Highlights and updates on

TB/HIV management

Ignacio Monedero, MD, MPH

International Union against Tuberculosis

and Lung Disease
(The Union)
The HIV/AIDS pandemic has inflicted the
single greatest reversal in human
development
(United Nations’ Human Development Report 2005)
 Changing the TB landscape…
1. Epidemiological
2. Clinical
3. Diagnose
4. Case management
5. Prevention
 1. EPI:
Effects of HIV on Incidence of TB

Nunn P, JID; 2007 196(s1):S5–S14

ISTC Training Modules 2008
How HIV fuels TB
 2. Clinical Facts: TB in HIV
Cannot rely on “typical” indicators of TB
• Fever and weight loss are important
symptoms
• Cough is less common
• Chest radiographic pattern more variable
• More extrapulmonary and disseminated TB
• Differential diagnosis is broader

ISTC Training Modules 2008

 Features of the HIV infected with
sensible TB
• Difference with the HIV neg patient
• More likely to get infected, develop disease and die
• More likely to develop disease by other
Mycobacterium species than TB (MOTTs)
• Different clinical presentation:
– More extrapulmonar cases, less cavitation
– Immune reconstitution syndrome

• Do HIV patients infect more?

• HIV is not globally a risk factor for MDR
However major risk for outbreaks!!
• The presence of
• cough of any duration
• fever of any duration
• or night sweats lasting 3
or more weeks in the
preceding 4 weeks
• was 93% sensitive and
36% specific for
tuberculosis.
•Cough any duration
•Fever
•Night sweets

•Weight lose,

Search for TB
Abscence of them NO TB
 Extrapulmonary
Tuberculosis

ISTC Training Modules 2008

 Can this be TB?
Atypical pattern: Primary TB
• Distribution: Any lobe involved
(slight lower lobe
predominance)
• Air-space consolidation
• Cavitation is uncommon
(< 10%)
• Adenopathy is common (esp. in
children and HIV)
• Miliary pattern

ISTC Training Modules 2008

 3. Diagnosing TB in HIV
Generally, Microbiological techniques
profitability does not differ from HIV-

Except for smears…

Smear –ve TB in HIV +:

unmeasured source of
deaths and lost
oportunities
 <50 CD4 >500 CD4

CULTURE + +
SPUTUM - +
CHEST X RAY - +

Chest X ray and sputum are insensitive to rule out

Pulmonary TB in advanced inmunosupression

Several post mortem studies from subsaharian Africa have

demonstrated that 50% HIV infected dead patients had TB
From TB diagnose in the HIV likelyhood of TB/HIV

• The most severly TB/HIV ill and likely to die is

• CXR negative
• Smear negative
• Atipical symptoms
• Culture not available
• Sorry
• I think you have TB
• But all results are negative, you don’t have TB
• The patient never returns:
• dead? Frequent TB in postmorten studies
• Asymptomatic active pulmonary TB
• Screening: symptoms + induced sputum
Some authors in certain settings of Africa are starting to treat TB
without diagnose to those patient <50 CD
 Genexpert utility in Coinfection
• Greater sensitivity than smear
• Avoid loosing patients
• 71.7% sensitivity in smear -ve
• Specie differentiation
• MDR vs MOTT
• Quick
• Expensive…
J Clin Microbiol. 2011 Jun 15. [Epub ahead of print]
Cepheid GeneXpert MTB/RIF Assay for Mycobacterium tuberculosis
Detection and Rifampin Resistance Identification in Patients with High
Clinical Suspicion of TB and Smear Negative Microscopy.
Ioannidis P, Papaventsis D, Karabela S, Nikolaou S, Panagi M, Raftopoulou E,
Konstantinidou E, Marinou I, Kanavaki S.

Source
National Reference Laboratory for Mycobacteria (NRLM), Sotiria Chest Diseases Hospital, Athens,
Greece.

Abstract
The GeneXpert MTB/RIF assay was evaluated in microscopically negative and positive pulmonary
and extra-pulmonary specimens from patients highly suspected for tuberculosis. For the
pulmonary samples, sensitivity, specificity, positive and negative predictive values
were 90.6%, 94.3%, 93.5%, 91.7%, and for the extra-pulmonary 100%, 91.6%, 50%, 100%,
respectively.
For microscopically negative specimens, the respective values were 86.3%, 93%, 79%
and 95.6%.

The assay correctly detected rifampin resistance in all but one specimen harboring a mixed
population. The GeneXpert was highly effective for tuberculosis diagnosis and rifampin
resistance identification in smear negative samples.

PMID:21677069
 4. Case management
Recommendations for initiating ART on the basis of immunological and
clinical stage

Start HAART at
350 CD4 to avoid
TB risk Gilks CF, et al. Lancet 2006; 368: 505–10

*PRIORITY INTERVENTIONS HIV/AIDS

prevention, treatment and care in the health
sector. World Health Organization. HIV/AIDS
Department. Version 1.2 – April 2009
 ARV Improves Outcomes
Antiretroviral Therapy (ARV)
significantly reduces TB incidence
Decrease in TB
incidence after
starting ART in
resource-limited,
high-burden area

Lawn SD, et al, Am J Respir Crit Care Med, 2008;177:680-685

ISTC Training Modules 2008
 Universal HIV testing and immediate start of ART

• Could reduce HIV

transmission by 95% and TB
incidence by 50% within 5
years

• Could reduce HIV

prevalence and TB incidence
by 95% within 40 years

• Works by individual immune

reconstitution and reduction in
HIV transmission
 4. Management Features of the
coinfected
• Worst TB drug absorption
• Linked to resistances in Bostwana
• Rifampicin Monoresistance: avoid intermittent treatments
• Parasites, diarrhea: treat!
• Frequent malnutrition: worst immune response

• Immune reconstitution syndrome (with or without ARV)

• All HIV-positive TB patients regardless of the CD4 count
should receive:
• Daily TB treatment
• Cotrimoxazole Preventative Therapy (CPT) at least for the whole
duration of anti-TB treatment
• ART
• Interactions RIF-ARV
New MDR-TB guidelines 3
days ago, all MDR-TB with
HIV should start ARV
 Changes in the future ?

Clinical Infectious diseases May 2010:

• Rifampicine is the corner stone of the TB/HIV coinfected
• Daily better than 3 days/w
• 8 months with RIF better than 6
 Optimal timing of ART initiation is not known…

When to start HAART in the TB patient

• The first thing to do: CD4 Time to initiate
HAART in coinfected
start TB treatment patient already taking
• Early HAART anti-TB drugs
• Risk of drug <50 cels/ml 2 weeks
interactions
• Risk of IRIS
50-100 cels/ml From 2 to 8 weeks
• Delayed HAART
• Increased risk of death
>100 cels/ml 2 months

>200 cels/ml Initiate HAART after

TB treatment
The sooner,
the better
Beware of Cryptococcus
meningitis
IRIS was not a deadly
issue if treated
 CAMELIA Study
• Cambodian Early versus Late Introduction of
Antiretroviral Drugs
• Recently completed, not yet published
• In severe immune deficient
• <200 CD4, median: 25 CD4
 CAMELIA Study
• Early arm
• Better outcomes (50% less mortality)
• Starting at 2 weeks 33% mortality reduction
compared to 8 weeks
• More IRIS but easily treated
• If treating with HAART during the first 2
weeks of TB treatment potentially
• 150.000 out of the 450.000 deaths among
coinfected could be prevented.
 Problems with cotreatment
1. TB- IRIS
2. Drug-drug interactions
• RIFAMPICIN - ARVs

3. OTHERS: adherence, logistics burden of pills

 1. Immune reconstitution syndrome (IRIS):

2 types
Paradoxical TB IRIS Unmasking TB-IRIS
• Patient on TB treatment who start • Patient on ARVs who suddenly
ARVs develop TB symptoms
• Improve • Patient with undiagnose or
• After 4 weeks of ARTs paradoxical subclinic TB not receiving TB
reaction treatment
• Fever, lymph nodes, pulmonary • Important cause of early
infiltrates, worsen of previous mortality after ARVs
lesions, meningitis • Initiate TB treatment
• Almost 10% of HIV cases (Müller,
2010)

Exagerated inmune recostitution against living or

death pathogens
TB IRIS IMPACT: multiple visit to hospital,
hospitalisation, default (TB/HIV treatments),
confusion on the health care provider.
Difficult to defferentiate from drug toxicity, disease progression,
opportunistic infection and drug resistance.
 Paradoxical TB IRIS
• More often linked to
• High severity of illness and low CD4 count
• High mycobacterial load antigens and disseminated disease
• Short tinme between TB treatment and HAART
• Clinical diagnose. Diferential diagnose
• MDR-TB: 10% in South Africa
• Treatment
• Mild cases: symptomatic treatment (eg. Aspiration, pain killers)
• Prednisone 1.5mg/kg/day 2 weeks followed by 0.75mg/kg/d another
2 week
• Corticosteroids only when Paradoxical TB-IRIS is certain: risk of
Kaposi’s, herpes reactivation and others
• Interrupt ART when:
• Life threaten situation
• Severe neurological involvement (beware cryptococal meningitis)
High mortality in the first 3
months of HAART initiation

•Progresion of underlying desease?

•IRIS when CNS inflamated?
 HAART initial treatments for
TB/HIV using RIF
• Rifampicin decrease blood levels of:
• PI by 80%
• NVP by 30-50%
• EFV by 25%: not significant, can be used in protocols increase to
800mg/day (>60kg). BEWARE: teratogenic, hep tox, cross resistance
with NVP, quick resistance
• Proposed protocols, Efavirenz based HAART (change into
NVP when finish RIF)
• AZT/3TC (Combivir) + EFV
• D4T/3TC + EFV
• Avoid if possible PI
• If not possible: lopinavir (400mg) + increase ritonavir (400mg BD)
• Other possibilities
• 3TC + AZT or D4T + ABC or TDF Preferable not change
TB treatment
• If possible
• Monitor viral load
• Use Rifabutin (less CYP3A4 inductor) logistic disadvantages
 ART and RIF-based TB Rx (1)
Recommended ART regimen:
• Efavirenz or Tenofovir plus two
nucleosides
(EFV or TDF + two NRTIs)
– Use efavirenz for adults and children
>3 years old
– Avoid 1st trimester of pregnancy
– Efavirenz dose 600mg (or 800mg)

ISTC Training Modules 2008

 Human Immunodeficiency Virus and the
Outcome of Treatment for Pulmonary
Tuberculosis in African Patients

*HIV infected tuberculosis patients have a higher proportion

of death as compared with the HIV-negative. Also treatment failure and relapse.

Murray J, Am J Respir Crit Care Med 1999;159:733–740 Courtesy: CHIANG Chen-Yuan, MD, MPH
 Features of the HIV infected and
MDR
• Beware IRIS
• Considered DST and Mycobacterium identification:
• MOTTs more common especially MAC
• High risk of outbreaks and nosocomial transmission
• if MDR and HIV patients are mixed…
• A threat to many African countries
• INFECTION CONTROL: cost effective, essential
• Interaction ARV / anti-TB SLD
• Not enough evidence
• No RIF hence no RIF interactions
 Current WHO recomendations
• Treat at 350: avoid the TB margin
• Avoid D4T: toxic profile
• Avoid NVP:
• however there are succeful experiences
• Promotion of EFV and specially TDF
• Due to EFV probable teratogeneity
• Strong bet for long lasting IPT

Is it really feasible??
5. Prevention of TB in HIV high rate
countries
• Infection control, crucial
• Specially now after MDR-TB epidemic
• IPT relevant,
• Current new WHO guidelines
• Great results in studies, but very bad on the field
 IPT
BOTSWANA EXPERIENCE

Oaitse I Motsamai RN, MW, B Ed, MPH

Ministry of Health
Botswana

11th November 2008

Addis Ababa, Ethiopia
 Enrollment 2001-2007*
Registered
N=75,235

Eligible
n= 73,263

Eligible and started IPT

n= 71,541

Completed Other Non-completers

n=25,075 exclusions n=43,313
(33%) (7%) (59%)

Unknown
reason
(70%)
 IPT and The Union

• Efficacy proven in PLHIV with latent TB

• Challenges remain particularly determining who

really needs IPT, ruling out active TB and being
sure of optimum length of treatment

• We want “well done integrated IPT”, but we

should not support “sloppy IPT”
 No symptoms: IPT

YES symptoms: NO IPT

investigate TB

No symptoms: IPT 6
months

No symptoms: IPT 36
months

TST not necessary but if

Is it really feasible?? it is available OK

WHO current
recomendations for
IPT on PLHIV
Infection Control
 HIV-associated multidrug-resistant
tuberculosis (MDR-TB) outbreaks in
industrialized countries, 1988–1995

Wells CD, et al. JID 2007:196:s86-s107

 PROPORCION DE CASOS EN TRATAMIENTO PARA TB MDR EN PERSONAL DE
SALUD REGISTRADOS EN LA UTTBMDR

Fuente: UTTBMDR/ESN-PCT/DGSP/MINSA/PERU
Sistema de Registro de Re-tratamientos
 Modeling XDR Transmission
S. Basu, et. al. Lancet 2007; 370:1500-07
Intervention Est. % XDR averted

Community-based treatment and < 10%

deferred hospitalization
Rapid drug susceptibility assays 2 – 4%

Involuntary detention (without isolation 3%

rooms)
Improved natural ventilation, 33%
Air filtration, UV air disinfection
Personal protective measures 2% total cases
- Respirators and masks – enforced 1/3 cases in staff
Voluntary counseling and testing with 1% of admitted patients
ARV therapy 24% in the community.
Edward A. Nardell, MD
 Modeling XDR Transmission
S. Basu, et. al. Lancet 2007; 370:1500-07

Intervention combinations Est. % XDR averted

Reducing length of stay + enforced 28% (21-33%)
use of respirators and masks

Add natural ventilation 37% (26-40%)

Add drug susceptibility assay, 48% (34-50%)
hospital based VCT with ARV, and
separation of patients in 5 bed units

Edward A. Nardell, MD
PloS Med 2007;4-e68:309-17
 Ventilation and protection against TB transmission among new
and old buildings

PloS Med 2007;4-e68:309-17

30 decades of
HIV/AIDS
epidemic

3 impossible
things
in 1 picture
Muchas gracias, Many thanks!!!