Inclusion of Trans Women in Pre-Exposure Phrophylaxis (PrEP): A Review

Abstract

Trans women are at high-risk of HIV infection. We conducted a review to determine the extent to which trans women were eligible for inclusion in and enrolled into pre-exposure prophylaxis (PrEP) efficacy trials. Out of seven trials analyzing PrEP efficacy, we found that trans women comprised only 1.2% of one trial, and 0.2% of total trial enrollments. Although an additional PrEP trial to determine efficacy among trans women may not be warranted, further research is needed to determine the effectiveness of PrEP in this marginalized population, through observational and feasibility studies. These studies should focus on unique barriers that trans women may experience while obtaining access to PrEP, such as gender discrimination, transphobia, and violence.

Background

In countries around the world, transgender women (trans women), are at high-risk of HIV infection. A 2013 meta-analysis found that trans women across fifteen countries had 49 times the odds of being infected with HIV, compared with all adults of reproductive age (Baral et al., 2013). Recent studies demonstrate that trans women are less likely to be enrolled in antiretroviral therapy (ART) than non-transgender persons (Melendez et al., 2006), and among those on therapy, are less likely to be adherent to ART (Sevelius, Carrico, & Johnson, 2010). Highlighting this leaking treatment cascade, a 2014 study in San Francisco estimated that only 65% of trans women infected with HIV were on ART, the lowest ART coverage of any gender or high-risk group in San Francisco (San Francisco Department of Health, 2012; Santos et al., 2014).

In addition to risks from unprotected sexual exposures, substance use, sex work, depression, unstable housing, and high levels of victimization and violence are commonly reported by trans women (Duncan, Hatzenbuehler, & Johnson, 2014; Herbst et al., 2008; Hoffman, 2014; Santos et al., 2014), indicating the potential for multiple, concurrent HIV risks and underlying vulnerabilities. Structural forms of discrimination may contribute to these risk factors, possibly leading to poor outcomes such as unemployment or underemployment, and also create barriers to HIV preventive and other health services. For many of the same reasons, trans women may lack access to gender sensitive health services. Given this context, a biomedical intervention such as pre-exposure prophylaxis (PrEP), which can address risks from multiple types of exposure (i.e., sexual or parenteral), may be integral for comprehensive prevention packages. Due to the greatly elevated risk of HIV infection among this population worldwide, and the multi-level factors highlighted here, which may hinder access to regular preventive HIV services, biomedical intervention strategies may be particularly effective.

PrEP has been found to be efficacious in preventing HIV acquisition among several high-risk populations, including men who have sex with men (MSM) (Grant et al., 2010), serodiscordant heterosexual couples (Baeten et al., 2012), and people who inject drugs (Choopanya et al., 2013). Although trial results have spurred recommendations for PrEP among these high-risk groups (Centers for Disease Control and Prevention, 2011, 2012, 2013), research involving (and specific recommendations for) trans women have been largely absent, despite the elevated risk for HIV within these communities. A notable exception are the World Health Organization (WHO) PrEP guidelines, which do include trans women in the context of demonstration projects (2012).

Although results and enrollment characteristics from completed oral PrEP trials have been described elsewhere (van der Straten, Van Damme, Haberer, & Bangsberg, 2012), we have not been able to identify a summary of the inclusion and enrollment of trans women in these studies. To inform future research examining the use of PrEP among communities of trans women, we conducted a review to assess the extent to which trans women have been eligible for and included in previously conducted oral PrEP efficacy trials. We also sought to determine the potential for sub-groups analyses in this population.

Methods

We reviewed all published results from randomized controlled trials that included an analysis of oral PrEP (i.e., tenofovir or tenofovir/emtricitabine), as identified by a non-systematic literature review and from reference lists of summary publications (Baeten, Haberer, Liu, & Sista, 2013; Molina et al., 2013; van der Straten et al., 2012). Our results our limited to English-language publications. PubMed and Medline searches, and well as reviews of HIV/AIDS conference abstract databases (e.g., IAS and CROI) were also conducted using search terms that included “transgender,” “trans women,” PrEP,” and “pre-exposure prophylaxis.” Studies examining the efficacy of only non-oral PrEP formulations (i.e., topical) were excluded. The online clinical trial registry, http://www.clinicaltrials.gov, was used where appropriate to supplement published information. For in-progress or halted trials, available descriptions of study enrollment criteria were used to determine inclusion of trans women in these studies. When information was not available, attempts were made to contact the study’s corresponding author.

Results

We identified seven trials that analyzed the efficacy of oral PrEP for HIV prevention. Three trials, FEM-PrEP (Van Damme et al., 2012), TFV Phase II (Peterson et al., 2007), and VOICE (Microbicides Trials Network, 2011), enrolled cisgender women (cisgender is defined here as those who identify with the gender they were assigned at birth). Two trials reported enrollment of MSM: iPrEX (Grant et al., 2010), and the Bangkok Tenofovir Study (Choopanya et al., 2013). Two other trials, PartnersPrEP (Baeten et al., 2012), and TDF2 (Thigpen et al., 2012), were designed specifically to analyze PrEP efficacy in preventing heterosexual transmission of HIV. One trial, the Bangkok Tenofovir Study, was designed to enroll people who inject drugs (PWID). According to published results, and a review of information available on http://www.clinicaltrials.gov, FEM-PrEP, TFV Phase II, and VOICE were the only trials which explicitly excluded the enrollment of trans women. One attempt was made to confirm enrollment and analytic data from a study author; however this was unsuccessful, and we instead relied on existing published information for our assessment.

Upon further review of trial data, only one study, iPrEx, was confirmed to enroll transgender people, and enrollment was limited to trans women. iPrEx was a multinational PrEP trial involving 2,499 MSM and trans women, among whom 29 (1.2%) self-identified as transgender at baseline (Table 1). Additionally, no trial reported enrollment of transgender men. Based on the small number of trans women identified in these trials, sub-group efficacy analysis was not deemed feasible.

Table 1.

Oral PrEP Efficacy Trial Characteristics, Including Transgender Enrollment

Trial	Primary Population	Setting(s)	Enrollment	Trans Women Enrollment (%)
TFV Phase II*	Women	Cameroon, Ghana, Nigeria	936	0 (0%)
iPrEx	MSM and TGW	Ecuador, Brazil, Peru, South Africa, Thailand, USA	2,499	29 (1.2%)
FEM-PrEP*	Women	Kenya, South Africa, Tanzania	1,951	0 (0%)
TDF2	HSM and HSW	Botswana	1,200	0 (0%)
PartnersPrEP	SDC	Kenya, Uganda	4,747 (Couples)	0 (0%)
VOICE*	Women	South Africa, Uganda, Zimbabwe	5,029	0 (0%)
Bangkok Tenofovir Study	PWID	Thailand	2,413	0 (0%)
Total			18,775	29 (0.2%)

Abbreviations: Men who have sex with men (MSM), transgender women (TGW), heterosexual men (HSM), heterosexual women (HSW), serodiscordant couples (SDC), people who inject drugs (PWID)

^*Enrolled only cisgender women

Discussion

The results of this review demonstrate that inclusion of trans women in PrEP trials has been minimal. There are several potential explanations for a lack of transgender enrollment in these trials. The relatively small size of transgender communities throughout the world—possibly 1 in 500 persons worldwide according to a 2007 estimate (Olyslager & Conway, 2007)—may lead investigators to believe that the application of PrEP to this population may be of lesser priority. Whether or not the application of PrEP is perceived to be a lesser priority than other high-risk groups (i.e., MSM, commercial sex workers, serodiscordant couples, PWID), the potential impact of PrEP on incidence among trans women remains significant, given the very high risk for HIV within this population (Baral et al., 2013).

Finally, the difficulty of recruiting members of a low prevalence group may present a significant challenge to researchers. Among trials for which trans women were theoretically eligible, specific protocols to identify and recruit trans women did not appear to be in place, or could not be identified (Baeten et al., 2012; Choopanya et al., 2013; Grant et al., 2010; Thigpen et al., 2012). Often, trans women are categorized alongside MSM, which may lead to difficulties in their recruitment, since studies not seeking trans women independent of MSM may be viewed negatively by trans women, or otherwise ignored. Also, the trial settings themselves may have affected potential recruitment, as many took place in countries with high levels of stigma and discrimination experienced by transgender persons, which may have severely limited the capacity to recruit transgender participants.

As the most fundamental aspect of improving transgender enrollment, use of evidence-based recruitment strategies for this population must be considered in future studies. Although a previous study assessing the use of long-chain peer referral to specifically recruit MSM and trans women has demonstrated only limited success, further efforts to determine effective recruitment strategies may yield different results (Coombs et al., 2014). It is likely that without protocol designed specifically to enhance participation of transwomen in PrEP research studies, or HIV prevention studies as a whole, minimal enrollment will persist, leading to continued difficulty applying results and subsequent clinical recommendations to this population. Closely related to the difficulties of recruiting trans women, trial investigators may have been concerned with statistical ‘noise’ that may be introduced by enrolling small numbers of trans women among a larger cisgender population. Moreover, without sufficient enrollment to perform subgroup analysis among trans women, either within an individual trial or pooled across trials, the perceived benefits may have been minimal. However, we note that recruitment of trans women in PrEP studies may allow for pooled analyses in the future.

Despite limited participation of trans women in PrEP trials, observational studies regarding the use of PrEP among trans women have increased the body of knowledge regarding issues such as adherence (Golub, Gamarel, Rendina, Surace, & Lelutiu-Weinberger, 2013), risk-compensation (Golub, 2014; Marcus et al., 2013), acceptability (Galea et al., 2011; Golub, 2014; Yang et al., 2013), and epidemic impact (Gomez et al., 2012). Overall, this preliminary body of literature suggests that PrEP represents an important opportunity to prevent incident HIV infections among trans women; however, significant barriers to its effective use and retention among PrEP programs have yet to be overcome. Unfortunately the majority of the studies within this growing literature do not provide insights into the challenges faced specifically by transgender communities in accessing PrEP, instead conclusions tend to be directed simultaneously to MSM and trans women, which may obscure distinctions between the ideal application of PrEP programs between these populations.

Although this analysis focused on trans women alone, it should be noted that published literature concerning HIV risk and subsequent prevention modalities for trans men is extremely scarce. This understudied population may also benefit from increased research attention, since presently not even adequate estimates of HIV risk or risk behavior are available.

Given the growing evidence of PrEP efficacy in MSM and other populations, a specific randomized clinical trial for trans women may not be needed, and such a study may even violate the principal of clinical equipoise. However, in light of evidence that the inclusion of trans women in PrEP trials has been limited, we recommend that, to ensure optimal uptake of PrEP among this population, concerted efforts should be made to include trans women in acceptability, implementation, and evaluation studies. Such studies will be critical to informing clinical, programmatic and policy decisions regarding the use of PrEP by trans women, as it has previously been with other populations, such as MSM, serodiscordant couples, and PWID. Some barriers to PrEP effectiveness among trans women have already been identified, such as the complex and heterogeneous psychosocial motivations for engaging in risk compensation among trans women (Golub, 2014), as well as many correlates to poor PrEP adherence (Golub, et al., 2013). Particular attention should also be paid to unique barriers that trans women may experience while obtaining access to PrEP, such as gender discrimination, transphobia, and violence, which have been observed to play an important role in reducing acceptability of and access to other HIV testing, preventive and treatment services (Golub & Gamarel, 2013; Golub et al., 2013; Sevelius, Patouhas, Keatley, & Johnson, 2014; Sevelius, Saberi, & Johnson, 2014).