臺灣首次接受愛滋病毒感染治療者使用第一線推薦處方結果分析：著重dolutegravir使用結果

Abstract

背景 自2016年起，臺灣疾病管制署將含efavirenz（EFV）、rilpivirine（RPV）、或dolutegravir（DTG）的三合一複方列為愛滋病毒感染治療之第一線推薦處方。在政府公費提供每日一次一顆複方藥物的情況下，藥物顆數（pill burden）下降，因此藥物耐受性與交互作用對病人服藥順從性及後續治療結果的影響將更為重要。 2015年在臺灣上市的DTG為愛滋病毒嵌合酶抑制劑，相較於臨床試驗中展現的高效能與極佳耐受性，許多上市後觀察性研究呈現不一致的安全性結果，部分研究顯示其神經-精神相關副作用導致的停藥比例遠比預期高。

研究目的 針對臺灣首次接受愛滋病毒感染治療者，分析使用第一線推薦處方之耐受性與藥物交互作用；並深入探討DTG於臺灣核可上市後之臨床療效與安全性。

研究方法 本研究為回溯性病歷回顧，於2016年10月至2018年4月間一所大學附設醫院收納首次接受愛滋病毒感染治療之成年病人，從開始接受抗愛滋病毒藥物治療到首次處方停止使用、滿一年使用或研究期間結束，蒐集基本資料、免疫與病毒學檢驗資料及臨床資料。主要研究指標為首次使用第一線推薦處方時，因不良反應導致之停藥，以及含DTG處方之病毒學療效與安全性。其他指標包括第一線推薦處方與併用藥間交互作用情形。以發生率來呈現比較第一線推薦處方之耐受性，不良反應與藥物之相關性利用Naranjo scale評估，含DTG處方病毒學療效則參考FDA Snapshot流程歸類，藥物交互作用偵測使用Liverpool HIV drug interaction checker。

研究結果 在19個月的研究期間共收納163名首次接受抗愛滋病毒感染治療者，絕大部分（98%）為男性，平均年齡約32 ± 8歲，用藥前平均CD4數量約363 ± 252 cells/mm3。超過一半之病人（54%）首次處方含DTG；而使用含RPV處方病人（19%），有最高之用藥前CD4數量與最低之病毒量。 總共124追蹤人年（PYFU）中，每100追蹤人年因藥物不良反應而停藥之發生率於含EFV、RPV、DTG處方分別為：34.6、4.2、7.0 （P=0.0032）；事後分析顯示含EFV與DTG處方間耐受性達統計顯著差異（P=0.0033）。因為藥物不良反應而停藥之中位發生時間為32天（IQR 15-194），三者無統計顯著差異。過敏（5.5%）為最常導致停藥之不良反應，神經-精神相關（4.9%）次之，並均以含EFV處方最常見（過敏13.6%、神經-精神相關11.4%）；共五名（5.7%）使用含DTG處方病人曾因藥物不良反應而停藥，以神經-精神相關最多（3/88，3.4%），腸胃道相關次之（2/88，2.3%）。 潛在藥物交互作用於含EFV、RPV、DTG處方發生比例分別為43%、27%、16%。主要為EFV組與鎮靜安眠類藥物間（32%）、DTG組與含多價陽離子制酸劑、胃乳等（26%）；RPV組與制酸劑交互作用發生比例約3%。 在使用含DTG處方並至少有一次用藥後病毒量資料者，病毒學抑制失敗（定義為第七、十二個月血漿HIV病毒量分別大於200、50 copies/mL）各為4.7% （4/85）、10.6%（5/47）。在第七、十二個月仍持續使用含DTG處方者，病毒學抑制失敗分別為1%（1/77）、8%（3/39）。追蹤期間最常發生之含DTG處方相關不良反應為神經-精神（42%）與腸胃道系統（41%）相關不良反應。

結論 本研究顯示三種第一線推薦處方於臺灣首次接受愛滋病毒感染治療者之耐受性有顯著差異，接受含EFV處方者因藥物不良反應而停藥之發生率最高。藥物交互作用多發生於EFV與鎮靜安眠類藥物，以及DTG與含多價陽離子制酸劑、胃乳間。含DTG處方具臨床療效，然而長期病毒是否成功抑制需要定期監測與探討。使用含DTG處方的病人最常發生之不良反應為神經-精神與腸胃道系統如失眠、睡眠障礙、噁心、腹部不適等，但絕大部分病人能耐受。本研究為單一醫學中心研究，受限於樣本數與追蹤時間，第一線推薦處方與含DTG處方之臨床使用結果尚需更長期、較大規模之研究追蹤。

Background Efavirenz (EFV)-, rilpivirine (RPV)- or dolutegravir (DTG)-based single-tablet regimens have been recommended as first-line antiretroviral therapy (ART) for the treatment of human immunodeficiency virus (HIV) infection by the Taiwan Centers for Disease Control since 2016. With more convenient ART regimens provided by the government and reduced pill burden, the tolerability and drug interactions of each regimen become more crucial for optimizing medication adherence and subsequent clinical outcomes. DTG, approved in Taiwan in 2015, is an HIV integrase strand transfer inhibitor (INSTI) with high virologic efficacy and tolerability demonstrated in clinical trials. However, several observational studies reported inconsistent safety profiles of its use in real-world setting, with some showing unexpected high discontinuation (DC) due to neuropsychiatric adverse drug reaction (ADR).

Objectives This study aimed to assess the tolerability and drug interactions of the first-line ART as well as clinical outcomes of DTG-based regimens in treatment-naïve HIV-positive Taiwanese since its availability for prescription in Taiwan.

Methods We conducted a retrospective medical record review, collecting demographic, immuno-virologic and clinical data of enrolled patients at a university hospital between October 2016 and April 2018. Patients were followed from ART initiation to DC, up to 1 year, or study end date. Primary outcomes included DC due to ADR of the first-line ART, virologic response and safety of DTG-based regimens. Other outcome included drug interactions between ART and concomitant medications. Incidence rate was calculated. Naranjo scale and FDA Snapshot algorithms were utilized for causality assessment of the first-line ART ADR and virologic response evaluation of DTG-based regimens, respectively. Drug interactions between the first-line ART and concomitant medications were examined with Liverpool HIV drug interaction checker.

Results During the 19-month study period, 163 ART-naïve patients starting ART were included. Most of them (98%) were male with a mean age of 32 ± 8 years and baseline CD4 363 ± 252 cells/mm3. More than half (54%) of patients started their first regimen with DTG. Patients on RPV-based regimens (19%) had a higher baseline CD4 cell count and lower plasma HIV RNA load. During the follow-up period, 163 patients contributed to a total of 124 person-years of follow-up (PYFU). Incidence of DC due to ADR per 100 PYFU were 34.6, 4.2 and 7.0 in EFV-, RPV- and DTG-based regimens, respectively (P=0.0032). The post-hoc analysis showed statistically significant difference between EFV- and DTG-based regimens (P=0.0033). Median time to DC due to ADR was 32 days (IQR 15-194), with no statistically significant difference between three regimens. Hypersensitivity (5.5%) was the most common ADR leading to DC followed by neuropsychiatric disorders (4.9%). They occurred most frequently in EFV-based regimens (13.6% and 11.4% respectively). DC due to ADR occurred in 5 patients (5.7%) with DTG-based regimens. Neuropsychiatric and gastrointestinal ADR accounted for 3.4% (3/88) and 2.3% (2/88), respectively. Drug interactions occurred in 43%, 27% and 16% of EFV-, RPV- and DTG-based regimens, respectively. The most frequent interacting medications were sedatives in 32% of EFV group, polyvalent cation containing agents in 26% of DTG group. Interactions between antacids and RPV group occurred in 3%. Virologic nonresponse, defined as plasma HIV RNA ≥200 copies/mL and ≥50 copies/mL at 7th and 12th month in DTG-treated patients with at least one follow-up virologic data, were 4.7% (4/85) and 10.6% (5/47), respectively. In patients continuing the DTG-based regimens at 7th and 12th month, virologic nonresponse rate were 1% (1/77) and 8% (3/39). During the follow-up period, the most prevalent ADR associated with DTG-based regimens were neuropsychiatric (42%) and gastrointestinal (41%).

Conclusions This study demonstrates significantly different tolerability profiles among the three recommended first-line ART in treatment-naïve HIV-positive Taiwanese. Incidence of DC due to ADR was highest in patients on EFV-based regimens. Drug interactions occurred mostly between EFV and sedatives as well as DTG and polyvalent cation containing agents. DTG-based regimens were clinically effective; while the long-term virologic suppression requires regular monitoring and assessment. The most frequently occurring ADR in DTG-based regimens were neuropsychiatric and gastrointestinal ADR such as insomnia, sleep disturbance, nausea and abdominal discomforts; while most of them were tolerable. This is a single-center study with relatively limited numbers of subjects and short follow-up period. Outcomes related to the first-line ART as well as DTG-based regimens warrant a larger study of a longer observation duration.