Daily oral PrEP regimen remains protective in cisgender women despite missed doses

Oral pre-exposure prophylaxis (PrEP) with emtricitabine plus tenofovir disoproxil fumarate (F/TDF) works well to prevent HIV in cisgender women even if daily doses are occasionally missed, according to a study.

Pooled data from 11 F/TDF PrEP postapproval studies conducted across six countries showed that the overall HIV incidence was very low at 0.72 per 100 person-years (95 percent CI, 0.51–1.01), which corresponded to 32 incident HIV cases among 6,296 women. [JAMA 2024;doi:10.1001/jama.2024.0464

In an analysis stratified by F/TDF adherence, none of the women with consistently daily adherence (7 doses/week) contracted HIV. Even among women who sometimes missed doses—ie, consistently high adherence (4–6 doses/week)—only one case of HIV infection was documented, yielding an incidence rate of 0.13 per 100 person-years (95 percent CI, 0.02–0.92).

The highest incidence of HIV infection was recorded among women with consistently low adherence (less than 2 doses/week; 1.27 per 100 person-years, 95 percent CI, 0.53–3.04), followed by those whose adherence was initially high but had since declined (from a mean of 4–6 doses/week then declining; 0.49 per 100 person-years, 95 percent CI, 0.22–1.08).

“This analysis of the effectiveness of F/TDF for PrEP in cisgender women in real-world settings supports that HIV prevention effectiveness is high with adherence to greater than 4 doses per week,” the investigators said.

A total of 6,296 women were included in the analysis, of which 46 percent were from Kenya, 28 percent were from South Africa, 21 percent were from India, 2.9 percent were from Uganda, 1.6 percent were from Botswana, and 0.8 percent were from the US. The mean age at PrEP initiation across all studies was 25 years, and most of the participants (61 percent) were younger than 25 years.

Take a pill every day

Current PrEP guidelines for women seem stricter than those for men who have sex with men (MSM). In its 2021 guideline update, the US Centers for Disease Control and Prevention (CDC) urges healthcare providers to counsel their patients on the importance of daily PrEP use and emphasize that the consequence of missed doses may be less “forgiving” for women. [https://www.cdc.gov/hiv/pdf/risk/prep/cdc-hiv-prep-guidelines-2021.pdf]

The recommendation for daily PrEP dosing in women is based on biological factors that influence drug levels at the exposure site. Studies using pharmacokinetic modelling have shown that when taken at the same dose, tenofovir diphosphate, a key component of PrEP, reaches lower concentrations in women’s cervicovaginal tissue than in men’s rectal tissue. This suggests that women may be more vulnerable to HIV infection if they miss doses, unlike MSM who may have some leeway with missed doses without compromising protection. [J Infect Dis 2016;214:55-64; Clin Infect Dis 2022;75:1873-1882]

However, a direct link between tissue concentration and PrEP effectiveness has not been definitively established. A 2023 study that analysed adherence data from the HPTN 083 & 084 trials found that even with less-than-daily dosing, PrEP remained highly effective (>80 percent) at preventing HIV in cisgender women. For example, participants with tenofovir diphosphate levels indicative of taking 4 to 6 doses per week had a nearly 90-percent reduction in HIV risk in the HPTN 084 trial, consistent with the results observed with consistently high adherence in the present study. This aligns with other modelling studies leveraging F/TDF clinical trial data in cisgender women, indicating that the observed differences in PrEP efficacy between women and men may be due to varying adherence and not biology. [Clin Infect Dis 2023;76:1850-1853; Nat Med 2023;29:2753-2762; Nat Med 2023;29:2748-2752]

Limited adherence data

In an accompanying editorial, Dr Anandi Sheth of the Emory University School of Medicine in Atlanta, Georgia, US, wrote that the findings from the present study “shed insight into the adherence–protection relationship for F/TDF in cisgender women during ‘real-world’ use… [and] end any notion that F/TDF PrEP may not be effective in [this population].” [JAMA 2024;doi:10.1001/jama.2024.0432]

But they noted that the question of whether cisgender women retain the same degree of protection with less-than-perfect PrEP adherence as MSM should be considered in light of the study’s limited adherence data.

“First, adherence measures were only available for 47 percent of participants, and the availability of adherence data declined over time. In 92 percent of participants, adherence was assessed using only subjective (rather than pharmacologic) measures, which can overestimate adherence,” Sheth and colleagues said. [Transl Behav Med. 2015;5:470-482]

Indeed, of the 2,955 participants with adherence data, only 147 provided objective measures of adherence, such as tenofovir diphosphate quantification in dried blood spots, which reflected adherence over the past 8 to 12 weeks, and tenofovir quantification in plasma, which reflected adherence over the past 2 to 7 days. For the rest of the participants, adherence was measured using electronic pill cap monitoring, pill counts, self-report, or a study-reported adherence scales.

Adherence reporting plummeted over time, from 147 participants at week 16 down to only 22 participants at week 96 among those with objective adherence data, and from 2,775 to 318 participants, respectively, among those with subjective adherence data.

Sheth and colleagues also noted that the potential shifts in adherence based on perceived risk or upcoming clinic visits were not captured in the study, nor was the timing of doses relative to sex tracked. The timing of doses, they said, could have informed the potential effectiveness of event-driven PrEP for cisgender women.

What is clear is “the requirement for strict adherence to achieve protection poses an additional burden for cisgender women and, for some, can be a barrier to initiating PrEP,” they said, pointing to the fact that despite the reassuring finding of high protection among those consistently taking at least 4 doses per week, such a benchmark was achieved only by less than 40 percent of participants.

Good-enough adherence

“Although questions remain about the role of biological factors, findings from this study, coupled with recent pharmacologic studies, indicate that the protection achieved in cisgender women is more similar to that in MSM than previously thought,” according to Sheth and colleagues.

Showing that cisgender women can also benefit with “high but less-than-perfect adherence can alleviate anxiety around missed doses,” and help increase PrEP uptake, they added.

PrEP counselling can then be refocused toward understanding individual motivations for PrEP use and the challenges to using it consistently, they added. Reasons for missing doses can vary by local context, but low perception of HIV risk, stigma, poor social support are among the most common across settings.

Sheth and colleagues also highlighted the importance of a continued and consistent commitment to supporting PrEP adherence as well as a need to expand options to prevent HIV among cisgender women. “This goal can only be accomplished through purposeful inclusion of cisgender women in PrEP studies and incorporation of detailed behavioural and pharmacologic measures at the time of design to avoid gender-specific data gaps in future HIV/STI prevention and help correct long-standing gender inequities in HIV prevention and treatment, which is critical to ending the HIV epidemic.”