Transcript Reduce the burden of TB in PLHIV: Isoniazid Preventive Therapy

Isoniazid preventive therapy in a
time of HIV, TB, and MDR
Why do TB and HIV programs and
the HIV community itself ignore IPT?
WHO Recommended Policy on Collaborative TB/HIV Activities
1. HIV/AIDS programmes should provide isoniazid preventive
therapy as part of the package of care for people living with
HIV/AIDS when active TB is safely excluded.
• Countries have been ignoring WHO’s advice for IPT for at least a
decade. Paper policies do not lead to actual program
implementation in practice.
2. Information about isoniazid preventive therapy should be made
available to all people living with HIV/AIDS.
• TB programs provide inaccurate information about IPT and deride its
effectiveness while HIV programs ignore IPT.
• Community activist groups and PWA groups have not done
enough to educate their peers about IPT and create demand.
How strong is the evidence?
Q:
How strong is the evidence that IPT
works?
A:
Overwhelming.
Effect of IPT on TB in PPD+ve
PLWHA:
meta-analysis of clinical trials
Relative risk, 95% CI
1.0
Placebo
Overall
0.67
0.36
TST+
0.86
TST-
Woldehanna 2004, Cochrane review
How much IPT is being done?
Q: How much IPT is being done as part of worldwide
scale-up of HIV prevention, care, and treatment
services?
A: Pathetically little.Only 27,056 in 2006 – equivalent to
less than 0.1% of the estimated 33 million people
estimated to be infected with HIV globally…
While 84 countries reported the existence of an IPT
policy, only 25 reported any provision… Numbers on
IPT are dominated by Botswana, which accounted
for 70% of the total number… globally in 2006.”
-- WHO TB report 2008
Excuses for not implementing IPT
1.
2.
3.
4.
5.
6.
IPT worsens drug resistance.
It’s not needed if you’re on ART.
It’s too toxic.
It’s too hard to rule out active TB.
IPT is too complicated and costly.
IPT adherence is poor.
Objection 1: Resistance
• Claim: IPT promotes drug resistant
disease and renders first-line therapy less
effective when active TB occurs.
• Fact: IPT does not promote drug resistant
disease; it reduces TB incidence by 4060%; and when active TB occurs among
those given IPT, standard four-drug firstline therapy works.
Does IPT promote INH resistant TB?
• IPT effective even if relatively high
prevalence of INH resistance – eg 17% in
Haiti in 1990s (Chaisson ARRCCM 1996;154:1034)
• If TB is latent, few organisms, dividing
slowly, thus low risk of selection of DR-TB
• Standard quadruple therapy is effective for
INH-r TB (Nolan IJTLD 2002;6:952)
Does IPT promote isoniazid
resistance?
Balcells Emerg Infect Dis 2006;12:744
Does IPT promote isoniazid
resistance?
• Combined average of previous 13 studies
analyzed shows risk of increased
resistance, if any, is small:
–
summary RR = 1.45 (95% CI 0.85, 2.47)
• most resistance arises from suboptimal
treatment of active disease, so preventing
active disease will reduce resistance
• need for surveillance for resistance
• need for implementation research
Objection 2: IPT not necessary
because ART is good enough
•
Claim: IPT is not necessary because
ART alone is good enough in reducing TB
incidence.
• Fact: IPT and ART are synergistic in
reducing TB incidence among people with
HIV taking both.
Risk factors for TB on ART: UK
Unadj rate ratio (95% CI)
Adj. rate ratio (95% CI)
Ethnic group
White
Other
Black African
1
2.29 (1.50, 3.51)
4.81 (3.48, 6.65)
1
1.96 (1.24, 3.11)
2.49 (1.51, 4.11)
HIV exposure
Heterosexual
Sex between men
Other
1
0.26 (0.19, 0.35)
0.45 (0.26, 0.81)
1
0.54 (0.32, 0.89)
0.58 (0.30, 1.11)
CD4 count*
500+
350-499
200-349
51-199
≤ 50
1
2.52 (1.30, 4.91)
3.33 (1.78, 6.25)
9.51 (5.26, 17.21)
24.58 (13.01, 46.46)
1
2.89 (1.41, 5.93)
3.67 (1.75, 7.71)
10.81 (4.87, 24.00)
33.92 (13.68, 84.12)
Nadir CD4 (per 50 cell increase)
0.89 (0.83, 0.96)
1.18 (1.08, 1.28)
Time since ART start (per yr inc)
0.68 (0.62, 0.75)
0.78 (0.69, 0.89)
Calendar year* 2002-2004
1999-2001
1996-1998
1
1.58 (1.15, 2.17)
1.68 (1.08, 2.58)
1
1.09 (0.78, 1.76)
0.55 (0.31, 0.98)
* time-updated
Grant CROI 2007 abs 846
Effect of ART on TB (South Africa)
Lawn AIDS 2005;19:2109
Effect of ART + IPT in Brazil
Retrospective review of TB incidence in 11,026 HIV+ at 29 public clinics in RJ
between 1 Sep 03-1 Sep 05.
TB reduction
(%)*
No ART, no IPT
4.01 cases/100 person years
0
ART, no IPT
1.90 cases/100 py
52.5%
IPT, no ART
1.27 cases/100 py
68.3%
ART + IPT
0.80 cases/100 py
80.0%
* Compared with no ART/no IPT.
After adjusting for age, previous TB, and baseline CD4 count the overall
reduction seen with ART+IPT was 76% vs. no intervention.
-- Golub JE, Saraceni V, Cavalcante SC, et al. The impact of ART and isoniazid
preventive therapy on TB incidence in HIV-infected patients in Rio de Janeiro, Brazil.
AIDS. 2007 Jul 11;21(11):1441-8.
Objection 3: Toxicity
Claim: IPT is too toxic for people with
HIV (on or not on ART) and has
additive toxicity with ART>
Fact: IPT is far less toxic than HRZE
and has far fewer interactions with
ART than R; IPT toxicity is rare and
can be managed.
IPT: hepatotoxicity rare
Uganda RCT
• 7/931 AST>135u; total 3 stopped with
any adverse event (Whalen NEJM 1997;337:801)
South Africa, routine, pre ART
• 1/777 stopped INH with asymptomatic
raised AST ref?AMA 2005;293:2719)
South Africa, ART cohort
• IPT not associated with higher risk of
hepatotoxicity (Hoffmann AIDS 2007;21:1301)
Objection 4: It’s too hard to
rule out active TB
Claim: It’s too hard to rule out active
TB among HIV+ persons.
Fact: If countries use intensified case
finding and implement the new WHO
diagnostic algorithm for smearnegative and extrapulmonary TB
active TB case detection will increase.
Objection 5: IPT is too costly &
complicated
“IPT is an effective intervention on an individual
basis if patients can complete the 6-9 months
regimen and if there is a system to support
them… Screening, sensitizing the HIV
community and ensuring that people living with
HIV can complete the entire duration of
treatment is resource intensive…”
-- Saidi Egwaga, NTLP Program Manager,
Tanzania
IPT is cheaper and easier than
treating active TB disease!
Claim: IPT is too costly and complicated.
Fact: It’s a lot easier to take one very
effective and non-toxic drug for six to nine
months to prevent potentially fatal TB than
it is to take six months of TB treatment
when you’ve got a high risk of early
mortality (up to 33%) even if you’re on
ART. In this case prevention really is
cheaper than treatment.
Objection 6: IPT adherence is poor
Claim: IPT adherence is poor.
Fact: Lack of clarity about who is responsible for
IPT means that no one is responsible for
providing IPT or for promoting adherence.
Fact: People with HIV have amazingly high
adherence to ART; why don’t HIV treatment
programs use HIV adherence training and
support methods to increase uptake and
adherence to IPT.
Retention on IPT: Zambia
number of patients
23%
months on IPT
Ayles Int Conf on AIDS, Durban 2000 [Abstract ThPeB5212]
What is needed?
• HIV programs must take responsibility.
• HIV community/PHA group must take
responsibility.
• Operational research should be done but
not as an excuse to delay implementation.
• Failure to provide IPT is a violation of
human rights and will worsen the DR-TB
epidemic among people with HIV.
Issues to consider
• Duration IPT; shorter 2 drug PT regimens?
• Better HIV cohort reporting & recording
integrating IPT and CTX.
• Lack of standard guidelines for follow-up of
healthy (pre-ART) HIV patients in RLS.
• Need to record active TB incidence in districts
with + without IPT.
• Need to measure impact if any on DR-TB.
• Evaluate different adherence approaches.
Acknowledgments
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Aurum
CREATE
JHU
LSHTM
THRio
WHO HIV + STB Departments
Bill & Melinda Gates Foundation
TB, HIV, and TB/HIV activist colleagues
TAC TB march, 2007