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Arvs and ART – Looking to the Future

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Arvs and ART – Looking to the Future 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 7th IAS Conference on Pathogenesis, Treatment and Prevention, Kuala Lumpur, 30th June – 3rd July, 2013 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 cheaper and better antiretrovirals 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 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 Lower doses can be effective, reduce toxicities…and reduce cost Drug Doses studied Outcome Study NNRTI Efavirenz 600mg vs 400mg No difference in Hicks vs 200mg %<400 c/ml Riplivarine 150mg vs 75 mg All doses non inferior Pozniak vs 25mg to EFV Protease inhibitors LPV/r 400/100 vs Improved outcomes for Murphy 200/100 mg low dose Integrase inhibitors Raltegravir 600 vs 400 vs HIV RNA < 50 c/ml in Markowitz 200 vs 100 mg 85%, 83%, 88% and 88% New ARVs in development NRTI NNRTI PI Entry Inh InSTI Phase 3 TAF cenicriviroc dolutegravir Phase 2 apricitabine BILR 355 BMS-663068 GSK744 DAPD MK-1439 ibalizumab dexelvucitabine PF-232798 festinavir Phase 1/2 amdoxovir TMC HGS004 elvucitabine 310911 Phase 1 RDEA 806 CTP-298 SCH532706 BI 224436 CTP-518 VIR-576 INH-1001 PPL-100 SPI-256 Gulick, 20th CROI, Atlanta, GA, March 2013 Tenofovir alenofenamide (TAF): reduced renal toxicity and cost 100 TDF/FTC/EVG/c 90% (n=58) 90 80 TAF/FTC/EVG/c 88% (n=112) 70 60 50 40 TAF/FTC/EVG/COBI 1 RNA <50 c/mL 1 RNA 30 - 20 10 % HIV % 0 2 4 8 12 16 24 Time (Weeks) Change in serum creatinine at Week 24 TAF +0.07 mg/dL TDF +0.12 mg/dL (p=0.02) Rx-naïve, VL >5000, CD4 >50 (N=170) Zolopa CROI 2013, Atlanta, GA # 99LB 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 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 reduce long term morbidity Increased age-related complications on ART 6 5 5 3.9 4 3.3 3 2 2.2 2 1.5 1 1000 person years person 1000 Mean AMI events per AMI events Mean 0 40-49 years 50-59 years 60-69 years HIV+ HIV- Increased risk of AMI in HIV compared to HIV uninfected HR = 1.48 (CI = 1.27 – 1.72) Further increase HR if CD4<200 or HIV RNA>500 N=82,459; Veterans Ageing Cohort Study Virtual Cohort Frieberg et al., JAMA Internal Med 2013 HIV and aging in Africa In 2040, the number of persons over 50 years of age living with HIV is expected to be 9 million Mills et al., N Engl J Med 2012; 366:14 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 cART toxicity Non-AIDS events Persistent Lifestyle (e.g. smoking) inflammation (immune activation) Deeks SG, Phillips AN. Br Med J 2009;338:a3172 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 the very distant future HIV cure is rare and possible – but a very long term goal The Berlin Patient THE VISCONTI PATIENTS The Mississippi baby Acknowledgements . The Alfred Hospital, Melbourne – Julian Elliott – Jennifer Hoy – Edwina Wright . Elsewhere – Steve Deeks – Diane Havlir – Trip Gulich – Judith Currier – Andrew Ball – Adeeba Kamarulzaman .
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