長效型抗反轉錄病毒藥物的使用與耐藥性
資料來源： www.thelancet.com/hiv 2022 年 6 月 9 日 e375；財團法人台灣紅絲帶基金會編譯
2021 年，長效 cabotegravir 加 rilpivirine 作為首個長效型抗反轉錄病毒療法 (ART) 獲得批准，鑑於其有可能解決與每日攝入藥丸相關的污名和其他挑戰，因此引發了對服藥順從性具挑戰性患者使用的熱情。有幾個因素可能會阻止長效cabotegravir 加 rilpivirine在資源匱乏環境中的實施，例如冷鏈的需求、長效cabotegravir 加 rilpivirine對Ｂ型肝炎無活性、以及每月或每 2 個月給藥一次的要求；這些都與允許患者每 6 個月就診一次的差異化服務所提供模式相衝突。然而，在撒哈拉以南非洲實施長效cabotegravir 加 rilpivirine的最大挑戰，還涉及其面對廣泛的非核苷酸反轉錄酶抑製劑 (NNRTI) 在療效上的耐藥性。
由於rilpivirine耐藥突變的出現，加上基準線上 HIV-1 之A6/A1亞型或是身體質量指數 (BMI) 為 30kg/m2 或更高，是長效cabotegravir 加 rilpivirine在病毒學上失敗的預測因素。由撒哈拉以南非洲國家來自全國代表性的監測數據之調查顯示，治療前rilpivirine耐藥的發生率為 12.0% (95% CI 9.7–14.5)。在 C 亞型占主導地位的南部非洲，盛行率上升至 15.0（12.0–18.1）。事實上，rilpivirine耐藥性與 HIV之 C 亞型相關（C 亞型個體與其他亞型個體相比為13.7%比6.8%；p=0·046）。值得注意的是，這些值甚至高於導致 WHO 重新考慮基於 NNRTI 方案作為 HIV 初始治療的值。隨著愛滋病毒計畫的成熟，越來越多的人將會透過抗反轉錄病毒療法、預防母嬰傳播或透過接觸後預防投藥等方式接觸過非核苷酸反轉錄酶抑製劑 (NNRTI) ，從而增加對rilpivirine產生耐藥性的風險人群。此外，根據南非和烏干達的研究數據，對一線治療無反應之患者的耐藥率（45%）明顯高於開始使用抗反轉錄病毒藥物的患者。
在 FLAIR5 和 ATLAS6 等研究中，耐藥性測試用於排除對rilpivirine耐藥的參與者，因此，這些試驗的數據可能無法推廣到撒哈拉以南非洲。當存在賦予rilpivirine耐藥性的突變的情況下，cabotegravir 可能仍然是唯一具活性的藥物。儘管 NADIA7 研究證明基於 dolutegravir 的方案，儘管對核苷酸反轉錄酶抑製劑 (NRTI) 骨幹有耐藥性，但仍保持活性，但這尚未在非核苷酸反轉錄酶抑製劑 (NNRTI) 或兩種藥物方案中得到證實。 rilpivirine 耐藥性的高盛行率和缺乏常規耐藥性測試等狀況之結合，對常規使用 cabotegravir 加 rilpivirine 作為初始治療提出了重大挑戰。
同樣，耐藥狀態可能在確定對tenofovir, lamivudine, 和 dolutegravir聯合治療無反應的患者轉換為長效cabotegravir 加 rilpivirine的安全性方面發揮作用。儘管臨床試驗數據顯示出現對dolutegravir的耐藥性並不常見，但 NADIA 試驗中的 14 名個體中有 4 名在病毒學失敗時對dolutegravir產生耐藥性，並且dolutegravir和cabotegravir之間存在交叉耐藥性的可能性。 LATITUDE 試驗正在進行評估長效型 cabotegravir 加 rilpivirine 用於病毒沒有被抑制的患者，但像 FLAIR 和 ATLAS 研究，在收案前針對rilpivirine 和 cabitegravir 的突變篩查是納入研究對象之標準。
為了證明採用長效 cabotegravir 加 rilpivirine作為tenofovir, lamivudine, 和 dolutegravir聯合治療的替代方案之合理性，包括減少治療中斷和避完口服治療上相關的污名化等明顯的益處，必須能夠抵銷rilpivirine記錄中耐藥相關的理論擔憂。與tenofovir, lamivudine, 和 dolutegravir聯合用藥相比，長效cabotegravir 加 rilpivirine還需要證明在存留於照護、給藥方便、長期病毒學抑制、安全性和成本效益等方面上具有顯著優勢。
因此，需要針對耐藥性、Ｂ型肝炎合併感染和冷鏈上的限制以及新興的dolutegravir耐藥性監測等進行實施上之研究。鑑於新藥類別中的衣殼（病毒蛋白質外殼）抑製劑和核苷酸反轉錄酶易位抑製劑（NRTTI， 是一種腺苷類似物，既可作為反轉錄酶鏈終止劑，又可防止 DNA 易位）等長效型製劑在耐藥循環方面的優勢，也應進行評估。儘管長效注射型療法是實現聯合國愛滋病規劃署第三個 95 目標策略一個有希望的部分，但採用這些療法需要仔細注意它們在實踐中的可行性、有效性和可持續性。
*Juliana da Silva、Mark Siedner、Suzanne McCluskey、Nomathemba Chandiwana、Francois Venter、Elliot Raizes lxi7@cdc.gov
美國喬治亞州亞特蘭大 30329 疾病控制和預防中心全球健康中心全球愛滋病毒和結核病部門（JdS，ER）；美國麻薩諸塞州波士頓哈佛醫學院醫學系（MS）； Ezintsha，南非約翰尼斯堡，威特沃特斯蘭德大學，健康科學學院（SM、NC、FV）
Drug resistance and use of long-acting ART
www.thelancet.com/hiv Vol 9 June 2022 e375
The approval, in 2021, of long-acting cabotegravir plus rilpivirine as the first long-term antiretroviral therapy (ART) has engendered enthusiasm for its use among patients with adherence challenges, given its potential to address stigma and other challenges associated with daily pill intake. Several factors could prevent the implementation of long-acting cabotegravir plus rilpivirine in resource-poor settings, such as cold chain requirement; inactivity of long-acting cabotegravir plus rilpivirine against hepatitis B; and the requirement for dosing once a month or every 2 months, which conflicts with differentiated service delivery models that allow patients to attend clinics every 6 months. However, the greatest challenge to implementation of long-acting cabotegravir plus rilpivirine in sub-Saharan Africa involves its efficacy in the face of widespread nonnucleoside reverse-transcriptase inhibitor resistance (NNRTI).
The presence of rilpivirine drug resistance mutations, in addition to baseline HIV-1 subtype A6/A1 or body mass index of 30kg/m2 or higher, was a predictor of virological failure with long-acting cabotegravir plus rilpivirine. Surveillance data from nationally representative surveys in countries in sub-Saharan Africa demonstrated a prevalence of 12·0% (95% CI 9·7–14·5) of pretreatment rilpivirine resistance. In southern Africa, where subtype C is predominant, the prevalence rises to 15·0 (12·0–18·1; appendix p 1). In fact, rilpivirine drug resistance was associated with HIV subtype C (13·7% of individuals with subtype C compared with 6·8% of individuals with other subtypes; p=0·046). Notably, these values are higher than those that led WHO to reconsider NNRTI based regimens as initial treatment for HIV. As HIV programmes matures, a growing number of individuals will have had previous exposure to NNRTIs through ART, prevention of mother to child transmission, or through post-exposure prophylaxis, thereby increasing the pool of individuals at risk for resistance to rilpivirine. Furthermore, the prevalence of resistance is substantially higher (45%) in patients not responding to first-line treatment than in patients initiating antiretroviral drugs, according to data in studies from South Africa and Uganda.
Drug resistance testing was used to exclude participants with rilpivirine resistance in the FLAIR5 and ATLAS6 studies, therefore, data from these trials might not be generalisable to sub-Saharan Africa. In the presence of mutations that confer rilpivirine resistance, cabotegravir could remain the sole active drug. Although NADIA7 demonstrated that dolutegravir-based regimens retain activity despite resistance to an NRTI backbone, this has yet to be demonstrated for NNRTIs, or in two drug regimens. The combination of a high prevalence of rilpivirine resistance and a scarcity of routine drug resistance testing poses a major challenge to routine use of cabotegravir plus rilpivirine as an initial therapy.
Similarly, resistance profiles could play a role in determining the safety of switching patients to cabotegravir plus rilpivirine who are not responding to combined tenofovir, lamivudine, and dolutegravir. Although clinical trial data suggest emergence of drug resistance to dolutegravir is uncommon, four of 14 individuals in the NADIA trial had resistance to dolutegravir at time of virological failure, and there is a potential for cross-resistance between dolutegravir and cabotegravir. The LATITUDE trial is underway to evaluate long-acting cabotegravir plus rilpivirine for patients who are not virally suppressed, but like FLAIR and ATLAS, pre-enrolment screening for rilpivirine and cabitegravir mutations is an inclusion criteria.
To justify the adoption of long-acting cabotegravir plus rilpivirine as an alternative regimen to combined tenofovir, lamivudine, and dolutegravir, clear benefits, including reductions in treatment interruptions and stigmatisation associated with oral therapy use, must be counterbalanced by theoretical concerns related to archived resistance to rilpivirine. Longacting cabotegravir plus rilpivirine would also need to demonstrate substantial benefit in terms of retention in care, dosing convenience, long-term virological suppression, safety, and cost-effectiveness in comparison to combined tenofovir, lamivudine, and dolutegravir.
Implementation studies addressing drug resistance, hepatitis B coinfection, and cold-chain limitations, along with emerging dolutegravir resistance surveillance, are therefore needed. Long-acting formulations of new drug classes, such as capsid inhibitors and nucleoside reverse transcriptase translocation inhibitors, should also be evaluated given their advantages in terms of circulating drug resistance. Whereas long-acting injectable therapies are a promising part of the strategies to achieve the third 95 UNAIDS goal, the adoption of these therapies will require careful attention to their feasibility, effectiveness, and sustainability in practice.
*Juliana da Silva, Mark Siedner, Suzanne McCluskey, Nomathemba Chandiwana, Francois Venter, Elliot Raizes lxi7@cdc.gov
Division of Global HIV & Tuberculosis, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, GA 30329, USA (JdS, ER); Department of Medicine, Harvard Medical School, Boston, MA, USA (MS); Ezintsha, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa (SM, NC, FV)