In this module, Antonio Urbina, MD, Professor of Medicine for the Divisions of Infectious Diseases and Medical Director at the Institute for Advanced Medicine, Chelsea Comprehensive Clinic at Mount Sinai Hospital, discusses strategies to optimize HIV care and prevention in transgender people. 

The key points discussed in this module are illustrated with thumbnails from an accompanying downloadable PowerPoint slideset that can be found here or downloaded by clicking any of the slide thumbnails in this module alongside the expert commentary.

Clinical Care Options plans to measure the educational impact of this activity. One question will be asked twice: once at the beginning of the activity and then once again after the discussion that informs the best choice. Your responses will be aggregated for analysis, and your specific responses will not be shared.

Before continuing with this educational activity, please take a moment to answer the following questions.

It is estimated that approximately 0.4% to 0.6% of adults identify as transgender worldwide, which equates to approximately 25 million persons.¹ In the United States, the transgender population includes 1.0‑1.3 million adults.^2,3 A Youth Risk Behavioral Survey done in 2017 reported that for adolescents in grades 9-12, approximately 1.8% identified as transgender.⁴

Of importance, 31% of transgender people identify as nonbinary, and that means that they identify as neither male nor female but somewhere on that spectrum.⁵

As healthcare professionals (HCPs), we can support these individuals by asking all of our patients 2 simple questions: What gender was assigned to you at birth? And, what gender do you identify with now? If there is a discordance between their answers, then that is how we identify persons who are transgender.

Stigma and discrimination are key drivers for morbidity and mortality in transgender persons. Fifty documented transgender people were murdered in the United States in 2021, and there have been 19 murders in 2022 as of July 2022.⁶ This is a very vulnerable and stigmatized population.

In the 2015 US Transgender Survey, 58% of transgender people experienced discrimination in the previous year.⁵ Forty-seven percent reported sexual assault, and 9% reported physical assault. Of importance, 33% describe some type of healthcare discrimination, and in 23% of those patients, it prevented them from seeking care. There was also mistreatment in employment. Fifteen percent of transgender individuals surveyed were unemployed, and close to 30% were living in poverty. Housing discrimination is another driver for health disparities in this population. Thirty percent of respondents in this survey reported ever being homeless.

Stigma and the discrimination against transgender individuals may include family rejection, bullying, and harassment at school, leading to early dropout from education. Transgender individuals often experience early trauma, and this becomes evident when they seek medical care.

There is an increased risk for HIV acquisition in transgender persons. In 2019, the risk of acquiring HIV was 13 times higher for transgender adults than for other adults between the ages of 15 and 49 years.⁷ The prevalence of HIV is 19 times higher for transgender women than for other women aged 15-49 years. In some settings, up to 40% of transgender women are living with HIV.^8,9 And while we have seen a decrease in HIV incidence rates among women overall, there has been no similar decline in incidence rates among transgender women.

Stigma and discrimination drive poor health outcomes and prevent patients from seeking care, either for HIV infection or from HIV prevention services. In 2019, 32 countries reported criminalizing or prosecuting people based on their gender identity or expression.

As noted, an estimated 0.6% of adults (or 1.4 million) in the United States identify as transgender.³ The figure on the right of the accompanying slide shows the distribution of transgender persons across the United States by state.

A meta‑analysis including data from 2006-2017 reported the prevalence of HIV infection in transgender individuals to be approximately 9.2%.¹⁰ HIV prevalence in transgender women was 14.1% and 3.2% in transgender men, that is, people who were assigned female sex at birth but identify as male. Approximately 51% of Black transgender women are unaware of their HIV status.¹¹ The racial disparities that we see in the general US population regarding HIV prevalence are even more pronounced in persons who identify as transgender.

In 2018, there were approximately 38,000 new HIV diagnoses in the United States and dependent areas, and 2% of these diagnoses were among transgender individuals.¹² Most of these HIV diagnoses among transgender men and women occurred in Black patients. Of the approximately 544 HIV diagnoses in transgender women, almost one half of them (49%) were in Black patients who identify as transgender women. This was followed by Hispanic or Latinx at approximately 33%. For transgender men, 40% of HIV diagnoses were in Black transgender men. The next most commonly diagnosed group among transgender men were White transgender men, at approximately 34%. Again, these data demonstrate racial disparities in persons diagnosed with HIV who are transgender.

Racial and ethnic disparities are also evident when looking at HIV prevalence in transgender women in the United States, which I think reflects the structural and institutional factors that prevent equitable access to healthcare. The CDC HIV Surveillance Report for 2021 included data from 7 US cities gathered between 2019 and 2020.¹³ Among 1561 transgender women interviewed, 42% had HIV. Sixty-two percent of these HIV-infected women identified as Black, 35% as Hispanic or Latina, and 17% as White transgender women. These data offer important information to HCPs about populations who are more at risk for HIV infection, and the need to standardize the offering of HIV testing to everyone regardless of race, ethnicity, gender, and sexual orientation.

Data from the CDC’s 2020 HIV Surveillance Report on the distribution of transgender women living with HIV in the United States show that most HIV diagnoses in 2020 were in young adults between their late 20s and early 30s, with declining incidence with advancing age.¹⁴ These data should be interpreted with some caution, as they cover the period in which we were at the height of the COVID‑19 pandemic. The pandemic prevented a lot of people from accessing HIV testing and care.

We will review this issue in more detail later in this module, but data increasingly show that hormone therapy can be safely prescribed alongside medications used to treat and prevent HIV infection, including HIV PrEP.¹⁶ Retention in HIV care and HIV-1 RNA suppression among transgender women with HIV have been found to be increased if the primary HCP was also a hormone prescriber.¹⁷ We know that people with HIV people who adhere to their ART can live healthy lives into their 60s and beyond¹⁸ and that people with a sustained undetectable HIV-1 RNA on ART do not sexually transmit HIV.¹⁹ So, providing holistic and integrative gender‑affirming care is also an important public health intervention. 

The provision of gender‑affirming care has a significant effect on whether transgender individuals progress appropriately through the HIV care continuum. A study from Washington, DC, reviewed care outcomes in 219 transgender and 456 nontransgender women with HIV between 2008 and 2017.²⁰ Participants were at least 18 years of age and had at least 12 months of medical data and at least 1 HIV-1 RNA measurement documented 1 year after ART initiation.

Although retention in care was similar between transgender and nontransgender women, the rates of durable virologic suppression were significantly reduced in transgender women. In fact, nontransgender women living with HIV were 1.6 times more likely to achieve durable virologic suppression than transgender women (P <.05). Transgender women with HIV who received surgical referrals were more likely to achieve a durable virologic suppression vs nonreferrals (odds ratio: 2.9; P = .021).

This study shows that providing gender-affirming care can help achieve greater equity in HIV outcomes, such as maintaining durable virologic suppression. If HCPs taking care of transgender patients with HIV feel competent and confident prescribing hormone replacement therapy, partnering with their patients during their transition, and providing gender‑affirming care, virologic suppression rates may improve.

Programs in the United States and across the world that have integrated transgender education, outreach, provider training, and sensitivity training have seen improvements in virologic suppression among people with HIV. One such initiative in New York City, which offered 5 years of enhanced provider education, found that rates of virologic suppression increased over the period of the initiative (2007-2016).²¹ However, the greatest trajectory improvement was among transgender persons, where rates of virologic suppression were lower than in cisgender individuals. By the end of the study period, the gap in virologic suppression rates between transgender and cisgender people had narrowed.

PrEP is an effective and safe method of preventing HIV acquisition in at-risk populations. There are now 3 FDA-approved PrEP medications available in the United States. These include 2 options for daily oral therapy, as well as a long‑acting (LA) injectable therapy, cabotegravir, which was approved in December 2021 for at-risk adults and adolescents weighing at least 35 kg.²² Although these medications have been shown to be highly effective in clinical trials, their real-world efficacy is dependent on access and equitable distribution to all populations at risk.

Stigma, discrimination, and lack of employment opportunities lead to higher rates of sex work among transgender people, which is associated with HIV acquisition.²³ There is less awareness of PrEP in the transgender community than in the community of men who have sex with men (MSM). Marketing of PrEP is often not inclusive of transgender people. Finally, concerns about interactions between PrEP and hormone therapy lead some transgender women to prioritize hormones over PrEP, and ART more generally, despite the fact that these concerns can be dispelled by available data.

The FDA-approved oral PrEP options are TDF/FTC and tenofovir alafenamide (TAF)/FTC.^24,25  Both of these are coformulations of 2 antiretrovirals.

TDF/FTC has been evaluated in broad populations and is indicated for the prevention of sexually acquired HIV infection in at-risk adults and adolescents weighing at least 35 kg.²⁴ By contrast, the efficacy of TAF/FTC has been demonstrated in cisgender MSM and transgender women only,²⁶ and consequently it is indicated for the prevention of sexual acquisition of HIV in at-risk individuals, excluding via receptive vaginal sex.²⁵ Both are approved for use in adults and adolescents who weigh at least 35 kg.

There are also some safety differences between the 2 oral PrEP formulations.²⁷ TDF/FTC may affect renal tubular function, and it should be discontinued if creatinine clearance is <50 mL/min. TAF/FTC has less of an impact on renal biomarkers than TDF/FTC, and it can be used in patients with a  creatinine clearance ≥30 mL/min. TDF/FTC can cause a decrease in bone mineral density. Typically, this is reversible when the drug is interrupted or stopped.²⁸ TAF/FTC has a more favorable impact on bone biomarkers for cisgendered women and transgendered women who are at risk for osteoporosis. In addition, TDF/FTC may induce weight loss or be weight neutral, whereas TAF/FTC may cause mild weight gain. TDF/FTC can also cause small decreases in low-density lipoprotein cholesterol, whereas TAF/FTC may cause small increases. For an older person at risk for either kidney or bone disease, I would recommend TAF/FTC for PrEP over TDF/FTC, but for a young healthy person, I would be comfortable in recommending the use of TDF/FTC or its generic formulation.

One of the biggest drivers in the choice between TDF/FTC and TAF/FTC is cost. A low-cost generic version of TDF/FTC is available, but this is not the case for TAF/FTC.

Both oral PrEP regimens are approved for once-daily dosing.^24,25 However, there are data that support on‑demand or event‑driven dosing for TDF/FTC PrEP.²⁹ Typically, that strategy involves taking 2 tablets of TDF/FTC 2-24 hours before an exposure, then 1 tablet 24 hours after the first dose, and an additional tablet 48 hours after the first dose. There are no data to support on‑demand dosing of TAF/FTC.

Blumenthal and colleagues presented a study of the effects of hormone therapy on PrEP at the 2022 Conference on Retroviruses and Opportunistic Infections.³⁰ This study looked at tenofovir diphosphate concentrations in transgender women who were on feminizing hormones and transgender men on masculinizing hormones, both of whom were receiving TDF/FTC PrEP. After 12 weeks of daily PrEP therapy, there were no differences in tenofovir diphosphate concentrations in persons who were on either feminizing or masculinizing hormones and those who were not on hormone therapy. Hormone concentrations were not affected by PrEP; treatment was bidirectionally neutral. The study also found that satisfaction with body image and with hormone therapy did not differ between those who were on therapy and those who were not.

It is important that we inform our transgender patients that being on PrEP is not going to interact with their hormone therapies and that their hormone therapies will not interact with antiretrovirals used for HIV prevention.

To help us measure the educational impact of this activity, please provide an answer to the following question, which was presented to you in the pre-education section of the activity. As a reminder, your responses will be aggregated for analysis, and your specific responses will not be shared.

As noted, there is evidence of reduced PrEP awareness in transgender individuals compared with MSM.²³ A recent cohort study enrolled 1293 transgender individuals from across 6 cities in the southern and eastern United States.³¹ More than one half (57%) of participants in this trial were younger than 30 years of age, and 53% were White, 14% Black, and 9% Hispanic. Eighty percent had health insurance, and 38% were living below the poverty level. Thirty-five percent met the CDC criteria for a PrEP indication, and 47% met the study’s own criteria for PrEP, which was designed to be more specific to transgender persons.

At the time of the study, CDC PrEP indication criteria for MSM specified that individuals eligible for PrEP should be HIV negative, have had a cisgender male partner within the last 6 months, should not be in a monogamous relationship with an HIV-negative cisgender male, and should either have had a sexually transmitted infection or anal sex without a condom within the past 6 months. The LITE criteria expanded upon that list to include the reported use of post‑exposure prophylaxis, current sex work, any recent sex with a partner of unknown HIV status, and needle sharing for injection drugs in the past 12 months.

In this study, 611 transgender women were eligible for PrEP based on the LITE criteria. Of those, 83% were aware of PrEP, and of those who were aware, only 38% had ever taken it. Overall, 31% of patients eligible for PrEP had taken it, and 20% of eligible patients were taking PrEP at the time of the study. Just 13% were adherent to PrEP. So, although most individuals with PrEP indications in this study were aware of PrEP, overall uptake and adherence were low and needed to improve.

Now there are other studies that have shown a lower rate of PrEP awareness among transgender women,³² but this study shows low uptake and adherence. I think that means that we need to understand these gaps and better connect with patients and communities who are most at risk for HIV. 

A study looking at the PrEP continuum among transgender women in Thailand observed a similar pattern. PrEP has been part of universal health coverage in Thailand since October 2019.³³ An analysis of data from Thailand’s largest PrEP program, the Princess PrEP program, covered the period from January to November 2019. Among the 900 transgender women eligible for PrEP in this study, PrEP acceptance was low, particularly for those younger than 25 years of age. The main reasons for nonacceptance were that participants did not perceive themselves to be at risk (38%); they did not want to take pills (23%); they felt that condoms were sufficient protection (8%); or they were unable to return for follow-up (6%). Others wanted to delay PrEP (5%), and 3% were afraid of adverse events. Consequently, the PrEP cascade shows a sharp drop-off from eligibility to acceptance and retention.

The availability of LA injectable PrEP means that we now had a tool to address some of the concerns relating to adherence. LA cabotegravir was approved in December 2021 for at-risk adults and adolescents weighing at least 35 kg for PrEP to reduce the risk of sexually acquired HIV-1 infection.²² This includes the prevention of HIV in both MSM and transgender women.

The HPTN 083 study was an international, randomized, double‑blind phase IIb/III study that enrolled adult HIV‑negative MSM and transgender women who were at high risk for HIV infection.³⁴ Patients started with a 5-week lead-in of oral cabotegravir plus placebo vs oral FTC/TDF plus placebo. At Week 5, patients in the cabotegravir arm went on to receive LA cabotegravir dosed intramuscularly every 2 months with a daily oral placebo. Patients in the FTC/TDF arm received oral FTC/TDF daily with an injectable placebo given every 2 months. This study was unblinded at a median follow-up of 1.4 years after a significant reduction in incident HIV infections was observed in the cabotegravir arm.

It is important to understand that LA injectables have a “pharmacokinetic tail,” which means that once the patient stops treatment, the drug stays in the blood and in the tissue.^35-37 Cabotegravir can persist for approximately 1 year after treatment discontinuation.^35,36 At a certain point, falling drug levels will no longer protect against HIV acquisition but will be present at subtherapeutic levels, presenting a risk for development of drug resistance in people who acquire HIV in this setting. People who stop LA cabotegravir PrEP should consider taking oral PrEP if they continue to be at risk.

Of the 4566 participants in the HPTN 083 trial, 12.5% identified as transgender women.³⁸ Most (83%) of the transgender women were between the ages of 18 and 29 years, compared with 65% of the MSM. Patients in this trial were primarily from the United States, Latin America, and Asia, with 2.6% residing in Africa.

A subanalysis of HPTN 083 reported that HIV incidence in transgender women randomized to FTC/TDF was 1.8% compared with 0.54% in the LA cabotegravir arm.³⁸ This supports the main finding of the overall study that LA cabotegravir was superior to oral TDF/FTC for preventing HIV infection. These women also had high rates of sexually transmitted infections, although rates were similar across treatment arms, including syphilis infection (14-19%), rectal gonorrhea (approximately 12%), and rectal chlamydia (19-23%).

Rates of adverse events in transgender women were high, but these occurred at similar frequency across treatment arms. Injection-site reactions were an exception and are a recognized adverse event of LA injectable cabotegravir that do not typically result in discontinuation. Of importance, gender‑affirming hormonal therapy did not appear to affect concentrations of LA cabotegravir in this subset analysis.

LA cabotegravir is associated with fewer drug–drug interactions than other antiretrovirals. The antimycobacterials rifampicin and rifapentine should not be coadministered with cabotegravir because coadministration reduces cabotegravir exposure levels and hence its protective effects.^16,22,39 A similar effect occurs with rifabutin, which should be coadministered with caution. The anticonvulsants carbamazepine, oxcarbazepine, phenytoin, and phenobarbital should not be coadministered with cabotegravir due to reduced cabotegravir exposure. There is no expected interaction with feminizing hormones, such as estrogen or spironolactone.

In summary, persons who identify as transgender are a vulnerable population with unique needs. This population needs more outreach, as there is a significant history of trauma. As HCPs, we must work to increase our knowledge about transgender-related medical issues and treat the patient holistically. Given the high rates of trauma experienced by transgender individuals, it is important that we understand trauma-informed care and triggering events. HCPs must understand this so that they can provide culturally competent care. It is also important that we provide mental health and substance use treatment opportunities for our patients.

We can improve HIV care and HIV prevention efforts in our transgender population by improving the care environment.^40-43  We need knowledgeable providers and staff and a supportive physical environment. Transgender knowledge can be taught, and data show that with effort and time, we can transform clinics and improve patient experiences. Of importance, we must discuss the lack of an impact of HIV medications both for treatment and for prevention on hormone therapy, and that it is safe for patients to use both. We also need to integrate hormone therapy and HIV care. Data show that if HCPs are knowledgeable about hormone therapy and feel confident prescribing it, then we see improved retention and overall outcomes in transgender persons living with HIV.¹⁷ In patients who are HIV negative, HCPs should discuss PrEP, including newer LA options such as cabotegravir.

It is also important that we screen for and treat any sexually transmitted infections.⁴⁴ HCPs should complete a “3-site screening” for sexually transmitted infections, which includes extragenital, pharyngeal, and rectal screening.⁴⁵ Extragenital infections are often asymptomatic, but it is important that we screen and test for them, as having an active sexually transmitted infection can increase the acquisition and transmission of HIV. 

The main takeaways are that (1) transgender individuals experience high rates of discrimination, (2) HIV incidence is significantly higher in transgender adults than in cisgender adults, (3) most HIV infections in transgender individuals are in Black patients, and (4) PrEP is effective and safe in transgender women with no interactions with hormone therapy.