HIV and TB Co-infection North Dakota HIV Symposium May 19, 2010

1. HIV and TB Co-infection North Dakota HIV SymposiumMay 19, 2010 David McNamara, M.D. Clinical Assistant Professor of Medicine University of North Dakota Infectious Disease Division MeritCare, Fargo ND

2. Disclosures • No commercial disclosures • Dakota AIDS Education & Training Center

3. Learning Objectives • Learners should be familiar with: • Epidemiology of HIV-TB Co-infection • HIV screening in TB infection • Drug interactions between medications for HIV and TB

4. Overview • Scope of Problem • TB in HIV infection • Diagnosis • Treatment • Drug Interactions • Summary

5. Catastrophic collision of TB and HIV infection Worldwide 2008: 33.2 million persons HIV+ ~30% co-infected with TB 9.4 million new TB cases 40% increase from 1990 Driven by HIV epidemic Convergence of Two Epidemics Chaisson R. JID 2010:201 (1 March)

6. Epidemiology • ~1/3 HIV infected persons worldwide are infected with TB (usually latent) • 8-10% develop active disease each year • 2007 • 9.27 million new TB cases • 15% occurred in HIV+ persons • Africa 80% • India 11% • 450,000 deaths from TB in HIV+ persons Swaminathan S. CID 2010:50 (15 May)

7. Mortality • Worldwide • 1.8 million deaths from TB in 2007 • 25% (450,000) also HIV+ • 2 million deaths from HIV • 22% from TB • TB the leading cause of death in HIV • HIV infection contributes to ~1/4 TB deaths

8. Geographic Distribution WHO Global Tuberculosis Control 2009 Report

9. Swaminathan S. CID 2010:50 (15 May)

10. Estimated HIV Coinfection in Persons Reported with TB, United States,1993–2008* % Coinfection *Updated as of May 20, 2009. Note: Minimum estimates based on reported HIV-positive status among all TB cases in the age group. cdc.gov

11. Implications • Global TB incidence and mortality would be decreasing if not for HIV epidemic • Increasingly, need to manage patients with both HIV and TB • Why this deadly synergy between these two infections? Swaminathan S. CID 2010:50 (15 May)

12. Overview • Scope of Problem • TB in HIV infection • Diagnosis • Treatment • Drug Interactions • Summary

13. Biology of TB • If airborne TB inhaled, person becomes infected • Most develop latent (inactive) TB Infection • immune system sequesters TB bacilli and prevents active infection • can reactivate to active TB in future • ~5-10% lifetime risk for HIV negative • ~8-10% per year with untreated HIV • Some develop active TB right away • Will feel sick, spread disease to others • More likely if immunocompromised • HIV, chemotherapy, elderly, malnourished

14. Biology of HIV • HIV infection depletes CD4+ T cells • T-cell arm of immune system • Cellular control of infection with • Viruses • Fungi • Mycobacteria • HIV-infected patients vulnerable to infection with pathogens that immune system usually controls

15. HIV Infection: CD4 Cell Decline http://msl.cs.uiuc.edu/~yershova/bcb495/bcbProject-3.htm

16. Manifestations of TB in HIV+ persons • Depends on level of immunosuppression • Early HIV infection • similar to non-HIV patients • pulmonary disease predominates • AIDS: severe immunosuppression • extrapulmonary sites common • miliary, lymphadenitis • paucibacillary disease, lymphadenitis • Similar to childhood TB • AFB-smear negative pulmonary disease

17. HIV-TB Challenges • Prompt diagnosis • Effective treatment • Successful prevention strategies • TB Recurrence in HIV+ persons after therapy completion

18. Recurrence of TB • HIV-negative patients with 4-drug therapy and DOT • 2-3% recurrence • HIV-positive patients • 14+ % recurrence rate • Some relapse with original strain • Most re-infect with new strain • Often with MDR TB • Why this discrepancy? • TB treatment does not alter ongoing • immunosuppression • risk for TB exposure

19. What can reduce recurrence rates? • Complete DOT for all patients with TB • ART for patients with TB and HIV • Infection control in HIV and TB care settings

20. Overview • Scope of Problem • TB in HIV infection • Diagnosis • Treatment • Drug Interactions • Summary

21. Challenges in Diagnosis of HIV-associated TB • Fewer bacilli in sputum than HIV – • Sputum AFB smear standard diagnostic method in most regions • HIV+ patients more likely to have smear-negative pulmonary TB • Sputum AFB culture slow, not readily available • CXR: less sensitive in HIV+ • ~14-22% HIV + patients with pulmonary TB have normal CXR

22. Diagnostic Methods • Microscopy • AFB smear • Cheap, rapid • Depends on bacterial load • Low sensitivity in HIV ~45% • Culture • More sensitive than microscopy • Can use probes on +culture to differentiate TB from NTM (common in HIV+ patients)

23. Diagnostic Methods • Sputum direct Probe (MTD) • Sensitivity variable in smear negative disease • Expensive, complex to perform • PPD skin test • Poor sensitivity in HIV due to anergy • Can’t differentiate latent vs. active disease • Poor sensitivity in setting of active TB • In HIV negative patients, only ~50% +PPD • QuantiFERON blood test • Interferon gamma release assay • Can’t differentiate latent vs. active TB • Does not differentiate between IRIS and failure of TB treatment

24. Diagnosis of HIV • All patients with active TB need an HIV blood test • Order: HIV 1/2 Antibody • HIV/TB co-infection significantly impacts prognosis and drug treatment • Treat both HIV and TB • Protease Inhibitor Antiretrovirals • significant interaction with Rifampin

25. Reporting of HIV Test Results in Persons with TB by Age GroupUnited States, 1993–2008* % with Test Results *Updated as of May 20, 2009. Note: Includes TB patients with positive, negative, or indeterminate HIV test results. Persons from California reported with AIDS only through 2004. (HIV test results are not reported from California) cdc.gov

26. WHO Global Tuberculosis Control 2009 Report

27. Overview • Scope of Problem • TB in HIV infection • Diagnosis • Treatment • Latent TB in setting of HIV • Active TB with HIV co-infection • When to start ART (AntiRetroviral Therapy) • Drug Interactions • Summary

28. Latent TB and HIV infection • Screen for latent TB in HIV+ patients • PPD skin test (>5 mm positive) • QuantiFERON blood test can be used; limited data • Isoniazid 300mg PO daily x 9 months

29. Treatment of Active TB with HIV Co-infection • Refer to • physician expert in both HIV and TB treatment • Public Health RN for DOT • Why? • Risk for failure high • negative consequences to patient, close contacts and community

30. Treatment of Active TB with HIV Co-infection • Basic principles in HIV+ similar to non-HIV • HIV-TB specific challenges • Frequency of anti-mycobacterial administration • Drug interactions • Overlapping drug toxicities • IRIS: Immune Reconstitution Inflammatory Syndrome

31. First-line TB therapy • Induction phase: 8 weeks • INH, RIF, PZA, EMB daily or 3x/ week • Continuation phase: 18 weeks • INH, RIF daily or 3x/week • Every effort should be made to use rifamycin-based therapy for entire course • Continuation phase: avoid • once-weekly INH-rifapentine • 2x/ week dosing

32. Treatment: DOTDirectly Observed Therapy • Mandatory for all active tuberculosis • Critical for HIV-TB Co-infection • Risk of relapse is higher • Public Health RN

33. Treatment:When to start antiretroviral therapy? • Optimal timing of initiation of ART in active TB has been uncertain • Concerns • Drug interactions (rifampin and PIs) • Overlapping drug toxicities • IRIS • High pill burden • Programmatic challenges

34. Karim et al. NEJM 362;8. Feb. 25, 2010 • SAPIT Trial, South Africa • 642 patients with TB, HIV and CD4 <500 cells/uL • Randomized to 3 groups for ART initiation • Early Integrated: within 4 weeks • Late Integrated: within 4 weeks of completion of Intensive phase TB treatment • Sequential: After completion of TB therapy

35. Study stopped early due to decreased mortality in integrated therapy groups • 56% relative reduction in risk of death • Adverse effects similar between groups Karim et al. NEJM 362;8. Feb. 25, 2010

36. IRIS:Immune Reconstitution Inflammatory Syndrome • Worsening of symptoms or X Ray with immunologic recovery • Occurs with infections in settings of immunosuppression when immune system recovers • HIV, chemotherapy, immunosuppressants • Mycobacterial and fungal diseases • Common as CD4 cell count improves with ART • Hard to tell between treatment failure and IRIS • Treat with steroids • Occasionally may have to hold ART

37. Overview • Scope of Problem • TB in HIV infection • Diagnosis • Treatment • Drug Interactions • Summary

38. Drug Interactions • Significant drug interactions between cornerstone drugs • antimycobacterials • rifampin, rifabutin • antiretrovirals • Protease Inhibitors • NNRTIs: efavirenz • Despite this, imperative to treat TB with rifamycin-based therapy if at all possible

39. Sterling TR CID 2010; 50(S3):S223-230

40. Drug Interactions • Rifamycins and Protease Inhibitors • Rifampin will  PI levels • Avoid rifampin and PIs • Use efavirenz-based ART if possible • low dose Rifabutin ok with PIs • Rifabutin 150 mg 3x/week • Rifampin and NNRTI • use high dose efavirenz 800 mg daily • Avoid rifampin and raltegravir

41. Drug Interactions • Treatment of TB-HIV co-infection by physician expert in treatment of both • Verify regimens and dosing with references • Incorrect dosing leads to: • Resistance in both HIV and TB • Treatment failure • Spread of drug-resistant TB

42. Overview • Scope of Problem • TB in HIV infection • Diagnosis • Treatment • Drug Interactions • Summary

43. Summary • Screen for HIV • Maintain high index of suspicion for TB in HIV patients • Patients with HIV-TB co-infection should be managed by physician expert in both diseases • All patients with active TB need an HIV test • All patients with TB need DOT

44. Acknowledgments • Anne Grande, Education Coordinator, Dakota AIDS Education & Training Center • North Dakota Department of Health

45. Resources • Centers for Disease Control and Prevention • cdc.gov • National Jewish Medical Center • nationaljewish.org • Denver TB course