Richard E. Chaisson, MD Center for Tuberculosis Research Johns Hopkins University

1. TB/HIV Research Priorities and Recent Developments Richard E. Chaisson, MD Center for Tuberculosis Research Johns Hopkins University

2. Examples of Research Needed • Basic –immunology, molecular biology, genomics, drug discovery • Translational – pathogenesis • Clinical – observational, trials, outcomes • Public Health – intervention paradigms • Operational – functional strategies • Health Services – health system structure • Cost-effectiveness – impact on DALYs • Behavioral – health seeking behavior, delays, clinician behavior

3. So many questions, so little time… • Epidemiology of TB/HIV • Diagnosis of latent and active TB • TB/HIV clinical issues • Treatment of TB in setting of HIV • ART, drug interactions and MDR • IRIS • New drugs • Preventive therapy • Public health interventions

4. So many questions, so little time… • Epidemiology of TB/HIV • Diagnosis of latent and active TB • TB/HIV clinical issues • Treatment of TB in setting of HIV • ART, drug interactions and MDR • IRIS • New drugs • Preventive therapy • Public health interventions

5. Community TB Prevalence in Masipumelela, South Africa Bekker et al., CROI 2006

6. So many questions, so little time… • Epidemiology of TB/HIV • Diagnosis of latent and active TB • TB/HIV clinical issues • Treatment of TB in setting of HIV • ART, drug interactions and MDR • IRIS • New drugs • Preventive therapy • Public health interventions

7. Current Approaches to Diagnosing TB in Resource Poor Settings • Reliance on antiquated tools with poor sensitivity

8. Diagnosis of Latent and Active TBOpportunities for Research • Latent TB • Interferon-gamma based assays • Proteomic-based antigen or antibody detection • Lateral flow and other platforms • Active TB • MGIT based diagnostics • Novel culture systems • Antigen detection in sputum • Automated nucleic acid amplification

9. Clinical Markers for Confirming Smear Negative TB in HIV+ Patients in South Africa Cape Town Study, HIV+ • Follow up study in KZN • HIV+ and HIV- patients with suspected SNTB • Response to therapy monitored • Response to therapy at week 8 = 96% for TB patients D Wilson et al., Int J TB Lung Dis, 2006 D Wilson et al., WAC Toronto, Abstract MOPE0145

10. Time to Positive Culture by MODS or L-J in 1639 Respiratory Specimens from TB Suspects in Brazil and Honduras MODS – Sm+ LJ – Sm+ Arias, Dorman et al., 2006

11. So many questions, so little time… • Epidemiology of TB/HIV • Diagnosis of latent and active TB • TB/HIV clinical issues • Treatment of TB in setting of HIV • ART, drug interactions and MDR • IRIS • New drugs • Preventive therapy • Public health interventions

12. Impact of an Opt-Out vs. Opt-In Strategy for HIV Testing of TB Patients in the Eastern Cape, South Africa: A Cluster Randomized Trial Pope et al., WAC Toronto, Abstract #THKC205

13. So many questions, so little time… • Epidemiology of TB/HIV • Diagnosis of latent and active TB • TB/HIV clinical issues • Treatment of TB in setting of HIV • ART, drug interactions and MDR • IRIS • New drugs • Preventive therapy • Public health interventions

14. ART, Drug Interactions and MDR TB • TB in patients on ART (Lawn et al., WAC Toronto, #MOPE 0175) • 944 patients initiating ART in Western Cape • 25% prevalent TB, 10% with new TB • TB incidence after ART 10.4 cases per 100 PY • MDR TB (Vargas et al., WAC Toronto, Abstract #WEPE0166) • 209 HIV+/TB patients in Lima • 34% MDR, 10% INH-resistant, median CD4 = 44 • XDR TB (Gandhi et al., WAC Toronto,#THLB0210) • Epidemic MDR and XDR TB in KZN, South Africa • All XDR TB patients HIV+, 51% with no prior treatment

15. p =0.006 NS 4000 PPD 4000 CMV 3500 3500 3000 3000 2500 2500 PBMC PBMC 2000 2000 6 6 SFC/10 SFC/10 1500 1500 1000 1000 500 500 0 0 T BK M 0 T IRS M 3 M 6 T BK M 0 M1 M 3 M6 IRS+ n=9 (41%) IRS- n=13 DTH Responses Measured by Elispot in Patients with and without IRIS 22 HIV-TB co-infected patients prospectively followed after anti-mycobacterial (TBK) then ARV (M0) therapy initiation Bourgarit et al., AIDS. 2006;20:F1-7, CROI 2006

16. TBTC Study 27: Moxifloxacin vs. Ethambutol as 4th Drug in Initial Treatment of Smear+ TB P=0.02 P=0.003 Median Time to Culture Conversion: Moxi 43 d vs. EMB 56 d (p=0.01) Burman et al., AJRCCM 2006;174:331-8

17. TBTC Study 27Sputum culture conversion among key sub-groups Adjusted P 0.03 0.003 <0.0001 Culture conversion 66% (137/206) 84% ( 60/71) 66% ( 89/134) 76% (108/143) 63% (110/175) 85% ( 87/102) Cavitation No cavitation Age <31 years Age >31 years African North American Burman et al., AJRCCM 2006;174:331-8

18. Moxifloxacin and PA-824 in a Murine TB Model R, rifampin; M, moxifloxacin; Z, pyrazinamide; Pa, PA-824. Nuermberger et al., Antimicrob Agents Chemother 2006;50:2621

19. So many questions, so little time… • Epidemiology of TB/HIV • Diagnosis of latent and active TB • TB/HIV clinical issues • Treatment of TB in setting of HIV • ART, drug interactions and MDR • IRIS • New drugs • Preventive therapy • Public health interventions

20. TB Incidence in Brazilian HIVPatients by Treatment Category Golub et al., WAC Toronto, Abstract MOPE0395

21. Novel TB Preventive Regimens in HIV-Infected Adults in Soweto: PHRU/JHU Trial • Open label, randomized trial • HIV+/PPD+ adults not on HAART at enrollment • Active TB excluded (23% screen failures  TB+) • Regimens • Rifapentine 900 mg/INH 900 weekly for 12 weeks • Rifampin 600 mg/INH 600 mg twice weekly for 12 weeks • INH 300 mg daily continuously • INH 300 mg daily for 6 months • Endpoint – TB-free survival

22. Probability of TB After Enrollment (All Treatment Groups)

23. So many questions, so little time… • Epidemiology of TB/HIV • Diagnosis of latent and active TB • TB/HIV clinical issues • Treatment of TB in setting of HIV • ART, drug interactions and MDR • IRIS • New drugs • Preventive therapy • Public health interventions

24. C R E A E

25. Research in TB/HIV • The need is enormous • There are abundant opportunities to contribute • Interdisciplinary and novel approaches are needed • New paradigms must be developed • “The greatest obstacle to discovery is not ignorance - it is the illusion of knowledge.”--Daniel Boorstein