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 Thailand, CDC is conducting a trial to determine if once-daily oral tenofovir is safe and effective in reducing HIV transmission among injection drug users (IDUs). The trial is being conducted in collaboration with the Bangkok Metropolitan Administration and the Thailand Ministry of Public Health.

• In Botswana, CDC is conducting a trial in collaboration with the Botswana Ministry of Health to provide data on the safety and efficacy of a once-daily tenofovir plus emtricitabine pill in reducing transmission among young heterosexual men and women.

  The Botswana research will also provide important information on the safety of tenofovir alone in this population. Because the trial had originally planned to study tenofovir alone (before there was evidence to support initiating trials of tenofovir plus emtricitabine), the study had already enrolled 71 high-risk men and women. Researchers continued to follow these participants until the new trial was initiated to obtain data on the safety of tenofovir alone.

• In the U.S., CDC is evaluating the safety and tolerability of once-daily tenofovir alone among men who have sex with men (MSM). This trial will not be large enough to evaluate the drug’s effectiveness in reducing HIV transmission. It is being conducted in collaboration with the San Francisco Department of Public Health, the AIDS Research Consortium of Atlanta, and Fenway Community Health in Boston. (Note: The efficacy of a once-daily PrEP regimen among MSM in Peru and Ecuador is being evaluated independently by the National Institutes of Health.)

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What other issues will the trials examine?

All three CDC studies 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.

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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, double-blind, 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 18–29, 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 2,000 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, are being used to enroll 400 HIV-negative MSM who report having had anal intercourse during the past 12 months. To reflect the demographics of the U.S. HIV epidemic, a substantial proportion of participants will be MSM of color.

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 will allow researchers to compare risk behaviors among persons who are and persons who are not taking a daily pill. This analysis will be critical to understanding the potential impact of a daily drug regimen on HIV risk behavior.

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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 31% of the population 15–49 years of age are infected. Data suggest that new infections are increasing most rapidly among young heterosexual men and women. It is estimated that 24% of sexually active women aged 18–19 are infected with HIV and that almost 40% of those aged 20–24 are infected. Among men, the peak seems to occur later: 11% of men aged 20–24 and 28% 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 42% 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 data from the 33 states with long-standing HIV reporting systems indicate that in 2005, MSM accounted for 49% of new HIV diagnoses. Of the roughly one million people living with HIV in the U.S., an estimated 45% are MSM. Additionally, a recent five-city study of HIV prevalence among MSM found that 25% of MSM overall, and 46% of black MSM, were infected in those cities.

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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.

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Are similar trials being conducted else where?

Yes. In 2006, Family Health International, with funding from the Bill and Melinda Gates Foundation, has completed a similar trial of tenofovir for HIV prevention among young women in Ghana. That trial will soon provide important data on the safety and acceptability of a once-daily PrEP regimen. The study provided the first data showing PrEP with tenofovir to be both safe and acceptable for use by HIV negative individuals. The National Institutes of Health will be conducting a PrEP safety and efficacy trial among MSM in Peru and Ecuador.

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What is the cost of the CDC studies of PrEP?

CDC estimates that the total contribution for all three PrEP trials will be $47 million over 7 years. For the Botswana trial, CDC will provide approximately $23 million in support. In Thailand, CDC's contribution is estimated to be $14 million, and in the United States, CDC will provide $10 million in support of the three institutions conducting the trial.

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