Rochelle P. Walensky，醫學博士、公共衛生碩士和 Lindsey R. Baden，醫學博士/ 2024 年 7 月 24 日發表在 NEJM.org
即便是歷經 40 年的研究和為預防、診斷、治療和抑制人類免疫缺陷病毒 (HIV) 感染而開發的大量成功工具，在2024 年於南部非洲的年輕在女性中HIV 1 型 (HIV-1) 的發生率，怎麼可能在每100 人年中有超過3.5 例之感染？ 2010 年，具有里程碑意義的恩曲他濱- 替諾福韋 (emtricitabine–tenofovir disoproxil fumarate，F/TDF) 暴露前預防計畫 (iPrEx) 試驗，首次顯示了在MSM 中暴露前預防 (PrEP ) 對預防HIV 感染的效力。2012 年7 月，當美國食品和藥物管理局批准F/TDF 用於MSM 中的HIV-1 PrEP 時，隨後引發了關於這些發現是否可以推斷以支持在其他高危險群（例如順性別女性）中使用PrEP 的激烈討論。
貝克爾等人。現在在《期刊》上報告了在南非和烏干達針對順性別女性進行的 PrEP 一項出色的大型隨機對照試驗 (PURPOSE 1) 的結果。參與者以2:2:1 的比例分配，接受每年兩次皮下注射的來那帕韋（lenacapavir，一種HIV-1 capsid 衣殼抑制劑）、每日口服恩曲他濱-替諾福韋艾拉酚胺(emtricitabine–tenofovir alafenamide , F/TAF) 或每日口服F/TDF（主動對照）。鑑於納入安慰劑組被認為是不道德的，該試驗還納入了經過篩檢但未入組的人作為無 PrEP 觀察組。
無 PrEP 組的愛滋病毒背景發生率不幸的與先前的估計相符，為每 100 人年 2.41 例。在三個介入組參與者中發生的 55 例感染事件中，來那帕韋組沒有發生感染，F/TAF 組有 39 例，F/TDF 組有 16 例，發生率分別為每100 人年為0、2.02 和 1.69。此效力超出了預定的停止標準，試驗提前停止。薈萃分析之前已顯示出PrEP之劑量反應功效，具體取決於依從性。儘管完全理解隨機化後評估總是具有挑戰性，因為藥物依從性和其他行為可能會一起追踪，但PURPOSE 1 試驗證實了這些梯度發現。然而，在暴露於 HIV-1 的時間和部位時的依從性和活性藥物對於有效預防可能都很重要。PURPOSE 1 試驗的結果低估了堅持每日口服藥物的挑戰，當記錄的依從性較低時，HIV-1 感染的發生率與背景發生率沒有什麼不同。每年兩次的來那帕韋注射的參加率約為92%，PURPOSE 1 試驗不僅證明女性可以可靠地遵守這一給藥計畫，而且HIV-1 衣殼抑製劑的水平可以在一段時間內保持足夠高的水平。
PURPOSE 1 試驗的結果將提出科學問題。例如，我們如何應對罕見急性 HIV-1 感染的診斷挑戰（如《期刊》現已報導的 cabotegravir PrEP 研究所示）？對抗大量伴隨性傳播感染的最佳策略是什麼？出現病毒抗藥性的潛力有多大？這些數據如何為其他愛滋病毒感染高風險族群提供潛在用途？我們如何為感染愛滋病毒的高危險群女性改善避孕選擇。鑑於 PURPOSE 1 試驗參與者的懷孕率較高，評估妊娠期萊那帕韋的安全性是當務之急。然而，也許最關鍵的問題是——在美國首次批准 PrEP 十多年後，以及在 MSM 中取得有希望的 DISCOVER 結果幾年之後——我們卻長期地讓愛滋病毒感染高風險女性失望。
降低愛滋病毒感染率的一個關鍵挑戰是識別高風險族群（尤其是女性），讓他們參與進來，並為他們提供簡單、低門檻和低成本的取得有效且可以堅持的 PrEP 方案。由於先前的 PrEP 方案已被證明在處方服用時非常有效，因此 PURPOSE 1 試驗僅解決了這些障礙中的最後一個障礙。
南非是 PURPOSE 1 試驗的主要招募國，於 2021 年更新了 PrEP 指南，支持對 HIV 感染風險最大的人群使用 PrEP，包括少女和年輕女性以及 MSM 等。南非的人口統計數據顯示，大約有450 萬名年齡在16 歲至25 歲之間的少女和年輕婦女（PURPOSE 1 遴選標準），聯合國愛滋病毒/愛滋病聯合規劃署估計還有75 萬南非人處於PrEP 人群中。截至 2021 年，南非有超過 525 萬名符合資格的人，其中只有 35 萬人（<7%）曾接受過 PrEP 處方；而持久使用的可能要低得多。
據報道，非洲年輕人使用 PrEP 的障礙包括社會恥辱、對副作用的恐懼、長途路程或預約等待時間、不方便的臨床操作時間和藥物費用。為了彌合當前 PrEP 效力和有效性之間的鴻溝，未來的努力必須應對這些挑戰。首先，被證明有效的 PrEP 藥物應該能夠為所研究國家的民眾提供經濟上的支持。 F/TDF 在南非的售價每年不到 50 美元。同時，根據 Red Book Online (Truven Health Analytics) 的數據，目前在美國，lenacapavi 的每年費用約為 43,000 美元，而在南非，lenacapvir 的取得嚴重受到限制。但是，PURPOSE 1 試驗的結果現在已經產生了道德上的責任，即讓登記者以及所有具有類似資格並可能受益的人能夠廣泛獲得和負擔得起的來那卡韋作為 PrEP。
所以現在我們有了一個高效力的PrEP產品。這對科學來說是個好消息，但對女性來說還不是個好消息。現在，當務之急是在獲取、實施和交付方面投入時間、資源和政治意願。該計畫必須包括一個為這些藥物提供資金的機制，以便那些承受著令人無法接受的高愛滋病毒感染負擔和幾十年來自願從事愛滋病毒預防研究的婦女，能夠獲得PrEP 的好處並保持遠離愛滋病毒的狀態。
作者提供的揭露表格可與本社論全文一起在 NEJM.org 上取得。來自哈佛大學甘迺迪政府學院和哈佛商學院，劍橋，麻薩諸塞州 (R.P.W.)。這篇社論於 2024 年 7 月 24 日發表在 NEJM.org。
The Real PURPOSE of PrEP — Effectiveness, Not Efficacy
Rochelle P. Walensky, M.D., M.P.H., and Lindsey R. Baden, M.D.
Given the 40 years of research and the wealth of successful tools that have been developed to prevent, diagnose, treat, and suppress human immunodeficiency virus (HIV) infection, how is it possible that in 2024 the incidence of HIV type 1 (HIV-1) infection is more than 3.5 per 100 person-years among young women in southern Africa? The efficacy of preexposure prophylaxis (PrEP) to prevent HIV infection was first shown in 2010 in the landmark Preexposure Prophylaxis Initiative (iPrEx) trial of emtricitabine–tenofovir disoproxil fumarate (F/TDF), largely in men who have sex with men (MSM). In July 2012, the time of Food and Drug Administration approval of F/TDF for HIV-1 PrEP in MSM, heated discussion ensued about whether these findings might be extrapolated to support PrEP use in other high risk populations, such as cisgender women.
Bekker et al. now report in the Journal the results of a well-done, large, randomized, controlled trial in South Africa and Uganda of PrEP for cisgender women (PURPOSE 1). Participants were assigned in a 2:2:1 ratio to receive twice yearly subcutaneous lenacapavir (an HIV-1 capsid inhibitor), daily oral emtricitabine–tenofovir alafenamide (F/TAF), or daily oral F/TDF (active control). Given that inclusion of a placebo group was considered to be unethical, the trial also included screened but unenrolled persons as a no-PrEP observational group.
The background HIV incidence in the no-PrEP group sadly mirrored previous estimates, at 2.41 per 100 person-years. Of the 55 incident infections among participants in the three intervention groups, there were none in the lenacapavir group, 39 in the F/TAF group, and 16 in the F/TDF group, with an incidence of 0, 2.02, and 1.69 per 100 person-years, respectively. This efficacy exceeded the predefined stopping criteria, and the trial was stopped early. Meta-analyses have previously shown a dose-responsive PrEP efficacy, depending on adherence. Although it is always challenging to fully understand a postrandomization assessment, because medication adherence and other behaviors may track together, the PURPOSE 1 trial corroborates these gradient findings. Nevertheless, adherence and active drug at the time and site of HIV-1 exposure are probably both important for effective prevention. Findings from the PURPOSE 1 trial under score the challenges of adherence to a daily oral medication, and the incidence of HIV-1 infection was no different from background incidence when documented adherence was low. With approximately 92% attendance for the twice-yearly lenacapavir injections, the PURPOSE 1 trial exemplifies not only that women can dependably adhere to this administration schedule but also that levels of an HIV-1 capsid inhibitor can remain high enough over a period of 6 months to reliably prevent infection.
The results of the PURPOSE 1 trial will raise scientific questions. For example, how can we address the diagnostic challenges of rare acute HIV-1 infection (as shown in the cabotegravir PrEP studies also now reported in the Journal)? What are the best tactics to combat the large number of concomitant sexually transmitted infections? What is the potential for emergent viral resistance? How do these data inform
potential use for other groups at high risk for HIV infection? And how can we improve contraceptive options for women at high risk for HIV infection. Given the high pregnancy rate among participants in the PURPOSE 1 trial, assessment of the safety of lenacapavir in pregnancy is a priority. Perhaps, however, the most critical question is how — more than a decade after PrEP was first approved in the United States and several years after the promising DISCOVER results among MSM — we have failed women at high risk for HIV infection for so long.
A key challenge to decreasing the incidence of HIV infection is identifying high-risk populations (especially women), engaging them, and providing them easy, low-barrier, and low-cost access to a PrEP regimen that works and to which they can adhere. Because previous PrEP regimens have proven to be highly effective when taken as prescribed, the PURPOSE 1 trial uniquely ad dresses only the last among these hurdles.
South Africa, the primary country of enrollment in the PURPOSE 1 trial, updated its PrEP guidelines in 2021, endorsing PrEP use for persons at greatest risk for HIV infection, including adolescent girls and young women as well as MSM, among others. Demographic data for South Africa suggest there are approximately 4.5 million adolescent girls and young women between the ages of 16 and 25 years (PURPOSE 1 enrollment criterion), and the Joint United Nations Program on HIV/AIDS estimates an additional 750,000 South Africans among PrEP-eligible key populations. With more than 5.25 million eligible South Africans, as of 2021 a mere 350,000 ( <7%) had ever received a PrEP prescription; durable use is probably far lower.
Reported barriers to PrEP use among young persons in the African context include social stigma, fear of side effects, long travel or wait times for appointments, inconvenient clinical operating hours, and drug costs.8 To bridge the current canyon between PrEP efficacy and effectiveness, future efforts must address these challenges. To start, PrEP drugs proven to work should be financially accessible to the populations in the countries studied. F/TDF is available in South Africa for less than $50 per year. Mean while, lenacapavir currently costs approximately $43,000 annually in the United States, according to Red Book Online (Truven Health Analytics), and access to lenacapavir in South Africa is severely limited. But, the results of the PURPOSE 2 1 trial have now created a moral imperative to make lenacapavir broadly accessible and afford able as PrEP to persons who were enrolled, as well as all those who are similarly eligible and could benefit.9
So now we have a PrEP product with high efficacy. That is great news for science but not (yet) great for women. Now, the imperative is to spend time, resources, and political will on access, implementation, and delivery. And that plan must include a mechanism to finance these drugs so that the women who have borne an unacceptably high HIV infection burden and who have volun teered for decades in studies of HIV prevention can reap the PrEP benefits and remain HIV free. Disclosure forms provided by the authors are available with the full text of this editorial at NEJM.org. From the Harvard Kennedy School of Government and Harvard Business School, Cambridge, MA (R.P.W.).
This editorial was published on July 24, 2024, at NEJM.org.