Isoniazid Preventive Therapy: A Call to Action

Prof Harry Hausler, Medical Director

Project Integrate, TB/HIV Care Association

School of Public Health, University of the Western Cape

1 October 2009

Overview

• Efficacy of isoniazid preventive therapy (IPT)

• IPT guidelines

• IPT implementation

• Reasons for limited implementation

• Recommendations

0.36

0.86

0.67Overall

TST+

TST-

Placebo

Relative risk, 95% CI

Woldehanna 2004, Cochrane review

Effect of IPT on TB:Meta-analysis of 7 randomised clinical trials (N=4134)

1.0

WHO Guidelines

• Recommend 6 months of IPT for HIV+ with a positive tuberculin skin test (TST) who do not have active TB (asymptomatic, normal CXR)

• When not feasible to perform TST, also recommended for those living or working in high risk area for TB infection (>30% prevalence of infection)Weekly Epi Record 1999;74:385-400

• Prevalence of TB infection (TST+) in HIV+ in Cape Town was 55% in 2002 Hausler 2007

International Advocacy for IPT

• WHO 3 I’s meeting, April 2008• Global Leaders Forum, 9 June 2008• WHO HIV/AIDS Department Priority

Interventions, IAS Mexico, August 2008• Stop TB Partnership, March 2009• Stop TB Partnership Consensus Statement:

“IPT works, IPT is safe, IPT works with ART or by itself. Ensure that all people living with HIV in countries where TB is common are offered IPT”

IPT Implementation in 2007

• Only 41 countries reported provision of IPT• 29,000 people started on IPT - less than

0.1% of the estimated 33 million people estimated to be infected with HIV globally Global TB Report, 2009

• In comparison, 3 million on ART globally and 2.1 million on ART in sub-Saharan Africa

TB screening, diagnosis and prevention, 2002-2007

444 337 267284 1017

14

2558

44

41

77

71

0

100000

200000

300000

400000

500000

600000

700000

Screened for TB Diagnosed with TB IPT

2002

2003

2004

2005

2006

2007

Collaborative TB/HIV activities, 2002–2007,

GLOBAL PROGRESS

AFRO implementation of IPT, 2007

Countries with reported

policy on IPT (N=17)

Countries reported provision of IPT (N=7)

• One more country in AFRO reporting (8) in 2007 vs 2006

•Only <1% of PLHIV put on IPT in AFRO (and globally)

• Botswana reported 6042 (39%) of the AFRO PLHIV on IPT, a marked decrease from 19,034 in 2006

•South Africa reported 2227 on IPT in 2006, 7869 in 2007 and 6818 (incomplete data) in 2008

IPT in South Africa

Indicators 2008 Q1 2009HIV tested 1,372,167 526,958HIV-positive 455,150 33% 178,261 34%Tuberculin (PPD) skin test done

4063 0.9% 978 0.5%

HIV pos started on IPT

6818 1.5% 2185 1.2%

Department of Health, 2009

Number started IPT per provinceSouth Africa, 2008

DOH, 2009 NB: Missing data for EC, KZN, MP, NW

Proportion HIV+ started on IPT South Africa, 2008

DOH, 2009 NB: Missing data for EC, KZN, MP, NW

IPT Gap in KwaZulu-Natal

• Living with HIV: 1.5 million• TB incidence: 1054/100,000 (1%)/year• Eligible for IPT

– 25% eligible if use TST: 375,000– 40% eligible if no TST: 600,000

• 10% of co-infected would develop TB with no IPT: 37,500 cases

• IPT would prevent 24,000 TB cases per year (64% decrease)

South African DOH Guidelines

• Only offer if– VCT available

– Patients can be effectively screened for TB

– Patient can be monitored monthly

– IPT does not interfere with detection and cure of sm+ PTB

– Local AIDS programme takes responsibility for implementation with strong collaboration with TB programme

Department of Health. TB and HIV/AIDS, 2000 and National ART Guidelines, 2004

SA DOH Guidelines, 2004

• Eligibility: – HIV+– No TB signs or symptoms (cough, fever, night

sweats, pleuritic chest pain, loss of appetite, tiredness and weakness, chest pain, haemoptysis)

– CXR not recommended for screening– Positive tuberculin skin test (>5 mm induration)

• If one or more symptoms, do not provide IPT and do 2 smears, 1 culture

SA DOH Guidelines, 2004

• Exclusion criteria:– Active liver disease– History of TB treatment in past 2 years– Don’t offer to those on ART but can

complete course – needs to be revisited

• Regimen:– 5 mg/kg (max 300 mg) daily for 6 months

SA DOH GuidelinesProposed Revisions 2009

• Tuberculin test not required for screening

• IPT should be given to those on ART with no symptoms of TB

• No need to wait for these revisions to start implementing!

Excuses for not implementing IPT

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

2. IPT worsens drug resistance

3. It’s not needed if you’re on ART

4. It’s too toxic

Claim: It’s too hard to rule out active TB among HIV+ persons

Fact: Although TB diagnosis is more complex in HIV+, symptom screening is very sensitive, especially in immuno-suppressed patients. Nonetheless, some subclinical cases will be missed.

Objection 1: It’s too hard to rule out active TB

Difficulty of TB screening in HIV-infected persons

• HIV-infected TB patients often lack classic TB symptoms

• Up to 30% of HIV-infected TB patients with pulmonary TB have a normal chest radiograph

• Sputum smears may be negative in 50% or more

Mohammed, et.al. – South AfricaInt J Tuberc Lung Dis 2004;8(6):792-795

Setting South Africa

Study pop.

129 stage 3 and 4 HIV+ referred for IPT (TB suspects were not referred)

TB def’n Definite = cx confirmed, probable = smear+, possible = clinical dx with response to treatment

# with TB 11 (9%) with TB (10 culture-confirmed)

Cough Cough >2 weeks 82% sensitive, 89% specific

Algorithm Two or more of: measured weight loss (>2.5%), cough, night sweats, or fever (all>2 weeks) Sensitivity 100%, Specificity 88%

Kimerling, et.al – Cambodia, Int J Tuberc Lung Dis 2002;6(11):988-994

Setting Cambodia

Study pop.

441 HIV+ in home care network

TB def’n Single sputum culture

# with TB 41 (9%) with culture-confirmed TB

Cough Cough >3 weeks 65% sensitive, 33% specific

Algorithm Any 1 of: cough>3 wks, hemomptysis, weight loss, fever, night sweats, or weakness – 95% sensitivity, 10% specificity

Diagnosis of TB in HIV+

• Evaluated different algorithms among 2050 HIV+ from Cambodia, Thailand, Viet Nam:– Newly diagnosed with HIV at VCT– Persons with previous HIV diagnosis newly presenting to

HIV clinic or CD4 test site– Persons already enrolled in HIV care, some of whom are

already on ART

• Sensitivity of cough, fever, weight loss:– CD4<250 – 97%– CD4>250 – 81%

• Cain, CROI 2008

Objection 2: Resistance

• Claim: IPT promotes drug resistant disease and renders first-line therapy less effective when active TB occurs

• Fact: There is no strong evidence that IPT promotes drug resistant disease. When active TB occurs among those given IPT, standard four-drug first-line therapy works Nolan IJTLD 2002;6:952

Mitchison Am Rev Respir Dis 1986;133(3):423-30

Does IPT promote isoniazid resistance?

Balcells Emerg Infect Dis 2006;12:744-51

Effect of IPT on prevalence of resistance

Isoniazid Control

Prevalence of resistance: 50%

Incidence of resistance: 10% individuals exposed to INH

Prevalence of resistance: 25%

Incidence of resistance: 10% individuals exposed to control

INH-sensitive INH-resistant

Latent TB Latent TB

Active TB Active TB

• If TB is latent, few organisms, dividing slowly, thus low risk of selection of DR-TB

• Early studies of isoniazid monotherapy showed 70% cure MRC Br Med J 1952;2(4787):735-46

• 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

IPT does not increase resistance

Objection 3: 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

Synergistic effect of IPT plus ART on decreasing TB: Brazil

cases / pycases / py incidence incidence /100py/100py

IRR (95% CI)IRR (95% CI)

NeitherNeither 155/3865155/3865 4.014.01 1.01.0

ARTART 221/1162221/116277

1.901.90 0.48 (0.38-0.48 (0.38-0.59)0.59)

IPTIPT 5/3955/395 1.271.27 0.32 (0.10-0.32 (0.10-0.76)0.76)

ART/IPTART/IPT 10/125310/1253 0.800.80 0.20 (0.09-0.20 (0.09-0.91)0.91)

Golub AIDS 2Golub AIDS 2007;2007;211:1441:1441

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 4: Toxicity

Uganda RCT• 7/931 AST>135u/L (N 7-27 u/L); 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 Grant JAMA 2005;293:2719-2725

South Africa, ART cohort• IPT not associated with higher risk of

hepatotoxicity Hoffmann AIDS 2007;21:1301-8

IPT: hepatotoxicity rare

Systems Issues• IPT is feasible

– 1576 started out of 4110 in care in PHC sites in Ugu, Bohlabela and Cape Town in SA TB/HIV Pilots (1999-2002)

– 9633 started out of 29,197 in care in 18 PHC sites in Kenya (2004-7), 76% completion Diero et al, PEPFAR HIV Implementers Meeting, Kampala 2008

• IPT is cost effective– Cost to prevent TB case ($486-$962) less then

the cost of treating TB ($823-$1362) Hausler. Bulletin of WHO

2006;84(7):528-36

Summary

• Fears about difficult diagnosis, resistance, co-administration with ART and toxicity are unfounded

• Need to educate programme managers and clinicians about the scientific evidence

Remaining Questions

• What is best protocol for excluding active TB in HIV+?

• What is optimal duration of IPT?

• What is best way to ensure good adherence?

Recommendations• Public health leadership should drive implementation

at PHC level and ART sites through HIV programme • Implement IPT concurrently with infection control and

routine TB screening as part of pre-ART care • HIV community/PHA group must advocate for access

to IPT• Guidelines should be revised to remove barriers

(TST, allow IPT with ART) and operational research should be done but not as an excuse to delay implementation

Call to Action• IPT is important pre-ART intervention

• Failure to provide IPT is a violation of human rights and will worsen the TB epidemic among people with HIV

• TB/HIV Care Association and TAC handed a memorandum to Minister of Health on 24 March 2009 calling for partnerships and implementation of 3 I’s

• Let’s just do it!

Acknowledgements

Kevin de Cock, WHOHaileyesus Getahun, WHOReuben Granich, WHOAlison Grant, LSHTMMark Harrington, TAGVincent Tihon, BTC