針對非洲女性的研究顯示，每年兩次注射來那卡韋(Lenacapavir)可提供 100% 的保護
Kai Kupferschmidt / 2024 年 7 月 30 日 / 新聞 / 科學
Lenacapavir 是一種新型藥物，可附著在包裹 HIV 基因組的衣殼上。
目錄/這個故事的一個版本出現在《科學》，第 385 卷，第 6708 期。
慕尼黑—科學家很少能在展示他們的數據時獲得起立鼓掌。但上週南非研究員琳達-蓋爾貝克爾 (Linda-Gail Bekker) 在 2024 年愛滋病會議上完成有關愛滋病毒預防試驗的演講後，觀眾起立鼓掌近 1 分鐘。 「這顯示人們有多熱情」，波昂大學愛滋病毒研究員於爾根·羅克斯特羅 (Jürgen Rockstroh) 說。
Bekker 告訴觀眾，在 2,000 多名非洲女性中，每年兩次注射抗病毒藥物來那卡韋 (Lenacapavir) 作為暴露前預防 (PrEP)，沒有一人感染愛滋病毒。有些人認為這一結果改變了遊戲規則。 「想像一下，如果你有一種對順性別女性 100% 有效疫苗，且你每 6 個月只需要加強接種一次」，杜克大學全球健康研究所的流行病學家 Chris Beyrer 說。「你會說，『就是這樣，我們終於有了一個可以結束這種流行病的工具』」。
該藥物的製造商吉利德科學公司 (Gilead Sciences) 在 6 月的新聞稿中介紹了 PURPOSE 1 試驗的主要結果，但一些研究人員保留了判斷，直到看到更多細節，例如副作用和研究方法。貝克爾 (Bekker)描述該研究的完整結果，並於上週發表在《新英格蘭醫學雜誌》上，「比任何人預期的都要好」。位於奈洛比的 IAVI 疫苗研究員文森特·基奧伊 (Vincent Kioi) 說，它們肯定會使愛滋病毒疫苗的長期探索變得更加複雜，他補充說道。
科學家仍然想知道在美國和其他六個國家針對男男性行為者進行的第二次療效試驗的結果是否同樣有希望。 （數據預計在今年年底或2025 年初公佈。）同樣不清楚的是，藥物製造監管機構批准和生產該藥物的速度有多快，其成本是多少（尤其是在低收入和中等收入國家），以及病毒發展出抗藥性的速度有多快。
儘管如此，研究結果在關鍵時刻帶來了希望。全球新增愛滋病毒感染人數已從 2010 年的 200 萬以上下降到去年的 130 萬人。但聯合國愛滋病毒/愛滋病聯合規劃署 (UNAIDS) 上週發布的一份報告顯示，進展已經停滯，世界似乎可能無法實現到 2025 年感染人數僅為 37 萬的目標。
現有的 PrEP 策略已被證明安全有效，但效果有限。在愛滋病毒負擔較高的國家，每天服用一粒藥的治療方案並沒有大大降低年輕女性的風險，因為恥辱和缺乏隱私或自主權等因素使許多女性無法按規定服用藥物。另一種長效注射藥物 cabotegravir 由製藥公司 ViiV Healthcare 開發，每 2 個月注射一次，於 2021 年獲得許可，並於 2022 年獲得世界衛生組織推薦用於高危險群；一項針對順性別女性的試驗顯示，與口服 PrEP 相比，它可將 HIV 感染風險降低 88%。但其推出進展緩慢，部分原因是價格談判正在進行。
在PURPOSE 1中，南非和烏干達的 2,134 名少女和年輕女性每 6 個月接受一次來那帕韋(Lenacapavir) 注射。當一半參與者已入組 1 年且該藥物顯示 100% 的保護作用時，試驗結束。該試驗另外兩個組別的 3,000 多名參與者要麼每天服用恩曲他濱/替諾福韋 (emtricitabine/tenofovir) 藥片（在許多國家獲得許可作為 PrEP），要麼便是服用副作用較少的新版本藥片。其中，新增愛滋病毒感染者 55 例，並未顯著地低於符合試驗條件的女性背景感染率。研究人員透過測量 10% 參與者的血液藥物水平發現，大多數人每週服用三粒或更少的藥片，而不是每天服用一粒，服用最少藥物的人最有可能感染愛滋病毒。
從長遠來看，注射劑型是否會更容易使用仍然是一個問題。來那帕韋 (Lenacapavir) 被注射到皮下組織中，通常是腹部。如果不小心操作，可能會產生疼痛的結節和發炎。貝克爾說，由於護理師顯然沒有將藥物注射得足夠深，一些試驗參與者出現了潰瘍。美國國家過敏和傳染病研究所所長珍妮·馬拉佐 (Jeanne Marrazzo) 指出：「這是在進行良好的臨床試驗的情況下進行的」。隨著該藥物的使用規模擴大，培訓醫護人員如何正確注射將變得至關重要，她說。
活動人士已經在推動生產lenacapavir 在世界各地以實惠的價格提供。吉利德表示將授權仿製藥公司為低收入國家生產這種藥物。 「但他們將中等收入國家排除在外，因為他們認為在那裡可以獲得更高的價格」，聯合國愛滋病規劃署執行董事溫妮·拜安伊瑪 (Winnie Byanyima) 表示。
來那帕韋 (Lenacapavir) 是一種新型藥物，它附著在包裹病毒基因組的衣殼上並中斷病毒的生命週期。南非愛滋病研究中心的流行病學家薩利姆·阿卜杜勒·卡里姆 (Salim Abdool Karim) 表示，到目前為止，科學家們還沒有發現愛滋病毒對這種藥物產生抗藥性的跡象，但這可能只是時間問題。他擔心，當人們停止服用來那帕韋 (Lenacapavir) 時，該藥物會在體內停留數週，濃度低到足以讓病毒生存和適應。卡里姆說：「如果你在那條長尾中被感染，可能會產生抗藥性病毒」。
另一個關鍵時期是療程開始時，由卡博特韋 (cabotegravir ) 的經驗顯示，儘管任何開始使用這種藥物的人都必須進行愛滋病毒檢測呈陰性，但有些人在第一次注射時就感染了病毒，並逃脫了檢測，導致感染緩慢發展，很難被發現，檢測結果在陽性和陰性之間反覆變化。約翰霍普金斯大學臨床病理學家蘇珊·埃什勒曼 (Susan Eshleman) 表示：「這會使這些病例的管理變得非常困難」。研究人員擔心，當患者的病毒量太低而無法進行標準抗藥性測試時，抗藥性菌株可能會悄悄發展。
這些被遺漏的感染似乎很少見；PURPOSE 1 的研究人員回顧性地確定了四名在接受來那卡韋(Lenacapavir)治療後患有急性HIV 感染的參與者。一旦接受 PrEP，此類患者可能會不太可能傳播病毒，但隨著患者數量的增加，對其進行管理將變得非常重要。
與此同時，愛滋病毒疫苗研究人員正在思考這一突破對其領域意味著什麼。基伊說，一方面，現在可能需要更令人信服的數據來證明候選疫苗可能提供非常好的保護才能進行功效試驗。當存在提供 100% 保護的其他選項時，研究人員將不得不考慮在道德上如何去設計此類試驗。巴西奧斯瓦爾多·克魯茲基金會的愛滋病毒研究員 Beatriz Grinsztejn 表示：「我們對潛在疫苗進行的任何研究都需要考慮此類產品的使用」，「當然，這會讓研究變得更加困難」。
更正，8 月 5 日下午 3:20：這個故事的早期版本稱，在一名護士顯然將藥物注射得太深後，一些試驗參與者出現了潰瘍。事實上，它注入得不夠深。
澄清，7 月 31 日下午 2:25：引用 Susan Eshleman 的段落已稍作編輯，以更好地反映她的想法。
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doi: 10.1126/science.zxvk4so
Landmark trial may herald new era in HIV prevention
Twice-yearly lenacapavir injections provided 100% protection in study in African women
Kai Kupferschmidt / 30 Jul 2024 / News / Science
Lenacapavir is a new type of drug that attaches to the capsid enveloping HIV’s genome.Nardus Engelbrecht/AP
Table of contents / A version of this story appeared in Science, Vol 385, Issue 6708.
Munich—It’s rare for scientists to get a standing ovation for presenting their data. But after South African researcher Linda-Gail Bekker finished her talk about an HIV prevention trial at the AIDS 2024 conference here last week, the audience stood up and clapped for almost 1 minute. “It shows how much enthusiasm there is,” says Jürgen Rockstroh, an HIV researcher at the University of Bonn.
Bekker told the audience that among more than 2000 African women who had received a twice-yearly injection of the antiviral drug lenacapavir as pre-exposure prophylaxis (PrEP), not one contracted HIV. Some view the result as a game-changer. “Imagine if you had a vaccine that was 100% effective in cisgender women, and you needed a booster every 6 months,” says Chris Beyrer, an epidemiologist who runs the Duke Global Health Institute. “You would be saying, ‘That’s it, we finally have a tool that can end this epidemic.’”
The drug’s manufacturer, Gilead Sciences, had presented the main outcomes of the PURPOSE 1 trial in a June press release, but some researchers had reserved judgment until seeing more details, for example on side effects and the study’s methodology. The full results, described by Bekker and also published in The New England of Journal of Medicine last week, “were better than anyone had hoped,” says Vincent Kioi, an IAVI vaccine researcher based in Nairobi. He adds they are sure to complicate the long quest for an HIV vaccine.
Scientists still want to know whether the results of a second efficacy trial in the United States and six other countries, in men who have sex with men, are similarly promising. (Data are expected late this year or in early 2025.) Also unclear is how fast the drug can be approved by regulators and produced, how much it will cost—especially in low- and middle-income countries—and how fast the virus will develop resistance.
Still, the findings provide hope at a crucial moment. New HIV infections have come down from more than 2 million globally in 2010 to 1.3 million last year. But a report released last week by the Joint United Nations Programme on HIV/AIDS (UNAIDS) shows progress has stalled, and the world seems likely to miss its target of just 370,000 infections by 2025.
Existing PrEP strategies have proved safe and effective, but they have had limited impact. Regimens consisting of one pill a day haven’t reduced the risk much for young women in countries with a high HIV burden because factors such as stigma and a lack of privacy or autonomy keep many women from taking the pills as prescribed. Another long-acting injectable drug, cabotegravir, developed by the pharma company ViiV Healthcare and given every 2 months, was licensed in 2021 and recommended by the World Health Organization for at-risk groups in 2022; a trial in cisgender women showed it lowered the risk of HIV infection by 88% compared with oral PrEP. But its rollout has been slow, in part because of ongoing price negotiations.
In PURPOSE 1, 2134 adolescent girls and young women in South Africa and Uganda received injections of lenacapavir every 6 months. The trial was ended when half the participants had been enrolled for 1 year and the drug was shown to be 100% protective. The more than 3000 participants in the trial’s two other arms received either a daily pill of emtricitabine/tenofovir, licensed in many countries as PrEP, or a newer version of the pill that has fewer side effects. Among them, there were 55 new HIV infections, not significantly less than the background rate of infection in women eligible for the trial. From measuring blood drug levels in 10% of participants, researchers learned that the majority took three or fewer pills per week, instead of one every day. Those taking the fewest pills were most likely to acquire HIV.
Whether injectables will be easier to take in the long term is still a question. Lenacapavir is injected into the tissue under the skin, usually in the abdomen. If not done carefully, this can create painful nodules and inflammation. A few trial participants developed ulcers after a nurse apparently did not inject the drug deep enough, Bekker says. “And that is in the context of a well-conducted clinical trial”, notes Jeanne Marrazzo, director of the U.S. National Institute of Allergy and Infectious Diseases. As use of the drug is scaled up, it will be crucial to train health care workers in how to give the shots correctly, she says.
Activists are already pushing to make lenacapavir available at an affordable price around the world. Gilead has said it will license generics companies to produce the drug for low-income countries. “But they lock out the middle-income countries because they think they can get a higher price there,” says UNAIDS Executive Director Winnie Byanyima.
Lenacapavir is a novel type of drug that attaches to the capsid enveloping the viral genome and interrupts the viral life cycle. So far, scientists have seen no signs of HIV developing resistance against the drug, but that’s likely a matter of time, says Salim Abdool Karim, an epidemiologist who runs the Centre for the AIDS Programme of Research in South Africa. He worries that when people stop taking lenacapavir, the drug will linger in the body for weeks at concentrations low enough to allow the virus to survive and adapt. “If you get infected in that long tail, that could create resistant viruses,” Karim says.
Another critical period is when the regimen begins, experience with cabotegravir has shown. Although anyone starting on that drug must have tested negative for HIV, some acquire the virus around their first injection and escape detection, leading to a slow-developing infection that can be hard to detect, with test results flip-flopping between positive and negative. “That can make management of these cases really difficult,” says Susan Eshleman, a clinical pathologist at Johns Hopkins University. Researchers worry resistant strains could develop stealthily while the patients’ viral load is too low for standard resistance testing.
These missed infections seem rare; researchers in PURPOSE 1 retrospectively identified four participants who had an acute HIV infection when they received lenacapavir. Once on PrEP such patients may be unlikely to transmit the virus—but managing them will become important as their numbers increase.
HIV vaccine researchers, meanwhile, are pondering what the breakthrough means for their field. For one thing, it may now require more compelling data that a vaccine candidate is likely to provide very good protection to stage an efficacy trial, Kioi says. And researchers will have to think about how to ethically design such trials when there is an option available that gives 100% protection. “Any study that we do with a potential vaccine will need to take into account the use of such products,” says Beatriz Grinsztejn, an HIV researcher at Brazil’s Oswaldo Cruz Foundation. “And of course, it makes studies much more difficult.”
Correction, 5 August, 3:20 p.m.: An earlier version of this story said a few trial participants developed ulcers after a nurse apparently injected the drug too deep. In fact, it wasn’t injected deep enough.
Clarification, 31 July, 2:25 p.m.: The paragraph in which Susan Eshleman is quoted has been edited slightly to better reflect her thinking.
doi: 10.1126/science.zxvk4so