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Isoniazid Preventive Therapy: A Call to Action

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

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Isoniazid Preventive Therapy: A Call to Action

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  1. 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

  2. Overview • Efficacy of isoniazid preventive therapy (IPT) • IPT guidelines • IPT implementation • Reasons for limited implementation • Recommendations

  3. 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

  4. 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

  5. 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”

  6. 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

  7. TB screening, diagnosis and prevention, 2002-2007

  8. 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

  9. IPT in South Africa Department of Health, 2009

  10. Number started IPT per provinceSouth Africa, 2008 DOH, 2009 NB: Missing data for EC, KZN, MP, NW

  11. Proportion HIV+ started on IPT South Africa, 2008 DOH, 2009 NB: Missing data for EC, KZN, MP, NW

  12. 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)

  13. 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

  14. 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

  15. 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

  16. 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!

  17. 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

  18. 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.

  19. 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

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

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

  22. 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

  23. 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

  24. Does IPT promote isoniazid resistance? Balcells Emerg Infect Dis 2006;12:744-51

  25. Latent TB Latent TB Control Isoniazid ActiveTB ActiveTB 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-resistant INH-sensitive Effect of IPT on prevalence of resistance

  26. 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

  27. 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

  28. Synergistic effect of IPT plus ART on decreasing TB: Brazil Golub AIDS 2007;21:1441

  29. 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

  30. 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

  31. 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

  32. 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

  33. 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?

  34. 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

  35. 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!

  36. Acknowledgements Kevin de Cock, WHO Haileyesus Getahun, WHO Reuben Granich, WHO Alison Grant, LSHTM Mark Harrington, TAG Vincent Tihon, BTC

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