While studies exploring the effectiveness of antiretroviral (ARV) therapy for HIV prevention purposes have generally yielded encouraging results, a group of researchers at the University of North Carolina at Chapel Hill suggest that the way forward is not entirely clear and that additional research is needed, particularly in understanding the combined benefits of biomedical and behavioral interventions in specific at-risk communities.  

“Recent research developments in [pre-exposure prophylaxis, or PrEP] and [treatment of people living with HIV to curtail HIV transmission] provide a unique opportunity to highlight areas of advancement that have galvanized changes in HIV treatment and prevention, and to highlight topic areas that remain undecided and controversial,” write Myron Cohen, MD, and his colleagues in an editorial published ahead of print by the journal AIDS.

The paper reviews much of the scientific research that has contributed to our current understanding of ARV treatment as prevention, including pharmacologic and observational studies, ecological evaluations and various modeling and empirical data. And despite the completion of several sound clinical trials—also summarized by Cohen and his colleagues and reviewed here—gaps in knowledge remain.

The Limits of HPTN 052

Building on the results of cohort and mathematical modeling studies, the HIV Prevention Trials Network began a randomized clinical trial, called study 052 (HPTN 052), to confirm a prevention effect from ARV therapy. While the study is ongoing, its Data Safety and Monitoring Board recommended nearly a year ago that the interim results be made publicly available.

As previously reviewed by AIDSmeds, the trial demonstrated a 96 percent reduction in HIV transmission among monogomous heterosexual HIV-serodiscordant couples in which the HIV-positive partner was started on ARV therapy, compared with couples in which the positive partner had not started HIV treatment.

A key question from HPTN 052 is whether the results can be generalized to other contexts, Cohen and his colleagues explain. Examples include heterosexual couples with CD4 counts lower and higher than those studied in HPTN 052; high-risk heterosexual individuals, notably sex workers and their clients; men who have sex with men (MSM); and injection drug users (IDUs).

With regards to MSM and IDUs, the authors note, a World Health Organization expert committee concluded that there is no reason to presume that treated, HIV-positive MSM will not be rendered less contagious as a result of ARV therapy. “However,” Cohen and his colleagues write, “the biology of HIV transmission is sufficiently different in IDU and MSM as compared to heterosexual transmission, warranting further consideration and study.

“For example, the number of HIV variants acquired and the efficiency of transmission are higher in MSM and IDU than in heterosexual transmission,” they note in recalling one study. “Additionally, whether [ARV therapy] reduces infectivity through anal sex by the same order of magnitude as for vaginal sex remains uncertain. Although such an effect is widely assumed, this is a key missing piece of evidence.”

To address these lingering questions, at least two observational evaluations—the PARTNER study and the Opposites Attract study—are currently under way. Cohen and his fellow authors do not anticipate a randomized, placebo-controlled clinical trial to evaluate the efficacy of treatment as prevention among MSM or IDUs, given that such studies “may be unethical in light of the results of HPTN 052.”

They add: “Treatment as prevention, while exciting, cannot be guaranteed success at the population level. Can enough people be detected, linked to care, and properly treated to make a difference?” Cohen’s group notes that at least 50 community-based studies are in development to help answer this question. HPTN 065, for example, is being designed to determine whether people with HIV in New York City and Washington, DC, can be detected and efficiently linked to care.

Pre-Exposure Prophylaxis

Attempts to develop pre-exposure prophylaxis (PrEP) regimens for HIV have been challenging, and the results confusing. “To date, a limited number of agents have been used, selected primarily because they are well tolerated, and because they provide protection in a macaque model using either rectal or vaginal exposure to SIV,” the authors explain. “However, the relative safety of daily oral tenofovir for HIV-negative people has been questioned.”

Two trials—CAPRISA 004 and VOICE—have studied vaginal applications of 1 percent tenofovir gel, yielding different results. There have also been five studies of oral PrEP, includingiPrEx, TDF2, FEM-PrEP, VOICE and Partners PrEP, which have also yielded conflicting conclusions.

“These trials differ in many ways,” Cohen’s group writes. “However, clearly, poor adherence would limit success as reported for FEM PrEP and iPrEx. It is also possible that the drugs employed are not perfectly suited to PrEP, especially in women.”

Substantial differences in antiretroviral drug concentrations in anogenital tissues have been reported, which may help explain these discordant study findings, the authors suggest. For example, taking Truvada (tenofovir plus emtricitabine) orally resulted in concentrations of tenofovir that are 100-fold higher in rectal tissue compared with cervical or vaginal tissue. This, in part, may explain why Truvada had a modest effect in MSM enrolled in iPrEx, despite poor adherence, whereas efficacy has been lower in oral PrEP trials enrolling women.

Several ongoing studies--two by the HIV Prevention Trials Network (HPTN 067 and HPTN 069), one study sponsored by the French National Agency for AIDS Research (ANRS IPERGAY), as well as an extension of the iPrEx study (iPrEx OLE)—are addressing some of the limitations of the previous PrEP studies.

Alternative drugs and delivery systems more appropriate to PrEP are also being pursued and are reviewed in the paper by Cohen and his colleagues. Vaginal rings for women containing antiretrovirals would be similar in concept to vaginal rings currently used for contraception and hormone replacement therapy. An example is dapivirine (TMC120), currently in Phase III studies.

“These rings could maintain long-term, sustained antiretroviral release for local efficacy,” Cohen and his colleagues suggest. “Due to the long-term drug release, rings can be used in a coitally independent manner, and inserted monthly, which could have an adherence benefit over gels or pills.”

Also on the development horizon are long-acting injectable drugs that can be administered every 30 to 90 days. One such agent, a version of Tibotec’s rilpivirine modified using nanotechnology, is in early phase development for this purpose.

As for oral agents, Selzentry (maraviroc) is currently being evaluated in one PrEP study: HPTN 069 (NEXT-PREP). The 48-week trial is comparing three regimens for safety and tolerabitility: Selzentry plus Emtriva, Selzentry plus Viread and Viread plus Emtriva.

Other lingering issues to contend with, the authors point out, include drug resistance concerns, long-term safety, and the affects of ARV therapy as PrEP on sexual behavior.

Using the safety issue as an example, Cohen and his colleagues note that “tenofovir has been linked with renal injury and loss of bone mineral density (BMD) when used for HIV treatment. Individuals with pre-existing renal conditions have been excluded from PrEP studies. In the iPrEx study, a non-significant trend toward elevated creatinine levels”—a marker of kidney function—“was found among the intervention arm, and in a substudy, there was a small but significant (up to 1 percent) loss in BMD.”

The cost effectiveness of PrEP also needs to be addressed, including in circumstances where PrEP has thus far proven most effective in clinical trials: serodiscordant partners. According to various models referenced by the authors, cost effectiveness in this situation will depend on PrEP costing no more than 40 percent of standard ARV therapy, efficacy exceeding 70 percent, utilization in areas or the word where ARV therapy access hasn’t yet reached 65 percent, the actual prevalence of HIV in specific regions and the prevalence of HIV-discordant relationships in those regions.

“In general,” Myron and his colleagues point out, “these [mathematical modeling study] results do not support a [PrEP] focus on HIV discordant couples for public health purposes.”

Combination Approaches to the Fore

Cohen and his fellow authors conclude: “Implementation of [ARV therapy] as prevention faces substantial challenges, including logistic limitations, potential changes in risk-taking behaviors, and cost. Indeed, [ARV therapy] usage will need to be part of a combination strategy,” which will, they add, “need the continued efforts of behavioral interventions to increase condom use, reduce high-risk behaviors and address suboptimal ARV adherence and risk compensation.”

The authors reiterate that a combination prevention strategy has been embraced by many of the community-based clinical trials currently planned or under way to explore ARV therapy for prevention purposes. “It seems reasonable to expect that—after 30 years of work—the tools now available in the HIV prevention toolbox and those that will become available from ongoing research can be expected to control the spread of HIV.”