具有里程碑意義的研究發現，某些結核病治療可縮短至兩個月
資料來源：Elri Voigt / 新聞與特寫/2022 年 11 月 15 日/ Spotlignt / 財團法人台灣紅絲帶基金會編譯
具有里程碑意義的 TRUNCATE TB 試驗的早期結果顯示，一些結核病 (TB) 病例可以在短短兩個月內成功治療—
是當前六個月標準的三分之一。照片：TAC 存檔
一些結核病 (TB) 病例可以在短短兩個月內得到成功治療——這是南非和大多數其他國家現行六個月標準的三分之一。這是根據上週世界肺部健康聯合大會上提出的具有里程碑意義的 TRUNCATE TB 試驗的早期發現得出的。
新加坡國立大學傳染病學教授兼 TRUNCATE 試驗的首席研究員 Nick Paton 解釋說，針對藥物敏感結核病 (DS-TB) 的標準六個月治療實際上過度治療了很多罹患這種病的病人。結核病治療以六個月為標誌的原因是，少數結核病患者需要長期治療以避免復發，但大多數人會在六個月之前治癒。
從本質上講，它是一種用於保護少數結核病患者的鈍器，但通常是有效的工具。
短期初始治療
TRUNCATE 試驗旨在了解與標準的六個月（24 週）治療方案相比，為期兩個月（八週）的新型結核病治療方案組合是否可行。根據 Paton 的說法，該研究實驗組的試驗參與者最初接受了八週的治療，如果他們在八周治療後仍有持續的臨床疾病，可以選擇將治療延長至 10 至 12 週。如果此後仍有活動性結核病，參與者將轉為標準的六個月治療。
透過追蹤定期監測研究參與者，包括每月一次的結核病症狀篩查和每一到三個月的痰塗片檢查。
「[該策略] 的核心是它是一個非常短的初始治療期，再加上進行監測並儘早發現 [復發] 的人」，Paton 說。
從 2018 年 3 月到 2022 年 3 月，在泰國、印度尼西亞、菲律賓、烏干達和印度的 18 個地點共招募了 674 名試驗參與者。 4 名患者退出試驗，10 名參與者在試驗期間死亡。
Paton 告訴 Spotlight，總體死亡率很低，標準治療組和 TRUNCATE 策略組之間的死亡率沒有差異。他補充說，死因是複雜的，而且往往準確的死因不為人知
對於最終結果，在第 96 週對 660 名參與者進行了評估。換句話說，進行了大約兩年的追蹤。
Khayelitsha 的 Lizo Nobanda 結核病照護中心的一名患者正在服用結核病藥物。
照片：Jose Cendon/Médecins Sans Frontières
令人鼓舞的結果
Paton 解釋說，該試驗使用了 TRUNCATE 策略，該策略最初涉及使用包含新型結核病藥物組合的四個治療組，並將結果與包含標準六個月治療的對照組進行比較。隨後，選擇了兩個 TRUNCATE 策略組來完成研究的後半部分。他指出，停止其中兩個組是一個務實的決定，以確保獲得更好的數據。
在剩下的兩個實驗組中的第一個中，184 名研究參與者接受了包括高劑量利福平（rifampicin，35 毫克/公斤，在肝損傷相關死亡後作為預防措施減至 20 毫克/公斤）、異煙肼 (isoniazid)、吡嗪酰胺(pyrazinamide)、乙胺丁醇 (ethambutol)、和利奈唑胺（linezolid，600 毫克）。在第二項研究中，189 名研究參與者接受了由貝達喹啉（bedaquiline，400 毫克/天，持續兩週，然後 200 毫克，每週三次）、異煙肼 (isoniazid)、吡嗪酰胺 (pyrazinamide)、乙胺丁醇 (ethambutol) 和利奈唑胺（linezolid，600 毫克）組成的治療方案。標準治療組有 181 名參與者。
在標準治療組中，98% 的患者完成了治療，3% 的患者必須在第 96 週之前再次接受治療。
在 TRUNCATE 策略組中，總體而言，91% 的參與者完成了為期八週的治療並在第 12 週停止了治療。17%（按組別範圍從 13% 到 23%）進行了再治療，並且 2% 的參與者沒有完成初始治療係由於退出試驗、死亡或治療失敗而導致。
圖片：Health 24
兩個實驗性 TRUNCATE 組與標準治療組的比較顯示，使用貝達喹啉和利奈唑胺的 TRUNCATE 組不劣於標準治療組，而高劑量利福平和利奈唑胺組剛好不符合非劣效性標準。根據第 96 週時不滿意結果的比例計算療效。不滿意結果被歸類為死亡、仍患有活動性結核病或在第 96 週時仍在接受結核病治療。
「我們的想法是，如果我們將那些[不令人滿意的結果]加起來，並且在標準治療組中與 TRUNCATE 策略組相同，那麼這顯示該策略原則上是可行的」，Paton 告訴 Spotlight。
與標準治療組（180 天）相比，TRUNCATE 策略組的平均治療總天數減少。對於高劑量利福平-利奈唑胺，平均總治療天數為 106 天，而在貝達喹啉-利奈唑胺組，則為 85 天。
「因此，很明顯，最終效果是減少了平均治療時間」，Paton 說。「確實大大減少了整體治療時間」。
他補充說，發生 3 級或 4 級不良事件、嚴重不良事件或死亡的參與者比例在標準治療組和 TRUNCATE 策略組之間沒有差異。第 96 週時患有呼吸障礙的參與者比例也沒有差異。
僅有的獲得性耐藥病例是在貝達喹啉和利奈唑胺組中觀察到的兩例。根據 Paton，這是 1.1% 的頻率。其中一名參與者錯過了幾次治療劑量，而另一名參與者則沒有錯過任何劑量。兩人都成功地接受了再治療。
最初，他們想在試驗的後期招募同時感染 HIV 的參與者，但沒有人能及時招募，因此目前還沒有數據顯示它在 HIV 感染者和結核病患者中的效果如何, 佩頓說。
「該試驗顯示，系統性過度治療絕大多數結核病患者的替代方法是可以成功的。這是一個重要的新研究方向，有望改善患者和計畫的結果」，Paton 說。「未來可能會改進該策略，以使用替代藥物治療方案或替代監測方法來改善結果。對試驗的持續分析將進一步加深我們的理解」。
圖片：medicinenet.com/my health 1st.com
藥物代謝動力學 (PK) 和安全數據
在上週的會議上，TRUNCATE 試驗的計畫負責人 Christopher Cousins 介紹了該試驗的第一級藥物代謝動力學 (pharmacokinetic, PK) 分析。 PK 結果取自研究的第八週。
禁食一夜後，參與者在試驗地點服用了觀察劑量的藥物，並在 12 小時內進行了血液採樣。數據基於兩個實驗組的 96 名參與者。
他說，高劑量利福平的 AUC（代表隨時間推移的總藥物暴露量 – AUC = 曲線下面積）比標準劑量高 4 到 6 倍，並且超過了大多數患者提出的療效目標。這支持了這樣的假設，即高劑量利福平會增強 8 周方案中的治療殺菌作用。
數據還顯示利福平和利奈唑胺之間似乎存在藥物間交互作用，但這似乎不足以消除抗分枝桿菌的功效。
根據 Cousins 的說法，貝達喹啉和利奈唑胺組在第 8 週結束時的貝達喹啉濃度與耐藥結核病治療 24 週後觀察到的濃度相當（目前貝達喹啉和利奈唑胺都是耐藥結核病 (DR- TB) 治療，但不適用於 藥敏結核病( DS-TB) 治療）。
誇祖魯-納塔爾省耐多藥結核病住院治療機構中一名患者早上的藥物負擔。
照片：Amelia Rutter，由 Photoshare 提供
當被問及在停止治療後監測 TRUNCATE 組的參與者如何能夠檢測出那些仍然患有活動性結核病的人時，Paton 告訴 Spotlight，對痰塗片樣本的進一步分析將能夠告訴我們更多信息。該試驗使用了一種技術含量相對較低的方法，其中使用症狀篩查和痰塗片檢查來確定參與者是否仍患有活動性結核病並需要重新治療。
「我們需要運行額外的生物標誌物，更詳細地詢問數據集，以確定誰治癒了，誰沒有治癒，持續了多長時間以及其他的 [痰塗片測試和症狀篩查] 等這些事情如何影響它 [TB ] 的結果」，他說。
他補充說，這是一個起點，「但如果我們使用一些新的生物標記技術進行監測，我們可能會做得更好」。
調查結果的含義
「這些結果作為概念證明非常令人興奮——它們顯示有可能進一步縮短對藥物敏感的結核病的治療時間」，總部位於紐約的治療行動小組 (TAG) 的結核病計畫聯合主任 Lindsay McKenna 說。「但我們需要優化方案，並在更廣泛的人群中研究這種治療策略，包括愛滋病毒感染者——並沒有人參加這項研究——以及[在] 計畫背景下」，她說。
「還有其他正在計畫中的試驗，這些試驗旨在主動（例如，在治療開始時）根據已知與治療結果相關的可用指標或風險因素（例如疾病嚴重程度、BMI 和 HIV 狀態，稱為分層醫學方法），並相應地調整治療持續時間」，她補充道。「如果後一種分層醫學方法得到證實，那麼看看這兩種方法如何比較以及受影響之社區如何地看待計畫將會非常有趣」。
縮短療程的可行性
菲律賓肺臟中心 Truncate TB 試驗的現場聯合研究員 Nerissa Donato 在上週的會議上概述了 TRUNCATE 策略的可行性和可接受性。這是基於參與者問卷調查、臨床醫生調查、試驗描述數據和 Donato 的觀察結果。
「在臨床試驗的背景下，TRUNCATE 策略是可以接受和可行的。如果它得到 NTP（國家治療計畫）的支持並得到訓練有素的臨床醫生的支持，它就可以成功實施」，她說。
她解釋說，實施該策略的主要挑戰是患者擔心潛在的副作用和更大的藥劑負擔，但經過一些討論，由於可能會縮短治療療程，參與者對該方案感到滿意。參與者的密切追蹤和所需的追蹤與治療六個月和出院後的正常程序不同。但她說參與者通常很樂意回來進行後續追蹤訪問。
多納托表示，參與的臨床醫生最初對該方案是否安全以及是否有效持懷疑態度，但在試驗後，他們的看法更為積極。
她說，為了在現實世界中實施該戰略，國家治療計畫 (NTP) 需要採用它，這可能需要更多關於成本效益的數據。
需要更好的治療方法和方案
Paton 告訴 Spotlight，在高收入國家過度治療結核病患者和個性化醫療這兩個極端之間的某個地方，可以為結核病患者提供更好的治療選擇。一種不那麼單一的方法，而是基於對患者個別需求和反應的回應。
他說：「我們需要研究如何讓[結核病治療] 更個性化，但採用的方式則不是那麼的高科技，因而無法去進行計畫」。「至少如果你正在監測病人[patients] 那你就有了一個安全網。如果弄錯了，只要確保你能早點接住這個人並重新治療，那就不應該會造成嚴重的傷害」。
試驗的更多數據將在未來幾個月公佈。
TB treatment can be cut to two months for some, finds landmark study
Early findings from the landmark TRUNCATE TB trial show that some cases of tuberculosis (TB) can be successfully treated in as little as two months – a third of the current standard of six months. PHOTO: TAC Archive
TB treatment can be cut to two months for some, finds landmark study
News & Features / 15th November 2022 | Elri Voigt / Spotlight
Some cases of tuberculosis (TB) can be successfully treated in as little as two months – a third of the current standard of six months in South Africa and most other countries. This is according to early findings from the landmark TRUNCATE TB trial presented at last week’s Union World Conference on Lung Health.
Nick Paton, a professor of Infectious Diseases at the National University of Singapore and the chief investigator of the TRUNCATE trial, explains that the standard six-month treatment for drug-susceptible TB (DS-TB) is actually overtreating a lot of people who have the disease. The reason for the six-month mark for TB treatment is that a minority of TB patients need the long treatment regimen to avoid relapse, but the majority would be cured before the six-month mark.
Essentially, it’s a blunt, but generally, effective instrument used to protect a minority of TB patients.
Short initial treatment
The TRUNCATE trial set out to see if a two-month (eight weeks) novel combination of TB regimens would be feasible when compared to the standard six-month (24 weeks) treatment regimen. According to Paton, trial participants in the experimental arms of the study were initially given eight weeks of treatment, with the option of extending treatment to 10 to 12 weeks if they had persistent clinical disease after the eight-week treatment. If there was still active TB after that, participants were switched to the standard six-month treatment.
Study participants were monitored regularly through follow-up visits, which included TB symptom screening once a month and sputum smear tests every one to three months.
“The core [of the strategy] is it’s a very short period of initial treatment, plus you then do the monitoring and pick up people [who relapsed] early,” Paton says.
A total of 674 trial participants were recruited from March 2018 to March 2022 across 18 sites in Thailand, Indonesia, the Philippines, Uganda, and India. Four patients withdrew from the trial and 10 participants died during the trial.
Paton tells Spotlight that the overall death rate was low and there was no difference in the death rate between the standard treatment arm and the TRUNCATE strategy arms. The causes of death were mixed, he adds, and often the precise cause was unknown
For the final results, 660 participants were evaluated at week 96. In other words, about two years of follow-up occurred.
A patient at Lizo Nobanda TB Care Centre in Khayelitsha takes her TB medication. PHOTO: Jose Cendon/Médecins Sans Frontières
Encouraging results
Paton explains that the trial used the TRUNCATE strategy, which initially involved using four treatment arms containing a novel combination of TB drugs and comparing the results to a control arm consisting of the standard six-month treatment. Later, two TRUNCATE strategy arms were selected to complete the latter half of the study. He notes that it was a pragmatic decision to stop two of the arms, to ensure better data.
In the first of the two remaining experimental arms, 184 study participants received a regimen consisting of high-dose rifampicin (35mg per kg, reduced to 20mg per kg as a precaution following a liver injury-related death), isoniazid, pyrazinamide, ethambutol, and linezolid (600mg). In the second, 189 study participants received a regimen consisting of bedaquiline (400mg/d for two weeks then 200mg three times a week), isoniazid, pyrazinamide, ethambutol, and linezolid (600mg). The standard treatment arm had 181 participants.
In the standard treatment arm, 98% completed treatment and 3% had to be re-treated before week 96.
In the TRUNCATE strategy arms, overall, 91% completed the eight-week treatment and stopped treatment by week 12. 17%, (ranging from 13 to 23% by arm) had re-treatment, and 2% of participants did not complete initial treatment due to withdrawing from the trial, death, or defaulting on treatment.
Image: Health24
A comparison of the two experimental TRUNCATE arms with the standard treatment arm showed that the TRUNCATE arm with bedaquiline and linezolid was non-inferior to the standard treatment arm, while the high dose rifampicin and linezolid arm fell just short of meeting the non-inferiority criteria. Efficacy was calculated based on the proportion of unsatisfactory outcomes at week 96. Unsatisfactory outcomes were classified as death, still having active TB, or still being on TB treatment at week 96.
“The idea was that if we added those [unsatisfactory outcomes] up and that was the same in the standard treatment arm as the TRUNCATE strategy arm then that shows that this strategy in principle, can work,” Paton tells Spotlight.
The mean total days on treatment were reduced in the TRUNCATE strategy arms when compared to the standard treatment arm, which was 180 days. For high-dose rifampicin-linezolid, the average total days on treatment was 106 days, and in the bedaquiline-linezolid arm, it was 85 days.
“So, clearly the net effect is to decrease the average time on treatment,” Paton says. “You do substantially cut down the amount of time on treatment overall.”
He adds that the proportion of participants that had Grade 3 or 4 adverse events, serious adverse events, or who died did not differ between the standard treatment arm and the TRUNCATE strategy arm. The proportion of participants with respiratory disability at week 96 also did not differ.
The only cases of acquired drug resistance were two cases observed in the bedaquiline and linezolid arm. This is a frequency of 1.1% according to Paton. One of these participants missed several treatment doses, while the other did not miss any doses. Both were successfully re-treated.
Initially, they wanted to enroll participants who were co-infected with HIV in the later stages of the trial, but none could be enrolled in time, so currently there is no data on how well it works in people living with HIV who also have TB, says Paton.
“The trial has shown that alternatives to systematically over-treating the large majority of people with TB can be successful. This is an important new research direction which has the promise to improve outcomes for patients and programmes,” Paton says. “The strategy may be refined in future to improve outcomes using alternative drug regimens or alternative approaches to monitoring. Ongoing analysis from the trial will further enhance our understanding.”
IMAGE: medicinenet.com/myhealth 1st.com
PK and safety data
At last week’s conference, Christopher Cousins, project leader of the TRUNCATE trial presented the first level of pharmacokinetic (PK) analysis from the trial. The PK results were taken from week eight of the study.
After fasting overnight, participants took an observed dose of their medication at the trial site and had blood sampling done over a 12-hour period. The data is based on 96 participants in the two experimental arms.
He says the AUC (which represents total drug exposure over time – AUC = area under the curve) for the high-dose rifampicin was four to six times higher than in the standard dose and exceeded the proposed efficacy targets in the majority of patients. This supports the hypothesis that high-dose rifampicin would enhance treatment sterilisation in the eight-week regimen.
The data also showed what seems to be a drug-drug interaction between rifampicin and linezolid, but this didn’t appear to be significant enough to abolish anti-mycobacterial efficacy.
According to Cousins, the bedaquiline concentrations at the end of week eight in the bedaquiline and linezolid arm were comparable to the concentrations seen after 24 weeks of treatment for drug-resistant TB (currently both bedaquiline and linezolid are part of the standard treatment for DR-TB, but not for DS-TB).
The morning drug burden for a patient in an in-patient MDR-TB treatment facility in KwaZulu-Natal. PHOTO: Amelia Rutter, courtesy of Photoshare
When asked how well monitoring participants in the TRUNCATE arms after they stopped treatment was able to detect those who still had active TB disease, Paton tells Spotlight that further analysis of the sputum smears samples will be able to tell us more. The trial used a relatively low-technology approach where a symptom screening and a sputum smear test were used to determine if a participant still had active TB and needed to be re-treated.
“We need to run additional biomarkers, interrogate the data set in more detail to figure out who was cured, who wasn’t cured, over what duration and how well do these other things [sputum smear test and symptom screening] pick it [TB] up,” he says.
He adds that this was a starting point, “but we are likely to be able to do better if we use some of the new biomarker technologies for monitoring”.
Implications of findings
“These results are very exciting as proof of concept – they show it’s possible to shorten treatment for drug-sensitive TB even further,” says Lindsay McKenna, TB Project Co-Director at New York-based Treatment Action Group (TAG). “But we need to optimise the regimen and study this treatment strategy in broader populations, including people living with HIV – none were enrolled in the study – and [in] programme contexts,” she says.
“There are other trials that are being planned that look to proactively (for example, at time of treatment initiation) determine who might benefit from shorter versus longer treatment based on available indicators or risk factors known to be correlated with treatment outcomes, such as disease severity, BMI, and HIV status (called a stratified medicine approach), and to tailor the duration of treatment accordingly,” she adds. “If the latter stratified medicine approach is proven, it will be very interesting to see how these two approaches compare and are viewed by programmes and affected communities.”
Feasibility of shortened regimens
Nerissa Donato the site co-investigator for the Truncate TB trial from the Lung Centre in the Philippines outlined the feasibility and acceptability of the TRUNCATE strategy at last week’s conference. This was based on participant questionnaires, clinician surveys, description data from the trial, and observations from Donato.
“The TRUNCATE strategies were acceptable and feasible in the context of the clinical trial. It can be successfully implemented provided that it is supported by the NTP (national treatment programme) and embraced by trained clinicians,” she says.
She explains the main challenges to implementing the strategy were patients’ concerns about potential side effects and the greater pill burden, but after some discussion participants were comfortable with the regimen due to the possibility of a much shorter treatment regimen. The close following up of participants and follow-up visits required was different from the normal procedure of treating for six months and being discharged from care. But she says participants were generally happy to come back for the follow-up visits.
Clinicians who participated were initially sceptical of whether the regimen was safe and would work but after the trial, they had a more positive view, according to Donato.
She says that in order to implement the strategy in the real world, it would need to be adopted by the NTPs, which will likely require more data on cost-effectiveness.
Need better treatment approaches and regimens
Paton tells Spotlight that somewhere between the two extremes of overtreating TB patients and personalised medicine as seen in high-income countries, there can lie a better treatment option for TB patients.
“We need to look at how do we personalise it [TB treatment], but in a way that’s not so high tech so it becomes impossible for programmes,” he says. “At least if you’re monitoring [patients] you’ve got a safety net. If you get it wrong, you just make sure you pick the person up early and re-treat and there shouldn’t be serious harm from that.”
Additional data from the trial will be released in the coming months.