HIV infections continue to occur at a rate of >2 million globally each year with women accounting for a little over 50% of infections. Although the overall incidence of HIV infections in the United States has decreased in recent years, certain populations remain particularly vulnerable, including racial/ethnic minorities, adolescents/young adults, and people in the southern United States. Antiretroviral therapy has been highly successful in reducing AIDS outcomes and death in HIV-infected patients worldwide; however, transmission of HIV remains a major global health problem.
The approval of oral TDF-FTC for HIV pre-exposure prophylaxis (PrEP) represents an approved intervention to help control this epidemic; however, the tolerability of this regime and the subsequent discontinuation of therapy pose a threat to the efficacy, and therefore, the main purpose of this management approach. Maraviroc (MVC), a CCR5 antagonist HIV entry inhibitor, has been approved for treatment of HIV infection treatment-experienced participants and has many attributes that make it a viable candidate for HIV PrEP in women. Regimens containing MVC have been studied in terms of safety and tolerability in HIV uninfected men and transgender women who undertake risky sexual activity or with unknown sero-status men. The results of these studies showed the regimen to be largely well-tolerated with 84% of the participants completing the 48-week study. Notably, the reasons for discontinuation were similar across the regimens.
However, the participants in these studies were male and transgender women. Indeed, most clinical trials of antiretroviral agents tend to have limited female enrollment, and therefore, results from these predominantly male studies are extrapolated to the female population. Furthermore, many of these studies do not report gender subgroup analyses, and those that do are underpowered to detect differences between men and women, limiting the ability to assess if the results are equally applicable to both sexes. Women may have differential responses to and adverse events from HIV therapy, but to what extent remains unknown.
To this end, Gulick et al, from Weill Cornell Medical College, New York City compared 4 MVC-containing regimens as HIV PrEP in a US population of women. This study was not powered to determine efficacy but was a double-blind randomized controlled study conducted over 48-weeks. The 4 interventions were MVC, MVC plus emtricitabine (FTC), MVC plus tenofovir-disproxil fumarate (TDF), and a control of TDF-FTC.
When speaking on the study to Contagion®, lead author Roy M. Gulick, MD, Chief, Division of Infectious Diseases at Weill Cornell Medicine said, “HIV PrEP is a strategy where at-risk HIV negative people take medications to prevent them from acquiring HIV infection. Currently, there’s only 1 approved drug combination [for PrEP] in women—our study explored other unique drug combinations for HIV PrEP. It would be useful for people to have a range of options for HIV PrEP.”
Approximately 50 subjects were assigned to each intention to treat group. A total of 85% of the subjects completed follow-up, a similar result to the previous male tolerability study. The race/ethnicity of the enrolled women was about two-thirds black with the remainder split between white and Latino subjects. The median age was around 40 years.
Of the 11% who withdrew from the study early and an additional 4% lost to follow-up, they reported an inability to adhere to the visit schedule and thus declined further participation. Of the 7 subjects who discontinued because of adverse events, 4 were in the MVC-TDF cohort, while those in the MVC alone cohort reported no notable adverse events. The time to discontinuation was shortest in the MVC-TDF group at 51 days, and those in MVC alone reported a median time to discontinuation of 89 days this was not statistically different. Grade 3 or 4 adverse events were reported in 11% of the MVC alone group; 29% of the MVC-FTC group, 18% of the MVC-TDF group, and 17% of the TDF-TFTC group. However, many of these adverse events were considered not to be study drug-related. The most frequent adverse events were hypophosphatemia, with 13% overall reporting this event and the MVC-FTC group reporting the highest incidence (18%). Other events included diarrhea, nausea, vomiting, unintended weight loss, and elevated creatinine level, all at 4% or less.
This Phase 2 study showed that MVC-containing anti-retroviral regimens were generally safe and well-tolerated in a female population, compared with a TDF-FTC regimen. These results are similar to those reported earlier by the same group of cohorts in men and provide evidence that women tolerate MVC-containing PrEP regimens for the management of HIV disease and that further studies are warranted.
Dr. Tillotson is an infectious disease/medical microbiologist with over 30 years of pharmaceutical industry experience in clinical development and medical affairs. He has worked for multinational companies and small biopharma on a range of antibiotics including ciprofloxacin, fidaxomicin, and most recently, solithromycin. Dr. Tillotson has also authored over 150 peer-reviewed publications.