在等待長效型卡博特韋的同時優化口服 PrEP
資料來源：www.thelancet.com/hiv 2023 年 9 月 29 日線上發表 https://doi.org/10.1016/S2352-3018(23)00231-X
兩項大型暴露前預防 (PrEP) 隨機試驗顯示，在預防不同人群中的HIV 感染方面，每8 週肌肉注射一次長效卡博特韋 (long-acting cabotegravir) 優於每日口服富馬酸替諾福韋二吡呋酯加恩曲他濱 (oral tenofovir disoproxil fumarate plus emtricitabine)。這並不完全的令人驚訝，因為早期的安慰劑對照試驗即觀察到，有較低比例的參與者其藥物濃度與每日富馬酸替諾福韋二吡呋酯加恩曲他濱相匹配，尤其是撒哈拉以南非洲的順性別女性以及與男性和跨性別女性發生性關係的順性別男性，在《刺胳針》愛滋病毒雜誌上，Mark Marzinke 及其同事報告了愛滋病毒預防試驗網絡 (HPTN) 083 注射用cabotegravir 試驗的第二次分析，該試驗重點關注在跨性別女性的範圍內所登記的570 名參與者。儘管樣本量太小，無法達到統計顯著性，但效果的大小和方向與總體試驗人群的結果一致。性別認同僅在入組時獲得，作者建議在未來的試驗中對此進行縱向的評估，因為他們觀察到這一人口變項的流動性，自我認同的男男性行為者報告在入組時和追蹤期間接受了性別肯定荷爾蒙治療。而報告使用性別肯定荷爾蒙療法的跨性別女性與未使用性別肯定荷爾蒙療法的跨性別女性之間，其卡博特韋濃度沒有差異，這方面令人放心。然而，需要額外的藥理學研究來捕捉劑量細節，以全面評估藥物間之交互作用。注射卡博特韋治療組的依從性很高，92% 的跨性別女性和男男性行為者在規定時間後 2 週內接受注射。
在隨機分組的參與者中評估了富馬酸替諾福韋二吡呋酯加恩曲他濱的依從性，發現跨性別女性的依從性顯著低於與男男性行為者。儘管如此，58% 的人的藥物濃度與每週四劑或更多劑量的富馬酸替諾福韋二吡呋酯加恩曲他濱相匹配，這是先前在類似人群中研究所觀察到的兩倍多。儘管注射卡博特韋的效果要好得多，但富馬酸替諾福韋二吡呋酯聯合恩曲他濱的依從性的改善令人鼓舞。我們認為這種改善的原因是多因素的，包括社區對 PrEP 有效性的認識和信心增強。 Marzinke 及其同事指出，如果要提高社區的 PrEP 接受率，就需要將 PrEP 置於與跨性別女性產生共鳴的社會行為背景中。
世衛組織發布了一項新建議，可將注射用卡博特韋作為提供愛滋病毒綜合預防方法的一部分。該指引承認口服PrEP 的獲取和採用範圍不斷擴大，以及一些國家願意為順性別女性提供達匹韋林陰道環 (the dapivirine vaginal ring)，儘管尚未提供。這項有些謹慎的建議，平衡了實施兩個月一次注射方法之壓倒性的療效證據和選擇需求與實施該方法可能需要比低收入國家目前可用的更複雜的愛滋病毒診斷上的證據差距。儘管中等收入和高收入國家可能能夠獲得診斷方法，但與富馬酸替諾福韋二吡呋酯加恩曲他濱的仿製藥相比，這一要求增加了提供專利藥物的成本，並且價格昂貴，從而在國家計畫應以不同的方式獲取上產生限制。
當在收集注射用卡博特韋的實施證據的同時，我們必須充分利用富馬酸替諾福韋二吡呋酯加恩曲他濱和它的仿製藥。因此，世衛組織 2022 年關於愛滋病毒預防的差異化和簡化 PrEP 的技術簡報非常受歡迎。該簡報將自我測試作為 PrEP 使用者的額外選擇，並為兩類人群開始和停止口服 PrEP 提供了明確的指導。順性別男性、跨性別者和出生時被指定為男性並有性接觸且未服用外源性雌二醇激素的性別多樣化人群等屬於一類。他們可以在性行為前 2-24 小時開始服用雙倍劑量（兩片），並在服用單片 2 天後停止（按需要服藥之方案）。其他人都屬於第二類，建議他們進行 7 天開始和 7 天停止。支持雙劑量開始的證據等級可以從第一類隨機安慰劑對照試驗中獲得，但不能從第二類試驗中獲得，因為這些試驗僅評估了每日口服 PrEP。然而，已經有精心設計的藥理學研究來表徵組織部位內的PrEP 濃度，這些研究有助於對群體有效性進行建模並很好地映射到臨床試驗之有效性。一致支持富馬酸替諾福韋二吡呋酯加恩曲他濱雙劑量（兩片）將實現24小時內在週邊血、女性生殖道和結直腸組織中達到群體有效的藥物濃度。 PrEP 提供者必須確保上述第二類 PrEP 使用者接受有關雙劑量開始的教育，因為並非總是可以在暴露前 7 天開始每日 PrEP。
MLC 得到北卡羅來納大學教堂山愛滋病研究中心的支持，該中心是美國國家衛生研究院資助的計畫 (P30AI050410)。 SM 得到醫學研究委員會撥款 MC_UU_00004/03 的支持。 我們聲明不存在競爭利益。
*Sheena McCormack、Mackenzie Leigh Cottrell s.mccormack@ucl.ac.uk
英國倫敦大學學院臨床試驗與方法學研究所，MRC 臨床試驗單位 (SM)； 美國北卡羅來納州教堂山北卡羅來納大學埃謝爾曼藥學院藥物治療與實驗治療學部。
Optimising oral PrEP while awaiting long-acting cabotegravir
www.thelancet.com/hiv Published online September 29, 2023 https://doi.org/10.1016/S2352-3018(23)00231-X
Two large randomised trials of pre-exposure prophylaxis (PrEP) showed that long-acting cabotegravir administered intramuscularly every 8 weeks was superior to daily oral tenofovir disoproxil fumarate plus emtricitabine in preventing HIV infection in diverse populations. This was not a complete surprise because earlier placebo-controlled trials had observed a low proportion of participants with drug concentrations compatible with daily tenofovir disoproxil fumarate plus emtricitabine, particularly in cisgender women in sub-Saharan Africa, and cisgender men who have sex with men and transgender women in Latin America. In The Lancet HIV, Mark Marzinke and colleagues report a secondary analysis from the HIV Preventions Trials Network (HPTN) 083 trial of injectable cabotegravir, focused on the 570 participants enrolled under the umbrella of transgender women. Although the sample size was too small to achieve statistical significance, the magnitude and direction of effect were in line with the results from the overall trial population. Gender identity was only captured at enrolment and the authors recommend that this be assessed longitudinally in future trials as they observed fluidity in this demographic variable, with self-identified men who have sex with men reporting gender affirming hormonal therapy at enrolment and during follow-up. There were no differences in cabotegravir concentrations between transgender women reporting using gender affirming hormone therapy and those who did not, which is reassuring. However, additional pharmacological studies capturing the details of dosing are needed to fully assess drug–drug interactions. Adherence in the injectable cabotegravir treatment group was high, with 92% of both transgender women and men who have sex with men receiving an injection within 2 weeks of the prescribed schedule.
Adherence to tenofovir disoproxil fumarate plus emtricitabine was assessed in a random subset of participants and found to be significantly lower in transgender women than in men who have sex with men. Nonetheless, 58% had drug concentrations compatible with four or more doses of tenofovir disoproxil fumarate plus emtricitabine per week, which is more than twice that observed in preceding studies5 in similar populations. Even though injectable cabotegravir was much more effective, this improvement in adherence to tenofovir disoproxil fumarate plus emtricitabine is encouraging. We think the reasons for this improvement are multifactorial, including greater awareness and confidence in PrEP effectiveness in the communities. Marzinke and colleagues note the need to place PrEP in a sociobehavioural context that resonates with transgender women if PrEP uptake is to improve in this community.
WHO released a new recommendation that injectable cabotegravir might be offered as part of combination HIV prevention approaches.8 This guideline acknowledged the expansion of oral PrEP access and uptake, and the willingness of a few countries to include the dapivirine vaginal ring for cisgender women, albeit not yet provided. This somewhat cautious recommendation balances the overwhelming evidence for efficacy and a need for choice against the evidence gap for implementing a 2-monthly injectable method that might require more sophisticated HIV diagnostics than are currently available in low-income countries. Although middle-income and high-income countries are likely to have access to the diagnostics, this requirement adds to the cost of delivering a drug that is on patent and expensive compared with the generic equivalents of tenofovir disoproxil fumarate plus emtricitabine, limiting access in national programmes in a different way.
While the implementation evidence is being gathered for injectable cabotegravir, we must make the best of tenofovir disoproxil fumarate plus emtricitabine and generics. As such, WHO’s 2022 technical brief on differentiated and simplified PrEP for HIV prevention is most welcome. The brief embraces self-testing as an additional choice for PrEP users and provides clear guidance on starting and stopping oral PrEP for two categories of population. Cisgender men, transgender, and gender diverse populations assigned male at birth who have sexual exposure and are not taking exogenous estradiol-based hormones are in one category. They can start with a double dose (two tablets) 2–24 h before sex and stop after 2 days of single tablets (the on-demand regimen). Everyone else is in the second category, for whom a 7-day start and 7-day stop are recommended. The level of evidence supporting the double dose start is available from randomised placebo-controlled trials for the first category, but not for the second category, as the trials have only evaluated daily oral PrEP. However, there have been well designed pharmacological studies characterising PrEP concentrations within tissue sites that facilitate modelling population effectiveness and map well to clinical trial effectiveness. There is consistent support that a tenofovir disoproxil fumarate plus emtricitabine double-dose (two tablets) will achieve population effective drug concentrations within 24 h in the peripheral blood, female genital tract, and colorectal tissues. It is important for PrEP providers to ensure that PrEP users in the second category described above are educated about a double-dose start since it is not always possible to initiate daily PrEP 7 days before exposure.
MLC is supported by the University of North Carolina at Chapel Hill Center for AIDS Research, a National Institutes of Health funded programme (P30AI050410). SM is supported by Medical Research Council grant MC_UU_00004/03. We declare no competing interests.
*Sheena McCormack, Mackenzie Leigh Cottrell s.mccormack@ucl.ac.uk
MRC Clinical Trials Unit at University College London, Institute of Clinical trials and Methodology, London, UK (SM); Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, Chapel Hill, NC, USA