Injectable Long-Acting PrEP Is Safe, Highly Effective in Cisgender Women

Injectable long-acting cabotegravir (CAB LA) has been proven safe and highly effective in preventing HIV infection among cisgender women, according to interim results from a major study announced in late January. The findings complement previously established strong results for cabotegravir-based injectable pre-exposure prophylaxis (PrEP) in cisgender men who have sex with men (MSM) and transgender women who have sex men, adding to evidence that injectable PrEP could ultimately have greater real-world efficacy than daily oral PrEP in many populations, thanks to better adherence.

The new data come from HIV Prevention Trials Network (HPTN) Study 084, interim results of which were presented at the biennial HIV Research for Prevention (HIVR4P) conference, which took place virtually this year in late January and early February. “These results complement data from HPTN 083, and confirm cabotegravir as the first safe and effective injectable PrEP agent for cisgender women,” said Sinead Delany-Moretlwe, MBBCh, Ph.D., the protocol chair and director of research at the Wits Reproductive Health and HIV Institute within the University of the Witwatersrand in Johannesburg, who presented the study. “We hope that these results will lead to the expansion of HIV prevention options for at-risk cisgender women globally, and ultimately reductions or elimination of HIV acquisition.”

About HPTN 084: Injectable Long-Acting Cabotegravir PrEP in Women

HPTN 084 was a Phase 3, double-blind, safety and efficacy study comparing injectable CAB LA to daily oral emtricitabine/tenofovir disoproxil fumarate (FTC/TDF, Truvada) for PrEP among cisgender women at high risk for acquiring HIV infection. While HIVR4P hosted the first presentation of these data at a major medical meeting, the main findings were not a surprise, as topline results from this interim analysis had been announced in a press release in November 2020 on the recommendation of the independent data and safety monitoring board (DSMB).

At that time, a planned review of the data showed not only that a PrEP regimen of CAB LA once every eight weeks was safe, but also that it was superior to daily oral FTC/TDF among a study population of cisgender women in sub-Saharan Africa. The DSMB recommended that the study be unblinded and the results made public.

The presentation by Delany-Moretlwe at HIVR4P did, however, include some updated numbers and details not previously presented.

Study participants were divided into two groups: In the CAB LA arm, participants received a daily oral CAB loading dose along with an FTC/TDF placebo pill for the first five weeks; thereafter, participants received CAB LA injections every 8 weeks while continuing their daily FTC/TDF placebo. In the FTC/TDF arm, participants received daily FTC/TDF and oral CAB placebo for five weeks; thereafter, participants received intramuscular placebo injections every 8 weeks while continuing their daily TDF/FTC.

In the original study plan, participants in both arms were supposed to transition to open-label daily oral TDF/FTC for approximately one year after their last injection (be it active CAB LA or placebo). As noted, however, the open-label portion of the study was terminated when CAB LA crossed a pre-specified boundary demonstrating superior efficacy.

Overall, HPTN 084 enrolled 3,224 cisgender women at least 18 years old at 20 sites in Botswana, Eswatini, Kenya, Malawi, South Africa, Uganda, and Zimbabwe. The average age of study participants was 25; 57% were under 25. Of the women enrolled, 82% were not living with a partner at the time of enrollment. In the month before enrollment, 34% had a partner who was living with HIV or had an unknown HIV status; 54% had two or more sex partners; 41% reported transactional sex; and 6% had engaged in anal sex.

HPTN 084 Interim Findings: Adherence-Driven Superiority for CAB LA

A total of 40 HIV infections occurred during follow-up, with four infections in the CAB LA arm (incidence rate 0.2% per 100 person-years) and 36 infections in the FTC/TDF arm (incidence rate 1.86% per 100 person-years). The hazard ratio in the CAB LA versus the FTC/TDF arm was 0.11 (95% CI 0.01-0.31); women in the CAB LA group had an 89% lower risk of HIV infection compared to those in the FTC/TDF group.

The overall low incidence rate in each arm of the study showed that both regimens were highly effective at preventing HIV acquisition. The difference between the regimens, however, met the statistical criteria for superiority of CAB LA compared to FTC/TDF in the HPTN 084 study population. According to Delany-Moretlwe, this difference was “likely because of the adherence advantage conferred by 8-weekly injections.”

In a planned adherence subset, the investigators analyzed TDF concentrations in 375 participants within the FTC/TDF arm. Overall, 62% had detectable concentrations of TDF, and 46% had levels consistent with daily use (>40 ng/mL). However, while the proportion of those with detectable TDF concentrations began relatively high, they fell off over time, from 77% at week 4 to 53% by week 57, “reflecting the challenges of daily pill taking over a prolonged period of time,” Delany-Moretlwe observed.

By contrast, in the CAB LA group, injection coverage (i.e., the proportion of injections administered compared to the total number of expected injections, gauged at 6-month intervals) remained high, ranging from 94% at 6 months to 90% at 30 months, “highlighting the adherence advantage conferred by long-acting injections,” Delany-Moretlwe said.

Adverse Events in the HPTN 084 Interim Analysis

Both regimens were well tolerated, with the only significant difference in side effects between groups being the incidence of injection site reactions (ISRs). As might be expected, ISRs occurred at a higher rate with active CAB LA than with the placebo injections given to those in the FTC/TDF group. Most of these ISRs occurred after the first injection, and were associated with mild pain. There were no discontinuations due to ISR.

Careful attention was paid to the issue of weight gain, as integrase strand inhibitor (INSTI)-associated weight gain was of particular relevance to the study population, given that more than half the participants had a body mass index at baseline greater than 25 kg/m2 (thus classifying them as overweight). While there was a small but significant initial weight increase of about 0.4 kg among those on LA CAB, this was followed by steady weight gain of about 2 kg per year among participants in both study arms, such that overall weight gain did not differ significantly between study groups.

HPTN 084 Strengthens the Case for CAB LA as PrEP

The HPTN 084 results confirmed earlier findings of a closely related trial, HPTN 083, a phase 2b/3 double-blind study evaluating the safety and efficacy of CAB LA compared to FTC/TDF for PrEP among 4,570 men who have sex with men and transgender women who have sex with men at 43 sites in Argentina, Brazil, Peru, the United States, South Africa, Thailand, and Vietnam. HPTN 083 was launched in 2016; the study was unblinded and the results made public on the recommendation of the DSMB when interim study data reviewed in May 2020 showed that injectable CAB LA was superior to FTC/TDF.

HPTN 084 was sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and funded jointly by NIAID, the Bill & Melinda Gates Foundation, and ViiV Healthcare. (ViiV is the manufacturer of cabotegravir.) While ViiV has not yet been granted marketing approval for injectable CAB LA in the U.S., the FDA in November 2020 granted a breakthrough therapy designation for injectable CAB LA for PrEP. That designation facilitates expedited review for drugs that address serious or life-threatening medical conditions, and are supported by preliminary clinical evidence showing that the drug may offer substantial improvement over available therapies—that is, CAB LA gets special treatment by the FDA because it is better than FTC/TDF.

Other formulations of CAB have recently been approved by the FDA, including the oral tablet formulation Vocabria (indicated as part of a regimen for antiretroviral therapy, not PrEP), and as a component of Cabenuva, an injectable formulation of LA CAB along with the NNRTI rilpivirine (Edurant) as a complete regimen for antiretroviral therapy.