Bookmark

Transgender women have a high prevalence of HIV infection (8) and experience high HIV incidence rates compared to non-transgender men and women (9). Furthermore, transgender women have represented less than 1% of study participants in PrEP trials (10) and this paucity of data may help explain the overall low uptake of PrEP by transgender women (11).

The Iniciativa Profilaxis Pre-Exposición (iPrEX) clinical trial enrolled the highest number of transgender women to date and found that compared to MSM, transgender women were more likely to report transactional sex, condomless anal intercourse and more recent sexual partners (12). In iPrEX, no HIV infections were observed in transgender women whose blood levels were compatible with taking four or more doses of PrEP weekly. However, using stratified analyses, PrEP did not provide a benefit for transgender women in the iPrEX study [hazard ratio 1.1, 95% confidence interval (CI): (0.5 to 2.7) compared to the overall 44% reduced HIV incidence in the active study arm (12).

A recent retrospective analysis of the iPrEX study sought to determine whether the differential efficacy of PrEP in MSM versus transgender women was a result of different baseline clinical and behavioural factors that could make PrEP less efficacious in transgender women (10). The authors found that baseline characteristics between MSM and transgender women explained almost 100% of the difference in PrEP’s efficacy during the iPrEX study (11). However, the authors were not able to comment on whether the use of gender-affirming hormone therapy (GAHT) (13) may have contributed to PrEP being less effective in the transgender women study participants (11).

Oestrogen, which is used as part of GAHT, increases the activity of 5’-nucleotidase enzymes and can decrease the active metabolites of tenofovir and emtricitabine, or increase the nucleotides that compete against the active metabolites of tenofovir and emtricitabine within cells. Therefore, oestrogen could plausibly reduce cellular levels of tenofovir and emtricitabine in transgender women, making PrEP less efficacious. There have been some small studies in transgender women taking GAHT and PrEP. One study of 20 Thai transgender women commencing GAHT and PrEP showed a 12% reduction in plasma tenofovir levels in the presence of GAHT (14), although PrEP did not reduce oestrogen levels. In another study, 31% lower levels of plasma tenofovir were observed in eight transgender women taking GAHT compared to eight cis-gender men; plasma emtricitabine was also significantly lower in the transgender study participants (13). A further study compared the rectal tissue levels of the active metabolites of tenofovir and emtricitabine in four HIV-positive transgender women taking GAHT versus four HIV-positive post-menopausal cis-gender women. This study reported that there was a significantly lower ratio of the active metabolite of tenofovir diphosphate to its competing nucleotide dATP in the rectal tissue of the trans-gender versus cis-gender participants (15). However, this study did not find a decrease in the ratio of the active metabolite emtricitabine triphosphate to its competing nucleotide, dCTP. Further larger pharmacological studies are needed urgently to determine whether GAHT reduces the levels of tenofovir disoproxil* and emtricitabine (TD*/FTC), or vice versa in transgender women.

The ASHM PrEP Guidelines Panel will continue to monitor the data on potential drug-drug interactions between GAHT and TD*/FTC.

As noted, in a post-hoc analysis of transgender women in the iPrEX study, no HIV infections were observed in transgender women whose blood levels were compatible with taking four or more doses of PrEP weekly (12). Therefore, supporting transgender women to optimise their PrEP adherence is important until larger studies have determined whether GAHT reduces levels of TD*/FTC in transgender women taking GAHT. To help support transgender women to optimise their PrEP use and adherence, it is recommended that health practitioners provide gender-affirming care (16). Such clinical care includes appropriate use of preferred pronouns and names, safe access to bathrooms of choice and appropriate treatment and referral for hormone therapy and surgery (16).