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

Effect of IPT on TB: Meta-analysis of 7 randomised clinical trials (N=4134) Relative risk, 95% CI 1.0 Placebo Overall TST+ TST- Woldehanna 2004, Cochrane review

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

AFRO implementation of IPT, 2007 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

Prelimanary Report on TB Data 2004 CF & 2003 TO IPT in South Africa Indicators 2008 Q1 2009 HIV tested 1,372,167 526,958 HIV-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 Prepared by Carina Idema

Number started IPT per province South 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: Regimen: 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 Guidelines Proposed 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 It’s too hard to rule out active TB IPT worsens drug resistance It’s not needed if you’re on ART It’s too toxic

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

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 Africa Int 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% 10% individuals exposed to control INH-sensitive INH-resistant Latent TB Active TB

IPT does not increase resistance 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

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 / py incidence /100py IRR (95% CI) Neither 155/3865 4.01 1.0 ART 221/11627 1.90 0.48 (0.38-0.59) IPT 5/395 1.27 0.32 (0.10-0.76) ART/IPT 10/1253 0.80 0.20 (0.09-0.91) Golub AIDS 2007;21:1441

Objection 4: 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/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

Systems Issues IPT is feasible IPT is cost effective 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, WHO Haileyesus Getahun, WHO Reuben Granich, WHO Alison Grant, LSHTM Mark Harrington, TAG Vincent Tihon, BTC