Each year on TheBodyPro, we review the new research and critical events of the past 12 months that have had—or will have—the greatest impact on the way we provide HIV care and services in the U.S. This article is part of a series examining the most noteworthy clinical developments of 2022.
Objectively, Pre-Exposure Prophylaxis (PrEP) for HIV has been both a success and a failure. The advent of a medication that is highly effective at preventing infection following an exposure with HIV stands as a remarkable milestone in the history of this pandemic. However, the promise of tenofovir PrEP has not been matched by its real-world use. Uptake by those who can most benefit from PrEP including adolescent girls and young women in much of the world, and MSM of color here in the US, has been suboptimal. Persistence among those who do start oral PrEP is fairly abysmal.
Reasons for the limitations of oral PrEP are myriad and span the individual, interpersonal, community, and societal levels used to consider such challenges. Among these many factors is the need for PrEP to be taken in pill form, either daily or before and after sex. There are two types of people in the world: those who take pills well and those who don’t. People prescribed PrEP sort themselves into these camps pretty quickly, with a minority remaining on oral PrEP more than a few months. Certainly, there are other reasons to abandon oral PrEP besides aversion to taking pills, but alternatives to oral formulations of PrEP can provide options that are more attractive and even help address issues like stigma and privacy. The oft-mentioned parallels to the variety of contraceptive options (at least available to women) are instructive.
Cabotegravir (CAB) in combination with rilpivirine (RPV) is intramuscularly (IM) injected every one to two month to treat HIV infection. In a series of studies, the US federally funded HIV Prevention Trials Network (HPTN) has helped to develop IM CAB administered every 2 months as PrEP. The culmination of this work are HPTN 083 and HPTN 084, similarly designed trials that compared the safety and efficacy to prevent HIV infection of IM CAB and daily oral TDF/FTC.
The HPTN 083 results became available in 2020 and showed IM CAB to be superior to oral TDF/FTC in preventing HIV infection in MSM and TGW. The HPTN 084 trial enrolled cis-gender woman and its results were published this past year. The study was conducted November 2017 to November 2020 in seven African countries where HIV burden is high: Botswana, Eswatini, Kenya, Malawi, South Africa, Uganda, and Zimbabwe. Participants were HIV-uninfected cis-women, 18 to 45 years of age, reporting at least two episodes of vaginal sex during the prior 30 days, and who were assessed as being at risk for HIV acquisition based on a scale developed during earlier HIV prevention trials that included age, marriage/cohabitation, partner financial support, partner having other partners, alcohol use, and detection of STI. Pregnancy and breastfeeding were exclusions to enrollment.
Participants (N=3,224) were randomized 1:1 to IM CAB every 2 months or oral TDF/FTC daily or matching placebo for each. The enrolled population was exactly who you would want in a PrEP trial. They were young (median age was 25 years), more than half had two or more sexual partners during the month prior to enrollment, and 40% reported transactional sex.
IM injections were administered after a 5-week oral lead-in phase. Therefore, for the first weeks of the study half were taking oral CAB plus placebo and half oral TDF/FTC plus placebo. Once injections began, half received IM CAB plus took a placebo pill and half took a placebo shot along with an active TDF/FTC pill.
With almost 3,900 person-years of follow-up, there were 40 HIV infections detected: 4 in the IM CAB arm and 36 in the TDF/FTC arm. This translates to an 88% reduction in HIV incidence. But this understates the efficacy of IM CAB in this trial. Of the 4 cases of HIV infection in the CAB arm, 2 were in women who had not yet received IM and reported not taking CAB recently, and, importantly, a third was found on retrospective testing to have been HIV-infected at study entry. The last of the HIV infections in the CAB arm had a delay in her injection visit and was found with very low plasma levels of CAB. In the TDF/FTC arm, suboptimal levels of tenofovir diphosphate were found in all – pointing to poor adherence. A post hoc recalculation of the numbers finds more like a 91% reduction in HIV infection with CAB compared to TDF/FTC. Given these differences, the data and safety monitoring board stopped enrollment to the study in November 2020 and recommended unblinding to sites and participants.
None of the HIV infections in the CAB arm had drug resistance detected and only one of the TDF/FTC participants had evidence of emergent drug resistance, an M184V mutation conferring resistance to FTC. Random testing of a large subset of participants found overall low levels of adherence to the oral study product but very high rates of on time injections.
As expected, injection site reactions were more common among those receiving active CAB IM but none quit the drug for this reason. Overall, adverse events other than injection site reactions were similar in both arms.
At the International AIDS Society (IAS) conference, outcome data from the period after the unblinding were presented. After November 2020, participants maintained their initial treatment assignment but open label as plans for making IM CAB were formulated. At 12 months after unblinding, the cumulative number of HIV infections was 6 for CAB and 56 for TDF/FTC, which maintained the original 90% reduction in infections. As seen in the blinded phase, the HIV infections in the CAB arm were among women who had not received CAB completely. There were no breakthrough infections among any of the women who took CAB as directed.
The Bottom Line: The HPTN 083 and 084 trials clearly demonstrate the superiority of IM CAB over standard PrEP with oral TDF/FTC. There is no evidence though that molecule for molecule CAB is better than TDF/FTC. Rather, there was a stark difference between the arms in how many people got these molecules into their bodies. PrEP injected every two months, at least in the context of a clinical trial and among participants willing to take shots, was just better accepted and adhered to than daily oral PrEP. Testing for active drug levels in dried blood spots found only 18% of the TDF/FTC participants had levels consistent with daily dosing.
Unlike HPTN 083, in this study of cis-women, no drug resistant virus was detected in the few who became HIV-infected in the CAB arm. The number of infections was greater in HPTN 083 and there may have been more exposure, albeit suboptimal, to CAB among the participants in that study who became infected.
The promise of IM CAB is tempered by the lack of its availability, even among the participants who volunteered to be in these trials. Two years after the HPTN 084 was unblinded due to a profound advantage of CAB over TDF/FTC, the injectable drug is not available to women in these seven or any country in Africa. Even in the US use of IM CAB as PrEP is paltry given the cost and logistics that challenge a fragmented health care system. When? That is the question to keep asking each day that IM CAB is not available to people across the world who these trials tell us can benefit.