In the latest in an accumulating body of animal studies examining various types of pre-exposure prophylaxis (PrEP), CDC researchers have determined that two different strategies are effective against a monkey form of HIV in macaques.

In one study, CDC found for the first time that the oral administration of antiretroviral drugs before and after exposure to simian human immunodeficiency virus (SHIV) effectively prevented rectal infection in macaques; this approach is known as intermittent PrEP. And, in a second study, CDC researches found that when applied as a gel prior to vaginal SHIV exposure, a single antiretroviral drug was just as effective as two antiretroviral drugs in preventing SHIV infection in female macaques.

PrEP is one of the most promising areas of HIV prevention research, and several human trials of daily oral PrEP are underway around the world. While these human trials will provide the first answers as to whether PrEP can prevent HIV transmission in people, animal studies like these are essential to prepare for the next generation of PrEP research, should daily use prove effective in humans. If the monkey model proves to reflect human dynamics of transmission, these data suggest that simpler PrEP regimens may also prove effective.

First Animal Study to Show Effectiveness of Intermittent Oral PrEP

In a study examining intermittent oral pre- and post-exposure regimens in macaques, CDC's Dr. Gerardo Garcia-Lerma and colleagues investigated the effectiveness of tenofovir combined with emtricitabine (TDF/FTC, brand name Truvada). The drug was administered orally at human dosing levels at several different time intervals before exposure to SHIV; additionally, the study also looked at a post-exposure only regimen. All animals were rectally exposed to SHIV weekly for 14 weeks. All pre-exposure regimens were combined with a single post-exposure dose, given prior research indicating an additional protective benefit from this approach.

Researchers assigned 24 macaques to one of five groups (six animals in each group):

• 2 hours before and 22 hours after exposure (Group I)

• 22 hours before and 2 hours after exposure (Group II)

• 3 days (72 hours) before and 2 hours after exposure (Group III)

• 7 days (168 hours) before and 2 hours after exposure (Group IV)

• 2 hours and 26 hours after exposure (Group V received only intermittent post-exposure prophylaxis)

In addition, 32 untreated monkeys were the control group. Animals in all five treatment groups had significantly lower risk of infection compared to the untreated monkeys, though administering PrEP one to seven days prior to exposure was found to be more effective in preventing infection than administering the drug immediately before exposure or only intermittently after exposure.

Monkeys given PrEP three or seven days prior to exposure (Groups III and IV) were 14.3 and 16.7 times less likely to become infected than controls, respectively (p<.001), experiencing a level of protection similar to that of the monkeys given PrEP a day prior to exposure (Group II), who were 16.7 times less likely to become infected than controls (p < 0.001). By contrast, those animals given PrEP just two hours before exposure (Group 1) were 4.2 times less likely to become infected than controls (p=0.01), and those given treatment only after exposure (Group V) were four times less likely to become infected than controls (p=0.01).

While prior CDC animal research indicated that intermittent PrEP could be effective when high levels of drugs were administered subcutaneously (PLoS Medicine, Feb. 2008), this is the first animal data to show effectiveness of an intermittent approach using an oral dose of TDF/FTC in a manner much more similar to human dosing.

Animal PrEP Study Finds Application of a Single-drug Vaginal Gel Is as Effective as a Two-drug Gel in Preventing SHIV Transmission

In a second study, led by CDC's Drs. Charles Dobard and Walid Heneine, researchers compared the effectiveness of a topical tenofovir vaginal gel to a gel that included a combination of tenofovir and FTC. The study builds upon a recent CDC study that was the first to demonstrate efficacy of the tenofovir/FTC combination gel in preventing SHIV transmission in macaques through vaginal exposure (Presentation to the XVII International AIDS Conference, Mexico City, August 2008).

Researchers assigned 12 macaques to one of two treatment arms: six received the tenofovir-only gel, and another six received the tenofovir/FTC combination gel. Eleven macaques (two receiving no gel and nine receiving a placebo gel) served as the control group. All animals were vaginally exposed to SHIV twice weekly for 10 weeks. The gel was applied 30 minutes before each exposure.

The study found that both vaginal gel formulations were equally effective and provided complete protection against SHIV. None of the 12 animals in the treatment groups became infected after 20 vaginal exposures. By contrast, 10 of 11 untreated macaques became infected after a median of four exposures.

While human data will be required to determine if vaginal gels can prevent HIV transmission, these findings suggest that single-drug regimens may be effective for topical gels, given that both the single- and two-drug vaginal gels were equally protective in this study. This is in contrast to animal findings of oral PrEP regimens, which have consistently shown increased levels of protection against SHIV with two drugs when compared to one.

Studies Provide Step Forward in Search for New HIV Prevention Solutions

Additional HIV prevention approaches are urgently needed to stem the estimated 2.7 million new HIV infections that occur worldwide each year. Effective HIV vaccines are years away, and approaches that can be controlled by women are urgently needed. Additionally, when combined with existing behavioral prevention strategies, PrEP could provide an additional safety net for all individuals who remain at high risk

Although data from these animal studies are encouraging, the implications for humans are not yet known, as there are many differences between transmitted viruses, hosts (monkey versus human) and immune responses. Only human trials can tell us to what extent, if any, PrEP is safe and effective in reducing HIV transmission in humans.

Several human trials investigating the safety and efficacy of PrEP are well underway or planned. CDC is sponsoring two safety and efficacy trials of daily oral PrEP -- one examining TDF/FTC among heterosexuals in Botswana and another investigating TDF among injection drug users in Thailand -- and is participating in a University of Washington-sponsored efficacy trial of oral TDF/FTC and TDF among serodiscordant couples in Kenya and Uganda. CDC is also sponsoring a trial that will provide critical clinical and behavioral data on the safety of daily use of oral TDF among men who have sex with men (MSM) in the United States. Additionally, other agencies and organizations are also conducting human efficacy trials of oral PrEP among women and MSM.

Human trials of topical gels used either vaginally or rectally to prevent HIV transmission are also underway or planned by several institutions. Two trials are examining the effectiveness of a tenofovir vaginal gel, one of which will compare the effectiveness of a tenofovir vaginal gel with two different oral PrEP regimens (TDF and TDF/FTC). Two additional human trials are planned to examine whether a tenofovir gel is safe for rectal use.

When these trials are completed and the correlation between human results and the macaque model is better understood, animal data such as these will provide critical information to help guide next steps in research and practice. The combination of human trials and animal research is allowing researchers to move as quickly as possible in the urgent search for new prevention solutions.