Luzzati, Roberto MD; Zatta, Marta MD; Pavan, Nicola MD; Serafin, Maurizia PhD; Maurel, Cristina MD; Trombetta, Carlo MD; Barbone, Fabio MD

The burden of human immunodeficiency virus (HIV) and hepatitis B virus (HBV) and hepatitis C virus (HCV) infections in transgender individuals is an underestimated issue all over the world. The term transgender dysphoria refers to discomfort or distress that is caused by a discrepancy between a person's sex identity and that person's sex assigned at birth.¹ In detail, a transgender woman (male-to-female [MtF]) is a person who was assigned male at birth but whose sex identity is that of a woman. On the other hand, a transgender man (female to male [FtM]) is a person who was assigned female at birth but whose sex identity is that of a man. The HIV and HBV infections are more commonly found in key populations characterized by multiple sex partners and very frequent sexual activity, and are therefore considered among the most important sexually transmitted diseases (STD). Although HCV is not recognized a traditional cause of STD, HCV infection can be transmitted through sexual activity in HIV-infected men who have sex with men (MSM).^2–5 Transgender communities, and especially MtF subjects, are among the groups at highest risk for HIV and other STD.⁶ This might not be attributable only to individual behaviors such as unprotected sexual intercourse and promiscuity but also to many cultural, socioeconomic, and health-related factors. Namely, transgender subjects suffer from social stigma and marginalization, and often lack social support. Therefore, they are at major risk of illegal substance use, commercial sex work, homelessness, limited health care access, and negative health care encounters, incarceration, and sexual abuse as compared with nontransgender people.^7–9 Indeed, it is very difficult to collect reliable data on transgender population due to the great diversity in attitude and behavior in this population.

To obtain representative estimates of HIV, HBV, and HCV infections, we reviewed data regarding transgender individuals referred to an Italian center for total sex reassignment surgery (SRS).

MATERIALS AND METHODS

The setting of the present study is the department of Urology at the Hospital of Trieste, Italy, which is 1 of the 7 Italian referral centers for SRS. In Italy, transgender subjects, including HIV-infected persons, have free of charge access to SRS after a psychological evaluation and court ruling. The Italian surgical activity regarding sex dysphoria is coordinated by the “Osservatorio Italiano sulla Identità di Genere” (www.onig.it). In the present retrospective observational study, we included all consecutive transgender subjects undergoing SRS in our center from January 2000 to September 2014. A review of clinical and laboratory records was performed. Participant characteristics were collected including demographics, such as age, ethnicity and geographic place of birth, year at SRS. Up to 2007, HIV screening was performed by the immunoassay Enzygnost anti-HIV 1/2 Plus (Dade Behring, Marburg, Germany) confirmed by the immunoblotting New Lav Blot I/II (Bio-Rad, Marnes La Coquette, France); HCV screening by the immunoassay Ortho HCV 3.0 Elisa Test System (Ortho Clinical Diagnostics, Raritan, NJ) confirmed by the immunoblotting Chiron Riba HCV 3.0 SIA (Chiron, Dublin, Ireland); HBV screening by the immunoassays Enzygnost (Dade Behring). Since 2008, HIV and HCV screenings were performed by the Chemiluminescent Microparticle Immunoassay, CMIA (Abbott, Wiesbaden, Germany). Reactive samples were subsequently confirmed by Line Immune Assay (Innogenetics, Gent, Belgium). Markers of HBV infection were determined by CMIA (Abbott). The results of HBV serological markers were interpreted according to the CDC guidelines,¹⁰ simplified as follows. The HBV infection was defined by the presence of HBsAg, HBcAb, or both; HBV immunity (previous infection or vaccination) by the presence of HBsAb. We excluded cases with serological data performed in other centers than ours. The results for HIV, HBV, and HCV infections were available to all participants, and individuals found positive for HIV or HCV serology and those with HBV infection were referred for care and support. Considering the small number of subjects in the study, bivariate exact statistical analyses were conducted while comparing groups of subjects who differed by time, space, and other characteristics. Exact Fisher test and exact unilateral Cochran-Armitage test for trend analyses were applied rather than regular χ². To estimate the prevalence ratio, we adopted a generalized linear model with the binomial distribution and the log link as suggested for the SAS software.¹¹ These analyses were computed using SAS version 9.3 (Cary, NC).

RESULTS

A total of 498 transgender individuals referred to our center during the period 2000–2014 to be evaluated for SRS. Among these subjects, 243 underwent SRS and had confirmed serological data for HIV, HBV, or HCV infections (Fig. 1). Of them, 25 were FtM and 218 were MtF subjects. The mean age at SRS of our population ± standard deviation was 33.5 ± 7.7 years. As regards their origin, 91% were white, 6.1% Hispanics, and 2.9% of other ethnicity. Table 1 shows the prevalence of HIV, HBV, and HIV infections among FtM and MtF subjects.

Figure 1

Table 1

All FtM subjects were Italian. Among them, the prevalence of HIV, HBV, and HCV infections were 0%, 4.0% (1/25), and 8.0% (2/25), respectively. On the other hand, among MtF individuals, the prevalence of such infections were found to be 12.1% (21/173 and 45 missing), 4.6% (10/218), and 3.7% (8/214 and 4 missing), respectively.

Human Immunodeficiency Virus

As regards MtF subjects, the prevalence of HIV infection did not depend on year of birth, rather on calendar year of SRS (Table 2). Specifically, there was a statistically significant trend between earlier year of SRS and lower HIV prevalence (exact unilateral Cochran-Armitage test for trend P value: 0.0239). The trend between older age at SRS and higher HIV prevalence showed a borderline significant association (exact unilateral Cochran-Armitage test for trend P value: 0.0572). The HIV prevalence varied strongly by geographic area of origin and was somewhat higher among the few subjects coming from other European countries, and much higher among subjects from South America (exact Fisher test comparing origin in South America vs other origins P value: 0.0029). The 2 subjects from Asia and Africa were HIV-negative.

Table 2

Hepatitis B Virus

Table 3 describes HBV infection and immune status in MtF and FtM subjects. Among MtF, the prevalence of HBV infection was 10 (4.6%) of 218 with a significant trend (P = 0.0045) of higher infection with later year of SRS. Specifically, prevalence of HBV infection was 1 (1.1%) of 94 for SRS in 2000–2004; 2 (3.2%) of 62 for SRS in 2005–2009; and 7 (11.3%) of 62 for SRS in 2010–2014. Among FtM, overall HBV infection was 4.0% (1/25), restricted to 1 case with year of SRS 2002, age at SRS 26 years, and year of birth 1975.

Table 3

Among MtF subjects the prevalence of HBV immunity was 38.5% (84/218) and was associated with year of birth ≥1980 (P-value: 0.005) (Table 3). There was no linear trend of HBV immunity with age at SRS because HBV immunity was higher among subjects who underwent surgery younger than 30 years or older than 50 years. There was a slight, albeit not significant trend (P = 0.0814), increase of HBV immunity with more recent calendar year of SRS (data not shown). The HBV immunity was higher, but not statistically significant (P = 0.098), among subjects from South America. The HBV immunity was also frequent among the few subjects from Asia and Europe. After mutual adjustment in multivariate models, the prevalence ratios were 2.1 (95% confidence interval [95% CI], 1.3–3.4) for South American origin versus others and 2.2 (95% CI, 1.6–3.1) for year of birth ≥ 1980.

Among FtM subjects, the prevalence of HBV immunity was 24.0% (6/25), and it was higher among subjects born in year ≥1980. All HBV immune FtM subjects had SRS before year 2010 and younger than 40 years.

Hepatitis C Virus

In MtF subjects, HCV infection prevalence was 3.7% (8 of 214 tested) and without geographic or temporal variations. On the other hand, in FtM subjects, HCV prevalence was 8.0% (2/25).

Coinfections

Among FtM subjects, there were no double or triple HIV, HBV, HCV infections. Among MtF subjects, there were no triple HIV, HBV, HCV infections. Coinfection with 2 viruses was found in 6 (2.8%) of 218 MtF tested individuals (Table 4). Among the 6 HBV-positive MtF subjects, 2 were also HIV-positive (33.3%) but none was HCV-positive. Among the 7 HCV-positive MtF subjects, 4 were also HIV-positive (57.1%). Among the 21 HIV-positive MtF subjects, 2 were also HBV-positive (9.52%) and 4 (different) were HCV-positive (19.05%). From a multivariate logistic regression model, a strong, statistically significant association (P < 0.0001) was found between HIV and HCV positivity after adjustment for HBV infection, HBV immunity, subject's origin, and age and year at SRS.

Table 4

DISCUSSION

Our data show the high burden of HIV infection among MtF transgender individuals. On the contrary, no HIV-infected individual was found among the smaller number of FtM subjects. Unlike our data, there was no difference in HIV prevalence between MtF and FtM subjects referred to the municipal STD clinic in San Francisco, CA, during the period 2006–2008.¹² However, a recent systematic review estimated that prevalence rates of HIV and risk behaviors were low among FtM individuals in United States.⁸ As regards the frequency of HIV infection among MtF individuals, various studies have been published so far. The prevalence of HIV infection among our MtF subjects (12.1%) was lower than that found in a recent review and meta-analysis showing that HIV prevalence was 19.1% in MtF worldwide, with an odds ratio of 48.8 (95% CI, 21.2–76.3) compared with the general adult population.⁶ However, the authors comment that sampling biases could result in overestimation of the actual HIV prevalence, for example, when sampling transgender subjects who are seeking care in centers for STD or HIV/acquired immune deficiency syndrome. Similarly, the latter issue regards the systematic review on US transgender persons which found 27.7% (95% CI, 24.8–30.6) of MtF tested positive for HIV infection.⁸ To our opinion, recruitment of the target population in commercial sex locations or in centers for noninfectious medical conditions (as our center) could provide more reliable epidemiological results regarding sex-related infections. For instance, a cross-sectional survey showed HIV prevalence of 22% among sex location-recruited transgender sex workers in Jakarta, Indonesia, in 2002.¹³ Again, a study on MtF transgender persons in Bangkok, Thailand, showed overall HIV prevalence 13.5% using venue-day-time sampling as enrolling method in 2005.¹⁴ Conversely, in Rome, Italy, HIV prevalence was found to be very high (38.2%) among MtF transsexual sex workers who attended an “acquired immune deficiency syndrome unit” between 1993 and 1999.¹⁵ Most of the latter patients came from South America, especially Colombia and Brazil, countries known to be significantly associated with HIV infection. A subsequent study from the same center showed a decrease of HIV prevalence in such population up to 2003.¹⁶ This finding was attributed to an increase in regular condom use over time. In our series, HIV infection was significantly higher among transgender subjects from South America than among subjects from Italy and other countries. This confirms that immigrants are at an increased risk of acquiring HIV infection compared with natives as previously reported by others.^8,17 As regards to the year at SRS, the proportion of HIV positive subjects seems to increase over time among our population, especially since 2010. This worrying trend underlines the social and medical needs of this transgender population. Because individual prevention counselling has been shown to result in limited effectiveness in reducing HIV transmission,¹⁸ even other prevention methods, such as preexposure prophylaxis (PrEP) for HIV, should be proposed, especially to MtF individuals with multiple sex partners and receptive anal intercourses. Indeed, PrEP with daily oral doses of antiretroviral agents (ie, fixed-dose combination of tenofovir disoproxil fumarate and emitricitabine) appears to be a safe intervention that determines a substantial reduction in the rate of HIV acquisition for MSM and MtF individuals who have sex with men.^19,20

To our knowledge, very few data regarding HBV and HCV infections in transgender populations are available to date. During 1992–2003 in Rome, Italy, HBV and HCV prevalence among transsexual immigrants was quite high (53.5% and 13.3%, respectively).¹⁶ Similarly, from 2006 to 2009 in 7 cities of Argentina, HBV prevalence was found to be 40.2% among transgender workers.²¹ More recently, much lower prevalence of HBV (0.6–3.5%) and HCV (0.8–6.9%) infections were found among transsexuals in 4 cities of Dominican Republic.²²

Regarding HBV infection among our transgender population, the prevalence of HBV infection was similar between MtF and FtM subjects (4.6% vs 4.0, respectively) approaching to the value recently estimated among the general population in the intermediate-prevalence areas of the world.²³ The HBV immunity was higher among MtF (38.5%) than FtM (24%) individuals and was found to be significantly higher in younger subjects for both groups of transgenders. On the other hand, almost two thirds of MtF and three fourths of FtM individuals had no HBV immunity. This is indeed worrisome in Italy where HBV vaccination is mandatory for infants since 1991 and is strongly recommended and offered free of charge to people at increased risk of infection including the transgender population.

Lastly, the prevalence of HCV antibodies among MtF subjects was 3.7%, which is consistent with estimates recently reported in the general population of Western Europe and Latin America countries (1.5%–3.5%).²⁴ On the other hand, the prevalence of the latter infection in FtM subjects was 8.0%, but the overall number of FtM subjects was quite small. Interestingly, the prevalence of HCV infection among our HIV-infected MtF transgenders was found to be higher than that of the same HIV-uninfected population. Various studies from Europe and North America reported an increased incidence of HCV infection in HIV-infected men MSM with only sexual exposure as a risk factor.^2–4,25 Indeed, HCV has been found in the semen of HCV viremic suggesting that sexual transmission is possible.²⁶ Despite the absence of behavioural information, our findings seem to indicate that MtF HIV-infected subjects might be infected by HCV through unprotected receptive anal intercourses or other traumatic sexual practices (eg, fisting) before SRS. Anyway, this strongly suggests that MtF HIV-infected transgenders should be tested for incident HCV through frequent HCV antibody testing, similar to that recently recommended by the Centers for Disease Control and Prevention for HIV-infected MSM.²⁷ In fact, most HCV-infected patients are asymptomatic and unaware of their infection but remain a source of transmission to others and are at risk of chronic liver diseases and other HCV-related diseases, especially if HIV-coinfected.

To the best of our knowledge, this is the first study evaluating the prevalence of some relevant infections among transgender individuals referring to a center for SRS. However, this study has several limitations. First, the retrospective design of the study does not allow to investigate behavior variables, particularly sexual behaviors. Similarly, other data, such as testing for syphilis, HSV1, and HSV2 infections, Chlamydia, gonorrhoea, and hepatitis A virus are missing. For this purposes, we are enrolling prospectively transgender individuals referring to our center for SRS since 2014. We are offering to our population such screenings and administering a questionnaire targeted on their behavior. Among the first 23 MtF subjects enrolled, 96% of them have a male sexual partner, 46% have a steady sexual partner, 17% declared to be or have been sex worker. Their sexual intercourses were anal receptive except in a single case, and they reported no injective drug use except in a single case (data not shown). Second, the total number of FtM subjects is quite low and does not allow any reliable comparisons and comments. Third, the study period is prolonged, reaching almost 14 years, during which the epidemiology of some infections might have changed. However, this limitation has been controlled through analyses comparing groups of subjects by time. Lastly, our results relate to a relatively small number of subjects referring to a single clinical center and should not be generalized.

Keeping in mind these limitations, we believe that the value of this study could be to obtain some real-life information on this marginalized population. In perspective, the evaluation for HIV infection and other infections at SRS could turn out a crucial moment to provide social, behavioral, and medical support including PrEP for transgender subjects or their sexual partners.

In conclusion, the prevalence of HBV and HCV infections among our transgender individuals overlaps that reported in the general population. However, HCV prevalence was found to be much higher in HIV-infected MtF transgenders, and this strongly suggests enforced surveillance on HCV infection. The HBV vaccination should be more extensively proposed to both MtF and FtM subjects and, eventually, to their sexual partners. Regarding HIV infection, our data show the high burden of such infection among MtF individuals. Worryingly, the prevalence of HIV infection seems to increase in more recent years, pointing out that social and medical support including PrEP offering and counselling for safe sex behavior should be strongly promoted among MtF individuals.

REFERENCES