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The Role of ARVs in HIV Prevention: Microbicides and PrEP

December 2010

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Table of Contents


Introduction

The evolving list of HIV prevention interventions that currently rely on antiretrovirals (ARVs) include prevention of mother-to-child transmission (PMTCT), Post Exposure Prophylaxis (PEP), and highly active antiretroviral therapy (HAART) as prevention.1 Current research is underway to expand this list of interventions to include ARV-based microbicides, and Pre-Exposure Prophylaxis (PrEP); both of which recently demonstrated promising results in clinical trials.

Twenty years ago, these interventions were merely a wish list based on the logic that if a drug can lower the viral load of HIV in the body, then it should be able to reduce transmission of the virus. Further, if a drug can limit the replication of HIV, it can help abort HIV infection before it takes root in the body.2 Slowly, these wishes are becoming realities and some have been translated into standards of care.3 In this article, we discuss recent breakthroughs in ARV-based microbicides and PrEP, what the likely policy and programmatic implications and drawbacks may be, and how they can be addressed.


ARV-Based Microbicides

Tenofovir gel reduced HIV acquisition by an estimated 39% among participants.

In July 2010, microbicides researchers received a long awaited "proof of concept" with the results of the CAPRISA 004 trial. The double-blind, randomized, controlled trial was conducted to assess the effectiveness and safety of a vaginal gel formulation of 1% tenofovir gel, a nucleotide reverse transcriptase inhibitor (NRTI), for prevention of HIV in women.4 The study was conducted among 889 women, aged 18-40, in urban and rural KwaZulu-Natal, South Africa between May 2007 and March 2010. Results from the study found that tenofovir gel reduced HIV acquisition by an estimated 39% among participants. Further, the trial demonstrated no change in tenofovir resistance in HIV seroconverters. The only adverse event found more frequently in the tenofovir gel arm was diarrhea and gastrointestinal infections (16.9% vs. 11.0%, p=0.015), however the reported cases of diarrhea were mild and rarely required medication.

Though this is not the first microbicide trial to be conducted, it is the first to show efficacy. One hypothesis for the lack of effectiveness in past microbicide trials is that adherence had not been high enough to demonstrate effectiveness.5-7 The CAPRISA 004 trial showed that in high adherers, defined as women who had greater than 80% gel adherence, HIV incidence was 54% lower in the tenofovir arm. HIV incidence was reduced by 38% and 28% in intermediate and low gel adherers, respectively. It is important to note that women in the CAPRISA 004 trial followed a coitally dependent dosing strategy, known as "BAT24." Modeled on the proven strategy of dosing for preventing mother-to-child HIV transmission, women were instructed to use one dose of gel within 12 hours before sex and another dose as soon as possible within 12 hours after sex, and no more than two doses in a 24-hour time period. Due to the dosing strategy, no conclusions can be drawn about the effectiveness of the gel in relation to the timing of application.

The CAPRISA 004 trial results are only the first step towards an effective ARV-based microbicide. The trial was conducted on a specific population and the relatively small sample size limits the generalizability of the results. Additional studies are necessary to support and confirm the CAPRISA 004 findings, as well as provide further information on the use of daily versus coitally dependent gels, oral versus gel formulations, and the safety and effectiveness of the use of tenofovir gel rectally.


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Pre-Exposure Prophylaxis

In addition to the positive safety findings for tenofovir in a vaginal gel formulation, preliminary analysis suggests no safety concerns from the first study examining the safety of daily oral tenofovir for HIV prevention among gay and bisexual men. The Phase II study, conducted among 400 HIV-negative men who have sex with men (MSM) in San Francisco, Atlanta, and Boston, randomized men to one of four study arms: two arms of the study received either a daily 300 mg tablet of tenofovir or placebo immediately upon enrollment, and the two remaining arms received either tenofovir or placebo after nine months of enrollment.8 This study design allowed researchers to compare risk behaviors among those men taking a daily pill and those who are not.

Prior studies have found the daily tenofovir regimen safe among high-risk heterosexual women in Ghana, Nigeria, and Cameroon, but this is the first PrEP study to focus solely on safety among gay and bisexual men, as well as the first to assess the potential impact of a daily preventative drug on HIV risk behaviors. Preliminary analysis suggest there was no increased risk, or "behavioral dis-inhibition," in men taking a study pill compared to those not yet taking study pills.8

It is important to note that this study was not designed to provide conclusions about the potential efficacy of PrEP in preventing HIV infection. As analysis continues, this study will provide useful information on the relationship among adherence, perception of treatment arm, perception of efficacy and individual risk behavior, as well as acceptability and feasibility of daily PrEP for the study population.


Policy and Programmatic Implications

ARV-based microbicides will only be partially effective, thus it will be vital that it is promoted as part of a package of preventive interventions, rather than as a single magic bullet.

An over-arching programmatic implication for potential ARV-based microbicides and PrEP is the cost and provision of supply. Pharmaceutical industry partners have been generous in supplying certain drugs for the ongoing and planned clinical trials. Conversations surrounding the manufacturing, distribution, and pricing for these potential prevention options need to be ongoing throughout their development so as to establish a firm and sustainable process should trial results continue to be positive.

Further, the general consensus among leaders in HIV prevention is that both ARV-based microbicides and PrEP will be offered through prescription, not as an over-the-counter prevention method, such as condoms. There needs to be careful planning and development related to the infrastructure of how these prevention methods would be distributed, regulated, and overseen in the markets for which they are most needed.

Microbicides should be promoted as part of a prevention package: The target population for a vaginal ARV-based microbicide gel will be women in sub-Saharan African and other regions where women are having unprotected sex with multiple partners (such as sex workers), are unable to practice mutual monogamy, and/or are unable to negotiate condom use with their sexual partners. Further, should ARV-based microbicides prove effective in protecting HIV transmission through anal sex, receptive partners in MSM relations would also be a target population.

This suggests that both target populations will be largely self-identifying. Hence, the successful implementation of an ARV-based microbicide will depend on extensive community education and accessible and confidential counseling services, coupled with provision of condoms. Further, ARV-based microbicides will only be partially effective. Thus, it will be vital that it is promoted as part of a package of preventive interventions, rather than as a single magic bullet.

PrEP will require regular HIV testing and partner disclosure: The current regimens being explored for PrEP use a single ARV, tenofovir. If taken by a person who is HIV-positive, there is danger of the development of resistance. Logically, PrEP would only be considered for people proven to be HIV-negative, which would require initial HIV testing and consistent re-testing. This will require infrastructure and accountability.

If proven effective, PrEP will likely be targeted at individuals who are most at risk, such as HIV-negative partners in discordant couples. Theoretically, these partners may be easy to reach through their HIV-positive partners who are attending HIV care and treatment services. However, there are reports of people living with HIV/AIDS (PLHAs) who do not disclose their HIV status to their partners and continue to have unprotected sex.9 Thus, a key pre-requisite for PrEP among discordant couples is going to be increased counseling of PLHA about disclosure, provision of couples communication and counseling, and access to couples voluntary testing and counseling (CVCT).

PrEP may also be recommended for individuals, especially women, who are in a sexual relationship with an individual who is at high-risk, including sex workers and their clients, certain men who have sex with men (MSM), intravenous drug users (IDU), and polygamous men. If PrEP is proven effective, it will require extensive community education as well as the availability of confidential counseling and testing to enable such individuals at risk to seek services, and to receive HIV testing and counseling followed by PrEP.

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This article was provided by Gay Men's Health Crisis. It is a part of the publication GMHC Treatment Issues. Visit GMHC's website to find out more about their activities, publications and services.
 
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