台灣人類免疫缺乏病毒帶原者與男性性腺功能低下症之盛行率與相關因子研究

Abstract

背景簡介：男性性腺功能低下在HIV感染的族群相當常見，早期的流行病學研究盛行率高達29%至50%，先前國外流行病學調查顯示HIV男性族群性腺功能低下的盛行率大約在9%至16%之間。研究關於HIV感染的族群和男性性腺功能低下的可能相關因子包括體重下降程度、CD4數量、體脂肪等等。成年男性睪固酮不足的臨床表現包括性慾下降、勃起功能障礙、骨質密度降低、肌肉質量下降、憂鬱以及代謝症候群等等，而研究發現HIV陽性族群，血中低睪固酮濃度和體重下降、肌肉流失、運動表現及衰老指數呈現相關性。根據2018年美國內分泌學會治療指引，針對HIV陽性族群的男性性腺功能低下症合併體重減輕，建議短期睪固酮補充以維持體重和增加瘦體質量。在此研究之前，文獻尚無關於亞洲族群HIV帶原男性其性腺功能低下症的盛行率、危險因子及臨床表現之探討。 目的：研究台灣HIV帶原者其男性性腺功能低下症的盛行率，和未感染HIV的一般族群比較，並進一步分析可能的危險因子。 方法：在這單一中心、橫斷性研究中，自2021年2月至2022年11月這段期間，慢性HIV帶原、穩定服用抗病毒藥物且測不到病毒量的20歲以上男同志（men who have sex with men，下稱MSM）受試者透過臺大醫院和臺大雲林分院感染科門診加入試驗。未感染HIV的MSM對照組來自匿名篩檢計畫和政府補助之公費暴露前預防藥物（PrEP）門診。相關臨床資料包括年齡、身體質量指數、慢性病等透過問卷和電子病歷加以記錄。受試者填寫美國聖路易大學老化男人睪固酮低下問卷 （ADAM，Androgen Deficiency in Aging Male），以評估是否有睪固酮低下之症狀。受試者於早上空腹抽血檢驗血清總睪固酮、白蛋白、性荷爾蒙結合球蛋白以計算游離睪固酮之濃度，同時測量可能影響性腺功能的生化指數和賀爾蒙。生化意義的性腺功能低下（biochemical hypogonadism）定義為血清游離睪固酮濃度小於63.5 pg/mL。有症狀之性腺功能低下（symptomatic hypogonadism）定義為低血清游離睪固酮濃度合併ADAM問卷篩檢結果陽性。本研究使用多元線性回歸分析和血清游離睪固酮濃度相關的臨床因子。此外，在相同年齡分層下，我們比較HIV帶原者和未感染HIV之對照組在性腺功能低下症的盛行率有無差異。 結果：本研究一共納入447位HIV帶原者和124位HIV陰性的MSM受試者。HIV帶原組的年齡顯著大於對照組（中位數41歲 versus 29.5歲），慢性病的盛行率也較高。HIV帶原組診斷中位數8.5年，CD4數量中位數482顆/微升。分別有11.6%的帶原組和1.6%的對照組呈現生化意義的性腺功能低下，而分別有8.3%的帶原組和1.6%的對照組呈現有症狀之性腺功能低下。在HIV帶原組當中，最常見次發性性腺功能低下，佔8.9%。而亞臨床和原發性性腺功能低下分別佔5.4%和2.7%。在小於三十五歲的年輕次分群，HIV帶原的有無對於血清游離睪固酮濃度和性腺功能低下的盛行率無顯著差別。多元線性回歸分析顯示血清游離睪固酮濃度隨著年齡和身體質量指數的上升而顯著下降，而和HIV帶原狀態、甲狀腺功能、泌乳激素濃度以及其他共病症無顯著關聯性。進一步分析HIV帶原組別，血清游離睪固酮濃度和HIV感染時間呈現負相關，而和核類反轉錄抑制劑（NRTI）呈現正相關。 討論：這項研究是迄今針對華人MSM族群性腺功能低下症的最大規模之橫斷性研究。有症狀之性腺功能低下在研究中HIV帶原族群的盛行率為8.3%，略低於國外的研究族群。究其原因，原發性之性腺功能低下的比例和義大利的研究差不多，而次發性性腺功能低下的比例則低於文獻，因此我們推測HIV帶原族群整體健康狀況的改善、病毒量的抑制以及收案時排除干擾睪固酮測量的藥物等，應是本研究盛行率較低的原因。研究中大部分HIV帶原者（96.6%）皆使用NRTI，未使用的五名受試者其藥物組合dolutegravir和rilpivirine文獻中並未發現和睪固酮濃度相關，因此NRTI和睪固酮濃度的相關性仍有待進一步研究確認。最後，本研究的限制包括帶原組和對照組之年齡差距較大、使用單次睪固酮檢測作為診斷標準、以及排除正在使用睪固酮製劑的受試者，可能造成評估真正性腺功能低下盛行率的誤差。 結論：本研究發現台灣HIV帶原者其男性性腺功能低下症的盛行率較國外研究略低，但高於研究中未感染HIV的族群。HIV帶原和未感染HIV兩組之間性腺功能低下症之盛行率差異主要來自於年齡的差距。進一步分析發現血清游離睪固酮的濃度和年齡及身體質量指數呈現負相關，而和HIV感染與否沒有顯著相關。

Background: Hypogonadism is common among people with HIV (PWH), with prevalence around 9% to 16% in different studies. Risk factors associated with hypogonadism in PWH included weight loss, CD4 counts, body fat. Studies regarding androgen deficiency in PWH reported loss of lean body and muscle mass, deterioration in exercise functional capacity, frailty, and poor health status. Existing data regarding prevalence, clinical manifestations and risk factors associated with male hypogonadism are limited in PWH in Asian populations. Objective: We aimed to investigate the clinical manifestations and prevalence of hypogonadism among PWH in Taiwan and compare them with individuals without HIV infection. We further explored the factors associated with serum free testosterone levels in PWH. Methods: This cross-sectional study enrolled adult men who have sex with men (MSM) on stable antiretroviral therapy with suppressed plasma HIV-1 RNA levels from February 2021 to November 2022 at National Taiwan University Hospital (NTUH) and NTUH Yunlin Branch. MSM without HIV, including those seeking anonymous HIV testing, and participants in pre-exposure prophylaxis (PrEP) program, were enrolled as the comparison group. Clinical data, including demographics and comorbidities, were collected through questionnaires and electronic medical records. Androgen Deficiency in Aging Men (ADAM) questionnaire was performed to evaluate symptoms of hypogonadism in the participants. Morning fasting levels of serum free testosterone, sex hormone-binding globulin, and other related hormones were obtained. Biochemical hypogonadism was defined by serum free testosterone level < 63.5 pg/mL. Symptomatic hypogonadism was defined by low free testosterone plus positive ADAM questionnaire result. Multiple linear regression analysis was conducted to evaluate the relationship between serum free testosterone levels and the collected clinical variables. Furthermore, MSM without HIV infection were enrolled and compared with HIV-positive group within the same age stratification. Results: In our study, 447 MSM with HIV and 124 MSM without HIV were included. Compared to MSM without HIV, those with HIV were older (median age 41 versus 29.5 years) and had a higher prevalence of comorbidities such as HBsAg and anti-HCV positivity, hypertension, diabetes, and hyperlipidemia. In MSM with HIV, the median HIV infection duration was 8.5 years, with a median CD4 count of 482 cells/μL. Biochemical hypogonadism was more prevalent in MSM with HIV (11.6%) than in those without (1.6%). Symptomatic hypogonadism also showed higher prevalence in MSM with HIV (8.3% vs. 1.6%). Secondary hypogonadism was the most common in MSM with HIV (8.9%), followed by subclinical (5.4%) and primary hypogonadism (2.7%). Among MSM aged <35 years, there were no significant differences in serum free testosterone levels or prevalences of hypogonadism between the two groups. Multiple linear regression analysis revealed that serum free testosterone levels significantly decreased with increasing age (a decrease of 1.14 pg/mL per 1-year increase) and higher body-mass index (BMI) (a decrease of 1.07 pg/mL per 1-kg/m2 increase), but showed no significant association with HIV serostatus, thyroid function, prolactin levels, or comorbidities. In HIV-positive group, the serum free testosterone levels were negatively associated with longer duration of HIV infection and positively associated with use of nucleoside reverse transcriptase inhibitors (NRTIs). Discussion: This study is the largest Chinese Han cohort investigating hypogonadism in MSM. Primary hypogonadism accounts for 2.7% of MSM with HIV in our cohort, similar to rates observed in Italy. The lower prevalence of secondary hypogonadism (8.9%) in our study, compared to previous studies, may be due to better overall health, viral suppression, and exclusion of individuals on interfering medications. Our findings are consistent with the Multicenter AIDS Cohort Study (MACS), which also observed similar age-related declines in free testosterone levels in MSM with and without HIV. Using MSM without HIV as the control group may provide a more accurate comparison due to shared lifestyle behaviors. The positive association between NRTI use and serum free testosterone levels may be incidental due to the high prevalence of NRTI use (96.6%) in our study, which warrants further investigation. The limitations of our study include age discrepancy between the groups, single testosterone testing, and the exclusion of individuals on testosterone replacement therapy, which may lead to under- or over-estimation of true hypogonadism prevalence. Conclusion: We found that MSM with HIV had a higher prevalence of symptomatic hypogonadism than MSM without HIV in Taiwan, which could be attributed to age difference. Serum free testosterone levels were negatively correlated with age and BMI, but did not show a significant correlation with HIV serostatus.