ART in HIV-Infected Patients with TB: Research Priorities

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.