arv and art: looking to the future
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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
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 ARVsOptimising the active pharmaceutical
ingredient (API)– Optimise material sourcing– Change in manufacturing process– Improve bioavailability
Pharmaco-enhancementExtension of shelf-lifeReduce 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 costDrug Doses studied Outcome StudyNNRTIEfavirenz 600mg vs 400mg
vs 200mgNo difference in %<400 c/ml
Hicks
Riplivarine 150mg vs 75 mg vs 25mg
All doses non inferior to EFV
Pozniak
Protease inhibitorsLPV/r 400/100 vs
200/100 mgImproved outcomes for low dose
Murphy
Integrase inhibitorsRaltegravir 600 vs 400 vs
200 vs 100 mgHIV RNA < 50 c/ml in 85%, 83%, 88% and 88%
Markowitz
New ARVs in development
NRTI NNRTI PI Entry Inh InSTI
Phase 3 TAF cenicriviroc dolutegravir
Phase 2 apricitabine DAPD dexelvucitabinefestinavir
BILR 355 MK-1439
BMS-663068 ibalizumab PF-232798
GSK744
Phase 1/2 amdoxovir elvucitabine
TMC 310911
HGS004
Phase 1 RDEA 806 CTP-298 CTP-518 PPL-100 SPI-256
SCH532706 VIR-576
BI 224436 INH-1001
Gulick, 20th CROI, Atlanta, GA, March 2013
Tenofovir alenofenamide (TAF): reduced renal toxicity and cost
Zolopa CROI 2013, Atlanta, GA # 99LB
0102030405060708090
100
2 4 8 12 16 24
% H
IV-1
RN
A <5
0 c/
mL
Time (Weeks)
TAF/FTC/EVG/c 88% (n=112)
TDF/FTC/EVG/c 90% (n=58)
Change in serum creatinine at Week 24TAF +0.07 mg/dL
TDF +0.12 mg/dL (p=0.02)
TAF/FTC/EVG/COBI
Rx-naïve, VL >5000, CD4 >50 (N=170)
New technologies for delivery of ARVsNanotechnology
– 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
Frieberg et al., JAMA Internal Med 2013
Increased risk of AMI in HIV compared to HIV uninfectedHR = 1.48 (CI = 1.27 – 1.72)
Further increase HR if CD4<200 or HIV RNA>500
Mea
n A
MI e
vent
s pe
r 1
000
pers
on y
ears
40-49 years 50-59 years 60-69 years0
1
2
3
4
5
6
2
3.9
5
1.52.2
3.3
HIV+ HIV-
N=82,459; Veterans Ageing Cohort Study Virtual Cohort
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
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
cARTtoxicity
Persistentinflammation(immune activation)
Non-AIDS events
(e.g. smoking)
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 VISCONTI PATIENTS The Mississippi
baby
The Berlin Patient
Acknowledgements The Alfred Hospital,
Melbourne– Julian Elliott – Jennifer Hoy– Edwina Wright
Elsewhere– Steve Deeks– Diane Havlir– Trip Gulich– Judith Currier– Andrew Ball– Adeeba Kamarulzaman