最普遍的 HIV 藥物組合之長效注射版本將是可能的
皮下注射 TLD 可能每月注射一次
資料來源：基斯‧奧爾康 / 2023 年 9 月 26 日 / Aidsmap
有趣的天使/Shutterstock.com
西雅圖華盛頓大學的研究人員表示，他們已經解決了創造世界上最常用的抗反轉錄病毒組合藥物——富馬酸替諾福韋二吡呋酯 (tenofovir disoproxil fumarate)、拉米夫定(lamivudine)和多魯特韋( dolutegravir)［通常稱為TLD］的長效注射劑的挑戰。
但缺點是長效製劑只能維持一個月。
Rodney Ho 教授及其同事在《愛滋病》雜誌上報告了他們的發現，解釋了他們如何使用一種稱為藥物組合的技術將兩種不同類型的化合物（水溶性和不溶於水的化合物）組合在一種配方中的奈米粒子技術。
多家製藥公司正在開發長效抗病毒治療，以克服長期服藥所帶來的順從性和疲乏上的困難。
Cabenuva 是第一種長效注射抗反轉錄病毒治療藥物，在歐洲被稱為Vocabria 和Rekambys，它將整合酶抑制劑卡博特韋(cabotegravir) 和非核苷反轉錄酶抑制劑利匹韋林 (rilpivirine) 結合在肌肉注射中，必須每月或每兩個月注射一次。
注射用卡博特韋和利匹韋林在歐洲、北美和東亞等幾個高收入國家獲得批准。 注射用卡博特韋也已獲得藥品專利池許可，由非專利製造商開發為 PrEP 藥物，供應低收入國家。 但利匹韋林尚未獲得藥品專利池許可，因此在注射劑專利於 2026/2027 年到期之前，仿製藥製造商沒有動力開發用於治療的兩種藥物注射劑。
另一種抗病毒藥物 HIV 衣殼抑制劑 lenacapavir (Sunlenca) 也正在開發中，作為一種長效注射療法，可以每六個月注射一次。 開發商吉利德科學公司正在研究將lenacapavir與兩種長效廣泛中和抗體結合的潛力。
吉利德科學、ViiV Healthcare 和默克公司正在研究其他新型抗反轉錄病毒藥物作為潛在的長效治療方法，但它們仍處於開發的早期階段。
但迄今為止，愛滋病毒感染者人數最多的低收入和中等收入國家尚未提供任何形式的長效治療。 開發一種在這些地區負擔得起的低成本、長效注射療法可以滿足大部分難以堅持每日服藥的愛滋病毒感染者的需求。
世界衛生組織推薦富馬酸替諾福韋二吡呋酯、拉米夫定和多替拉韋［TLD］作為第一線抗反轉錄病毒治療的首選。 2023 年 8 月，全球基金表示，它已能夠以一年的供應量為 45 美元的價格獲得該組合，為其贈款接受者提供藥物。 柯林頓健康計畫 (Clinton Health Access Initiative) 表示，全球有 1,900 萬人正在服用這種組合藥物。
這種廣泛處方組合的注射形式將受益於三種抗反轉錄病毒藥物的低生產成本以及衛生系統對藥物潛在副作用的熟悉。
「在愛滋病毒感染者人數最多的低收入和中等收入國家，沒有任何形式的長效治療」。
華盛頓大學TLC-ART（標靶、長效和組合抗反轉錄病毒療法）小組利用藥物組合奈米顆粒技術，將從仿製藥製造商獲得的替諾福韋、拉米夫定和多替拉韋樣品配製為注射製劑。
奈米粒子的寬度只有幾個原子。 這些顆粒組裝成奈米結構後的特性使藥物避免在肝臟中分解並保留在血液中。 奈米技術還可以透過注射輸送難溶於水的藥物，並且可以創建一個載體將藥物輸送到特定組織或器官。
藥物組合並接受了測試，針對奈米顆粒混合物之藥物組合的五隻猴子和注射溶解在液體中但並未配製為奈米顆粒的三種藥物組合製劑的對照組之兩隻猴子。連續四周定期採集血樣，分離週邊血單核細胞以測定藥物含量。
血漿藥物濃度測試顯示，奈米顆粒製劑中的每種藥物在給藥後第一天就達到了與對照組接受的非奈米顆粒製劑藥物相當的峰值水平。 但儘管三天內即無法再檢測到非奈米顆粒製劑藥物的血漿藥物水平，而奈米顆粒製劑藥物仍然高於 IC90 水平（目標藥物濃度）至少四週。
奈米顆粒配製的個別藥物其細胞濃度高於血漿濃度。 每種藥物的細胞濃度在施用後7天比施用後兩天更高。
研究作者表示，所達到的藥物濃度允許每月皮下給藥，也可能自行給藥。 儘管這比注射卡博特韋/利匹韋林的兩個月給藥方案要少，但他們指出，本研究中觀察到的注射後快速達到高藥物濃度意味著不需要一個月的口服導入給藥，以建立卡博特韋和利匹韋林的穩定藥物濃度。
但每月一次的注射治療可能會對衛生系統造成挑戰。 自2016年以來，一直強調已穩定接受抗反轉錄病毒治療的患者應減少就診的頻率，以便診所能夠應對「治療所有人」時代時越來越多的接受抗反轉錄病毒治療的患者，但許多的注射產品需要冷鏈供應和冷凍醫療設施。 在今年的國際愛滋病協會愛滋病毒科學會議上，甘比亞傳染病研究中心的卡羅琳·博爾頓·摩爾博士呼籲開展試點計畫，以評估如何將注射抗反轉錄病毒療法引入甘比亞等國家的公共衛生系統。
該研究也顯示了替諾福韋 (tenofovir) 奈米製劑治療乙型肝炎的潛力。（替諾福韋單獨給藥可用於治療沒有愛滋病毒的人之乙型肝炎）。 根據世界衛生組織 2021 年的研究，全球有 2,600 萬人急需B型肝炎治療，根據現行指引，6,400 萬人可能有資格接受治療。 一種無需每日服藥的長效替諾福韋注射製劑對許多B型肝炎患者很有吸引力。
參考文獻：
佩拉佐羅 S 等人。 一種新的配方使 3 種 HIV 藥物替諾福韋–拉米夫定–多替拉韋 (TLD) 從短效注射劑轉變為長效注射。 愛滋病，2023 年 8 月 25 日線上發布。
Long-acting injectable version of the most popular HIV drug combination is possible
Subcutaneous injectable TLD might be dosed once a month
Keith Alcorn / 26 September 2023 / Aidsmap
funnyangel/Shutterstock.com
Researchers at the University of Washington in Seattle say they have cracked the challenge of creating a long-acting injectable form of the world’s most commonly prescribed antiretroviral combination, tenofovir disoproxil fumarate, lamivudine and dolutegravir, often known as TLD.
But the drawback is that the long-acting formulation only lasts for one month.
Reporting their findings in the journal AIDS, Professor Rodney Ho and colleagues explain how they have been able to combine two different types of compounds – those that are soluble in water and those that aren’t – in one formulation using a technique called drug-combination nanoparticle technology.
Long-acting forms of antiretroviral treatment are being developed by several pharmaceutical companies to overcome difficulties with adherence and fatigue with long-term pill-taking.
The first long-acting injectable antiretroviral treatment, Cabenuva, known as Vocabria and Rekambys in Europe, combines the integrase inhibitor cabotegravir and the non-nucleoside reverse transcriptase inhibitor rilpivirine, in an intramuscular injection that must be given once monthly or every two months.
Injectable cabotegravir and rilpivirine is approved in several high-income countries, including in Europe, North America and east Asia. Injectable cabotegravir has also been licensed to the Medicines Patent Pool for development as a PrEP drug by generic manufacturers to supply lower-income countries. But rilpivirine has not been licensed to the Medicines Patent Pool, so until the injectable patent runs out in 2026/2027, there is no incentive for generic manufacturers to develop the two-drug injectable for treatment.
Another antiretroviral, the HIV capsid inhibitor lenacapavir (Sunlenca), is also being developed as a long-acting injectable treatment that can be given every six months. Developer Gilead Sciences is investigating the potential for combining lenacapavir with two long-acting broadly neutralising antibodies.
Gilead Sciences. ViiV Healthcare and Merck are investigating other novel antiretrovirals as potential long-acting treatments, but they are still at early stages of development.
But as yet, no form of long-acting treatment has been made available in lower- and middle-income countries where the number of people living with HIV is greatest. Developing a low-cost, long-acting injectable treatment that is affordable in these settings could meet the needs of a substantial fraction of people with HIV who experience difficulties with adherence to daily pill taking.
Tenofovir disoproxil fumarate, lamivudine and dolutegravir is recommended as a preferred option for first-line antiretroviral treatment by the World Health Organization. In August 2023 the Global Fund said it had been able to secure the combination at a price of US$45 for a year’s supply for its grant recipients. The Clinton Health Access Initiative says 19 million people worldwide are taking this combination.
An injectable form of this widely prescribed combination would benefit from the low production costs of the three antiretroviral agents as well as familiarity in health systems about the potential adverse effects of the drugs.
“No form of long-acting treatment is available in lower- and middle-income countries where the number of people living with HIV is greatest.”
The University of Washington TLC-ART (Targeted, Long-acting and Combination Anti-Retroviral Therapy) group formulated samples of tenofovir, lamivudine and dolutegravir obtained from generic manufacturers into an injectable formulation using drug-combination nanoparticle technology.
Nanoparticles are a few atoms in width. The properties of these particles when assembled into nanostructures allows drugs to avoid being broken down in the liver and enables them to remain in the bloodstream. Nanotechnology also enables delivery by injection of drugs that are poorly soluble in water and allows the creation of vehicles for the delivery of drugs to specific tissues or organs.
The combined formulation was tested in five monkeys who received the drug combination nanoparticle mixture and a control group of two monkeys who received injections of the three drugs dissolved in liquid but not formulated into nanoparticles. Blood samples were collected at regular intervals for four weeks and peripheral blood mononuclear cells were isolated to measure drug content.
Drug concentration tests on blood plasma showed that each of the drugs in the nanoparticle formulation reached equivalent peak levels to the non-formulated drugs received by the control group on the first day after dosing. But whereas plasma drug levels of the non-formulated drugs could no longer be detected within three days, the nanoparticle-formulated drugs remained above the IC90 level (the target drug concentration) for at least four weeks.
Cellular concentrations of the individual nanoparticle-formulated drugs were higher than plasma concentrations. The cellular concentrations of each drug were greater seven days after administration than two days after administration.
The study authors say that the drug concentrations achieved would permit monthly subcutaneous dosing, possibly self-administered. Although this is less than the two-monthly dosing schedule for injectable cabotegravir / rilpivirine, they point out that the rapid achievement of high drug concentrations after injection observed in this study means that there is no need for one-month oral lead-in dosing required to establish stable drug concentrations of cabotegravir and rilpivirine.
But monthly injectable treatment is likely to prove challenging to deliver for health systems. Since 2016, there has been an emphasis on reducing the frequency of clinic visits for people on stable antiretroviral therapy, to enable clinics to deal with the increasing numbers of people taking antiretroviral treatment in the “treat all” era. Many injectable products need cold supply chains and health facility refrigeration. At this year’s International AIDS Society Conference on HIV Science, Dr Carolyn Bolton Moore of Zambia’s Centre for Infectious Disease Research called for pilot projects to assess how injectable ART could be introduced into the public health system in countries like Zambia.
The study also shows the potential for the nanoformulation of tenofovir as treatment for hepatitis B. (Tenofovir is dosed alone as a treatment for hepatitis B in people without HIV). According to a 2021 World Health Organization study, 26 million people worldwide are in urgent need for hepatitis B treatment and 64 million may be eligible for treatment under current guidelines. A long-acting injectable formulation of tenofovir that removed the need for daily pill-taking would be attractive for many people with hepatitis B.
References