In the absence of an effective vaccine, HIV continues to spread globally, emphasizing the need for novel strategies to limit its transmission. Pre-exposure prophylaxis (PrEP) with antiretroviral drugs could prove to be an effective intervention strategy if highly efficacious and cost-effective PrEP modalities are identified. We evaluated daily and intermittent PrEP regimens of increasing antiviral activity in a macaque model that closely resembles human transmission.
Methods and Findings
We used a repeat-exposure macaque model with 14 weekly rectal virus challenges. Three drug treatments were given once daily, each to a different group of six rhesus macaques. Group 1 was treated subcutaneously with a human-equivalent dose of emtricitabine (FTC), group 2 received orally the human-equivalent dosing of both FTC and tenofovir-disoproxil fumarate (TDF), and group 3 received subcutaneously a similar dosing of FTC and a higher dose of tenofovir. A fourth group of six rhesus macaques (group 4) received intermittently a PrEP regimen similar to group 3 only 2 h before and 24 h after each weekly virus challenge. Results were compared to 18 control macaques that did not receive any drug treatment. The risk of infection in macaques treated in groups 1 and 2 was 3.8- and 7.8-fold lower than in untreated macaques (p = 0.02 and p = 0.008, respectively). All six macaques in group 3 were protected. Breakthrough infections had blunted acute viremias; drug resistance was seen in two of six animals. All six animals in group 4 that received intermittent PrEP were protected.
This model suggests that single drugs for daily PrEP can be protective but a combination of antiretroviral drugs may be required to increase the level of protection. Short but potent intermittent PrEP can provide protection comparable to that of daily PrEP in this SHIV/macaque model. These findings support PrEP trials for HIV prevention in humans and identify promising PrEP modalities.
Using a repeat-exposure macaque model, Walid Heneine and colleagues find that pre-exposure prophylaxis with combination antiretroviral drugs provides protection against rectal challenge with a SHIV virus.
Each year, some 2.5 million people become newly infected with HIV, the virus that causes AIDS. A vaccine that protects people against HIV infection is not likely to become available for at least several years. Condoms can prevent infection, but they are not 100% effective, and people do not always use them. Until a vaccine becomes available, other methods of preventing HIV could save many thousands of lives.
One possibility for preventing HIV is pre-exposure prophylaxis (PrEP). In this approach, people who are likely to be exposed to the virus could take medicine to prevent them from becoming infected, in the same way that medication to protect against malaria is often taken by people traveling to high-risk areas.
Why Was This Study Done?
PrEP has never been shown to be effective against sexual transmission of HIV in humans. Studies of PrEP in people at risk for HIV are currently in progress or being planned, but it is not clear which medications or dosing schedules should be used. The researchers in this study wanted to explore several possible ways of giving PrEP in monkeys in order to learn more about how to design strategies for testing PrEP in humans.
What Did the Researchers Do and Find?
The researchers simulated human exposure to HIV by exposing rhesus macaques (a type of monkey) to SHIV, a monkey virus (SIV) that has been modified to contain the same outer protein as HIV. They exposed the macaques to repeated low doses of SHIV given rectally once per week, to simulate a common route of HIV transmission in humans. They used five groups of macaques that were all given the same viral exposure, but received different PrEP regimens: one group of six animals received only the anti-HIV drug emtricitabine (FTC), by injection under the skin every day; another six received FTC in combination with an oral form of the anti-HIV drug tenofovir every day, both by mouth; six received by injection FTC in combination with a higher tenofovir dose every day, and six also received by injection FTC in combination with the high-dose tenofovir, but the treatment was given only before and after the weekly viral exposure instead of every day. For comparison, the fifth group of nine macaques (plus another nine from a previous study) received no anti-HIV medications.
The researchers found that the macaques in any of the four treatment groups were less likely to become infected than those in the comparison group. In particular, all of the macaques receiving both FTC and high-dose tenofovir, whether daily or only around the time of exposure, were protected from infection. Macaques that did become infected in the other treatment groups had lower levels of virus in their blood than those that became infected in the comparison group, but some that became infected in the treatment groups went on to develop virus that was resistant to FTC.
What Do These Findings Mean?
These results show that PrEP can be effective in this animal model, and that higher doses and combination treatments may be more effective than single drugs or lower doses. The results also suggest that PrEP might work if taken only around the time of exposure and therefore might not need to be taken every day in order to be effective. Further, by reducing the levels of HIV in people who do become infected, PrEP might reduce the chance that these people will transmit HIV to others before realizing that they themselves are infected. However, this study also demonstrates that partially effective PrEP can result in infection with drug-resistant virus, which might make treatment difficult. Also, the doses of tenofovir used to achieve maximum protection in these macaques may be higher than would be safe in humans. Carefully designed human studies will be needed to determine which, if any, PrEP strategies will be effective in practice.
Please access these Web sites via the online version of this summary at http://dx.doi.org/doi:10.1371/journal.pmed.0050028.
The US Centers for Disease Control and Prevention (CDC) is conducting several trials of PrEP
The AIDS Vaccine Advocacy Coalition and the UCLA Program in Global Health provide information at PreP Watch
The UCSF Center for HIV Information's HIV InSite includes resources on HIV prevention and treatment