What safeguards are in place to ensure protection of the volunteers?

To ensure that each of these trials remains on a solid scientific and ethical foundation, all procedures and plans are reviewed and approved by scientific and ethical review committees at CDC (called institutional review boards, or IRBs), as well as by IRBs established by each host country and research site.  Additionally, data on safety, enrollment, and efficacy will be reviewed at standard intervals by an independent data safety and monitoring board (DSMB) for the Botswana and Thai trials and by an independent safety review committee for the U.S. trial.  These committees review emerging data to ensure that continuing the trial is safe and during the Phase III components, to determine the point at which the results are conclusive.  If scientific questions arise during the trials, these committees will meet more frequently.

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Will trial participants increase their risk behavior when they begin taking daily pills?

Several critical steps are being taken to guard against this possibility.  First, it is important to ensure that participants understand that trial participation may not protect them from HIV infection―because they may receive a placebo, or they may receive tenofovir, the efficacy of which remains unproven.  This and other key aspects of the trial, including potential risks and benefits of participation, are explained to potential volunteers in depth in language they understand, prior to their enrollment.  To ensure participants fully understand all aspects of their participation, all volunteers are required to pass a comprehension test prior to providing written informed consent.

Second, to assist participants in eliminating or reducing HIV risk behaviors, extensive counseling is provided at each study visit, and more often if needed.  The interactive counseling to be provided has been proven to reduce the risk of HIV and other STDs in multiple populations, including past participants of similar trials.  Participants are also offered free condoms and STD testing and treatment to reduce their risk for HIV infection.  Additionally, injection drug users are referred to, and/or offered follow-up in, a methadone treatment program and will receive bleach and instructions on how to use it to clean needles.  Consistent with Thai government policy, sterile syringes will not be provided but are widely available in Thailand without a prescription and at low cost (one sterile syringe and one needle cost about 5 Thai baht, or about $0.12).

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How will CDC evaluate the impact of PrEP if participants reduce their risk behavior?

Although participants will likely be at lower risk for infection because of the prevention services received during the trial, the design of the trial will enable CDC to distinguish between the impact of these services and the impact of the study drugs. Because all participants will receive equivalent prevention services but only half will be given the study drugs, any difference in the rate of HIV infection between the two groups should be due to the study drugs.

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What will happen to participants who do become infected during the trial?

Despite optimal prevention counseling, some participants will become HIV infected during the trial. To ensure that infected participants are quickly referred to the best available medical and psychosocial services, they receive free rapid HIV testing at every visit. Participants who become infected will receive confirmatory testing for infection, post-test risk-reduction and support counseling, as well as help enrolling in local HIV care programs. Both Thailand and Botswana have antiretroviral treatment and HIV care programs in place at minimal or no cost to patients. In the United States, participants will be referred to local health care providers or public programs for needed medical and social services.

To help guide treatment decisions and to determine whether prior exposure to tenofovir or tenofovir plus emtricitabine affects the course of disease, testing will be provided for viral load, CD4 count, and HIV resistance mutations, and infected participants will be followed up for an additional 12 months.

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What are the most common side effects associated with the drugs being tested?

These trials are among the first to evaluate the safety of tenofovir alone and tenofovir plus emtricitabine in HIV-negative persons. However, among HIV-positive persons who have taken tenofovir in combination with other antiretroviral drugs, the most common side effects are nausea, vomiting, and loss of appetite. There have also been reports of uncommon, but more serious effects, such as impaired kidney function or reductions in bone density. These effects have largely been reversible when the person stopped taking the drug.

Tenofovir plus emtricitabine has also been associated with a relatively low level of side-effects, which include diarrhea, nausea, fatigue, headache, dizziness, and rash. There have been infrequent reports of more serious side effects, including impaired kidney function and lactic acidosis (a build-up of lactic acid in the blood). As with tenofovir, these effects have largely been reversed after use of the drug was discontinued.

Laboratory testing is used to carefully monitor all participants for signs of these conditions so that the study drugs can be stopped immediately should problems be identified. Researchers anticipate that healthy, HIV-negative participants will experience fewer side effects than do HIV-infected populations taking multiple medications. In the single study of tenofovir safety among uninfected individuals completed to date, there were no serious side effects found to be associated with the drug.

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Will health care be provided for any health problems related to the drugs?

In all three trials, researchers are monitoring participants closely for drug-related side effects. If problems requiring treatment occur, participants will be quickly linked to needed medical care. Care systems differ by country.

In Botswana, the government will provide any needed medical care through the national health care system. In the United States, participants will access needed care through private health insurance or if uninsured, will be provided facilitated referrals to public health care providers. In Thailand, care will be provided in local government clinics.

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