HIV 相關中樞神經系統感染：將夢想變為現實
資料來源：www.thelancet.com/hiv Vol 10 October 2023
減少愛滋病毒相關死亡的措施仍然是全球公共衛生的優先事項。 低收入和中等收入國家 (LMIC) 衛生系統薄弱，無法獲得基本的診斷測試和藥物，導致這些死亡更加嚴重。 在全球範圍內，預計2022 年將有630,000 名愛滋病毒感染者死亡。 估計有430 萬的晚期愛滋病毒感染者其死亡風險最高，世界衛生組織將其定義為青少年和成人之CD4 計數低於每微升200 個細胞，或世界衛生組織臨床上為第3或4階段之疾病。在非洲改善愛滋病毒治療和照護的公共衛生介入措施往往主要關注門診照護環境，而未能改善資源欠佳的公立醫院中的愛滋病毒感染者其治療和照護上的需要。
患有晚期愛滋病毒的患者經常需要住院診斷和治療嚴重的伺機性感染，包括隱球菌性腦膜炎、結核病和嚴重的細菌感染。 在 2023 年的系統性回顧中，Burke 及其同事強調，已發表的研究很少評估減少晚期 HIV 住院患者死亡的介入措施，並建議優先考慮此類研究。
在《刺胳針愛滋病毒》中，Sayoki Mfinanga 及其同事 報告了在喀麥隆、馬拉威和坦尚尼亞五家公立醫院的常規照護服務中開展的「降低愛滋病相關腦膜炎死亡率(the Driving Reduced AIDS associated Meningo-encephalitis Mortality , DREAMM)」實施科學計畫的調查結果。 最重要的結果是，在實施一種演算法來快速識別、分類、診斷和治療疑似中樞神經系統感染的愛滋病毒感染者後，其死亡率顯著降低。
Mfinanga 及其同事發現，在觀察階段，中樞神經系統感染導致的2 週死亡率為49%（129 例中的63 例），這與非洲常規照護的其他數據一致，顯示隱球菌性腦膜炎、結核性腦膜炎和肺炎鏈球菌性腦膜炎的短期死亡率在44 % 和 54%之間變化。
DREAMM 介入措施包括共同設計的教育計劃、優化實驗室和臨床路徑、建立實踐社區、實施包括床邊快速診斷測試在內的演算法以及提供隱球菌性腦膜炎測試、藥物和設備，以允許世界衛生組織2018 年隱球菌性腦膜炎的指導方針被實踐。 在對地點、年齡、性別和抗反轉錄病毒治療 (ART) 暴露進行調整後，這種方法使 CNS 感染引起的 2 週全因死亡率降低了 23%。 研究使用了前後設計，因此一些潛在的偏差可能會影響結果，但研究人員提供的基準線數據顯示觀察和實施階段世代的相似臨床特徵。 重要的是，實施階段報告的死亡率與在非洲進行的隱球菌性腦膜炎臨床試驗報告的死亡率相似。研究結果顯示，擴大DREAMM 介入措施可以在常規照護環境中挽救愛滋病毒相關之中樞神經系統感染者的生命。
觀察階段的 139 名患者中有 113 名 (82%) 缺乏 CD4 檢測結果。 透過使用CD4 檢測及早識別患有晚期HIV 疾病的人，有助於利用世界衛生組織一系列之照護進行適當的管理，可以降低晚期HIV 相關疾病的死亡率。用於CD4 檢測的新PIMA 機器的停止生產，這在中低收入國家中具有挑戰性。 然而，增加新的一站式照護 (point-of-care) 之 CD4 Visitect 測試的可及性，可能會改善 CD4 測試的取得。
Mfinanga 及其同事發現，268 名中樞神經系統感染參與者中有173 名(65%) 接觸過ART。這些參與者中近一半沒有堅持接受ART 或已脫離照護，這限制了預防晚期HIV疾病死亡的努力。 擴大抗病毒治療的可及性必須與強大的衛生系統相匹配，以確保愛滋病毒感染者得到照顧並支持最佳的順從性。
這項務實的研究結合了社會、行為、實施科學和傳統研究的要素，使這些結果更加有趣，因為該方法超出了臨床試驗的範圍，可以更好地了解現實世界醫療保健環境中實踐的變化，即複雜系統中的人類行為。
未來計畫發布 DREAMM 健康經濟學分析。 考慮到本研究中用於診斷和管理愛滋病毒相關中樞神經系統感染的藥物和商品是免費提供的，中低收入國家必須為擴大這種介入措施創建經濟上可持續的模式。
DREAMM 計畫的調查結果清楚地提醒我們，如果全球衛生界不面對與薄弱衛生系統內的取得和實施等相關的挑戰，而僅僅只依靠我們將產生的新證據並將其納入國際指南，以減少常規臨床服務中晚期愛滋病毒所造成的可預防之死亡，則新證據所承諾的生存益處將不會轉化為現實世界的影響。 DREAMM 計畫顯示，透過與當地領導層平等合作，構思、實施和評估一套務實的介入措施，就有可能在常規照護環境中實現新證據的承諾。 同樣令人印象深刻的是，這一結果是在與愛滋病毒相關的中樞神經系統感染的背景下得到證明的，眾所周知，這種感染的診斷和治療具有挑戰性，並且死亡率很高。
為了擴大這一系列介入措施的規模，有必要確保政治意願和資金協調一致。 我們期待看到擴大這一系介入措施，對因中樞神經系統感染和其他晚期愛滋病毒疾病之併發症而到非洲醫院就診的愛滋病毒感染者，其死亡率降低所產生的效果。
DBM獲得了美國國家衛生研究院、英國醫學研究委員會（MRC）、Cepheid和吉利德科學公司的資助； 曾為吉利德科學公司提供諮詢服務； 是烏干達衛生部高級愛滋病毒技術工作小組的成員； 並在被忽視疾病診斷贊助的研究數據和安全監測委員會任職。 GM已獲得美國國家衛生研究院、Wellcome Trust、EDCTP、南非政府機構、ImmunityBio、英國國家衛生研究院的資助； 和 MRC， 為愛滋病援助組織和吉利德科學公司提供諮詢； 並在大塚、美國國家衛生研究院和蓋茲基金會贊助的數據和安全監測研究委員會任職。
*David B Meya, Graeme Meintjes dmeya@idi.co.ug
烏干達，坎帕拉，麥克雷雷大學健康科學學院傳染病研究所PO Box 22418 (DBM)； 美國明尼蘇達州明尼亞波利斯市明尼蘇達大學醫學與國際健康系 (DBM)； 南非開普敦大學傳染病與分子醫學研究所、威康非洲傳染病研究信託中心 (GM)； 南非開普敦大學健康科學學院醫學系（GM）
HIV-related CNS infections: translating DREAMM into reality
Initiatives to reduce HIV-related deaths remain a global public health priority. These deaths are compounded by weak health systems and lack of access to essential diagnostic tests and medications in low-income and middle-income countries (LMICs). Globally, an estimated 630000 people living with HIV died in 2022. The mortality risk is highest among the estimated 4·3 million people living with advanced HIV disease, defined by WHO in adolescents and adults by a CD4 count less than 200 cells per μL or WHO clinical stage 3 or 4 disease. Public health interventions to improve HIV treatment and care in Africa have tended to have a predominant focus on ambulatory care settings, while failing to address the need to improve treatment and care for people living with HIV in under-resourced public hospitals.
Patients with advanced HIV disease frequently require hospitalisation for the diagnosis and treatment of severe opportunistic infections including cryptococcal meningitis, tuberculosis, and severe bacterial infections. In a 2023 systematic review, Burke and colleagues highlighted the paucity of published studies evaluating interventions to reduce deaths among hospitalised patients with advanced HIV disease and recommended that such studies should be prioritised.
In The Lancet HIV, Sayoki Mfinanga and colleagues report findings of the Driving Reduced AIDS associated Meningo-encephalitis Mortality (DREAMM) implementation science project conducted in routine care services in five public hospitals in Cameroon, Malawi, and Tanzania. The headline results were a significant reduction in mortality after implementation of an algorithm to rapidly identify, triage, diagnose, and treat people living with HIV who presented with suspected CNS infections.
The 49% (63 of 129) 2-week mortality from CNS infections in the observation phase that Mfinanga and colleagues found is consistent with other data from routine care in Africa showing that short term mortality from cryptococcal, tuberculous, and pneumococcal meningitis varied between 44% and 54%.
The DREAMM interventions included a co-designed education programme, optimising laboratory and clinical pathways, establishing communities of practice, implementation of an algorithm that included bedside rapid diagnostic tests and provision of cryptococcal meningitis tests, medication, and equipment to allow the WHO 2018 cryptococcal meningitis guidelines to be implemented. This approach resulted in a reduction in 2-week all-cause mortality from CNS infections by 23% after adjustments for site, age, sex, and antiretroviral therapy (ART) exposure. The study used a before-andafter design and therefore several potential biases could affect the results, but the investigators present baseline data showing similar clinical characteristics for the observation and implementation phase cohorts. Importantly, the mortality reported during the implementation phase is similar to that reported from cryptococcal meningitis clinical trials done in Africa.6 The findings suggest that scale-up of the DREAMM interventions could save lives from HIV-related CNS infections in routine care settings.
113 (82%) of 139 patients in the observation phase were missing CD4 test results. The earlier identification of people with advanced HIV disease by use of CD4 testing facilitates appropriate management with the WHO package of care could decrease advanced HIV disease related mortality. The ceasing of production of new PIMA machines for CD4 testing could make access to CD4 testing more challenging in LMICs. Increasing access to the new point-of-care CD4 Visitect test might, however, improve access to CD4 testing.
Mfinanga and colleagues found that 173 (65%) of 268 participants with CNS infections were exposed to ART.9,10 Almost half of these participants did not adhere to ART or had disengaged from care, which limited the efforts to prevent advanced HIV disease deaths. Expanding access to ART must be matched by strong health systems to ensure people living with HIV are retained in care and optimal adherence is supported.
This pragmatic study combined social, behavioural, implementation science, and elements of traditional research, making these results even more interesting because the approach went outside the scope of a clinical trial to better engage with what changes practices within real world health-care settings, namely human behaviour within a complex system.
Future publication of the DREAMM health economics analysis is planned. It is imperative that LMICs create economically sustainable models for this intervention to be scaled up, considering that drugs and commodities for the diagnosis and management of HIV-related CNS infections in this study were provided free of charge.
The findings of the DREAMM project are a stark reminder that it is not sufficient for the global health community to only generate new evidence and incorporate this into international guidelines to reduce preventable deaths from advanced HIV disease in routine clinical services. Without confronting challenges related to access and implementation within weak health systems the survival benefits that new evidence promises will not be translated into real world impacts. The DREAMM project illustrates that with a pragmatic set of interventions conceived, operationalised, and evaluated in equitable partnership with local leadership it is possible to realise the promise of new evidence in routine care settings. What is also impressive is that this outcome is demonstrated in the context of HIV-related CNS infections, which are notoriously challenging to diagnose and to treat and associated with very high mortality.
To scale up this set of interventions, it will be necessary to ensure political will and funding align. We look forward to seeing the effect that scaling up of this set of interventions will have on decreasing mortality among people living with HIV who present to hospitals in Africa with CNS infections and other complications of advanced HIV disease.
DBM has received grants from the US National Institutes of Health, UK Medical Research Council (MRC), Cepheid, and Gilead Sciences; has consulted for Gilead Sciences; is a member of the Technical Working Group on Advanced HIV at the Uganda Ministry of Health; and serves on the Data and safety monitoring board of studies sponsored by Diagnostics for Neglected Disease. GM has received grants from the US National Institutes of Health, Wellcome Trust, EDCTP, South African government agencies, ImmunityBio, UK National Institute of Health Research; and MRC; consults for AID for AIDS and