Table of Contents
Why is CDC conducting trials of pre-exposure prophylaxis for HIV prevention?
CDC is sponsoring these trials because safe and effective new approaches to HIV prevention are urgently needed. More than 7,000 people continue to become infected around the world every day (approximately 2.7 million per year, including 56,000 in the U.S.). Although behavior change programs have contributed to dramatic reductions in the number of annual infections in the United States and many other nations, far too many people remain at high risk.
With an effective vaccine years away, there is mounting evidence that antiretroviral agents may be able to play an important role in reducing the risk for transmission. Researchers believe that an HIV drug approved by the U.S. Food and Drug Administration (FDA) -- tenofovir disoproxil fumarate (tenofovir, brand name Viread) used alone or in combination with emtricitabine (together, known by the brand name Truvada) -- taken daily as an oral preventive drug, is among the most important new prevention approaches being investigated today. The approach is called pre-exposure prophylaxis, or PrEP.
If proven safe and effective, PrEP could help address the urgent need for a female-controlled prevention method for women worldwide who are unable, because of cultural and other barriers, to negotiate condom use. Furthermore, if effective, it could provide an additional safety net for all men and women at risk due to sexual or drug-using behaviors, when combined with reducing the number of sexual partners, HIV counseling and testing, condom use, use of sterile syringes, and other prevention measures.
How would HIV treatment drugs work to protect against HIV infection?
The concept of providing a preventive drug before exposure to an infectious agent is not new. For example, travelers to an area where malaria is common are advised to take medication before and during travel to prevent the disease. The medicine to prevent illness is then already in their bloodstream if they are exposed to the malaria parasite. Researchers believe that the same concept may work to protect people from HIV infection. Theoretically, if HIV replication can be inhibited from the moment the virus enters the body, it may not be able to establish a permanent infection.
What data suggest that this approach may be safe and effective?
Several sources of data suggest that an antiretroviral drug, taken regularly, may prove effective in reducing a person's risk for HIV infection:
- Providing a single dose of the antiretroviral drug nevirapine to HIV-infected women during labor and to their newborns immediately after birth has reduced the risk for mother-to-child transmission of HIV by about 50 percent.
- In observational studies, the antiretroviral drug zidovudine, taken soon after exposure and continued for several weeks, has been associated with an 80 percent reduction in the risk of HIV infection among health care workers after needlesticks or other accidental exposures.
- Animal studies have shown that tenofovir, administered before and immediately after a single retroviral exposure, can reduce the transmission of a virus similar to HIV in monkeys.
- Finally, animal studies have also demonstrated that pre-exposure administration of tenofovir plus emtricitabine provided significant protection to monkeys exposed repeatedly to an HIV-like virus.
The safety and efficacy of tenofovir and a tenofovir-emtricitabine combination pill for the treatment of HIV infection has been well established in clinical studies and medical settings. The FDA licensed tenofovir for use as an HIV treatment in adults in October 2001, and licensed the tenofovir-emtricitabine combination pill for use as an HIV treatment in August 2004. Data from Gilead Sciences, Inc., the manufacturer of the drugs, indicate that more than one million HIV-infected patients around the world have now used these drugs. Among these patients, tenofovir has resulted in a relatively low level of side effects, compared to other HIV treatments. The most common side effects include rash, diarrhea, headache, pain, depression, fatigue, and nausea. Tenofovir plus emtricitabine has also been associated with a relatively low level of side effects, which include diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash.
One of the key objectives of these trials is to determine for certain whether the study drugs are safe and well tolerated by HIV-negative persons; and safety is being closely monitored throughout the trials. Researchers expect side effects to be even less common in the healthy, HIV-negative volunteers in these HIV prevention trials.
Why study two different drugs?
Globally, more than 7,000 new HIV infections occur daily, and additional prevention approaches are urgently needed. A combination of studies -- of both tenofovir alone and tenofovir plus emtricitabine -- will allow us to move forward as quickly and effectively as possible in the search for new solutions.
There are significant data suggesting the promise of both of these HIV treatment drugs. Because we don't yet know for sure how the animal data will correlate to human protection, we believe it is essential to move forward as quickly as possible to evaluate both of these promising interventions.
Trial Designs and Objectives
What specific PrEP studies is CDC conducting?
In July 2010, CDC completed a study of the clinical and behavioral safety of once-daily oral tenofovir among 400 men who have sex with men (MSM) in the United States. Participants in the study were randomly assigned to one of four arms. Two arms received either tenofovir or placebo immediately upon enrollment, while the other two arms received either tenofovir or placebo after nine months of enrollment. This design will allow researchers to compare risk behaviors among those taking a daily pill and those not taking pills. The trial was not designed to evaluate the drug's effectiveness in reducing HIV transmission.
Preliminary findings suggest no serious safety concerns. While analysis of behavioral safety data are not yet complete, preliminary analyses suggest there was no increased risk in men taking a study pill compared to those not taking a study pill during their first nine months of study participation. Additional analyses of clinical, behavioral, and adherence data are underway.
The study was 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, Ecuador, the U.S., and other countries is being evaluated independently by the National Institutes of Health.)
CDC is currently sponsoring two separate trials in Thailand and Botswana, which will answer important questions about the safety and efficacy of PrEP among high-risk populations. These trials involve approximately 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 which will provide data on the behavioral and clinical safety of tenofovir plus emtricitabine and adherence to the regimen among heterosexual men and women. This trial began as a safety and efficacy trial, but key challenges, including lower than anticipated HIV incidence and retention rates in the trial population -- meant that the trial would be unable to determine efficacy. However, the study will still examine critical questions related to safety and adherence.
In addition to the two 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 emtricitabine -- 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 persons 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 current trials begin and how are they designed?
The Thailand trial of tenofovir began in 2005, and the Botswana trial of tenofovir plus emtricitabine began in early 2007. Both 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.
The Thailand trial is examining the safety and efficacy of tenofovir. It is being conducted in collaboration with the Bangkok Metropolitan Administration and the Thailand Ministry of Public Health and has enrolled 2,400 HIV-negative injection drug users (IDUs) at 17 drug-treatment clinics in Bangkok. Participants -- male and female -- were recruited at the drug treatment clinics, at community outreach sites, and through a peer referral program.
The Botswana study is examining the behavioral and clinical safety of tenofovir plus emtricitabine and adherence to the regimen. The trial is being conducted in collaboration with the Botswana government and has enrolled 1,200 HIV-negative heterosexual men and women, aged 18-39, in the nation's two largest cities, Gaborone and Francistown. Participants were 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.
This trial began as a safety and efficacy trial, but key challenges -- including lower than anticipated HIV incidence and retention rates in the trial population -- meant that the trial would be unable to determine efficacy. However, the study will still examine critical questions related to safety and adherence.