As 2020 draws to a close, we asked David Alain Wohl, M.D., a professor of medicine in the Division of Infectious Diseases at the University of North Carolina and a highly respected HIV clinician-researcher, to take stock of the year's most momentous research developments and other critical events. In this exclusive series of articles, Wohl calls attention to 10 such developments that have tremendous short-term implications for our day-to-day efforts to improve HIV prevention, treatment, patient care, and policy in the U.S., and analyzes each development with his trademark wit and clinical savvy.
Pre-exposure prophylaxis (PrEP) for HIV is a pill. It has always been a pill. But it will not always be a pill, thanks to two major trials evaluating cabotegravir (CAB), an integrase inhibitor formulated for intramuscular (IM) injection, as PrEP.
HIV Prevention Trial Network (HPTN) studies 083 and 084 both demonstrated that CAB IM administered every eight weeks was superior to daily oral tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC). HPTN 083 yielded these findings in men who have sex with men (MSM) and transgender women (TGW), while HPTN 084 focused on cisgender women.
The 083 study results were first announced over the summer, when any health-related news not about COVID-19—even as major as this—had little chance of being much noticed. The double-blind, placebo-controlled trial enrolled 4,750 MSM and TGW across 43 sites in Argentina, Brazil, Peru, South Africa, Thailand, the U.S., and Vietnam. Participants were randomized to either CAB IM every eight weeks (following a 5-week lead-in with oral CAB) or daily oral TDF/FTC.
The study established recruitment thresholds for at least 50% of participants to be under age 30 and at least 10% to be TGW. In addition, for the U.S. sites, at least 50% of participants had to be Black. These goals were achieved.
After reviewing interim data, an independent data and safety monitoring board (DSMB) recommended termination of the blinded study because pre-specified stopping criteria had been met. Specifically, there were 52 HIV infections among trial participants: 39 in the TDF/FTC arm and 13 in the CAB arm—a 66% reduction in risk afforded by CAB IM. Participants receiving TDF/FTC will be offered IM CAB, when available.
The role of adherence in the incident infections detected during this trial is not completely clear. Most of those receiving TDF/FTC who acquired HIV were dispensed the drug on time. But drug levels from a subset of the participants assigned TDF/FTC found creeping levels of suboptimal adherence over time; at week 81, two-thirds of participants had concentrations of tenofovir-di-phosphate (TFV-DP) in dried blood spot samples that were predicted to be adequate. Meanwhile, among the 13 CAB recipients who became HIV infected, all but five had a lapse in their injection schedule.
Injection site reactions were common but rarely led to treatment discontinuation—a finding that mirrors the experience in HIV treatment studies involving IM CAB and rilpivirine.
HPTN 084 had a similar design: It enrolled 3,223 cis-gender women in Botswana, eSwatini (formerly Swaziland), Kenya, Malawi, South Africa, Uganda, and Zimbabwe. To be eligible, participants had to be at risk for acquisition of HIV, as assessed by a score of five or higher on an HIV risk tool developed using data from the VOICE trial of PrEP in women. The variables weighed by the tool include age, whether a person is married or living with a partner, the partner’s financial or material support, whether the partner has other partners, alcohol use, sexually transmitted infection status, and herpes simplex virus 2 serostatus.
As in HPTN 083, a DSMB halted the blinded 084 study after an interim review. At that time, 38 incident HIV infections had occurred among the participating women, but only four were in the IM CAB arm (and two of the four had stopped receiving the injections). As the press release announcing this news included only the topline results, no additional data have yet been made available.
The Bottom Line on Injectable PrEP
While the superiority of IM CAB to oral TDF/FTC is important and impressive, it is also worth noting that in both trials the total number of incident infections was incredibly low. Combined, there were 90 infections among almost 8,000 participants in these studies. This speaks to the activity of both PrEP strategies, as well as a drop in HIV incidence in general as more people with the virus are treated.
The low incidence also makes studies of new PrEP agents and strategies challenging, as it (fortunately!) becomes harder to find people who are likely to become infected with HIV. (In one potential solution to this problem, my UNC colleague, Adaora Adimora, M.D., M.P.H., and collaborators have proposed an innovative approach for studying PrEP in low-incident settings by applying data from studies conducted in high-incidence settings to generate estimates of incidence that can approximate a control condition).
That said, a lot of people still do get infected with HIV, including roughly 40,000 annually in the U.S. An every-two-month injectable PrEP option is a major—and overdue—advance for HIV prevention that offers an alternative to tablets.
Clearly, a shot in the butt is not for everyone—and it does not have to be. What IM CAB offers is a choice, the first of what will likely be many, so that people can select which of multiple options is the best fit for them.
There is more to the HPTN 083 and 084 stories, and no doubt we will get details in the coming months. Future analyses focusing on adherence will help us understand how much of the results was driven by suboptimal adherence to oral PrEP. Further, we are left hanging until drug resistance data from the IM CAB group are shared—especially given the implications of integrase inhibitor resistance to subsequent HIV treatment options.
We have been waiting a long while for IM CAB along with rilpivirine to be approved and available for HIV therapy. With these fantastic results, hopefully, IM CAB for PrEP will be here sooner, not later, and cheaper not dearer—so even more people can remain protected from HIV infection.