Sung-Hsi Huang、 Guan-Jhou Chen , Hsun-Yin Huang , Chia-Chi Lee , Stephane Wen-Wei Ku , Yen-Fang Huang h, Po-Hsien Kuo , Chien-Ching Hung , Kuan-Yin Lin

Sung-Hsi Huang 等人，《微生物學、免疫學和感染雜誌》，2024 年 11 月 13 日線發布，https://doi.org/10.1016/j.jmii.2024.11.003

摘要

         自 1984 年診斷出第一例 HIV 感染以來，我們回顧了過去 40 年來台灣 HIV 感染的流行病學、政策和控制方案。相關的伺機性疾病和死亡率顯著下降。然而，儘管愛滋病毒檢測和治療的機會有所改善，但愛滋病毒感染的晚期表現仍然很常見。自 2003 年至 2007 年為控制注射藥癮者爆發的愛滋病毒感染所實施之減害計畫以來，無保護的性行為，特別是男男間性行為，仍然是愛滋病毒傳播的主要風險。相繼推出的耐受性良好、有效的單錠型抗反轉錄病毒之治療方案，促進了2016 年「全民治療」政策的實施，在2018 年於診斷後7 天內快速啟動ART，並於 2021 年使用免疫層析法 (ICT) 快速確認HIV感染的當天即啟動 ART。政府資助的愛滋病毒感染暴露前預防實驗計畫於 2016 年啟動，隨後於 2018 年擴大了愛滋病毒高危群體的參與範圍，同時伴隨著與愛滋病毒照護、ART 啟動、病毒抑制和存留於照護等之間的聯繫極高，台灣自 2018 年以來，愛滋病毒感染率持續下降。但實現消除愛滋病毒和長期成功地管理愛滋病毒感染的挑戰仍然存在，其中包括標籤和歧視、愛滋病毒感染者的延遲診斷以及愛滋病毒感染者中伴隨共病率增加而加速的老齡化。

1. 簡介

自1984年台灣確診首例愛滋病感染者以來，截至2023年底，台灣疾病管制署共報告了本土病例44,263例，其中， 21,585人（48.8%）已確診為愛滋病，有 8,510人死亡（19.2%）。同時，台灣目前有 35,566 名愛滋病毒感染者，估計感染率佔總人口的 0.1%。為了控制愛滋病毒的流行，台灣政府實施了愛滋病毒檢測計畫，並引入了耐受性良好、有效的聯合抗反轉錄病毒療法（ART）、免疫層析測試（ICT）以促進確診當天快速啟動ART，以及暴露前預防（PrEP） 。在這裡，我們回顧了台灣過去 40 年來之愛滋病毒流行病學、政策和為控制愛滋病毒流行而實施的控制計畫的演變，並探討了在消除愛滋病毒感染作為公共衛生威脅，並取得愛滋病毒感染管理長期成功上所面臨的挑戰。

2. 台灣HIV感染之流行病學

台灣於1984年報告第一例輸入性HIV感染病例，並於1986年報告第一例本土感染病例。隨後，愛滋病毒感染者（PWH）的發生數在接下來的34年持續增加，傳播途徑也隨著時間的推移而演變（圖1）。20 世紀 80 年代初期的第一波 HIV 感染是由輸入受污染的抗血友病產品所引起的，導致至少 53 例 HIV 感染。第一例與輸血相關的 HIV 感染可能發生在 1985 年，一名婦女在子宮切除術期間接受了 HIV-1 陽性全血輸注。隨著1988年實施常規捐血者篩檢（圖2）和2013年納入核酸擴增試驗（NAAT）作為篩檢方法，2014年後沒有發生與輸血相關的愛滋病毒傳播病例。

在台灣愛滋病流行的前二十年，男性間無保護的性行為是愛滋病毒傳播的主要途徑。 2003年至2007年，注射藥癮者（PWID）中爆發了愛滋病毒感染，注射藥癮者佔每年報告病例的比例從2002年的1.7%上升到2005年的75%以上。分子流行病學研究發現注射藥癮者流行的HIV CRF07_BC病毒株與中國注射藥癮者中曾經流行傳播的病毒株相關聯，也觀察到愛滋病毒陽性藥癮者中C型肝炎病毒（HCV）感染率較高。 2005 年實施減害計畫後，注射藥癮者罹患愛滋病毒感染率顯著下降。此後，無保護的性接觸，特別是男性間（67%）和異性間（15%）接觸，成為主要的傳播途徑。

截至2023年底，台灣通報的愛滋病毒感染病例中94.9%為男性，大多數診斷出愛滋病毒時的年齡在25歲至34 歲之間（43.3%），其次是 35-49 歲（26.3%）和 15-24 歲（23.4%）。 15歲以下感染者比例仍較低，佔確診感染者總數的0.14%。 1988 年報告了第一例周產期愛滋病毒感染病例，2005年起對孕婦實施常規（opt-out，選擇性退出）愛滋病毒檢測後，愛滋病毒母嬰傳播已變得罕見。 2015年至2023年，報告了8例兒童愛滋病毒感染病例，包括由未遵循產前保健母親所垂直感染的嬰兒和透過性接觸感染的青少年。

台灣透過愛滋病感染篩檢計畫和生物醫學介入措施的實施，在實現聯合國愛滋病規劃署「95-95-95」目標方面取得了重大進展，實現的目標從2012年的「71-62-81」進展為 2018 年的「84-88-94」，到2023 年的「91-96-95」。因此，愛滋病毒感染率連續六年（自2018 年以來）下降，已達到每年報告的940人（4.1 人/每十萬人口）。雖然未確診感染的百分比在同性戀、雙性戀和其他男男性行為者（GBMSM）人口中急劇減少，但在異性戀者和 15 至 24 歲的年輕人中觀察到更高比例的未確診感染，仍顯著地未能實現第一個 95%目標。

儘管愛滋病毒檢測、抗病毒治療覆蓋率和病毒抑制率方面取得了進步，但愛滋病毒的晚期診斷和愛滋病毒的性傳播仍然對台灣的愛滋病毒控制和照護服務構成相當大的挑戰。每年，台灣有超過30% 的感染者被發現處於疾病晚期（接受愛滋病毒診斷後3 個月內進展為愛滋病），自2019 年以來這一比例增加至35% 以上。導致ART 的延遲啟動，從而增加不良臨床結果和持續 HIV 傳播的風險。在晚期診斷出 HIV 感染的個體中，口腔食道念珠菌症和肺囊蟲肺炎仍然是最常見的愛滋病定義中的伺機性感染。有幾個因素已被確定與愛滋病毒晚期診斷有顯著相關，包括年齡較大、性伴侶不固定以及根據症狀就診而不是透過常規篩檢進行診斷。這些發現強調了向一般民眾和醫療保健提供者提供資訊和教育、定期風險評估、在醫療接觸期間常規地提供愛滋病毒檢測以及提高自願愛滋病毒檢測的可及性等措施的重要性。雖然與愛滋病毒診斷相關的標籤和歧視阻礙了弱勢群體獲得愛滋病毒篩檢和照護，但事實證明，擴大愛滋病毒檢測以實現愛滋病毒早期診斷是非常有益的，可以延長健康壽命。

性傳播愛滋病毒的長期爆發主要透過GBMSM（ gay, bisexual, and other men who have sex with men ）之間無保護的性接觸傳播，可能與使用非鴉片類娛樂性藥物有關。 鑑於 GBMSM 中性行為中使用藥物 (藥愛，chemsex) 與 HIV 之間已確定的關聯，需要制定量身定制的減少傷害策略來消除 HIV 感染。這些策略應超越傳統計畫，包括精神健康服務、藥物使用管理和復健支持，以及向 GBMSM 提供以社區為基礎的健康服務。

圖1.  台灣於1984-2023年間依傳播類型區分的HIV新感個案數之流行趨勢

圖2. 台灣於1984-2023年間愛滋病毒流行演變過程中愛滋篩檢服務的進展。

縮寫：ICT，免疫層析測試； STI，性傳播感染。

• 台灣的法律與政策

在愛滋病毒流行的40 年間，預防和控制政策的制定已從積極主動的衛生教育、接觸者追蹤和增加抗反轉錄病毒治療覆蓋率的介入措施演變為檢測和照護獲得之改善、伴侶服務、減少傷害計畫、母嬰傳染的預防和暴露前預防性投藥。在政府機構和以社區為基礎之組織（CBOs）之間建立溝通和協調機制，以改善公私合作，成功地實現了公眾參與，使各種問題和政策能夠透過多部門和委員會之機制得到有效溝通和實施，從而為感染者創造一個友善和非歧視的環境。

為了便於全面評估台灣過去四十年在愛滋病控制和人權保護方面所實施的法律和政策，我們利用愛滋病政策實驗室制定的愛滋病政策指標來檢驗其成就，其中分為四類，包括臨床/治療、檢測/預防、結構和衛生系統，以及33個指標（補充表1）。

在 20 世紀 80 年代至 90 年代，由於對愛滋病毒的缺乏了解，恐慌和污名盛行，社會對感染者懷有恐懼和歧視，將病毒與某些高危險群（例如男同性戀者和注射藥癮者）聯繫起來。 1988年，台灣開始在指定醫院向感染者免費提供齊多夫定（zidovudine, AZT）和愛滋病照護（圖3），隨後於1990年制定《後天免疫缺乏症候群防治條例》，為愛滋病檢測和治療提供了法律依據，以及感染者隱私保護。並對被認為是高危險的族群進行了強制檢測，這在當時也引發了的人權擔憂。在愛滋病流行初期，外籍人士入境或在台居住三個月以上，必須接受愛滋病毒檢測，檢測結果呈陽性者將被驅逐出境，導致本國籍國民的外籍配偶被強制驅逐出境。隨後，這些限制逐漸取消，以維護合法的伴侶關係並遵守人道主義原則。

1990年代至2010年，是從疾病控制過渡到人權保障的時期。儘管政府繼續強調疾病預防和控制，但對愛滋病感染者的歧視仍然普遍存在。 1994年，一名透過輸血感染愛滋病毒的學童被迫轉學，促使1997年修訂法律，保護感染者獲得醫療、教育和就業的權利。同年（1997年），推出組合型的ART。

當2003年愛滋病毒於注射藥癮者中流行並於2005年達到頂峰時（圖1），政府向外國專家尋求建議以制定減少傷害的計畫。 2005 年7 月，台灣23 個行政區中的4 個行政區開始了包括針頭和注射器交換以及衛生教育在內的實驗計畫，並於2006 年2 月推出阿片類藥物替代療法 (OST)，並於2007 年合法化。

圖 3. 過去四十年來台灣抗愛滋病毒療法和治療策略的演變。

縮寫：ART（antiretroviral therapy，抗病毒治療）； AZT（zidovudine，齊多夫定）； CAB（cabotegravir，卡博特韋）； EFV（efavirenz，依非韋倫）； FTC（emtricitabine，恩曲他濱）； INSTI，（integrase strand-transfer inhibitors，整合酶鏈轉移抑制劑）；LA（long-acting injectables，長效注射劑）； NNRTIs（non-nucleoside reverse-transcriptase inhibitors，非核苷類反轉錄酶抑制劑）； NPV（nevirapine，奈韋拉平）； PVL（plasma HIV RNA load，血漿HIV RNA量）； PWH（people with HIV，愛滋病毒感染者）； RAL（raltegravir，拉替拉韋； RPV（rilpivirine，利匹韋林）； STR（single-tablet regimen，單錠藥方）； TDF（tenofovir disoproxil fumarate，富馬酸替諾福韋二吡呋酯）； TFDA（台灣食品藥物管理署）； TwCDC（台灣 疾病管制署）

為了加強對愛滋病毒感染者的照護和支持，台灣啟動了愛滋病毒病例管理實驗計劃，隨後於2007 年在全國範圍內實施。此計畫旨在提高抗病毒藥劑治療的依從性以實現愛滋病毒感染者病毒的持久抑制。目前，以社區為基礎之組織發揮了更突出的作用，特別是在為弱勢愛滋病患者、青少年和從事藥愛性行為的人提供支持方面。

2007年，針對社區組織所收容社會經濟弱勢的感染者面臨到社會排斥的情況，明確禁止公立和私立護理機構拒絕接納感染者，以保護他們的照護和居住權。此外，還採取措施保障愛滋病毒感染者的權利，包括建立一個框架，倡導團體、社區組織、公共衛生專家、醫療保健提供者和相關政府機構的代表共同合作促進愛滋病毒預防和愛滋病毒感染者權利的保護。同年，該法案更名為《人類免疫缺乏病毒傳染防治及感染者權益保障條例》，反映出其立法目的超越了最初的疾病預防目標，涵蓋了人權保護。

從2010年代至今，從反對到合作的時期，儘管法律保護有所改善，但愛滋病毒感染者仍面臨歧視。 2013年，一名感染愛滋病毒的大學生被開除，引起大眾對愛滋病毒相關歧視的關注，並促使人權組織進一步反思愛滋病毒感染者的待遇。 2015年，台灣取消了對感染愛滋病毒的外國人的入境禁令，使其政策與日益包容和尊重人權的全球趨勢保持一致。到了2019年，性別平等運動的興起和同性婚姻合法化進一步提高社會對愛滋病相關議題和性別議題的接受度。 2020年，一項法律修訂澄清，接受穩定抗病毒藥劑治療並已實現病毒抑制的感染者不存在明顯的愛滋病毒傳播風險，從而使他們免於被歸類為從事「危險性行為」，並鼓勵感染者堅持治療而不必擔心。

在其他主要政策方面，台灣遵循世界衛生組織的指導方針，於2016年對所有感染者無論其CD4計數或愛滋病狀況如何均實施抗反轉錄病毒治療（ART）； 2018 年和 2021 年分別實施了快速啟動抗反轉錄病毒治療和當日啟動抗反轉錄病毒治療。PrEP 實驗計畫於 2016 年啟動，自 2018 年以來已擴大覆蓋範圍，擴大了愛滋病毒感染風險族群的覆蓋範圍。國家愛滋病毒自我檢測計畫於 2017 年實施，已被證明可以改善愛滋病毒感染病例之發現。

為了減少污名或歧視，《2030年消除愛滋病毒/愛滋病第一期計畫》框架分為政府/結構、社區、組織/機構、人際和個人五個層面。策略包括健康教育、普遍檢測、推廣U=U（無法檢測–等於–不會傳播）的最新證據、針對多部門組織和社區組織的不同亞群體的培訓計畫，以及為愛滋病毒指定醫院和社區組織提供補貼以開展團體諮詢或支持團體。

截至 2023 年底，台灣估計有 9% 的感染者仍未確診，促進常規 HIV 篩檢和提供以顧客為中心的 HIV 檢測的策略正在進行中，並將在下一節中討論。此外，4% 的已知悉 HIV 診斷之患者沒有接受照護，5% 開始 ART 的感染者未能實現病毒抑制，這可能導致社區持續存在傳播風險。需要投資可持續的資源，以加強系統的能力，最大限度地提高和維持治療和預防服務的存留水準。

4. HIV篩檢和診斷的進展

愛滋病毒篩檢觸發了愛滋病毒之診斷和治療或預防措施的後續確認，在愛滋病毒控制計畫中發揮關鍵和基礎作用。為了因應愛滋病毒大流行，台灣於 1988 年首先開始對捐血者進行常規愛滋病毒篩檢，1989 年針對應徵入伍新兵篩檢，1990 年入監受刑人篩檢（圖 2）。在接下來的幾十年裡，台灣見證了篩檢計畫的全面擴展，其中包括針對孕婦、性傳播感染 (STI) 患者、參加 替代療法 (OST) 計畫的注射藥癮者以及高風險新生兒的篩檢計畫分別自 2000 年、2003 年、2004 年和 2008 年推出。

自1990 年以來，一些醫療機構首次提供免費匿名自願諮詢和檢測 (voluntary counseling and testing，VCT)，並於1997 年在幾家醫院、診所和社區組織啟動了全國範圍內的匿名自願諮詢和檢測(VCT) 計畫，旨在提供友善的愛滋病毒篩檢和諮詢服務。

事實證明，這些服務在識別有愛滋病毒感染風險的顧客方面是有效的，因為這群人的愛滋病毒血清陽性率和伴隨性傳播感染的盛行率很高（愛滋病毒血清陽性率高達3.6-4.1%）。此外，從 2005 年到 2016 年，匿名 VCT 服務發現的愛滋病新診斷病例比例從 5.2% 上升到 29.3%。過去十年，社區動員、多通路自我篩檢服務、網路平台、社交移動VCT等愛滋病檢測等創新，體現了國家對提高愛滋病檢測覆蓋率的承諾。

透過這些集體努力，每年提供的愛滋病毒篩檢檢測數量在 2019 年已達到 833,843 人次，在 2020 年 COVID-19 大流行期間下降至 667,133 人次，並在 2023 年大流行後緩慢回升至 721,436 人次，未確診的感染者比例呈現下降趨勢（2012 年為21.5%，2019 年為12.1%，2023 年為9%）。在實現第一個「95」目標方面持續存在的差距可能是由於，低估了愛滋病毒風險、恥辱、對歧視的恐懼以及特定人群（女性、跨性別者、移工、老年人、和青少年）。除了努力改善公眾教育和溝通外，其他新的愛滋病毒篩檢管道也在實施中，包括同儕篩檢、合作夥伴服務以及將愛滋病毒篩檢納入常規健康檢查。台灣疾病管制署提倡對所有有性經驗的人進行普遍篩檢，以消除愛滋病毒檢測的污名並提高覆蓋率。最近的一項分析顯示，台灣實施常規愛滋病毒檢測與晚期診斷率的降低以及愛滋病毒相關死亡率和全因死亡率的降低有關。 這些發現支持進一步將通用的、選擇性退出的測試擴展到更廣泛的環境，儘管實用性和成本效益在台灣仍有待進一步進行檢驗。

在過去的幾十年裡，HIV篩檢工具不斷發展，從使用重組抗原的第二代檢測，發展到結合IgM檢測的第三代酵素免疫分析/顆粒凝集分析（EIA/PA），再到第四代/第五代檢測，在抗原/抗體組合試驗中添加了p24抗原，大大縮短了空窗期。 2019年免疫層析測試 (ICT) 的引入促進了愛滋病毒感染的一站式的篩檢和確認。台灣疾病管制署2021 年指南中認可NAAT 和ICT 確認HIV 診斷， 取代傳統的西方墨點測定，顯著縮短了確認愛滋病毒等待時間並加速將新診斷出的愛滋病毒感染者與照護和抗反轉錄病毒治療之啟動間的聯繫。

儘管國家治療指南建議在治療失敗時進行基因型抗藥性檢測，但在台灣，在開始 抗病毒藥劑治療時並未常規地進行 HIV-1 抗反轉錄病毒抗藥性檢測，且國民健康保險 (NHI) 並不予給付抗藥性檢測。而台灣多個研究實驗室所提供的抗藥性檢測和監測，無論是初次接受抗反轉錄病毒治療還是有抗愛滋病毒治療經驗的病人，則在政策制定和指導ART 處方方面發揮關鍵的作用。值得注意的是，在多項監測研究中觀察到非核苷逆轉錄酶抑制劑 (NNRTI) 治療前抗藥性 (PDR) 的發生率增加。在一項納入2016 年至2022 年期間約25% 未接受過抗反轉錄病毒治療的感染者的研究中，第一代整合酶鏈轉移抑製劑 (INSTI)（即埃維特格韋和拉替格韋，elvitegravir and raltegravir）的治療前抗藥性 (PDR) 盛行率已從2016 年的1.1% 上升到2022 年3.6%，而第二代INSTI（多魯特韋、比克替拉韋和卡博特拉韋，dolutegravir, bictegravir, and cabotegravir）的PDR 盛行率穩定在1% 左右。其他研究也顯示，在未接受 INSTI 的感染者中，對 INSTI 產生抗藥性的情況仍然不常見（表 1）。由於不同國家已經出現第二代INSTI的中度或高度抗藥性，台灣應繼續進行抗愛滋病毒藥物之抗藥性監測，並實施政策以提高其可及性和永續性。

5. ART治療策略的演變

在過去的三十年中，抗病毒治療已被證明可以抑制愛滋病毒複製，防止繼續傳播，並減少愛滋病毒感染者的疾病進展。自 1988 年首次出於同情心使用 AZT 治療愛滋病以來，國家 ART 治療策略不斷發展（圖 3）。 1990年代中期，與其他已開發國家一樣，台灣的ART包含一種或兩種不同的核苷反轉錄酶抑制劑（NRTI）。 1997 年，行政院衛生署更新了其治療指南，向所有台灣 PWH 提供免費的多片 ART，其中包括兩種 NRTI 加一種 NNRTI 或追加或未追加的蛋白酶抑制劑 (PI)。隨後，在現代的ART 時代，台灣感染者的生存率顯著提高，伺機性疾病顯著減少。當初級和次級預防使 CD4 數增加並實現病毒抑制時，可以停止多種伺機性感染疾病。

台灣ART 歷史的重大轉變發生在2016 年，當時推出了第一個單片治療方案 (single-tablet regimens ，STRs)，即富馬酸替諾福韋二吡呋酯 (tenofovir disoproxil fumarate，TDF) /恩曲他濱(emtricitabine，FTC)/依非韋倫 (efavirenz) 組合配方。隨後，TDF/FTC/利匹韋林 (rilpivirine，RPV)、阿巴卡韋(abacavir) /拉米夫定 (lamivudine ，3TC)/ 度魯特韋(dolutegravir，DTG)、艾拉酚替諾福韋(tenofovir alafenamide，TAF) /FTC/RPV、 TAF/FTC/考比司他追加艾維拉韋(cobicistat-boosted elvitegravir)、DTG/RPV、TAF/FTC/ bictegravir (BIC) 和 DTG/3TC 相繼推出，並推薦作為一線治療或作為穩定的轉換方案。十年之內，單片治療方案(STR) 已成為台灣 ART 的中流砥柱，將多片治療方案降級到具有抗反轉錄病毒抗藥性或不耐受性的選定 之愛滋感染者。

由於HIV-1 對NNRTI 的治療前抗藥性 (PDR)增加，在多項監測研究中超過10%（表1），過去十年中，包含第二代INSTI、DTG 或BIC 的單片治療方案已成為未接受過抗反轉錄病毒治療的感染者抑或興具治療經驗者兩種病患之主要治療選擇。 2021年，台灣食品藥物管理局批准了首個長效（long-acting， LA）注射型抗反轉錄病毒藥物，LA-cabotegravir和RPV組合於2024年被台灣疾病管制署列為二線ART。

隨著 ART 的進步，開始啟動 ART 的適應症和時機也隨著時間的推移而發生了顯著變化。 2016 年發生了一個關鍵轉變，當時建議所有愛滋病毒感染者在確診後接受 ART，放棄了先前依賴 CD4 淋巴細胞計數或血漿中 HIV RNA 負荷來啟動 ART 的標準（圖 3）。此後，台灣疾病管制署將重點轉向盡量減少愛滋病毒診斷和開始抗病毒治療之間的延遲。到2018 年，建議台灣各地愛滋病毒照護指定醫院提供快速啟動抗反轉錄病毒治療，目標是在新診斷的愛滋病毒感染者進行愛滋病毒確證檢測後7 天內啟動抗反轉錄病毒治療。與世界其他地區的研究類似，在實際情況台灣的證據還顯示，與在確診HIV 診斷後≥7 天開始ART 的感染者相比，快速開始ART 的感染者更有可能參與照護，並且不太可能失訪。抗反轉錄病毒治療。為了進一步改善新診斷出的愛滋病毒感染者與照護的聯繫，台灣疾病管制署於2021年實施了當天開始抗反轉錄病毒治療計畫，其中建議在確診愛滋病毒的同一天開始接受抗反轉錄病毒治療。隨著免疫層析測試 (ICT) 或NAAT 利用率的增加，到2023 年，從HIV 篩檢檢測呈陽性到開始ART 的中位間隔已縮短至僅一天，有超過60% HIV 篩檢呈陽性的新診斷感染者在前兩天內便開始ART。

截至今日，由第二代INSTI 組成的單片治療方案(STR)已顯著提高了耐受性，提供了更高的抗藥性遺傳屏障，並在台灣的實際環境中表現出顯著的有效性。但必須承認有一小部分愛滋病毒感染者仍面臨依從性、治療失敗之風險和 HIV-1 抗藥性相關突變出現等的挑戰。例如，使用娛樂性藥物或藥癮者被認為具有較低的依從性。此外，越來越多的國際證據顯示，仍然有可能出現對第二代 INSTI 的抗藥性，特別是在不遵從的感染者中。

表1.台灣已發表之不同的研究中，在未接受過抗病毒治療的 HIV 感染者當中所觀察到的

     HIV-1治療前之抗藥性。

6. 暴露前預防

自2015 年9 月起，世衛組織採用基於TDF 的口服PrEP 方案，作為HIV 感染高風險族群綜合預防的一部分。台灣愛滋病學會2016 年 5 月發布的國家 PrEP 指南版本，建議 GBMSM 和跨性別女性、血清不一致關係中的 HIV 陰性伴侶、性活躍的異性戀順性別男性和女性以及注射藥癮者每日服用 TDF/FTC 作為 PrEP。此後進行了多次更新，包括2018年5月推薦的事件驅動之給藥方案，以及2023年9月推薦的其他新藥，例如TAF和FTC的固定劑量組合、長效卡博特韋 (cabotegravir) 肌肉注射和達匹韋林 (dapivirine) 陰道環。

在地的研究也顯示，與台灣其他的高風險族群相比，GBMSM 明顯更了解並願意啟動 PrEP，尤其是那些認為自己對 HIV 感染具高度風險的人群，但很少有人願意為品牌的TDF/FTC作為PrEP而自行付費。台灣 GBMSM 優先選擇事件驅動的 PrEP，且事件驅動和每日給藥方案之間的切換並不罕見。一項調查顯示，在不考慮成本的情況下對長效 PrEP 選擇方面，目前服用 PrEP 的台灣 GBMSM 更傾向於每月口服 PrEP，然後是六個月的皮下注射，然後是每兩個月一次的肌肉注射。

同時，台灣疾病管制署於2016年11月啟動了PrEP實驗計畫，旨在5家醫院招募1000名參與者，這也是亞洲第一個由政府資助的PrEP計畫。該實驗計畫於2017 年9 月因宗教保守派的反對而停止，導致參與人數不到目標人數的三分之一，儘管初步結果顯示參與者的愛滋病毒血清轉換率低得令人興奮（0.3% ）。為了進一步擴大PrEP 覆蓋範圍，台灣疾病管制署自2018 年9 月起實施了擴大計畫，為30 歲以下的年輕人、血清不一致的夫婦、商業性工作者和性藥物使用者提供政府資助的TDF /FTC。這些計畫與綜合性健康服務一起推出，包括愛滋病毒自我檢測、一站式檢測和治療、M痘疫苗接種以及藥愛之介入。截至2023年12月，已有超過5,700人在全台63家醫院和診所參加政府資助的PrEP計畫。這些計畫也證明了，在性傳播感染患者和存留在計畫的參與者可以防止愛滋病毒感染。

然而，與HIV 感染的治療不同，備受讚譽的台灣全民健康保險 (NHI) 並未提及PrEP 等預防措施，這與英國國家醫療保險的情況不同。此外，儘管品牌 TDF/FTC 的專利已於 2020 年到期，但通用形式之學名藥尚未可用。政府資助的計畫逐漸增加，不符合資格或無法獲得這些計畫的 GBMSM 不斷尋求來自亞洲鄰國互聯網或藥房「灰色市場」的自付費用通用 型之TDF/FTC。 台灣目前 PrEP 使用者的真實數量可能被低估，因此，需要闡明 PrEP 對近期愛滋病毒發生率下降的實際影響。消除所有人的財務障礙提供負擔得起的 PrEP，仍然是進一步擴大台灣覆蓋範圍的最大挑戰。

圖 4. 台灣實施暴露前預防的時間表。

縮寫：CDC，台灣疾病管制署；PrEP，暴露前預防；TFDA，台灣食品藥物管理署；KPCC，台北市立醫昆明疫情防治中心.

7. 病毒抑制之外：愛滋病毒合併症和整體照護

隨著愛滋病毒檢測和照護方面的上述進展，如今感染者的壽命已經延長，接近一般人群的壽命。 2023年，台灣50歲以上的感染者佔全部感染者的23%。雖然因愛滋病相關疾病導致的死亡人數已從2014 年的31% 下降到2023 年的11%，但在台灣，愛滋病患者與未感染愛滋病毒的人相比，罹患合併症的風險較高，包括高血壓、糖尿病、血脂異常、冠狀動脈疾病、腎臟疾病和骨礦物質密度減少。2008 年和 2009 年的一項單中心研究顯示，近四分之一的台灣感染者患有代謝症候群。在一項調查40-75 歲感染者的橫斷面研究中，心血管疾病高風險的盛行率各不相同，以 D:A:D (R) 風險評分計算，盛行率為 3.7%，動脈粥狀硬化性心血管疾病風險評分為 22.2%，佛明罕風險評分為 30.6%。 合併症的增加給愛滋病患者和醫療保健系統帶來了挑戰。在一項分析全民健康保險研究資料庫 (NHIRD) 數據的研究中，從 2010 年到 2013 年，感染者合併症的藥物總支出幾乎翻了一番。

感染者合併症風險增加可能歸因於多種因素，包括基因、年齡、生活方式、吸菸、慢性發炎和抗反轉錄病毒藥物。在已發表的研究中，不同類別的抗反轉錄病毒藥物的影響各不相同。台灣的真實數據顯示，病毒抑制的感染者在轉用基於 INSTI 的治療方案後，出現了輕微的體重增加和血脂異常。雖然他汀類 (statins) 藥物作為主要預防藥物已被證明可以顯著減少低風險或中風險感染者的主要不良心血管事件，但它們在臨床實踐中並未得到充分利用；例如，根據美國心臟協會的建議，只有不到40% 的符合他汀類藥物使用標準的感染者，在大學醫院的HIV 治療期間接受了他汀類藥物治療，這顯示預防心血管疾病的綜合措施尚未納入到治療方案中。

性生活活躍的孕婦持續面臨性傳播感染 (STIs) 的風險，包括梅毒、沙眼衣原體感染、淋病、滴蟲病、生殖支原體感染和人類乳突病毒 (HPV) 感染。台灣的一項研究顯示，感染者中衣原體、淋病和/或滴蟲病的總體盛行率為 30%。 另一項研究顯示，患有性傳播感染的 HIV 陽性 MSM 中 32.9% 伴隨細菌感染。一項調查肛門鏡標本的研究顯示，90.8% 的參與者感染了至少一種 HPV 基因型。應推廣預防措施，包括安全性行為、衛生教育和疫苗接種（例如 HPV 疫苗接種），以控制性傳播感染症候群。最近的隨機試驗已證明，用於接觸後預防細菌性之性傳播感染的多西環素 (doxycycline) 可有效降低衣原體感染、梅毒和可能的淋病之風險。  雖然更廣泛使用多西環素對細菌攜帶多西環素抗藥性和腸道微生物群的影響仍有待研究，但應促進關於用多西環素預防細菌性傳播感染的討論。

         作為B型肝炎病毒（HBV）感染高發生國家，2012 年至2016 年間，台灣的HBV 感染總體盛行率為11.6%。1986年全國新生兒B型肝炎疫苗接種計畫實施前後出生的感染者的盛行率已從18.1%顯著下降至3.4%。對於 HIV/HBV 雙重感染者，建議使用含有 TDF 或 TAF 的 ART。台灣研究顯示，2011 年引入 TDF 後，HIV/HBV 合併感染族群的死亡率顯著降低，並且在該族群中使用含 TDF 和 TAF 的方案可持久有效地控制 HBV 複製。儘管在新生兒階段進行了全國性疫苗接種，血清學保護可能會逐漸減弱，儘管使用含有 TDF 的 ART 或TAF，高風險族群仍可能發生 HBV 感染。研究顯示，重新接種 3 劑疫苗後，血清學反應為 74.0%。建議對血清反轉者定期進行血清學評估和 HBV 追加疫苗接種。

D型肝炎病毒 (HDV) 與 HIV/HBV 合併感染者的不良肝臟結果和死亡率風險增加有關。一項單中心研究顯示，從 1992 – 2001 年到 2007- 2011 年，近期 HDV 感染的發生率顯著增加。 研究顯示，每 1000 人年追蹤的總發生率為 12.65。由於診斷和治療的局限性，D型肝炎病毒合併感染可能未被充分診斷​​。隨著更新的診斷和治療方案的出現，有必要對 HIV/HBV 合併感染者中D型肝炎病毒雙重感染進行監測，特別是注射藥癮者，因為他們感染D型肝炎病毒的風險較高。

為了實現到2025 年消除HCV 的目標，自2017 年起，台灣國民健康保險已對直接作用之抗病毒藥物 (DAA) 進行給付核銷。消除C肝的障礙包括診斷方法欠佳、治療連動不完整以及關鍵亞組的高再感染率。在一項回顧性研究中，74.9% 的 HCV 病毒血症患者開始了抗 HCV 治療，其中 94% 的患者實現了病毒清除。與未感染愛滋病毒的人相比，HIV感染者感染C肝病毒的再感染風險更高。隨著 DAA 治療計畫的實施後，感染者中 HCV 的盛行率和發生率有所下降，而再感染的比例則有所上升。建議採用更頻繁的篩檢和混合血漿HCV RNA 檢測的診斷策略可能有助於及時識別急性HCV 感染，最新數據顯示2020年至2023年HCV 再感染率從已顯著下降。對高風險族群進行定期監測、及時診斷以及與有效的 DAA 治療相結合，是台灣實現C型肝炎微消除的關鍵。

為了實現病毒抑制以外的整體照護，其他重要但常被忽視的問題，包括骨骼健康、惡性腫瘤、腎臟疾病、性健康、疫苗接種、心理健康、認知功能下降、污名化、藥物濫用、生活品質(QoL) 和長期照護，應在常規愛滋病毒照護中進行評估和管理。對台灣所有合併症及其管理的全面審查超出了本次審查的範圍。本文將簡要討論惡性腫瘤、心理健康、認知功能下降和生活品質等選定主題。

在綜合式抗反轉錄病毒療法時代，愛滋病定義和非愛滋病定義的惡性腫瘤的發生率均顯著下降。然而，與未感染愛滋病毒的人相比，感染者罹患惡性腫瘤的整體風險仍然較高。在一項分析 NHIRD 數據的研究中，男女肛門癌的標準化發生率最高。 在一項橫斷面、單中心研究中，只有 46.9% 的符合條件的感染者完成了免費癌症篩檢，這凸顯出應提高感染者中惡性腫瘤篩檢的認識和實施。

失眠、焦慮、憂鬱等精神障礙在台灣愛滋感染者中很常見。在一項研究中，超過 30%穩定接受 ART 的參與者報告了認知和心理症狀。一項基於 NHIRD 的研究顯示，在HIV 診斷後的平均為 3.3 年，有23.8% 的新診斷之感染者被診斷出患有精神疾病。在另一項 NHIRD 研究中，與 HIV 陰性對照組相比， 感染者任何使用和長期使用苯二氮平類藥物和Z 藥物（藥理作用與苯二氮類藥物類似的藥）者之風險更高。

一項橫斷面研究顯示，平均年齡為 37.5 歲的感染者當中，認知能力下降的盛行率為 2.25%。 年齡較大、教育程度較低、愛滋病毒感染持續時間較長與認知障礙有顯著相關。 另一項利用全民健康保險研究資料的研究發現，神經系統疾病的發生率為每 1000 人年 13.67 例。確定的相關因素包括年齡、物質使用、創傷性腦損傷、精神疾病、愛滋病毒相關伺機性感染、急診就診頻率、ART依從性、都市化程度和每月收入。

世衛組織在愛滋病毒照護目標中增加了旨在優化健康相關生活品質（HRQoL）的「第四個90」。在台灣，關於感染者生活品質的研究仍然很少。最近一項針對120 名病毒抑制的感染者進行的線上調查顯示，與未感染愛滋病毒的人相比，在不同維度（包括活動能力、日常活動、自我照顧、疼痛/不適和焦慮/憂鬱）上可以實現相似的HRQoL。這項發現令人鼓舞，但可能不適用於女性、老年人、社區組織支持較少或居住在農村地區的台灣愛滋病感染者。要實現所有感染者之第四個「90」的宏偉目標，需要以患者為中心涵蓋上述各個方面的整體式照護。

8.結論

台灣正走在消除愛滋病毒感染這一公共健康威脅的正確道路上，透過不斷努力和投資擴大愛滋病毒檢測和暴露前預防，並提供免費、最先進的抗反轉錄病毒治療方案。為了進一步擴大愛滋病毒檢測範圍，以顧客為中心的方法受到了強烈的歡迎。隨著與愛滋病毒治療連結上的不斷進展，需要更加重視存留於治療和預防以維持這項成就。提供資訊、教育和交流對於減少愛滋病毒感染的恥辱和歧視，並促進公私夥伴關係以確保愛滋病毒控制計畫的成功實施至關緊要。雖然愛滋病毒感染者繼續面臨現代ART 時代之代謝併發症、性傳播感染、惡性腫瘤和心理障礙等各種合併症的持續挑戰，但全面的愛滋病毒照護需要定期監測和評估合併症，並採取個人化的預防措施，除了抑制病毒之外，更還可以提高感染者的生活品質。

CRediT 作者貢獻聲明

Sung-Hsi Huang：寫作 – 評論和編輯、寫作 – 初稿、視覺化、驗證、形式分析、資料管理。 Hsun- Yin Huang：寫作 – 評論和編輯，寫作 – 初稿，驗證，形式分析，資料管理。 Stephane Wen-Wei Ku：寫作 – 評論與編輯、寫作 – 初稿、視覺化、驗證、形式分析、資料管理。 Po-Hsien Kuo：寫作 – 審查與編輯、寫作 – 初稿、驗證、形式分析、資料管理。 Kuan-Yin Lin：寫作 – 審查和編輯、寫作 – 初稿、視覺化、驗證、形式分析、資料管理。陳冠週：寫作——評論與編輯、寫作——原稿、視覺化、驗證、形式分析、資料管理。 Chia-Chi Lee：寫作－審查與編輯、驗證、形式分析、資料管理。 Yen-Fang Huang：寫作——評論和編輯、寫作——原稿、視覺化、驗證、監督、形式分析、概念化。 Chien-Ching Hung：寫作——審查和編輯、寫作——原稿、驗證、監督、資料管理、概念化。

Forty years of HIV infection and AIDS in Taiwan: Reflection on the past and looking toward the future

Sung-Hsi Huang、 Guan-Jhou Chen , Hsun-Yin Huang , Chia-Chi Lee , Stephane Wen-Wei Ku , Yen-Fang Huang h, Po-Hsien Kuo , Chien-Ching Hung , Kuan-Yin Lin

Sung-Hsi Huang et al., Journal of Microbiology, Immunology and Infection, Available online 13 November 2024 , https://doi.org/10.1016/j.jmii.2024.11.003

ABSTRACT

We review the epidemiology, policies, and control programs of HIV infection in Taiwan in the past 40 years since the first case of HIV infection was diagnosed in 1984. With the introduction of combination antiretroviral therapy (ART) in Taiwan in 1997, the incidences of HIV-related opportunistic illnesses and mortality have significantly declined. However, despite improved access to HIV testing and treatment, late presentation of HIV infection remains common. Unprotected sex, particularly among men who have sex with men, continues to be the leading risk for HIV transmission after implementation of harm reduction program to control an outbreak of HIV infection among people who inject drugs that occurred in 2003–2007. The sequential introduction of well- tolerated, effective, single-tablet antiretroviral regimens has facilitated the implementation of “treat-all” policy in 2016, rapid ART initiation within 7 days of diagnosis in 2018, and same-day ART initiation in 2021 when immunochromatography was used for rapid confirmation of HIV infection. Government-funded pilot program of pre-exposure prophylaxis for HIV infection, which was launched in 2016 followed by wider enrollment of people at high risk for HIV acquisition in 2018, have contributed to sustained declines of the incidence of HIV infection since 2018, along with high rates of linkage to HIV care, ART initiation, viral suppression, and retention in care in Taiwan. Challenges remain to achieve HIV elimination and long-term successful management of HIV infection, which include stigma and discrimination, late presentation of HIV infection, and accelerated ageing with increasing rates of co-morbidities among people with HIV.

1. Introduction

Since the first case of HIV infection was diagnosed in Taiwan in 1984, a total of 44,263 autochthonous cases were reported to Taiwan Centers for Disease Control (CDC) by the end of 2023, among whom 21,585 (48.8%) were diagnosed with AIDS and 8510 (19.2%) died. Meanwhile, 35,566 people were living with HIV in Taiwan, representing an estimated prevalence of 0.1% of the population. To control the HIV epidemic, Taiwanese government implemented programs of HIV testing and introduced well-tolerated, effective combination antiretroviral therapy (ART), immunochromatographic test (ICT) to facilitate rapid and same-day ART initiation, and pre-exposure prophylaxis (PrEP). Here, we review the evolution of HIV epidemiology, policies, and control programs implemented for the control of HIV epidemic in the past 40 years, and examine the challenges ahead to achieve elimination of HIV infection as a public health threat and long-term successful management of HIV infection in Taiwan.

• Epidemiology of HIV infection in Taiwan

The first imported case of HIV infection in Taiwan was reported in 1984 and the first locally acquired case in 1986. Subsequently, the incident case number of people with HIV (PWH) continued to increase in the next 34 years and transmission routes have evolved over time (Fig. 1). The initial wave of HIV infections in the early 1980s was caused by transfusion of contaminated antihemophilic products that had resulted in at least 53 cases of HIV infection. The first case of blood transfusion-related HIV infection probably occurred in 1985 in a woman who received HIV-1-positive whole blood transfusion during hysterectomy. With the implementation of routine blood donor screening in 1988 (Fig. 2) and incorporation of nucleic-acid amplification test (NAAT) as a screening method in 2013, no cases of transfusion-related HIV transmission occurred after 2014. 

During the first two decades of HIV epidemic in Taiwan, male-to- male unprotected sex was the predominant route of HIV transmission. From 2003 to 2007, there was an outbreak of HIV infection among people who inject drugs (PWID), with the proportion of PWID among annually reported cases rising from 1.7% in 2002 to >75% in 2005. Molecular epidemiology studies linked the epidemic among PWID to HIV CRF07_BC that used to circulate among PWID in China. A high prevalence of hepatitis C virus (HCV) infection among HIV-positive PWID was also observed. Following the implementation of harm reduction program in 2005, notable declines in HIV infection have been observed among PWID. Thereafter, unprotected sexual contact, particularly male-to-male (67%) and heterosexual (15%) contact, became the predominant transmission route.

By the end of 2023, 94.9% of the reported cases of HIV infection in Taiwan were male and the majority were aged between 25 and 34 years at the time of their HIV diagnoses (43.3%), followed by those aged 35–49 years (26.3%) and 15–24 years (23.4%). The proportion of PWH aged 15 years or less remained low, accounting for 0.14% of all PWH diagnosed. The first case of perinatal transmission of HIV was reported in 1988. After implementing routine (opt-out) HIV testing for pregnant women in 2005, mother-to-child transmission of HIV had become a rare occurrence. Between 2015 and 2023, 8 cases of pediatric HIV infection were reported, including infants vertically infected by their mothers who did not adhere to antenatal care and adolescents infected through sexual contact.

Due to implementations of screening programs and biomedical intervention for HIV infection, Taiwan has made significant progress towards achieving the UNAIDS “95-95-95” targets, with the targets reached progressing from “71-62-81” in 2012, “84-88-94” in 2018, to “91-96-95” in 2023. Consequently, the incidence of HIV infection has been declining for six consecutive years (since 2018) and has reached to an annually reported number of 940 (4.1 persons per 100,000 population) in 2023. While the percentage of undiagnosed infections in gay, bisexual, and other men who have sex with men (GBMSM) population sharply decreased, a significant gap remains in achieving the first 95% target and higher proportions of undiagnosed infections were observed among heterosexuals and younger individuals aged between 15 and 24 years.

Despite the advancements in HIV testing, ART coverage, and viral suppression rates, late HIV diagnosis and sexual transmission of HIV still pose considerable challenges to HIV control and care delivery in Taiwan. Annually, more than 30% of PWH in Taiwan were identified at an advanced stage of the disease (progression to AIDS within 3 months after receiving HIV diagnosis), with the rate increasing to over 35% since 2019. Late HIV diagnosis leads to delayed initiation of ART, thereby increasing the risk of poor clinical outcomes and ongoing HIV transmission.  In individuals with late diagnosis of HIV infection,

oro-esophageal candidiasis and Pneumocystis jirovecii pneumonia continued to be the most common AIDS-defining opportunistic infections. Several factors have been identified as significantly associated with late HIV diagnosis, including older age, having non-fixed sexual partners, and being diagnosed due to symptoms rather than through routine screening. These findings emphasize the importance of information and education delivered to the general population and health care providers, regular risk assessment, routine provision of HIV testing during medical encounters, and improving accessibility to voluntary HIV testing. While the stigma and discrimination linked to an HIV diagnosis hamper access to HIV screening and care among vulnerable populations, expanding HIV testing to achieve early HIV diagnosis has been shown to be highly beneficial, resulting in gains in healthy life years.

The prolonged sexually transmitted HIV outbreak, primarily transmitted through unprotected sexual contact among GBMSM, could be linked to the use of non-opioid recreational drugs. Given the established association between drug use in sexual contexts (chemsex) and HIV among GBMSM, tailored harm reduction strategies are needed to achieve elimination of HIV infection. These strategies should go beyond traditional programs and include mental health services, drug use management and recovery support, as well as the provision of GBMSM with community-based health services.

• Law and policy in Taiwan

During the 40 years of HIV epidemic, prevention and control policy development has evolved from proactive health education, contact tracing, and interventions to increase ART coverage towards improve ment of access to testing and care, partner services, harm reduction programs, prevention of mother-to-child transmission, and PrEP. Establishing communication and coordination mechanisms between government agencies and community-based organizations (CBOs) to improve public-private collaboration has resulted in successful public participation, which has enabled various issues and policies to be effectively communicated and implemented through multisectoral and committee mechanisms, thereby creating a friendly and non-discriminatory environment for PWH.

To facilitate comprehensive assessment of the law and policies implemented for HIV control and human rights protection in Taiwan in the past four decades, we examined the accomplishment using the HIV policy indicators developed by the HIV Policy Lab, in which there are four categories, including clinical/treatment, testing/prevention, structural, and health systems, and 33 indicators (Supplementary Table 1).

In the 1980s–1990s when panic and stigma were prevalent due to a lack of understanding about HIV, the society at large harbored fear and discrimination against PWH, associating the virus with certain risk groups (such as gay men and injection drug users). In 1988, Taiwan started to provide free zidovudine (AZT) and HIV care to PWH at designated hospitals (Fig. 3), followed by enactment of the AIDS Prevention and Control Act in 1990, which provided legal grounds for HIV testing and treatment and privacy protection for PWH. Mandatory testing was also imposed on perceived high-risk groups, raising human rights concerns at the time. In the early years of HIV epidemic, foreigners entering or residing in Taiwan for more than three months were required to undergo HIV testing and those found to be HIV-positive were subject to deportation, which had resulted in instances where foreign spouses of Taiwanese nationals found to be PWH had to face forced deportation. Subsequently, these restrictions were gradually lifted to uphold legitimate partner relationships and adhere to humanitarian principles.

In the 1990s to 2010, it was the times of transition from disease control to human rights protection. While the government continued to emphasize disease prevention and control, discrimination against PWH remained widespread. In 1994, a school child who contracted HIV through blood transfusion was forced to transfer schools, prompting the 1997 revision of laws to protect the rights of PWH in accessing medical care, education, and employment. In the same year (1997), combination ART was introduced.

When the HIV epidemic occurred among PWID occurred in 2003 and reached its peak in 2005 (Fig. 1), the government sought advice from foreign experts to develop harm reduction programs. A pilot program, including needle and syringe exchange and health education, was started in four of 23 administrative areas in Taiwan in July 2005, and opioid substitution therapy (OST) was introduced in February 2006 which became legalized in 2007.

 To enhance care and support for PWH, Taiwan initiated the pilot program of HIV case management, which was subsequently imple mented nationwide in 2007. 38 Initially focusing on hospital-based management, this program aimed to improve adherence to ART to achieve durable viral suppression among PWH. Presently, CBOs have assumed a more prominent role, particularly in providing support to disadvantaged PWH, adolescents, and those engaged in chemsex.

In 2007, in response to cases in which CBOs housing socio- economically disadvantaged PWH faced social exclusion from their neighborhoods, both public and private care institutions were explicitly prohibited from refusing to admit PWH to protect their rights to care and residence. Furthermore, measures were implemented to safeguard the rights of PWH, including the establishment of a framework where advocacy groups, CBOs, public health experts, health care providers, and representatives from relevant government agencies collaborated to promote HIV prevention and protect the rights of PWH. In the same year, the legislation was renamed the HIV Infection Control and Patient Rights Protection Act, reflecting that its legislative purpose extended beyond the original objectives of disease prevention to encompass human rights protection.

From 2010s to the present, a period marked by a shift from opposition to collaboration, PWH continue to face discrimination despite improved legal protections. In 2013, a university student with HIV was expelled, drawing public attention to HIV-related discrimination and prompting further reflection by human rights groups on the treatment of PWH. In 2015, Taiwan abolished its entry ban on foreigners with HIV, aligning its policies with global trends of increasing inclusivity and respect for human rights. By 2019, the rise of the gender equality movement and the legalization of same-sex marriage further advanced the social acceptance of HIV-related and gender issues. In 2020, a legal revision clarified that PWH who were on stable ART and had achieved viral suppression posed no significant risk of HIV transmission, thus exempting them from being classified as engaged in “risky sexual behavior” and encouraging PWH to adhere to treatment without fear.

With regard to other major policies, Taiwan followed the WHO guidelines to implement ART initiation for all PWH in 2016, regardless of CD4 count or AIDS status ; and rapid ART initiation and same-day ART initiation were implemented in 2018 and 2021, respectively. PrEP pilot program was started in 2016 and has been expanded to increase the coverage of people at risk for HIV infection since 2018. The national HIV self-testing program was implemented in 2017, which has been demonstrated to improve HIV case finding.

In order to reduce stigma or discrimination, the framework of The First Phase Plan to Eliminate HIV/AIDS by 2030 was divided into five levels, including governmental/structural, community, organizational/ institutional, interpersonal, and intrapersonal. Strategies included health education, universal testing, promotion of the updated evidence of U=U (undetectable-equals-untransmittable), training programs tar geting different subgroups of multisectoral organizations and CBOs, and subsidies for HIV-designated hospitals and CBOs to develop group counseling or support groups.

At the end of 2023, an estimated 9% of PWH in Taiwan remained undiagnosed, strategies to promote routine HIV screening and to provide client-centered HIV testing are ongoing and will be discussed in the next section. Moreover, 4% of those with a known HIV diagnosis were not engaged in care, and 5% of PWH who had started ART failed to achieve viral suppression, potentially leading to ongoing transmission risks in the community. Sustainable resources will need to be invested to strengthen the system’s ability to maximize and maintain the level of retention in treatment and prevention services.

4.Progress in HIV screening and diagnosis

HIV screening, which triggers subsequent confirmation of HIV diagnosis and treatment or preventive measures, plays a critical and fundamental role in HIV control programs. In response to the HIV pandemic, Taiwan started its routine HIV screening first among blood donors in 1988, (Fig. 2). military draftees in 1989, and inmates in 1990 In the following decades, Taiwan has witnessed a comprehensive expansion of screening initiatives, which included screening programs among pregnant women, clients with sexually transmitted infections (STIs), PWID enrolled in OST programs, and at-risk newborns since 2000, 2003, 2004, and 2008, respectively.

Free anonymous voluntary counseling and testing (VCT) was first provided at a few healthcare facilities since 1990, and a nationwide anonymous VCT program was initiated in 1997 at several hospitals, clinics, and CBOs aiming at providing HIV screening and counseling services that were friendly, accessible, and safe to at-risk clients. The services proved to be effective in identification of clients at risk for HIV infection, as the HIV seroprevalence and the prevalence of concomitant STIs were high among this group of individuals (HIV seroprevalence up to 3.6–4.1%).  Moreover, the proportion of cases of new HIV diagnosis identified by anonymous VCT services had increased from 5.2% to 29.3% from 2005 to 2016. In the past decade, innovations on HIV testing such as community mobilization, multi-channel self-testing services, and mobile VCT through social networking platform  showcased the nation’s commitment to increasing HIV testing coverage.

With these collective efforts, the annual number of HIV screening tests provided each year had reached 833,843 in 2019, which dropped to 667,133 in 2020 during the COVID-19 pandemic and slowly climbed back to 721,436 after the pandemic in 2023, 23 and the proportion of PWH who were undiagnosed had been on the decrease (21.5% in 2012, 12.1% in 2019, and 9% in 2023). The lingering disparity in attaining the first “95” target could be attributed to underestimation of HIV risk, stigma, fear of discrimination, and lack of accessible preven tive information in specific populations (females, transgender people, migrant workers, elderly, and adolescents). Other than efforts to improve public education and communication, implementation of additional novel channels for HIV screening are also ongoing, including peer screening, partner services, and integrated HIV screening into routine health examination. Universal screening was advocated for all people with sexual experience by Taiwan CDC to de-stigmatize HIV testing and to improve coverage. A recent analysis showed that the implementation of routine HIV testing in Taiwan was associated with a decreased rate of late diagnosis and lower HIV-related mortality and all-cause mortality. Such findings support further expansion of uni versal, opt-out testing to broader settings, although the practicability and cost-effectiveness remain to be examined in Taiwan.

In the past decades, the tools for HIV screening have evolved, pro gressing from 2nd generation tests that used recombinant antigen, to 3rd generation enzyme immunoassay/particle agglutination assays (EIA/ PA) that incorporated IgM detection, and then to the 4th/5th generation that adds p24 antigen in the antigen/antibody combination tests, which significantly shortens the window period. The introduction of ICT in 2019 had facilitated one-stop screening and confirmation of HIV infection. The endorsement of NAAT and ICT for confirmation of HIV diagnosis in the Taiwan CDC guidelines in 2021, replacing traditional Western blot assay, have significantly reduced the turnaround time for HIV confirmation and expedited the linkage of people newly diagnosed with HIV to care and ART initiation.

Testing of antiretroviral resistance of HIV-1 at the time of ART initiation was not performed routinely in Taiwan and is not reimbursed by the National Health Insurance (NHI). While genotypic resistance testing at the time of treatment failure is recommended by national treatment guidelines, resistance testing and surveillance provided by several research laboratories in Taiwan play a pivotal role in policy- making and in guiding ART prescription in both antiretroviral-naïve and antiretroviral-experienced PWH. Notably, increases in the prevalence of pre-treatment drug resistance (PDR) to non-nucleoside reverse-transcriptase inhibitors (NNRTIs) have been observed in several surveillance studies. In a study that included around 25% of antiretroviral-naïve PWH during 2016–2022, the prevalence of PDR to 1st generation integrase strand-transfer inhibitors (INSTIs) (i.e. elvite gravir and raltegravir) had increased from 1.1% at 2016 to 3.6% at 2022, while the prevalence of PDR to 2nd generation INSTIs (dolute gravir, bictegravir, and cabotegravir) was stable at around 1%.Other studies also showed that resistance to INSTIs among PWH who were naïve to INSTIs remained uncommon (Table 1). As intermediate- or high-level resistance to second-generation INSTIs has emerged in different countries, surveillance of antiretroviral resistance in Taiwan should be continued and policies should be implemented to improve its access and sustainability.

5. Evolution of ART treatment strategies

In the past three decades, ART has been demonstrated to suppress HIV replication, prevent onward transmission, and reduce disease pro gression among PWH. National ART treatment strategies have evolved since 1988, when compassionate use of AZT for AIDS was first provided (Fig. 3). In the mid-1990s, like other developed countries, ART in Taiwan comprised one or two different nucleoside reverse-transcriptase inhibitors (NRTIs). In 1997, Taiwan CDC updated its treatment guide lines by providing free-of-charge, multi-tablet ART consisting of two NRTIs plus one NNRTI or boosted or unboosted protease inhibitor (PI) to all Taiwanese PWH. Subsequently, the survival of PWH in Taiwan has significantly improved and opportunistic illnesses decreased in the modern ART era. Primary and secondary prophylaxis for several opportunistic infections could be discontinued when CD4 count increased and viral suppression was achieved.

A significant shift in the ART history in Taiwan occurred in 2016, when the first single-tablet regimens (STRs), co-formulated tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC)/efavirenz, was intro duced. Subsequently, TDF/FTC/rilpivirine (RPV), abacavir/lamivudine (3TC)/dolutegravir (DTG), tenofovir alafenamide (TAF)/FTC/RPV, TAF/FTC/cobicistat-boosted elvitegravir, DTG/RPV, TAF/FTC/bicte gravir (BIC), and DTG/3TC were sequentially introduced and recom mended as the first-line treatment or as stable switch regimens. Within a decade, STRs have become the mainstay of ART in Taiwan, relegating multi-tablet regimens to selected PWH with antiretroviral resistance or intolerance.

Because of increased PDR of HIV-1 to NNRTIs, which exceeded 10% in several surveillance studies (Table 1), STRs containing second-generation INSTIs, DTG or BIC, have emerged as the primary treatment options for both antiretroviral-naïve and antiretroviral-experienced PWH in the past decade. In 2021, Taiwan Food and Drug Administration approved the first long-acting (LA) injectable antiretrovirals, and the combination of LA-cabotegravir and RPV was listed as a second-line ART by Taiwan CDC in 2024.

Alongside the advancements in ART, the indications and timing for initiation of ART have also evolved significantly over time. A pivotal shift occurred in 2016, when ART was recommended for all PWH upon confirmed HIV diagnosis, moving away from previous criteria that relied on CD4 lymphocyte counts or plasma HIV RNA loads to initiate ART (Fig. 3). Thereafter, Taiwan CDC switched its focus towards minimizing the delay between HIV diagnosis and ART initiation. By 2018, hospitals designated for HIV care around Taiwan were advised to offer rapid initiation of ART, aiming to start ART within 7 days of a confirmatory HIV test for newly diagnosed PWH. Similar to studies in other parts of the world, real-world evidence in Taiwan also suggested that PWH on rapid ART initiation were more likely to be engaged in care and less likely to become lost to follow-up compared to PWH who initiated ART ≥7 days after a confirmed HIV diagnosis. To further improve the linkage of people newly diagnosed with HIV infection to care, Taiwan CDC implemented same-day ART initiation program in 2021, in which ART initiation on the same day of a confirmed HIV diagnosis was advised. With the increased utilization of ICT or NAAT, the median interval from a positive HIV screening test to initiation of ART has been reduced to just one day by 2023, with more than 60% of newly diagnosed PWH initiating ART within the first two days of testing positive on HIV screening.

As of today, STRs consisting of second-generation INSTIs have significantly improved tolerability, provide a higher genetic barrier to resistance, and demonstrate remarkable effectiveness in real-world set tings in Taiwan. However, it is critical to acknowledge that a small proportion of PWH still face challenges with adherence, risking treatment failure and emergence of resistance-associated mutations of HIV-1. For instance, PWH who use recreational drugs or PWID are recognized as having lower adherence rates. Moreover, there is growing interna tional evidence that suggests emerging resistance to second-generation INSTIs is still a possibility, especially among PWH with non-adherence.

6. Pre-exposure prophylaxis

Since September 2015, WHO has adopted oral PrEP with TDF-based regimen as part of comprehensive prevention for populations at sub stantial risk of HIV infection. Taiwan AIDS Society published the first version of national PrEP guidelines in May 2016, recommending GBMSM and transgender women, HIV-negative partners in a serodiscordant relationship, sexually-active heterosexual cisgender men and women as well as PWID to take daily TDF/FTC as PrEP. Several updates have been made since, including recommendation on event-driven dosing regimen in May 2018, and other novel agents such as fixed-dose combination of TAF and FTC, long-acting cabotegravir intramuscular injection, and dapivirine vaginal ring in September 2023. (Fig. 4)

Local studies have also shown that, compared to other at-risk populations in Taiwan, GBMSM were significantly more aware of and willing to initiate PrEP, especially among those who perceived a high susceptibility to HIV infection, but few would like to pay out-of-pocket to buy branded TDF/FTC for PrEP. 79–81 Event-driven PrEP has been chosen preferably by Taiwanese GBMSM, and switching between event-driven and daily dosing regimens is not uncommon. Regarding long-acting PrEP options without considering the cost, Taiwanese GBMSM currently taking PrEP prefer monthly oral PrEP, followed by a six-month subcutaneous injection, and then a bimonthly intramuscular injection in one survey.

Meanwhile, Taiwan CDC launched the pilot PrEP program aiming to enroll 1000 participants in 5 hospitals in November 2016, which also served as the first government-funded PrEP program in Asia. The pilot program came to a halt due to opposition by religious conservatives in September 2017, resulting in enrollment of less than one third of the target number, although the preliminary result showed an excitingly low HIV seroconversion rate (0.3%) among the participants. To further expand PrEP coverage, scale-up programs have been implemented by Taiwan CDC since September 2018, providing government-funded TDF/FTC to young adults aged below 30 years, serodiscordant couples, commercial sex workers, and people with sexualized drug use. The programs were rolled out with integrated sexual health services including HIV self-testing, one-stop testing and treatment, Mpox vaccination, and chemsex intervention. As of December 2023, there have been more than 5700 people enrolled in the government-funded PrEP programs at 63 hospitals and clinics around Taiwan. The programs also demonstrated protection against HIV acquisition for individuals with STIs and participants who retained in the programs.(Fig. 4)

Nevertheless, unlike treatment for HIV infection, preventive mea sures such as PrEP have been left uncovered by the highly acclaimed, universal NHI in Taiwan, not as in the case of National Health Service in the United Kingdom. In addition, generic forms have yet to be available even though the patent of branded TDF/FTC expired in 2020. While the uptake of PrEP among at-risk populations from government-funded programs has gradually increased, GBMSM who are not eligible or have no access to these programs keep seeking out-of-pocket generic TDF/FTC from “gray market” on the internet or pharmacies in the neighboring countries in Asia. The true number of current PrEP users in Taiwan is likely to be underestimated, and hence, the actual impact of PrEP on the recent decline of HIV incidence needs to be elucidated. Removal of the financial barriers to affordable PrEP for all remains the greatest challenge to further expand its coverage in Taiwan.

7. Beyond viral suppression: HIV comorbidities and holistic care

With the above-mentioned progress in HIV testing and care, PWH nowadays have extended longevity, approaching that of general population. In 2023, PWH aged over 50 years accounted for 23% of all PWH in Taiwan. While deaths attributable to AIDS-related diseases have declined from 31 % in 2014 to 11% in 2023 In Taiwan, PWH are at a higher risk for comorbidities including hypertension, diabetes mellitus, dyslipidemia, coronary artery disease, renal disease, and reduced bone mineral density, as compared to people without HIV. One single-site study in 2008 and 2009 showed nearly a quarter of Taiwanese PWH had metabolic syndrome. In a cross-sectional study investigating PWH aged 40–75 years, the prevalence of high cardiovascular disease risk varied, ranging from 3.7% by D:A:D (R) risk score, and 22.2% by Atherosclerotic Cardiovascular Disease risk score, to 30.6% by Fra mingham Risk Score. 95 Increased comorbidities have posed challenges to PWH and the healthcare system. In one study analyzing data from NHI Research Database (NHIRD), the overall spending on medications for comorbidities among PWH nearly doubled from 2010 to 2013.

The increased risk for comorbidities among PWH could be attribut able to multiple factors, including gene, age, lifestyle, smoking, chronic inflammation, and antiretroviral agents. The impact varied among different classes of antiretroviral agents across the published studies. Real-world data in Taiwan demonstrated mild weight gain and dyslipidemia for virally suppressed PWH switching to INSTI-based reg imens. While statins as primary prophylaxis have been shown to significantly reduce major adverse cardiovascular events among PWH at low or moderate risk, 98 they were underutilized in the clinical practices; for example, only less than 40% of PWH who met the criteria for statin use according to the recommendations of American Heart Association received statins during their HIV care at a university hospital, gesting that comprehensive measures to prevent cardiovascular diseases have yet to be integrated in the HIV care services in Taiwan.

Sexually active PWH are at ongoing risk for STIs, including syphilis, Chlamydia trachomatis infection, gonorrhea, trichomoniasis, Mycoplasma genitalium infection, and human papilloma virus (HPV) infection. In one Taiwanese study, the overall prevalence for chlamydia, gonorrhea, and/ or trichomoniasis was 30% among PWH. Another study demonstrated 32.9% of concomitant bacterial infections in HIV-positive MSM who presented with STIs. One study investigating anoscopic specimen showed 90.8% of the participants had infections with at least one HPV genotype. Preventive measurements including safe sex practice, health education, and vaccination (e.g., HPV vaccination) should be promoted to manage the STIs syndemics. Doxycycline for post-exposure prophylaxis against bacterial STIs have been proven effective in reducing the risk for chlamydial infection, syphilis, and possibly gonorrhea in recent randomized trials. While the impact of wider use of doxycycline on the carriage of bacteria with emergent resistance to doxycycline and the intestinal microbiota remain to be studied, discussion about prevention of bacterial STIs with doxycycline should be promoted.

As a country with hyperendemicity of hepatitis B virus (HBV) infection, the overall prevalence of HBV infection in Taiwan was 11.6% between 2012 and 2016. The prevalence has decreased significantly from 18.1% to 3.4% among PWH born before and those after 1986, when nationwide universal neonatal HBV vaccination program was implemented. For people with HIV/HBV coinfection, ART containing TDF or TAF is recommended. Taiwanese studies demonstrated significant mortality reduction among people with HIV/HBV coinfection after the introduction of TDF in 2011  and durable effectiveness in controlling HBV replication with TDF- and TAF-containing regimens in this population. Despite nationwide vaccination at neonatal stage, serological protection may wane gradually and incident HBV infections may occur in at-risk populations despite use of ART containing TDF or TAF.  Studies showed modest serological response of 74.0% after a 3-dose revaccination. Periodic serological evaluation and HBV  booster vaccination among seroreverters are recommended.

Hepatitis D virus (HDV) was associated with increased risk of adverse hepatic outcomes and mortality among people with HIV/HBV coinfec tion. The incidence of recent HDV infection increased significantly from 1992-2001 to 2007–2011 in one single-center study. 115 study showed an overall incidence rate of 12.65 per 1000 person-years of follow-up. Due to limitations of diagnosis and treatment, HDV coinfection is likely underdiagnosed. As newer diagnostics and treat ment options emerge, surveillance of HDV superinfection among people with HIV/HBV coinfection is warranted, especially among PWID due to their higher risk of HDV infection.

To achieve the goal of HCV elimination by 2025, direct-acting an tivirals (DAAs) have been reimbursed by NHI in Taiwan since 2017. Barriers to elimination included suboptimal diagnostic approach, incomplete treatment linkage, and high reinfection rate among key subgroups. In one retrospective study, 74.9% of PWH with HCV viremia initiated anti-HCV treatment and 94% of these individuals achieved viral clearance. Compared to people without HIV, PWH have a higher risk of HCV reinfection. After implementation of DAA treatment program, the prevalence and incidence of HCV have declined while the proportion of reinfections increased among PWH. Recent studies suggested diagnostic strategies with more frequent screening and pooled-plasma HCV RNA testing may help to identify acute HCV infection timely and the latest data showed the rate of HCV reinfection has decreased significantly from 2020 to 2023. Regular surveillance, timely diagnosis, and linkage to effective DAA treatment among at-risk populations are key to achieving micro-elimination of HCV in Taiwan.

To achieve holistic care beyond viral suppression, other important yet commonly overlooked issues, including bone health, malignancy, renal diseases, sexual health, vaccination, mental health, cognitive function decline, stigmatization, substance use, quality of life (QoL), and long-term care, should be evaluated and managed in routine HIV care. Comprehensive review for all comorbidities and their management in Taiwan is beyond the scope of this review. Selected topics of malig nancy, mental health, cognitive function decline, and QoL will be briefly discussed.

The incidences of both AIDS-defining and non-AIDS-defining ma lignancies have decreased significantly in the era of combination ART. However, the overall risk for malignancy remains higher among PWH compared to people without HIV. In one study analyzing data from NHIRD, the highest standardized incidence ratio was present in anal cancer in both sexes. In a cross-sectional, single-center study, only 46.9 % of eligible PWH had completed free-of-charge cancer screening, highlighting that awareness and implementation of screening for malignancy among PWH should be promoted.

Mental disturbances, including insomnia, anxiety, and depression, are common among Taiwanese PWH. In one study, over 30% of the participants receiving stable ART reported cognitive and psychological symptoms. 128 An NHIRD-based study showed that 23.8% of newly diagnosed PWH were dianogsed with psychiatric disorders after an average of 3.3 years of HIV diagnosis. In another NHIRD study, PWH had a higher risk of any use and long-term use of benzodiazepines and Z-drugs compared with HIV-negative controls.

The prevalence of cognitive decline was 2.25 % among PWH with an average age of 37.5 years in a cross-sectional study. An older age, being less educated, and having a longer duration of HIV infection were significantly associated with cognitive impairment. Another study utilizing NHIRD found an incidence of 13.67 per 1000 person-years for neurological disorders. The associated factors identified included age, substance use, traumatic brain injury, psychiatric illness, HIV-associated opportunistic infections, frequency of emergency department visits, ART adherence, urbanization, and monthly income.

WHO has added a “fourth 90” aiming at optimizing health-related QoL (HRQoL) to the goal of HIV care. Research on QoL among PWH remains scarce in Taiwan. In a recent online survey of 120 virally suppressed PWH, similar HRQoL could be achieved compared to people without HIV across different dimensions including mobility, usual ac tivities, self-care, pain/discomfort, and anxiety/depression. The finding is encouraging, yet probably not generalizable to Taiwanese PWH who are female, older, less supported by CBOs, or living in rural areas. Patient-centered, holistic care covering aspects mentioned above will be needed to achieve the ambitious target of the fourth “90” for all PWH.

8. Conclusions

Taiwan is on the right track to achieve elimination of HIV infection as a public health threat by continued efforts and investment in expanding HIV testing and PrEP and providing free-of-charge, state-of- the-art antiretroviral regimens. Client-centered approaches are war ranted to further scale up HIV testing. With continued progress of linkage to HIV treatment, more emphasis on the retention in treatment and prevention is needed to sustain the achievement. Delivery of in formation, education, and communication is imperative to reduce the stigma and discrimination surrounding HIV infection and to facilitate public-private partnership to ensure successful implementation of HIV control programs. While PWH continue to experience ongoing chal lenges of various comorbidities such as metabolic complications, sexually transmitted infections, malignancy, and mental disorders in the modern ART era, holistic HIV care requires regular surveillance and evaluation of comorbidities with individualized preventive measurements to enhance the quality of life for PWH beyond viral suppression.

CRediT authorship contribution statement

Sung-Hsi Huang: Writing – review & editing, Writing – original draft, Visualization, Validation, Formal analysis, Data curation. Hsun- Yin Huang: Writing – review & editing, Writing – original draft, Vali dation, Formal analysis, Data curation. Stephane Wen-Wei Ku: Writing – review & editing, Writing – original draft, Visualization, Validation, Formal analysis, Data curation. Po-Hsien Kuo: Writing – review & editing, Writing – original draft, Validation, Formal analysis, Data curation. Kuan-Yin Lin: Writing – review & editing, Writing – original draft, Visualization, Validation, Formal analysis, Data curation. Guan- Jhou Chen: Writing – review & editing, Writing – original draft, Visu alization, Validation, Formal analysis, Data curation. Chia-Chi Lee: Writing – review & editing, Validation, Formal analysis, Data curation. Yen-Fang Huang: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Formal analysis, Conceptualiza tion. Chien-Ching Hung: Writing – review & editing, Writing – original draft, Validation, Supervision, Data curation, Conceptualization.