1. Welcome to I-TECH HIV/AIDS Clinical Seminar Series November 19, 2009 Tuberculosis in Persons with HIV/AIDS: Opportunities for Prevention Charles Nolan, M.D.

2. Case for discussion A 22 yr old woman, recently diagnosed with HIV infection at the time of delivery of her second child, was referred for clinical and laboratory staging The evaluation revealed clinical stage 2 HIV infection (weight loss of perhaps a few kg over the past two months), and her CD4 cell count was 240 cells/mm3 The patient said that she has experienced a dry cough for around 3 weeks. She denied having fever.

3. Case for discussion (continued) How would you proceed to evaluate and manage this patient?

4. Considerations for this patient Further clinical evaluation because of symptoms – yes/no Antiretroviral therapy – yes/no Cotrimoxazole preventive therapy – yes/no Screening for TB - yes/no Isoniazid preventive therapy – yes/no

5. Strategies for prevention of TB in persons with HIV infection The “three I’s” (from WHO) 1.Intensified TB case finding 2. Isoniazid preventive therapy 3. Infection control in health care facilities Anti-retroviral therapy

6. Tuberculosis pathogenesis 6 1. 2. 3.4.

7. Natural history of TB Exposure to an infectious case Focus in infection in lung Silent dissemination of infection and containment by host defenses (98%) Latent TB infection Pt asymptomatic, TST positive Activation of latent infection (5-10%) Patient symptomatic, based on site of activation (70% pulmonary) Lifetime dormancy (90-95%)

8. Preventive Interventions against TB Exposure to an infectious case Focus in infection in lung Dissemination of infection and/or containment by host defenses Latent TB infection Activation of infection Patient symptomatic, based on site of activation (70% pulmonary) immunization Treatment of Latent TB Infection Treatment of active TB

9. Natural history of TB in persons with HIV infection Exposure to an infectious case Focus in infection in lung Silent dissemination of infection and containment by host defenses (98%) Latent TB infection Pt asymptomatic, TST pos/neg Activation of latent infection (Lifetime odds of disease 5-10%) Patient symptomatic, based on site of activation (70% pulmonary) Lifetime dormancy (??) Clinical dissemination And disease (1-2%) 25% Annual risk of disease 10% 75%

10. Preventive Interventions against TB in Persons with HIV infection Exposure to an infectious case Focus in infection in lung Dissemination of infection and/or containment by host defenses Latent TB infection Activation of infection Patient symptomatic, based on site of activation Immunization Treatment of Latent TB Infection Treatment of active TB ART Infection control ART

12. Summary of the effect of antiretroviral therapy on rates of active TB In multiple studies done in a variety of settings, use of antiretroviral therapy decreases the rate of active TB in the population being treated The effect of antiretroviral therapy is greatest in areas with high rates of TB and among patients with lower CD4 cell counts Decreasing the risk of active TB is an important benefit of antiretroviral therapy

13. Traditional DOTS approach to TB case detection A patient seeks medical care, generally in aprimary health center, because of feelingunwell The patient is identified as a TB suspect on thebasis of typical symptoms: cough >2 weeks induration, fever, loss of weight The diagnosis of TB is made most often bymicroscopic examination of sputum for acid-fast bacilli

14. TB treatment

15. The advantages of early detection of TB cases in persons with HIV infection Early case detection leads to early institution of treatment, and to  A better chance for cure for the sick patient, and  Early termination of infectiousness and transmission Early case detection allows early assessment of contacts, including children, for TB and HIV infection

16. The importance of early detection of TB in persons with HIV infection A study from South Africa* found that patients with HIV infection who were found to have active TB on routine screening were six times less likely to die during TB treatment that those who sought care for TB associated symptoms *Churchyard et al. Int J Tuberc Lung Dis 4:705-712, 2000

17. Proposed flow chart for IPT in patients with HIV infection Ait-Khaled et al. Int J Tuberc Lung Dis 13:927, 2009 TST?

18. TB Rates by ART and INH Treatment Status, 2003-2005 Exposure category Person- Years TB Cases Incidence Rate (per 100 PYs) Incidence Rate Ratio No Rx3,8651554.01 (3.40-4.69)1.0 ART only11,6272211.90 (1.66-2.17)0.48 (0.39-0.59) IPT only39551.27 (0.41-2.95)0.32 (0.10-0.76) Both1,253100.80 (0.38-1.47)0.20 (0.09-0.91) Total17,1403912.28 (2.06-2.52) Golub et al., AIDS 2007;21:1441-8

19. Efficacy of IPT in reducing the risk of TB in HIV+ Adults 11 randomised trials with 8,130 HIV+ participants  overall reduction in TB = 36%, reduction PPD+ = 62% Woldehanna and Volmink, Cochrane Review 2006

20. Despite good evidence of IPT efficacy, recommendations from WHO guidelines, and the adoption of national guidelines, in 2007 only 0.1% (29,000) of the estimated 33.2 million people living with HIV infection were put on IPT. Why is this?

21. Unresolved issues with IPT Who should supervise IPT? Should tuberculin skin testing be used to identify IPT candidates? How and in whom should active TB be ruled out? Does IPT lead to an increased risk of INH resistance? How durable is a 6-9 month course of IPT? How safe is IPT in patients receiving ART?

22. Side effects of INH GI intolerancePIs, ZDV, ddI Skin rashABC, NNRTIs, Peripheral neuropathy ddI, d4T, ddC (Rare if pyridoxine is given concomitantly) Hepatotoxicity PIs, NNRTIs Effect also seen with ARVs

23. Types of adverse events from INH for latent TB in persons with HIV infection - Zambia Adverse event leading to drug discontinuation Hepatitis Rash GI symptoms Others Placebo (n = 360) 0 1 (0.3%) 2 (0.6%) INH (n = 360) 3 (0.8%) 1 (0.3%) 5 (1.4%) 3 (0.8%) AIDS 1998;12:2447-57

24. effect of IPT on drug susceptibility of subsequent TB cases – South African gold miners TB Cases following IPT (n = 57) TB cases in comparison group (n = 97) INH resistant cases 7 (13.2%) 8(8.2%) Churchyard G, et al. Unpublished observations

25. Topic for discussion How does your institution protect its staff members, including those with HIV infection, from acquiring TB?

26. The importance of TB infection control in HIV care Because undiagnosed TB is so common in PLWHA, TB is being transmitted in health care facilities from patient to patient and to health care workers Health care workers are 5-fold more likely to acquire TB compared to the general population Outpatient and inpatient sites are potential sites of TB spread: Emergency rooms, hospital wards, primary health care clinics, ART clinics, PMTCT clinics, VCT sites, and other sites inclujding jails, drug rehab centers…. Approximately half of cases in the XDR-TB outbreak in Kwa-Zulu Natal, South Africa were associated with health care sites

27. To reduce the spread of TB, all HIV care facilities should implement… Good work practices and administrative control measures Environmental control measures WHO 2009

28. The hallmark of good work practices to control TB is a TB infection control plan Through screening, identify TB suspects and and separate them from other patients in a well ventilated space Institute cough hygiene for TB suspects, including tissues and face masks Minimize time TB suspects spend in clinic, but deliver services they came for Evaluate TB suspects promptly or have a plan to refer them for evaluation Identify an Infection Control Officer to administer the plan

29. Environmental control measures for prevention of TB spread Environmental control is secondary to good work practices Mechanical ventilation systems are expensive and suitable for referral hospitals Natural ventilation can be utilized in many health care settings Open windows, open doors, and fans can efficiently bring outside air into a room, diluting droplet nuclei containing M.tb.

30. Thank you! Listserv: itechdistlearning@u.washington.eduitechdistlearning@u.washington.edu Email: DLinfo@u.washington.eduDLinfo@u.washington.edu Next session: December 3 – HIV and Women

31. Thank you! Next session: December 3, 2009 Dr Scott McClelland HIV and Women, Part 2