The finding:
This HIV Prevention Trials Network (HPTN 084) clinical trial compared long-acting injectable cabotegravir to daily oral tenofovir diphosphate plus emtricitabine (TDF-FTC) for prevention of HIV in HIV-uninfected women at risk for acquiring HIV through sexual transmission. Among 3224 participants over 3898 person-years, there were significantly fewer incident infections observed in the cabotegravir group vs the TDF-FTC group: 4 vs 36 participants, p<0.0001. Three of the participants in the cabotegravir group who seroconverted had cabotegravir concentrations significantly lower than required for adequate viral suppression. The fourth participant was found to have been infected with HIV at study entry. No major integrase strand transfer inhibitor resistance mutations were found in any of these participants. None of the 36 participants in the TDF-FTC group with incident infections had drug concentrations consistent with adequate adherence. Nucleoside reverse transcriptase and non-nucleoside reverse transcriptase inhibitor resistance mutations were detected in several of these participants. There were no deaths and only 6 serious adverse events overall, attributable to study product. The 2 serious adverse events in the cabotegravir group comprised one hospitalization for fetal distress and one respiratory tract infection. Compared to the TDF-FTC group, there were significantly more injection site reactions in the cabotegravir group, none of which resulted in discontinuation of study product. The incidence of pregnancy was similar in both groups and no congenital anomalies were observed. Incidence of chlamydia and gonorrhea also did not vary by group. Initial weight gain was greater in the cabotegravir group.     

Strength and weaknesses:
This phase 3 study’s strengths included its large number of subjects and location in sub-Saharan Africa where women, especially those ages 15-24 years, accounted for a large majority of new HIV infections. The study covered a wide geographic area across 7 countries with high HIV prevalence; there were multiple, established research sites within each country. The design was randomized, double-blind, and double-dummy, with an active control arm. HPTN methodology was used with standardized measures for HIV risk scores and adverse events, and established protocols for randomization and laboratory monitoring. Study findings may not apply to women living in other geographic regions, in areas with better resources, and in different ethno-cultural groups. While scientifically rigorous in design, findings may not capture real world conditions and thus not permit identification of important factors influencing the effectiveness of injectable HIV pre-exposure prophylaxis (PrEP) used in a community setting. Women aged younger than 18 years were not eligible for inclusion, thus findings may not apply to this group with unique considerations for care.       

Relevance:
These findings are the first to provide strong evidence that cabotegravir is a safe and effective biomedical method for preventing HIV in women. Previous HIV prevention trials in women in sub-Saharan Africa have been limited by barriers unique to women. HIV and HIV medications were associated with significant stigma. The use of HIV medications, by either oral or vaginal routes, placed women at risk for rejection by family and community, discrimination, judgment, and violence in intimate relationships. Oral and vaginal medication delivery routes also conferred a biological disadvantage for women, compared to male-to-male transmission. It takes longer to achieve antiretroviral concentrations necessary for HIV prevention in vaginal tissue. Vaginal concentrations are also generally lower compared to rectal tissue. Cabotegravir was thought to be a good candidate because it had been shown to prevent HIV transmission in non-human primates. Injectable PrEP may also be more acceptable to women in light of the widespread use and acceptance of injectable contraception. PrEP is a cornerstone in the global strategy to end the HIV pandemic. This study offers a new, safe PrEP agent that appears to be as effective in cis-gender women as it is in men and transgender women.