Shaping the Science of Prevention

Next month, researchers from around the globe will  gather in Cape Town, South Africa, for the first  conference focused on all HIV prevention strategies.

By Robin Shattock

Many people have been asking how the HIV R4P (Research for Prevention) conference to be held in Cape Town in October will differ from other HIV conferences. HIV R4P will be the first conference to focus exclusively on prevention science. This marks an important turning point in HIV biomedical prevention research that in many ways reflects the maturity of the field. Having brought different prevention approaches to a certain scientific standard and level, it now makes sense to draw the different branches together. This conference provides a critical opportunity to build in a coordinated way on the significant gains made in recent years across a variety of prevention modalities.

As with any change, some will be nostalgic for separate meetings of the past where vaccines, microbicides, and pre-exposure prophylaxis (PrEP) were seen as distinct areas of focus. But having the meeting in South Africa provides a natural backdrop for this move. South Africa has already hosted an HIV vaccine and a microbicide meeting, and so it was logical to build on that experience. More importantly, sub-Saharan Africa is also the focus of a major part of the epidemic, where prevention is not seen as the domain of any individual scientific discipline, but as an urgent unmet need, where communities and individuals are eager for things that work and are applicable to their daily lives. Holding the inaugural HIV R4P conference in Africa will help to bring together scientists working across the discovery end of prevention research with those working on the ground who understand the practical challenges of carrying out prevention trials and engaging communities and stakeholders.

Advances in prevention

There have been some really promising developments in the area of PrEP, following the licensure by the US Food and Drug Administration of the HIV drug Truvada for use as a once-a-day prevention option for HIV-uninfected men and women. It’s clear that adherence to daily PrEP dosing is likely to be difficult for many people, especially for young people, who are often those most in need of new HIV prevention options. Researchers are looking at a range of new options that may be less dependent on strict adherence to a daily pill and therefore may be easier and more desirable for people to use.

Many groups are investigating intermittent use of PrEP that might reduce the compliance burden. Two groups in the US (the Aaron Diamond AIDS Research Center and the US Centers for Disease Control and Prevention) have also been evaluating long-acting, injectable antiretrovirals. These groups report that injection of long-acting HIV drugs can completely prevent infection in monkeys (see CROI: Progress on Prevention and CureIAVI Report, Vol. 18, Issue 1, 2014). This is significant because, if it works in humans, it might be possible to get a shot every three months to protect against HIV. It would also be useful if it could be administered along with injectable forms of long-acting contraception to prevent pregnancy. This may be more acceptable in resource-limited settings, specifically sub-Saharan Africa, where the trajectory for daily oral PrEP implementation is much less clear.

It’s also possible that the same technology could be used to treat those already infected with the virus. Drug resistance happens mostly when patients miss taking their drugs. Long-acting, injectable antiretrovirals will get around this problem as patients won’t need to remember to take tablets everyday, or be left without drugs should there be a disruption to access. This might be very beneficial in hard to reach communities, highly mobile groups, or those in areas of instability where maintaining a supply of oral drugs might be problematic.

Long-acting injectable antiretrovirals may also have a role to play in implementation of treatment as prevention (TasP), particularly where targeted toward the most at-risk populations. This will raise other questions for prevention researchers. As TasP approaches drive down the incidence of HIV, this in turn will increase the intrinsic research value of higher-incidence cohorts, raising ethical issues over how and when to introduce different biomedical interventions as they become available. It’s likely we will see more promising developments in this area at the R4P meeting and active discussion over changing and appropriate standards of care.

Microbicide development, too, is at a critical stage with pivotal trials currently ongoing. Should the FACTS 001 Phase III efficacy trial confirm earlier observations of CAPRISA 004, which first established the protective efficacy of a tenofovir gel-based microbicide, we may see the first licensed microbicide become widely available to at-risk populations. This has important implications, as this vaginal microbicide may become the baseline intervention for future AIDS vaccine trials if it gains licensure. Its licensure will also fuel efforts to accelerate the development and clinical assessment of rectal microbicides.

Two other microbicide trials are currently assessing the efficacy of the drug Dapivirine administered via a vaginal ring (the Microbicide Trials Network ASPIRE trial and the International Partnership for Microbicides Ring Study). It’s hoped that the ring will ease the burden of compliance, releasing the antiretroviral over a month, and therefore avoid the need to plan for dosing around sex. It’s too early to anticipate data from these efficacy trials at the R4P meeting. However, there is an explosion in developing novel delivery strategies not only for microbicides, but also for co-delivery with contraceptive options and other multi-purpose technologies designed to be active not only in preventing pregnancy and protecting against HIV infection, but also protecting against other sexually transmitted infections.

Meanwhile, vaccine development has been energized by the increasing number of broadly neutralizing antibodies (bNAbs) isolated from a small number of HIV-infected subjects.  The field now has a very clear picture of the evolutionary pathways leading to the induction of bNAbs in infected subjects, matched by rapid advances in structural insight into bNAb docking strategies and the envelope architectures underlying these surfaces. It’s anticipated that these discoveries will drive the development of immunogens and strategies needed to induce bNAb responses in those at risk of infection. Recent understanding that this may be critically dependent on effective engagement of the human germline encoded B-cell receptors are driving efforts to screen immunogens in human experimental medicine trials. These trials focus on screening immunogens in small numbers of volunteers with an emphasis on immunogen discovery rather than traditional product development.

Alongside this fast paced effort to improve immunogen design are the international efforts to build on the potential promise of the RV144 vaccine trial conducted in Thailand—the first AIDS vaccine trial to show any protective effective effect. This involves plans to test the same strategy in a sub-Saharan setting. This required changing the component immunogens of the vaccine to those relevant to a clade C setting, reflective of circulating strains in sub-Saharan Africa. Early immunogenicity data for these new constructs is eagerly awaited and will likely be featured at the R4P meeting.

Bringing it all together

Given these advances across the different prevention fields, and the many crosscutting issues in prevention research that need to be addressed, a combined biomedical HIV prevention conference makes sense.

All prevention strategies are impacted by the mechanisms of HIV transmission—the nature of the virus transmitted, the virology behind that transmission, and the factors influencing susceptibility to infection. One challenge is to understand exactly where and when the first target cells become infected. In terms of antiretroviral-based prevention, the answer to this question determines where the drugs have to be and at what concentration. This is also relevant to vaccine development, in terms of ensuring that protective antibodies or effector cells reach the same sites at sufficient levels to provide immunity that prevents infection.

Another key crosscutting area concerns animal models of infection. Having animal models that can represent transmission to humans as closely as possible will be vital to all biomedical prevention strategies and their pre-clinical modeling.

Yet another issue that cuts across disciplines is the increased use of adaptive trial design that takes account of what we hope will be continuing decreases in HIV incidence as we implement a growing array of different biomedical prevention strategies. Having all of these issues covered by a single conference will ensure the very best science in this area is shared across prevention fields.

As HIV prevention research progresses, the advantages of collaborating—and the disadvantages of working in silos—increase. Ultimately, all investigators want to have the greatest possible impact on reducing HIV transmission. Understanding the overlapping issues that impact prevention research and implementation are essential to getting the best out of prevention.

As different approaches mature along different timescales, they will start to coalesce in various ways. It is clear that we need to understand how all of these prevention options will interact in the field, and potentially within individuals. Indeed, it is highly likely that many prevention trials will be conducted in the context of an increasing background of licensed biomedical options. This is already the case with respect to PrEP. And it is highly likely that both the tenofovir gel and the two Dapivirine ring studies will be completed before the start of trials to evaluate a vaccine regimen similar to that tested in RV144 in sites across sub-Saharan Africa. Should either or both of these microbicide approaches be licensed, they may become the default background to all further vaccine trials. Therefore, understanding the interaction of these different technologies could be critical. There is a range of potential synergies between different prevention approaches and studying them together could help us understand the potential benefits of combining different strategies that on their own might be partially effective in reducing HIV acquisition.

Another potential benefit of a combined prevention meeting is the impact on advocacy. HIV R4P will provide a focus for maintaining progress and funding for HIV prevention as scientific progress increases and competition for resources becomes greater.

To make the most of these emerging approaches and their potential combinations there is a need to accelerate the testing of these different concepts in randomized clinical trials. Ideally, this will involve adaptive trial designs. We have to be sure that any approach is safe, effective, affordable, accessible, and wanted by those most at risk of infection. There is no point in developing something that nobody can afford or will want to use. This can only be accomplished by involving broad groups of individuals from the development sector and affected communities, and these partnerships will be a focus of the HIV R4P conference.

The theme of the conference, Shaping the Science of Prevention, seems particularly timely. Through scientific investigation we can develop a growing toolbox of new biomedical prevention options and understand how to use those to bring down incidence most effectively. To me, shaping the science of prevention means learning how to get the best out of different prevention approaches. The sooner we can do that and the smarter we are at employing those different approaches, the more effective we can be at protecting at-risk individuals. It’s hard to argue against that.

Robin Shattock is one of the co-chairs of the HIV R4P conference and is Professor of Mucosal Infection and Immunity at the Department of Medicine, Imperial College London.