猴痘：我們如何知道治療是否有效？
資料來源：www.thelancet.com/infection Vol 22 September 2022；財團法人台灣紅絲帶基金會編譯
臨床的治療試驗是新發傳染病爆發的優先事項。當我們設計試驗時，適合目的的終點至關重要，因為這些終點將為有關病例管理、監管批准以及公共衛生資金和介入優先等級的決策提供信息。
Monkeypox 強調了為新興的疾病設計主要終點的困難。在全球範圍內，我們對典型的猴痘是什麼——常見和最嚴重的症狀、對患者造成最大痛苦的症狀、傳染性持續時間和潛在併發症的了解有限。此外，疾病的模式可能會有所不同，無論是在個體之間還是在不同的病毒分支之間。對進化枝 I 疾病的描述強調播散性皮疹，死亡率約為 10%。非洲以外進化枝 IIb 或 III 疾病的經驗顯示泌尿生殖器和肛周病變佔優勢，伴有新的併發症（如直腸炎），並且在當前的爆發中，這些進化枝沒有造成死亡。儘管不能排除病例確定偏倚，但需要確定較輕疾病的原因，並且可能與病毒的傳播方式有關。我們治療猴痘的主要動機取決於嚴重程度和傳播風險，因此可能會在緩解症狀、預防併發症、縮短患者隔離時間或防止疾病傳播之間轉移重點。
我們對疾病的理解隨著病例數量的增加而增加，在新發感染領域，透過使用標準化的臨床表徵和生物取樣方案。然而，在開始試驗之前等待最佳的臨床理解是不切實際的——許多暴發都是短暫存活的（尤其是在監管機構的地理邊界內工作時），我們永遠冒著為時已晚的風險，因為在試驗招募之前就宣布疫情結束。
尋找疾病多樣性和反映主要結果，以滿足患者、監管機構和公共衛生官員的需求的艱鉅工作正在進行中。一個主要結果是否在試驗中可行，以通過薈萃分析促進數據共享和綜合並不確定，或者一系列具有不同結果的試驗是否可以更好地滿足這些需求。
在評估猴痘治療安全性和有效性的臨床試驗中，有各種建議的結果正在考慮中（附錄 p 1）。在剛果民主共和國進行的 PALM 007 tecovirimat 隨機對照試驗將使用猴痘病灶消退的時間作為其主要結果。這一結果是透過對剛果民主共和國 I 型疾病患者數年臨床數據的分析而確定的，並且適合這種情況，但可能難以推斷出新出現的疾病表型。就藥物作用而言，活動性（假定感染性）病變的消退是一種精確的測量方法，但可能不能代表越來越多的具有其他器官表現的多形性疾病。即便如此，對於何時解決病變仍未達成共識 – 例如，是否需要僅存在結痂或已經脫落，或者底層皮膚或粘膜是否必須完全癒合。病灶完全消退對患者來說是一個更有意義的結果，但長期存在的病灶可能代表細菌二重感染，而抗病毒治療不會對此產生直接影響。
對患者進行評估的臨床醫生之間的病變評估可能容易出現差異。解決血液、拭子或咽喉樣本中病毒存在的時間對於感染控制計畫特別有用，但缺乏縱向生物樣本來告知這些樣本的使用。疾病嚴重程度的順序量表結果可能是可能的，但如果大多數病例是輕度的，這些結果可能並不精確。對於受影響的個體，如果他們有持續性潰瘍的症狀，那麼已經癒合的病變可能沒有什麼影響。一些研究包括探索性結果來捕捉這種現象，但在某些情況下，將這種潰瘍性病變的消退作為主要結果可能更合適。
前進的道路應該是雙管齊下的。目前有緊急審議（包括由世衛組織帶頭的審議），重點關注如何安全地開始試驗招募所需的內容。這些要求需要科學界就有助於塑造未來研究的重要定義去達成共識（例如什麼構成活動性病變、嚴重病例或併發症）。審議應盡可能協調一致，但也有助於探索正在觀察的疾病的多樣性，並適應我們日益增長的理解。我們主張在長期使用其他疾病（如皮膚利甚曼病，它與猴痘分享組織上有異質性皮膚損傷的問題和解決的定義）的策略，這些策略在長期內得到鞏固，這些策略對患者對結果的偏好等考慮進行了適當的處理，並促成進一步的自然歷史之利用和累積的生物取樣證據。
所有作者都是中非共和國猴痘 MOSAIC 世代研究和tecovirimat 擴大使用計畫的調查人員。 JD 是 PALM 007 試驗的研究員。
* Amanda Rojek, Jake Dunning, Piero Olliaro amanda. amanda.rojek@ndm.ox.ac.uk
英國牛津大學大流行科學研究所，國際嚴重急性呼吸道和新發感染聯盟（AR，JD，PO）； 澳大利亞維多利亞州墨爾本皇家墨爾本醫院急診科（AR）；英國倫敦皇家自由倫敦 NHS
基金會信託基金傳染病科 (JD)
Monkeypox: how will we know if the treatments work?
www.thelancet.com/infection Vol 22 September 2022
Clinical trials of treatments are a priority for emerging infectious disease outbreaks. When we design trials, fit-for-purpose endpoints are crucial, as these will inform decisions on case management, regulatory approval, and priority for public health funding and interventions.
Monkeypox highlights the difficulties in designing primary endpoints for emerging diseases. Globally, we have a limited understanding of what typical monkeypox is—the common and most severe symptoms, the symptoms that cause most distress to patients, the duration of infectivity, and potential complications. Furthermore, patterns of disease might vary, both between individuals and between different clades of virus. Descriptions of clade I disease emphasise disseminated rash and describe a mortality of around 10%. Experience of clade IIb or III disease outside Africa suggests a predominance of genitourinary and perianal lesions, with new complications (such as proctitis), and there have been no deaths caused by these clades in the current outbreak. Although case ascertainment bias cannot be excluded, causes for milder disease need to be established and might be linked to the way the virus is being transmitted. Our primary motivations for treating monkeypox vary depending on severity and risk of transmission and, therefore, might shift focus between symptom relief, preventing complications, shortening the duration of patient isolation, or preventing spread of disease.
Our understanding of a disease grows with the number of cases and, in the field of emerging infections, by use of standardised clinical characterisation and biological sampling protocols. However, waiting for optimal clinical understanding before starting a trial is impractical—many outbreaks are short-lived (especially when working within the geographical borders of regulatory agencies) and we perpetually risk being too late, with the outbreak being declared over before the trial recruit.
The challenging work to find primary outcomes that reflect the diversity of disease and meet the needs of patients, regulators, and public health officials is underway. It is uncertain whether one primary outcome will be feasible across trials to facilitate data sharing and synthesis through meta-analysis, or whether a range of trials with different outcomes might better meet these needs.
There are various proposed outcomes being considered for clinical trials evaluating treatment safety and efficacy for monkeypox (appendix p 1). The PALM 007 randomised controlled trial of tecovirimat in the Democratic Republic of the Congo will use time to monkeypox lesion resolution as its primary outcome. This outcome was determined by analysis of several years’ worth of clinical data from patients in the Democratic Republic of the Congo with clade I disease5 and is appropriate for that context, but might be difficult to extrapolate to emerging disease phenotypes. In terms of pharmaceutical action, resolution of active (presumed infectious) lesions is a precise measure, but might not be representative for what is increasingly a polymorphic disease with other organ manifestations. Even so, there is no consensus on when a lesion is resolved—for example, whether a scab needs to be merely present, or have fallen off, or whether the underlying skin or mucosa must be fully healed. Complete lesion resolution is a more meaningful outcome for patients, but prolonged lesion presence might represent bacterial superinfection for which an antiviral treatment will not have a direct effect. Lesion assessment is likely to be prone to variation between clinicians reviewing patients.
Time to resolution of viral presence in blood, swab, or throat samples is particularly informative for infection control planning, but there is a paucity of longitudinal biological sampling to inform the use of these. Ordinal scale outcomes for disease severity might be possible, but these might not be precise if most cases are mild. For an affected individual, lesions having healed might be of little consequence if they have symptoms from a persistent ulcer. Some studies include exploratory outcomes to capture this phenomenon, but including resolution of such ulcerating lesions as a primary outcome might be more appropriate in some instances.
The way forward should be two-pronged. There are urgent deliberations at present (including those led by WHO) to focus on what is needed to safely commence recruitment in trials. These require the scientific community to reach a consensus over important definitions that will help to shape future research (such as what constitutes an active lesion, or a severe case, or a complication). Deliberations should harmonise where possible, but also facilitate exploration of the diversity of disease being observed and adapt with our growing understanding. We advocate that these are consolidated in the longer-term using strategies employed for other diseases (such as cutaneous leishmaniasis, which shares with monkeypox the issues of heterogenous skin lesions and definitions of resolution) that do due process to considerations such as patients’ preferences for outcomes, and make use of further natural history and biological sampling evidence as it accrues.
All authors are investigators on the MOSAIC cohort study for monkeypox and the Expanded Access Programme of tecovirimat in the Central African Republic. JD is an investigator on the PALM 007 trial. *Amanda Rojek, Jake Dunning, Piero Olliaro amanda. rojek@ndm.ox.ac.uk
International Severe Acute Respiratory and Emerging Infections Consortium, Pandemic Sciences Institute, University of Oxford, Oxford OX3 7DQ, UK (AR, JD, PO); Emergency Department, Royal Melbourne Hospital, Melbourne, VIC, Australia (AR); Department of Infectious Diseases, Royal Free London NHS Foundation Trust, London, UK (JD)