Gender-Affirming Care in Persons Living With HIV

Gender-affirming care consists of comprehensive services including medical, surgical, mental health, and social services to support and affirm an individual’s gender identity.^1,2 Gender identity refers to a person’s individual experience of gender.¹ A transgender, gender nonconforming, gender nonbinary, or genderqueer person’s gender identity differs from the sex they were assigned at birth.³

In 2019, approximately 1 million individuals living in the United States identified as transgender or gender nonconforming.⁴ Transgender individuals made up approximately 2% of all new HIV diagnoses that year.⁵ Transgender persons are at high risk for acquiring HIV, with approximately 14% of trans women and 3% of trans men already living with HIV and even higher rates among racial minority transgender persons.⁶ Transgender individuals may prioritize gender-affirming hormone therapy (GAHT) over antiretroviral therapy (ART) if they perceive ART to decrease efficacy of GAHT.³ Previous literature suggests provision of gender-affirming care to persons living with HIV improves quality of life as well as engagement and retention in care.⁷

GENDER-AFFIRMING HORMONE THERAPY
GAHT therapy consists of administration of exogenous hormones and suppression of endogenous hormone production, with the goal of obtaining characteristics more congruent with an individual’s gender identity.⁸ Currently, there are several clinical practice guidelines to inform gender-affirming care, but it is important to note that data to guide treatment decisions in persons living with HIV specifically are scarce.^3,8,9

In general, goals of GAHT should be individualized to each patient and target acquisition of secondary sex characteristics that better align with the patient’s gender identity.^3,8,9 Some may prefer limiting hormonal effects or maintaining a mix of feminine and masculine characteristics.³ Therefore, recommendations for specific serum level monitoring targets herein are based on cisgender adult normal ranges to avoid long-term complications of supratherapeutic levels, with the goal of total feminization or masculinization.^8,9

FEMINIZING HORMONE THERAPY
Estrogen is the cornerstone of feminizing hormone therapy (FHT). However, because estrogen therapy alone is not enough to suppress testosterone levels, FHT also typically consists of an antiandrogen and sometimes progestogen and/or gonadotropin-releasing hormone (GnRH) agonist.^3,8,9

Estrogen Therapy
There are several preparations of estrogen available: oral conjugated estrogens, ethinyl estradiol (EE), and oral or sublingual, injectable, or transdermal 17β-estradiol. 17β-Estradiol is biochemically identical to the estrogen released from the ovary and is preferred to EE and oral conjugated estrogens because of its more favorable safety profile. EE is commonly formulated into oral contraceptives and increases risk for venous thromboembolism. In addition to venous thromboembolism risk, conjugated estrogens also increase cardiovascular (CV) risk.^8,9 The transdermal formulation is thought to have the least thromboembolic risk of all preparations.^8,10

Sublingual administration of micronized tablets and the injectable formulations have been found to have variable pharmacokinetics and higher serum concentrations, as they bypass first-pass metabolism.^9,11 Injectable estradiol can result in peak levels of 250 pg/mL and troughs of 50 pg/mL; decreasing the dosing interval between injections may decrease these fluctuations in levels.³ The most common adverse effects of 17β-estradiol preparations are mood swings, migraines, hot flashes, and weight gain.¹⁰ Dosing and considerations for monitoring can be found in TABLE 1. Studies comparing the efficacy of the agents look primarily at postmenopausal women, with no 1 formulation more efficacious than the others for all outcomes. Moreover, the desired effects in the study population differ from the desires of transgender persons.¹² Therefore treatment decisions should be based on patient preference.

Monitoring parameters for 17β- estradiol therapy include maintenance of serum estradiol levels between 100 and 200 pg/mL and serum testosterone less than 50 ng/dL. Timing of monitoring is further described below in TABLE 2. Conjugated and synthetic estrogens cannot be evaluated via blood testing and are not recommended for use as GAHT.⁹

Estrogen therapy is also associated with increased triglycerides (TG) without significant effects on high- and low-density lipoproteins (HDL and LDL).¹³ Ritonavir- and cobicistat-boosted ART, efavirenz, and tenofovir alafenamide (TAF) are also associated with dyslipidemias.¹³ Prior to initiating estrogen therapy in individuals taking these antiretrovirals (ARV), providers should discuss interventions tailored to decrease CV risks, such as smoking cessation and lifestyle modifications.⁹ Currently, there is conflicting evidence regarding the risk of CV events with abacavir. Nonetheless, abacavir should be used with caution in patients taking estrogen, especially those with CV risk.

Ritonavir-boosted protease inhibitors, efavirenz, etravirine, and nevirapine are expected to decrease serum concentrations of estradiol. Therefore, the US Department of Health and Human Services (DHHS) guidelines recommend increasing the dose of estradiol in patients taking these medications concomitantly to achieve desired clinical effects. These ARVs are no longer commonly prescribed in the United States but may still be used in other countries. Because of conflicting information provided in the DHHS guidelines, it is unclear the effect of cobicistat-boosted regimens may have on estradiol concentrations.¹³ Current evidence has investigated only the impact of these regimens on EE exposure, showing decreased EE exposure with boosted darunavir and elvitegravir but no difference with boosted atazanavir.^14,15 Closer monitoring of serum estradiol levels may be required to achieve desired clinical effects.

Antiandrogens
Antiandrogens suppress production of testosterone and suppress male characteristics. These medications include spironolactone, GnRH agonists, and 5-α reductase inhibitors.

Spironolactone is a potassium-sparing diuretic with androgen receptor–blocking properties at high doses as well as dose-dependent gynecomastia.^3,10 Doses of 200 to 400 mg daily have been reported without negative effects.3 Total daily doses greater than 50 mg should be divided into 2 doses.³ Hyperkalemia rarely occurs and is more likely in patients with impaired renal function or concomitant use of angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, or sulfamethoxazole-trimethoprim.^3,10 Because of its diuretic effect, hypotension can occur and patients may experience self-limiting polydipsia and polyuria.^10,8

GnRH agonists, such as histrelin and leuprolide, block the release of follicle-stimulating and luteinizing hormones, leading to full gonadal blockade.^8,10 Histrelin is a surgically inserted implant that lasts 12 to 36 months, whereas leuprolide requires injections ranging from daily to every 3 to 4 months.⁹ Although more commonly used to delay puberty in adolescents, these medications may be used in combination with estrogen to lower testosterone levels.^3,8,10 Redistribution of body fat toward the affirmed gender can occur; however, most studies simply report an increase in body fat and decrease in muscle mass, which may or may not be desired.¹⁶ Effects of GnRH agonists on bone mineral density (BMD) have not been well studied but may be of less concern when used as an adjunct to estradiol. Exogenous estrogen therapy has been shown to be sufficient in maintaining normal BMD.¹⁷ Because tenofovir disoproxil fumarate (TDF) has been associated with a decrease in BMD, it should be used with caution in transgender patients who are at higher risk for osteopenia and osteoporosis, including those on GnRH agonists in the absence of hormone therapy.¹³ Hypertension has also been reported with GnRH agonists.⁹

Lastly, 5-α reductase inhibitors block the conversion of testosterone to dihydrotestosterone. Because they do not suppress testosterone production or activity, these inhibitors have less of an antiandrogen effect when compared with GnRH agonists. Dutasteride is more selective of the pilosebaceous unit compared with finasteride and therefore may have more feminizing effects. These agents are a good option for patients seeking only partial feminization or experiencing hair loss after total androgen blockade.^3,10 Normal dosing in gender-affirming care is finasteride 1 to 5 mg daily and dutasteride 0.5 mg daily. Both are associated with decreased libido and ejaculation disorders.^3,10,18

Boosted ART is expected to increase concentrations of these agents. Conversely, efavirenz, etravirine, and nevirapine may result in decreased 5-α reductase inhibitor concentrations; therefore, increased doses may be required to achieve desired clinical effects.¹³

Progestogens
To date, evidence from well-designed trials for progestogens as FHT is lacking. Nevertheless, progestogens are thought to improve breast development, mood, and libido without evidence to suggest harm.^3,8,9 Commonly used progestogens include micronized progesterone 100 to 200 mg at bedtime or medroxyprogesterone 2.5 to 10 mg at bedtime.³ Depot medroxyprogesterone acetate is less common in transgender women but may be used in transgender men to induce amenorrhea.^3,8,9

Physical changes with FHT can be expected between 3 and 12 months after treatment initiation. Decreased sexual desire and spontaneous erection may occur within 1 to 3 months of starting hormone therapy. Within 3 to 6 months, redistribution of body fat, decrease in muscle mass, skin softening, breast growth, and decrease in testicular volume can be expected. Finally, after 6 to 12 months, terminal hair growth declines.

MASCULINIZING HORMONE THERAPY
The general approach to masculinizing hormone therapy (MHT) is the administration of exogenous testosterone, with the goal of developing male secondary sex characteristics and suppression or minimization of female sex characteristics.

Testosterone
Testosterone is available in injectable and transdermal formulations, which are all thought to be equally efficacious. Dosing is summarized in Table 1. Adverse effects of injectable formulations include acne, polycythemia, sleep apnea, and dyslipidemia, whereas transdermal formulations (including the patch) may also cause skin irritation and hypersensitivity.¹⁰

According to the Endocrine Society guidelines, the normal male range for total testosterone levels is between 320 and 1000 ng/dL, but reference values may vary by assay.⁹ If patients experience decreased libido and mood, testosterone should be uptitrated to target midrange values. Further uptitration to the upper end of the reference range is unlikely to produce further masculinizing results and is not recommended.³ Depot medroxyprogesterone acetate 150 mg every 3 months may be used in transgender men to induce amenorrhea until full effects of testosterone are seen.^3,8,9

Physical changes with MHT expected to occur within 1 to 6 months of the initiation include the cessation of menstruation, increased libido, increased body and facial hair, increased muscle mass, and redistribution of body fat. Deepening of the voice, clitoromegaly, and sometimes male pattern baldness can be expected within 12 months of testosterone therapy.⁹

Testosterone therapy has a similar drug interaction profile to that of 5-α reductase inhibitors regarding ART. Boosted ARVs are expected to increase concentrations of testosterone, whereas efavirenz, etravirine, and nevirapine may result in decreased concentrations; therefore, increased doses of testosterone may be required. Exogenous testosterone also increases LDL and TG while decreasing HDL in transgender men. Therefore, caution should be used when initiating boosted ART, efavirenz, abacavir, and TAF.¹³

CONSIDERATIONS FOR PRE-EXPOSURE PROPHYLAXIS
The CDC and the United States Preventive Services Task Force recommend use of preexposure prophylaxis (PrEP) in all high-risk individuals, including transgender persons.¹⁹ Small pharmacokinetic studies have found lower serum concentrations of emtricitabine (F)/TDF and F/TAF in transgender women. However, these lower concentrations were still within the expected ranges for patients taking these medications and above the levels necessary to confer 90% protection from HIV infection.²⁰ F/TDF has no effect on serum levels of gender-affirming hormones, more specifically testosterone and estradiol.²¹ Long-acting injectable cabotegravir (CAB) is not expected to have any drug-drug interactions (DDIs) with GAHT and was found to be superior to oral PrEP for prevention of HIV infection.^22,23 Therefore, F/TDF and CAB can each be safely used as PrEP in the setting of GAHT. F/TAF is expected to remain efficacious in transgender women on FHT, but it is currently not approved for transgender men.^19-22

CONCLUSIONS
Modern ARV regimens have few, if any, expected DDIs with GAHT, including agents used for PrEP. Clinicians should discuss the benefits of adherence to agents used for HIV treatment and prevention, as well as the minimal risk for DDIs with GAHT.

References

1.Gender. World Health Organization; 2022. Accessed July 20, 2022. https://www.who.int/europe/health-topics/gender#tab=tab_1

2.HHS Office of Population Affairs. Gender-Affirming Care and Young People. Department of Health and Human Services Accessed July 20, 2022. https://opa.hhs.gov/sites/default/files/2022-03/gender-affirming-care-young-people-march-2022.pdf

3.Deutsch M. Guidelines for Primary and Gender-Affirming Care of Transgender and Gender Nonbinary People. 2nd ed. Center of Excellence for Transgender Health; 2016.

4.Caughey AB, Krist AH, Wolff TA, et al. USPSTF Approach to Addressing Sex and Gender When Making Recommendations for Clinical Preventive Services. JAMA. 2021;326(19):1953. doi:10.1001/jama.2021.15731

5.HIV and Transgender People. Centers for Disease Control and Prevention; 2022. Accessed July 20, 2022. https://www.cdc.gov/hiv/pdf/group/gender/transgender/cdc-hiv-transgender-factsheet.pdf

6.Becasen JS, Denard CL, Mullins MM, Higa DH, Sipe TA. Estimating the Prevalence of HIV and Sexual Behaviors Among the US Transgender Population: A Systematic Review and Meta-Analysis, 2006-2017. Am J Public Health. 2019;109(1):e1-e8. doi:10.2105/AJPH.2018.304727

7.Sevelius JM, Patouhas E, Keatley JG, Johnson MO. Barriers and facilitators to engagement and retention in care among transgender women living with human immunodeficiency virus. Ann Behav Med. 2014;47(1):5-16. doi:10.1007/s12160-013-9565-8

8.Standards of Care for the Health of Transsexual, Transgender, and Gender Nonconforming People. In: Vol 7. World Professional Association of Transgender Health; 2012. https://www.wpath.org/publications/soc

9.Hembree W, Cohen-Kettenis P, Gooren L, et al. Endocrine Treatment of Gender-Dysphoric/ Gender Incongruent Persons: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2017;102(11):3869-3903.

10.Badowski ME, Britt N, Huesgen EC, et al. Pharmacotherapy considerations in transgender individuals living with human immunodeficiency virus. Pharmacotherapy. 2021;41(3):299-314. doi:10.1002/phar.2499

11.Cirrincione LR, Winston McPherson G, Rongitsch J, et al. Sublingual Estradiol Is Associated with Higher Estrone Concentrations than Transdermal or Injectable Preparations in Transgender Women and Gender Nonbinary Adults. LGBT Health. 2021;8(2):125-132. doi:10.1089/lgbt.2020.0249

12.Ansbacher R. The pharmacokinetics and efficacy of different estrogens are not equivalent. American Journal of Obstetrics and Gynecology. 2001;184(3):255-263. doi:10.1067/mob.2001.109656

13.Panel on Antiretroviral Guidelines for Adults and Adolescentse. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV. Department of Health and Human Services. Accessed August 22, 2021. Department of Health and Human Services

14.Majeed SR, West S, Ling KH, Das M, Kearney BP. Confirmation of the drug-drug interaction potential between cobicistat-boosted antiretroviral regimens and hormonal contraceptives. Antivir Ther. 2019;24(8):557-566. doi:10.3851/IMP3343

15.Genvoya(elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide) [package insert]. Food and Drug Administration. Published online 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/207561s023lbl.pdf

16.Klaver M, de Mutsert R, Wiepjes CM, et al. Early Hormonal Treatment Affects Body Composition and Body Shape in Young Transgender Adolescents. J Sex Med. 2018;15(2):251-260. doi:10.1016/j.jsxm.2017.12.009

17.Mueller A, Dittrich R, Binder H, et al. High dose estrogen treatment increases bone mineral density in male-to-female transsexuals receiving gonadotropin-releasing hormone agonist in the absence of testosterone. Eur J Endocrinol. 2005;153(1):107-113. doi:10.1530/eje.1.01943

18.Chiriacò G, Cauci S, Mazzon G, Trombetta C. An observational retrospective evaluation of 79 young men with long-term adverse effects after use of finasteride against androgenetic alopecia. Andrology. 2016;4(2):245-250. doi:10.1111/andr.12147

19.US Centers for Disease Control and Prevention and Public Health Service Task Force. PREEXPOSURE PROPHYLAXIS FOR THE PREVENTION OF HIV INFECTION IN THE UNITED STATES – 2021 UPDATE.; 2021.

20.Yager JL, Anderson PL. Pharmacology and drug interactions with HIV PrEP in transgender persons receiving gender affirming hormone therapy. Expert Opinion on Drug Metabolism & Toxicology. 2020;16(6):463-474. doi:10.1080/17425255.2020.1752662

21.Yager J, Brooks KM, Brothers J, et al. Gender-affirming hormone pharmacokinetics among adolescent and young adult transgender persons receiving daily F/TDF. AIDS Research and Human Retroviruses. Published online July 10, 2022:AID.2022.0044. doi:10.1089/AID.2022.0044

22.Delany-Moretlwe S, Hughes JP, Bock P, et al. Cabotegravir for the prevention of HIV-1 in women: results from HPTN 084, a phase 3, randomised clinical trial. The Lancet. 2022;399(10337):1779-1789. doi:10.1016/S0140-6736(22)00538-4

23.Landovitz RJ, Donnell D, Clement ME, et al. Cabotegravir for HIV Prevention in Cisgender Men and Transgender Women. N Engl J Med. 2021;385(7):595-608. doi:10.1056/NEJMoa2101016

24.Oriowo MA, Landgren BM, Stenström B, Diczfalusy E. A comparison of the pharmacokinetic properties of three estradiol esters. Contraception. 1980;21(4):415-424. doi:10.1016/s0010-7824(80)80018-7

25.Small DS, Ni X, Polzer P, Vart R, Satonin DK, Mitchell MI. Effect of Deodorant and Antiperspirant Use and Presence or Absence of Axillary Hair on Absorption of Testosterone 2% Solution Applied to Men’s Axillae. The Journal of Sexual Medicine. 2014;11(11):2809-2817. doi:10.1111/jsm.12658

26.Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab. 1999;84(10):3666-3672. doi:10.1210/jcem.84.10.6079