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CDC's Clinical Studies of Daily Oral Tenofovir for HIV Prevention

June 2005

Trial Designs and Objectives

What specific CDC studies are planned?

CDC is sponsoring three separate trials, which together are designed to answer important questions about the safety and efficacy of daily oral tenofovir for several of the populations now at greatest risk for infection worldwide: heterosexual men and women in Botswana, injection drug users (IDUs) in Thailand, and men who have sex with men (MSM) in the United States. In all, the trials will involve 3,200 participants.The trials are being conducted in collaboration with (a) the Botswana Ministry of Health, (b) the Bangkok Metropolitan Administration and the Thailand Ministry of Public Health, and (c) the San Francisco Department of Public Health and the AIDS Research Consortium of Atlanta.

What are the goals of these trials?

The Botswana and Thailand trials are primarily designed to determine if once-daily oral tenofovir is safe and effective in reducing HIV transmission among young heterosexual men and women, and intravenous drug users, respectively. The U.S. trial is designed to evaluate the safety and tolerability of the once daily regimen among men who have sex with men, but will not be large enough to evaluate its effectiveness in reducing HIV transmission. Much larger, multi-city studies will be required to assess efficacy among this population, should safety be demonstrated.

All three 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.

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Impact on behavior: Understanding the potential impact of a daily drug regimen on HIV risk behaviors will be critical should tenofovir 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 strategy will be 100% effective against HIV transmission, reducing transmission will require determining how to best integrate all available prevention strategies -- both biomedical and behavioral. During the trials, all participants will receive state-of-the-art HIV risk-reduction counseling.

Adherence and acceptability: Even if these trials demonstrate that tenofovir can reduce HIV transmission, we must understand whether persons at risk will be willing and able to maintain the daily regimen. These trials will therefore closely examine participants’ adherence to, and acceptance of, a daily oral regimen of tenofovir.

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 with HIV while taking tenofovir alone. The result could be HIV-infected persons for whom tenofovir could not be used for treatment.

Regular testing with a rapid HIV test, combined with immediate discontinuation of study pills if participants become infected, should help guard against the development of drug resistance during the trial. Additionally, resistance testing will be provided to all persons infected during the trial and will be continued for 12 months after infection is detected. 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 will the trials begin and how are they designed?

All three of CDC’s trials are scheduled to begin in early 2005 and are randomized, double-blind, placebo-controlled trials. In each trial, all participants will receive risk-reduction counseling and other prevention services, including condoms. In addition, half of the participants will be assigned by chance to receive one 300 mg tenofovir pill daily, and the other half will be assigned by chance to take one daily placebo pill (a similar pill without active medication). Neither researchers nor participants will 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 tenofovir versus persons taking the placebo.

Botswana and Thailand

The trials in Botswana and Thailand are Phase II/III safety and efficacy trials. This means that each trial will begin by examining safety alone (Phase II). After participants have completed a predetermined amount of follow-up, data will be assessed by an independent panel of experts (the data safety and monitoring board, or DSMB). If the DSMB determines that the once-daily regimen is safe for participants, the trials will not only continue to monitor safety but will be expanded to assess whether tenofovir reduces HIV transmission (Phase III).

Botswana:

The Botswana trial is being conducted in collaboration with the Botswana government and will enroll 1,200 HIV-negative heterosexual men and women, aged 18-29, in the nation’s two largest cities, Gabarone and Francistown. Participants will be 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 will enroll 1,600 HIV-negative injection drug users (IDUs) at 17 drug-treatment clinics in Bangkok. Participants will be recruited at the drug treatment clinics and through a peer referral program.

United States

The U.S. trial is a Phase II trial 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 two sites in collaboration with the San Francisco Department of Public Health and the AIDS Research Consortium of Atlanta. A variety of previously successful recruitment techniques, including outreach and referrals through clinician and community-based service organizations, will be used to enroll 400 HIV-negative MSM who report having had anal intercourse during the past 12 months. To reflect the demographics of the HIV epidemic, a substantial proportion of participants will be MSM of color.

Participants will be randomly assigned to one of four study groups. Two groups will receive either tenofovir or placebo immediately; the other two groups will 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.

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 tenofovir will determine if the drug 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 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. A recent study found that even when HIV risk-reduction counseling was available, HIV incidence among Thai IDUs was 3% per year. Given the estimated number of IDUs in Bangkok, this incidence rate means that approximately 1,000 men and women in this 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 32 states with long-standing HIV reporting systems indicate that during 2000-2003, MSM accounted for 44% of new HIV diagnoses. During this period, new HIV diagnoses for MSM increased 11%, raising concerns that the number of new infections may also be increasing in this population.

Who will be eligible to participate in the tenofovir trials?

Because the trials are designed to determine the drug’s safety and efficacy 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 breastfeeding, 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.

Are similar trials being conducted elsewhere?

Yes. Family Health International, with funding from the Bill and Melinda Gates Foundation, is conducting similar trials of Tenofovir for HIV prevention among young women in Ghana. The National Institutes of Health will be conducting a similar trial among MSM in Peru.

What is the cost of the CDC studies of tenofovir?

CDC funding of all three tenofovir HIV prophylaxis trials will total $19 million over 3 years.

For the Botswana trial, CDC will provide a total of $8 million in support. In Thailand, CDC’s contribution will be $7 million, and in the United States, CDC will provide $4 million to the two institutions conducting the trial.




  
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This article was provided by U.S. Centers for Disease Control and Prevention. Visit the CDC's website to find out more about their activities, publications and services.
 

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