感染愛滋病毒的男性中有許多猴痘病例，但尚無不良結果的跡象
關於疫苗策略的問題仍然存在
Liz Highleyman / 2022 年 8 月 30 日 / aidsmap / 財團法人台灣紅絲帶基金會編譯
圖片：弗拉德 .奧爾洛夫 / Shutterstock.com
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在當前疫情爆發近四個月後，我們現在知道很大一部分猴痘患者感染了愛滋病毒。雖然 HIV 控制良好且 CD4 計數較高的人似乎沒有更嚴重的猴痘疾病，但對於那些感染更晚期 HIV 疾病的人來說，情況可能並非如此。更重要的是，愛滋病毒陽性者可能對猴痘疫苗反應不佳，這顯示他們應該接受最有效的治療方案。
截至 8 月 29 日，英國衛生安全局 (UKHSA) 已確定 3,413 例猴痘病例。截至 8 月 26 日，美國疾病控制與預防中心 (CDC) 在美國報告了 17,432 例病例。在全球範圍內，現在有超過 47,600 例病例，主要是在該病毒流行的中非和西非國家之外。
雖然任何人都可以透過密切的身體接觸感染猴痘，但病例仍然集中在男同性戀、雙性戀和其他與男性發生性關係的男性中。最新的 UKHSA 技術簡報顯示，有可用人口統計信息的病例中有 97% 是男男性行為者。非洲以外其他國家的流行病學情況相似。
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愛滋病毒感染者中的猴痘病例
在幾個大型病例系列中，感染 HIV 的猴痘患者比例很高。 UKHSA 的分析發現，26% 的已知 HIV 感染狀況的猴痘病例是 HIV 感染者，而歐洲疾病預防和控制中心認為歐洲國家的這一比例為 37%。
但其他地方的愛滋病毒感染率更高。美國疾病預防控制中心最近的一份報告顯示，在美國有 41% 的已知狀況的人感染了愛滋病毒，但在喬治亞州，這一比例上升到 67%。
最近發表在《新英格蘭醫學雜誌》（NEJM）上的對多個國家 500 多例病例的分析也將這一比例定為 41%。 《刺胳針》的一份報告對西班牙巴塞隆那和馬德里的近 200 例病例進行了調查，發現其中 40% 的病例呈 HIV 陽性。
在患有猴痘的 HIV 陰性男性中，大多數人接受了暴露前預防 (PrEP)。 UKHSA 分析發現，79% 的人曾經服用過 PrEP。在 NEJM 病例係列中，57% 的人在猴痘出現前一個月接受了 PrEP。
這些報告中愛滋病毒陽性者的比例大大高於男男性行為者的總體愛滋病毒感染率，英國可能約為 5%，美國約為 15%。猴痘病例中愛滋病毒感染者人數過多的原因尚不完全清楚。
愛滋病毒陽性者更有可能參與醫療保健，他們接受治療的愛滋病毒和性健康診所對猴痘非常了解。目前尚不清楚有多少未經照護的 HIV 感染者患有猴痘。由於無法檢測到病毒載量的人不會傳播 HIV，因此接受抗反轉錄病毒治療的 HIV 陽性者以及接受 PrEP 的 HIV 陰性者可能更有可能放棄使用保險套，這可能對猴痘的性傳播提供一定的保護。雖然這也不清楚。
最後，雖然 HIV 控制良好且 CD4 計數高的人通常不被認為免疫功能低下，但他們可能有更輕微的免疫損傷或持續性炎症，這可能會增加他們對猴痘的易感性。
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HIV感染者的猴痘結果
好消息是，這些病例系列中的 HIV 陽性者的猴痘結果並未惡化。由倫敦瑪麗女王大學的 Chloe Orkin 教授及其同事撰寫的 NEJM 報告提供了有關 HIV 和猴痘患者的更多詳細信息。幾乎所有（96%）都在接受抗反轉錄病毒治療，大多數人服用整合酶抑製劑。大多數人的 HIV 控制良好：95% 的人病毒載量檢測不到（少於 50 個拷貝），CD4 計數中位數很高，為 680。
研究作者寫道：「感染 HIV 的人和未感染 HIV 的人的臨床表現相似」。愛滋病毒陽性者住院的可能性不大，但其中兩種更嚴重的併發症發生在愛滋病毒感染者身上。一名 CD4 計數低於 200 的男子患上了會厭炎，或喉嚨後部的組織瓣發炎。有兩例心肌炎（心肌炎症），一例發生在 CD4 計數高的 HIV 陽性患者中，另一例發生在 HIV 陰性患者中。
「隨著疫情越來越多地向低收入社區蔓延，免疫功能受損較嚴重的人群中的猴痘可能會越來越受到關注」。
英國愛滋病協會（BHIVA）主席勞拉·沃特斯博士說：「雖然迄今為止愛滋病毒感染者佔病例的 40% 以上，但令人欣慰的是，愛滋病毒感染狀況與猴痘嚴重程度無關」。
在西班牙巴塞羅那附近的德國人 Trias i Pujol 大學醫院的 Oriol Mitjà 教授及其同事的西班牙案例系列中，99% 的 HIV 陽性猴痘患者正在接受抗反轉錄病毒治療，89% 的 CD4 計數為 500 或更多。研究人員寫道：「我們沒有註意到臨床特徵有任何差異，包括報告為 HIV 陽性的患者和未報告的患者之間的病變數量或潛伏期」。
然而，對於愛滋病毒控制不佳的人來說，情況可能並非如此。奈及利亞先前的報告顯示，接受最佳治療的人數較少，愛滋病毒感染者的病情更嚴重、時間更長，死亡率更高。最近爆發的一份報告描述了一名 40 歲的德國男子，他患有未經治療的 HIV（CD4 計數 127）和梅毒，他患上了嚴重的猴痘，包括鼻子壞死。他接受了抗病毒藥物 tecovirimat (TPOXX) 治療，目前正在康復中。
隨著疫情越來越多地轉移到有更多有色人種的低收入社區、愛滋病毒感染率較高但不太可能接受治療和有效治療的人群中，猴痘病毒感染在病毒未抑制且免疫功能受損的人群可能會越來越受到關注治療。美國最近的報告顯示，猴痘現在不成比例地影響著黑人和拉丁裔男性。
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愛滋病毒感染者的疫苗接種和治療指南
英國愛滋病協會最近發布了關於猴痘的快速指南。雖然總體而言，愛滋病毒陽性者似乎沒有更大的風險導致更糟糕的結果，但該指南建議對那些 CD4 計數低於 200、持續可檢測到的病毒載量、近期與愛滋病毒相關的疾病或其他條件或治療可能導致免疫抑制的人進行專科照護。
猴痘與天花有關，天花疫苗也可以預防猴痘。 MVA-BN（品牌名稱為 Imvanex、Imvamune 或 Jynneos）是一種使用非複制病毒的新疫苗，在 HIV 感染者中安全且耐受性良好。 ACAM2000 是一種較老的活病毒疫苗，免疫系統較弱的人不應使用。
「對於 CD4 計數低的人的疫苗反應知之甚少」。
最初的 MVA-BN 適應症要求每隔 4 週進行兩次皮下注射。為了擴大有限的疫苗供應，一些國家採取了單劑策略，以盡快為兩倍多的人提供部分保護。此外，有些人正在使用分次劑量方法，允許透過皮內注射施用疫苗，將單個小瓶分成五劑。美國聯邦政府支持分次給藥，並在英國進行試點。
皮膚含有大量的免疫細胞，稱為樹突狀細胞，可以識別疫苗中的病毒抗原並引發強烈的免疫反應。皮內注射方法已經用於其他一些疫苗和結核病檢測，但它需要特殊訓練，並且會導致注射部位更多的發紅和瘙癢。有限的研究顯示，皮下和皮內給藥導致相似的抗體反應，但兩種方法都缺乏真實世界的疫苗有效性數據。
一些專家警告說，單劑量策略和皮內給藥可能不適合 HIV 感染者，因為他們的免疫反應可能較弱。研究顯示，MVA-BN 可為具有足夠 CD4 計數的 HIV 陽性者提供良好的保護，但他們的抗體效價可能較低，並且在單次給藥後可能反應不佳。對於 CD4 計數低的人的疫苗反應知之甚少。這顯示 HIV 感染者——尤其是那些 CD4 水平較低的人——應優先接受使用最有效給藥方法的最佳劑量。
「所有愛滋病毒感染者都應該接受兩劑完整的疫苗」，BHIVA 指南指出。「雖然疫苗供應有限，但 CD4 細胞計數 <200 個細胞/mm3 或持續性病毒血症的人應優先接受第一劑完整疫苗，並儘快接受第二劑完整疫苗」。
Tecovirimat (TPOXX) 是一種用於治療天花和猴痘的抗病毒藥物，其數據也有限。在動物研究中發現它是有效的，小型人體研究顯示它是安全且耐受性良好的。其他可以考慮的治療方法包括布林西多福韋和西多福韋 (brincidofovir and cidofovir)。
BHIVA 指南指出，沒有關於常規抗病毒藥物治療猴痘的指南，「住院患者應根據具體情況做出決定」。美國疾病預防控制中心在其最近的指南中提供了更多信息，指出應考慮對 HIV 感染者進行猴痘治療，同時考慮到疾病的嚴重程度和免疫抑製程度。沒有發現藥物-藥物相互作用會妨礙 tecovirimat 與抗反轉錄病毒治療的給藥。然而，西多福韋 (cidofovir) 可引起腎毒性，不應與富馬酸替諾福韋二吡呋酯 (tenofovir disoproxil fumarate) 一起使用。可以使用利物浦大學網站查看具體的互動。
有感染猴痘風險或感染猴痘的 HIV 感染者應繼續進行抗反轉錄病毒治療。「應支持可檢測到病毒血症的人實現病毒抑制，以最大限度地提高疫苗效力」，BHIVA 指南指出。「治療中斷可能導致 HIV 病毒血症反彈，這可能使猴痘的管理複雜化，包括疾病嚴重程度的惡化」，CDC 指南補充道。
參考文獻：
Thornhill JP et al。 16 個國家的人類猴痘病毒感染——2022 年 4 月至 6 月。新英格蘭醫學雜誌 387：679-691，2022 年（開放獲取）。DOI: 10.1056/NEJMoa2207323
Tarín-Vicente EJ et al 。 西班牙確診人類猴痘病毒病例的臨床表現和病毒學評估：一項前瞻性觀察性世代研究。刺胳針 400：661-669, 2022（開放獲取）。DOI：https://doi.org/10.1016/S0140-6736(22)01436-2
Many monkeypox cases among men living with HIV, but no sign yet of poorer outcomes
Questions remain on vaccine strategy
Liz Highleyman / 30 August 2022 / aidsmap
VladOrlov/Shutterstock.com
Almost four months into the current outbreak, we now know that a substantial proportion of people with monkeypox are living with HIV. While people with well-controlled HIV and a high CD4 count do not appear to have more severe monkeypox illness, this might not be the case for those with more advanced HIV disease. What’s more, HIV-positive people may not respond as well to monkeypox vaccines, suggesting they should receive the most effective regimen possible.
As of 29 August, the UK Health Security Agency (UKHSA) has identified 3413 cases of monkeypox. As of 26 August, the US Centers for Disease Control and Prevention (CDC) reports 17,432 cases in the United States. Worldwide, there are now more than 47,600 cases, mostly outside countries in central and west Africa where the virus is endemic.
While anyone can get monkeypox through close physical contact, cases remain concentrated among gay, bisexual and other men who have sex with men. The latest UKHSA technical briefing shows that 97% of cases with available demographic information have been among men who have sex with men. The epidemiological picture is similar in other countries outside Africa.
Cases in people living with HIV
The proportion of people with monkeypox who are living with HIV is high in several large case series. The UKHSA analysis found that 26% of cases with a known HIV status are living with HIV, while the European Centre for Disease Prevention and Control puts the proportion at 37% across European countries.
But HIV rates are higher elsewhere. A recent report from the US CDC shows that 41% of those with a known status in the US are living with HIV, but in the state of Georgia, this rises to 67%.
A recent analysis of more than 500 cases in multiple countries, published in The New England Journal of Medicine (NEJM), also put the proportion at 41%. And a report in The Lancet, looking at nearly 200 cases in Barcelona and Madrid, found that 40% were HIV positive.
Among HIV-negative men with monkeypox, a majority have been on pre-exposure prophylaxis (PrEP). The UKHSA analysis found that 79% had ever taken PrEP. In the NEJM case series, 57% were on PrEP during the month prior to monkeypox presentation.
The proportion of HIV-positive people in these reports is substantially higher than the HIV rate among men who have sex with men overall, which might be around 5% in the UK and 15% in the US. The reasons for the heavy overrepresentation of men living with HIV among monkeypox cases are not fully understood.
HIV-positive people are more likely to be engaged with health care, and the HIV and sexual health clinics where they receive care are well aware of monkeypox. It is not known how many people with HIV who are not in care have monkeypox. Because people with an undetectable viral load do not transmit HIV, HIV-positive people on antiretroviral therapy—as well as HIV-negative people on PrEP—may be more likely to forgo using condoms, which may provide some protection against sexual transmission of monkeypox (though this, too, remains unclear).
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Finally, while people with well-controlled HIV and a high CD4 count generally are not considered immunocompromised, they may have more subtle immune impairment or persistent inflammation that might increase their susceptibility to monkeypox.
Monkeypox outcomes in people with HIV
The good news is that HIV-positive people in these case series did not have worse monkeypox outcomes. The NEJM report, by Professor Chloe Orkin of Queen Mary University of London and colleagues, provided more details about people with HIV and monkeypox. Almost all (96%) were on antiretroviral therapy, with a majority taking integrase inhibitors. Most had well-controlled HIV: 95% had an undetectable viral load (less than 50 copies) and the median CD4 count was high, at 680.
“The clinical presentation was similar among persons with HIV infection and those without HIV infection,” the study authors wrote. HIV-positive people were not more likely to be admitted to hospital, but two of the more serious complications occurred in people with HIV. One man with a CD4 count below 200 developed epiglottitis, or inflammation of the flap of tissue at the back of the throat. There were two cases of myocarditis (heart muscle inflammation), one in an HIV-positive person with a high CD4 count and one in an HIV-negative person.
“Monkeypox among people with greater immune impairment is likely to become a growing concern as the outbreak increasingly moves into lower-income communities.”
“Whilst people with HIV account for more than 40% of cases so far, it is reassuring that HIV status was not linked with monkeypox severity,” said British HIV Association (BHIVA) chair Dr Laura Waters.
In the Spanish case series, by Professor Oriol Mitjà of University Hospital Germans Trias i Pujol near Barcelona and colleagues, 99% of HIV-positive people with monkeypox were on antiretroviral therapy and 89% had a CD4 count of 500 or more. “We did not notice any difference in clinical features, including the number of lesions or incubation period between patients who reported being HIV-positive and those who did not,” the researchers wrote.
However, this may not be the case for people with poorly controlled HIV. Prior reports from Nigeria, where fewer people are on optimal treatment, showed that people with HIV had more severe and prolonged illness and higher mortality. One recent report from the current outbreak describes a 40-year-old man in Germany with untreated HIV (CD4 count 127) and syphilis who developed severe monkeypox, including necrosis of the nose. He was treated with the antiviral medication tecovirimat (TPOXX) and is recovering.
Monkeypox among people with unsuppressed HIV and greater immune impairment is likely to become a growing concern as the outbreak increasingly moves into lower-income communities with more people of colour, groups that have higher HIV rates but are less likely to be in care and on effective treatment. Recent reports from the US show that monkeypox is now disproportionately affecting Black and Latino men.
Vaccination and treatment guidance for people with HIV
The British HIV Association recently issued rapid guidance on monkeypox. While HIV-positive people overall do not appear to be at greater risk for worse outcomes, the guidance advises specialist care for those with a CD4 count below 200, a persistent detectable viral load, recent HIV-related illnesses, or other conditions or treatments that may cause immune suppression.
Monkeypox is related to smallpox, and smallpox vaccines can prevent monkeypox as well. MVA-BN (brand names Imvanex, Imvamune or Jynneos), a new vaccine that uses a nonreplicating virus, is safe and well tolerated in people living with HIV. ACAM2000, an older live-virus vaccine, should not be used by people with a weakened immune system.
“Little is known about vaccine response in people with low CD4 counts.”
The original MVA-BN indication calls for two doses administered as subcutaneous injections four weeks apart. In an effort to stretch the limited vaccine supply, some countries have resorted to a one-dose strategy to give twice as many people partial protection as soon as possible. In addition, some are using a fractional-dose approach that allows the vaccine to be administered by intradermal injection, splitting a single vial into five doses. The US federal government supports fractional dosing and a pilot in underway in the UK.
The skin contains plentiful immune cells, known as dendritic cells, that can recognize viral antigens in the vaccine and trigger a strong immune response. The intradermal method is already used for some other vaccines and for tuberculosis testing, but it requires special training and can cause more redness and itching at the injection site. Limited research shows that subcutaneous and intradermal administration lead to similar antibody responses, but real-world vaccine effectiveness data are lacking for both methods.
Some experts caution that the one-dose strategy and intradermal administration may not be appropriate for people living with HIV, who may have weaker immune responses. Studies indicate that MVA-BN provides good protection for HIV-positive people with adequate CD4 counts, but they may have lower antibody titres and may not respond as well after a single dose. Little is known about vaccine response in people with low CD4 counts. This suggests that people with HIV—especially those with lower CD4 levels—should be prioritised to receive the optimal number of doses using the most effective administration method.
“All people with HIV should receive two full vaccine doses,” the BHIVA guidance states. “While vaccine supplies are limited, people with a CD4 cell count <200 cells/mm3 or persistent viraemia should be prioritised to receive a full first vaccine dose, and to receive a second full vaccine dose as soon as available.”
Tecovirimat (TPOXX), an antiviral medication used to treat smallpox and monkeypox, also has limited data. It was found to be effective in animal studies, and small human studies showed that it is safe and well tolerated. Other treatments that can be considered include brincidofovir and cidofovir.
The BHIVA guidance notes that there are no guidelines for routine antivirals to treat monkeypox, and “inpatient decisions should be made on a case-by-case basis.” The US CDC provides a bit more information in its recent guidance, stating that monkeypox treatment should be considered for people with HIV, taking into account disease severity and degree of immunosuppression. No drug-drug interactions have been identified that would preclude administration of tecovirimat with antiretroviral therapy. However, cidofovir can cause kidney toxicity and should not be used with tenofovir disoproxil fumarate. Specific interactions can be checked using the University of Liverpool website.
People with HIV who are at risk for or who contract monkeypox should continue their antiretroviral therapy. “People with detectable viraemia should be supported to achieve viral suppression to maximise vaccine efficacy,” the BHIVA guidance states. “Treatment interruption might lead to rebound HIV viraemia that could complicate the management of monkeypox, including worsening illness severity,” adds the CDC guidance.
References
Thornhill JP et al. Monkeypox virus infection in humans across 16 countries – April-June 2022. New England Journal of Medicine 387: 679-691, 2022 (open access).
DOI: 10.1056/NEJMoa2207323
Tarín-Vicente EJ et al. Clinical presentation and virological assessment of confirmed human monkeypox virus cases in Spain: a prospective observational cohort study. The Lancet 400: 661-669, 2022 (open access).
DOI:https://doi.org/10.1016/S0140-6736(22)01436-2