1. HIV and TB CO-INFECTION Susan Swindells MBBS Nebraska AIDS Education & Training Center University of Nebraska Medical Center

2. Opportunistic Infections Highest Priority Worldwide Tuberculosis Andrew Speaker

3. Emergence of XDR TB 17,690 isolates worldwide 2004-5, 20% MDR, 2% XDR Latvia- 19% of MDR TB cases S. Korea- 15% of MDR TB cases Latin America-6% of MDR TB cases USA-4% MDR TB cases Africa-<1% MDR TB cases India? China?

4. High Prevalence and Mortality from Extensively Drug-Resistant (XDR) TB in TB/HIV Coinfected Patients in Rural South Africa NR Gandhi, A Moll, R Pawinski, U Lalloo, AW Sturm, K Zeller, J Andrews, G Friedland Yale University School of Medicine, New Haven CT USA Nelson R. Mandela School of Medicine, Durban, South Africa Philanjalo, Tugela Ferry, KwaZulu Natal, South Africa

5. Results 1539 Patients with Isolates sent 544 (35%) Culture-Positive for M.tb 995 (65%) Culture-Negative 221 (41%) Resistant to INH and RIF (MDR TB) 128 cases of MDR TB in US in 2004 53 (24% of MDR, 10% Culture-Positive) Resistant to all tested drugs (XDR TB) 347 cases XDR TB worldwide

6. Survival from Sputum Collection

7. Mortality 52 of 53 (98%) XDR TB patients died Median survival from sputum collection 16 days (range 2-210 days) 2 healthcare workers died with confirmed XDR TB –4 other workers died with suspected XDR TB 64% of patients hospitalized for any cause before onset of XDR TB 26/30 (87%) XDR TB isolates genetically similar 86% HIV-infected

9. Majority of patients infected with the same KZN strain Databases 1994 to 2005 searched for resistance patterns in isolates of M.TB with KZN strain fingerprint. In 1994, KZN strain cases with MDR TB, with some STM resistance From 1994, MDR isolates found with resistance to additional drugs First XDR isolate in 2001 Resistance to up to 7 drugs developed in a decade. Evolution of the extensive drug resistant (XDR) KZN strain of M.TB in KwaZulu-Natal Courtesy of G. Friedland

10. Survival by level of resistance 1= non-MDR 2 = MDR 3 = 4/5 XDR 4 = 6 XDR NonDR=57 MDR=52 XDR=61 Courtesy of G. Friedland

11. Tuberculosis and HIV Disease and TB Drug Resistance-A Perfect Storm Enormous cost of worldwide neglect of TB Lack of resources, basic research, modern diagnostics and new treatments Estimated $20 billion needed in next decade Areas of high TB and HIV prevalence particularly vulnerable – Failing TB programs – Poverty/crowding/migration – Primitive infection control – Lack of interaction with HIV programs

13. XDR TB: High Research Priority Global XDR TB Task Force met Oct ’06 Revised case definition: Occurrence of TB with isolates resistant to INH and RIF plus any fluroquinolone and at least one of three injectable 2 nd -line drugs (amikacin, kanamycin, capreomycin) MMWR Nov 3, 006/55(43);1176

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15. Interaction of HIV & TB Lifetime risk of disease with MTB infection: 10-20% Annual risk with HIV co-infection 10% Leading cause of death with HIV in sub-Saharan Africa Occurs at all CD4 levels Risk of TB increases soon after HIV infection Incidence doubled in 1 st year after infection in SA gold miners [Sonnenberg et al; JID 2005] Reinfection and reactivation

16. Unanswered questions in Management of HIV/TB co-infection When to start ART What to start Optimal diagnostic tests Role of INH prophylaxis How to prevent drug resistant TB IRIS issues Pregnancy Drug-drug interactions

17. Estimated TB incidence rates, 2004 The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement.  WHO 2005. All rights reserved 0 - 24 25 - 49 50 - 99 100 - 299 No estimate 300 or more Estimated new TB cases (all forms) per 100 000 population

18. A global view of HIV infection 38.6 million people [33.4 ‒ 46.0 million] living with HIV, 2005 2.4

19. Estimated HIV prevalence in new adult TB cases The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement.  WHO 2005. All rights reserved HIV prevalence in TB cases, 15-49 years (%) 0 - 4 5 - 19 20 - 49 50 or more No estimate

20. ANTIRETROVIRRAL THERAPY 0 MONTH ON ARV 964862 TB in patients receiving ART NEW TB Undiagnosed TB Activation of latent TB IRIS Transmitted TB New Pulmonary TB Treatment failure Recurence Reinfection Courtesy of F. Scano, WHO

21. TB Skin Testing ≥ 5 mm positive in HIV-infected 55% HIV+ pts in sub-Saharan Africa TST+ Can be read after 2 -7 days [personal communication R.Chaisson]

23. TB Diagnosis WHO strategy using sputum smears misses half of incident cases at 1 st presentation Misses extra-pulmonary disease 5% detection in children HIV-infected pts more likely smear-negative Multiple visits and months of delay common Lack of standardized diagnostic tests to in/exclude TB in ART clinical trials/rollout programs

24. Smear negative TB in PLHIV Higher chance for smear negative disease –SN pulmonary = 24 – 61% –Extrapulmonary = 4 – 40% Autopsy studies = 14 – 54% Scale of problem is underestimated –Studies are institution based –Most TB services look for smear positives –Early death before diagnosis is established Getahun H et al Lancet 2007 DOI:10.1016/S0140-6736(07)60284-0

25. Key changes in the new policy Vigilance and flexibility to start empiric treatment for suspected extrapulmonary TB in peripheral health facilities TB care should include HIV care – HIV staging (clinical, immunological) – PCP treatment –Co-trimoxazole preventive therapy Clinical management of extrapulmonary TB be included as TB control programme activity Recording and reporting of SN TB improved

26. Clinical Predictors of Active TB in Rural Uganda (n=1995) Sign/symptom Cough ≥ 3 weeks BMI ≤ 18 Night sweats Fever ≥ 1 month Weight loss Lymphadenopathy Sensitivity 76% 67% 63% 59% 58% 37% Sensitivity and specificity improved with 1 or more of: cough, fever, lymphadenopathy, BMI Were et al; CROI 2007 abstr# 848

27. Role of DOTS Directly Observed Treatment Short-Course Public health based Passive detection using sputum smear Standardized regimens 6-8 months with DOT for at least first 2 Targets: 70% detection, 85% cure

29. 2006 ReferenceLab PeripheralLab FIND Product Deliverables 2006-2013 Clinic Health post 2007 200820092010201120122013 % Access after 5 years 95% 70% 10-40% Liquid culture MTB & DST Phage based resistance test Automated NAAT LED Fluor Microscopy POC NAAT Urinary AG detection Reader based LAT Flow Speciation test Urinary NAAT Improved AG/AB strip test

30. Role of INH CDC recommends for TST ≥ 5 mm WHO recommends INH for all HIV+ in high prevalence countries Most of Asia and Africa do not use: officially discouraged in S. Africa and India Limited resources to screen for active disease Concern about drug resistance

31. INH preventive therapy (IPT) IPT reduces risk of TB in HIV+ people by 62% in PPD+ By 36% overall Evidence of survival benefit in children and in adults in cohort studies Benefit of IPT may wane after 1-2 years in high prevalence settings

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

33. Treatment of Latent TB in HIV+ Patients and Survival in Brazil Pinho, AIDS 2001

34. TB Preventive Therapy and Drug Resistance Review of 13 IPT trials with ~35,000 participants shows low risk of selecting resistance (RR 1.45, 95% CI 0.85-2.47) For INH-resistant LTBI, rifampin effective For MDR or XDR exposure, no regimen has been shown to be effective Drugs with potential utility: –Linezolid –Clofazimine –Amoxicillin/clavulanic acid Balcells et al. EID 2006;12:744; Nuermberger et al. AJRCCM 2005;172:1452

35. MDR TB Treatment Peru, Philippines & Eastern Europe cohort data N = 729 70% success rate Required individualized regimens with at least 4 drugs including 1 injectable + fluroquinolone MDR-TB can be treated in resource poor countries (but not very poor ones) Nathanson et al; Emerg Inf Dis Sep 2006

36. Discovery - 17Preclinical - 4Clinical Testing - 5 Dihydrolipoamide Acyltransferase Inhibitors NIAID, Cornell University Dipiperidines Sequella Inc. InhA Inhibitors GlaxoSmithKline, TB Alliance Isocitrate Lyase Inhibitors (ICL) GlaxoSmithKline, TB Alliance Macrolides TB Alliance, University of Illinois at Chicago Methyltransferase inhibitors Anacor Pharmaceuticals Translocase I Inhibitors Sequella Inc., Sankyo Synthase Inhibitor FAS20013 FASgen Inc. Moxifloxacin Bayer Pharmaceuticals, CDC TBTC, Johns Hopkins University, NIAID, TBRU Diarylquinoline R207910 Johnson & Johnson Proprietary Compound Otsuka Natural Products Exploration NIAID, TAACF, California State University, University of Auckland Nitroimidazole PA-824 Chiron Corporation, TB Alliance Diamine SQ-109 Sequella Inc. Gatifloxacin OFLOTUB – TDR, Tuberculosis Research Centre, NIAID, TBRU Cell Wall Inhibitors NIAID, Colorado State University Novel Antibiotic Class GlaxoSmithKline, TB Alliance Picolinamide Imidazoles NIAID, TAACF) Pleuromutilins GlaxoSmithKline, TB Alliance Pyrroles (TB Alliance, Private Sector Partner) Quinolones KRICT/ Yonsei University, NIAID, TAACF, TB Alliance Proprietary Compounds AstraZeneca Thiolactomycin Analogs NIAID, NIH Nitroimidazole Analogs Novartis Institute for Tropical Diseases, NIAID, TB Alliance Nitrofuranylamides NIAID, University of Tennessee Pyrrole LL-3858 Lupin Limited

37. Role of Vaccines Pre or post exposure vaccines could decrease disease/death Pre or post exposure vaccines could decrease disease/death Use in combination with antibiotics? Use in combination with antibiotics?

38. Role of ART: WHO Guidelines 2006 for ART Initiation Stage IV illness TB ; serious bacterial infections if CD4 <350 Before CD4 count falls to 200 Start ART treatment 2 - 8 weeks after TB for active disease

39. WHO Guidelines

40. Prevention Optimal timing of ART initiation in those on TB treatment? EARLYDELAYED IRIS Pill Burden Drug-drug interactions Toxicity Cost Increased disease progression and death

41. Cape Town cohort of 264 pts on ART and 770 not; 1992-2001 [Badri Lancet 2002] On ART NotRR P value CD4 count # cases (incidence) <200 5 (3.4%) 41 (17.5%) 0.18<.0001 200-350 2 (1.7%) 27 (12%) 0.12<.0001 >350 2 (2%) 14 (3.6%) 0.360.78 Overall 9 (2.4%) 82 (9.7%) 0.19<.0001

42. Rifampin Interactions: Is dose adjustment required? EFV and NVP are reduced 20-40% with rifampin 1,2,3,4 Small PK studies support dose increase of EFV (800 mg) and NVP(300 mg bid) 5,6 Large interpatient variability due to genetic determinants of metabolism 7 Clinical outcome studies to date do not support dose adjustment of EFV or NVP 1 Ribera, JAIDS, 2001; 2 Lopez-Cortes, Clinical PK, 2002; 3 Manosuthi, AIDS, 2005 ; 4 Manosuthi, CID, 2006 5 Lopez-Cortes, Clinical PK, 2002; 6 Ramachandran, JAIDS, 2006; 7 Haas, AIDS, 2004; Friedland J, Antimicrob. Chemotherapy 2006.

43. TB-IRIS: Incidence and Risk Factors Lawn et al; AIDS 2007

44. TB-IRIS: Incidence and Risk Factors Risk of IRIS high with low CD4 count and early treatment Most cases self-limiting Mortality rate low (1%) Lawn et al; AIDS 2007

45. Conclusions ART reduces TB risk, but not enough Risk of selecting for resistance with IPT appears low Active TB can be ruled out by clinical or laboratory screening in most patients Need for improved diagnostics Treatment of TB and HIV concurrently is complex

46. TB Control in HIV-Endemic Areas Requires Reassessment of traditional approaches to TB control (active vs passive case finding, DOTS) Development of new tools and technologies Increased drug availability and new drugs; shorter, simpler regimens Vaccine? Joint approaches with HIV-related programs Earlier access to ART