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After CAPRISA 004: time to re-evaluate the HIV lexicon - 'oral PrEP has greater likelihood for success'
 
 
  "As a semantic starter, we might use the generic category "pre-exposure prophylaxis", and break it down by the mode of delivery: oral, topical, injectable, etc"
 
"Our belief structure was that the oral regimen, used daily, would have the greatest likelihood of demonstrating proof of concept....future evaluations of antiretroviral prophylaxis will focus on methods of delivery (oral, topical [vaginal, rectal], injectable), regimens (daily, monthly, intermittent/exposure related, pre and post), single versus combination products, and what works in specific target populations (defined by risk, behaviour, and infection status)."

 
Tenofivir Once-Daily PrEP in MSM Friday Late Breaker Jul 25, 2010 ... Pre-exposure prophylaxis -- or PrEP -- is being studied as a way to prevent transmission of the disease in several countries, ...www.natap.org/2010/IAS/IAS_85.htm
 
The Lancet Aug 14 2010
 
Willard Cates a
a FHI, Research Triangle Park, NC 27709, USA
 
Results of the CAPRISA 004 microbicide randomised trial1 recently electrified the AIDS 2010 Conference in Vienna, Austria. This groundbreaking safety and effectiveness study (funded by the US Agency for International Development [USAID]) showed that a vaginal gel containing 1% tenofovir significantly reduced a woman's risk of being infected with HIV or genital herpes. Tenofovir gel, used before and after sex, reduced the risk of HIV infection by 39% in the primary intent-to-treat analysis. The absolute difference in HIV-infection rates between the two groups was 35 infections per 100 women-years (56 vs 91 in the tenofovir and placebo groups, respectively). High adherence to the gel seemed to reduce the risk by 54% in an exploratory non-randomised comparison. Additionally, the pre/post gel regimen reduced the risk of HSV-2 infection by 51%.
 
Establishing proof of concept for a topical antiretroviral regimen, used intermittently, has thrown many in the HIV-prevention field into a spin. Some scientists had even questioned whether a topical microbicide would ever be effective in preventing HIV acquisition.2 Our belief structure was that the oral regimen, used daily, would have the greatest likelihood of demonstrating proof of concept. As a result, most of our prevention trials of pre-exposure prophylaxis with antiretrovirals were oriented toward this oral daily regimen (table). The theory was that the daily oral approach would produce better adherence and higher concentrations of drug in tissues, and thus it was the best first step. Only after success with the daily oral regimen, could the other approaches, such as intermittent topical and oral dosing, be evaluated for their relative effectiveness. However, CAPRISA 004 has leapfrogged this projected development timeline. We all need to go back to the drawing board.
 

Fortunately, the ongoing VOICE trial (MTN-003, funded by the US National Institutes of Health [NIH])3 is examining the relative safety and effectiveness of the oral/topical antiretroviral regimens when used daily. VOICE is a five-group randomised phase 2b trial, comparing three oral groups (tenofovir, emtricitabine/tenofovir, and placebo) with two topical groups (tenofovir gel vs placebo gel). This trial is underway and has recruited about 25% of the 5000 participants anticipated. It will provide not only the essential evidence to support or challenge the CAPRISA 004 findings, but will also contribute to understanding the relative value of the oral versus topical regimens in preventing HIV acquisition in women.
 
The question of intermittent versus daily administration of a pre-exposure prophylactic antiretroviral is currently being addressed in three small head-to-head trials (IAVI E001,4 IAVI E002,5 HPTN 067). Other studies are evaluating the feasibility, pharmacokinetics, and behavioural aspects of intermittent oral therapies. But larger comparative studies of these different regimens need to begin soon.
 
CAPRISA 004 also challenges the HIV-prevention field to question its semantic silos. The current HIV-prevention terminology compartmentalises pre-exposure prophylaxis methods by mode of delivery. The term "microbicides" defines topical delivery, whereas the term "PrEP" defines oral delivery. These categories are outdated and inefficient. They spawn separate scientific meetings, publications, and discourse. Thus they limit a more integrated approach to combination prevention of HIV infection. Just as the VOICE trial is able to compare these two modes of delivery, similarly, the antiretrovirals for prevention field needs to consolidate its terminology.
 
In 2008, we had suggested a new lexicon to categorise HIV-prevention interventions.6 As we have seen with CAPRISA 004, use of antiretrovirals to prevent HIV transmission has become a broad field of its own, encompassing many overlapping scientific issues.7 As with hormonal contraception as a method to prevent unintended pregnancy, future evaluations of antiretroviral prophylaxis will focus on methods of delivery (oral, topical [vaginal, rectal], injectable), regimens (daily, monthly, intermittent/exposure related, pre and post), single versus combination products, and what works in specific target populations (defined by risk, behaviour, and infection status).
 
As a semantic starter, we might use the generic category "pre-exposure prophylaxis", and break it down by the mode of delivery: oral, topical, injectable, etc
. Future scientific meetings would address these topics jointly. Collaboration has been the hallmark of shared information across the microbicide and PrEP fields. It is time now to unify the terminology and share information even more broadly.
 
CAPRISA 004 changes the model for HIV-prevention research. A WHO/UNAIDS meeting in South Africa in late August will examine the next steps for the many trials already underway, in addition to those on the drawing board. A careful, coordinated, and cooperative approach among the four main HIV-prevention research funders-NIH, the US Agency for International Development, the Bill & Melinda Gates Foundation, and the UK Department for International Development-is crucial to assure the research portfolio for HIV prevention will advance in the most efficient way. Proposed next steps involve investigations at multiple levels: molecular, clinical, and population. A new era indeed.
 
I am an FHI member of the CAPRISA 004 Trial Oversight Committee. FHI is one of the five CAPRISA 004 partners who provided support to the trial. FHI helped with study design, protocol development, behavioural intervention assessment, statistical and safety oversight, and clinical monitoring. My participation on the CAPRISA 004 team was funded by USAID grant #GHO-A-00-09-00016-00.
 
References
 
1 Karim Q Abdool, Karim SS Abdool, Frolich JA, et alon behalf of the CAPRISA 004 Trial Study Group. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science 201010.1126/science.1193748. published online July 19. PubMed
 
2 Grant RM, Hamer D, Hope T, et al. Whither or wither microbicides?. Science 2008; 321: 532-534.
 
3 Anon. Safety and effectiveness of tenofovir 1% gel, tenofovir disproxil fumarate, and emtricitabine/tenofovir disoproxil fumarate tablets in preventing HIV in women (VOICE, MTN-003). http://clinicaltrials.gov/ct2/show/NCT00705679. (accessed Aug 1, 2010).
 
4 Anon. A pilot study of pre-exposure prophylaxis (PrEP) to evaluate safety, acceptability, and adherence in at-risk populations in Kenya, Africa (IAVI E001). http://clinicaltrials.gov/ct2/show/NCT00971230. (accessed Aug 1, 2010).
 
5 Anon. A pilot study of pre-exposure prophylaxis (PrEP) to evaluate safety, acceptability, and adherence in at-risk populations in Uganda, Africa (IAVI E002). http://clinicaltrials.gov/ct2/show/NCT00931346. (accessed Aug 1, 2010).
 
6 Padian NS, Buve A, Balkus J, Serwadda D, Cates W. Biomedical interventions to prevent HIV infection: evidence, challenges, and way forward. Lancet 2008; 372: 585-599.
 
7 Cohen MS, Gay C, Kashuba ADM, Blower S, Paxton L. Narrative review: Antiretroviral therapy to prevent the sexual transmission of HIV-1. Ann Intern Med 2007; 146: 591-601.
 
 
 
 
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