1. ARVs and ART – looking to the future Sharon R Lewin Professor and Head, Department of Infectious Diseases, Monash University and Alfred Hospital Co-head, Centre for Biomedical Research, Burnet Institute, Melbourne, Australia 7 th IAS Conference on Pathogenesis, Treatment and Prevention, Kuala Lumpur, 30 th June – 3 rd July, 2013

2. ARV and ART: looking to the future  Better antiretrovirals –Reduce cost –Reduce toxicity –Enhance durability of control  Reduce long term morbidity  The very distant future

3. cheaper and better antiretrovirals

4. Strategies to reduce cost of current ARVs  Optimising the active pharmaceutical ingredient (API) –Optimise material sourcing –Change in manufacturing process –Improve bioavailability  Pharmaco-enhancement  Extension of shelf-life  Reduce dose Crawford et al., Lancet Infect Dis 2012; 12:550; Conference on Antiretroviral Dose Optimisation (CADO), 2010

5. New source of raw material Mg tert-butoxide reduces cost of TDF Similar strategies currently being evaluated for efavirenz, ATZ/r, DRV/r Crawford et al., Lancet Infect Dis 2012; 12:550

6. Lower doses can be effective, reduce toxicities…and reduce cost DrugDoses studiedOutcomeStudy NNRTI Efavirenz600mg vs 400mg vs 200mg No difference in %<400 c/ml Hicks Riplivarine150mg vs 75 mg vs 25mg All doses non inferior to EFV Pozniak Protease inhibitors LPV/r400/100 vs 200/100 mg Improved outcomes for low dose Murphy Integrase inhibitors Raltegravir600 vs 400 vs 200 vs 100 mg HIV RNA < 50 c/ml in 85%, 83%, 88% and 88% Markowitz

7. New ARVs in development NRTINNRTIPIEntry InhInSTI Phase 3 TAF cenicrivirocdolutegravir Phase 2apricitabine DAPD dexelvucitabine festinavir BILR 355 MK-1439 BMS-663068 ibalizumab PF-232798 GSK744 Phase 1/2amdoxovir elvucitabine TMC 310911 HGS004 Phase 1RDEA 806CTP-298 CTP-518 PPL-100 SPI-256 SCH532706 VIR-576 BI 224436 INH-1001 Gulick, 20 th CROI, Atlanta, GA, March 2013

8. Tenofovir alenofenamide (TAF): reduced renal toxicity and cost Zolopa CROI 2013, Atlanta, GA # 99LB 0 10 20 30 40 50 60 70 80 90 100 2 48 12 1624 % HIV-1 RNA <50 c/mL Time (Weeks) TAF/FTC/EVG/c 88% (n=112) TDF/FTC/EVG/c 90% (n=58) Change in serum creatinine at Week 24 TAF +0.07 mg/dL TDF +0.12 mg/dL (p=0.02) TAF/FTC/EVG/COBI Rx-naïve, VL >5000, CD4 >50 (N=170)

11. New technologies for delivery of ARVs  Nanotechnology –Efavirenz 300mg –Pediatric LPV/r in development  Injectables, implants, slow release –GSK744 + rilpivarine LA –GSK744 + 2NRTI (Latte study) –Vaginal rings e.g., dapivirine / maraviroc  Multipurpose prevention technologies –HIV + STI + pregnancy

12. Long and short term priorities to improve ARVs  First-line –fixed-dose combination regimens that are equally or more potent and more durable and affordable than TDF/XTC/EFV  Post Treatment –failure –fixed dose boosted, dose-optimized darunavir in replacing atazanavir or lopinavir as the protease inhibitor of choice –A one pill once daily second-line regimen. –Studies of reduced-dose darunavir/ritonavir (DRV/r),  Enhancing Trial Participant Criteria –including girls and women of reproductive age, TB co-infection, and comorbidities (such as hypertension).  Longer Term Research Priorities –oral and injectable long-acting drugs (including GSK744 and TMC278) as well as nano-formulations and implantable devices. CADO2 report, South Africa, April 2013

13. reduce long term morbidity

14. Increased age-related complications on ART Frieberg et al., JAMA Internal Med 2013 Increased risk of AMI in HIV compared to HIV uninfected HR = 1.48 (CI = 1.27 – 1.72) Further increase HR if CD4 500 Mean AMI events per 1000 person years N=82,459; Veterans Ageing Cohort Study Virtual Cohort

15. HIV and aging in Africa Mills et al., N Engl J Med 2012; 366:14 In 2040, the number of persons over 50 years of age living with HIV is expected to be 9 million

16. Lifestyle Etiology of non-AIDS-related events  Non-AIDS-related events are more common in HIV disease, even after adjustment for age, cART exposure and traditional risk factors Deeks SG, Phillips AN. Br Med J 2009;338:a3172 cART toxicity Persistent inflammation (immune activation) Non-AIDS events (e.g. smoking)

17. Prevention of non AIDS events needs a different model of care  Lifestyle modifications –Reduce smoking, healthy diet, exercise  Reduce modifiable risk factors –Assessment of blood pressure, glucose and lipids  Counselling and screening for common cancers  Enhance CD4 recovery and reduce inflammation

18. the very distant future

19. HIV cure is rare and possible – but a very long term goal THE VISCONTI PATIENTS The Mississippi baby The Berlin Patient

20. Acknowledgements  The Alfred Hospital, Melbourne –Julian Elliott –Jennifer Hoy –Edwina Wright  Elsewhere –Steve Deeks –Diane Havlir –Trip Gulich –Judith Currier –Andrew Ball –Adeeba Kamarulzaman