Willem Daniel Francois Venter, Monica Gandhi, Simiso Sokhela, Kenly Sikwese, Helen Bygrave, Louis Da Gama, Ndiviwe Mphothulo, Lise Jamieson, Mark J Siedner, Anton Pozniak, Pablo Rojo, Solange L Baptiste, Jacque Wambui, Gesine Meyer-Rath, Brian Honerman, Mitchell Warren, Linda Gayle-Bekker, Phumla Sinxadi, Simon Collins, Jessica Burry, Karlien Möller, Polly Clayden, Andrew Owen, Andrew Hill /www.thelancet.com/hiv / 線上發布 2024 年 8 月 16 日/ https://doi.org/10.1016/S2352-3018(24)00173-5
用於預防和治療愛滋病毒的新型長效藥物的大型隨機研究顯示出高有效性和可接受性。儘管模型研究顯示這些藥物可能對消除愛滋病毒至關重要，但協調它們進入衛生保健市場至關重要，特別是在愛滋病毒感染率高的低收入和中等收入國家，儘管聯合國愛滋病規劃署指出，全球愛滋病毒感染率很高，但這些國家的協調程度很低。研究和實施計畫受到原始製藥公司的嚴格控制，只有一小部分符合條件的愛滋病毒感染者或受愛滋病毒影響的人從這些計畫中受益。世衛組織、財政捐助者、製造商和政府需要考慮世界各地利益相關者採取緊急協調行動，類似於將多替拉韋(dolutegravir)成功引入低收入和中等收入國家的治療計畫。如果不立即進行協調，長效愛滋病毒藥物的大規模取得將被推遲，並可能延續到 2030 年代。考慮到既定的全球愛滋病毒目標，這種拖延是不可接受的。
引言
用於治療的新技術正在改變包括愛滋病毒在內的一系列疾病的醫療保健。這些進步允許新藥物、現有藥物配方的改變、給藥間隔時間較長的新藥物（每週一次、每月一次、2個月和6個月一次，甚至可能每年一次），以及各種給藥物方式（包括肌肉注射、皮下注射）。需要延長現有和新型抗反轉錄病毒藥物的給藥間隔，超越第一線使用的每日固定劑量的口服片劑。
術語「長效」寬鬆地適用於於超過每24 小時間隔施用的抗反轉錄病毒藥物，通常至少為每週一次或更多長，並以口服、陰道、注射劑（肌肉或皮下注射）或植入製劑的形式給藥。目前，美國食品藥物管理局 (FDA) 批准了三種長效 HIV 藥物。對於治療，卡博特韋（cabotegravir ，ViiV Healthcare，英國倫敦）和利匹韋林（rilpivirine ，Johnson and Johnson [J&J；以前稱為Janssen] New Brunswick，新澤西州，美國）每月一次或每2 個月單獨肌肉注射一次，獲得許可用於治療愛滋病毒感染者，且其先前沒有證據顯示對這些藥物具有抗反轉錄病毒抗藥性者。被共同包裝的組合型名為Cabenuva，並在波札那（2022 年）、高收入國家加拿大（2020 年）和美國（2021 年）獲得批准，單獨分開型別亦分別在歐盟（2020 年）獲得批准，名稱為Vocabria（即卡博特韋林，cabotegravir ）和Rekambys（即利匹韋林，rilpivirine），並且在越來越多的不同國家的註冊。
關鍵訊息
• 長效抗愛滋病毒藥物可能是十多年來愛滋病治療領域最偉大的進步，並為實現全球愛滋病預防和控制規劃目標提供了巨大希望
• 目前的長效藥物牢牢地處於原廠製藥公司的控制之下，並且在全球大部分地區仍然無法獲得或成本過高
• 如果更廣泛的愛滋病毒社群界的行動停滯不前，最需要這些長效藥物的人群直到 2030 年代才可能從其中獲得任何益處，從而將導致大量可預防的愛滋病毒之感染
• 複雜的研究和藥物獲取計畫需要國際機構的協調，並在相關財政捐助者和利益相關者的協助下，為愛滋病毒感染者或受愛滋病毒影響的人，提供這些不可或缺產品的廣泛使用
繼Cabotegravir 單獨注射劑於2020 年首次顯示療效後，2021 年，FDA 批准 cabotegravir 作為單獨注射劑（由英國倫敦 ViiV Healthcare 生產，商品名為 Apretude），每 2 個月肌肉注射一次。澳洲於2022 年獲得批准，歐盟於2023 年獲得批准，其他多個國家（包括2022 年至2023 年期間的七個非洲國家）也獲得批准。 而用於PrEP 的Cabotegravir 已自願獲得藥品專利許可池（MPP），一個旨在透過自願許可和專利池降低藥品價格的國際組織。仿製藥製造商必須根據世界衛生組織的資格預審程序進行為期42 週的生物等效性測試，該程序為成員國設定了有品質保證的保健品的最低標準，並且通常是政府和財政捐助者購買的標準
Lenacapavi，一種衣殼抑制劑（由美國加州舊金山吉利德科學公司製造；於 2022 年在歐盟、加拿大和美國註冊），被許可作為針對具有廣泛抗藥性者之治療藥物，每 6 個月皮下注射一次，並與優化的每日口服療法施用。最近已證明 Lenacapavir 對順性別女性具有完全預防功效，預計將於 2024 年稍後對順性別男性進行第二項研究。
儘管迄今為止長效藥物的數量很少，但愛滋病毒感染者或有感染愛滋病毒風險的人和臨床醫生社群仍然感到非常興奮，並且報告中報告了大量的臨床前活動，專注於新型長效技術的學術文獻。大規模引入基於卡博特韋的 PrEP 的模型研究顯示出加速愛滋病毒預防的希望。也模擬了在高流行地區使用卡博特韋加利匹韋林作為轉換劑治療愛滋病毒的益處。
2024 年的一項隨機試驗顯示，對於依從性差的 HIV 感染者來說，卡博特韋聯合利匹韋林優於口服抗反轉錄病毒療法 (ART)。在五個國家的青少年中，卡博特韋聯合利匹韋林維持了病毒學抑制率。2024 年在非洲進行的一項試驗顯示，當改用注射型 ART 時，卡博特韋加利匹韋林在維持高病毒學抑制率 (>97%) 方面並不遜色於口服 ART。在 2024 年的一項研究中，卡博特韋作為標準照護之口服 PrEP 的額外選擇，將 HIV 發病率從 1·8% 降低至 0；使用這些藥物的人的數據顯示臨床醫生的接受度很高，
已經開始在無法堅持口服藥物的人群中成功地開出藥物處方。自 2017 年以來，主要 HIV 期刊的社論、評論和整個版本都致力於這些藥物的前景。
低收入和中等收入國家獲得治療的機會
最初，ViiV Healthcare 宣布計畫成為卡博特韋 (cabotegravir) 的全球唯一生產商，並開始限制操作研究的獲取，並且不公開獲取價格。這些決定令人驚訝，因為ViiV Healthcare 擁有向低收入和中等收入國家的仿製藥製造商授權關鍵抗反轉錄病毒藥物［特別是多洛格韋(dolutegravir) ］的成功歷史，從而使數百萬愛滋病毒感染者能夠一次性獲得該藥物。倡導團體對 Cabotegravir 的生產決定立即做出了憤怒的反應。 ViiV Healthcare 隨後放棄了這一立場，於2022 年7 月向MPP 授予卡博特韋 (cabotegravir) 許可（儘管將許多中等收入國家排除在外）。該許可證僅允許使用卡博特韋仿製藥來預防愛滋病毒，但不允許使用卡博特韋 (cabotegravir) 來治療。 2023 年3 月，三家公司（海得拉巴的Aurobindo、孟買的Cipla 和Canonsburg 的Viatris）獲得了許可證，並在完成WHO 要求的生物等效性測試後承諾進行技術轉讓（ViiV Healthcare 與各製造商之間在保密合約中協商）資格預審。
迄今為止，吉利德科學公司（Lenacapavi的製造商）和強生公司（rilpivirine的製造商）都沒有採取行動為其產品授予自願許可，儘管這兩種產品已經在許多高收入國家上市。吉利德科學公司在 MPP 流程中授權其他常用藥物有著悠久的歷史，允許與仿製藥製造商進行直接授權交易。強生尚未向 MPP 甚至雙邊向仿製藥製造商授予注射劑利匹韋林（rilpivirine）許可，這與 2011 年立即向仿製藥製造商授予口服利匹韋林雙邊許可形成鮮明對比。
ViiV Healthcare 是卡博特韋和利匹韋林組合 (the combination of cabotegravir and rilpivirine) 在高收入國家的市場授權持有人，而強生公司在未公佈的低收入和中等收入國家名單中擁有相同的角色。尚未授予用於治療的卡博特韋或利匹韋林的仿製藥生產許可證。在非高收入國家，治療組合的註冊也很少，這使得研究人員使用該藥物組合的研究談判變得極其複雜，他們必須獲得 ViiV Healthcare 和強生的批准。在強生最初批准資助後，至少一項此類研究已被取消，原因似乎是擔心卡博特韋試驗後缺乏保證。
依賴 ViiV醫療保健捐贈的卡博特韋的多項 PrEP 操作研究，因公司的密集審查和變更而被推遲，即使該公司沒有為這些研究提供資金。在施加公眾壓力之前，ViiV Healthcare 仍然不願公開披露其符合條件的國家名單的價格（截至撰寫本文時，2024 年每瓶價格為 30 美元，不包括分銷成本）。
Médecins sans Frontières 希望獨立於ViiV Healthcare 的審批流程採購卡博特韋用於運營研究，並且無需對價格保密，經過2 年多的漫長談判，才於2024 年1 月達成直接採購該藥物的協議，用於ViiV Healthcare 符合條件的國家名單中包含的國家，每瓶的使用價格為 23·49 英鎊（不包括分銷成本）. 由社區主導的組織進行的其他可行性研究，例如摩洛哥和模里希斯的 Coalition Plus，則未能確保從 ViiV Healthcare 取得。
美國總統愛滋病緊急救援計劃2024年2月宣布捐贈卡博特韋給尚比亞衛生部。尚比亞是少數獲得該藥物的國家之一，這筆捐款僅夠 2000 名符合 PrEP 資格的受助者使用一年，佔 2023 年啟動 PrEP 的 275 ,000 名尚比亞人的不到 1%。
未來潛在的治療組合
肌肉注射卡博特韋加利匹韋林 (cabotegravir plus rilpivirine) 是一種有效的愛滋病毒長效治療組合，但其可用性有限、成本高昂，並且有抗藥性病例報告；然而，據報道，在口服治療依從性差的人群中成功進行了標籤外使用，妊娠期藥物動力學的複雜性需要進一步研究。在操作上，組合型藥物的使用面臨著巨大的挑戰，需要對醫護人員進行管理培訓、利匹韋林冷鏈以及協調肌肉注射兩次於單獨的位置，並為超過特定體重的患者使用特殊的針頭。人們擔心，先前存在的高非核苷反轉錄酶 (NNRTI) 抗藥性會導致該組合的療效降低，這一擔憂更受到了非洲大型隨機臨床轉換試驗的挑戰，因顯示有效率很高。
一種建議的組合，特別是對於具有 NNRTI 抗藥性的 HIV 感染者，是每 2 個月施用一次卡博特韋，每 6 個月施用一次來那卡韋。一種新的長效卡博特韋製劑可能允許兩種藥物更同步地給藥。這兩種藥物都有值得注意的地方即懷孕期間的安全資料。愛滋病臨床試驗小組最初提議在大型試驗中測試 lenacapavi 和 cabotegravir，但吉利德科學公司和 ViiV Healthcare 建議樣本數僅為 20 名參與者。歐洲愛滋病毒、肝炎和全球傳染病治療網絡等提出的類似提案，已被吉利德科學公司和 ViiV Healthcare 拒絕。 ViiV Healthcare 和吉利德科學公司 (Gilead Sciences) 是商業競爭對手，儘管他們曾向結合其產品的獨立調查研究捐款，但他們都有追求競爭對手產品的歷史。
Islatravir 是默克公司（美國新澤西州拉威市）正在開發的一種核苷反轉錄酶易位抑制劑，它被探索作為PrEP 和治療的長效植入劑和口服片劑，但由於毒性原因而停止了PrEP 和一些治療劑量。
每週口服一次 lenacapavi 和 islatravir 的 2 期研究顯示，在維持病毒學抑制方面是安全有效的。使用長效藥物（包括中和抗體）的其他治療組合距離商業化還有很多年的時間，並且在獲得批准時不太可能有任何值得注意的懷孕和哺乳安全數據。一個例外是目前一線治療的潛在長效版本。
對於低收入和中等收入國家公共衛生計畫中用於愛滋病毒治療的長效產品，按當前價格計算的成本效益和操作問題上存在合理的擔憂。然而，與許多其他新產品（包括抗反轉錄病毒藥物本身）一樣，改變抗反轉錄病毒療法是醫療保健系統的一個問題，該系統確定如何最好地在現場部署藥物［例如，在低收入和中等收入國家，富馬酸替諾福韋二吡呋酯取代司他夫定和齊多夫定 (tenofovir disoproxil fumarate replacing stavudine and zidovudine）］，獲得大量長效藥物，同時開展業務研究，解決低收入和中等收入國家衛生保健系統中第一代長效藥物管理的複雜性，找出如何在低收入和中等收入國家提供這些創新藥物是必要的第一步。與口服 PrEP 一樣，支持足夠大的藥品市場，將實現規模經濟並最終降低價格，降低至使藥物具有成本效益的值。
根據克林頓健康倡議，在低收入和中等收入國家，可以以每人每年 30-40 美元的價格推出仿製長效注射劑卡博特韋，與當前口服 PrEP 的價格相似，最終達到最低價格每人每年14 -18 美元。
時間表
新的預測是，在最好的情況下，用於 PrEP 的卡博特韋 (cabotegravir)只能在 2027 年（顯示療效 7 年後）透過仿製藥製造商獲得，且數量有限，價格仍不確定。在此之前，卡博特韋將透過 ViiV Healthcare 獲得。人們擔心仿製藥製造商可能會因為這需要大量的資本投資而避免擴大卡博特韋的生產規模。仿製藥製造商預計，來那卡韋 (lenacapavir) 作為口服 PrEP 的首選替代品將得到越來越多的使用，這可能會取代卡博特韋。為了使藥物商業化並獲得捐助者和國家的訂單，仿製藥製造商在購買生產機械、開發藥物生產流程、完成生物等效性研究並獲得監管機構批准時已經承擔了巨大的投資風險。（包含世界衛生組織的資格預審程序）。
WHO對新仿製藥生物等效性研究的要求從52週縮短至42週；然而，藥物上市時間仍然有相當大的延長，如果可以並行進行審查，則可以進一步縮短。而其他藥效更長、價格可能更便宜的藥物可能會進入市場。 ViiV Healthcare 對市場的限制意味著，包括仿製藥製造商在內的利害關係人對卡博特韋的真實需求知之甚少。 ViiV Healthcare 本身除了對瞄準經濟利潤豐厚的商業市場之外的營銷可能興趣不大，當注意到註冊的行政負擔和隨後擴大的生產能力以供應這些市場，而來那卡韋(lenacapavir) 有可能在獲得批准後，幾乎立即取代卡博特拉韋 (cabotegravir) 成為PrEP 的首選藥物。
治療愛滋病毒的長效組合藥物的時間表更加黯淡。卡博特韋加利匹韋林 (cabotegravir plus rilpivirine) 尚無專利、生產或營運擴張計畫。此外，目前還沒有明確的計畫支持大規模的卡博特韋加來那卡韋 (cabotegravir plus lenacapavir) 研究，這是唯一似乎可以立即進行臨床試驗的藥物組合，並且可以使用經典的非劣效性研究設計在4 年內完成。如此大規模的研究需要同時關注智慧財產權壁壘和促進技術轉移（意味著原廠公司的合作），以允許透過 MPP 自願授權使用這兩種藥物。此外，需要準備醫療保健基礎設施，以便在關鍵業務地點建立高效的注射中心，以便立即擴大任一藥物組合的規模。多項此類試驗涉及多種潛在藥物，將有助於快速推出臨床上有趣的長效 ART 組合，並接納某些藥物組合和方法不會成功的可能性。
當前現狀的影響
公司、機構和捐助者之間的協調是零散且脫節的。無論是為低收入和中等收入國家提供指導方針還是為操作提供指導，用於由研究者驅動研究的長效藥物之供應很少。即使在高收入國家，獲得新型聯合治療的機會也僅限於少數受益者。
在非洲進行的著名 cabotegravir PrEP 研究 (HPTN 084) 的知情同意書支持 FDA 的批准，其中指出「在這項研究中收集的資訊可能有助於預防 HIV 的傳播，這可能對您和您的社區有益」。人們似乎很少考慮如何去為這十年來每年感染愛滋病毒的50 萬名非洲婦女，提供更多的卡博特韋 (cabotegravir) 作為愛滋病毒預防選擇，而這些婦女幾乎沒有機會獲得當初係對她們進行測試的卡博特韋。
幾十年來，民間社會組織和愛滋病毒活動人士在促使製藥公司、金融捐助者、政府和國際組織對國際愛滋病毒治療應對措施的承諾負責方面發揮了重要作用。這些組織和活動家需要提高定價的透明度，挑戰限制性專利實踐，倡導藥物創新的可負擔性和廣泛可用性，防止製藥公司限制藥物的廣泛獲取，並需要資金來允許這項工作獨立完成。
結論
正如卡博特韋(cabotegravir) 的例子所示，只將第三階段研究的實施和擴大規模等留給製藥公司，並不會導致長效治療的大規模推廣。我們需要一個大規模的計畫，正如多替拉韋 (dolutegravir) 的引入所看到的那樣，解決用於PrEP 和治療的長效藥物，並承認此類藥物代表著愛滋病毒感染者和愛滋病毒高危險群向前邁出的下一個重大步驟。
貢獻者：WDFV 完成了初稿並協調了所有作者的意見。 MG、SS 和 AH 對初稿做出了重要貢獻。所有作者都對後續草稿做出了貢獻。
利益申報WDFV 獲得比爾及梅琳達蓋茲基金會、南非醫學研究理事會、美國國家衛生研究院(NIH)、國際藥品採購機制、創新診斷基金會、兒童投資基金基金會、美國國際開發署向金山大學提供的資助（美國國際開發署）、ViiV Healthcare 和默克；來自吉利德科學公司、ViiV Healthcare、默克公司和強生公司的藥物捐贈；來自吉利德科學公司、ViiV Healthcare、Mylan-Viatris、默克公司、Adcock-Ingram、阿斯彭、雅培、羅氏、強生公司、賽諾菲和病毒學教育的教育講座和顧問委員會成員的酬金；為默克和諾和諾德進行商業藥物研究；是國際 NIH HIV 資料安全監測委員會以及 WHO 和南部非洲 HIV 臨床醫生協會 HIV 指南委員會的成員。 MG 得到 NIH 的財政支持。 SLB 是愛滋病疫苗倡導聯盟董事會、全球結核病活動家聯盟財政贊助商的成員，也是全球公共投資網絡和全球基金倡導網絡指導委員會的成員。 LJ 得到美國國際開發署和比爾及梅琳達蓋茲基金會的財政支持。 BH 獲得 ViiV Healthcare 對 amFAR 提供的撥款支持。 MW 獲得比爾及梅琳達蓋茲基金會和愛滋病疫苗倡導聯盟的支持。 KM 已收到強生公司的酬金。 LG-B 因向默克 (Merck)、ViiV Healthcare 和吉利德科學 (Gilead Sciences) 提供諮詢而獲得酬金；是獲得藥物基金會、愛滋病疫苗倡導聯盟和國際愛滋病疫苗倡議的無薪董事會成員；她的單位（德斯蒙德圖圖愛滋病毒中心）已從 ViiV Healthcare 和強生公司獲得了一種研究藥物，用於比爾及梅琳達蓋茲基金會資助的研究。 AO 報告吉利德科學 (Gilead Sciences)、ViiV Healthcare 和 Assembly Biosciences 的諮詢費用；他是 Tandem Nano 的董事兼首席科學官，在藥物傳輸方面擁有已頒發和正在申請的專利。 AP 獲得 NIH、國家心肺血液研究所、歐盟（透過 VERDI 聯盟）、吉利德科學公司、ViiV Healthcare 和默克公司向 NEAT ID 提供的商業藥物研究的資助；獲得吉利德科學公司、ViiV Healthcare、默克公司和病毒學教育公司的教育演講和顧問委員會成員的報酬；是 MRC-PENTA 研究資料安全監測委員會的成員；是歐洲愛滋病臨床學會和英國愛滋病毒協會愛滋病毒治療指南小組的成員；是 NEAT ID 的總裁；也是英國非洲 CUAMM 醫生協會的董事會成員。 PR 已獲得 ViiV Healthcare 的資助，並為 Gilead Sciences 提供諮詢。所有其他作者均聲明不存在競爭利益。
The long wait for long-acting HIV prevention and treatment formulations
Willem Daniel Francois Venter, Monica Gandhi, Simiso Sokhela, Kenly Sikwese, Helen Bygrave, Louis Da Gama, Ndiviwe Mphothulo, Lise Jamieson, Mark J Siedner, Anton Pozniak, Pablo Rojo, Solange L Baptiste, Jacque Wambui, Gesine Meyer-Rath, Brian Honerman, Mitchell Warren, Linda Gayle-Bekker, Phumla Sinxadi, Simon Collins, Jessica Burry, Karlien Möller, Polly Clayden, Andrew Owen, Andrew Hill /
www.thelancet.com/hiv Published online August 16, 2024
Large randomised studies of new long-acting medications for the prevention and treatment of HIV have shown high effectiveness and acceptability. Although modelling studies indicate these agents could be fundamental in HIV elimination, coordination of their entry into health-care markets is crucial, especially in low-income and middle-income countries with high HIV prevalence, where coordination is low despite UNAIDS flagging that global HIV targets will not be met. Research and implementation projects are tightly controlled by originator pharmaceutical companies, with only a small percentage of eligible people living with or affected by HIV benefiting from these projects. WHO, financial donors, manufacturers, and governments need to consider urgent coordinated action from stakeholders worldwide, akin to the successful introduction of dolutegravir into treatment programmes across low-income and middle-income countries. Without this immediate coordination, large-scale access to long-acting agents for HIV will be delayed, potentially extending into the 2030s. This delay is unacceptable considering the established global HIV targets.
Introduction
New technologies for therapeutic delivery are trans forming health care for a range of conditions, including HIV. These advances allow for new medications, altered formulations of existing drugs, new drugs with a longer duration between dosing (weekly, once every month and 2 months and 6 months, and potentially even annually), and various modalities of administration (including intramuscular, subcutaneous, implantable, vaginal, and novel transdermal patches). Antiretroviral potency and safety have substantially improved, with attention shifting to removing the need for daily pills, extending dosing intervals of existing and new antiretrovirals beyond daily fixed-dosed oral tablets used in first-line treatment, and improving uptake of pre-exposure prophylaxis (PrEP) in populations at risk.
The term long acting is loosely applied to antiretrovirals administered at intervals longer than every 24 h, usually at least once per week or more, and given orally, vaginally, as an injectable (intramuscular or subcutaneous), or as implantable preparations. Currently, three long-acting HIV medications are approved by the US Food and Drug Administration (FDA). For treatment, cabotegravir (ViiV Healthcare, London, UK) and rilpivirine (Johnson and Johnson [J&J; previously known as Janssen] New Brunswick, NJ, USA),
administered once per month or every 2 months as separate intramuscular injections, is licensed for the treatment of people living with HIV with no previous evidence of antiretroviral resistance to these drugs. This combination is co-packaged as Cabenuva and was approved in Botswana (2022) and the high-income countries Canada (2020) and the USA (2021), and separately in the EU (2020) as Vocabria (ie, cabotegravir) and Rekambys (ie, rilpivirine), as well as a growing number of different registrations in various countries.
Key messages
• Long-acting antiretrovirals are perhaps the greatest advance in HIV care in over a decade and provide great promise towards achieving global HIV prevention and control programme targets
• Current long-acting agents are firmly under the control of originator pharmaceutical companies and remain unavailable or cost-prohibitive across much of the globe
• If action from the broader HIV community is stagnant, the populations who are most in need of these long acting agents are unlikely to receive any benefit until well into the 2030s, resulting in a large number of preventable HIV infections
• Coordination by international agencies, with assistance from relevant financial donors and stakeholders, will be needed in the complex research and access programmes required to provide widescale use of these indispensable products to people living with HIV or affected by HIV
In 2021, the FDA approved cabotegravir as an injectable alone (manufactured as tradename Apretude by ViiV Healthcare, London, UK), administered once every 2 months intramuscularly. Approval was also granted in Australia in 2022, the EU in 2023, and multiple other countries, including seven countries in Africa between 2022 and 2023, after cabotegravir injectable alone initially showed efficacy in 2020. Cabotegravir for PrEP has been voluntarily licensed to the Medicines Patent Pool (MPP), an international organisation that aims to reduce drug prices through voluntary licensing and patent pooling. Generic manufacturers have to undergo 42-week bioequivalence testing per the WHO prequalification process, which sets a minimum standard for quality assured health products for member countries and is often the criterion for purchase by governments and financial donors
Lenacapavir, a capsid inhibitor, is licensed as a treatment for people with extensive drug resistance as a subcutaneous injection once every 6 months, administered with optimised daily oral therapy (manufactured by Gilead Sciences, San Francisco, CA, USA; registered in the EU, Canada, and the USA in 2022). Lenacapavir has recently been shown to have complete prevention efficacy in cisgender women, with a second study in cisgender men anticipated later in 2024.
Despite the small number of long-acting medications to date, there has been intense excitement among people living with HIV or at risk of HIV and clinician communities, as well as substantial preclinical activity reported in academic literature focusing on novel long-acting technologies. Modelling studies of the mass introduction of cabotegravir-based PrEP have shown promise for accelerated HIV prevention. The benefits for HIV treatment with cabotegravir plus rilpivirine as a switch agent in high-prevalence areas has also been modelled. A 2024 randomised trial showed that cabotegravir plus rilpivirine was superior to oral antiretroviral therapy (ART) in people with HIV with poor adherence. Among adolescents in five countries, cabotegravir plus rilpivirine maintained rates of virological suppression. A 2024 trial in Africa showed that cabotegravir plus rilpivirine was non-inferior to oral ART in maintaining high rates of virological suppression (>97%) when switched to injectable ART. Cabotegravir as an additional choice with standard-of-care oral PrEP reduced the HIV incidence rate from 1·8% to 0 in a 2024 study. Data from people using these medicines suggest high acceptance and clinicians have begun prescribing the agents successfully in
populations who are not able to adhere to oral agents. Since 2017, editorials, reviews, and entire editions of major HIV journals have been devoted to the promise of these agents.
Access of low-income and middle-income countries to treatment
Initially, ViiV Healthcare announced plans to be the sole producer of cabotegravir globally, and proceeded to restrict access for operational research and not make the price of access public. These decisions came as a surprise, as ViiV Healthcare had a successful history of licensing crucial antiretrovirals (specifically dolute gravir) to generic manufacturers in low-income and middle-income countries, thus allowing access to the drug for millions of people with HIV in one of the most important public health advancements for HIV programmes in modern times. Reaction to the cabote gravir sole manufacturing decision from advocacy groups was immediate and angry. ViiV Healthcare subse quently retreated from this position, licensing cabotegravir to the MPP in July, 2022 (albeit excluding many middle-income countries from access).15,16 This licence only allows the use of generic cabotegravir in the prevention of HIV, but not treatment. In March, 2023, the licence was awarded to three companies (Aurobindo, Hyderabad; Cipla, Mumbai; and Viatris, Canonsburg) with promised technology transfer (negotiated in a confidential contract between ViiV Healthcare and each manufacturer) after the bioequivalence testing required by WHO prequalification.
To date, neither Gilead Sciences (the manufacturer of lenacapavir) nor J&J (the manufacturer of rilpivirine) have taken action to grant a voluntary licence for their products, despite both products already being marketed in many high-income countries. Gilead Sciences has a long history of licensing other commonly used drugs to the MPP process, allowing direct licensing deals with generic manufacturers. J&J has not licensed injectable rilpivirine to the MPP or even bilaterally to generic manufacturers, which is a notable contrast to the near immediate bilateral licensing of oral rilpivirine to generic manufacturers in 2011.
ViiV Healthcare is the market authorisation holder for the combination of cabotegravir and rilpivirine in high income countries, whereas J&J is responsible for the same role in an unpublished list of low-income and middle-income countries. No licence for generic manu facture of cabotegravir or rilpivirine for treatment has been granted. There is also minimal registration for the treatment combination in countries that are not high income countries, which makes negotiation of research studies that use the drug combination exceedingly complex for researchers, who have to gain approval from both ViiV Healthcare and J&J. At least one such study has been cancelled in what appears to be concern for the absence of guarantee of post-trial cabotegravir, after J&J initially approved funding.
Multiple operational PrEP studies reliant on ViiV Healthcare-donated cabotegravir have been delayed by intensive company reviews and alterations, even when the company has not provided funding to these studies. ViiV Healthcare remained reluctant to publicly disclose the price for their list of eligible countries until after public pressure was applied (US$30 per vial in 2024 at the time of writing, not including distribution cost).18 Médecins sans Frontières, who wanted to procure cabote gravir for operational research independent of ViiV Healthcare’s approval process and without having to keep the price confidential, underwent lengthy negotia tions for over 2 years before reaching an agreement to procure the medicine directly in January, 2024, for coun tries included in ViiV Healthcare’s list of those eligible for the access price of £23·49 per vial (not including distribution cost).19 Other feasibility studies by community-led organisations, for example Coalition Plus in Morocco and Mauritius, have failed to secure access from ViiV Healthcare.
The US President’s Emergency Plan for AIDS Relief announced a donation of cabotegravir to the Zambian Ministry of Health in February, 2024. Zambia was one of the few countries to receive the drug, and the donation was sufficient for only 2000 PrEP-eligible recipients for 1 year, accounting for less than 1% of the 275 000 Zambians initiated on PrEP in 2023.
Potential future treatment combinations
Intramuscular cabotegravir plus rilpivirine, an available long-acting treatment combination for HIV, has limited availability, high cost, and reported cases of resistance; however, successful off-label use has been reported in populations with poor adherence for oral therapy. Pharmacokinetic complexity in pregnancy requires further investigation. Operationally, use of the drug combination faces substantial challenges, requiring health-care worker training in administration, a cold chain for rilpivirine, and two separate location-coordi nated intramuscular injections, with a special needle for patients over a particular bodyweight. Concerns that preexisting, high non-nucleoside reverse transcriptase (NNRTI) resistance would render the combination less effective have been challenged by the large, randomised clinical switch trial in Africa,10 suggesting high efficacy rates.
One proposed combination, especially among people with HIV with NNRTI resistance, is cabotegravir admin istered once every 2 months and lenacapavir administered once every 6 months.25 A new longer-acting formulation of cabotegravir might allow both medications to be given more synchronously.26 Both medications have noteworthy safety data in pregnancy.12 An initial proposal to test lenacapavir and cabotegravir in a large trial was made by the AIDS Clinical Trials Group, but Gilead Sciences and ViiV Healthcare suggested a sample size of only 20 participants. Similar proposals by The European Treatment Network for HIV, Hepatitis, and Global Infectious Diseases and others have been rejected by Gilead Sciences and ViiV Healthcare. ViiV Healthcare and Gilead Sciences are commercial rivals, with a history of pursuing competitor products, although they have donated to independent investigator studies combining their products.
Islatravir, a nucleoside reverse transcriptase transloca tion inhibitor in development by Merck (Rahway, NJ, USA), was explored as both a long-acting implant and oral tablet for PrEP and treatment, with PrEP and some treatment doses discontinued for toxicity reasons. A phase 2 study of lenacapavir and islatravir given orally once per week showed safety and efficacy in maintaining virological suppression.28 Other treatment combinations using long-acting agents, including neutralising anti bodies, are many years away from commercial availability and are unlikely to have any noteworthy pregnancy and lactation safety data by the time they are approved. An exception is a potential long-acting version of the current f irst-line treatment.
There are legitimate concerns about cost-effectiveness and operational issues regarding long-acting products for HIV treatment in public health programmes in low income and middle-income countries at current prices.15,30 However, as with many other novel products, including antiretrovirals themselves, changing ART is a question of health-care systems establishing how best to deploy medications in the field (eg, tenofovir disoproxil fuma rate replacing stavudine and zidovudine in low-income and middle-income countries). Access to a large volume of long-acting medications, along with simultaneous operational research addressing the complexity of admin istration of the first generation of long-acting drugs in health-care systems of low-income and middle-income countries, is a necessary first step to working out how to deliver these innovative new medicines in low-income and middle-income countries. As with oral PrEP, supporting large enough pharmaceutical markets will allow economies of scale and eventually prices to be reduced to values that render the drugs cost-effective. According to the Clinton Health Access Initiative, generic long-acting injectable cabotegravir could be introduced at US$30–40 per person per year in low-income and middle-income countries, similar to the current price of oral PrEP, and eventually reach as little as $14–18 per person per year.
Timelines
The new projection is that, in a best-case scenario, cabotegravir for PrEP will only be available through generic manufacturers in 2027 (7 years after showing efficacy), in small volumes only, and at a price that remains uncertain. Until that time, cabotegravir access will be through ViiV Healthcare. There is concern that generic manufacturers might refrain from scaling up the production of cabotegravir, which requires substantial capital investment. Generic manufacturers anticipate the increased use of lenacapavir as the preferred alternative for oral PrEP, which could displace cabotegravir. To make a drug commercially available and receive orders from donors and countries, generic manufacturers have already taken substantial investment risks by the time they have acquired manufacturing machinery, developed the drug-manufacturing process, completed bioequivalence studies, and garnered approval from regulatory authorities (including via the WHO prequalification process).
WHO requirements for bioequivalence studies of new generic medications have been shortened from 52 weeks to 42 weeks; however, there is still a considerable extension to the timelines of drugs being marketed that could be shortened further if reviews could be conducted in parallel. Other medicines that might be longer acting and possibly less expensive could be reaching the market. ViiV Healthcare’s restrictions on the market mean stake holders, including generic manufacturers, have little idea of the true demand for cabotegravir. ViiV Healthcare itself might have little interest in marketing beyond targeting financially lucrative commercial markets, noting the administrative burden of registration and subsequent expanded manufacturing capacity to supply these markets, with the possibility of lenacapavir replacing cabotegravir as the preferred agent for PrEP almost immediately on approval.
The timeline for long-acting combinations for treatment of HIV is even more bleak. There is no patent, manufacturing, or operational expansion plan in place for cabotegravir plus rilpivirine. Moreover, there is no apparent plan to support a large-scale cabotegravir plus lenacapavir study, which is the only drug combination that seems feasible for an immediate clinical trial and could be accomplished within 4 years using a classic non-inferiority study design. Such a large-scale study would need a parallel focus on intellectual property barriers and facilitation of technology transfers (implying cooperation from originator companies) to allow voluntary licensing via the MPP to use both medicines. Moreover, preparation of health-care infra structure to allow for efficient injection centres in key operational locations would be needed to allow for immediate scale-up for either drug combination. Several such trials, with multiple potential agents, would allow for a rapid launch of clinically interesting, long-acting ART combinations, and accommodate the likelihood that some drug combinations and approaches will not succeed.
Lessons from dolutegravir introduction
Increasing recognition of the side-effects associated with efavirenz and community-wide NNRTI resistance justified the introduction of the more potent antiretroviral dolutegravir, a major public health advancement in HIV treatment, with almost immediate benefits at a public health level.34 However, the introduction required a massive coordination of resources, involving the entire expanded HIV community, including: originator and generic manufacturers, governments of high-prevalence countries, supply-chain actors, international agencies and donors, advocacy organisations, civil society organisations, and substantial investment in treatment literacy for both people with HIV and health-care worker communities.
The long-acting medicine field is in its infancy, with much of the fundamental technology development activity taking place in academia. Individual academics, technology transfer offices, and universities should familiarise themselves with the mechanisms available for alignment with downstream equitable access provision, including technology platforms developed within the public sector. Academic groups can play important roles in early voluntary licensing, facilitating earlier access to medicines, health benefits, and economic savings, as was the case with dolutegravir.
Implications of the current status quo
Coordination among companies, agencies, and donors is fragmentary and disjointed. There is little supply of long-acting medication for investigator-driven studies, either to inform low-income and middl-income countries guidelines or for operational guidance. Even in high-income countries, access to novel combination treatment is restricted to a small minority of people who would benefit.
The informed consent form from the notable cabotegravir PrEP study conducted in Africa (HPTN 084), which supported FDA approval, states “the information gathered during this study may help to prevent the spread of HIV. This may be beneficial to you and your community.” There seems to have been little consideration as to how more cabotegravir as an HIV prevention option will become available for the 500 000 African women who are estimated to acquire HIV annually this decade, with little access to the cabotegravir initially tested on them.
Civil society organisations and HIV activists have been instrumental in holding pharmaceutical companies, financial donors, governments, and international organisations accountable for commitments to the international HIV treatment response for decades. These organisations and activists are needed to promote transparency in pricing, challenge restrictive patent practices, advocate for affordable and widespread availability of drug innovations, prevent companies from restricting broad access to medications, and require funding to allow this work to be done independently.
Conclusion
Leaving implementation and scale-up of phase 3 studies to pharmaceutical companies will not lead to mass intro duction of long-acting treatments, as the cabotegravir example has shown. We need a large-scale programme, as seen with the introduction of dolutegravir, addressing long-acting agents for both PrEP and treatment, acknowledging that this class of drugs represents the next major step forward for people living with HIV and people at risk of HIV.
Contributors
WDFV completed the first draft and coordinated input from all authors. MG, SS, and AH had major input into the initial draft. All authors contributed to subsequent drafts.
Declaration of interests
WDFV receives grants paid to University of the Witwatersrand from the Bill & Melinda Gates Foundation, South African Medical Research Council, National Institutes of Health (NIH), Unitaid, Foundation for Innovative New Diagnostics, Children’s Investment Fund Foundation, United States Agency for International Development (USAID), ViiV Healthcare, and Merck; drug donations from Gilead Sciences, ViiV Healthcare, Merck, and Johnson and Johnson; honoraria for educational talks and advisory board membership from Gilead Sciences, ViiV Healthcare, Mylan-Viatris, Merck, Adcock-Ingram, Aspen, Abbott, Roche, Johnson and Johnson, Sanofi, and Virology Education; conducts commercial drug studies for Merck and Novo Nordisk; and is a member of the international NIH HIV data safety monitoring board and WHO and Southern African HIV Clinicians Society HIV guideline committees. MG is supported financially by NIH. SLB is a member of the AIDS Vaccine Advocacy Coalition board, a Global Coalition of Tuberculosis Activists fiscal sponsor, and is a member of the Global Public Investment Network and Global Fund Advocate Network steering committees. LJ is financially supported by USAID and the Bill & Melinda Gates Foundation. BH receives grant support from ViiV Healthcare to amFAR. MW’s receives support from the Bill & Melinda Gates Foundation to the AIDS Vaccine Advocacy Coalition. KM has received honoraria from Johnson and Johnson. LG-B has received honoraria for advisories to Merck, ViiV Healthcare, and Gilead Sciences; is an unpaid board member for Access to Medicine Foundation, AIDS Vaccine Advocacy Coalition, and International AIDS Vaccine Initiative; and her unit (Desmond Tutu HIV Centre) has received a study drug from ViiV Healthcare and Johnson and Johnson for studies funded by the Bill & Melinda Gates Foundation. AO reports consulting fees for Gilead Sciences, ViiV Healthcare, and Assembly Biosciences; and is Director and Chief Science Officer for Tandem Nano, with patents issued and pending in drug delivery. AP receives grants paid to NEAT ID from NIH, National Heart, Lung, and Blood Institute, the EU (via the VERDI Consortium), Gilead Sciences, ViiV Healthcare, and Merck for commercial drug studies; receives honoraria for educational talks and advisory board membership from Gilead Sciences, ViiV Healthcare, Merck, and Virology Education; is on a data safety monitoring board for MRC–PENTA studies; is a member of the European AIDS Clinical Society and British HIV Association HIV treatment guidelines panels; is the President of NEAT ID; and is a board member of Doctor’s with Africa CUAMM UK. PR has received grants from ViiV Healthcare and consulted for Gilead Sciences. All other authors declare no competing interests.