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ARV and ART: looking to the future

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ARV and ART: looking to the future

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  1. ARVs and ART – looking to the futureSharon R LewinProfessor and Head, Department of Infectious Diseases, Monash University and Alfred HospitalCo-head, Centre for Biomedical Research, Burnet Institute, Melbourne, Australia 7th IAS Conference on Pathogenesis, Treatment and Prevention, Kuala Lumpur, 30th June – 3rd 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

  7. New ARVs in development Gulick, 20th CROI, Atlanta, GA, March 2013

  8. 100 90 80 70 60 50 % HIV-1 RNA <50 c/mL 40 30 20 10 0 16 24 2 12 4 8 Time (Weeks) • TAF/FTC/EVG/COBI Tenofovir alenofenamide (TAF): reduced renal toxicity and cost TDF/FTC/EVG/c 90% (n=58) TAF/FTC/EVG/c 88% (n=112) • 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)

  9. 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

  10. 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

  11. reduce long term morbidity

  12. Increased age-related complications on ART Mean AMI events per 1000 person years 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

  13. 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

  14. Etiology of non-AIDS-related events cART toxicity Non-AIDS events Lifestyle Persistent inflammation(immune activation) (e.g. smoking) 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

  15. 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

  16. the very distant future

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

  18. 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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