全球愛滋病毒預防策略的實施

資料來源：www.thelancet.com/hiv Published online June 26, 2023

     儘管替諾福韋和恩曲他濱（商品名舒發泰，Truvada）的暴露前預防(PrEP) 於2012 年首次獲得美國食品和藥物管理局批准，但PrEP 的應用進展緩慢，在政策制定、實施和社會接受等多個層面面臨挑戰。 PrEP 實施方面的創新，例如基於社區的實施和自我照護介入措施，可以解決其中一些挑戰，以改善口服 PrEP 的使用。 HIV 預防界的首要任務是實施差異化的服務提供模式，並尋求創新，以提高口服 PrEP 的採用率和持久性。然而，愛滋病毒疫情控制（即愛滋病毒新增感染總數低於愛滋病毒感染者全死因死亡總數，新增感染人數和死亡人數均較低且呈下降趨勢），透過僅限於每日口服PrEP 片劑的一級預防來實現將很難實現。此外，服用藥物還存在許多障礙，包括獲取途徑有限、感染愛滋病毒的風險不準確、恥辱、醫療不信任以及堅持每天服用藥物的困難。

     為了滿足可能從 PrEP 中受益的不同人群的需求，有必要具選擇性之預防方案。因此，採用不同配方和方式的愛滋病毒生物醫學預防方法一直在開發中，其中兩種最近（2016-21）顯示出有效性——每月使用達匹韋林陰道環（the monthly dapivirine vaginal ring）和長效注射劑卡博特韋（long-acting injectable cabotegravir）。青春期女孩和年輕女性以及其他重點人群（例如男男性行為者、女性性工作者、注射吸毒者和跨性別者）往往並不知道也無法獲得口服的 PrEP；恥辱和藥物負擔給開始和堅持於 PrEP 中帶來了挑戰。因此，長效和更謹慎的選擇可能是首選。

     2016 年，ASPIRE 試驗顯示，達匹韋林陰道環是安全的，可將 HIV 發生率降低 27%，並且在順從性較高的亞組中療效更高。隨後的仿單外推廣研究顯示，非洲女性對於陰道環的接受率和持續使用率均有所提高，順從性、有效性和接受度也有所提高。世衛組織於 2021 年對達匹韋林陰道環進行了資格預審，許多國家調整了政策，允許實施該環，並為女性預防愛滋病毒提供了額外的選擇。在撒哈拉以南非洲地區，少女和年輕婦女受愛滋病毒影響尤為嚴重，並且愛滋病毒預防需求未得到滿足； REACH (MTN 034) 交叉研究顯示，如果能有選擇，並提供多種順從性支持選項，讓參與者可以同時選擇使用口服 PrEP 和達匹韋林陰道環，則對該二者均具有較高的順從性。三分之二的參與者在使用這兩種方法各 6 個月後選擇了陰道環。如果正確且持續地使用，達匹韋林環的功效非常高。在可能接觸 HIV 期間有效使用 PrEP 產品非常重要；因此，與口服 PrEP 相比，達匹韋林環的易順從性是一個重要的考慮因素，並且該環可能是女性一個可行的選擇，因為它們每月更換一次。如果青春期女孩和年輕女性願意使用達匹韋林環，那麼與完全沒有使用或口服 PrEP 順從性不佳相比，它可能會帶來更好的覆蓋和保護。模型研究顯示，達匹韋林陰道環在誇祖魯–納塔爾省等高發地區可能具有成本效益，如果優先考慮性工作者，則更可以達到節省成本。

    2021 年，FDA 批准了長效卡博特韋，對於男男性行為者、跨性別者和順性別女性者而言，該藥物高效、安全且優於口服替諾福韋和恩曲他濱。cabotegravir 在所有研究人群中都非常有效，且突破性感染很少見，但對於少數具有整合酶抑製劑耐藥性風險的偶發感染的延遲診斷則對其實施提出了真正的挑戰，特別是在HIV RNA 實驗室監測資源有限的匱乏環境中。鑑於需要專門的注射培訓，物流和較高的服務成本構成了進一步的障礙。此外，如果患者錯過劑量、無法獲取或停止 CAB-LA，則必須對在長藥代動力學尾期存在持續風險的患者進行口服 PrEP。

理想情況下，所有預防方案都應提供給易感染愛滋病毒的人。然而，物流和成本可能會在未來幾年限制達匹韋林環和長效卡博特韋的供應，從而可能阻礙許多高負擔國家的愛滋病毒流行控制。因此，公共衛生當局應考慮創新的給藥方法，以鼓勵繼續使用並改善口服 PrEP之結果。需求創造和教育以評估口服 PrEP之需求將促進其他生物醫學預防方式的採用。此外，實施上的需求（如表所列）和必要的操作研究均需要考慮以促進及時推出新的生物醫學預防方式。實施的關鍵問題包括教育使用者有關產品的相對有效性，並了解有效性較低的產品的效用，作為不能堅持每日口服 PrEP 的個人的另一種選擇。如果沒有對實施和服務提供的各個方面採取協調一致的行動和深思熟慮的關注，達匹韋林環和長效卡博特韋的潛力可能無法實現，以提高PrEP 覆蓋率並實現人口層面對愛滋病毒預防的影響。生物醫學預防領域是動態的，隨著新模式的出現，幫助個人認識到不同預防方案的特徵如何適合他們自己的生活方式非常重要，從而使個性化的最佳愛滋病毒預防能成為實現。

CC 擔任默克和吉利德的顧問。 LGB 已獲得 Janssen、Gilead、Merick、CEPHEID 和 ViiV Healthcare 的酬金。 PP 聲明不存在競爭利益。 本報告中的調查結果和結論屬於作者的觀點，並不一定代表其資助機構的官方立場。

*Pragna Patel、Connie Celum、Linda G Bekker plp3@cdc.gov

疾病控制和預防中心全球健康中心全球愛滋病毒和結核病處，亞特蘭大，GA 30329，美國（PP）； 美國華盛頓州西雅圖華盛頓大學全球健康、醫學和流行病學系 (CC)； 南非開普敦開普敦大學傳染病和分子醫學研究所德斯蒙德·圖圖愛滋病毒中心 (LGB)

Implementation of HIV prevention strategies globally

www.thelancet.com/hiv Published online June 26, 2023

    Although pre-exposure prophylaxis (PrEP) with tenofovir and emtricitabine was first approved by the US Food and Drug Administration in 2012, uptake of PrEP has been slow, with challenges at many levels, including policy development, implementation, and societal acceptance. Innovations in PrEP delivery, such as community-based delivery and self-care interventions could address some of these challenges for improved oral PrEP use. A priority for the HIV prevention community is to implement differentiated service delivery models and pursue innovations to improve the uptake and persistence of oral PrEP. However, HIV epidemic control (ie, the point at which the total number of new HIV infections is less than the total number of deaths from all causes among people living with HIV, with both new infections and deaths low and declining) will be hard to realise with primary prevention limited to daily oral PrEP tablets. In addition, there are many barriers to uptake, including limited access, an inaccurate perceived risk of HIV acquisition, stigma, medical mistrust, and difficulties consistently taking a daily pill.

    A choice of prevention options is necessary to meet the needs of the diverse populations who might benefit from PrEP. Thus, biomedical HIV prevention with different formulations and modalities have been under development, with two recently (2016–21) demonstrating effectiveness—the monthly dapivirine vaginal ring and long-acting injectable cabotegravir. Adolescent girls and young women and other key populations (eg, men who have sex with men, female sex workers, people who use injection drugs, and transgender people) are often not aware of and cannot access oral PrEP; stigma and pill burden have posed challenges with initiating and persisting on PrEP.1 Therefore, long acting and more discreet options might be preferred.

    In 2016, the ASPIRE trial3 showed that dapivirine rings are safe and lowered the incidence of HIV by 27%, with increased efficacy among subgroups with higher adherence. Open-label extension studies subsequently showed high uptake and persistent use of the ring with improved adherence, effectiveness, and high acceptability among African women. WHO prequalified the dapivirine ring in 2021, and many countries adapted their policies to allow for implementation of the ring and to offer an additional choice to women for HIV prevention. Adolescent girls and young women are disproportionately affected by HIV in sub-Saharan Africa and have an unmet need for HIV prevention; the REACH (MTN 034) crossover study showed participants could use both oral PrEP and the dapivirine ring with high adherence when given a choice and offered several options for adherence support. Two-thirds of participants chose the ring after having used both methods for 6 months each. The efficacy of dapivirine rings is high when used correctly and consistently. Effective use of a PrEP product during periods of possible exposure to HIV is important; thus the ease of adherence to the dapivirine ring compared with use of oral PrEP is an essential consideration, and the ring might be a viable option for women because they are replaced monthly. If adolescent girls and young women are comfortable using dapivirine rings, it might lead to better coverage and protection compared with nothing, or with suboptimal adherence to oral PrEP. Modelling studies showed dapivirine rings could be cost-effective in high-incidence settings, such as KwaZulu-Natal, and cost-saving if priority is given to sex workers.

    In 2021, the FDA approved long-acting cabotegravir, which was highly effective, safe, and superior to oral tenofovir and emtricitabine among men who have sex with men, and transgender and cisgender women who have sex with men. Although long-acting cabotegravir was highly effective in all study populations and breakthrough infections were rare, delayed diagnosis of a small number of incident infections with risk of integrase inhibitor resistance presents a real challenge for implementation, particularly in low-resource settings with limited HIV RNA laboratory monitoring. The logistics and higher cost of service delivery pose further barriers, given the need for specialised training to administer injections. Additionally, oral PrEP must be given to people with ongoing risk during the long pharmacokinetic tail if they miss doses, cannot access, or discontinue CAB-LA.

Ideally, all prevention options should be available to people susceptible to HIV acquisition. However, logistics and cost might restrict availability of dapivirine rings and long-acting cabotegravir for years to come, possibly hindering HIV epidemic control in many high-burden countries. Therefore, public health authorities should consider innovative delivery approaches for continued use and improved outcomes of oral PrEP. Demand creation and education that assess the need for oral PrEP will facilitate uptake of other biomedical prevention modalities. Also, implementation needs (table) and essential operations research necessary to fac