ARVs and ART – looking to the future

Sharon 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 cost

Drug Doses studied Outcome Study

NNRTI

Efavirenz 600mg vs 400mg vs 200mg

No difference in %<400 c/ml

Hicks

Riplivarine 150mg vs 75 mg vs 25mg

All doses non inferior to EFV

Pozniak

Protease inhibitors

LPV/r 400/100 vs 200/100 mg

Improved outcomes for low dose

Murphy

Integrase inhibitors

Raltegravir 600 vs 400 vs 200 vs 100 mg

HIV 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 <

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 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

even

ts p

er 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