對愛滋病毒感染者進行為期六個月的耐多藥結核病口服治療是安全有效的
基思·奧爾康 / 2022 年 8 月 2 日 / aidsmap /財團法人台灣紅絲帶基金會編譯
Louisa Dunn 博士是 TB PRACTECAL 臨床試驗的副研究員,他在與南非的一名患者進行諮詢。
無國界醫生照片。
週日在蒙特婁舉行的國際愛滋病大會(AIDS 2022)。無國界醫生組織的 Ilaria Motta 博士 24 日報導,世界衛生組織最近推薦作為新的治療標準的耐多藥結核病 (MDR-TB) 的全口服治療方案對 HIV 感染者有效且安全。
然而,會議上的活動人士表示,對於受影響最嚴重的國家的許多人來說,全口服治療仍然遙不可及,因此他們發起了 1 / 4 / 6 x 24 的運動,以激勵公共衛生計畫投資於足夠的「工作人員、物資、空間、系統和支持」,以便在 2024 年之前為所有人提供新的更短療程的結核病治療方案。
結核病實踐:耐多藥結核病的全口服治療
與藥物敏感性結核病相比,耐多藥結核病需要更長的治療過程,尤其是對多種抗生素耐藥的結核病患者。耐多藥結核病的治療需要使用具有嚴重毒性的藥物和注射藥物才能治癒,而使用較舊的治療方案可能會持續長達兩年。當人們不能耐受或堅持於治療時,治療的持續時間和毒性會導致很高的失敗率,這通常會導致廣泛耐藥 (XDR) 結核病的發展。
在過去的十年中,人們一直在努力確定治療耐多藥結核病和廣泛耐藥結核病的方案,以避免使用注射藥物,降低治療成本並最大限度地減少接觸有毒藥物。
TB PACTECAL 是一項大型、隨機比較三種 6 個月的全口服方案以治療耐多藥結核病,對照組則接受世界衛生組織傳統標準的照護,根據當地指引結合口服和注射之治療進行包括 9 至 24 個月的療程。
TB PRACTECAL 的核心實驗方案包括貝達喹啉 (bedaquiline) , pretomanid ,和利奈唑胺 (linezolid , BPaL)。治療 16 週後,利奈唑胺的劑量從 600mg 減少到 300mg,以盡量減少毒性。一個實驗分組接受了貝達喹啉、pretomanid 和利奈唑胺,而其他實驗分組接受了貝達喹啉、pretomanid 和利奈唑胺再加上氯法齊明 (clofazimine ) 100 毫克抑或是莫西沙星 (moxifloxacin) 400 毫克。
對 HIV 感染者的抗反轉錄病毒治療亦進行了修改,以避免藥物相互作用,在大多數情況下,參與者接受了基於整合酶抑製劑為基礎的治療。
該試驗在白俄羅斯、烏茲別克斯坦和南非進行。
在 IAS 2021 上,ZenIX 試驗報告稱,三藥 BPaL 方案在治療高度耐藥和廣泛耐藥結核病中的耐多藥結核病方面非常有效。結果顯示,縮短利奈唑胺的暴露時間可以提高耐受性,但不會影響療效。
TB PRACTECAL 的主要結果分別在 2021 年世界肺健康聯盟大會和今年 3 月的反轉錄病毒和伺機性感染大會上公佈,顯示 BPaL 加莫西沙星治療的不良結果發生率最低,實驗治療組和照標準方法治療組兩者之間的結果正向差異最大。
5 月,世界衛生組織發布了指引,建議使用 BPaL 加莫西沙星或 BPaL 作為治療耐多藥結核病或耐利福平結核病 (rifampicin-resistant TB) 的首選照護標準。
在 2022 年愛滋病大會上,Ilaria Motta 對 153 名愛滋病毒感染者(佔所有研究參與者的 27%)的治療結果進行了分析,其中大多數人生活在南非。
愛滋病毒感染者均勻分佈在研究組之間。研究組的 CD4 計數中位數約為 300,約 40% 為女性,約有三分之二在基準線上為痰塗陽結核病。氟喹諾酮耐藥性 (Fluoroquinolone resistance) ,顯示在標準治療特別難以治療的病例,出現在不到 20% 的所有參與者和大約 10% 的 HIV 陽性參與者中。
主要研究結果是每個研究組中在隨機分組後第 72 週參與者出現不良結果的比例,以及到第 72 周經歷嚴重不良事件或 3 級不良事件的比例。不良結果被分類為死亡、治療停藥、治療失敗、耐多藥結核病復發或失訪。
BPaL/莫西沙星組的不良結局發生率最低,實驗組和標準照護組分別有 28% 和 40% 出現不良結局,風險差異為 11.4%。在 HIV 陰性人群中,實驗組中有 6% 的人出現了不利的結果,而標準照護組中這一比例為 51%。儘管 HIV 陽性和 HIV 陰性參與者之間的風險差異百分比臨界於統計顯著(p=0.08),但研究人員警告說,因數量少我們很難得出該治療方案相較於HIV 陰性者有較低成效的結論。
同樣,其他調查研究組中 HIV 陽性和 HIV 陰性參與者之間的風險差異沒有統計學意義,但研究人員再次警告說,數字太小,無法得出負面結論。
與 BPaL 或 BPaL/莫西沙星相比,含氯法齊明的實驗方案(clofazimine-containing experimental regimen) 的耐受性較差; 29% 的 HIV 陰性人群和 40% 的 HIV 感染者經歷了 3 級或更高級別或嚴重的不良事件。在 HIV 陰性和 HIV 陽性參與者中,BPaL/莫西沙星組中 3 級或更高級別或嚴重不良事件的發生率分別為 20% 和 17%。
在任何研究組中,HIV 陽性和 HIV 陰性參與者之間的不良事件發生率沒有顯著差異。最常觀察到的嚴重不良事件(3 級或更高級別)是肝病、貧血和中性粒細胞減少症。
1 / 4 / 6 x 24 活動系列
最近的進展使得在短短 1 個月或 3 個月內治療結核病感染成為可能,而大多數形式的藥物敏感和耐藥性結核病則在 4 個月和 6 個月內治療,分別如(運動名稱中的 1 / 4 / 6)。然而,卻幾乎沒有人能夠接觸到這些更短、更有效的治療方案。
Treatment Action Group、Partners in Health 和 Médecins sans Frontières 在 AIDS 2022 上發起了 1 / 4 / 6 x 24 活動。該活動呼籲:
• 快速更新國際和國家指引以推薦更短程的治療方案
• 開發較短程治療方案的固定劑量組合,以支持實施和順從性
• 開發新的診斷方法以幫助診斷結核病和耐多藥結核病
• 用於短程治療的新產品快速註冊,並透過專利池、技術轉讓和許可改善以獲得新藥和診斷方法的機會
• 新產品和診斷上的可負擔價格
• 快速研究以解決短程治療方案的使用和實施方面的知識差距
• 增加對結核病計畫和診斷上的投資。
有關上述運動之優先事項和突出的研究問題等相關的更多信息業經治療行動小組發布。
參考文獻
Motta I et al. TB-PRACTECAL 臨床試驗對與HIV感染共病者的療效和安全性結果。第 24 屆國際愛滋病大會,蒙特婁,摘要 OAB0402,2022 年。
Oral six-month treatment for MDR-TB is safe and effective in people with HIV
Keith Alcorn / 2 August 2022 /aidsmap
Dr Louisa Dunn, a sub-investigator on the TB PRACTECAL clinical trial consults with a patient in South Africa. Photo by MSF.
An all-oral treatment regimen for multidrug-resistant tuberculosis (MDR-TB) recently recommended as a new standard of care by the World Health Organization is effective and safe in people living with HIV, Dr Ilaria Motta of Médecins sans Frontières reported at the 24th International AIDS Conference (AIDS 2022) in Montreal on Sunday.
However, activists at the conference say that all-oral treatment remains out of reach for many people in the worst-affected countries, as they launched the 1 / 4 / 6 x 24 campaign to galvanise public health programmes into investing in sufficient “staff, stuff, space, systems, and support” to make new shorter regimens for TB treatment available to all by 2024.
TB PRACTECAL: all-oral treatment for MDR-TB
MDR-TB requires a longer treatment course than drug-sensitive TB, especially in people who have TB resistant to multiple antibiotic classes. Treatment of MDR-TB has required the use of drugs with serious toxicities as well as injectable drugs in order to achieve a cure, and treatment with older regimens may last up to two years. The length and toxicity of treatment has led to a high failure rate when people cannot tolerate or adhere to treatment, often leading to the development of extensively drug-resistant (XDR) TB.
Over the past decade there have been intensive efforts to identify regimens for the treatment of MDR-TB and XDR-TB that avoid the use of injectable drugs, reduce the cost of treatment and minimise exposure to toxic drugs.
TB PRACTECAL was a large, randomised comparison of three 6-month all-oral regimens for the treatment of MDR-TB, with a control group that received the World Health Organization standard of care, consisting of a 9- to 24-month course of treatment combining oral and injectable treatments depending on local guidelines.
The core experimental regimen in TB PRACTECAL consisted of bedaquiline, pretomanid and linezolid (BPaL). The dose of linezolid was reduced from 600mg to 300mg after 16 weeks of treatment to minimise toxicity. One study arm received bedaquiline, pretomanid and linezolid, while the other experimental arms received bedaquiline, pretomanid and linezolid plus either clofazimine 100mg or moxifloxacin 400mg.
Antiretroviral therapy in participants living with HIV was modified to avoid drug interactions and in most cases, participants took integrase inhibitor-based treatment.
The trial was carried out in Belarus, Uzbekistan and South Africa.
At IAS 2021, the ZeNIX trial reported that the three-drug BPaL regimen was highly effective in curing MDR-TB in highly drug-resistant and XDR-TB. It showed that shortening exposure to linezolid improved tolerability without compromising efficacy.
The primary results of TB PRACTECAL were presented at the Union World Conference on Lung Health in 2021 and Conference on Retroviruses and Opportunistic Infections in March this year, showing that BPaL plus moxifloxacin treatment resulted in the lowest rate of unfavourable outcomes and the largest positive difference in outcome between an experimental treatment and the standard of care.
In May, the World Health Organization issued guidance recommending the use of BPaL plus moxifloxacin or BPaL as the preferred standard of care for treatment of MDR-TB or rifampicin-resistant TB.
At AIDS 2022, Ilaria Motta presented an analysis of treatment outcomes in the 153 study participants who were living with HIV (27% of all study participants), most of them living in South Africa.
People with HIV were evenly distributed between study arms. The median CD4 count across study arms was around 300, approximately 40% were female and around two-thirds had smear-positive TB at baseline. Fluoroquinolone resistance, indicating a case that is especially hard to treat with standard therapy, was present in just under 20% of all participants and around 10% of HIV-positive participants.
The primary study outcomes were the proportion of participants in each study arm who had unfavourable outcomes at week 72 after randomisation, and the proportion who experienced a serious adverse event or grade 3 adverse event by week 72. An unfavourable outcome was classified as death, treatment discontinuation, treatment failure, recurrence of MDR-TB or loss to follow-up.
The lowest rate of unfavourable outcome occurred in the BPaL/moxifloxacin arm, where 28% in the experimental arm and 40% in the standard of care arm had an unfavourable outcome, a risk difference of 11.4%. In HIV-negative people, 6% in the experimental arm had an unfavourable outcome compared to 51% in the standard of care arm. Although the percentage in risk difference between HIV-positive and HIV-negative participants was of borderline statistical significance (p=0.08), the study investigators warn that the small numbers make it difficult to conclude that the regimen is less effective than in HIV-negative people.
Similarly, the risk differences between HIV-positive and HIV-negative participants in the other investigational study arms were not statistically significant, but again, the investigators caution that numbers are too small to draw a negative conclusion.
The clofazimine-containing experimental regimen was less well tolerated than BPaL or BPaL/moxifloxacin; 29% of HIV-negative people and 40% of people with HIV experienced a grade 3 or higher, or serious adverse event. Grade 3 or higher, or serious adverse events were least common in the BPaL/moxifloxacin arm in both HIV-negative and HIV-positive participants, occurring in 20% and 17% respectively.
There was no significant difference in the rate of adverse events between HIV-positive and HIV-negative participants in any study arm. The most commonly observed serious adverse events (grade 3 or higher) were hepatic disorder, anaemia and neutropenia.
1 / 4 / 6 x 24 campaign
Recent advances have made it possible to treat TB infection in as little as one or three months and most forms of drug-sensitive and drug-resistant TB in four and six months, respectively (the 1 / 4 / 6 in the campaign name). Yet virtually no one has access to these shorter, more potent regimens.
Treatment Action Group, Partners in Health and Médecins sans Frontières launched the 1 / 4 / 6 x 24 campaign at AIDS 2022. The campaign is calling for:
•rapid updates in international and national guidelines to recommend shorter regimens
•development of fixed-dose combinations of shorter treatment regimens to support implementation and adherence
•development of new diagnostics to aid diagnosis of TB and MDR-TB
•rapid registration of new products for use in short-course treatment and improve access to new medicines and diagnostics through patent pools, technology transfer and licensing
•affordable pricing of new products and diagnostics
•rapid research to address knowledge gaps in the use and implementation of shorter-course regimens
•increased investment in TB programmes and diagnostics.
Further information on campaign priorities and outstanding research questions has been published by Treatment Action Group.
References
Motta I et al. Efficacy and safety results in participants co-infected with HIV from TB-PRACTECAL Clinical Trial. 24th International AIDS Conference, Montreal, abstract OAB0402, 2022.