The more than 300 transgender women in the pivotal iPrEx pre-exposure prophylaxis (PrEP) trial had similar overall HIV infection rates whether they were randomised to take Truvada or placebo, but those with drug levels indicating consistent PrEP use appeared to be protected, researchers reported in the November 5 advance online edition of The Lancet.
"While this analysis did not include a large enough sample group to draw firm conclusions, we did find strong evidence pointing to efficacy," said senior study author Robert Grant of the University of California at San Francisco. "Additional research designed specifically for transgender women is needed to confirm this finding."
US Food and Drug Administration approval of Truvada (tenofovir/emtricitabine) for PrEP in July 2012 was based in part on data from the phase 3 iPrEx trial, which enrolled 2,499 mostly gay and bisexual men from Brazil, Ecuador, Peru, South Africa, Thailand and the US between 2007 and 2009. Participants were randomly assigned to take oral Truvada or a placebo once-daily. Follow-up in the randomised portion of the study continued for a median of 1.2 years. Afterwards participants had the option to receive Truvada in an open-label extension of the study, which ended in 2013.
Primary results, published in November 2010, showed that once-daily Truvada reduced the risk of HIV infection by 42% overall compared to placebo, rising to 73% among participants who reported good adherence and 92% among those with blood drug level measurements indicating regular use. In the open-label extension no one who took Truvada at least four times a week became infected.
Transgender women have one of the highest rates of HIV infection. One meta-analysis of 22 studies found that 28% of transgender women in the US are HIV-positive, while a 2013 meta-analysis looking at 15 countries found that 19% of trans women were living with HIV, the researchers noted as background.
To date, no randomised clinical trials have looked specifically at PrEP for transgender women, and it is not known whether hormone use or other factors might affect its safety and effectiveness for this group. This is the first separate analysis of trans women in a Truvada PrEP trial.
Dr Grant, Madeline Deutsch and fellow investigators performed an unplanned analysis of PrEP efficacy, overall effectiveness and adherence among trans women in iPrEx, comparing PrEP outcomes between trans women and men who have sex with men (MSM).
While most of the 2,499 iPrEx participants were gay and bi men, a total of 339 (14%) were classified as transgender women, including 29 (1%) who identified as women, 296 (12%) who identified as trans or 'travesti', and 14 (1%) who identified as men but reported use of feminising hormones. Of these 192 joined the open-label extension, 79% of whom opted to take Truvada.
The initial published iPrEx report said the study included 29 trans women, but a "more sophisticated method" for determining who was transgender turned up a larger number, Grant said in a UCSF press release.
In the US just 3% of participants were classified as transgender women, rising to 6% in South Africa, 10% in Brazil, 15% in Ecuador and Peru, and 38% in Thailand. The median age of trans women was 26 years (a year younger than the MSM). Only 4% were circumcised, which has been linked to increased HIV risk in some populations. One-fifth reported use of feminising hormones.
Compared with MSM, transgender women more frequently reported sex work or transactional sex (64% vs 38%), condomless receptive anal intercourse (86% vs 55%), sexually transmitted infections during the past six months (38% vs 24%) and more than five sex partners during the past three months.
In the randomised trial transgender women had lower drug levels in their blood and were less likely to take PrEP on a daily basis than MSM. PrEP use was not linked to behavioural risk among trans women – and in fact those who reported condomless anal sex tended to be less likely to use PrEP consistently – unlike MSM, for whom those at highest risk had better adherence.
Among transgender women, 11 new HIV infections occurred in the PrEP group and 10 in the placebo group during the randomised study – essentially no difference (hazard ratio 1.1). Two transgender women receiving PrEP seroconverted in the open-label extension.
None of the 11 trans women who seroconverted in the randomised trial had detectable blood drug levels. In the open-label extension transgender women were half as likely as MSM to have drug levels indicating they took four or more doses of Truvada a week (18% vs 36% of follow-up time, respectively). Trans women who took feminising hormones were less likely to have detectable drug levels or protective drug levels.
However, none of the trans women with drug levels indicating they took at least four doses a week became infected, as was the case for MSM. HIV incidence among trans women was 0 if drug was detected and 4.9 per 100 person-years if drug was not detected, compared with 0.4 and 2.8 per 100 person-years, respectively, among MSM.
Truvada PrEP was generally well-tolerated. Moderate or severe adverse events were rare among transgender women, with no differences between the PrEP and placebo groups. Bone mineral density tended to be less affected by PrEP among trans women than among MSM, which the researchers suggested might reflect less actual use of PrEP or a protective effect of feminising hormones. There was no evidence of liver toxicity.
"PrEP seems to be effective in preventing HIV acquisition in transgender women when taken, but there seem to be barriers to adherence, particularly among those at the most risk," the study authors concluded. "Studies of PrEP use in transgender women populations should be designed and tailored specifically for this population, rather than adapted from or subsumed into studies of MSM."
"Transgender women face several structural barriers including lack of legal protection against discrimination and resulting difficulties in employment, access to income, food and housing, Deutsch said in the UCSF press release. "They desperately need a tool that they control, one they can use without their partners' consent or knowledge."
"We think that one factor leading to lower rates of pill-taking may be due to either a fear of, or lack of information about drug-drug interactions between PrEP and gender-affirming hormone medications. For transgender women, their gender-affirming medications are a higher priority," she continued. "And while there may be a negative behavioural interaction between the two therapies that is affecting pill-taking, we have no evidence to date for a biological interaction between the two, though further research is needed."
"When transgender women take PrEP as prescribed, it appears to work, but to retain and encourage PrEP use, research should be conducted and interventions should be delivered in gender-affirming environments," said co-author JoAnne Keatley, director of the UCSF Center of Excellence for Transgender Health. "One example would be to integrate PrEP delivery with gender-affirming services, including provision of gender-affirming hormone therapies. Social marketing campaigns and PrEP delivery programs should not lump transgender women in with MSM, but should be explicitly designed to support transgender women."
Deutsch MB et al. HIV pre-exposure prophylaxis in transgender women: a subgroup analysis of the iPrEx trial. The Lancet, 2015 (online ahead of print).