Table of Contents
Research Rationale
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.
Thailand:
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.
Botswana:
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.
Why did CDC select these populations to take part in PrEP 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: The Botswana government estimates that 25 percent of the population 15-49 years of age is infected, with young heterosexual men and women particularly hard hit. It is estimated that 16 percent of women aged 20-24 are infected with HIV and that 34 percent of those aged 25-29 are infected. Among men, 7 percent of men aged 20-24 and 16 percent of men aged 25-29 are believed to be HIV infected.
In Thailand, HIV prevalence is high among injection drug users (IDUs): Surveillance data from the Thailand Ministry of Public Health suggests 40 percent of IDUs are already infected. Although HIV incidence among IDUs participating in research trials in the Bangkok drug treatment clinics has declined by 40% since 1995, likely due to extensive risk reduction counseling and other prevention services provided, a recent study found that over 3% of Thai IDUs continue to become infected each year.
In the United States (safety trial completed in July 2010), 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. A recent CDC study found that MSM have an HIV diagnosis rate 44 times that of other men.
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 are healthy and HIV-negative. To protect the health of participants and ensure that trial data are accurate, several conditions 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.
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 nine 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 elsewhere?
Yes. In 2006, Family Health International, with funding from the Bill & Melinda Gates Foundation, completed a similar trial of tenofovir for HIV prevention among young women in Ghana, Nigeria, and Cameroon. The study provided the first data showing PrEP with tenofovir to be both safe and acceptable for use by HIV-negative women, 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 heterosexual men and women in Africa are underway. A full list of trials can be found here.
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, with NIH contributing an additional $1 million. In Thailand, CDC's contribution is estimated to be $16 million. In the United States, CDC provided $11 million in support of the three institutions conducting the trial.
Safeguards and Services for Trial Participants
What safeguards are in place to ensure protection of the volunteers?
To ensure that trials remain on solid scientific and ethical foundations, 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 or equivalent ethical review bodies established by each host country and research site.
Additionally, data on safety, enrollment, and efficacy are reviewed regularly by an independent data safety and monitoring board (DSMB) for the Botswana and Thai trials. An independent safety review committee reviewed data for the U.S. trial.
These committees examine emerging data to ensure that continuing the trial is safe and to determine the point at which the results are conclusive. If scientific questions arise during the trials, the committees meet more frequently. No serious safety concerns have been identified to date.
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 the study drug, 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 are not 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 $0.15).
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.
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 were 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 is provided for viral load, CD4 count, and HIV resistance mutations, and infected participants are followed up for an additional six months.
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 rash, diarrhea, headache, pain, depression, fatigue, and nausea. There have also been reports of uncommon, but more serious effects, such as impaired kidney function, reductions in bone density, redistribution/accumulation of body fat, or lactic acidosis (a build-up of lactic acid in the blood). Side effects usually resolve after use of the drug is discontinued.
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. There have been infrequent reports of more serious side effects, including impaired kidney function, reductions in bone density, redistribution/accumulation of body fat, and lactic acidosis (a build-up of lactic acid in the blood). As with tenofovir, minor side 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 studies of tenofovir safety among uninfected individuals completed to date, there were no serious side effects found to be associated with the drug.
Will health care be provided for any health problems related to the drug?
Yes. In all CDC-sponsored trials, researchers are monitoring participants closely for drug-related side effects. If any problems requiring treatment occur, participants are quickly linked to needed medical care. Care systems differ by country.
In Botswana, the government is providing any needed medical care through the national health care system. In Thailand, care is provided in local government clinics. In the United States, participants accessed needed care through private health insurance or, if uninsured, were provided facilitated referrals to public health care providers.
Community Involvement in These Studies
What is being done to solicit input from the communities in which these trials are being conducted?
CDC is working closely with community partners at each research site to ensure active community participation during the planning and implementation of these trials.
Botswana: In Botswana, community advisory boards have been established at each site. The boards comprise representatives from local governments (elected and traditional), as well as community members and representatives from key stakeholder organizations. Participant advisory boards have also been established. These groups are providing input to researchers throughout the trial. Additionally, community liaisons at each site conduct outreach to community organizations and respond to any questions or concerns.
Thailand: In Thailand, a community relations committee, composed of injecting drug users from each of the 17 drug treatment clinics, family members, and representatives of local community organizations, meets regularly and provides advice to trial staff on all aspects of trial design, implementation, and trial conduct.
United States: In the United States (trial completed in July 2010), all three sites established active community advisory boards that were consulted regularly about trial procedures and educational materials for potential participants. Members of these boards provided advice throughout the trials. Community educators at each site worked to ensure that community organizations were updated on trial progress and responded to questions or concerns.
In addition to the regular input received by these established committees, broader outreach and consultations with advocates and community-based organizations representing populations at risk for HIV are held, as needed, to address plans for HIV prevention research and programs.
Anticipated Results and Impact
When will the results of the Botswana and Thailand trials be available?
Results of the trials will be available once sufficient data have been collected and analyzed to determine whether the drugs are safe and effective. Independent panels of experts are monitoring the trials closely so that the trials can be concluded as soon as definitive answers are available. Results from the trials are expected within the next year.
If PrEP does prove to be effective at preventing HIV infection in these trials, how will the drugs be made available to people who need or want it?
If the efficacy trial in Thailand proves that tenofovir is effective as PrEP for injection drug users, participants in that trial and their community will be the first to benefit. All trial participants will receive tenofovir for at least one year after efficacy is proven while CDC works with the Thai Food and Drug Administration for approval of use by the Thai health care system. CDC is also prepared to provide technical assistance and support to its international partners in designing PrEP implementation plans in those countries where CDC-sponsored trials are being conducted. Additionally, CDC will assist WHO and UNAIDS in their efforts to develop international normative guidelines for implementing PrEP, if proven effective.
In the U.S., CDC has begun to examine potential implementation strategies with a wide range of stakeholders. Experts are examining a number of critical issues including possible funding streams, risk assessment tools, and delivery of PrEP as part of a comprehensive prevention program. Additionally, CDC is conducting research to determine effective models for reaching the populations at greatest risk in the U.S.
If the drugs prove safe and effective in one population, will they work equally well in other populations?
CDC and other researchers are conducting studies in different populations to help address this question. In general, HIV is more readily transmitted through injection drug use than through sexual exposure and more easily transmitted during rectal intercourse than during vaginal intercourse. However, the correlates of protection for various modes of transmission are not fully understood. It is therefore not known what level of antiretroviral drug activity at which sites (e.g., in the blood, the vaginal mucosa, or the rectal mucosa) will be needed to interrupt transmission. For these reasons, the efficacy of particular drugs in reducing HIV transmission in one population may not necessarily apply to other at-risk populations.
If studies show that PrEP reduces the risk of HIV transmission, will people still have to practice other risk-reduction behaviors for HIV?
Yes. Regardless of the outcome, CDC will not recommend PrEP as a first-line defense against HIV infection. Abstinence and mutual monogamy with an HIV-negative partner will remain the only 100% effective ways to prevent infection. However, if effective, PrEP could provide an additional safety net to sexually active persons at risk, when combined with reduction in the number of sex partners, HIV counseling and testing, consistent and correct condom use, and other prevention strategies.
It is also important to remember that taking PrEP drugs will not prevent acquisition of syphilis, gonorrhea, chlamydia, herpes, hepatitis, or other sexually transmitted diseases, many of which play a role in facilitating HIV transmission or speeding HIV disease progression.
Will support for these trials take away funding from behavioral interventions?
Absolutely not. As we move forward with our search for new prevention strategies, it will be critical to determine how the approaches that are proven effective can best be integrated into programs. Effective behavior-change programs have greatly reduced the rate of HIV infection in the United States and many other nations during the past 2 decades of the HIV epidemic. Because no strategy will be 100% effective in preventing HIV infection, their future impact will ultimately be determined by how effectively strategies are used in combination to provide the greatest protection to individuals at risk.
Are physicians in certain places already prescribing the drugs being studied for HIV prevention?
While one study suggested that some gay men were using PrEP despite the lack of evidence of effectiveness, subsequent CDC studies have found such "off-label" PrEP use among gay men to be rare or nonexistent. Individuals who take HIV medications before engaging in high-risk behavior to avoid infection are doing so in the absence of clinical data demonstrating that the drugs are safe and effective, and at potentially serious risk. This is especially true if the drugs are used instead of, rather than in addition to, existing prevention methods.
That is why CDC is conducting these important trials -- to contribute to the work of scientifically evaluating the safety and efficacy of PrEP among persons who are at risk. The trials will answer important questions about the impact of a daily pill on risk behavior and help us to determine how PrEP, if effective, can be used in combination with other proven strategies.