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.

0.36

0.86

0.67Overall

TST+

TST-

Placebo

Relative risk, 95% CI

Woldehanna 2004, Cochrane review

Effect of IPT on TB in PPD+ve PLWHA:

meta-analysis of clinical trials

1.0

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. IPT worsens drug resistance.

2. It’s not needed if you’re on ART.

3. It’s too toxic.

4. It’s too hard to rule out active TB.

5. IPT is too complicated and costly.

6. 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 40-60%; and when active TB occurs among those given IPT, standard four-drug first-line 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 Balcells Emerg Infect Dis 2006;2006;1212:744:744

• 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

Does IPT promote isoniazid resistance?

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: UKUnadj rate ratio (95% Unadj rate ratio (95% CI)CI)

Adj. rate ratio (95% CI)Adj. rate ratio (95% CI)

Ethnic groupEthnic group WhiteWhite

OtherOther

Black AfricanBlack African

11

2.29 (1.50, 3.51)2.29 (1.50, 3.51)

4.81 (3.48, 6.65)4.81 (3.48, 6.65)

11

1.96 (1.24, 3.11)1.96 (1.24, 3.11)

2.49 (1.51, 4.11)2.49 (1.51, 4.11)

HIV exposureHIV exposure HeterosexualHeterosexual

Sex between Sex between menmen

OtherOther

11

0.26 (0.19, 0.35)0.26 (0.19, 0.35)

0.45 (0.26, 0.81)0.45 (0.26, 0.81)

11

0.54 (0.32, 0.89)0.54 (0.32, 0.89)

0.58 (0.30, 1.11)0.58 (0.30, 1.11)

CD4 count*CD4 count* 500+500+

350-499350-499

200-349200-349

51-19951-199

≤ ≤ 5050

11

2.52 (1.30, 4.91)2.52 (1.30, 4.91)

3.33 (1.78, 6.25)3.33 (1.78, 6.25)

9.51 (5.26, 17.21)9.51 (5.26, 17.21)

24.58 (13.01, 46.46)24.58 (13.01, 46.46)

11

2.89 (1.41, 5.93)2.89 (1.41, 5.93)

3.67 (1.75, 7.71)3.67 (1.75, 7.71)

10.81 (4.87, 24.00)10.81 (4.87, 24.00)

33.92 (13.68, 84.12)33.92 (13.68, 84.12)

Nadir CD4 (per 50 cell Nadir CD4 (per 50 cell increase)increase)

0.89 (0.83, 0.96) 0.89 (0.83, 0.96) 1.18 (1.08, 1.28)1.18 (1.08, 1.28)

Time since ART start (per yr Time since ART start (per yr inc)inc)

0.68 (0.62, 0.75)0.68 (0.62, 0.75) 0.78 (0.69, 0.89)0.78 (0.69, 0.89)

Calendar year*Calendar year*2002-20042002-2004

1999-20011999-2001

1996-19981996-1998

11

1.58 (1.15, 2.17)1.58 (1.15, 2.17)

1.68 (1.08, 2.58)1.68 (1.08, 2.58)

11

1.09 (0.78, 1.76)1.09 (0.78, 1.76)

0.55 (0.31, 0.98)0.55 (0.31, 0.98)

* time-updated* time-updated Grant CROI 2007 abs 846Grant CROI 2007 abs 846

Effect of ART on TB (South Africa)

Lawn AIDS Lawn AIDS 2005;2005;1919:2109:2109

Effect of ART + IPT in BrazilRetrospective 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.

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.

Objection 3: ToxicityObjection 3: Toxicity

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)

IPT: hepatotoxicity rareIPT: hepatotoxicity rare

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 smear-negative and extrapulmonary TB active TB case detection will increase.

Objection 4: It’s too hard to Objection 4: It’s too hard to rule out active TBrule out active TB

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

Ayles Int Conf on AIDS, Durban 2000 [Abstract ThPeB5212]

number of patients

months on IPT

23%

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

• Aurum• CREATE• JHU• LSHTM• THRio• WHO HIV + STB Departments• Bill & Melinda Gates Foundation• TB, HIV, and TB/HIV activist colleagues

TAC TB march, 2007