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Q&A: CDC's Clinical Studies of Pre-Exposure Prophylaxis for HIV Prevention: Trial Designs and Objectives

January 26, 2009

What specific CDC studies are under way or planned?

CDC is currently sponsoring three separate trials in Thailand, Botswana, and the United States, which together are designed to answer important questions about the safety and efficacy of PrEP for several of the populations now at greatest risk for infection worldwide. In all, these trials will involve 3,600 participants.

In addition to the three CDC-sponsored trials currently underway, CDC also co-manages two trial sites in Uganda as part of the University of Washington Partners PrEP Study, which is examining the safety and efficacy of two drug regimens -- tenofovir and tenofovir plus emtracitabine -- among heterosexual couples in which one partner is infected and the other is not.

What other issues will the trials examine?

CDC's trials are also designed to address several issues that will be critical to the design of future studies, as well as HIV prevention and treatment programs.

Impact on behavior: Understanding the potential impact of use of a daily preventive drug on HIV risk behaviors will be critical should any PrEP drug prove effective in reducing HIV transmission. One of the greatest risks, as efforts progress to identify new biomedical prevention approaches, is that persons at risk for HIV infection will reduce their use of proven behavioral prevention strategies. Because no single prevention strategy will be 100% effective against HIV transmission, reducing transmission will require determining how best to integrate all available prevention strategies -- both biomedical and behavioral. During the trials, all participants will receive state-of-the-art HIV risk-reduction counseling and other proven HIV prevention interventions.

Adherence and acceptability: Even if these trials demonstrate that PrEP can reduce HIV transmission, it is critical to understand whether persons at risk will be willing and able to maintain consistent use of a daily drug. These trials will therefore closely examine participants' adherence to, and acceptance of, daily oral preventive drug use.

Resistance: A key question about resistance will be addressed during the trials. Although resistance to tenofovir is uncommon among HIV-infected persons when used in combination with other drugs, it is unclear how often resistance may develop if prophylaxis fails and persons become infected while taking tenofovir alone. Similarly, while the risk of drug-resistant virus will likely be lower in the tenofovir plus emtricitabine trial, due to the presence of two drugs, it will be important to assess any resistance to either drug that emerges.

Several study procedures have been designed to minimize the risk of resistance among any individuals who become infected despite receiving PrEP. Regular HIV testing with a rapid HIV test and immediate discontinuation of study pills if participants become infected will result in a very low risk of resistant virus emerging. Additionally, HIV resistance testing will be provided to all persons infected during the trial. These data will provide important information on the degree to which resistance occurs and will help guide treatment decisions as infected persons are referred to treatment and care.

When did the trials begin and how are they designed?

The Thailand and U.S. trials of tenofovir began in 2005 and the Botswana trial of tenofovir plus emtricitabine began in early 2007. All three trials are randomized, doubleblind, placebo-controlled trials. In each trial, all participants receive risk-reduction counseling and other prevention services, including condoms. In addition, half of the participants are assigned by chance to receive one antiretroviral pill daily (either tenofovir alone or tenofovir plus emtricitabine, depending on the trial site), and the other half are assigned by chance to take one daily placebo pill (a similar pill without active medication). Neither researchers nor participants know a participant's group assignment. This design allows the researchers to determine in a scientifically valid way whether the risks for side effects and HIV infection are different for persons taking the study drug versus persons taking the placebo.

Botswana and Thailand

The trials in Botswana and Thailand are safety and efficacy trials. The Botswana trial is examining the safety and efficacy of tenofovir plus emtricitabine, and the Thailand trial is examining the safety and efficacy of tenofovir.

Botswana: The Botswana trial is being conducted in collaboration with the Botswana government and is enrolling 1,200 HIV-negative heterosexual men and women, aged 18-39, in the nation's two largest cities, Gaborone and Francistown. Participants are being recruited at a number of venues, including HIV voluntary counseling and testing centers, sexually transmitted disease and family planning clinics, youth organizations, and community events.

Thailand: The Thailand trial is being conducted in collaboration with the Bangkok Metropolitan Administration and the Thailand Ministry of Public Health and is enrolling 2,400 HIV-negative injection drug users (IDUs) at 17 drug-treatment clinics in Bangkok. Participants are being recruited at the drug treatment clinics, at community outreach sites, and through a peer referral program.

United States

The U.S. trial is designed to assess the clinical and behavioral safety of once-daily tenofovir among HIV-negative men who have sex with men (MSM). The trial is being conducted at three sites in collaboration with the San Francisco Department of Public Health, the AIDS Research Consortium of Atlanta, and Fenway Community Health in Boston. A variety of previously successful recruitment techniques, including outreach and referrals through clinician and community-based service organizations, were used to enroll 400 HIV-negative MSM who reported having had anal intercourse during the prior 12 months.

Participants are randomly assigned to one of four study groups. Two groups receive either tenofovir or placebo immediately; the other two groups receive either tenofovir or placebo 9 months after enrollment. This design allows researchers to compare risk behaviors among persons who are and persons who are not taking a daily pill. This analysis is critical to understanding the potential impact of a daily drug regimen on HIV
risk behavior.

Why have these populations been selected to take part in the trials?

It is critical to evaluate new prevention methods among the populations who most urgently need them. These and other studies of PrEP will determine if the strategy is safe and effective in reducing transmission among individuals at highest risk for HIV infection around the world.

Botswana has one of the most widespread HIV epidemics in the world: an estimated 24 percent of the population 15-49 years of age is infected. Despite the fact that recent data suggest that new infections are stabilizing among young heterosexual men and women, it is estimated that 26 percent of women aged 20-24 are infected with HIV and that 41 percent of those aged 25-29 are infected. Among men, 9 percent of men aged 20-24 and 23 percent of men aged 25-29 are believed to be HIV infected. These data suggest very high incidence among young men and women.

In Thailand, HIV prevalence is high among injection drug users (IDUs): an estimated 40 percent of IDUs are already infected. As a result of the extensive risk reduction counseling and other prevention services provided, HIV incidence among IDUs participating in research trials in the Bangkok drug treatment clinics has declined by over 50% since 1996. Still, a recent study found that HIV incidence among Thai IDUs was over 3% per year. Given estimates of the number of IDUs in Bangkok, this means that approximately 750 men and women in the city become infected through this transmission route every year.

In the United States, MSM continue to be at the greatest risk for HIV infection. Recent CDC data indicate that in 2006, MSM accounted for 53 percent of new HIV infections. Of the more than one million (1,106,400) people living with HIV in the U.S., an estimated 48 percent are MSM. Additionally, a five-city CDC study of HIV prevalence among MSM found that 25 percent of MSM overall, and 46 percent of black MSM, were infected in those cities.

Who is eligible to participate in the PrEP trials?

Because the trials are designed to determine the safety and efficacy of PrEP as an HIV prevention strategy, all participants will be healthy and HIV-negative. To protect the health of participants and ensure that trial data are accurate, several conditions would render some persons ineligible for participation. These include the ongoing use of prescription medication, pregnancy or breast feeding, a history of kidney or bone disease, and participation in any other HIV clinical trial. Additional conditions, including active, untreated syphilis, hypertension, and alcohol or substance use, may also prevent some MSM from participating in the U.S. trial.

What is the University of Washington Partners PrEP Study and how is CDC involved?

The University of Washington is working with collaborators in Kenya and Uganda to conduct the Partners PrEP Study, which is examining the safety and efficacy of two different PrEP regimens - once-daily tenofovir and once-daily tenofovir plus emtricitabine - among heterosexual couples. CDC co-manages two trial sites in Uganda, in conjunction with The AIDS Support Organization (TASO), the largest indigenous non-governmental organization providing HIV care in Uganda.

This randomized, double-blind, placebo-controlled study operates at eight trial sites in Kenya and Uganda and will include 3,900 serodiscordant couples (couples in which one person is HIV-infected and the other is not). Stable serodiscordant couples are the largest risk group for HIV infection in Africa, and this trial will provide important data on whether PrEP could be used to prevent new HIV infections among this population. HIV-uninfected partners are assigned to three groups: tenofovir, tenofovir plus emtracitabine, and placebo. All participants receive ongoing risk reduction counseling and HIV testing, and volunteers' safety is monitored by the study's independent data and safety monitoring board (DSMB) and local institutional review boards, or IRBs. HIV-infected members of the discordant couples receive ongoing HIV care.

The trial is the first to test the safety and efficacy of both tenofovir and tenofovir plus emtricitabine in the same population and will allow investigators to simultaneously evaluate the two drugs as candidates for use as PrEP.

Are similar trials being conducted else where?

Yes. In 2006, Family Health International, with funding from the Bill and Melinda Gates Foundation, completed a similar trial of tenofovir for HIV prevention among young women in Ghana. The study provided the first data showing PrEP with tenofovir to be both safe and acceptable for use by HIV negative individuals, but did not indicate if it was effective in preventing new infections.

The National Institutes of Health (NIH) is currently evaluating the safety and efficacy of PrEP among MSM in Peru, Ecuador, South Africa, Brazil, Thailand, and the U.S. Additional trials investigating PrEP among women in Africa are being launched by FHI and the Microbicide Trials Network (MTN).

Why are there so many different trials currently ongoing?

A PrEP regimen that is proven effective in reducing HIV transmission in one population may not necessarily work in other at-risk populations. Because of this, CDC and other researchers are conducting trials in population groups representing multiple routes of HIV transmission, including heterosexuals, MSM, and IDUs. These trials will help inform the development of public health guidance for different populations.

What is the cost of the CDC studies of PrEP?

CDC estimates that its total contribution for the CDC-sponsored PrEP trials will be $53 million over 7 years. For the Botswana trial, CDC will provide approximately $26 million in support. In Thailand, CDC's contribution is estimated to be $16 million, and in the United States, CDC will provide $11 million in support of the three institutions conducting the trial.




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