在美國獲得長效注射劑的公平性
資料來源：www.thelancet.com/hiv Vol 9 March 2022；財團法人台灣紅絲帶基金會編譯
Cabotegravir 是一種整合酶鏈轉移抑製劑，而 rilpivirine 是一種非核苷類反轉錄酶抑製劑，最近在加拿大、歐盟和美國獲得了藥品監管機構的批准，可作為每月一次的肌內長效注射 (LAI) 抗反轉錄病毒治療方案，用於病毒被抑制且沒有治療失敗歷史的HIV-1感染之成人。每 2 個月注射一次的可注射 cabotegravir 最近也獲得了美國監管部門的批准，作為暴露前預防 (PrEP)。其他 LAI 治療和預防配方正在開發中。
這些新技術消除了每天服用藥丸的需要，並有可能從根本上改變愛滋病毒流行的現狀。 LAI 可能會引導出患者參與之新策略，特別是那些在日常口服藥物之順從性和存留於照護上面臨挑戰的患者。然而，如果不為重點人群開發靈活的給付模式，LAI 也有可能加劇現有的健康不平等。在美國，非裔和拉丁裔之男男性行為者、跨性別女性、青年和年輕人面臨著不成比例的愛滋病毒負擔，且更有可能在愛滋病毒預防和照護方面遇到差距。隨著 LAI 方案的推出，實施方面的一些挑戰需要緊急關注，以確保這些關鍵人群的公平獲得。
LAI cabotegravir + rilpivirine（ATLAS1 和 FLAIR）在註冊試驗時的嚴格納入標準，要求參與者在開始每月 LAI 方案之前，至少要有 4 個月口服 ART 達病毒學上的抑制和 4 週的口服 cabotegravir 和口服 rilpivirine（儘管一項單獨的研究顯示，沒有口服而直接導入注射上是安全的）。當前的藥品仿單要求醫療保健提供者每月注射一次，並使用在註冊試驗時所使用的相同標準上（即口服治療上之病毒學抑制和由於 rilpivirine 對耐藥性的低遺傳性屏障，口服導入時需要高順從性）。這些要求將引導公共衛生反應，並對有效和公平地提供 LAI提出重大挑戰。不靈活地遵守這些要求將特別影響那些在與個人、社會和結構上之障礙奮鬥的人們，以及受困於人員和資源不足而緊張的愛滋病毒和初級保健診所。患者報告說，為 LAI 頻繁就診可能會加劇 HIV 的污名和污名化，增加不必要的披露風險，並導致自付費用和往返差旅費用增加。對於無法缺勤或無交通工具的人來說，頻繁就診也可能會令人望而卻步。同樣，臨床醫生表示，擔心注射診所就診的數量和頻率可能會使人員配備和其他診所資源不堪重負。實施研究的數據顯示，平均而言，每次就診注射 cabotegravir + rilpivirine持續約 32 分鐘（不包括往返診所的旅行時間），這對於許多規模較大的診所就可能不可行。
由於 cabotegravir 與 rilpivirine 現在已獲得美國監管部門的批准，臨床醫生可以在密切監測的情況下，對沒有病毒學抑制且無口服導入的患者選擇性提供藥物。此外，由受過訓練的非專業人士（如家庭成員）在醫療保健環境之外進行 LAI（用於治療或預防）可以減輕已識別的障礙並優化現實環境中的有效性。迄今為止，沒有研究檢查過家庭 LAI 管理，儘管該策略已成功用於其他醫療目的。例如，對自行使用肌肉注射荷爾蒙避孕藥的研究顯示，家庭給藥是可行的，降低了醫療保健成本，並提高了患者的滿意度。由社區組織（如住房和社會服務機構）的非專業人士進行給藥，也可能提供一種替代策略，可以幫助減輕影響最弱勢群體的社會結構問題，包括交通、安全、污名和歧視。 COVID-19 大流行凸顯了透過社區組織建立有效的社區夥伴關係，如何能夠建立信任並改善醫療保健參與，特別是在可能對醫療機構猶豫或不信任的少數族裔社區。
到目前為止，這些照護模式還無法用於 HIV 治療或預防上。然而，新一代抗反轉錄病毒藥物的安全性和有效性特徵，包括 cabotegravir 加上 rilpivirine 以及 cabotegravir 用於暴露前預防 (PrEP)，使其成為非醫療保健環境中的候選藥物。有先例和數據支持在社區環境中提供愛滋病毒照護的好處。在一項基於社區的 HIV 治療模型的薈萃分析中，護士和非專業衛生工作者在傳統醫療保健環境之外提供抗反轉錄病毒治療，與 HIV 感染者的吸收、存留和病毒抑制上之改善有關。目前在這些模型中對於 LAI 交付上的適用性應積極去探索。可能阻礙創新的監管障礙，包括有關圍繞在將孕婦和青少年納入藥物開發試驗的法規以及由誰可以使用 LAI 藥物上的限制（即目前僅由醫療保健提供者給予），也需要重新考慮。
需要研究去評估靈活的 LAI 交付策略，以支持公平地擴大這些有希望的方案對關鍵人群的影響。有關實施上的重要問題；如 LAI cabotegravir 加 rilpivirine 在病毒未抑制個體上的有效性、處方、保險範圍以及仿單外藥物的提供，還有患者的監測等仍未得到答復。對 LAI 實施一刀切的方法並不是一種有效的公共衛生策略，響應不同人群需求的適應性介入措施至關重要。充分代表種族、族裔和性別少數群體，以及在未來試驗中的其他弱勢群體，如青年、年輕人、孕婦、沒有穩定住房者以及藥癮者或有心理健康挑戰等人，確定該人群–特定的障礙至關重要，並能確保廣泛地獲得有前途的技術。隨著全球範圍內對 LAI 的批准越來越多，我們必須關注全球公平和可及性，以實現終結 HIV 的目標。有必要進一步探索用於 HIV 治療的 LAI 交付模式與預防模式有何不同。在我們準備擴大 LAI 的可用性時，迫切需要與患者和利益相關者參與合作，以評估一系列可以提高公平獲取、增加患者使用這些新技術的意願，並能最大限度地提高公共衛生影響的交付策略。
*J Carlo Hojilla, Monica Gandhi, Derek D Satre, Mallory O Johnson, Parya Saberi carlo.hojilla @ alumni.ucsf.edu
（JCH，DDS）威爾神經科學研究所，精神病學和行為科學系，
(MG)愛滋病毒科、傳染病和全球醫學部，和(MOJ, PS)預防科學部，加利福尼亞州立大學醫學系，美國加州舊金山；
(JCH, DDS)北加州Kaiser Permanente 研究部，美國加州奧克蘭， 94612
www.thelancet.com/hiv Vol 9, 2022 年 3 月
Equity in access to long-acting injectables in the USA
Cabotegravir, an integrase strand transfer inhibitor, and rilpivirine, a non-nucleoside reverse transcriptase inhibitor, recently received regulatory approval in the Canada, the EU, and the USA as a monthly intramuscular long-acting injectable (LAI) antiretroviral therapy regimen in adults with HIV-1 who are virologically suppressed and have no history of treatment failure. Injectable cabotegravir administered every 2 months also recently received US regulatory approval as preexposure prophylaxis (PrEP). Other LAI treatment and prevention formulations are in development.
These new technologies eliminate the need for daily pill taking and have the potential to change the current state of the HIV epidemic substantially. LAIs could lead to new strategies to engage with patients, especially with those who face challenges to daily oral medication adherence and retention in care. However, LAIs also have the potential to exacerbate existing health inequities if flexible models of delivery are not developed for key populations. In the USA, African American and Latinx men who have sex with men, transgender women, youth, and young adults face a disproportionate HIV burden, but are more likely to experience gaps in HIV prevention and care. As LAI regimens are rolled out, several challenges to implementation require urgent attention to ensure equitable access for these key populations.
The stringent inclusion criteria for the registration trials for LAI cabotegravir plus rilpivirine (ATLAS1 and FLAIR) required participants to have at least 4 months of virological suppression on oral ART and 4 weeks of oral cabotegravir and oral rilpivirine before starting the monthly LAI regimen (although a separate study showed that direct-to-inject without an oral lead-in was safe). The current drug label requires monthly injections administered by health-care providers and uses the same criteria used in the registration trials (ie, virological suppression on oral treatment and an oral lead-in requiring high adherence due to rilpivirine’s low genetic barrier to resistance). These requirements will drive the public health response and pose critical challenges to effective and equitable LAI delivery. Inflexible adherence to these requirements will particularly affect people struggling with individual, social, and structural barriers, as well as HIV and primary care clinics strained by inadequate staffing and resources. Patients report that frequent clinic visits for LAIs could worsen HIV stigma and stigmatisation, increase the risk of unwanted disclosures, and lead to increased costs from copays and travel. Frequent clinic visits might also be prohibitive for people who are unable to miss work or for those without transportation. Similarly, clinicians have expressed concerns that the number and frequency of injection clinic visits could overwhelm staffing and other clinic resources. Data from an implementation study suggest that, on average, each visit for injection of cabotegravir plus rilpivirine lasted about 32 minutes (excluding travel time to and from the clinic), which might not be feasible for many clinics on a larger scale.
Since cabotegravir with rilpivirine has now received US regulatory approval, clinicians can, with close monitoring, provide the agents to select patients who are not virologically suppressed and without an oral lead-in. Additionally, administration of LAIs (for treatment or prevention) by trained laypeople (such as family members) outside health-care settings could mitigate the identified barriers and optimise effectiveness in real-world settings. To date, no study has examined home LAI administration, although this strategy has been used successfully for other medical purposes. For example, studies of self-administered intramuscular hormonal contraceptives have shown that home administration was feasible, lowered healthcare costs, and resulted in greater patient satisfaction. Administration by laypeople in community-based organisations, such as housing and social service agencies, might also provide an alternative strategy that could help mitigate the social structural issues affecting the most vulnerable, including transportation, safety, stigma, and discrimination. The COVID-19 pandemic has underscored how effective community partnerships through community-based organisations can build trust and improve health-care engagement, particularly in minority communities that might be hesitant or distrustful of medical institutions.
Until now, these models of care have not been possible for HIV treatment or prevention. However, the safety and efficacy profiles of newer generation antiretrovirals, including cabotegravir with rilpivirine and cabotegravir for PrEP, make them candidates for delivery in non-health-care settings. There is precedent for and data to support the benefits of providing HIV care in community settings. In a meta-analysis of community-based HIV treatment models, provision of antiretroviral therapy by nurses and lay health workers outside of traditional health-care settings was associated with improved uptake, retention, and viral suppression in people living with HIV. The suitability of these models to LAI delivery should now be actively explored. Regulatory barriers that can impede innovation, including regulations around the inclusion of pregnant people and youth in drug-development trials and limitations on who can administer LAI medications (ie, currently, only administered by a health-care provider), also require reconsideration.
Research evaluating flexible LAI delivery strategies is needed to support equitable scale-up of these promising regimens for key populations. Important questions around implementation; the effectiveness of LAI cabotegravir plus rilpivirine in non-suppressed individuals; prescribing, insurance coverage, and dispensation of an off-label medication; and patient monitoring remain unanswered. A one-size-fits-all approach to LAI delivery is not an effective public health strategy, and adaptive interventions that are responsive to the needs of different populations are crucial. Adequate representation of racial, ethnic, and gender minorities, as well as other vulnerable groups such as youth, young adults, pregnant people, those without stable housing, and those who use drugs or have mental health challenges in future trials is essential to identify population-specific barriers and to ensure broad access to promising technologies. With increased approval of LAIs worldwide, it is imperative that we focus on global equity and access to achieve the goal of ending HIV. Future exploration of how models of LAI delivery for HIV treatment can differ from prevention is warranted. As we prepare to broaden the availability of LAIs, there is an urgent need to engage with patients and stakeholders to evaluate a range of delivery strategies that can enhance equitable access, increase patient willingness to use these new technologies, and maximise public health impact.
*J Carlo Hojilla, Monica Gandhi, Derek D Satre, Mallory O Johnson, Parya Saberi carlo.hojilla@alumni.ucsf.edu
Weill Institute for Neurosciences, Department of Psychiatry and Behavioral Sciences (JCH, DDS),
Division of HIV, Infectious Diseases, and Global Medicine (MG), and Division of Prevention Science (MOJ, PS), Department of Medicine, University of California, San Francisco, CA, USA; Division of Research, Kaiser Permanente Northern California, Oakland 94612, CA, USA (JCH, DDS)
www.thelancet.com/hiv Vol 9 March 2022