 82.0% NR NR 82% No
al [86] (Mbarara) al 8 months months at 12 clinic in (tracing
IAS Hospita after mont previous sub-
(2010) l expected hs 3 months study
return and on altered
ART in retention
previous estimate
30 days to 89%)
Mossd Tanzania District Public, MOH No 2005-2008 1 1463 40, 35%, 76% 12 NR 12.9 Unclear 8.8% NR NR NR NR NR 78.3% NR
Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011

orf et al (Ifakara) Hospita NGO and 118, NNRTI months %


[89] IAS l partner 24.8% regimen
(2010) WHO
Stage IV
Vandela Swaziland Hospita Public MOH No 2006-2009 1 39 NR, NR, NR 12 NR NR NR NR NR NR NR NR NR 56.0% NR
notte et (Mankayan l 106, NR months
al [93] e)
IAS
(2010)
as 49 NR, NR, 12 67% NR
above 120, NR months
as 72 NR, NR, 12 73% NR
above 91, NR months
Burliso Mozambiq NR NR NR NR June 2006 NR 2790 NR, NR 12 patients 18.7 Similar to 10.6 NR NR NR NR NR 70.4% NR
n et al ue - Mar 2009 49.4%, months not % EWI %
[77] IAS (Zambezia) NR, NR returning
(2010) for
medication
within 60
days of
scheduled
42
pickup

Auld et Mozambiq Mixed Mixed Mixed NR 2004-2007 30 2596 34, 38%, 88% on 1.3 NR 22.8 Unclear 4.3% NR NR NR NR NR 72.9% NR
al [74] ue 153, NR NRTI or years % (3.4
IAS (nationally NNRTI (19.8 /100
(2010) represent. regimens /100 pers
sample) pers on
on year
year s)
s)
Darin et Nigeria Mixed Mixed Mixed No Jan 2006 - NR 8418 35.2, 100% 48 NR 19.8 Unclear 0.5% 1.2% NR NR NR NR 78.50% NR
al [82] (Abuja, Dec 2007 77.9%, NNRTI weeks %
IAS Ibadan, NR, NR regimen
(2010) Lagos)
Jahn et Malawi Mixed Public MOH No 2004-2009 339 2531 NR, NR, NR 12 NR NR NR 5% NR Alive and 79% NR NR 79% NR
al [87] (Lilongwe) 54 NR, 10% months on ART
IAS Stage IV
(2010)
Chaso Thailand NR Public MOH No 2006 6 304 38, 1.2:1 100% 12 NR NR NR 8.9% NR NR NR NR NR 88.5% NR
mbat (Nonthabur M:F, 56, NNRTI months
[78] et i, Chiang NR regimen
al IAS Rai,
(2010) Lumpang,
Lumphun)
Asiimw Lesotho Clinics Private Private No May 2006 14 3394 30, 6%, 100% Median NR 9.7% Unclear 3.0% NR NR NR NR NR 87.3% NR
e et al (Apparel clinicia - Dec 2008 173, NNRTI duratio (includes
[73] IAS Alliance) ns 19.1% regimen n F/U stops, TF
(2009) Stage 13 out but
III/IV months values
NR)
Khan et South District Public Public No July 2004 - 1 685 NR, 27%, NR 12 NR 0.7% Unclear 13.2 NR Failure to 84.1% 85.3% 1.2 84.1% NR
al [88] Africa hospita June 2005 NR, NR months % collect
IAS (Ladysmith l ARVs due
(2009) Provincial to death,
Hospital) LTFU or
TF out
Cohen Lesotho 10 care Public, MOH, No 2006-2008 15 4064 NR NR 12 NR 2.5% Unclear 9.3% NR NR NR NR NR 88.2% NR
et al (Scott) (14), NGO MSF months
[80] IAS district
(2009) hospita
l (1)
Ehmer Lesotho, mixed Mixed Mixed No 2005-2008 8 4362 38, 35%, NR 12 NR 13.9 Unclear 10.3 NR NR NR NR NR 75.8% NR
et al Mozambiq ART 121, 73% months % %
[84] IASue, initiation Stage
(2009) Tanzania, III/IV
Zimbabwe
(Solidarme
d)
Somi et Tanzania mixed Public MOH No Initiated 43 2,78 37, 32%, NR 12 NR 20.0 Unclear 5.0% 5% Alive and 70% NR NR 70% NR
al [92] (National Oct 2004 - 1 114, 77% months % (LTFU not on ART
CROI Represent Aug 2007 Stage defined)
(2011) ative III/IV
Sample)

43
Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators

77
78
Ahonkh South NR NGO PEPFA No Initiated 71 11,3 NR, 48- NR 12 missing all 17.0 Lower NR NR NR NR NR NR NR NR
ai et al Africa R and Jan 2004 - 97 106, NR, months scheduled % (missing (9%
[72] (Catholic NGO Dec 2008 NR appointme for 12 died
CROI Relief (CRS) nts during months) in
(2011) Services) the first 12 the
months first
7
mont
hs)
Bertagn Africa NR Public MOH NR 2002 - 6 829 NR NR 12 WHO EWI 12.9 Same 9.2% 0.8% On first 86.1% 80.3% 14. 65.9% NR
olio et (multiple 2010 months definition % (76/8(5/633 line ART (545/633 (666/82 5% (546/829)
al [76] countries) (excludes (82/6 29) ) at 12 ) 9) (12
CROI TF out and 33) months 0/8
(2011) death from (exclude 29)
denominat TF out
or) and death
from
denomina
tor)
Balestr IeDEA- Mixed NR NR NR 92.5% of NR 19,1 40, NR, 85% ART 12 NR 32.8 Unclear 4.3% NR NR Unclear NR NR 62.90% NR
e et al West patients 31 159, 85% nave, months %
[75] Africa after 2004 advanced 87%
CROI (Benin clinical started
2011 Cote stage NNRTI
d'Ivoire, regimens
Gambia,
Mali
Nigeria,
Senegal)
Notes: HC, healthcare; ART, antiretroviral therapy; WHO, World Health Organization; LTFU, lost to follow up; EWI, early warning indicator; TF, transfer; NR,
not reported; F/U, follow up; MOH, ministry of health; NGO, non-governmental organization; MSF, medecines sans frontiers; NNRTI. Non-nucleoside reverse
transcriptase inhibitors; PI, protease inhibitors; NRTI, nucleoside reverse transcriptase inhibitors;
Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011

44
Table 4. EW I 4 (On tim e ARV pick up) Papers and Abstracts

ART Proportio
Characteristics Study definition will
regimens Duration of n who
of study likely lead to lower
(all ART adherence were
HC Dates Sampl population Type of pharmacy or higher estimates
Simila HC Patien Sites nave at assessme 100%
Author Country settin Provider observe e size Design (median age, adherence measure of on time ARV pick
r EWI facility t pays (n) baseline nt (months adherent
g d (n) %male, median and study definition up than EWI (3
unless over which using
baseline CD4, pickups (a), or 12
otherwise assessed) study
clinical stage) months (b))
stated) definition
4b Chi et al Zambia Mixed Public MOH No Initiated 18 27115 Retrospectiv 35, 38%, 132, NNRTI 12 months MPR measure. 28% Higher (excluded
[37] (2009) Apr 2004 e cohort Stage I or II 33% regimens (0 12) 100% - [(days late to (estimated those who died,
- Apr Stage III 59% pharmacy visits 3) / from LTFU, stopped ART
2007 Stage IV 9% days on ART] graph) who may have been
NB: "less 3" to less adherent)
account for routine
provision of 3 days
extra ART
4b Muyingo et Uganda Research Public DART No Initiated 3 2957 RCT NR, 35%, NR, Triple NRTI 12 months DPR measure. 12% Higher (excluded
al [95] (Kampala, Centers (Trial) Trial Jan 2003 NR 83%, NNRTI (0 12) (Days ART dispensed those who died,
(2008) Entebbe), - Oct regimens - Days ART returned) LTFU, stopped ART
Zimbabwe 2004 17% / Days between visits who may have been
(Harare)) less adherent)
4a Nachega et 9 sub-Saharan Clinics Private Private insure Jan 1998 Multiple 946 Retrospectiv Mean 37, 37%, 100% NNRTI 6 months MPR measure. 60% Higher (all achieved
al [96] countries clinicians d - Mar e Cohort 130 to 157, NR. regimens (varied) Months ART claims viral suppression
(2007) 2003 (NB: All had to submitted (all ARVs) / before adherence
achieve viral months from start to assessed)
suppression to death/leaving/censor (NB: 35% of the
be included) larger study
population [n=2821]
were 100% adherent,
followed median 2.2
yrs)
4a Toure et al Cote d'Ivoire, Clinics NGO, Public Partial Initiated 18 10211 Retrospectiv 36, 30%, 123, 94% NNRTI Variable, MPR measure. 47% Higher (If LTFU
[67] (2008) Abidjan public and ART May e cohort Stage I and II regimens Median 7.7 Days ART given to adherence
(CEPREF and and private 2004 - 19% Stage III months patient / Days since assessment stopped
Aconda private clinicians Feb 2007 69% Stage IV (from ART ART start to last visit, at last visit)
program) 12% start) or censor if last visit
was after censor date
4a Ross- Ethiopia, Hospitals NGO, Public NR Unclear 16 (4 / 488 Retrospectiv Mean 36, 37%, NNRTI and Variable MPR measure. 64% Higher (Had to have
Degnan et Kenya, Rwanda and public and (study country) e cohort NR, Stage I 9% PI regimens Median 6 Days with ART / Days at least 6 months
al [97] and Uganda Clinics and private conducte Stage II 25% II (proportions months since ART start follow up to be in
(2010) private clinicians d after 19% Stage III NR). (from ART study)
2006) 54% Stage IV 4% prior start)
11% ART
4a Gill et al China Clinic Public MOH NR June 1 69 Prospective Mean 36, 74, NNRTI 6 months Pill count measure. 43% Higher (excluded
[94] (2010) 2006 - cohort 319, NR regimens, (varied) Actual number of pills those who died,
May 25% nave at in bottle / expected stopped ART who
2007 baseline number of pills may have been less
adherent)
4b Ceccato et Brazil (Belo Clinic Public MOH No 2006 1 531 Cross 31-40, NR, NR, 46% 12 months MPR measure. 14% Higher (with study
al [98] IAS Horizonte) sectional NR NNRTI (NR) Average time definition may
2010 regimens, between potentially not be on
12% PI dispensations over 12 time every month)
regimens. months was 35
47
Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators

79
80
NR if nave days

Notes: EWI, early warning indicator; HC, healthcare; ART, antiretroviral therapy; PC, Pill Count; MPR, Medication Possession Ratio; ARV,
Antiretroviral; NNRTI. Non-nucleoside reverse transcriptase inhibitors; WHO, World Health Organization; LTFU, lost to F/U; NR, not reported;
NRTI, nucleoside reverse transcriptase inhibitors;
F/U, follow up; MOH, ministry of health; PI, protease inhibitors; TF, transfer
Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011

48
Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators

Table 5. Sum m ary estim ates for EW I 4. On tim e ARV pick -up

Outcome of interest Cohorts Starting Range of List of


(n) ART (n) estimate estimates (%)
s (%)
EWI 4a original definition (studies 4 11714a 43 - 64 43, 47, 60, 64
reporting proportion 100%
adherent)
EWI 4b original definition (studies 3 30603b 12 -28 12, 14, 28
reporting proportion 100%
adherent)
EWI 4a with revised definition 11 14723a 49 - 89 49, 52, 56, 63,
(studies reporting proportion > 76, 77, 80, 82,
95% adherent)c 84, 86, 89
EWI 4b with revised definition 5 31340b 37 - 87 37, 49, 63, 83,
(proportion > 95% adherent)d 87

a
Includes one cohort [67] with 10211 patients
b
Includes one cohort [37]with 27115 patients
c
Includes 2 papers from original definition [67, 94] and 6 new papers [99-104]. 1
study [103] reported different adherence estimates for a standard of care (SOC) and
intervention arm, the SOC estimate was used. 1 paper reported [104] a Pill Count (PC)
and a Medication Possession Ratio (MPR) measure, the MPR measure was used.
d
Includes 2 papers from original definition [37, 95] and 3 new papers [102, 105,
106]. 1 paper [106] reported different adherence estimates for a SOC and
intervention arm, the SOC estimate was used. 1 paper reported [95] a PC and a MPR
measure, the MPR measure was used.

49
81
82
Table 6. EWI 5 (On time appointment keeping) Papers and Abstracts

ART
Characteristic Study definition will
regimen Proportion
s of study Duration of likely lead to lower
s (all meeting
population adherence or higher estimates
Dates ART Study definition of on study
HC HC Patien Sites Start (median age, assessme of on time
EWI Author Country Provider observe Design nave at time appointment definition of
facility setting t pays (n) ART (n) %male, nt (months appointment
d baseline keeping on time
median over which keeping than EWI (3
unless appointment
baseline CD4, assessed) pickups (a), or first
otherwis keeping
clinical stage) 12 months (b))
e stated)

5a Chalker et Kenya Hospitals Public MOH NR Oct 2006 19 373 Retrospectiv 37, 32%, NR, NR 4 months Percentage attending 78.3% Higher (did not
al [100] and and NGO and - June e cohort NR (varied) appointments on or include patients
(2010) Clinics others 2007 before the scheduled LTFU)
day Lower (did not miss
by up to 7 days)
As As above Rwanda Hospitals Public MOH NR Oct 2006 20 285 Retrospectiv 37, 38%, NR, NR 4 months as above 78.4% As above
above and - June e cohort NR (varied)
Clinics 2007
As As above Uganda Hospitals Public MOH NR Oct 2006 19 408 Retrospectiv 37, 32%, NR, NR 4 months As above 71.7% As above
above and and NGO and - June e cohort 79% Stage (varied)
Clinics others 2007 III/IV
As As above Ethiopia Hospitals Public MOH NR Oct 2006 20 565 Retrospectiv 33, 45%, NR, NR 4 months As above 73.5% As above
above - June e cohort 83% Stage (varied)
2007 III/IV
As As above Rwanda Hospitals Public MOH NR Oct 2006 20 285 Retrospectiv 37, 38%, NR, NR 4 months Percentage attending 93.4% As above
above and - June e cohort NR (varied) within 3 days of
Clinics 2007 scheduled
appointment
As As above Uganda Hospitals Public MOH NR Oct 2006 19 408 Retrospectiv 37, 32%, NR, NR 4 months As above 76.3% As above
above and and NGO and - June e cohort 79% Stage (varied)
Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011

Clinics others 2007 III/IV


As As above Ethiopia Hospitals Public MOH NR Oct 2006 20 565 Retrospectiv 33, 45%, NR, NR 4 months As above 87.9% As above
above - June e cohort 83% Stage (varied)
2007 III/IV
5b Blacher et Kenya Referral Public MOH No Initiated 3 566 Clinical trial 32, 100%, 41% 12 months Attend all 49.0% Lower (only late for 4
al [108] (Nairobi), Hospital ART May Stage I and II previous (7 appointments within 3 days to not be on
(2010) Zambia and 2005 - 43% Stage III sdNVP, appointmen days of scheduled time)
(Lusaka) Clinics Jan 2007 49% Stage IV 100% ts) appointment
8% NNRTI
regimens
5b As above Kenya Referral Public MOH No Initiated 3 566 Clinical trial 32, 100%, 41% 12 months Never arriving 4-7 days 79.0%
(Nairobi), Hospital ART May Stage I and II previous (7 late for a scheduled
Zambia and 2005 - 43% Stage III sdNVP, appointmen appointment
(Lusaka) Clinics Jan 2007 49% Stage IV 100% ts)
8% NNRTI
regimens
5b As above Kenya Referral Public MOH No Initiated 3 566 Clinical trial 32, 100%, 41% 12 months Attend all 70.0% Similar
(Nairobi), Hospital ART May Stage I and II previous (7 appointments within 8
Zambia and 2005 - 43% Stage III sdNVP, appointmen days of scheduled
(Lusaka) Clinics Jan 2007 49% Stage IV 100% ts) appointment
8% NNRTI

51
regimens

5a Atukunda Uganda NR NR NR NR Aug 15 763 Cross NR, NR, NR, NR 3 months Not missed 93% Similar to EWI 5a
et al [109] (Kampala) 2008 sectional NR (varied) appointments in the (unclear if LTFU
IAS 2010 last 3 months included)
5a Ugoji et al Nigeria Hospital Public MOH NR May - 1 1140 Retrospectiv NR, NR, NR, NR 3 months Attended within 7 days 53% Similar to EWI 5a
[111] IAS and NGO and October e cohort NR (0-3) of scheduled (included patients
2010 partners partners 2009 appointment LTFU)
(IHV,
PEPFAR)
? 5a or Duong et al Vietnam Mixed Mixed Mixed NR Data 31 11432 ? Cohort or NR, NR, NR, NR NR EWI study Range 52- EWI definition
5b [83] IAS collected adults cross NR 99% across
2010 2009 789 sectional 31 sites. (5
children sites < 80%)
5a Neethling South Clinic Public MOH No May 1 9603 Cross NR, NR, NR, NR 4 months Attended within 7 days 87% Similar to EWI 5a
et al [110] Africa 2007 - sectional NR (NR) of scheduled (unclear if LTFU
IAS 2009 (Themba Aug appointment included)
Lethu) 2008
5b Ahonkhai et South NR NGO PEPFAR No Initiated 71 11,397 Retrospectiv NR, 48-106, NR 12 months Not missed any 63% Similar
al [72] Africa and NGO Jan 2004 e cohort NR, NR appointments in first
CROI 2011 (Catholic (CRS) -Dec 12 months ART
Relief 2008
Services)
Notes: HC, healthcare; ART, antiretroviral therapy; ; EWI, early warning indicator; NGO, non-governmental organization; MOH, ministry of health; LTFU, lost to F/U; TF,
transfer; NR, not reported; F/U, follow up; IAS, International AIDS Society meeting; IHV, Institute of Human Virology; PEPFAR, Presidents Emergency Fund for AIDS
Relief

52
Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators

83
Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011

Table 7. Summary estimates for EWI 5. ART clinic appointment keeping

Outcome of interest Cohort Sampl Range of List of Weighted


s (n) e size estimates estimates Mean (%)
(n) (%) (%)
EWI 5aa 7 13137 53 93.4 53, 76, 78, 84.0
87, 88, 93,
93
EWI 5aa (less one cohort [110] 6 3534 53 93.4 53, 76, 78, 75.8
with 9603 patients) 88, 93, 93
EWI 5b 2b 11963 63, 70 63.3

a
For 1 paper [100] reporting on 4 sub-Saharan countries with 2 different definitions for on time
appointment keeping, one estimate was taken for each country with the more lenient definition (up to 3
days late) used where possible
b
One cohort [72] (n=11397, 63% patients on time), the other cohort [108] (n=566, 70% patients on time)

53
84
Table 8. EWI 6 (Stock-outs) Papers and Abstracts

Characteristi Study definition


ART
cs of study likely lead to lower
regimens Proportio
population or higher estimates
Country (all ART Time n meeting Associations
HC Dates Sampl (median age, of ARV stock-out
Study (cohort or HC Patien Sites nave at since Study definition of study with virological
EWI settin Provider observe e size Design % male, than EWI (site
(year) data facility t pays (n) baseline start of ARV stock out definition or clinical
g d (n) median stock-outs in 12
source) unless ART of ARV outcomes
baseline months (a and b), or
otherwise stock out
CD4, clinical patients affected by
stated)
stage) stock-out)
6c1 Marcellin Cameroon Hospitals Public MOH Yes Recruite 6 533 Cross 37, 29%, 315, 79% on Variable, Patients reporting 17% Lower (survey Stock shortages
et al d Sep - sectional NR first line Median (survey) a shortage doesn't cover whole associated with
[114] Oct 2006 ART 13.9 of all drugs in the 12 months. Excludes ART
(2008) months ART regimen in the death, LTFU, stop interruptions >
(from ART previous 3 months who may have had 48 hrs (self
start) / patients problems with drug report)
interviewed supply)
6b Hedt et Malawi NR Public MOH NR Jan - 103 NR Retrospectiv NR 100% first 12 months EWI definition. 0% of EWI definition
al [115] Dec e line (varied) Sites with stock- sites had
(2008) 2006 regimen out in any 3-month stock-outs
period over 12
months.
6c1 Diabate Cote Hospital Public MOH NR Feb - 1 614 Cross Mean age 36- NNRTI and Variable, "a drug supply 10% Unclear (median
et al d'Ivoire Sep sectional 39, 37%, PI regimens Median 6- interruption in the duration follow up
[117] (Abidjan - 2005 Mean CD4 (proportion 28 months pharmacy" as unclear)
(2007) Unite de 124 - 149, NR s NR) (from ART determined by
Soins start) survey
Ambulatoir
e)
6c1 Eholie et Cote Clinics Public MOH Partial Mar 3 308 Cross Mean 38, 37% Variable, ARV stock-out that 28% Unclear (variable
al [116] d'Ivoire 2002 sectional 47%, NR, NR NNRTI, Mean 19 lead to missing pill period of patient
(2007) (Abidjan - 58% PI and months intake when recall on survey)
Treichville) 5% 3NRTI questioned on
regimens survey
6c2 Pasquet Cote Clinics NGO,
NGO Partial Feb 2006 3 1554 Prospective 36, 27%, 136, 94% Variable, Proportion with 11% Lower (had to result For 975 patients
et al d'Ivoire Public
(CEPREF - Feb cohort Stage I 4% NNRTI Median 13 ARV substitution or in a DC of > 1 month followed for > 6
[118] (Abidjan - and
), Public 2008 Stage II 16% regimens months discontinuation to be considered a months. The
(2010) Aconda) Private
and Stage III 65% (DC) for > 1 month stock out) group with DCs
Private Stage IV 15% due to a stock-out due to stock-out
clinicians (pharmacy records) associated with
, death or LTFU
ACONDA
program
6c1 Spacek Uganda Hospital Public MOH Yes Aug - 1 137 Cross Mean 39, 91% Variable, Missed taking ARV 1% Lower (only asks
et al (Kampala - Dec sectional 46%, , Stage I NNRTI , Median 11 in the prior 2 about a 2 week recall)
[113] Mulago) 2003 0% Stage II 8% PI months weeks as pills not
(2006) 6% Stage III regimens available for
28% Stage IV purchase (survey)
66%
6c1 van Malawi Hospital Public MOH Yes Jul - Nov 1 176 Cross 30, 45%, 100- 100% Variable, Interruption of ART 26% Unclear (median
Oosterho (Blantyre) 2003 sectional 199, Stage I NNRTI Median 6- due to duration follow up
ut et al 4% Stage II regimens 12 months unavailability of unclear)
[112] 23% Stage III Triomune in the
(2005) 32% Stage IV hospital pharmacy
54
Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators

85
86
12% (survey)

6c2 McCurdy Uganda Clinic Public MOH No Initiated 1 453 Retrospectiv 34, 29%, 135, 100% 12 months Proportion who 7% Lower (no data on
et al (Mbarara - 2005 - e Cohort NR NNRTI change active drug stop, incomplete
[120] UARTO) 2009 regimens components of dispensing)
CROI ART excluding
(2010) clinical reasons
(clinic and
pharmacy records)
6c1 Ssali et Uganda Clinic NR NR NR 2005 - 1 3738 Retrospectiv NR, NR, NR, NR NR (< 5 Substituted within 1.5% Unclear (duration of
al [119] (Masaka) 2009 (6.5% e Cohort NR years) the first line F/U unclear, only for
IAS paed) regimen due to drug substitution)
(2010) drug stock out
(clinic and
pharmacy records)
6b Jack et Caribbean NR NR NR NR 2008 58 20794 Cross NR, NR, NR, NR NR EWI definition. 64% of EWI definition
al [121] (10 sectional NR Sites with stock- sites had
IAS countries) out in any month stock-outs
(2010) over 12 months. over 12
months
Notes: EWI, early warning indicator; HC, healthcare; ART, antiretroviral therapy; ARV, Antiretroviral; MOH, ministry of health; LTFU, lost to follow up; NR, not reported;
NNRTI. Non-nucleoside reverse transcriptase inhibitors; PI, protease inhibitors; NRTI, nucleoside reverse transcriptase inhibitors; NGO, non-governmental organization;
F/U, follow up;
Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011

55
Table 9. EWI 8 (Virological suppression) Papers

Baseline Study
ART
features definition will
regimen %
(median Study Proportion likely lead to
s (all Time to HIVDR
Patie Dates Site Start age, % definition meeting study lower or % %
Study HC HC Provid Study ART since % % 2nd outcomes if
Country nt observe s ART male, of VL definition of VL higher ART TF
(year) facility setting er Design nave at ART Died LTFU line reported
pays d (n) (n) median suppressio suppression +/- estimates of stop out
baseline start AR
CD4, WHO n EWI definition VL
unless T
clinical suppression
stated)
stage) than EWI
Bussma Botswana Clinics Public MOH No Initiated 5 650 RCT 33, 31%, 100% 12 VL < 400 92% (OT, Higher (RCT 3.4% 2.4% NR NR At 1 year,
n et al (Gaborone Dec 199, Stage I NNRTI months copies/mL n=586) and OT 5.3% of
[132] - Princess 2002 - 31% Stage regimens 86% ITT (n=624 analysis, also patients on
(2009) Marina 2004. II 25% [Include those ITT analysis ZDV/ddI
Hospital) Followed Stage III who died or doesn't containing
to Apr 34% Stage LTFU]) include stop ART had VF
2006 IV 9% and switch) with
resistance
compared
with 1.0% on
nonZDV/ddI
containing
ART
Bourge Cameroon Clinic Public MOH Partial Initiated 1 109 Cohort 36, 34%, 100% 12 VL < 400 97.3% (OT, Higher (for OT NR at NR at NR NR 4 of 9
ois et al (Yaound) and Jan 2001 150, Stage I NNRTI months copies/mL n=75) analysis) 12 12 at 12 at 12 patients with
[130] NGO - Apr 12% Stage II regimens 86.9% (ITT, Lower mths mths mths mths VL > 5000
(2005) (MSF) 2003 14% Stage n=84 [not (threshold copies
III 54% defined]) 400 copies) developed
Stage IV HIVDR over
20% 30 months
F/U
Seyler Cote Clinic Public MOH Partial Mar Mul 101 Prospe 36, 38%, 100% 12 VL < 200 51% (OT, n=29) Higher (for OT NR at NR NR NR
et al d'Ivoire and 1999 - tipl ctive 135, Stage I NNRTI months copies/mL ITT not possible analysis) 12
[152] (Abidjan - UNAID Aug e Cohort 2% Stage II regimens and not defined Lower mths
(2003) Cotrame) S 2002 12% Stage (threshold
III 48% 200 copies)
Stage IV
39%
Ferradin Malawi District Public MOH No Jan - 1 398 Cross 34, 31%, 99% Median VL < 1000 87% (OT, Higher (OT, NR in NR in NR NR In 52 samples
i et al (Chiradzulu Hospita and April section 114, Stage I NNRTI duratio copies/mL n=397) shorter this this in (> 1000
[45] ) l NGO 2004 al and II 18% regimens n 9.5 duration of sampl sampl this copies), 84%
(2006) (MSF) Stage III , 98% months F/U) e e sam had NRTI
58% Stage ART ple mutations,
IV 24% nave 94% had
NNRTI
mutations
Laurent Senegal Unclear Public MOH Partial Initiated Unc 176 Prospe 38, 48%, 47% 12 VL < 500 77% (OT, Higher (for OT 8.8% NR NR NR 12.5% (n=22)
et al (Free Aug lear ctive 144 NNRTI, months copies/mL n=143) 63% analysis) (at 9.1 developed
[143] if in 1998 - Cohort 43% PI (ITT, n=176 Lower mths HIVDR at
(2005) clinica Apr 2001 (n=80 and 10% [based on entire (threshold media median 30
l trial) also in 2NRTI sample]) 500 copies) n F/U) months F/U.
Clinical regimens (Resistance
trial) . 92% by class: 10%
ART NRTI, 9%

56
Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators

87
88
nave NNRTI, 8%
PI)
Gandhi Sth Africa District Public MOH, No Initiated 1 119 Prospe Mean 34, 100% 12 VL < 400 94% (OT, n=98) Lower 11.0% 5.9% NR NR 5 of 6
et al (Msinga) Hospita and ART Oct ctive 44%, 79, NNRTI months copies/mL 88% (ITT, (threshold patients with
[136] l Partner 2003 - cohort regimens n=105, [Study 400 copies) detectable VL
(2009) Jan 2006 definition, at 12 months
includes LTFU had HIVDR
and not death])
78% (ITT, n=118
[Includes LTFU
and death])
Ahoua Uganda Region Public MOH No Initiated 1 229 Retrosp 37, 34%, NNRTI 12 VL < 1000 89% (OT, ITT same as 5.0% 17.0% 1.0% 5.0% In 20 samples
et al (Arua) al and Sept ective 100, Stage regimens months copies/mL n=229), 69% EWI definition > 1000 copies
[126] Hospita NGO 2004 - cohort III and IV , 98% (ITT, n=297 70% had
(2009) l (MSF) Jul 2005 with 18% ARV [Includes those HIVDR to 1
cross nave at who died, LTFU, ARV. (15% to
section baseline stopped]) EFV and NVP,
al VL 45% to 3TC
analysis and NNRTI,
and 10%
extensive
HIVDR)
Mujugir Botswana Hospita Public MOH No Initiates 1 349 Retrosp 35, 41%, 22 100% 9 VL < 400 92% (OT, n is Higher (OT, 22% 13.5% NR 1.1%
a et al (Gaborone) l Feb - ective NNRTI months copies/mL unclear) also ITT (at 12 (at 12 (at
[146] (Prince Mar cohort regimens 60% (ITT, n is analysis, as a mths) mths) 12
(2009) ss 2002 unclear 9 mth mths
Marina [Includes death outcome) )
/ IDCC) and LTFU])
Fielding Sth Africa Hospita Private Compa No Initiated 39 1760 Retrosp 41, 97%, NNRTI 12 VL < 400 72% (OT, Lower 9.9% 11.4% See 12.1 1.2
et al ls and (Workpl ny prior Jul ective 156, 73% regimens months copies/mL n=953) 51% (threshold (LTFU LTFU % %
[135] Clinics ace) (Anglo 2004. cohort Stage III and (ITT, n=1328 400 copies) +
(2008) Americ Followed IV [Excludes TF out stop)
an) to Mar and those with
2006 no VL test])
Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011

Bisson sub- NR Private Private Privat Initiated Mul 872 Retrosp 55% < 35 100% 12 VL < 1000 74% (OT, Higher (OT NR NR NR NR
et al Saharan (workpl clinicia e Dec tipl ective yrs old, NNRTI months copies/mL n=872) analysis)
[129] Africa (9 ace) ns insura 2000 - e cohort 37%, 165 regimens
(2008) countries) nce Feb
2003
Nacheg sub- Clinics Private Private No Initiated Mul 7776 Retrosp 37, 38%, 97% 12 VL < 400 62% (OT, Higher (OT) NR NR NR NR
a et al Saharan (workpl clinicia (insure Jan 1999 tipl ective 146 NNRTI, months copies/mL n=3192) Lower
[148] Africa (9 ace) ns d, no - Aug e cohort 3% PI (threshold
(2009) countries) copay 2006 regimens 400 copies)
ment)
Garrido Angola Clinic NR NR NR NR 1 294 Cross 36, 28%, 89% Median VL < 1000 74% (OT, Higher (OT NR NR NR NR 18 of 23
et al section 144 NNRTI Duratio copies/mL n=294) analysis) samples had
[137] al regimens n 12.6 HIVDR
(2008) , 20% months mutations
prior (including 15
ARV with M184V,
exposur 9 with K103N)
e
Vanni et Brazil Clinic Public MOH No Jan 2002 1 126 Retrosp 37, 69% 60% 12 VL < 400 65% (ITT, n=? Lower NR NR NR NR
al [153] (Ribeira - Dec ective EFV months copies/mL [Dropouts and (threshold
(2007) Porto) 2003 cohort regimens switches were 400 copies)
, 40% treatment
57
Nelfinavi failures])
r
regimens
.
Ndembi Uganda Resear Public DART No Initiated 2 600 RCT 37, 28%, 99, 50% 48 VL < 50 77% NNRTI Lower 4.2% 2.0% 1.0% 0% 0%
et al (Kampala, ch (Trial) Trial Jan - (300 WHO stage NNRTI , weeks copies/mL group (threshold
[149] Entebbe - Centers Oct 2004 in III 55% 50% 62% 3NRTI <50 copies)
(2010) DART sub each Stage IV 3NRTI group (ITT, Higher (RCT)
study) arm) 18% regimen n=600)
As 600 48 VL < 1000 87% NNRTI Higher (RCT) 4.2% 2.0% 1.0% 0% 0% 89 specimens
above (300 weeks copies/mL group (> 1000
in 79% 3NRTI copies) had
each group (ITT, genotypic
arm) n=600) results.
NVP arm -
75% K103N
and 71%
M184V,
Abacavir arm
- 88% M184V
Anonwa Thailand Resear Public STACC No Initiated 7 272 RCT Mean age 100% 48 VL < 400 96% (OT, n=164 Lower NR 6.0% NR NR NA
ronich ch (Trial) ATO ART 34, 39%, boosted weeks copies/mL [All on (threshold
et al Centers Trial after CDC Cat A PI continuous 400 copies)
[127] 2001 71%, Cat B regimen. treatment from Higher (RCT,
(2008) 28% Cat C both arms]) also OT)
2% 79% (ITT n=129
[Exclude
treatment
interruption arm
and ITT for all in
continuous
treatment arm])
As 48 VL < 50 93% (OT, Lower NR 6.0% NR NR NA
above weeks copies/mL n=164) (threshold 50
69% (ITT n=129) copies)
Analysis as Higher (RCT,
above also OT)
Idoko et Nigeria Referral Public 175 Clinical 35, 40%, 67, 100% 48 VL < 400 (All OT, n=145) Lower
al [139] (Jos) Hospita trial Stage I 3% NNRTI weeks copies/mL 91% daily DOT, (threshold
(2007) l Stage II 12% regimens 88% twice 400 copies)
Stage III weekly DOT, Higher (OT)
43% Stage 84% weekly
IV 38% DOT, 79% no
DOT
Bussma Botswana Region Public MOH No Initiated 1 633 Retrosp 35, 40%, 67, 100% 12 VL < 400 91% (OT, n = Higher (OT) 17.3% 8.9% NR NR
n et al (Gaborone al Jan - ective Stage I 3% NNRTI months copies/mL 467 67% (ITT, Lower at 12
[131] - Princess Hospita Aug Cohort Stage II 12% regimens n=633 [Includes (threshold mths
(2008) Marina l 2002 Stage III 43 death and LTFU) 400 copies)
Hospital) Stage IV 38
(NB
different to
[132])
Kouanf Cameroon Hospita Public MOH Partial Enrolled 1 249 Cross 35 to 40 99% 12 VL < 500 78% (OT, Higher (OT) NA NA NA NA NA 11 of 34
ack et (Yaound) l Nov section years, 29%, NNRTI months copies/mL n=249) Lower samples (>
al [141] 2006 - al NR, NR regimens (threshold 1000 copies)
(2009) Oct 2007 500 copies) had 1 major
58
Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators

89
90
mutation
As 12 VL < 1000 84% (OT, Higher (OT) NA NA NA NA NA
above months copies/mL n=249)
Djoman Cote Clinics Public
MOH Partial Initiated 6 276 Retrosp 35, 50%, 80% PI, 1 year VL < 200 50% (ITT, Lower unclea unclea
d et al d'Ivoire and ART Aug ective 182 (study 19% copies/mL n=276. [ITT (threshold r r
[28] (Abidjan) partner 1998 - cohort patients NNRTI defined as those 200 copies)
(2003) s May from a group or 1% who returned for
(UNAID 2000 with these 3NRTI 1 visit after
S, features) regimens start])
CDC)
Sarna Kenya Clinics Public MOH No Initiated 3 137 RCT 37, 36%, 96 NNRTI 12 VL < 400 82% (OT, n=137 Higher (OT) unclea unclea
et al (Mombasa) (2), and Sept to 106, NR regimens months copies/mL [78% control Lower r r
[103] Private partner 2003 - arm 88% DOT (threshold
(2008) (1) s Nov arm]) 400 copies)
2004
Landma Senegal Hospita Public MOH No Initiated 1 40 Clinical Mean 38, 100% 12 VL < 400 94% (OT, n=35) Higher (OT, 7.5% 5.0% 0% 0%
n et al (Dakar) l and Jun - trial 40%, NNRTI months copies/mL 83% (ITT, n=40) RCT)
[142] Partner Dec Median 111, regimens Lower
(2009) (Pharm 2004 CDC cat A (threshold
a) 7.5% cat B 400 copies)
70% cat C
22.5%
As VL < 50 83% (OT, n=35) Higher (OT, 7.5% 5.0% 0% 0%
above copies/mL73% (ITT, n=40) RCT)
Lower
(threshold 50
copies)
Barth et Sth Africa Clinic NGO Local No Initiated 1 609 Retrosp 35, 29%, 67, 100% 12 VL < 400 83% (OT, Higher (OT) 19.0% 15.0% NR NR
al [31] (Ndlovu) NGO Sept ective Stage I 10% NNRTI months copies/mL n=407) 55% Lower
(2008) 2003 - Cohort Stage II 10% regimens (ITT, n=609) (threshold
Apr 2006 Stage III 400 copies)
62% Stage
IV 17%
As VL < 50 70% (OT, Higher (OT) 19.0% 15.0% NR NR
Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011

above copies/mL n=407) 46% Lower


(ITT, n=609) (threshold 50
copies)
Bedelu Sth Africa Hospita Public NGO No Initiated 1 430 Retrosp NR Regimen median VL < 400 78% (OT, n=41) Higher (OT) 13.5% 19.3% NR NR
et al (Lusikisiki) l (MSF) Jan - ective s NR 12 copies/mL Lower
[128] and June cohort months (threshold
(2007) DOH 2005. 400 copies)
Followed
to July
2006
As Clinic Public NGO No Initiated 12 595 Retrosp NR Regimen median VL < 400 90% (OT, Higher (OT) 16.8% 2.2% NR NR
above (MSF) Jan - ective s NR 12 copies/mL n=296) Lower
and June cohort months (threshold
MOH 2005. 400 copies)
Followed
to July
2006
Nacheg Sth Africa Hospita Public MOH No Feb 1 274 RCT 36, 42%, 98, 100% 13 VL < 400 90% (OT, Higher (RCT, 11% 7% NR NR
a et al (Soweto) l 2005 - Stage III NNRTI months copies/mL n=213) 71% OT) (over (over
[147] Jul 2008 45% Stage regimens (ITT, n=272) Lower 96 96
(2010) IV 46% (threshold weeks weeks

59
400 copies) F/U) F/U)
Ramad Tanzania Referral Public MOH Partial Jun - 1 150 Cross 41, 37%, 100% median VL < 400 68% (OT, Higher (OT) NA NA NA NA 15 of 27 (>
hani et (Kilimanjaro Hospita Aug section 114 NNRTI 12 copies/mL n=150) Lower 1000 copies)
al [151] ) l 2008 al regimens months (threshold had 1
(2007) 400 copies) mutation to
NRTI or
NNRTI
As VL < 1000 77% (OT, Higher (OT) NA NA NA NA
above copies/mL n=150)
Kamya Uganda Clinic Public MOH No Initiated 1 526 Prospe Mean 37, 100% 12 VL < 400 87% (OT, Lower 10% 0.4% NR NR
et al (Makerere, Apr 2004 ctive 31%, 99, NNRTI months copies/mL n=454) 75% (threshold (for a (for a
[140] Ulago) - Jun Cohort Stage I 0.4% regimens (range (ITT, n=523) 400 copies) larger larger
(2007) 2005 Stage II 11% 285 - cohort cohort
Stage III 485 ) )
54% Stage days)
IV 34%
Charles Haiti Clinic NGO NGO No Initiated 1 146 Retrosp NR, 34%, 78% 12 VL < 50 49% (OT, n=79) Higher (OT) 19% 15% NR NR
et al (GHES ART Mar ective 129, Stage I NNRTI months copies/mL Lower (with (with
[133] KIO) 2003 - Cohort 12% Stage II regimens (threshold 50 media media
(2008) Dec and III 40% copies) n F/U n F/U
2005 Stage IV 18 18
49% mths) mths)
Blacher Kenya, Referral Public MOH No Initiated 3 661 Clinical 32, 100%, 41% 12 VL < 400 87% (OT, Higher (OT NR NR NR NR 4.8
et al Zambia Hospita ART May trial Stage I and previous months copies/mL n=563) 74% analysis) %
[108] l and 2005 - II 43% Stage sdNVP, (ITT, n=661) Lower
(2010) Clinics Jan 2007 III 49% 100% (threshold
Stage IV 8% NNRTI 400 copies)
regimens

Fatti et South Hospita Public MOH No Initiated 59 2920 Retrosp 34, 32%, 100% 12 VL < 400 87% (OT, Higher (OT 6.3%
al [134] Africa ls and and ART Dec 3 ective 114, Stage NNRTI months copies/mL n=6725) analysis)
(2010) (Western Clinics NGO 2004 - Cohort III and IV regimens Lower
Cape, (Absolu Dec 76% (threshold
Eastern te 2007 400 copies)
Cape, KZ- return
Natal, for kids)
Mpumalan
ga [not
IeDEA])
Hegazi The Clinic Public MOH No Initiated 1 147 Retrosp 36, 39%, 75% 12 VL < 100 75% (OT, n=79) Higher (OT
et al Gambia and ART Oct ective NR, NR NNRTI months copies/mL analysis)
[138] NGO 2005 - Cohort regimens Lower
(2010) (NIH Jan 2007 , 25% (threshold
study boosted 100 copies)
site) PI
regimens
Lester Kenya Hospita Public MOH No Initiated 3 538 RCT 37, 35%, 100% 12 VL < 400 71% (OT, Higher (OT 10.2% 8.2% NR 0.9% NR
et al (Nairobi l and ART May 161-168, NNRTI months copies/mL n=402), 53% analysis)
[144] [Pumwani, Clinics 2007 - Stage I 21%, regimens (ITT, n=533 Lower
(2010) Coptic Oct 2008 Stage II excludes TF out (threshold
Hope 23%, Stage from denom) 400 copies)
center], III 38%,
Kajiado) Stage IV 4%
Lyagob Uganda Resear Public DART No Initiated 2 300 RCT NR, NR, 100% 12 VL < 200 71% (OT, Higher (OT 6.3%
a et al (Kampala, ch (Trial) Trial Jan - (DART 108, Stage 3NRTI months copies/mL n=272), 64% analysis)
[145] Entebbe - Centers Oct 2004 substu III 51%, (AZT/3T (ITT, n=300) Lower
60
Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators

91
92
(2010) DART sub dy) Stage IV C/TDF) (threshold
study) 25% 400 copies)
As VL < 1000 77% (OT, Higher (OT 6.3% 47 /64 +ve
above copies/mL n=272), 69% analysis) VLs had
(ITT, n=300) genotype and
no baseline
HIVDR. 41/47
(87%) had an
NRTI
mutation
Moore Malawi Region Public MOH No Initiated 1 300 Prospe mean 36, 100% 12 VL < 400 83% (OT, Higher (OT 14.3% 2.7% 5.3% 5.3% NR
et al (Blantyre) al 2005 ctive 39%, mean NNRTI months copies/mL n=212), 62% analysis)
[58] Hospita cohort 157, Stage regimens (ITT, n=284 i.e. Lower
(2010) l IV 29% excludes TF out (threshold
from denom) 400 copies)
Muteve Sth Africa Hospita Public MOH No Initiated 16 3010 Retrosp 34-37, 22%, 100% 12 VL < 25 77% (OT, Higher (OT 10.9% 3.7% NR 1.4% NR
dzi et al (KZ- Natal l and ART Oct ective 91-128, NR NNRTI months copies/mL n=758) analysis)
[59] [not IeDEA- Clinics 2004 - Cohort regimens Lower
(2010) SA]) Sept (threshold 25
2007 copies)
Oyomo Asia Mixed Mixed Mixed NR Initiated 17 784 Prospe NR, 75%, 69% 12 VL < 400 79% (OT, n=204 Higher (OT
pito et (TAHOD) ART ctive NR, NR NNRTI months copies/mL from low income analysis)
al [150] after cohort regimens sites), 84% (OT, Lower
(2010) 2000 , 29% PI n=581 from high (threshold
regimens income sites) 400 copies)
, 2%
3NRTI
regimens
Zhou et Asia Mixed Mixed Mixed NR Recruite 18 1676 Prospe 36, 74%, 63% 12 VL < 400 82% (OT, Higher (OT
al [154] (TAHOD) d after ctive 140, CDC NNRTI months copies/mL n=1676. analysis)
(2010) 2003 cohort Stage A regimens Includes high Lower
(date of 58% Stage , 35% PI income sites) (threshold
ART B 6% Stage regimens 400 copies)
initiation C 38% , 2%
Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011

NR)
Notes: HC, healthcare; ART, antiretroviral therapy; WHO, World Health Organization; LTFU, lost to follow up; EWI, early warning indicator; TF, transfer; HIVDR, HIV
drug resistance; RCT, randomized clinical trial; NNRTI. Non-nucleoside reverse transcriptase inhibitors; VL, viral load; OT, on treatment; ITT, intention to treat; NR, not
reported; F/U, follow up; ZDV, zidovudine; VF, virological failure; MOH, ministry of health; NGO, non-governmental organization; MSF, medecines sans frontieres; mths,
months; PI, protease inhibitors; NRTI, nucleoside reverse transcriptase inhibitors; VL, viral load; 3NRTI, triple nucleoside reverse transcriptase inhibitors; EFV, efavirenz;
NVP, nevirapine; DOT, directly observed therapy; NA, not applicable;

61

Table 10. EWI 8 (Virological suppression) Abstracts

Baseline
Study
features
ART Proportion definition will
(median Proportion
HC regimens Study meeting likely lead to
age, % Time Study meeting Translate VL % to Association
Author facility, Start (all ART definition study lower or % %
Patient Dates Sites Study male, since definition of study failure / % % 2nd with HIVDR
and Country HC ART nave at of VL definition higher ART TF
pays observed (n) Design median ART VL definition of rebound into Died LTFU line outcome
meeting setting, (n) baseline failure / of VL estimates of stop out
CD4, start suppression VL VL suppression ART
Provider unless rebound failure / VL
WHO suppression
stated) rebound suppression
clinical
than EWI
stage)

Marconi Argentina NR, NR, No NR 1 104 Retrosp 35, 100% 1 NR NR NR 7.7% (OT, 92.3% (OT, Higher (OT), NR NR NR NR NR All patients
et al (Rosario) NR ective "mostly HAART year n=104) n=104) Unclear (no who had VF
[162] IAS cohort male", threshold had baseline
2010 NR, NR defined) HIVDR
Kiragga Uganda Hospital, No NR 1 559 Prospect NR, 100% 12 NR NR NR 24.9% (OT, 75.1% (OT, Higher (OT), NR NR NR NR NR
et al (IDI cohort) Mixed, ive 71.2%, NNRTI mths n=105) n=105) Lower (all had
[160] IAS Mixed cohort regimen immunolgical
2010 failure)
Unclear (no
threshold
defined)
Chasom Thailand Mixed, No Initiated 6 304 Retrosp 38; 1.2:1 100% 12 NR NR > 1000 5.9% (OT, 94.1% (OT, Higher (OT) 8.9% NR NR NR NR 1of 5 with
bat et al (Nonthabu Public, Feb Sep ective M:F; 56; NNRTI mths copies/mL n=269) n=269), baseline
[78] IAS ri, Chiang MOH 2006 cohort NR regimen 83.2% (ITT, HIVDR had
2010 Rai, n=304 [include VF at 1 year.
Lumpang, those who died 15 of 264
Lumphun) and remaining with no
2%]) baseline
HIVDR had
VF at 1 yr. (7
of the 15
developed
HIVDR)
Crabtree Mexico Clinic No 2001- 1 348 Retrosp 33, 72%, 100% 12 NR NR any VL > 50 7.5% (OT, 93.3% (OT, Higher (OT) NR at NR at NR NR NR
-Ramirez (INCMNS 2007 ective NR, NR HAART mths copies/mL n=348) n=348) Lower 12 12
et al Z), Public, cohort from 6 - 12 (threshold 50 mths mths
[157] IAS MOH months copies)
2010
Scarsi et Nigeria NR, NR, No Jan 2006 - NR 5894 Retrosp 34.2, 74.6% 48 NR NR >1000 10.1% (OT, 89.9% (OT, Higher (OT) 19.6 See NR See
al [167] (PEPFAR NR Dec 2007 ective 24.8%, AZT/3TC/ week copies/mL n=2366), n=2366) Lower (VL % died died
IAS 2010 programs) cohort NR, NR NVP; s at 24 AND 29.7% (ITT, 70.3% (ITT, outcome at 6 died
25.4% 48 weeks n=? Include n=?) and 12 LTFU,
TDF/3TC/ 19.6% months) or TF
NVP (n=5894) out
to OT data)
Stafford Uganda, NR, AIDS No NR NR 737 Cross- NR 100% 9-15 NR 88.1% (OT, NR NR NR Higher (OT) NR NR NR NR NR
et al Zambia relief sectiona NNRTI mths n=737)
[168] IAS (IHV) sites, NR l regimens
2009
Chang et Uganda Clinic, NR, No May 2006 15 1338 RCT NR NR 48 NR NR >400 10.6% (OT, 89.4% (OT, Higher (OT) NR NR NR NR NR
al [156] (Rakai) NR - June week copies/ml n=606) n=606) Lower
IAS 2009 2008 s (threshold
58
Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators

93

94

400 copies)
Calmy et IeDEA of Mixed, No NR NR 3020 Retrosp 34, 37%, 96% 12 < 500 89% (OT, NR NR NR Higher (OT) NR NR NR NR NR
al [155] ART-LINC Mixed, ective 91, NR NNRTI mont copies/mL n=3020) Lower
IAS 2009 countries Mixed cohort regimen hs (threshold
500 copies)
Messou Cote Clinic, NR, No Feb 2006 3 1545 Prospect NR 100% 12 NR NR 300 25% (OT, 75.0% (OT, lower 39.1 NR NR NR NR 51% with VF
et al d'Ivoire NR - May ive NNRTI mont copies/ml n=928) n=928) (threshold % had 1
[164] 2007 cohort regimen hs 300 copies) mutation
CROI (NNRTI
2010 91.5%,
3TC/FTC
69% and
ZDV and/or
d4T 9.4%).
McIntire 7 African NR, NR, NR NR NR 500 RCT 34, NR, 50% 48 NR NR <1 log VL 14% (ITT, 86% (ITT, Higher (RCT) NR NR NR NR NR
et al countries NR (OCTAN 121, NR NNRTI week drop at 12 n=500) n=500) Lower
[163] E II) regimen, s weeks , (threshold
CROI 50% or > 400 400 copies
2010 LPV/r copies/mL and need for
regimen at or after early VL drop)
24 weeks
Ratsela South NR, NR, No 2004- 6 1771 Random NR, NR, PI or 12 < 400 66% (ITT, NR NR NR Lower NR NR NR NR NR
et al Africa NR 2008 ized 106, NR NNRTI mths copies/mL n=1771) (threshold at 48
[165] (Military) factorial regimen 400 copies) week
CROI trial s
2009
Geng et Uganda Clinic, No June 6 350 Prospect NR 100% 1 NR NR 400 8.8% (OT, 91.2% (OT, Higher (VF NR NR NR NR NR
al [159] (Mbarara Mixed, 2005-Aug ive NNRTI year copies at 3 n=350 n=350) threshold
CROI UARTO MOH 2008 cohort or 6 mths [cumulativ 10,000
2009 cohort) followed e copies/mL,
by >10,000 incidence]) initial VL
copies/mL suppression)
Lower
(cumulative
Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011

incidence of
VF)
Lockman Botswana NR, NR, No NR 1 178 RCT NR, 0%, 100% 12 NR NR > 400 7.9% (ITT, 92.1% (ITT, Higher (RCT) NR NR NR NR NR
et al (Mashi NR NR, NR NNRTI nths copies/mL n=178) n=178) Lower
[161] Study) regimen (threshold
CROI 400 copies,
2009 cumulative
incidence of
VF)
Bertagno Africa NR, NR 2002 - 6 829 Prospect NR NR 12 WHO EWI 90% (OT, higher (OT) 9.2% 12.9 0.8 14.5 0.2 Of the 10%
lio et al (many Public, 2010 ive mont definition n=460) % % % % (n=46) not
[76] countries) MOH cohort hs (threshold suppressed,
CROI NR) 43% (i.e.
2011 n=20) had
HIVDR
Fox et al IeDEA-Sth NR, NR, NR NR 8 44,20 Retrosp NR, 41%, 100% 12 2 VLs ( 2 96% (OT, Higher (OT, NR NR NR NR NR
[158] Africa NR progr 4 ective 121, > NNRTI mont weeks apart) n=32525) need 2
CROI ams cohort 65% regimen hs < 400 copies positive viral
2011 Stage after 24 loads)
III/IV weeks ART Lower (lower
VL threshold)

59


As above ` 2 VLs ( 2 96% (OT, Higher (OT, NR NR NR NR
weeks apart) n=32603) need 2
< 1000 positive viral
copies after loads)
24 weeks
ART
As above 2 VLs ( 2 97% (OT, Higher (OT, NR NR NR NR
weeks apart) n=32759) need 2
< 5000 positive viral
copies after loads, higher
24 weeks VL threshold)
ART
As above 2 VLs ( 2 98% (OT, Higher (OT, NR NR NR NR
weeks apart) n=32847) need 2
< 10000 positive viral
copies after loads, higher
24 weeks VL threshold)
ART
Wester Botswana NR, NR, NR NR NR 434 RCT 34, 32%, 100% 12 NR 97% (OT, Higher (OT) 5.5% NR NR NR NR
et al NR 199, NR NNRTI mont n=? 410 i.e.
[169] regimen hs 434 less
CROI deaths)
2011
Reynolds Uganda Institute, NR 2004 - 1 559 Prospect NR, NR, Regimens 12 VL < 400 88% (OT, Higher (OT) NR NR NR NR NR HIVDR
et al (Kampala - NR, NR 2008 ive 86-96, NR NR mont copies/mL n=441) Lower outcomes
[166] IDI) cohort hs 69% (ITT, (threshold reported
CROI n=559) 400 copies) after 3 years
2011 of ART

Notes: HC, healthcare; ART, antiretroviral therapy; WHO, World Health Organization; LTFU, lost to F/U; EWI, early warning indicator; TF, transfer; HIVDR, HIV drug
resistance; HAART, highly active antiretroviral therapy; NNRTI. Non-nucleoside reverse transcriptase inhibitors; mths, months; VL, viral load; OT, on treatment; ITT,
intention to treat; NR, not reported; F/U, follow up; MOH, ministry of health; RCT, randomized clinical trial; VF, virological failure

60
Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators

95

Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011

Table 11. Summary estimates for EWI 8 (Virological suppression)

Virological suppression Cohort Startin Median Range of Weighte


Outcome of interest s (n)a g ART estimat estimates d mean
(n) e (%) (%) (%)
On treatment (all available)b 53 69115 87 49 - 97 90.6c
On treatment (thresholds 13 42804 89 74 - 96 94.3d
1000 copies/mL)
On treatment (threshold 1000 11 38161 87 74 - 96 94.4e
copies/mL)
On treatment (thresholds 41 61383 83 49 - 97 89.2f
500 copies/mL)
Intention to treat (all 29 19527 70 50 - 92 69.8
available)b
Intention to treat (threshold 4 1201 76 69 - 87 77.1g
1000 copies/mL)
Intention to treat (thresholds 26 13032 70 50 - 92 68.9
500 copies/mL)

a
Includes papers and abstracts
b
If proportions reported for 2 different thresholds in the one cohort then data for the threshold closest to
1000 copies/mL used
c
Same analysis excluding 1 abstract (Fox et al [158]) accounting for 32603 subjects resulted in weighted
mean 85.8%
d
Same analysis excluding 1 abstract (Fox et al [158]) accounting for 32603 subjects resulted in weighted
mean 88.9%
e
Same analysis excluding 1 abstract (Fox et al [158]) accounting for 32603 subjects resulted in weighted
mean 85.3%
f
Same analysis excluding 1 abstract (Fox et al [158]) accounting for 32603 subjects resulted in weighted
mean 81.6%
g
An additional abstract (Scarsi et al [167]) accounting for 5894 subjects was excluded from this analysis.
When included, weighted mean for the 5 cohorts (n=7095) was 71.4%

65
96
Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators

APPENDIX 1

Search Strategy: Lost to follow up and retention


--------------------------------------------------------------------------------
1 exp Antiretroviral Therapy, Highly Active/ (13213)
2 exp HIV Infections/ (198617)
3 exp HIV/ (70704)
4 exp Anti-Retroviral Agents/ (51271)
5 1 or 2 or 3 or 4 (237850)
6 (resource limited or resource constrained or developing countr* or low income countr* or
"low and middle income countr*").tw. (32450)
7 (africa* or afrika* or "sub sahara*" or southern africa* or asia* or latin america* or south
america*).tw. (166542)
8 exp Africa/ (151724)
9 exp Asia/ (394665)
10 caribbean region/ or central america/ or latin america/ or south america/ (15057)
11 6 or 7 or 8 or 9 or 10 (657853)
12 exp African Americans/ (33865)
13 exp Asian Americans/ (4265)
14 12 or 13 (37133)
15 11 not 14 (638182)
16 lost to follow up.tw. (9266)
17 lost to followup.tw. (427)
18 loss to follow up.tw. (1249)
19 loss to followup.tw. (22)
20 retention.tw. (93003)
21 attrition.tw. (4883)
22 exp Patient Dropouts/ (5674)
23 16 or 17 or 18 or 19 or 20 or 21 or 22 (112858)
24 5 and 15 and 23 (478)
25 limit 24 to (english language and yr="2003 -Current") (376)
26 limit 25 to clinical trial, all (80)
27 25 not 26 (296)
28 limit 27 to ("all infant (birth to 23 months)" or "preschool child (2 to 5 years)" or "child (6 to
12 years)") (59)
29 27 not 28 (237)

66

97
Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011

APPENDIX 2

Search Strategy: On time ARV drug pick-up


--------------------------------------------------------------------------------
1 exp Antiretroviral Therapy, Highly Active/ (13213)
2 exp HIV Infections/ (198617)
3 exp HIV/ (70704)
4 exp Anti-Retroviral Agents/ (51271)
5 1 or 2 or 3 or 4 (237850)
6 (resource limited or resource constrained or developing countr* or low income countr* or
"low and middle income countr*").tw. (32450)
7 (africa* or afrika* or "sub sahara*" or southern africa* or asia* or latin america* or south
america*).tw. (166542)
8 exp Africa/ (151724)
9 exp Asia/ (394665)
10 caribbean region/ or central america/ or latin america/ or south america/ (15057)
11 6 or 7 or 8 or 9 or 10 (657853)
12 exp African Americans/ (33865)
13 exp Asian Americans/ (4265)
14 12 or 13 (37133)
15 11 not 14 (638182)
16 exp Medication Adherence/ (2510)
17 exp Patient Compliance/ (42699)
18 complian*.mp. or adheren*.tw. [mp=protocol supplementary concept, rare disease
supplementary concept, title, original title, abstract, name of substance word, subject heading
word, unique identifier] (158451)
19 16 or 17 or 18 (159244)
20 exp Pharmacy/ (17680)
21 exp Prescriptions/ (21284)
22 (pill* count* or pick* up* or pickup* or on time or ontime or MPR or drug possession or
medication possession).tw. (12844)
23 20 or 21 or 22 (51495)
24 5 and 15 and 19 and 23 (54)
25 limit 24 to (english language and yr="2003 -Current") (47)
26 limit 25 to ("all infant (birth to 23 months)" or "preschool child (2 to 5 years)" or "child (6 to
12 years)") (5)
27 25 not 26 (42)

67
98
Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators

APPENDIX 3

Search Strategy: On time appointment keeping


--------------------------------------------------------------------------------
1 exp Antiretroviral Therapy, Highly Active/ (13213)
2 exp HIV Infections/ (198617)
3 exp HIV/ (70704)
4 exp Anti-Retroviral Agents/ (51271)
5 1 or 2 or 3 or 4 (237850)
6 (resource limited or resource constrained or developing countr* or low income countr* or
"low and middle income countr*").tw. (32450)
7 (africa* or afrika* or "sub sahara*" or southern africa* or asia* or latin america* or south
america*).tw. (166542)
8 exp Africa/ (151724)
9 exp Asia/ (394665)
10 caribbean region/ or central america/ or latin america/ or south america/ (15057)
11 6 or 7 or 8 or 9 or 10 (657853)
12 exp African Americans/ (33865)
13 exp Asian Americans/ (4265)
14 12 or 13 (37133)
15 11 not 14 (638182)
16 exp "Appointments and Schedules"/ (12325)
17 exp "Referral and Consultation"/ (49238)
18 appoint*.mp. or attend*.tw. [mp=protocol supplementary concept, rare disease
supplementary concept, title, original title, abstract, name of substance word, subject heading
word, unique identifier] (101390)
19 16 or 17 or 18 (152818)
20 exp Time Factors/ (884377)
21 on time.tw. (6363)
22 exp Chronology as Topic/ (756)
23 date.tw. (107337)
24 20 or 21 or 22 or 23 (990703)
25 5 and 15 and 19 and 24 (85)
26 limit 25 to (english language and yr="2003 -Current") (60)
27 limit 26 to ("all infant (birth to 23 months)" or "preschool child (2 to 5 years)" or "child (6 to
12 years)") (8)
28 26 not 27 (52)

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APPENDIX 4

Search Strategy: ARV Stockouts


--------------------------------------------------------------------------------
1 exp Antiretroviral Therapy, Highly Active/ (13213)
2 exp HIV Infections/ (198617)
3 exp HIV/ (70704)
4 exp Anti-Retroviral Agents/ (51271)
5 1 or 2 or 3 or 4 (237850)
6 (resource limited or resource constrained or developing countr* or low income countr* or
"low and middle income countr*").tw. (32450)
7 (africa* or afrika* or "sub sahara*" or southern africa* or asia* or latin america* or south
america*).tw. (166542)
8 exp Africa/ (151724)
9 exp Asia/ (394665)
10 caribbean region/ or central america/ or latin america/ or south america/ (15057)
11 6 or 7 or 8 or 9 or 10 (657853)
12 exp African Americans/ (33865)
13 exp Asian Americans/ (4265)
14 12 or 13 (37133)
15 11 not 14 (638182)
16 (stockout* or stock out* or drug suppl* or stock shortage* or out of stock).tw. (608)
17 5 and 15 and 16 (56)
18 limit 17 to (english language and yr="2003 -Current") (34)
19 limit 18 to ("all infant (birth to 23 months)" or "preschool child (2 to 5 years)" or "child (6 to
12 years)") (5)
20 18 not 19 (29)

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APPENDIX 5

Search Strategy: Virological suppression


--------------------------------------------------------------------------------
1 exp Antiretroviral Therapy, Highly Active/ (13213)
2 exp HIV Infections/ (198617)
3 exp HIV/ (70704)
4 exp Anti-Retroviral Agents/ (51271)
5 1 or 2 or 3 or 4 (237850)
6 (resource limited or resource constrained or developing countr* or low income countr* or
"low and middle income countr*").tw. (32450)
7 (africa* or afrika* or "sub sahara*" or southern africa* or asia* or latin america* or south
america*).tw. (166542)
8 exp Africa/ (151724)
9 exp Asia/ (394665)
10 caribbean region/ or central america/ or latin america/ or south america/ (15057)
11 6 or 7 or 8 or 9 or 10 (657853)
12 exp African Americans/ (33865)
13 exp Asian Americans/ (4265)
14 12 or 13 (37133)
15 11 not 14 (638182)
16 exp Viral Load/ (15677)
17 hiv rna.tw. (3224)
18 virologic*.tw. (14502)
19 (resistance or genotyp* or drug resistance).tw. (478442)
20 16 or 17 or 18 or 19 (501445)
21 5 and 15 and 20 (3361)
22 (1 year or one year or 12 month* or twelve month* or first year*).tw. (253768)
23 exp Time Factors/ (884377)
24 22 or 23 (1107096)
25 21 and 24 (411)
26 limit 25 to (english language and yr="2003 -Current") (338)
27 limit 26 to ("all infant (birth to 23 months)" or "preschool child (2 to 5 years)" or "child (6 to
12 years)") (90)
28 26 not 27 (248)

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135. Fielding KL, Charalambous S, Stenson AL, et al. Risk factors for poor virological outcome at 12
months in a workplace-based antiretroviral therapy programme in South Africa: a cohort study.
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antiretroviral therapy in The Gambia. AIDS Care 2010 Nov;22(11):1340-5.
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ugandan children and adults treated with antiretroviral therapy. J Acquir Immune Defic Syndr
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routine clinic in Cameroon that uses the World Health Organization (WHO) public health approach
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142. Landman R, Poupard M, Diallo M, et al. Tenofovir-emtricitabine-efavirenz in HIV-I-infected adults
in Senegal: a 96-week pilot trial in treatment-naive patients. J Int Assoc Physicians AIDS Care
(Chic Ill) 2009 Nov-Dec;8(6):379-84.
143. Laurent C, Ngom Gueye NF, Ndour CT, et al. Long-term benefits of highly active antiretroviral
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144. Lester RT, Ritvo P, Mills EJ, et al. Effects of a mobile phone short message service on
antiretroviral treatment adherence in Kenya (WelTel Kenya1): a randomised trial. Lancet 2010 Nov
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145. Lyagoba F, Dunn DT, Pillay D, et al. Evolution of drug resistance during 48 weeks of
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146. Mujugira A, Wester CW, Kim S, et al. Patients with advanced HIV type 1 infection initiating
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148. Nachega JB, Hislop M, Nguyen H, et al. Antiretroviral therapy adherence, virologic and
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149. Ndembi N, Goodall RL, Dunn DT, et al. Viral rebound and emergence of drug resistance in the
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150. Oyomopito R, Lee MP, Phanuphak P, et al. Measures of site resourcing predict virologic
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151. Ramadhani HO, Thielman NM, Landman KZ, et al. Predictors of incomplete adherence, virologic
failure, and antiviral drug resistance among HIV-infected adults receiving antiretroviral therapy in
Tanzania. Clin Infect Dis 2007 Dec 1;45(11):1492-8.
152. Seyler C, Anglaret X, Dakoury-Dogbo N, et al. Medium-term survival, morbidity and
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153. Vanni T, Morejon KM, Santana RC, et al. Comparison of the effectiveness of initial combined
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154. Zhou J, Sirisanthana T, Kiertiburanakul S, et al. Trends in CD4 counts in HIV-infected patients with
HIV viral load monitoring while on combination antiretroviral treatment: results from The TREAT
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155. Calmy A, Balestre E, Boulle A, et al. Prediction of CD4 cell count slope in patients with virological
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156. Chang L, Kagaayi J, Nakigozi G, et al. Effect of peer health workers and a mobile phone support
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157. Crabtree-Ramrez B, Caro-Vega Y, Sierra-Madero J. Late diagnosis of HIV infection results in a
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158. Fox M, van Cutsem G, Giddy J, et al. Rates and Predictors of Failure of First-line ART and Switch
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159. Geng E, Emenyonu N, Hunt P, et al. Frequent Occurrence of Virologic Re-suppression without
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160. Kiragga A, Castelnuovo B, Kamya M, Moore R, Manabe Y. WHO immunologic criteria are more
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161. Lockman S, Smeaton L, Ogwu A, et al. Long-term Maternal and Pediatric Virologic Outcomes on
Nevirapine-based HAART following Receipt of Peripartum Single-dose Nevirapine or Placebo,
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11/23/2010.
162. Marconi L, Parenti P, Weskamp M, Salztman A, Palazzi J, Lupo S. Start of HAART with and
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163. McIntyre J, Hughes M, Mellors J, et al. Efficacy of ART with NVP+TDF/FTC vs LPV/r+TDF/FTC
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164. Messou E, Marie-Laure Chaix, Gabillard D, et al. Strong Association between Medication
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166. Reynolds S, Sendagire H, Newell K, et al. Routine VLM Reduces the Rate of Accumulated
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169. Wester W, Blevins M, Bussmann H, et al. ZDV/3TC vs d4T/3TC Outcomes among HIV-1-infected
Adults Receiving First-line Combination ART in Botswana: Results from a Clinical Trial. Available
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APPENDIX 6

EARLY WARNING INDICATOR


TARGETS AND PEDIATRIC
POPULATIONS

Deborah Persaud, M.D.


Johns Hopkins University School of Medicine

Methods
Similar search strategies were performed in Ovid
Medline for the following EWIs
EWI 2 and 3 (Lost to follow up and retention on
first-line ART)
EWI 4 (on-time ARV pick-up)

EWI 5 (on-time appointment keeping)

EWI 6 (ART stock-outs)

EWI 8 (virologic suppression)

Limiting to children (2003-present)

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Articles Identified for Children


EWI 2 and 3:Lost to Follow-up and Retention on ART
(N=16)

EWI 4: On time ARV pick up


(N=5); 1 Review with additional references
EWI 5: ART clinic appointment keeping
(N=8)

EWI 6: ARV drug stockouts


(N=5)

EWI 8: Virological suppression


(N=85)

Relevant Articles
EWI 2 AND 3:Lost to Follow-up and Retention on ART
6 of16
EWI 4: On time ARV pick up
N=5; 1 Review with additional references-
Final N=12
EWI 5: ART clinic appointment keeping
0 of 8
EWI 6: ARV drug stockouts
N=2 of 6
EWI 8: Virological suppression (N=85)
N=23

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Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators

EWI 2 AND 3:LTFU and Retention on


First-Line ART ( Data from 6 studies)
Study Country
Dates observed Sites (n) Star6ng ART (n)
(year) (cohort or data source)
Collins et al (2010) Thailand Ini6ated ART 40 578
Jan 199 9- Jan 2009
Davies et al (2008) Cape Town, South Africa Ini6ated ART July 2002 1 122
Jan 2004
Fenner et al (2010) South Africa Ini6ated ART 10 8225
Malawi 1998-2008
Mozambique
Zimbabwe
Reddi et al Kwa-Zulu Natal, South Africa Ini6ated ART 1 151
(2007) August 31, 2003-October
31, 2005
KIDS-ART-LINC Mul6-country (16) in sub- Ini6ated ART May 16 2405
CollaboraAon Saharan 2007-2008
(2008) Africa
Barth RE. South Africa Sept.-2003-April 2006 1 66
(2008)
N=11457
(Range 66-8225)

EWI 2 AND 3:LTFU and Retention on


First-Line ART ( Data from 6 studies)
Baseline features
Study ART regimens (all ART nave at baseline
(median age, % male, median CD4, WHO
(year)/loca6on unless stated)
clinical stage)
Collins et al (2010) 6.7 yrs, 47%, 7%, 25% CDC-Stage C <2003-Dual/Triple NRTI
>2003-NNRTI-83%;PI-6%
Davies et al (2008) 37 mos, 57%, 11.1%, 44% advanced
55% NNRTI;45% PI
Fenner et al (2010)/ 49 mo,50.6%, 11.6%, 78.4% NR for 22.5%
advanced 59.4%_NNRTI-based;18.1% PI-
based
Reddi et al 5.7 yrs,49%,70.2% WHO 3 or 4 76.3% NNRTI
(2007) 23.7% PI

KIDS-ART-LINC 4.9 yrs,52.4%,NR, 69.5% severe NNRTI-based-58.6%


CollaboraAon immune-deciency PI-based-40.5%
(2008) NNRTI+P1=0.23%

Barth RE.(2008) 57 months,50%;NR,NR NNRTI-based

3-7 year olds initiating ART with advanced disease; regimens appropriate

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Report of the Early Warning Indicator Advisory Panel Meeting Geneva, Switzerland, 1112 August 2011

EWI 2 AND 3:LTFU and Retention on


First-Line ART ( Data from 6 studies)
Study
Time since ART start Study deni6on LTFU % LTFU
(year)/loca6on
Collins et al (2010) Median F/U=53 Months Missed visit and no contact 6.6%
(IQR 34-72 mos) for > 6 months
Davies et al (2008) Max 1 yr Not provided 10%

Fenner et al (2010) Median F/U: Not aeend clinic for > 6 9.6%
17.3 mos (Max 25.7 mos) months unAl study site
closure
Reddi et al (2007) Median F/U:8 mos No communicaAon and 0%
(IQR 3.5-13.5) missing at least 3 monthly
follow-up appointments/or
failure to collect medicaAon
KIDS-ART-LINC CollaboraAon Median F/U-20.3 mos Not aeended clinic for 6 10.3%
(2008) (IQR;11.7-27.9) mos months before closure of the
local database, known to not
died or moved
Barth RE.(2008) 12 months aier HAART NR 17%

Median follow-up =15 months Range 0-17%

Outcome of interest Cohorts Star6ng Median Range of Mean (%)


(n) ART (n) es6mate (%) es6mates (%)

LTFU any deni6on 6 11547 9.8 0.0 17 8.9

LTFU deni6on most similar to EWI 5 11396 10.0 6.6-17 10.7


2b
LTFU deni6on will likely classify less 1 151 0.0 0.0 0
people as LTFU compared with EWI 2c

LTFU with pa6ent tracing 3 795 6.6 0-17 7.8


LTFU without pa6ent tracing or 3 10752 10 9.6-10.3 10
pa6ent tracing not reported

Reten6on retained on ART including 3 339 98 74-100 90.7


TF out
Reten6on retained on ART at 2 273 80.4 72-88.7 80.4
original site/s (Excluding TF out.
Excluding stop / switch if reported)

TF out 3 8498 1% 0.66-14.3 5.32


Died 6 11547 8% 4.8-16% 8.8%

ART stop 1 122 2% na na

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Assessment of World Health Organization HIV Drug Resistance Early Warning Indicators

EWI 4-On Time ARV Pick up (12 Studies in 8 Countries)


Sample
Author Country Dates observed Sites (n) Design
size (n)
Nabukeera-Barungi et al Uganda Sept 2004-Feb 2005 1 170 Cross-
(2007) secAonal
Byakika-Tusiime et al Uganda IniAated: April 2004-March 1 41 Cross-
(2009) 2005 secAonal
Plipat et al (2007) Thailand NR NR 162 Longitudinal
ABSTRACT Cohort Study
Evans-Gilbert et al. (2004) Jamaica 2001-2003 NR 37 ProspecAve
ABSTRACT
Fassinou et al. (2004) Cote dIvoire October 2000-Sept 2002 1 78 ProspecAve

Safreed-Horman et al. Thailand Feb-June 2004 1 29 ProspecAve


(2007)
Bikaako-Kajura et al. Uganda October 2002-Jan 2003 1 42 ProspecAve
(2006)
Nyandiko et al. (2006) Kenya August 2002-Feb 2005 9 279 ProspecAve
Reddi et al. (2007) South Africa August 2003-Oct 2005 1 151 RetrospecAve
Eley et al. (2004) South Africa August 2002-June 2003 NR 17 ProspecAve
ABSTRACT
Myung et al. (2007) Cambodia August 2002 October 2004 MulAple 95 ProspecAve

Natu et al. (2007) India NR NR 25 IntervenAonal


ABSTRACT
N=1126; range 17-279

EWI 4-On Time ARV Pick up


ART regimens (all ART
Characteris6cs of study popula6on (median
Sample size nave at baseline
Author Country age, %male, median baseline CD4, clinical
(n) unless otherwise
stage)
stated)
Nabukeera-Barungi et al Uganda 170 10 yrs; 42.9%; NR; NR 97% NNRTI regimens
(2007)
Byakika-Tusiime et al (2009) Uganda 41 NR; NR;NR; NR (32% on HAART; 68%
HAART iniAated)
Plipat et al (2007) ABSTRACT Thailand
162 NR NR

Evans-Gilbert et al. (2004) Jamaica 37 6 yrs; 54.1%; NR; CDC Stage C 59.5%, Stage B 21.6%, NR
ABSTRACT Stage A 16.2%, Stage N 2.7%
Fassinou et al. (2004) Cote dIvoire 78 7.2 yrs; 56.4%; < 2 yrs 402, 2-5 yrs 266, >5 yrs 145; NNRTI 22%, PI 78%
Clinical Stage C 12,8%, Stage B 57.6%, Stage A 26.9%,
Stage N 2.6%
Safreed-Horman et al. Thailand 29 6.1 yrs; 52%; 12%; NR
(2007)
Bikaako-Kajura et al. (2006) Uganda 42 12 yrs; 48%; NR; NR NNRTI

Nyandiko et al. (2006) Kenya 279 6 yrs; 51%; 176; CDC Stage B or C 75% NNRTI

Reddi et al. (2007) South Africa 151 5.7 yr; 49%; 7.4%; WHO Stage 4 22.5%, Stage 3 NNRTI 71%, PI 22%
47.7%, Stage 2 12.6%, Stage 1 17.2%
Eley et al. (2004) ABSTRACT South Africa 17 NR; NR; NR; NR NR

Myung et al. (2007) Cambodia 95 Mean 5.5 yrs; 57%; 255; NR NNRTI

Natu et al. (2007) ABSTRACT India 25 NR; NR; mean 488; NR NR

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Dura6on of adherence
Type of pharmacy adherence measure and Propor6on who were 100%
Author assessment (months over
study deni6on adherent using study deni6on
which assessed)

Nabukeera-Barungi et al NR Clinic pill counts, 3day self report, clinic-based >= 95%: 72-94%
(2007) pill counts,home based unannounced pill counts (89 %, 94.1%,72%)
Byakika-Tusiime et al ON-HAART:One Unannounced pill count, 3-day self report, 30 On-HAART mean: 88100
(2009) assessment; day visual analogue scale 87.7/100/100 )
HAART nave: 6 months IniAaAng HAART;mean: 98-100
(100/98.1/97.8 )
Plipat et al (2007) 12 months Pill count, calendar method, recording missed Mean at 12 months:92%
ABSTRACT (2, 6, 12 months) doses, physician assessment (99%,100%,97%)
Evans-Gilbert et al. (2004) 6 months Caregiver Reports, Pharmacy Records 95%
ABSTRACT
Fassinou et al. (2004) 21 months (median) Caregiver Reports 79.5%

Safreed-Horman et al. NR Caregiver Reports, Pill Counts 98.8%


(2007) (average of 99.3 and 98.2)
Bikaako-Kajura et al. NR Self Reports 29% excellent;
(2006) Never missed a dose (excellent) 40% good-
Occasionally missing a dose (good) Overall 69% good-excellent
Frequently missed doses (poor)
Nyandiko et al. (2006) Median 34 weeks Caregiver and Self Reports / pill counts and 75%
volume returned
Reddi et al. (2007) Median followup 8 mos Caregiver and Self Reports 59.6% with excellent
IQR 3.5-13.5 months No missed doses; some missed doses not to 94.4 % with good -excellent
exceed > 2 doses in a month combined
Eley et al. (2004) 6 months (0-6 month) Pill Counts >=85%: adherence (range 65-100%)
ABSTRACT
Myung et al. (2007) 6 months (0 6 month) DOTS 99%

Natu et al. (2007) NR Clinic Visit Adherence 88% of children with >85%
ABSTRACT

EWI 4-On Time ARV Pick up (12 Studies in 8 Countries)

Outcome of interest Cohorts (n) Samples size (n) Mean of es6mates (%)

EWI 4 original deni6on 1 41 96 (on-HAART)


(studies repor6ng propor6on 100% adherent) 98.6 (InitIa6ng HAART)
1 162 92
1 37 95
1 78 79.5
1 29 98.8
1 42 69
1 279 75
1 151 94.4
1 95 99
EWI 4 with revised deni6on (studies 1 170 85
repor6ng propor6on > 95% adherent)
studies repor6ng propor6on > 85% 1 17 Only range provided (65-100)
adherent) 1 25 88

Overall (Range) 75-99

Average 89

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EWI 5 ART-Clinic Appointment Keeping

No studies identified reporting on children

EWI 6: ARV STOCKOUTS(N=2 Studies)

Characteris6cs of study ART regimens (all


Dates popula6on (median age, % ART nave at
Study (year) HC facility Pa6ent pays Sites (n)
observed male, median baseline CD4, baseline unless
clinical stage) otherwise stated)

Weigel et al (2009) Public Paid for tx Sept 2002- 1 98 months; 51%; NR; WHO NNRTI
Clinic and peds Jan 2004 N=47 Stage 3 53%, Stage 2 47%
Malawi formula6on

Prospec6ve
Libamba et al (2007) Public No 2004-2005 60 NR*; NR*; NR*; NR* NR
Clinic N=1999
Malawi

Retrospec6ve

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EWI 6: ARV STOCKOUTS(N=2 Studies)

Associa6ons
Propor6on
with
Time since Study deni6on of ARV mee6ng study
Study (year) Sites (n) virological or
start of ART stock out deni6on of ARV
clinical
stock out
outcomes

Weigel et al (2009) 1 6 months Reason for missed doses 2 % NR


Malawi N=47 due to no stock in
ProspecAve pharmacy/pa6ents who
September 2002-Jan missed doses
2004
Libamba et al (2007) 60 6 month, ART procurement and 0% of sites had NR
Malawi N=1999 12 months distribu6on system with no stockouts
RetrospecAve available stock of
an6retroviral drugs

EWI 8 Virological Suppression


(Data from 23 studies)
Published between 2006-2011
10 countries
South Africa (N=12)
Thailand (N=3)
Uganda (N=2)
Kenya, Colombia, China, Cambodia, Haiti, Cote dOvoire,
Ireland (N=1)
21 studies reporting on number of sites
163 (range 1-54; median number of sites per study=1)
Totalnumber of subjects:
12,488 (range; 30-5,485)
median number of participants per study=216

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EWI 8 Virological Suppression (Data


from 23 studies)
Median follow-up: 12 months (range up to a median
of 50 months)
Study definition of viral load suppression:

<1000 (N=1)
<400 (N=12)*

<250 or 300 copies (N=1)

<50 (N=6)

<25 (N=2)

*one study by both <400 and <50

EWI 8 Virological Suppression


Median virologic suppression at a median of 12-
months was 72% (range 14.3%-90%)

Median% LTFU was 4.8% (range 0-35%)


mean LTFU was 7.8%

Median mortality was 7% (range 2-16%)


mean mortality:8%

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EWI 8 Virological Suppression


% stopping ART: reported in only two studies
2% and 2.9%

% transferred out reported in 9/23 studies


Median 2.5% (range 0.8-16%); mean 4.9%

% second-line ART reported in six studies


(Median:5.6%; range 0.4-13.6%); mean 6.3%

Genotypic resistance reported in two studies


94% and 95% of failures with drug resistance, respectively
M184V, NNRTI-Mutations and TAMS (D67N, T215Y, L210W)

Conclusions from Literature Review


EWI WHO Suggested Pediatric Literature
TARGET/ADULTS
(2010)
EWI 2 (lost to follow-up) 20% Mean LTFU (8.9%)
Median LTFU (9.8%)
(Range 0-17%)
EWI 3a (appropriate first-line regimen) 70% Mean-(90.7)
retention of first-line ART Median (98)
(Range: 74-100)
EWI 3b 0% Median (5.6%)
(ART Switch, including for toxicity) Mean (6.3%)
(Range:0.4-13.6%)
EWI 4a (on-time drug pick up-two consecutive after 90%
baseline)/EWI 7 adherence Mean: 89%
EWI 4b (on-time drug pick up-first 12 months) 90% Range (75-99%)

EWI 5 (on time appointment keeping) 80% No data

EWI 6 ( No ARV stockouts) 100% 98-100%

EWI 8 (viral load <1000 copies/ml after 12 70% 72%


months) (14.3-90%)

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Limitations/Special Considerations
Little data on adherence and virologic suppression
in infants and children <three years of age
Little data on adolescence

Antiretroviral therapy adherence, virologic and immunologic outcomes in


adolescents compared with adults in southern Africa.Nachega JB,
Hislop M, Nguyen H, Dowdy DW, Chaisson RE, Regensberg L, Cotton M,
Maartens G. 2009

Setting; Private Sector, Patients Paid but were reimbursed


Retrospective study of 144 youth from Jan 1999-August 2006
Median age of youth: 16.4 yrs (11-19) ; mostly girls 73.7%
Median CD4 was 144
Regimen : NNRTI 92%

Adherence: A significantly smaller proportion of adolescents achieved 100% adherence


at each time point
Adolescents: 20.7% at 6 months, 14.3% at 12 months and 6.6% at 24 months
Adults: 40.5%, 27.9%, and 20.6% at each time point, respectively;( P < 0.01)

Virologic Suppression <400 copies/ml


6 month; 12 month; 18 month; 24 month was 36%; 45.7%; 45.3%; 43.6%, respectively

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Early Therapy and Children Under Two


Years of Age
Study N HAART Virologic Suppression
Reitz C et. al. JID 254 Lopinavir/r-based 84% of surviving children
2010 (6-104 weeks of age) HAART achieved suppression by 39
Mortality Rate 14% weeks
39% (N=99) Co-Treated 94.8% (No TB treatment)
for TB 74.2% (TB treatment at ART
initiation)
51.6% (TB treatment while on
ART)
Palumbo P NEJM 164 sd-nvp-exposed Lopinavir/r-based < 12 months
2010 HIV-infected infants HAART vs. NVP- 54.7% in NVP arm
based HAART 76.7% in LPV/R
>12 months
71.1% in NVP-arm
82.5% in LPV/r arm
Coovadia A 325 sd-nvp exposed Lopinavir-/r HAART 80% of 247 suppressed in first
JAMA 2010 year
Chadwick EG 31 Lopinavir-/r HAART 71% <400 at one year
2011 (< 6 months)

Primary Week 24 Endpoint Failure Rates

NVP LPV/r NVP - LPV/r

Stratum N fail% N fail% % 95% CI p-value

<12m 41 41.5 36 19.4 22.0 (2.2, 41.9) 0.030

>=12m 106 40.6 104 19.2 21.3 (9.3, 33.4) 0.001

All (unwtd) 147 40.8 140 19.3 21.5 (11.2, 31.8) <0.001

All (wtd)* 147 40.8 140 19.3 21.5 (11.2, 31.8) <0.001

* Difference in week 24 KM proportions weighted by age strata


Palumbo P; CROI 2011; Abstract 129LB

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Thank you

Acknowledgements:
Katie Lobner, MLIS; Welch Library; Johns Hopkins

University School of Medicine


Carrie Ziemniak, M.S.; Johns Hopkins University

School of Medicine

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APPENDIX 7
WHAT IF YOU CANT SAMPLE ALL CLINICS? SAMPLE SOME CLINICS!

Representative sample
Which clinics to sample?
Sample to include at least one examples of each mode / level of
delivery
Probability of inclusion approximately proportional to the
frequency of each mode / level of delivery (improves over time).
Where to sample?
Need a spatially representative sample if any reason to believe that
performance is likely to be geographically patchy. For example:
ARV stock-outs may be more frequent in outlying areas
Patient churn may be more likely in some urban sites
Additionally sample should be efficient even with small numbers

Type of sample
Sample to include all types of clinics
Purposive / hierarchical / stratified (i.e. fixed / program effects)
sample using an organogram of a program ...
Nurse-led
Primary
CO-led
URBAN Secondary

Tertiary

PROGRAM
Nurse-led
Primary
CO-led
RURAL
Cottage Hospital
Secondary
District
General Hospital

Stratification will vary between settings

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The sample
First round :
At least one site from each end category / pathway is required :
All modes of delivery represented
Additional sites selected with probability proportional to the
number of sites at each end category / pathway

Subsequent rounds :
Previous round sample maintained and expanded with (e.g.)
additional sites selected with probability proportional to the number
of sites at each end category / pathway.
Process continues until all sites report EWIs it takes as long as it
takes but we get there in the end

What might an analysis look like?


Analysis by score-carding
Nurse-led
Primary
CO-led

URBAN Secondary

Tertiary

PROGRAM
Nurse-led
Primary

CO-led
RURAL

Cottage Hospital

Secondary
District
General Hospital

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APPENDIX 8

Secondary Sampling for HIVDR early warning indicator monitoring

The sampling strategy is based on calculating a minimum sample size for each indicator at each site, based on
the number of eligible patients for each EWI. There are two types of 'eligible patients' -- those that initiated ART
for the first time, and those that were on ART (which includes both patients initiating ART and those on ART).
Table 2 presents the definition of eligible patients, by EWI.

Table 1 Definitions of eligible patients

Early warning indicator Eligible patients

? Patients initiating ART

? Patients on ART
(includes patients initiating ART, continuing ART
and transferring in on ART)

For EWIs xxxxx, the number of eligible patients at each site is the number of patients who initiated ART during
the 12-month period to be monitored. That is, if the EWI sample start date is in 2008, the sample size is
based on the number of patients who initiated ART at the site in 2008.

For EWIs xxxx, the number of eligible patients at each site is the number of patients on ART during the 12-month
period to be monitored, regardless of whether they initiated ART in that year or in a prior year. The simplest
method to arrive at this number is to use the number of patients on ART at the site at the midpoint of the
year. An alternative method is to take the number on ART on 1 January of the selected year, add this number
to the number on ART on 31 December of the selected year, and divide by two. This simple calculation will
give you the mean number of patients on ART during the year.

Using the annual number of eligible patients (Table 1) the sample size can be calculated using Table 3.

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Table 2 Sample size by annual number of eligible patients

Annual number of 'eligible patients' Number to be sampled at the site


at the site (sample size)
Eligible patients for each EWI defined in Table 2

175 All

76110 75

111199 100

200250 110

251299 120

300350 130

351400 135

401450 140

451550 145

551700 155

701850 160

8511600 175

16012150 180

21514340 200

43415670 210

567110000 215

>10000 Consult WHO

Note that separate sample size calculations must be made for each group of eligible patients (those initiating
ART and those on ART) at the site. The sample size for EWIs based on patients initiating ART will be lower than
those for EWIs based on patients on ART.

The sample sizes in Table 2 are the minimum sample sizes required to achieve a 95% confidence interval of
7%. If greater numbers can be abstracted, a more precise estimate will be obtained.

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Normally EWI should be monitored annually. However, countries with adequate resources may choose to
monitor EWI more frequently, for example by month or quarter, provided that the sample size used for each time
period does not fall below the minimum required sample size

Countries may choose to integrate EWI monitoring into other routine programme monitoring and evaluation
activities, which have random sampling strategies that differ from the sampling methodology presented by the
WHO. In such cases, the country should consult the regional HIVDR focal point and the WHO HIVDR team at
Headquarters (Geneva) to discuss options and feasibility.

WHO guidance on sampling was modified in November 2009

WHO revised its guidance on sampling in EWI monitoring in November 2009 to include the use of a minimum
sample size for each indicator.

Under previous sampling guidance, countries selected EWI denominator periods rather than absolute number of
patients (sample size).

The new sampling guidance significantly decreases the burden of data abstraction and supports the calculation
of narrower confidence intervals.

The WHO discourages continued use of the former sampling strategy.

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