By Regina McEnery

A Phase II AIDS vaccine trial known as HVTN 505 will expand enrollment to determine whether two vaccine candidates administered sequentially in a prime-boost regimen are capable of protecting against HIV infection. The two candidates—a DNA-based vaccine and a candidate that employs an inactivated strain of the commonly circulating cold virus adenovirus serotype 5 (Ad5)—were developed by the Vaccine Research Center at the National Institute of Allergy and Infectious Diseases (NIAID).

The HVTN 505 trial, which was launched in 2009, was initially designed to determine whether individuals who become HIV infected through natural exposure, despite vaccination, have lower viral loads (the quantity of HIV circulating in blood) than those who receive placebo (see VAX July 2009, Global News). With only this endpoint, the trial was slated to enroll 1,350 circumcised men or transgendered women who have sex with men. Adding protection against infection as an additional endpoint requires expanding enrollment to 2,200 volunteers, who will be enrolled at 21 sites in 18 US cities. So far, investigators have enrolled 1,344 volunteers and are on track to enroll the remaining volunteers by mid-2012, according to Scott Hammer, principal investigator of the HVTN 505 trial.

Carl Dieffenbach, director of the Division of AIDS (DAIDS) at NIAID, says the expanded trial is a positive step for the field, but he cautioned observers to keep the scope of the trial and where it might lead in perspective. “We have to be careful that we continue to put this forward without trying to over-promise,” he says.

One Oral PrEP Arm Discontinued Early in VOICE Trial

One arm of a large clinical trial known as VOICE that was designed to test the safety, efficacy, and acceptability of one topical and two oral pre-exposure prophylaxis (PrEP) regimens in more than 5,000 women was discontinued in September after the trial’s independent data safety monitoring board (DSMB) concluded that the study would be unable to show any difference between a daily dose of the antiretroviral pill tenofovir (TDF) and placebo in preventing HIV infection. About 1,000 of the volunteers were randomized to the oral TDF arm. The DSMB found no safety concerns with oral TDF.

Unlike other large-scale PrEP trials that were recently completed or still ongoing, the VOICE study is the first to evaluate both oral and topical PrEP regimens in the same trial. The remaining arms of the trial, which are testing daily administration of the antiretroviral pill Truvada—a combination of TDF and emtricitabine—and the topical administration of a 1% tenofovir microbicide gel will continue in order to determine if they are safe and effective at preventing HIV infection as compared to pill and gel placebo groups.

The US$100 million VOICE trial, which is being conducted at 15 clinical sites in South Africa, Zimbabwe, and Uganda, began in 2009 and is sponsored by the US National Institute of Allergy and Infectious Diseases; the Microbicide Trials Network; Gilead Sciences (the maker of tenofovir and Truvada); and CONRAD, a reproductive health research institute.

The trial is scheduled to conclude in June, at which point investigators will be able to determine whether volunteers in the oral TDF arm were less adherent to the daily PrEP regimen than women in the Truvada or microbicide arms. Michael Chirenje, a principal investigator of the trial in Zimbabwe, says it would be speculation at this point to say what accounted for the failure of oral TDF to show any effect in this trial. “Obviously we are all disappointed and perplexed by the recent results,” says Chirenje. “But in science, we have to accept reality.”

Three other trials have found both oral tenofovir and Truvada to be effective at preventing HIV infection in men who have sex with men and serodiscordant couples—in which one partner is HIV infected and the other is not (see VAXJuly 2011 Spotlight article, An Antiretroviral Renaissance). However, one trial, known as FEM-PrEP, evaluating oral Truvada in women, was discontinued ahead of schedule after the DSMB concluded that it would be highly unlikely to demonstrate efficacy (see April 18, 2011, IAVI Report blog, Oral PrEP Trial in Women Stopped Early).

By Regina McNery

One arm of a large clinical trial known as VOICE that was designed to test the safety, efficacy, and acceptability of one topical and two oral pre-exposure prophylaxis (PrEP) regimens in more than 5,000 women was discontinued in September after the trial’s independent data safety monitoring board (DSMB) concluded that the study would be unable to show any difference between a daily dose of the antiretroviral pill tenofovir (TDF) and placebo in preventing HIV infection. About 1,000 of the volunteers were randomized to the oral TDF arm. The DSMB found no safety concerns with oral TDF.

Unlike other large-scale PrEP trials that were recently completed or still ongoing, the VOICE study is the first to evaluate both oral and topical PrEP regimens in the same trial. The remaining arms of the trial, which are testing daily administration of the antiretroviral pill Truvada—a combination of TDF and emtricitabine—and the topical administration of a 1% tenofovir microbicide gel will continue in order to determine if they are safe and effective at preventing HIV infection as compared to pill and gel placebo groups.

The US$100 million VOICE trial, which is being conducted at 15 clinical sites in South Africa, Zimbabwe, and Uganda, began in 2009 and is sponsored by the US National Institute of Allergy and Infectious Diseases; the Microbicide Trials Network; Gilead Sciences (the maker of tenofovir and Truvada); and CONRAD, a reproductive health research institute.

The trial is scheduled to conclude in June, at which point investigators will be able to determine whether volunteers in the oral TDF arm were less adherent to the daily PrEP regimen than women in the Truvada or microbicide arms. Michael Chirenje, a principal investigator of the trial in Zimbabwe, says it would be speculation at this point to say what accounted for the failure of oral TDF to show any effect in this trial. “Obviously we are all disappointed and perplexed by the recent results,” says Chirenje. “But in science, we have to accept reality.”

Three other trials have found both oral tenofovir and Truvada to be effective at preventing HIV infection in men who have sex with men and serodiscordant couples—in which one partner is HIV infected and the other is not (see VAX July 2011 Spotlight article, An Antiretroviral Renaissance). However, one trial, known as FEM-PrEP, evaluating oral Truvada in women, was discontinued ahead of schedule after the DSMB concluded that it would be highly unlikely to demonstrate efficacy (see April 18, 2011, IAVI Report blog, Oral PrEP Trial in Women Stopped Early).

What are the potential benefits of and complications with studying multiple prevention strategies in combination?

Over the last few years, several strategies have demonstrated success in preventing HIV infection. These strategies include adult male circumcision, pre-exposure prophylaxis (PrEP; the administration of antiretrovirals [ARVs] either orally or topically to HIV-uninfected individuals to prevent HIV infection), and the first evidence of vaccine-induced protection against HIV (see VAX July 2011 Spotlight article, An Antiretroviral Renaissance; Jan. 2011 Spotlight article,Prepping for the Future; Sep. 2009 Spotlight article, First Evidence of Efficacy from Large-Scale HIV Vaccine Trial).

However, all of these strategies are only partially effective at protecting against HIV infection (see table at right), with efficacies ranging from 31% for the vaccine regimen tested in the RV144 trial in Thailand to 73% for the use of oral PrEP in serodiscordant heterosexual couples (couples in which one person is HIV-infected and the other isn’t). This has led researchers to consider the feasibility of designing clinical trials to evaluate some of these prevention strategies in combination to see if a combination approach would be more effective at preventing HIV infection.

Vaccines plus PrEP

One combination of partially effective prevention strategies that some researchers believe might be worth testing is the use of PrEP along with a partially effective vaccine such as the prime-boost combination tested in the RV144 trial. Data from the trial showed vaccine efficacy was as high as 60% during the first year (although the efficacy at one year was not part of the pre-specified data analysis plan) but then waned over time. Researchers are still investigating the mechanisms that led to this protection (see Spotlight, this issue), and planning vaccine trials to try to improve upon this modest efficacy. Meanwhile, some researchers think that oral PrEP might boost vaccine-induced immune responses, based on evidence from studies in non-human primates. Therefore, they suggest, clinical trials of this combination should be conducted.

The combination of a partially effective vaccine and topical PrEP, which is most commonly delivered as a vaginal microbicide gel, is another combination strategy under consideration. The ARV-based microbicide gel and the vaccine candidate could even be administered in the same gel formulation. Researchers speculate that administering the vaccine candidate directly into the vagina along with an ARV-based microbicide might help strengthen immune responses at the site where transmission occurs, thereby boosting efficacy of the combined approach.

Another option, which is currently being explored as a delivery method for microbicides, is the use of intra-vaginal rings. These rings could deliver steady dosing of ARVs over a three-month period and also deliver the vaccine candidate over a period of hours or days.

The use of oral or topical PrEP in combination with a partially effective vaccine has another potential advantage. ARV prophylaxis would likely help lower HIV incidence in the clinical trial population, making it more likely that the vaccine candidate would have an effect. In the RV144 trial in Thailand, volunteers were predominantly heterosexuals at low-risk of acquiring HIV, and several researchers suggest that the low-risk population may have been key to the observed efficacy in the trial.

Challenges to combination prevention trials

Although it is theoretically possible that combining partially effective prevention strategies would result in a higher overall efficacy, this can only be determined by studying these approaches in clinical trials. However, there are many challenges to designing such trials. Because the trials will involve multiple interventions, the size, cost, and complexity of conducting such trials will increase. The duration of trials might also be greater.

For instance, should a trial be set up to evaluate the efficacy of a partially effective vaccine candidate combined with oral PrEP, the trial would need to involve multiple arms to determine whether the overall efficacy of this combination strategy is greater than that of PrEP alone, the vaccine candidate alone, or a placebo.

Monitoring the outcome of a combination prevention trial would also be more complicated. For instance, in a trial combining a partially effective vaccine candidate with oral or topical PrEP, the use of ARVs might alter the immune responses induced by a vaccine, making it more difficult to tease out how much the vaccine actually contributed to overall efficacy.

Different biomedical interventions may also present different safety concerns, which could complicate the process of informing volunteers about the risks of trial participation. And daily adherence to oral and topical PrEP could impact the outcome of combination prevention trials just as it has in previous PrEP-only trials, making it difficult to determine actual efficacy of the combined strategies. Despite these concerns, several researchers argue that clinical trials of different partially effective prevention strategies should be designed and conducted.