1. ART in HIV-Infected Patients with TB: Research Priorities Group II Facilitator: David Cohn Rapporteur: Soumya Swaminathan

2. ART for HIV-infected patients with TB Delay ART till TB treatment is completed, depending on stage of HIV disease Use any ART with non-Rifampicin anti- tuberculosis treatment (ATT) regimen Use ART with ATT including Rifampicin Triple drug with 2 NRTI and 1 NNRTI Triple nucleoside Boosted PI

3. Major Questions in Treatment Nevirapine (NVP) vs Efavirenz: Equivalent efficacy against HIV, different adverse event (AE) profile. No comparative studies in HIV/TB pts Nevirapine and Rifampicin (RIF): Concerns about resistance, efficacy and toxicity risk Risk factors for toxicity: Black race, female, high CD4, HBV/HCV co-infection Current recommendations: Use NVP and RIF with caution with close monitoring

4. Efavirenz in HIV/TB co-infection (600 mg vs 800 mg) Reduction in EFV levels by RIF: 13-33% AEs dose-related Inter-patient variability, effect of ethnicity 600mg effective, especially in pts < 60kg Patients weighing > 60kg: Need more evaluation ? Impact of food/high fat meal ? Correlation with stage of HIV disease

5. Protease Inhibitors and Rifampicin: Safety and Efficacy Impact of RIF on PI levels: 80-90% reduction Pharmacologic boosting with ritonavir (SQV or LPV + RTV): May increase AEs (hepatotoxicity) SQV/r 1600/200 mg: AUC of reduced 50% by RIF, but clinical efficacy maintained SQV/r 1000/100 mg: In HIV-, high rate of clinical hepatitis; unknown in HIV+ SQV/r 400/400 mg: Limited data More studies needed...

6. IRIS/IRD Incidence of IRIS in HIV-related TB: Europe, USA 11-43%; Africa 41%; India 15.2/100 p-y; Higher in pts with active TB at start of ART Risk factors: ART within 6 weeks, disseminated TB, low baseline CD4, rise in CD4%, fall in VL, ? high bacillary burden Clinical: Fever, abscesses, LN enlargement,, arthritis, GI, CNS, radiographic worsening, other manifestations Reaction to mycobacterial antigens vs live bacilli?

7. Research Issues: Treatment When and how to start ART in TB co-infected patients on ATT: Clinical and laboratory parameters? Patients on standard 3-drug ART regimens: Monitoring efficacy and toxicity, PK studies Special emphasis on NVP when used with anti-TB drugs, e.g., hepatotoxicity, drug interactions Alternative regimens: od vs bid (split-dose Efavirenz?), triple/quadruple nucleosides, SQV/r in HIV+ ? (in light of new findings in HIV-), new drugs Simplification of regimens, including use of fixed-dose combinations (ART and ATT) Use of rifabutin in developing countries, as it becomes available

8. Research Issues: IRIS What is the best clinical definition for IRIS for use in resource-constrained settings? - need for validation studies Define incidence in different settings and by disease stage Risk factors and predictors for IRIS Role of corticosteroids and other anti-inflammatory drugs in prevention and treatment of IRIS Laboratory/immunological parameters for diagnosis Pathophysiology

9. Research Issues: Other Developing simpler outcome definitions Monitoring: Clinical vs laboratory for AEs (minimal requirements) Strategies for drug delivery: DOT, mDOT Emergence of TB and HIV drug resistance Strategies for measuring and enhancing adherence for patients on ATT and ART

10. Research Issues: Health Systems Cost-effectiveness of different regimens and treatment strategies Different strategies of collaboration and integration: Settings, type of clinic, personnel, level of training Nosocomial transmission of TB

11. Special Populations All these issues to be evaluated in special populations: Pregnant women IDUs (Hep B and C, methadone, buprenorphine?) Children

12. Summary - 1 What is the optimal time to start ART in TB co-infected patients on ATT (in order to improve efficacy and decrease toxicity)? - relative risk of mortality and morbidity vs complications of treatment, stratified by stage of disease What are best ART regimens to use with ATT? In patients on standard 3-drug ART regimens, how to best monitor efficacy and toxicity - Need for PK studies - Special emphasis on Nevirapine when used with ATT, e.g., hepatotoxicity, drug interactions What are alternative regimens (e.g., dosing)? Would Rifabutin-containing ATT with ART be more advantageous than Rifampicin-containing regimens?

13. Summary - 2 What is the best clinical definition for IRIS for use in resource- constrained settings (validation studies)? What are the risk factors and predictors for IRIS and how best to prevent and treat IRIS? What are the optimal treatment delivery strategies, e.g., DOT, modified-DOT? What are the different strategies of collaboration and integration in TB and HIV programmes, by settings, types of clinic, and personnel? What is the cost-effectiveness of different regimens and strategies? What are the minimal requirements for clinical and laboratory monitoring for outcomes related to efficacy and safety? What are the best strategies for measuring and enhancing adherence for patients on ATT and ART? For all above questions, consideration in special populations, including their co-morbidities and unique charactersitics.