Apretude (long-acting cabotegravir) injections administered every two months are a safe and effective pre-exposure prophylaxis (PrEP) option for transgender women, according to an analysis from the HPTN 083 trial published in The Lancet HIV. However, the study authors concluded, HIV prevention can’t be addressed separately from trans women’s social and structural vulnerabilities.
Transgender women are at much greater risk for HIV compared with the population at large. Transgender people, who are thought to make up less than 1% of the U.S. population, accounted for 2% of new HIV diagnoses in 2019, according to the Centers for Disease Control and Prevention.
Many older studies incorrectly classified transgender women as men who have sex with men. More recent research has done a better job of correctly classifying trans people by using a two-step method that asks their assigned sex at birth as well as their current gender identity. The clinical trials that led to the approval of oral and injectable PrEP included trans women, but outcomes for this group have been hard to tease out from those of the much larger number of cisgender gay and bisexual men in the studies.
The Food and Drug Administration approved Apretude in December 2021 based on the results of two pivotal trials. HPTN 083 (NCT02720094) enrolled more than 4,500 cisgender men and transgender women who have sex with men in the United States, Latin America, Asia and Africa, while HPTN 084 (NCT03164564) enrolled more than 3,000 mostly young cisgender women in sub-Saharan Africa.
In both trials, the participants were randomly assigned to receive Apretude injections every two months or once-daily tenofovir disoproxil fumarate/emtricitabine, or TDF/FTC (Truvada or generic equivalents). The randomized portion of both studies was halted ahead of schedule after interim analyses found that Apretude injections were more effective than daily pills.
Overall, HPTN 083 showed that Apretude was at least 66% more effective for preventing HIV acquisition than TDF/FTC. This is a remarkable finding, given that daily oral PrEP itself reduces the risk of HIV by about 99% for gay and bisexual men who use it consistently.
Beatriz Grinsztejn, MD, of Fundação Oswaldo Cruz, in Rio de Janeiro, and colleagues looked in more detail at transgender women in the trial. Out of the 4,566 total participants, 570 (12.5%) were trans women, meeting the study’s minimum 10% recruitment target. They were primarily from Asia and Latin America. More than 80% were under age 30, and only about 14% said they were married or had a primary partner.
Under the umbrella of transgender women, 14% self-identified as queer, gender variant, gender nonconforming or other gender identities. More than half (58%) reported using gender-affirming hormone therapy. Of note, 32 self-identified cisgender men who have sex with men reported using gender-affirming hormones, “raising important considerations for how to adequately capture the range of gender identities in HIV research, consider the profile of gender-affirming hormone therapy users and be responsive to the evolution of gender identity and preferred pronouns and labels over time,” the study authors wrote.
Despite their decision to join an HIV prevention trial, more than a quarter of the participating trans women (28%) did not agree that they were at risk for HIV. But their incidence of sexually transmitted infections said otherwise: 20.6% were diagnosed with chlamydia, 16.3% with syphilis and 11.7% with rectal gonorrhea.
As was true for the full study population, Apretude appeared to offer greater HIV protection than daily PrEP pills for transgender women, though numbers weren’t high enough to reach statistical significance. There were two HIV seroconversions in the Apretude group and seven in the TDF/FTC group during the randomized portion of the trial, or 0.54 versus 1.80 cases per 100 person-years—a 66% risk reduction. The corresponding HIV incidence rates for the full study population were 0.41 and 1.22 per 100 person-years. None of the trans women who acquired HIV in the TDF/FTC group had protective drug concentrations, suggesting suboptimal adherence. None of the women who received Apretude injections on time acquired HIV. One did so during the oral lead-in phase, and the other tested positive 849 days after her last injection.
Both forms of PrEP were generally well tolerated. The frequency of adverse events was similar in the two groups and consistent with that of gay and bisexual men in the study. Injection site reactions were common in the Apretude group, but only one woman discontinued Apretude for this reason. Apretude recipients gained a median of 2.6 pounds per year versus 1.5 pounds per year in the daily oral PrEP group, possibly reflecting the fact that TDF suppresses weight gain.
A pharmacokinetic analysis of 53 trans women showed that cabotegravir concentrations did not differ significantly based on use of gender-affirming hormones. The researchers were unable to assess the impact of cabotegravir on hormone levels, and they said this “remains an important research gap.”
Beyond HIV incidence, the study authors reported some disconcerting findings about the trans women in the trial. Intimate partner violence was common, with 30% reporting physical abuse and 47% reporting emotional abuse. More than half (57%) said they had a history of childhood sexual abuse. Recreational drug and alcohol use were common, and a quarter screened positive for symptoms of depression. Many were unemployed and had a low income.
“Transgender women were well represented in HPTN 083 and should continue to be prioritized in HIV prevention studies,” the researchers concluded. “Our results suggest that injectable cabotegravir is a safe and effective pre-exposure prophylaxis option for transgender women.”
“Given the challenges faced by transgender women to adhere to oral [TDF/FTC] PrEP, an injection every two months is convenient and discreet and might address the barriers to daily oral pill-taking, such as competing life priorities, HIV stigma, discrimination and violence,” they wrote. “Of note, 83% of transgender women participants were younger than 30 years, making the preserved advantage of injectable cabotegravir among a young and at-risk population of transgender women a remarkable advance in global HIV prevention.”
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