1. HIV and TB Co-infection North Dakota HIV Symposium May 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 No commercial disclosures Dakota AIDS Education & Training Center Dakota AIDS Education & Training Center

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

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

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

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

7. Mortality Worldwide Worldwide 1.8 million deaths from TB in 2007 1.8 million deaths from TB in 2007 25% (450,000) also HIV+ 25% (450,000) also HIV+ 2 million deaths from HIV 2 million deaths from HIV 22% from TB 22% from TB TB the leading cause of death in HIV TB the leading cause of death in HIV HIV infection contributes to ~1/4 TB deaths 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 Global TB incidence and mortality would be decreasing if not for HIV epidemic Increasingly, need to manage patients with both HIV and TB Increasingly, need to manage patients with both HIV and TB Why this deadly synergy between these two infections? Why this deadly synergy between these two infections? Swaminathan S. CID 2010:50 (15 May)

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

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

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

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

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

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

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

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

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

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

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

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

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

25. % 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) Reporting of HIV Test Results in Persons with TB by Age Group United States, 1993–2008* cdc.gov

26. WHO Global Tuberculosis Control 2009 Report

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

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

29. Treatment of Active TB with HIV Co-infection Refer to Refer to physician expert in both HIV and TB treatment physician expert in both HIV and TB treatment Public Health RN for DOT Public Health RN for DOT Why? Why? Risk for failure high Risk for failure high negative consequences to patient, close contacts and community 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 Basic principles in HIV+ similar to non-HIV HIV-TB specific challenges HIV-TB specific challenges Frequency of anti-mycobacterial administration Frequency of anti-mycobacterial administration Drug interactions Drug interactions Overlapping drug toxicities Overlapping drug toxicities IRIS: Immune Reconstitution Inflammatory Syndrome IRIS: Immune Reconstitution Inflammatory Syndrome

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

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

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

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

35. Study stopped early due to decreased mortality in integrated therapy groups Study stopped early due to decreased mortality in integrated therapy groups 56% relative reduction in risk of death 56% relative reduction in risk of death Adverse effects similar between groups 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 Worsening of symptoms or X Ray with immunologic recovery Occurs with infections in settings of immunosuppression when immune system recovers Occurs with infections in settings of immunosuppression when immune system recovers HIV, chemotherapy, immunosuppressants HIV, chemotherapy, immunosuppressants Mycobacterial and fungal diseases Mycobacterial and fungal diseases Common as CD4 cell count improves with ART Common as CD4 cell count improves with ART Hard to tell between treatment failure and IRIS Hard to tell between treatment failure and IRIS Treat with steroids Treat with steroids Occasionally may have to hold ART Occasionally may have to hold ART

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

38. Drug Interactions Significant drug interactions between cornerstone drugs Significant drug interactions between cornerstone drugs antimycobacterials antimycobacterials rifampin, rifabutin rifampin, rifabutin antiretrovirals antiretrovirals Protease Inhibitors Protease Inhibitors NNRTIs: efavirenz NNRTIs: efavirenz Despite this, imperative to treat TB with rifamycin-based therapy if at all possible 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 Rifamycins and Protease Inhibitors Rifampin will  PI levels Rifampin will  PI levels Avoid rifampin and PIs Avoid rifampin and PIs Use efavirenz-based ART if possible Use efavirenz-based ART if possible low dose Rifabutin ok with PIs low dose Rifabutin ok with PIs Rifabutin 150 mg 3x/week Rifabutin 150 mg 3x/week Rifampin and NNRTI Rifampin and NNRTI use high dose efavirenz 800 mg daily use high dose efavirenz 800 mg daily Avoid rifampin and raltegravir Avoid rifampin and raltegravir

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

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

43. Summary Screen for HIV Screen for HIV Maintain high index of suspicion for TB in HIV patients 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 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 active TB need an HIV test All patients with TB need DOT All patients with TB need DOT

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

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