Building Global HIV/AIDS Clinical Pharmacology Research Capacity

1. Building Global HIV/AIDS Clinical Pharmacology Research Capacity HIV and TB: Capacity Challenges to the use of Current Drugs and Developing New Drugs Kimberly Scarsi, PharmD, MS Northwestern University Feinberg School of Medicine Center for Global Health

2. HIV and TB: Capacity Challenges to the use of Current Drugs and Developing New Drugs Presentation Outline • Overview of HIV and TB therapeutic challenges • Drug Interaction considerations in HIV-TB coinfection • Challenges in TB therapeutics research and drug development

3. HIV and TB: Capacity Challenges to the use of Current Drugs and Developing New Drugs Tuberculosis and HIV Prevalence WHO. Global TB Control. 2010

4. HIV and TB: Capacity Challenges to the use of Current Drugs and Developing New Drugs Paradigm of Disease Progression in Patients with HIV-TB Coinfection Slide adapted, courtesy of Dr. Holly Rawizza

5. HIV and TB: Capacity Challenges to the use of Current Drugs and Developing New Drugs SAPIT HIV-positive, CD4 <500 new TB infection N = 642 Early integrated (IP) Late Integrated (CP) Combined Integrated N = 429 Sequential (> 6m) N = 213 Slide courtesy of SayeKhoo AbdoolKarim et al. NEJM 2010;362:697

6. HIV and TB: Capacity Challenges to the use of Current Drugs and Developing New Drugs Treatment of TB Infection * Some countries use INH + ETB for 6 months for continuation phase as an alternative. Slide courtesy of Holly Rawizza, MD, 2009.

7. HIV and TB: Capacity Challenges to the use of Current Drugs and Developing New Drugs PharmacologyChallenges of Current TB Therapy • Complex regimens with high pill burden, particularly with concomitant HIV therapy • May impact adherence • Overlapping toxicities create clinical management challenges • Importance of pharmacovigilance programs • Lack of clinical PK-PD data • Urgent need to confirm “therapeutic” target concentrations • Unique Pediatric Challenges: • Suboptimal drug concentrations with standard doses • Absence of PK and PD data on 2nd-line TB agents • Significant HIV-TB drug interactions limit the effective options

8. A Focus on Drug Interactions

9. DRUG INTERACTION POTENTIAL No clinically significant interaction expected Potential interaction – may require close monitoring or dose alteration These drug should NOT be coadministered No clear data

10. HIV and TB: Capacity Challenges to the use of Current Drugs and Developing New Drugs Risk factors for Clinically Significant Drug Interactions in Kenya Slide courtesy of SayeKhoo. Kigen et al. HIV8, 2008 Abstract O121

11. HIV and TB: Capacity Challenges to the use of Current Drugs and Developing New Drugs Change (%) in AUC of ARVs when given with rifampicin - 86% - 89% - 82% - 72% - 26% - 63% - 80% - 35% - 82% - 73% - 40% - 40% ND ND • No significant interactions – NRTIs and T20 • Data are lacking with intermittent or high dose rifampicin regimens Slide adapted, courtesy of SayeKhoo www.hiv-druginteractions.org

12. HIV and TB: Capacity Challenges to the use of Current Drugs and Developing New Drugs Clinical outcome data: Essential to evaluate the impact of some pharmacokinetic changes Nevirapine Efavirenz JAMA 2008. 300(5):530-9.

13. HIV and TB: Capacity Challenges to the use of Current Drugs and Developing New Drugs Drug Interaction Research Questions • Ongoing research with accumulating data: • Avoidance of NVP lead-in dose with rifampicin • Optimal nevirapine dose escalation strategy with rifampicin • Use of LPV/r dose escalation strategies to overcome rifamipicin induction in both adults and children • Establishing the correct dose of TB agents for use in children • Appropriate rifabutin dose with protease inhibitors • Questions remaining to be answered: • Rifapentine drug interactions with antiretrovirals • Defining new TB agent drug interaction profiles • If twice daily atazanavir/r can overcome rifampin induction • Drug interactions with 2nd line TB agents and ART

14. HIV and TB: Capacity Challenges to the use of Current Drugs and Developing New Drugs One example of practical PK evaluations of rifampicin plus nevirapine • PK study in 18 adult Ugandan patients who had been on RIF-containing TB therapy for ≥ 2 wks • Lead-In (n = 9): NVP 200 mg x 14 days, then 200 mg bd • Full-dose (n = 9): NVP 200 mg bd from initiation • Full dose had more favorable PK: NVP minimum concentration and overall exposure was approximately 40% lower than Full-dose in the Lead-In group at Day 7 • Both groups had median trough levels below target at day 21 Lamorde M et al. CROI 2010 and JAC 2010.

15. A focus on new drug development

16. HIV and TB: Capacity Challenges to the use of Current Drugs and Developing New Drugs Goals of New TB Drug Regimens • Shorten and simplify TB treatment • Improve the treatment of MDR-TB and latent TB infection • Optimize TB therapy in combination with HIV treatment Working group on new TB drugs. http://www.newtbdrugs.org

17. HIV and TB: Capacity Challenges to the use of Current Drugs and Developing New Drugs Examples of the role of pharmacology in TB drug development • TB trial design: Combination therapy should be investigated early in the development process • Consider pharmacokinetic evaluations in TB co-infected patients when possible • Pediatric studies: Dose identification and optimization • Clinical trial capacity: Both clinical and analytic pharmacology resources must be an area of focus • Considerations for the practical constraints: Dose finding studies to overcome existing drug-drug interactions appropriate for resource limited settings Ma et al. Lancet 2010

18. HIV and TB: Capacity Challenges to the use of Current Drugs and Developing New Drugs Summary • Significant challenges exist in TB therapy, both with and without HIV co-infection. • New drugs and treatment strategies are encouraging, however capacity building is an essential component of the drug development process. • There is a significant role for pharmacology research in both current and future TB and TB-HIV therapy. • Afew acknowledgements: • SayeKhoo and Holly Rawizza for slide contributions • Kristin Darin for assisting with presentation development • The AIDS International Training and Research Program for sponsoring this program