What do we know about oral pre-exposure prophylaxis in cisgender women?

Pivotal studies supported by NIAID demonstrated that oral pre-exposure prophylaxis (PrEP) reduces an individual’s likelihood of acquiring HIV through sex by up to 99% when taken as prescribed. Since the release of those findings, 69 countries have approved HIV PrEP products, and an estimated 5.6 million people have initiated PrEP worldwide.

In addition to demonstrating oral PrEP’s high efficacy, research has revealed important differences in individual and population-group preferences in oral PrEP use, particularly that cisgender women participating in studies often did not take oral PrEP as prescribed—and the intervention’s effectiveness declined when doses were taken less frequently. The reasons cited for inconsistent use by the cisgender women who participated in those studies were numerous and suggest that while oral PrEP is safe and highly effective, consistently taking a daily pill for HIV prevention may not be acceptable or feasible for all lifestyles. 

In contrast to the experience of cisgender women, studies of oral PrEP in gay, bisexual and other men who have sex with men (hereafter referred to as men who have sex with men), as well as transgender women, showed high acceptability and efficacy, even when PrEP use was high but imperfect—between 4 and 6 doses per week.

Clinical guidelines currently suggest men who have sex with men can experience oral PrEP’s benefits even if they miss doses occasionally; conversely, effectiveness of oral PrEP among cisgender women in studies led to guidelines suggesting that they must consistently take PrEP daily, based on the available estimates of PrEP’s effectiveness in that population. These recommendations were also based on observed differences in the way oral PrEP drugs accumulate in cervicovaginal versus rectal tissues—drug concentrations in the cervix and vagina tended to be lower than in the rectum with similar dosing. Data remain inconclusive on the minimum necessary tissue drug levels for effective oral PrEP in cisgender women and on the relationship between dosing and efficacy. 

What are we learning now?

A new Gilead-supported analysis of combined data from post-marketing demonstration projects suggests that oral PrEP may work as well in cisgender women as it does in men who have sex with men. This analysis showed that oral PrEP maintained high efficacy in cisgender women who took between 4 and 6 doses per week. The findings were published today in the Journal of the American Medical Association.

In their research, an international multidisciplinary team of scientists led by Jeanne Marrazzo, MD, MPH, in her previous role at the University of Alabama at Birmingham, pooled data from 11 studies conducted after oral PrEP was approved by the Food and Drug Administration, 5 of which were funded by NIH, to characterize the relationship between oral PrEP use and its efficacy among cisgender women.

The authors reviewed data from 6,296 cisgender women in Botswana, India, Kenya, South Africa, Uganda and the United States. Measures of pill taking were available for 2,955 of 6,296 total study participants. Using a mathematical modeling approach used in previous PrEP use studies, the authors grouped data by the estimated frequency of participants’ oral PrEP use: consistently daily (7 doses per week), consistently high (4-6 doses per week), high, but declining (from 4-6 to 2-3 doses per week), and consistently low (less than 2 doses per week) and noted how many people acquired HIV in each group. 

Among their findings, the authors found that none of the 498 cisgender women in the consistently daily (7 doses per week) group acquired HIV. Further, they found that of the 658 cisgender women in the consistently high (4-6 doses per week) group, only one acquired HIV, which translated to an incidence rate similar to that observed in men who have sex with men who took oral PrEP with the same frequency in prior studies. The team concluded that cisgender women with consistently daily (7 doses per week) or consistently high (4–6 doses per week) oral PrEP use experienced very low HIV incidence.

“Evidence gaps have led to cisgender women being counseled to follow oral PrEP dosing with complete rigidity, which can undermine their motivation to use this highly effective tool,” said Dr. Marrazzo, now NIAID Director. “By combining data from several moderately sized studies, we have revealed a trend in prevention-effective use that suggests brief dosing interruptions should not stop cisgender women from experiencing the potentially life-changing benefits of oral PrEP.”

What’s next?

More data are needed to fully understand the mechanisms by which oral PrEP prevents HIV in cisgender women, including the role that cervicovaginal and rectal tissue concentrations have in its efficacy. Inclusion of cisgender women in HIV prevention research across their lifespan and collection of these data helps regulators, clinicians and cisgender women make informed decisions regarding any potential dosing interruptions when using oral PrEP. More data are also needed on the safety and efficacy of newer oral PrEP formulations in cisgender women.

In addition to oral PrEP, NIAID supports the development of long-acting PrEP formulations. Large studies found injectable PrEP administered every two months was more effective than daily oral PrEP at preventing HIV acquisition in cisgender women, cisgender men who have sex with men and transgender women. That formulation is being rolled out, and a twice-yearly injectable formulation is being studied for safety, efficacy, and acceptability. In addition, a vaginal ring containing dapivirine is approved for HIV prevention in Europe and several countries in sub-Saharan Africa.

Reference: J Marrazzo, et al., “HIV Pre-Exposure Prophylaxis with Emtricitabine and Tenofovir Disoproxil Fumarate Among Cisgender Women.” Journal of the American Medical Association DOI: 10.1001/jama.2024.0464 (2024)

This blog post was published by the National Institute of Allergy and Infectious Diseases on March 1, 2024.