Current and planned HIV prevention trials:

microbicides and PrEPPresented at:

XVIII International AIDS Conference, Vienna, 22 July 2010

Salim S. Abdool KarimPro Vice-Chancellor (Research): University of KwaZulu-Natal

Director: CAPRISAProfessor in Clinical Epidemiology, Columbia University

Adjunct Professor of Medicine, Cornell University

Outline Why the interest in PrEP? Historical overview of PrEP research Current PrEP trials Summary of the CAPRISA 004 findings Planned PrEP trials Key challenges in the implementation of

PrEP trials Conclusion

Pre-exposure prophylaxis (PrEP) Pre-exposure prophylaxis (PrEP) is an experimental

HIV prevention strategy that uses antiretroviral agents prior to exposure, to prevent HIV acquisition

PrEP for HIV prevention builds on the concept that medications can be used by healthy people to prevent other infections:• Mefloquine prophylaxis for malaria• INH prophylaxis for tuberculosis

Mathematical modeling impact: 2.7 - 3.2 million new HIV infections could be averted in southern Africa in 10 years by targeting PrEP (if 90% effective) to those at highest behavioral risk

Source: Abbas UL, PLoS ONE 2(9): e875. doi:10.1371/journal.pone. 0000875

Why the interest in PrEP…. Biological plausibility – effect of ARVs

on viral replication Numerous animal challenge since

since 1995 show protection Success of post-exposure prophylaxis

for needlestick exposure in observational data

pMTCT: Proof of concept via another route of transmission in humans

Initial efforts to test PrEP:Tenofovir PrEP studies halted by activists

At what cost? How many infections could have been prevented if these trials went ahead?

Tenofovir PrEP trial stopped due to low HIV incidence in study populations in

Ghana, Cameroon and Nigeria

Botswana PrEP trial stopped due to low HIV incidence & mobile populations

Current PrEP trialsTrial Product Target

population Sites

CDC Bangkok tenofovir trial Viread 2,400 IDUs Thailand

iPREX trial Truvada 3,000 MSM Peru, Ecuador, US, S Africa and Brazil

PartnersPrEP trial Viread & Truvada

4,700 discordant couples Kenya, Uganda

VOICETenofovir gel,

Viread & Truvada

5,000 womenMalawi, South Africa,

Uganda, Zambia, Zimbabwe

FemPrEP Viread & Truvada 3,900 women

Kenya, Malawi, South Africa,

Tanzania, Zambia

12Available for download from: http://www.sciencemag.org/sciencexpress/recent.dtl

Summary of CAPRISA 004 findings• Safety

No substantive safety concerns No tenofovir resistance identified Safe in Hepatitis B virus infected women No evidence of risk compensation / behavioral disinhibition

• Proof of concept that tenofovir gel can prevent HSV-2 infection in women 51% reduction in HSV-2

• Proof of concept that tenofovir gel can prevent HIV infection in women 39% protection against HIV overall 50% reduction in HIV after 1 year of tenofovir gel use 54% effective in women with high adherence

13

Comparison of HIV effectiveness: HIVNET 012 and CAPRISA 004

Efficacy

StudyPMTCT - HIVNET 01241

Tenofovir gel – high adherence54

Tenofovir gel – low adherence28

Tenofovir gel - CAP 00439

0% 10 20 30 40 50 60 70 80 90 100%CAPRISA 004 tenofovir gel

HIVNET 012 - nevirapineasap

72 hrs12 hrs

asap

Tenofovir gel – medium adherence38

PrEP trials being planned

Trial Product Target population Sites

IPM 009 Dapivirine ring TBD TBD

MDP 302 Tenofovir gel WomenSouth Africa,

Uganda, Kenya

South African tenofovir gel trial Tenofovir gel Women South Africa

Key challenges in future implementation of PrEP: impact on study design

Is it safe to give ARV drugs to healthy people?

Will those who get infected have HIV that is resistant to the PrEP antiretrovirals? Will this affect their subsequent care and choice of ARV treatment?

Will healthy people be willing to take medication everyday or at the time of sex for long periods?

Is this an affordable and practical HIV prevention strategy for scale-up if it is efficacious?

Will there be behavioural disinhibition / risk compensation?

Conclusion Oral and topical PrEP – promising & results awaited Current trials: tenofovir gel/pill and truvada pill in:

• IDUs, discordant couples, young women, MSM If effective, implementation programs will require

extensive community education to promote PrEP with integrated use of other prevention strategies

The provision of PrEP will require integration into existing HIV prevention and health care services

Need to include long term follow-up and surveillance in sentinel groups to monitor adverse events, adherence, drug resistance, impact of drug resistance on later AIDS treatment and behavioural disinhibition

Future questions for PrEP Which drug? Which formulation (oral or topical)?

Which dosing strategy? What impact on adherence, efficacy and safety

Do long-acting formulations such as vaginal rings or slow release bolus dosing impact on adherence and risk of drug resistance?

Are combinations of ARVs better in terms of safety, efficacy and drug resistance?

Should an ARV (or class) be set aside for PrEP?