www.thelancet.com/infection Vol 24 十一月 2024 / 線上發布 September 10, 2024 https://doi.org/10.1016/ S1473-3099(24)00591-7
Mpox 是一種病毒感染，可引起人類急性疾病並可能致命。 2024 年 8 月 14 日，世界衛生組織宣布目前持續的 MPOX 疫情為全球突發公共衛生事件。當前疫情的一個新特徵是改變模式透過性途徑傳播。初步調查結果強調，該病毒透過異性傳播，剛果民主共和國女性性工作者的風險增加。在剛果民主共和國，包括愛滋病毒在內的性傳播感染 (STIs) 的盛行率仍然很高，並且由於長達數十年的武裝衝突而導致的針對婦女的性暴力的高盛行率而加劇。應特別關注愛滋病毒感染者（PLWH），他們是易受傷害群體，因為他們的免疫力較弱，這可能使他們無法對MPOX產生有效的免疫反應。
在2022-23 年MPOX 爆發期間，CD4 細胞計數較低的愛滋病毒感染者 (PLWH-CD4 low) 患有嚴重疾病和致命結果的風險增加。替考維馬 (tecovirimat) 治療—一種針對天花所開發並用於治療天花的抗病毒藥物—在2022-23 年爆發期間減少了患者的病毒量，但可能對CD4 細胞計數較低的愛滋病毒感染者無效。 PALM007 試驗的最新新聞稿 (NCT05559099) 報告稱，儘管 tecovirimat 對人類使用是安全的，但它對剛果民主共和國流行的 MPXV 分支 1 無效。
tecovirimat (VP57) 所目標的蛋白其編碼 MPXV OP57 之基因的突變可能會導致抗藥性。賦予抗藥性的突變的獲得已在 2022-23 年出現，在免疫功能低下患者中所描述的抗病毒治療導致的病程延長和選擇性壓力，並且可能因而進一步加劇。
透過靶向 VP37，替考維馬 (tecovirimat) 最終抑制細胞外病毒的釋放。細胞內成熟病毒顆粒的形成不是替考維馬的目標，但這些顆粒如果在細胞死亡和裂解後釋放，則具有高度傳染性，這在CD4 細胞計數較低的愛滋病毒感染者 (PLWH CD4low ) 中經常發生，可能是這些患者病毒負荷高的原因。
關於免疫功能低下愛滋病毒感染者感染mpox或接種疫苗後中和抗體豐度的數據很少。 2022-23 年爆發的 MPOX 患者中描述了CD4 細胞計數較低的愛滋病毒感染者的單核細胞失調。此外，在 MPXV 驅動的深部組織病灶中，組織巨噬細胞無法清除CD4 細胞計數較低的愛滋病毒感染者的感染細胞。 T 細胞恢復對於組織巨噬細胞的正確指導和 MPXV 控制可能是必要的。
東非大湖地區愛滋病毒/愛滋病負擔沉重；因此，系統性的愛滋病毒檢測和抗病毒治療（ART）的實施應該在全球應對MPOX的行動中發揮不可或缺的作用。然而，在感染急性期對 PLWH-CD4low MPOX 患者實施 ART 可能會導致免疫重建發炎症候群 (IRIS)。在晚期 HIV 患者的病例系列中，開始 ART 後病情惡化和死亡的風險為 57%。臨床試驗需要去比較早期和延遲開始 ART 以及同時使用類固醇，就像預防結核病相關的免疫重建發炎症候群 (IRIS) 一樣。最重要的是，MPXV 感染高風險的HIV感染者應優先接種預防性疫苗，並在接種疫苗後評估這些人的免疫反應。
針對 MPXV 生命週期早期階段並抑制細胞內成熟病毒顆粒形成的替代抗病毒藥物，例如布西多福韋 (brincidofovir) 需要在病程早期施用。此外，PALM007 試驗最近顯示，住院治療和高品質的支持性照護改善了患者的生存率，將剛果民主共和國參與者的總體死亡率降低至1·7%，低於先前為超過3·6% 以上的數據。隨著 Ib 分支所驅動之持續的人際傳播，目前的病毒傳播途徑涉及多個分支，並且超過了先前的人畜共通徒徑和局部性的爆發，這顯示在生物學上存在潛在的變化。因此，縱向測量病變和黏膜拭子中的 MPXV 病毒效價將有助於監測長期病毒脫落並評估新病毒變異體的出現以及可能出現抗病毒藥物抗藥性。因此，在集中精力應對當前疫情，並更好地了解人類宿主中 MPXV 生物學變化的同時，確保獲得抗病毒藥物（尤其是 ART）和全面的愛滋病毒照護仍然至關重要。
我們聲明不存在競爭利益。
Wyvine Ansima Bapolisi、Susanne Krasemann、Misaki Wayengera、Bruce Kirenga、Esto Bahizire、Espoir Bwenge Malembaka、Joseph Nelson Siewe Fodjo、Robert Colebunders、*Patrick DMC Katoto katoto.chimusa@ucbukavu.ac.cd
熱帶疾病與全球健康中心，布卡武天主教大學醫學院，02 Bukavu，剛果民主共和國（WAB、EB、EBM、PDMCK）；神經病理學研究所，漢堡-埃彭多夫大學醫學中心，漢堡，德國（SK）；烏干達病毒研究所免疫性疾病科，烏干達坎帕拉（MW）；研究與創新部，麥克雷雷大學肺臟研究所，烏干達坎帕拉（BK）；麥克雷雷大學健康科學學院醫學系，烏干達坎帕拉（BK）；剛果民主共和國布卡武利維羅自然科學研究中心營養與健康系 (EB)；約翰霍普金斯大學彭博公共衛生學院流行病學系，美國馬裡蘭州巴爾的摩 (EBM)；安特衛普大學全球健康研究所，比利時安特衛普（JNSF，RC）；利物浦熱帶醫學院熱帶病生物學系，英國利物浦（RC）；南非開普敦斯泰倫博斯大學醫學與健康科學學院全球衛生系流行病學與生物統計學司 (PDMCK)； Cochrane 南非，南非醫學研究委員會，南非開普敦 (PDDMK)。
Mpox outbreak— tecovirimat resistance, management approaches, and challenges in HIV endemic regions
www.thelancet.com/infection Vol 24 November 2024 / Published Online September 10, 2024 https://doi.org/10.1016/ S1473-3099(24)00591-7
Mpox is a viral infection that causes acute disease in humans and can be fatal. On Aug 14, 2024, the WHO declared the ongoing mpox outbreak to be a global public health emergency. Shifting transmission patterns via sexual routes are a novel feature of the current outbreaks.1 Preliminary findings highlight spread via heterosexual transmission, with an increased risk in female sex workers in the DR Congo. The prevalence of sexually transmitted infections, including HIV, remains high in DR Congo and is exacerbated by the high prevalence of sexual violence against women associated with decades-long armed conflicts. Particular attention should be given to people living with HIV (PLWH), who represent a vulnerable population owing to their weakened immunity, which might render them unable to mount an effective immune response against mpox.
During the 2022–23 mpox outbreak, PWLH who had low CD4 cell counts (PLWH-CD4low) had an increased risk of severe disease and fatal outcome.3 Furthermore, they displayed a very high tissue viral burden.4,5 Treatment with tecovirimat—an antiviral developed for smallpox and used to treat mpox—reduced viral loads in patients during the 2022–23 outbreak but might be ineffective in PLWH CD4low.5,6 A recent press release of the PALM007 trial (NCT05559099) reported that tecovirimat was ineffective against the circulating mpox virus (MPXV) clade 1 in DR Congo, although it was safe for human use.
Mutations in the MPXV OP57 gene, which encodes the target protein of tecovirimat (VP57), might lead to resistance.8 Ongoing human-to human transmission might further spur mutations and adaptations to the human host. Acquisition of resistance-conferring mutations had already been shown in 2022–23 and might be further fuelled by the prolonged disease courses and selective pressure due to antiviral treatment that have been described in immunocompromised patients.
By targeting VP37, tecovirimat eventually inhibits the release of extracellular virus. Formation of intracellular mature virus particles is not targeted by tecovirimat, but these particles are highly infectious if released following cell death and lysis, which occur frequently in PLWH CD4low and might account for the high viral burden in these patients.
Data about the abundance of neutralising antibodies following infection with mpox or vaccination in immunocompromised patients are sparse. Dysregulated monocytes were described in PLWH-CD4low patients with mpox in the 2022–23 outbreak. Furthermore, tissue macrophages failed to clear infected cells in PLWH CD4 low in MPXV-driven deep tissue lesions. T-cell recovery is likely to be necessary for proper instruction of tissue macrophages and MPXV control.
The Great Lakes region of East Africa carries a substantial burden of HIV/ AIDS; thus, systematic testing for HIV and implementation of antiretroviral therapy (ART) should have an integral role in the global response against mpox. However, there is a risk that implementing ART in PLWH-CD4low patients with mpox during the acute phase of the infection might cause immune reconstitution inflammatory syndrome (IRIS). In a case series among people with advanced HIV, the risk of deterioration and death after initiation of ART was 57%. Clinical trials will need to compare early versus delayed initiation of ART and the concomitant use of steroids, as was done to prevent tuberculosis-related IRIS. Most importantly, PLWH who have a high risk of MPXV infection should be prioritised for a preventive vaccine, and immune response should be assessed in these individuals after vaccination.
Alternative antivirals targeting early stages of the MPXV life cycle and inhibiting formation of intracellular mature virus particles, such as brincidofovir, need to be administered early in the course of the disease.10 Moreover, the PALM007 trial recently showed that hospitalisation and high quality supportive care improved patients survival, reducing the overall mortality rate to 1·7% among participants in DR Congo, down from more than 3·6% in previous data.7 With sustained human-to-human spread driven by clade Ib, current virus transmission routes involve multiple subclades and exceed previous zoonotic and localised outbreaks, suggesting a potential change in biology. Thus, measuring MPXV viral titres in lesions and mucosal swabs longitudinally will help to monitor prolonged viral shedding and assess the emergence of novel viral variants with the potential emergence of resistance to antivirals. Therefore, while concentrating our efforts on responding to the current outbreak and gaining better insight into shifting MPXV biology in the human host, ensuring access to antivirals—particularly ART—and comprehensive HIV care remains crucial.
We declare no competing interests.
Wyvine Ansima Bapolisi, Susanne Krasemann, Misaki Wayengera, Bruce Kirenga, Esto Bahizire, Espoir Bwenge Malembaka, Joseph Nelson Siewe Fodjo, Robert Colebunders, *Patrick DMC Katoto katoto.chimusa@ucbukavu.ac.cd
Center for Tropical Diseases and Global Health, Faculty of Medicine, Catholic University of Bukavu, 02 Bukavu, Democratic Republic of the Congo (WAB, EB, EBM, PDMCK); Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany (SK); Department of Immunisable diseases, Uganda Virus Research Institute, Kampala, Uganda (MW); Department of Research and Innovation, Makerere University Lung Institute, Kampala, Uganda (BK); Department of Medicine, Makerere University College of Health Sciences, Kampala, Uganda (BK); Department of Nutrition and Health, Centre de Recherche en Sciences Naturelles de Lwiro, Bukavu, Democratic Republic of the Congo (EB); Department of Epidemiology, Johns Hopkins Bloomberg School of Public Heath, Baltimore, MD, USA (EBM); Global Health Institute, University of Antwerp, Antwerp, Belgium (JNSF, RC); Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Liverpool, UK (RC); Division of Epidemiology and Biostatistics, Department of Global Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa (PDMCK); Cochrane South Africa, South African Medical Research Council, Cape Town, South Africa (PDMCK).