Researchers Rally Around PrEP

Building on two efficacy trials showing antiretrovirals can prevent HIV infection, discussions about this prevention strategy dominated the annual retrovirus conference

By Regina McEnery

The 18th Conference on Retroviruses and Opportunistic Infections (CROI), which took place from February 27 to March 2 in Boston, turned into a PrEP rally.

Three of the six plenary talks dealt with aspects of pre-exposure prophylaxis (PrEP)—the administration of antiretrovirals (ARVs) either orally or topically prior to HIV exposure to protect against infection—and researchers discussed and debated new evidence from both clinical and preclinical PrEP studies, as well as the challenges involved in implementation of this strategy.

The momentum behind PrEP was already evident at last summer’s XVIII International AIDS Conference in Vienna, where researchers reported results of the CAPRISA 004 trial of 889 high-risk South African women that showed a vaginal microbicide gel candidate containing 1% of the antiretroviral tenofovir (TDF) was able to reduce HIV incidence by 39% (see VAX Sep. 2010 Spotlight article, Microbicides Finally Gel, Securing Spotlight in Vienna). This was followed in November by results of the large, international iPrEx trial of nearly 2,500 men and transgendered women who have sex with men, which found that daily administration of TDF combined with the ARV emtricitabine (FTC) was 44% effective in preventing HIV infection (see VAX Jan. 2011 Spotlight article, Prepping for the Future).

At CROI, iPrEx Principal Investigator Robert Grant, an associate professor of medicine at the University of California in San Francisco, presented an additional six months of follow-up data from the iPrEx trial that showed the daily TDF/FTC regimen resulted in a slightly lower, but still statistically significant efficacy of 42%. “I don’t think this efficacy is modest at all,” said Grant. The new HIV infections that occurred during the additional six months of monitoring were among volunteers who didn’t take the drugs consistently. “It was protective when used and not protective when not used,” Grant said. “Our data show that 50% [of volunteers] took the pill almost every day. That’s remarkable.”

But the focus now is on the other half of the trial volunteers who did not consistently take the daily PrEP regimen. Adherence was one of the main topics of discussion at a community forum on ARV-based prevention held on March 1, co-sponsored by the Boston-based Fenway Health and the New York-based prevention research advocacy organization AVAC. Grant challenged the notion that adherence will always be higher in a clinical trial and said that he suspects adherence to PrEP will likely be higher when volunteers are told they are receiving the PrEP drugs and not placebo, and that these drugs have now been shown to be effective in protecting against HIV only when taken reliably. “Adherence is a solvable problem,” said Grant.

To better understand what factors influence adherence, Grant said the iPrEx study group will conduct an unblinded, open-label study in which all of the HIV-uninfected participants from the iPrEx study will be eligible to participate. The intent of the open-label study is to measure the efficacy of PrEP and the adherence to the daily regimen when participants know they are taking a drug that can protect them against HIV infection. The study will also continue to assess the long-term safety of TDF/FTC in healthy individuals.

Researchers also reported more safety data on oral PrEP from a sub-analysis of the iPrEx trial and an unrelated safety study of 400 HIV-uninfected men who have sex with men (MSM) in the US. Both of these studies showed a small but statistically significant drop in bone mineral density—a marker for bone fractures—among HIV-uninfected men who received ARVs for prevention as compared to those who did not. Initiation of TDF has been associated with decreases in bone mineral density in HIV-infected individuals, but its impact in uninfected individuals was not known. Neither study saw an increased rate in bone fractures among volunteers receiving PrEP regimens, but more long-term data is necessary to fully assess this side effect, researchers said.

“We celebrate the fact we now have proof-of-concept through the iPrEx and CAPRISA 004 studies, but ongoing trials are still critical to providing additional data on safety, efficacy, adherence, and resistance,” said Connie Celum, director of the International Clinical Research Center at the University of Washington, during her plenary talk. Additional analyses of the iPrEx trial presented at CROI showed that there was no detectable drug-resistant virus in any of the trial volunteers who were uninfected at the start of the trial and became HIV infected despite receiving the PrEP drugs.

The US Centers for Disease Control and Prevention (CDC) expects to release guidelines soon on the use of PrEP among MSM, and Gilead (manufacturer of Truvada, a combination of TDF/FTC) says it intends to file a supplemental investigational new drug application with the US Food and Drug Administration for the use of Truvada for prevention. At the same time, PrEP efficacy trials are now being conducted in other populations, including injection drug users, serodiscordant couples, and heterosexual women at high risk of HIV infection.

While adherence may be a major challenge, the cost of PrEP also looms large, particularly in low- and middle-income countries where only about a third of the 15 million HIV-infected people who qualify for treatment are receiving it. Researchers are now using mathematical models to assess in which high-risk groups or settings PrEP might be most cost effective.

Researchers also presented data at CROI showing some women prefer using an ARV-based microbicide gel to taking oral PrEP. At the conclusion of a Phase II study comparing oral administration of TDF with topical application of a TDF microbicide gel in 144 HIV-uninfected sexually active women from Africa and the US, researchers from Johns Hopkins University found that while 100% of African women reported they would use either the pill or gel form of PrEP if it was found to be effective, the African women reported greater sexual satisfaction when using the gel. In contrast, 72% of US women said they preferred the pill. This study showed that the concentration of TDF in vaginal tissue was much higher following topical application. Still, it is unknown what concentration of drug is associated with protective efficacy, so it is unclear whether higher concentrations are necessary.

While most of the clinical trials of PrEP that are underway are testing either TDF or Truvada, other ARVs are also being explored pre-clinically for their ability to prevent HIV infection. New data presented at CROI by the CDC suggests another ARV may have a role in preventing HIV infection if administered vaginally soon after virus exposure, a strategy known as post-exposure prophylaxis, or PEP. Results of a non-human primate study showed for the first time that administration of a vaginal gel containing raltegravir—an ARV known as an integrase inhibitor because it blocks HIV’s enzyme that integrates the virus’ DNA into the genome of human cells—prevented HIV infection in five of six pigtailed macaques when applied topically three hours after the animals were exposed to SHIV (a combination of HIV and simian immunodeficiency virus, the monkey equivalent of HIV). The monkeys that received the gel remained uninfected after being exposed 20 times to the SHIV strain used in this study, while four animals that received a placebo gel became infected after an average of 10 SHIV exposures.

Because the raltegravir gel was able to protect the monkeys when applied right after SHIV exposure, researchers believe it may also be able to block infection in adults when used shortly before or after exposure to HIV.

Researchers also reported findings from a Phase I study of a microbicide gel containing 1% of TDF, the same formulation used as a vaginal microbicide in the CAPRISA 004 trial, when applied rectally in men and women. The study involved 18 HIV-uninfected men and women at two sites in the US. Trial participants in the rectal microbicide study were first given a single dose of oral TDF. Two weeks later, they were randomized to receive either a rectal dose of 1% tenofovir gel or a placebo gel. Two weeks after that they were asked to use either the tenofovir gel or the placebo gel once a day for seven days.

UCLA Professor of Medicine Peter Anton, who led the study, said three of the 18 participants experienced eight grade three adverse events that were considered to be severe after using the rectal microbicide, primarily diarrhea, cramps, and gastrointestinal discomfort.

Researchers collected more than 2,000 colon and rectal tissue samples from study participants and exposed the samples to HIV in a laboratory. Researchers found that the samples from participants who received the TDF gel showed significant inhibition of HIV, suggesting this approach may be useful in blocking rectal transmission. Other studies will be necessary to show whether a rectal microbicide can actually block HIV infection.