Brian Owens / 2024 年 7 月 5 日 / Medscape 醫學新聞

來那卡韋 (Lenacapavi ) 是一種每年注射兩次的 HIV-1 衣殼抑制劑，根據 3 期 PURPOSE 1 試驗的中期分析，它在預防高感染風險女性愛滋病毒方面顯示出 100% 的功效。

結果非常有希望，以至於獨立資料監測委員會建議吉利德科學公司停止試驗的盲法階段，並向所有參與者提供開放標籤的來那卡韋。

結果既出乎意料又令人興奮。 「我在 HIV 領域工作了很長時間，沒有其他 3 期 PrEP 試驗發現零感染」，加州福斯特城吉利德科學公司臨床開發執行董事 Moupali Das 醫學博士說。

PURPOSE 1 正在評估兩種治療方案的安全性和有效性：分別為每年兩次皮下注射來那卡韋用於暴露前預防，以及每天一次口服Descovy（恩曲他濱200 毫克和替諾福韋艾拉酚胺25 毫克，emtricitabine 200 mg and tenofovir alafenamide 25 mg）在16-25 歲的女性和女孩中的安全性和有效性。這兩種藥物正在與標準的每日一次口服 Truvada（恩曲他濱 200 毫克和富馬酸替諾福韋二吡呋酯 300 毫克，emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mg）進行比較。

來那帕韋組的2000多名女性中沒有出現HIV感染病例；相較之下，德斯科維 (Descovy) 組的愛滋病毒發生率為每100人年2.02例，特魯瓦達 (Truvada) 組的愛滋病毒發生率為每100人年1.69例。

在接受來那卡韋治療時HIV 的背景發生率（該試驗的主要終點之一）為每 100 人年 2.41 例。達斯表示，所有藥物都被證明是安全且耐受性良好的，試驗的整個中期數據將在即將舉行的會議上發布。

無新病例

加州大學舊金山分校-格拉斯頓愛滋病研究中心主任莫妮卡.甘地 (Monica Gandhi) 醫師說道，醫學界對迄今為止的結果感到「興奮」。「我們必須等待完整的數據，但到目前為止，它已經100%有效，並且遠遠優於其他治療方法」。

甘地說，她正在等待查看有關副作用和耐受性的更多細節，以及試驗的中止率和人們退出的原因。例如，來那卡韋往往會導致皮下形成結節，這些結節是藥物在 6 個月內釋放的儲存庫。甘地說，她感興趣的是其中是否有參與者覺得他們太麻煩而停止治療。

甘地表示，全球愛滋病毒流行仍在持續，到2022 年將有130 萬新感染者，現有的口服PrEP 方案，甚至長效注射劑卡博特韋 (cabotegravir)，迄今為止都未能像期望的那樣有效降低感染率。「我們一直在等待另一種選擇」。

與口服 PrEP 相比，每年兩次的來那帕韋注射給藥既簡單又方便。許多人，尤其是年輕人，例如那些參加PURPOSE 1 的人，發現很難記住每天服藥。

謹慎的選擇

許多試驗參與者表示，他們對 HIV PrEP 帶來的恥辱感到不安。他們不希望人們看到他們家裡的藥瓶或聽到它在錢包裡嘎嘎作響。因此，每年在醫生辦公室進行兩次注射是很有吸引力的。

「這是一個獨立的選擇。人們對隱私感到非常興奮，而且不必每天服用藥物，」達斯說。 「PrEP 只有能夠用它才有效」。

在治療方案上更好的順從性可能是來那卡韋優於口服 PrEP 的原因之一。但達斯說，作為多級病毒衣殼抑制劑，來那卡韋還具有獨特的作用機制。它在病毒整合到細胞核之前和之後都以衣殼為目標，這可能是其效力的另一個原因。

儘管結果令人鼓舞，但人們仍然擔心這種藥物的可近性，特別是在愛滋病毒負擔最高的低收入和中等收入國家。甘地說：「沒有人知道吉利德計畫如何讓這項服務變得可及」。

取得的問題

該公司尚未與藥品專利池組識（MPP）簽署，以允許公司生產萊那卡韋的仿製藥配方，甘地稱這是在較貧窮國家提供更便宜的替代品的傳統途徑。她說，注射型卡博特韋「災難性」的推出，在低收入國家尚未廣泛使用，這是一個令人擔憂的先例。

吉利德科學公司證實，PURPOSE 1 研究的所有 5,300 名參與者都可以選擇繼續接受lenacapavi，直到該藥物在其國家普遍上市。該公司致力於確保吉利德科學公司在最需要的國家提供專門的供應，直到自願許可的合作夥伴能夠提供高品質、低成本的來那卡韋。

吉利德科學公司沒有透過第三方的藥品專利池組織 (the third-party Medicines Patent Pool，縮寫：MPP)，而是直接與其他合作夥伴談判自願許可計畫，以在貧困地區提供該藥物的仿製藥。

來那卡韋已被批准用於治療多重抗藥性愛滋病毒，但尚未批准用於預防愛滋病毒。一項姊妹試驗PURPOSE 2正在進行中，正在對男男性行為者、跨性別男性、跨性別女性以及那些非二元性別個體與出生時被指定為男性的伴侶發生性關係者等人進行測試。如果預計到 2024 年底或 2025 年初的結果是積極的，該公司將進一步推進 lenacapavi PrEP 的藥品監管備案。

其他三項試驗也在進行中。PURPOSE 3 和PURPOSE 4 是在美國針對女性和注射毒品者進行的小型研究，PURPOSE 5 正在法國和英國招募愛滋病毒高危險群，為歐洲藥物監管機構提供歐洲數據。

引用此內容：每年兩次注射型 之PrEP 用後未出現 HIV 感染 – Medscape – 2024 年 7 月 5 日。

No HIV Infections After Twice-a-Year PrEP

Brian Owens / July 05, 2024 / Medscape Medical News

Lenacapavir, a twice-yearly injectable HIV-1 capsid inhibitor, has shown 100% efficacy in preventing HIV in women at a high risk for infection, according to an interim analysis of the phase 3 PURPOSE 1 trial.

The results were so promising that the independent data monitoring committee recommended that Gilead Sciences stop the blinded phase of the trial and offer open-label lenacapavir to all participants.

The results were both unexpected and exciting. “I’ve been in the HIV field for a really long time, and there’s no other phase 3 PrEP trial that found zero infections,” said Moupali Das, MD, PhD, executive director of clinical development at Gilead Sciences, Foster City, California.

PURPOSE 1 is evaluating the safety and efficacy of two regimens — twice-yearly subcutaneous lenacapavir for preexposure prophylaxis and once-daily oral Descovy (emtricitabine 200 mg and tenofovir alafenamide 25 mg) — in women and girls aged 16-25 years. The two drugs are being compared with the standard once-daily oral Truvada (emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mg).

There were no cases of HIV infection among the more than 2000 women in the lenacapavir group; in contrast, the incidence of HIV in the Descovy group was 2.02 per 100 person-years and in the Truvada group was 1.69 per 100 person-years.

The background incidence of HIV, one of the primary endpoints of the trial, was 2.41 per 100 person-years with lenacapavir. All the drugs were shown to be safe and well tolerated, and the full interim data from the trial will be released at an upcoming conference, according to Das.

No New Cases

The medical community is “thrilled” with the results so far, said Monica Gandhi, MD, director of the UCSF-Gladstone Center for AIDS Research. “We have to wait for the full data, but so far, it has been 100% effective and far superior to other treatments.”

Gandhi said she is waiting to see more details on side effects and tolerability, as well as discontinuation rates in the trial and the reasons people dropped out. For example, lenacapavir tends to cause nodules to form under the skin, which are the depots from which the drug is released over the course of 6 months. Gandhi said she is interested in whether any participants found them bothersome enough to discontinue the treatment.

The global HIV epidemic is still ongoing, with 1.3 million new infections in 2022, and existing oral PrEP options, and even the long-acting injectable cabotegravir, have so far failed to make as much of a dent in infection rates as hoped, said Gandhi. “We’ve been waiting for another option.”

The twice-yearly lenacapavir shot is easy and convenient to administer compared with oral PrEP. Many people — especially younger individuals such as those enrolled in PURPOSE 1 — find it difficult to remember to take the pills every day.

A Discreet Option

Many participants in the trial said that they were uncomfortable with the stigma that can be attached to HIV PrEP. They did not want people to see the pill bottle in their house or hear it rattling in their purse. So an injection given just twice a year in a doctor’s office is attractive.

“This is a discrete option. People were very excited about the privacy and not having to take daily pills,” said Das. “PrEP only works if you take it.”

Better adherence to the treatment regimen is likely one reason that lenacapavir outperformed oral PrEP. But lenacapavir also has a unique mechanism of action as a multistage viral capsid inhibitor, Das said. It targets the capsid both before and after the virus integrates into the nucleus, which could be another reason for its potency.

Although the results are encouraging, there is still some concern about how accessible the drug will be, especially in low- and middle-income countries where the burden of HIV is the highest. “No one has any clue on how Gilead plans to make this accessible,” said Gandhi.

Access Issues

The company has not signed up for the Medicines Patent Pool (MPP) to allow companies to manufacture generic formulations of lenacapavir, which Gandhi said is the traditional route to provide cheaper alternatives in poorer countries. The “disastrous” roll out of injectable cabotegravir, which is still not widely available in lower-income countries, is a worrying precedent, she said.

Gilead Sciences confirmed that all 5300 participants in the PURPOSE 1 study will have the option to continue receiving lenacapavir until the drug is generally available in their country. The company has committed to ensuring a dedicated Gilead Sciences supply in the countries where the need is the greatest until voluntary licensing partners are able to supply high-quality, low-cost versions of lenacapavir.

And rather than going through the third-party MPP, Gilead Sciences is negotiating a voluntary licensing program directly with other partners to supply generic versions of the drug in poorer countries.

Lenacapavir is already approved for the treatment of multidrug-resistant HIV but is not yet approved for HIV prevention. A sister trial, PURPOSE 2, is ongoing and is testing lenacapavir in men who have sex with men and in transgender men, transgender women, and nonbinary individuals who have sex with partners assigned male at birth. Should those results, expected by the end of 2024 or early 2025, be positive, the company will move forward with regulatory filings for lenacapavir PrEP.

Three other trials are also ongoing. PURPOSE 3 and PURPOSE 4 are smaller US-based studies of women and people who inject drugs, and PURPOSE 5 is enrolling people at a high risk for HIV in France and the United Kingdom to provide European data for European regulators.

Cite this: No HIV Infections After Twice-a-Year PrEP – Medscape – July 05, 2024.