預防愛滋病的銀彈和結構性障礙
資料來源：刺胳針愛滋病毒醫學期刊，www.thelancet.com/hiv Vol 6 November 2019，財團法人台編譯灣紅絲帶基金會
在預防愛滋病方面，過去十年是最好的時代也是最壞的時代。現代抗反轉錄病毒治療有效地預防了愛滋病毒的傳播，和以tenofovir為基底的暴露前預防（PrEP）當持續地使用時效果非常良好。此外，那些在人口水平中病毒抑制比率較高的地方（例如，新南威爾斯，澳大利亞；舊金山，美國；和英國的倫敦）， PrEP的加入已和愛滋病毒發生率的下降有關。然而，對最佳發展的挑戰仍然存在，因為感染愛滋病毒的風險通常伴隨著阻礙其順從性的問題（例如，物質濫用、抑鬱、貧窮、無支持功能的政府和不當的醫療保健系統）。因此，在資源有限的世界中，有關愛滋病毒控制的主要公共衛生問題正在出現。增加愛滋病毒感染者接受抗反轉錄病毒治療和高危人群接受PrEP的數量，可能導致零新感染這樣是合理的嗎？還是最終有必要擴大研究、評估和發展新預防技術的數量，才能遏制流行的傳播？要決定增加多少錢在當前模式上相對於投資在未來上越來越增添煩惱。
許多有希望且新的愛滋病毒預防方法已經是在地平線上了（如圖）。相較於常規的每日使用tenofovir disoproxil fumerate和emtricitabine，透過使用更少劑量的用藥，由事件驅動的PrEP已被證明可以減少愛滋病毒的發生率並且可能更具成本效益。以tenofovir alafenamide為基底每天使用的PrEP在安全性和耐受性方面亦似乎很有希望。
較新的方法預期基於不需要每天服藥的介入措施的假設或在規劃性生活上將更容易擴展，導致在人口層次上有更好的順從性。最首先的長效性抗反轉錄病毒預防方法是dapivirine陰道環，在非洲婦女中可降低愛滋病毒的發生率只要每月置入一次。新一代的抗反轉錄病毒環正在開發中，將抗反轉錄病毒藥物與荷爾蒙和其他抗菌劑藥物結合，可以預防愛滋病毒或其他性傳播感染和懷孕。其他局部治療方法的研究，包括直腸凝膠和沖洗，也正在進行中。但是，備受關注的則集中於長效愛滋病毒預防性注射或輸液，可以提供直接觀察給藥和不需經常給藥的承諾。Cabotegravir，一項安全且耐受良好的整合酶鏈轉移抑製劑每8週給藥一次，正於試驗HPTN 083和HPTN 084中與每日口服的emtricitabine和tenofovir disoproxil fumerate進行比較。其他已經研發的抗反轉錄病毒藥物其半衰期時間甚至更長。植入性的Islatravir（MK-8591或EFdA）棒在動物試驗中顯示出極好的耐受性，藥理測量顯示保護性藥物濃度可能會在放置棒後持續超過一年。第一代注入式的廣泛中和單克隆抗體（bNAb）亦是在兩項功效試驗中進行了評估。隨著多種愛滋病毒預防功效試驗正在持續的進行，長效抗反轉錄病毒藥物，bNAb和疫苗在最終將阻止愛滋病毒的傳播上存在著樂觀；但是這些新策略，要證明其效力和如何去實施仍然存在著很多挑戰。不像早期的試驗可以容易證明安慰劑組，新研究招募收高風險的個人需要考慮如果參與者他們願意的話，要如何去取得口服的emtricitabine和tenofovir alafenamide 之PrEP，因其已證明功效。但是，如果研究要為所有的參與者提供化學性預防，將需要有大量樣本以顯示新事物的非劣勢或優越性，亦導致巨額費用。每一種新的預防方法的發展都意味著將需要投資數億美元。成本效益的分析，將需要把每個新產品的好處與現有的PrEP技術可以用價格不到100美元部署在許多資源有限的國家/地區去做比較。成本花費在某些國家/地區仍然是PrEP擴大規模的限速步驟，因為非通用（非學名藥，專利藥）的emtricitabine和tenofovir disproxil fumerate之花費可能超過每人每年需要二萬美元。在許多地區無法獲得健康保險或未投保亦在PrEP的取得上產生了許多額外的阻礙，包括美國，一個國家有超過百萬人可能PrEP的取得而受益，但其中卻只有不到四分之一的人獲得，尤其是受愛滋病毒影響最嚴重的黑人和拉丁裔社區間更存在著誇張的不公平差異。儘管採注射、輸注和植入方式可能會允許不需頻繁給藥，但其臨床部署仍將需要可以確保產品安全交付的醫療保健系統和臨床監測，以及可以在兩次看診之間追踪被剝奪權利患者的基礎設施。或許最重要的是，依靠最新技術的解決方案錯失了現實，亦即許多全球愛滋病毒大流行的驅動因素仍然是社會和結構性因素，範圍從經濟上被剝奪權利的婦女到遭受不當對待在性行為、性別、種族和文化認同上的少數等。當新的愛滋病毒預防工具開發時需要考慮背景因素，更應在任何新方式產生時於評估的最早階段就予以考慮。由於在不同的環境中社會和結構動力的表現方式不同，了解這些差異至關重要，如此才能導向針對不同人群裁製發展不同的PrEP方法。此外，PrEP的交付在理想情況下應融合進入以理論為基礎的整合式預防套組中。新的PrEP介入措施的設計和開發需要包括所有的利益相關者，從受影響的社區到醫療保健提供者和決策者。最新的方法若缺乏有利的環境，包括採用受過良好訓練、具有文化背景的衛生保健工作者，和鼓勵參與預防服務的公民社會等，將無法最佳地實施。藥物開發商、研究資助者，和實施計劃需要與政府一起工作，以確保從這些新的預防方法中可以受益最大的那些人，大多數都確實能取得它們。要做到這一點，需要這些人的人權受到保護，如此存有風險人們才會樂於討論自己的行為、出來進行測試，並進而獲得預防服務。若沒有本地環境的支持並有足夠資源來承擔廣泛使用下一代預防措施的經費，所有這些令人興奮的新進步將是徒勞的。
* Kenneth H Mayer，Patrick S Sullivan，Chris Beyrer
哈佛醫學院，Beth Israel Deaconess醫療中心，Fenway Health，美國麻州，波士頓
(KHM); Emory Rollins
美國喬治亞州亞特蘭大市埃默里大學公共衛生學院（PSS）；以及美國馬里蘭州巴爾的摩約翰霍普金斯大學彭博公共衛生學院
Silver bullets and structural impediments to HIV prevention
For HIV prevention, the past decade has been the best of times and the worst of times. Modern antiretroviral treatment effectively prevents HIV transmission, and tenofovir-based pre-exposure prophylaxis (PrEP) works extremely well when used consistently. Moreover, where population levels of virological suppression are high (eg, New South Wales, Australia, San Francisco, USA, and London, UK), addition of PrEP has been associated with decreasing HIV incidence. However, challenges to optimal deployment exist because those at greatest risk of HIV often have concomitant issues that impede
adherence (eg, substance use, depression, poverty, unsupportive governments, and inadequate health-care
systems). Therefore, in a world of finite resources, major public health questions are emerging about HIV control. Is it plausible that increasing the number of people living with HIV accessing antiretroviral treatment and the number of at-risk people receiving PrEP could result in zero new infections? Or will scale-up of research, evaluation, and deployment of new prevention technologies ultimately be necessary to arrest epidemic spread? Deciding how much to spend on increasing access to current modalities versus investing in the future is increasingly fraught. Many promising new HIV prevention approaches are
on the horizon (figure). Event-driven PrEP has been shown to decrease HIV incidence and could be more costeffective than routine daily use of tenofovir disoproxil fumerate and emtricitabine by using fewer doses of medication. Daily tenofovir alafenamide-based PrEP also appears promising in terms of safety and tolerability. Newer approaches are predicated on the presumption that interventions that do not require daily pill taking or planning for sex will be more readily scalable and result in better population-level adherence. The first longer-acting antiretroviral prevention modality is the dapivirine vaginal ring, which decreases HIV incidence in African women when inserted monthly. Nextgeneration antiretroviral rings are in development that will combine antiretrovirals with hormones and other antimicrobials, allowing for protection from HIV or other sexually transmitted infections and pregnancy. Studies of other topical approaches, including rectal gels and douches, are also underway. However, much attention has focused on longer-acting HIV prophylactic injections or infusions, which offer the promise of directly observed administration and infrequent dosing. Cabotegravir, a safe and well tolerated integrase strand transfer inhibitor administered every 8 weeks, is being compared with daily oral driven emtricitabine and tenofovir disoproxil fumerate in the trials HPTN 083 and HPTN 084. Other antiretrovirals have been developed with even longer half-lives. Islatravir (MK-8591 or EFdA)-implanted rods have shown excellent tolerability in animals, with pharmacological measurements suggesting that protective drug concentrations could persist for more than a year after rod placement. The first generation of infused broadly neutralising monoclonal antibodies (bNAbs) is being evaluated in two efficacy trials. With multiple HIV prevention efficacy trials ongoing, there is optimism that long acting antiretrovirals, bNAbs, and vaccines will ultimately arrest the spread of HIV; however, many challenges remain to prove efficacy and to implement these new strategies. Unlike earlier trials that could readily justify a placebo arm, new studies enrolling high-risk individuals need to consider how participants might access oral emtricitabine and tenofovir alafenamide PrEP if they desire it, given its proven efficacy. However, if studies offer all participants access to chemoprophylaxis, huge sample sizes will be needed to show non-inferiority or superiority of the new agent, resulting in enormous costs. The development of each new preventive approach will entail investment of hundreds of millions of dollars. Cost-effectiveness analyses will need to compare the benefits of each new technology with existing PrEP, which can be deployed for less than US$100 in many resource-limited countries. Cost remains a rate-limiting step in scale-up of PrEP in certain countries, since non-generic emtricitabine and tenofovir disproxil fumerate can cost more than $20 000 per person per year. Insufficient access to health insurance or being uninsured has created additional impediments to PrEP access in many settings, including the USA, where less than a quarter of the more than one million individuals who might benefit from PrEP have accessed it, with exaggerated disparities in the black and Latino communities most heavily affected by HIV. Although injections, infusions, and implants might allow for infrequent dosing, their clinical deployment will require health-care systems that can ensure safe product delivery and clinical monitoring, and infrastructure that can track disenfranchised patients between visits. Perhaps most importantly, reliance on the latest technological solutions misses the reality that many of the drivers of the global HIV pandemic continue to be social and structural factors, ranging from the economic disenfranchisement of women to the mistreatment of sexual, gender, racial, and ethnic minorities. Context needs to be taken into consideration when developing new HIV prevention tools and should be considered at the earliest stages of evaluation of any new modality. Since social and structural dynamics play out differently in diverse enrivonments, it is crucial to understand these differences, which could lead to tailored development of different PrEP approaches for different populations. Moreover, PrEP delivery should ideally be integrated into theory-based combination prevention packages. Design and development of new PrEP interventions need to include all relevant stakeholders, from affected communities to health-care providers and policy makers. The newest approaches will not be optimally implemented without enabling environments that include well trained, culturally competent health-care workers, and civil societies that encourage engagement in preventive services. Drug developers, research funders, and implementing programmes need to work with governments to ensure that those who could benefit most from these new prevention approaches are able to access them. Achieving this will require that the human rights of such individuals are protected, so that at-risk people are comfortable in discussing their behaviour, presenting for testing, and accessing prevention services. Without supportive local environments and sufficient resources to underwrite the costs of widespread use of next-generation prophylactics, all these exciting new advances will be for naught.
www.thelancet.com/hiv Vol 6 November 2019
