更短期、更簡單的耐藥結核病治療方案預計今年晚些時候推出
資料來源：凱瑟琳.湯姆林森 / 2022 年 6 月 22 日 / Spotlight / 財團法人台灣紅絲帶基金會編譯
針對耐藥結核病新的六個月治療方案預計今年晚些時候將在公共部門推出。照片：TAC 檔案
南非正在進行修改該國耐藥結核病 (DR-TB) 國家指南的工作，以提供更短的 6 個月全口服方案作為新的照護治療標準。
該方案結合了新的和重新利用的藥物bedaquiline, pretomanid, linezolid, 和moxifloxacin。不包含moxifloxacin時稱為 BPaL，包含時稱為 BPaLM。治療方案中是否包括moxifloxacin取決於病患的結核病是否對一類稱為氟喹諾酮類 (fluoroquinolones) 的藥物產生耐藥性。moxifloxacin係屬於這一類藥物。
世界衛生組織 (WHO) 上個月發布了快速指南，建議在各國的國家結核病規劃中使用 BPaL/BPaLM。
南非結核病計畫主任 Norbert Ndjeka 博士希望，透過將 BPaL/BPaLM 作為照護方案的標準實施，南非將再次成為世界上第一個改善耐藥結核病治療和照護的國家。他指出，南非是第一個從耐藥結核病治療方案中去除具有嚴重副作用（例如聽力損失）之痛苦注射劑的國家，也是第一個將bedaquiline作為照護上標準治療之一部分的國家。這些舉措改善了該國的治療結果，有助於世衛組織修訂其關於耐藥結核病的全球指南——建議不要使用注射劑和使用bedaquiline。
Ndjeka 說，雖然這一次，在推薦 BPaL/BPaLM 時，WHO 的指導早於南非耐藥結核病治療指南的改變，但該國也不落人後。
根據 Ndjeka 的說法，衛生部正計劃在今年 9 月至 12 月期間實施 BPaL/BPaLM 作為耐藥結核病的標準照護方案。他說，到 2023 年 1 月，如果正在制定的新國家指南得到該國國家衛生委員會的批准，所有符合條件的耐藥結核病患者都應開始接受 BPaL/BPaLM 方案。
圖片：medicinenet.com/myhealth1st.com
實施 BPaL/BPaLM 將如何改變耐藥結核病治療方案？
結核病和愛滋病毒調查網絡的臨床試驗THINK計畫之負責人 Ronelle Moodliar 博士解釋說，南非目前的標準治療方案使用包括多達七種抗結核病藥物，持續時間為 9 到 18 個月，而 BPaL/BPaLM 療程為 6 個月。。
根據 Ndjeka 的說法，「許多耐藥結核病出版物顯示，縮短治療時間可以提高治療順從性，減少追蹤流失率，並且能夠增加有利的結果」。
他補充說，除了縮短治療時間外，新方案還將顯著減少患者在治療過程中必須服用的藥片數量。目前的照護方案之標準，要求接受耐藥結核病治療的人每天服用多達 23 片藥片。 Ndjeka 說，BPaL/BPaLM 將把這種藥丸負擔減少到每週 23 粒藥丸。「當你減少藥片負擔時，你會提高人們服用藥物的能力」，他說。
TB Proof（一個結核病倡導組織）的 Wieda Human 說：「耐藥結核病迫切需要實施高質量、毒性更低、時間更短、更有效的治療方案。因此，BPaLM 和 BPaL 方案代表了一項有重大進展能持續六個月且治愈率高的全口服方案」。
結核病醫學。照片：納西夫·馬尼/ Spotlight
在南非進行的關鍵研究
在南非進行的研究，為 BPaL/BPaLM 方案中使用之藥物的有效性和安全性數據，以及在為期六個月治療耐藥結核病的聯合療程中使用這些藥物之有效性的全球知識和證據，均做出了重大貢獻。
Moodliar 說：「在過去 20 年中，南非積極參與並為目前可用於治療耐藥結核病的所有三種新藥亦即bedaquiline、pretomanid 和 delamanid做出了重大貢獻，為該等藥物在國際和本地進行藥物註冊和核准計畫進行了第 II/III 期隨機對照臨床實驗」。
Ndjeka 補充說，pretomanid 係與 delamanid 屬於同一類之藥物，並以南非首都普利托利亞 (Pretoria) 命名，以表彰該國對該藥物開發的貢獻。
BPaL 方案在 TB Alliance 的 Nix 試驗下首次在南非試驗用於治療耐藥結核病。 Nix 試驗的積極結果導致了更大規模的多國 ZeNix 試驗，該試驗再次驗證了 BPaL 的療效，並證明該方案在減少linezolid劑量或持續時間的情況下仍然有效。南非也是無國界醫師 (Doctors Without Borders) 的 TB-Practecal 試驗的三個國家之一，其初步結果顯示接受 BPaLM患者的治愈率很高，這對於世衛組織更新其耐藥結核病之治療指南至關重要。
「我們很高興看到這些由南非科學界領導人進行的關鍵試驗正在影響政策和實踐」，TB Proof 的 Human 說。她補充說道，這些發展突顯了「支持和加強結核病高發國家研究能力的重要性」。Ndjeka 指出，南非正在進行進一步的業務研究，以評估 BPaL 對高度耐藥結核病的療效，這將為未來該族群的治療方案提供訊息和指導。
在 BPaL/BPaLM 於全國範圍內可取得之前還必須發生什麼呢？
Ndjeka 說，該國耐藥結核病專家委員會上週舉行會議，討論並計畫在南非實施 BPaL/BPaLM 作為照護方案的標準。他說，新的國家耐藥結核病治療指南將於 7 月編寫。一旦制定，新的指南，連同對 BPaL/BPaLM 成本效益的分析，必須提交給國家衛生委員會並獲得批准，然後才能實施新的治療方案。
Ndjeka 認為，正在進行的評估 BPaL/BPaLM 成本效益的工作，將證明該方案相對於現有治療的方案更具成本效益。「我願意相信我們將能夠負擔得起，因為我們將減少藥物……我們還將實驗室追蹤時間從 9 或 18 個月縮短至 6 個月，這些對取得更好結果將節省了大量資金」，Ndjeka 說。
Human 指出，在南非以外進行的研究發現，與現有照護標準相比，新方案具有成本效益。
除 pretomanid 外，BPaL/BPaLM 中使用的所有藥物均已透過招標方式採購，用於南非的耐藥結核病治療。 Ndjeka 表示，如果新指南獲得批准，則需要將 pretomanid 添加到招標案中，並補充說「好消息是它已在南非註冊」。Mylan製藥公司的 200 毫克 pretomanid 錠劑於 2021 年 3 月在南非註冊。
BPaL/BPaLM 方案所需的藥物其可負擔的價格為何？
無國界醫生強調了bedaquiline和 pretomanid 的高價是發展中國家擴大 BPaL/BPaLM 的潛在障礙。人們認為linezolid, 和moxifloxacin的價格問題不大。
據無國界醫生組織稱，pretomanid 和bedaquiline佔BPaLM 四藥方案成本的四分之三。
在南非，只有楊森 (Janssen) 製藥公司的bedaquiline產品可用，以 Sirturo 品牌銷售。每 100 毫克錠劑的成本為 28.72 蘭特，作為 BPaL/BPaLM 方案一部分的bedaquiline其全療程費用約為 5 ,744 蘭特（358 美元）。
利物浦大學的研究人員計算出，在足夠的數量和學名藥競爭的情況下，為期 6 個月的bedaquiline療程的價格可能會降至 1,600 蘭特左右（100 美元）。
全球基金專家審查小組最近批准了Macleods製藥公司 的bedaquiline學名藥產品，如果 SAHPRA 批准該產品且如果楊森公司對bedaquiline持有的專利沒有阻止其進入市場，其中一些只會在 2027 年到期，那麼bedaquiline的學名藥將在南非有上市的前景。
衛生部目前沒有採購 pretomanid 產品。根據 Ndjeka 的說法，「我們現在擁有的藥物是一項對研究計畫的捐獻」。由於只有 Mylan藥廠的 pretomanid 在該國註冊，如果新指南獲得批准，很可能會採購 Mylan 的產品。
雖然南非還沒有 pretomanid 的價格，但該藥物是透過全球藥物基金（係一種為參與的發展中國家集中採購結核病藥物的機制）以 6 個月的療程 5,841 蘭特（364 美元）左右的價格採購。利物浦大學的研究人員估計，在數量充足和競爭激烈的情況下，為期六個月的 pretomanid 療程的成本可能會降至 1,043蘭特（65 美元）和3,290蘭特（205 美元）之間。
雖然目前只有 Mylan藥廠的 pretomanid 在南非註冊，但擁有該藥物智慧財產權的組織 TB Alliance 也已授權 Macleods公司生產和銷售這種藥物。
Shorter, simpler DR-TB regimen expected later this year
Catherine Tomlinson / 22nd June 2022 / Spotlight
A new six-month treatment regimen for drug-resistant forms of tuberculosis is expected to be rolled out in the public sector later this year.
PHOTO: TAC Archive
Work is underway in South Africa to amend the country’s national guidelines for drug-resistant tuberculosis (DR-TB) to provide a shorter, six-month, all-oral regimen as a new standard of care treatment.
This regimen combines the new and repurposed medicines bedaquiline, pretomanid, linezolid, and moxifloxacin. It is known as BPaL when moxifloxacin is not included and BPaLM when it is. Whether or not moxifloxacin is included in the regimen depends on whether a person’s TB is resistant to a class of drugs called fluoroquinolones. Moxifloxacin falls into this class.
The World Health Organization (WHO) last month issued rapid guidance recommending the use of BPaL/BPaLM in countries’ national TB programmes.
Dr Norbert Ndjeka, director of South Africa’s TB programme, hopes that by implementing BPaL/BPaLM as a standard of care regimen, South Africa will once again be the world’s first in improving DR-TB treatment and care. He notes that South Africa was the first country to remove painful injectables with difficult side-effects (such as hearing loss) from DR-TB treatment regimens, as well as the first country to introduce bedaquiline as part of standard of care treatment. These moves, which resulted in improved treatment outcomes in the country, contributed to the WHO amending its global guidance on DR-TB – advising against the use of injectables and for the use of bedaquiline.
Ndjeka says that while, this time around, in recommending BPaL/BPaLM, the WHO’s guidance has preceded changes to South Africa’s DR-TB treatment guidelines, the country is not far behind.
According to Ndjeka, the Department of Health is planning to implement BPaL/BPaLM as a standard of care regimen for DR-TB between September and December this year. By January 2023, all eligible DR-TB patients should be initiated onto a BPaL/BPaLM regimen, if new national guidelines under development are approved by the country’s National Health Council, he says.
IMAGE: medicinenet.com/myhealth1st.com
How will implementing BPaL/BPaLM change DR-TB treatment regimens?
Dr Ronelle Moodliar, head of clinical trials at THINK: Tuberculosis and HIV Investigative Network, explains that South Africa’s current standard of care regimen involves the use of up to seven TB drugs for a duration of nine to 18 months, compared to six months for BPaL/BPaLM.
According to Ndjeka, “there are a number of DR-TB publications that have shown reducing duration of treatment improves adherence to treatment, your loss to follow up goes down, and you are able to increase favourable outcomes”.
He adds that in addition to reducing the length of treatment, the new regimen will significantly reduce the number of pills that patients must take over the course of their treatment. Current standard of care regimens require people receiving DR-TB treatment to take up to 23 pills per day. BPaL/BPaLM will reduce this pill burden to 23 pills per week, says Ndjeka. “When you decrease the pill burden you enhance ability for people to take tablets,” he says.
Wieda Human, of TB Proof (a TB advocacy group), says, “There is an urgent need to implement high-quality, less toxic, shorter, effective regimens for DR-TB. The BPaLM and BPaL regimens thus represent a major advance in enabling all-oral regimens for a six-month duration with high cure rates.”
TB Medicine. PHOTO: Nasief Manie/Spotlight
Crucial research conducted in SA
Research conducted in South Africa has significantly contributed to global knowledge and evidence on the efficacy and safety data of the drugs used in the BPaL/BPaLM regimen, as well as the effectiveness of using these drugs in a six-month combination course to treat DR-TB.
Moodliar says, “South Africa has actively participated and significantly contributed to all three of the new drugs now available for the treatment of DR-TB in the last 20 years, namely bedaquiline, pretomanid, and delamanid, running the phase II/III randomised control clinical trials and access programmes for the registration of the drugs both internationally and locally.”
Ndjeka adds that pretomanid, which is in the same class of drugs as delamanid, was named after South Africa’s capital Pretoria in recognition of the country’s contribution to the drug’s development.
The BPaL regimen was first trialled for treatment of DR-TB in South Africa under the TB Alliance’s Nix trial. Positive results from the Nix trial led to the larger, multi-country ZeNix trial, which once again validated the efficacy of BPaL and demonstrated that regimen remained effective with reduced dosages or durations of linezolid. South Africa is also one of three countries in Doctors Without Borders’ TB-Practecal trial, whose initial results have shown high cure rates among patients receiving BPaLM and was critical to the WHO updating its DR-TB treatment guidelines.
“We are delighted to see that these pivotal trials, conducted by South African scientist leaders, are impacting policy and practice,” said TB Proof’s Human. She adds that these developments highlight “the importance of supporting and strengthening research capacity in high TB incidence countries”. Ndjeka notes that further operational research is underway in South Africa to evaluate BPaL’s efficacy against highly drug-resistant TB, which will inform future treatment options and guidance for this group (Read more about this research here.)
What must still happen before BPaL/BPaLM is available nationally?
Ndjeka says that the country’s expert committee on DR-TB met last week to discuss and plan for the implementation of BPaL/BPaLM as a standard of care regimen in South Africa. He says that new, national DR-TB treatment guidelines will be written in July. Once developed, the new guidelines, together with an analysis of the cost-effectiveness of BPaL/BPaLM, must be presented to and approved by the National Health Council before the new regimen can be implemented.
Ndjeka is positive that work underway to evaluate the cost-effectiveness of BPaL/BPaLM will demonstrate the regimen’s cost-effectiveness over existing treatments. “I like to believe that we are going to be able to afford it because we are going to cut drugs… we are also going to cut lab follow-up from nine or 18 months to six months, so those are massive savings to get better results,” says Ndjeka.
Human notes that research conducted outside of South Africa has found that the new regimen is cost-effective when compared to existing standards of care.
All of the medicines used in BPaL/BPaLM except pretomanid are already procured via tender for DR-TB treatment in South Africa. Ndjeka says that pretomanid will need to be added to the tender if the new guidelines are approved, adding that “the good news is it is registered in South Africa”. Pharmaceutical company Mylan’s 200 mg pretomanid tablets were registered in South Africa in March 2021.
How affordable are the drugs needed for BPaL/BPaLM?
Doctors Without Borders have highlighted the high prices of bedaquiline and pretomanid as potential impediments to the scale-up of BPaL/BPaLM in developing countries. The prices of linezolid and moxifloxacin are thought to pose less of a problem.
According to Doctors Without Borders, pretomanid and bedaquiline account for three-quarters of the cost of a four-drug BPaLM regimen.
In South Africa, only pharmaceutical company Janssen’s bedaquiline product is available, sold under the brand name Sirturo. At a cost of R28.72 per 100 mg tablet, a full course of bedaquiline as part of a BPaL/BPaLM regimen costs around R5 744 (US$358).
Researchers at the University of Liverpool have calculated that, with adequate volume and generic competition, the price of a six-month course of bedaquiline could come down to around R1 600 ($100).
The recent approval of pharmaceutical company Macleods’ generic bedaquiline product by the Global Fund’s Expert Review Panel raises the prospect of generic bedaquiline becoming available in South Africa, if SAHPRA approves the product and if market entry is not prevented by patents held by Janssen on bedaquiline, some of which will only expire in 2027.
No pretomanid product is currently procured by the Department of Health. According to Ndjeka, “what we have now is [a] donation for research projects”. As only Mylan’s pretomanid is registered in the country, it is likely that Mylan’s product will be procured if the new guidelines are approved.
While South Africa does not yet have a price for pretomanid, the medicine is procured through the Global Drug Facility (a mechanism that pools procurements of TB medicines for participating developing countries) at a price of around R5 841 ($364) for a six-month treatment course. University of Liverpool researchers have estimated that with adequate volume and competition, the cost of a six-month course of pretomanid could come down to between R1 043 ($65) and R3 290 ($205).
While currently only Mylan’s pretomanid is registered in South Africa, TB Alliance, the organisation that owns the intellectual property on the drug, has also licensed Macleods to manufacture and market this drug.