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
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
NNRTI
Protease inhibitors
LPV/r
400/100 vs
200/100 mg
Improved outcomes for Murphy
low dose
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
Phase 3
TAF
Phase 2
apricitabine
DAPD
dexelvucitabine
festinavir
Phase 1/2
amdoxovir
elvucitabine
Phase 1
NNRTI
PI
Entry Inh InSTI
cenicriviroc
BILR 355
MK-1439
RDEA 806
dolutegravir
BMS-663068 GSK744
ibalizumab
PF-232798
TMC
310911
HGS004
CTP-298
CTP-518
PPL-100
SPI-256
SCH532706 BI 224436
VIR-576
INH-1001
Gulick, 20th CROI, Atlanta, GA, March 2013
% HIV-1 RNA <50 c/mL
Tenofovir alenofenamide (TAF):
reduced renal toxicity and cost
TDF/FTC/EVG/c 90% (n=58)
100
90
80
70
60
50
40
30
20
10
0
TAF/FTC/EVG/c 88% (n=112)
TAF/FTC/EVG/COBI
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
Mean AMI events per
1000 person years
6
5
5
3.9
4
3
2
3.3
2
2.2
1.5
1
0
40-49 years
50-59 years
HIV+
60-69 years
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
Lifestyle
(e.g. smoking)
Persistent
inflammation
(immune activation)
Deeks SG, Phillips AN. Br Med J 2009;338:a3172
Non-AIDS
events
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