Understanding the Rationale for Combination Prevention Trials

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.