Safety and tolerability of injectable Rilpivirine LA in HPTN 076: A phase 2 HIV pre-exposure prophylaxis study in women
Safety and tolerability of injectable Rilpivirine LA in HPTN 076: A phase 2 HIV pre-exposure prophylaxis study in women
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DOI：
10.1016/j.eclinm.2020.100303
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发表时间：
2020-04-01
影响因子：
15.1
通讯作者：
Sista, N. D.
中科院分区：
文献类型：
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作者：
Bekker, L. G.;Li, S.;Sista, N. D.
背景：每日口服 TDF/FTC 用于暴露前预防 (PrEP) 时可预防 HIV 感染。然而，对于许多人来说，每天坚持口服 PrEP 很困难；因此，寻找替代的 PrEP 策略仍然是当务之急。 HPTN 076 评估了长效注射剂利匹韦林 (RPV)（称为 RPV LA）的安全性、药代动力学和可接受性。方法：HPTN 076 (NTC 02165202) 是一项 2 期、双盲、2:1 随机试验，比较 1200mg RPV LA (IA) 与安慰剂 (P) 的安全性。该研究包括为期 28 天的口服磨合期，每日自行口服 RPV（25 毫克），直接观察口服剂量约六次。在 136 名登记的性活跃、未感染艾滋病毒、艾滋病毒风险低的非洲 (100 名) 和美国 (36 名) 成年女性中，在口服磨合阶段后，每八周对 122 名参与者进行两次臀部肌内 (IM) 注射。 48 周内最多发生 6 个注射时间点。在整个研究过程中收集了可接受性、安全性、耐受性和药代动力学（PK）数据。本文包括截至入组后第 52 周收集的主要终点数据。结果：入组人群的中位年龄为 31 岁 (IQR: 25,38)，中位体重 75 公斤 (IQR: 64, 89)，中位体重指数 (BMI) 30 (IQR: 27, 35)，46% 已婚，94% 黑人，60% 失业。共有 122 名女性（80 名 LA，42 名女性）接受了至少一次注射，98 名女性（64 名洛杉矶，34 名女性）接受了全部六次注射。在注射阶段，3 名女性退出研究（2 名 LA，1 名 P），16 名女性停止使用研究产品（10 名 LA，6 名 P）。 14 名女性（11 名 IA 和 3 名 P）停止口服研究产品，并且没有进入注射阶段。研究产品的停药情况自始至终两组之间没有显着差异。在注射阶段停药的产品中，LA 组中的 8% 和 P 组中的 5% 是由于不良事件 (AE)，其中包括 1 例随机分配至 P 组且心电图 QTc 间期延长的患者。在注射阶段经历 2 级或以上 AE 作为主要结局的女性比例在两组之间没有显着差异 [IA 为 73.8%, 95% CI: (63.2%, 82.1%)，IA 为 73.8%, 95% CI: (58.9%, 84.7%), p>0.99]。 LA 组中 14% 的女性发生短暂性 >2 级肝脏异常，而 P 组中这一比例为 12%。三名洛杉矶女性 (4%) 出现 3 级注射部位反应，而 P 组则没有。在至少接受 1 次注射的参与者中，总体 RPV 谷浓度 (Ctrough) 的几何平均值为 62.2 ng/mL。在接受全部六次注射的参与者中，注射阶段和最后一次注射后的 CTrough 几何平均值分别为 72.8 ng/mL 和 100.9 ng/mL。第 52 周（最后一次注射后 8 周），RPV Ctrough 的几何平均值为 75.0 ng/mL。在最后一次注射就诊时（第 44 周），回答可接受性问题的女性中有 80% 强烈同意她们会考虑使用 PrEP，而 68% 的女性肯定会在未来使用 PrEP 注射剂。解释：对于非洲和美国女性，每八周进行一次 RPV LA IM 注射是安全且可接受的。总体而言，尽管接受 RPV LA 的参与者有更多的注射部位反应和疼痛，但注射的耐受性良好。这项研究的数据支持可注射 PrEP 药物的进一步开发。 (C) 2020 年由爱思唯尔有限公司出版。
Background: Daily oral TDF/FTC is protective against HIV infection when used for pre-exposure prophylaxis (PrEP). However, daily adherence to oral PrEP is difficult for many; therefore, finding alternative PrEP strategies remains a priority. HPTN 076 evaluated the long-acting injectable form of rilpivirine (RPV), known as RPV LA for safety, pharmacokinetics and acceptability.Methods: HPTN 076 (NTC 02165202) was a phase 2, double-blind, 2:1 randomized trial comparing the safety of 1200mg RPV LA (IA) to placebo (P). The study included a 28-day oral run-in phase of daily, self- administered oral RPV (25 mg), with directly observed oral dosing about six times. Of 136 enrolled sexually active, HIV-uninfected, low HIV-risk African (100) and US (36) adult women, injectable product was administered in two gluteal, intramuscular (IM) injections once every eight weeks to 122 participants following the oral run-in phase. A maximum of six injection time points occurred over a 48-week period. Acceptability, safety, tolerability and pharmacokinetic (PK) data were collected throughout the study. This paper includes primary endpoint data collected up to the week 52 post enrollment.Findings: The median age of the enrolled population was 31 years (IQR: 25,38), median weight 75 kg (IQR: 64, 89), median body mass index (BMI) 30 (IQR: 27, 35), 46% married, 94% Black and 60% unemployed. A total of 122 (80 LA, 42 P) women received at least one injection and 98 (64 LA, 34 P) received all six injections. During the injection phase, three women withdrew from the study (2 LA, 1 P) and 16 women discontinued study product (10 LA, 6 P). Fourteen women (11 IA and 3 P) discontinued oral study product and did not enter the injection phase. Study product discontinuations were not significantly different between the two arms throughout. Of the product discontinuations in the injection phase, 8% in LA and 5% in P arm were due to adverse events (AEs), including one randomized to the P arm with prolonged QTc interval on EKG. The proportion of women who experienced Grade 2 or higher AEs during the injection phase as the primary outcome was not significantly different between the two arms [73.8%, 95% CI: (63.2%, 82.1%) for IA and 73.8%, 95% CI: (58.9%, 84.7%), p>0.99]. Transient Grade >2 liver abnormalities occurred in 14% of women in the LA arm compared with 12% in P arm. Three LA women (4%) developed Grade 3 injection site reactions compared with none in P arm. In participants who received at least 1 injection, the geometric mean of overall RPV trough concentrations (Ctrough) was 62.2 ng/mL. In participants who received all six injections, the geometric mean of CTrough through the injection phase and after the last injection were 72.8 ng/mL and 100.9 ng/mL, respectively. At week 52 (eight weeks after last injection), the geometric mean of RPV Ctrough was 75.0 ng/mL. At the last injection visit (Week 44), 80 % of women who answered acceptability questions strongly agreed that they would think about using- and 68% that they would definitely use a PrEP injectable in the future.Interpretation: RPV LA IM injections every eight weeks in African and US women were safe and acceptable. Overall, despite more injection site reactions and pain in the participants receiving RPV LA the injections were well tolerated. Data from this study support the further development of injectable PrEP agents. (C) 2020 Published by Elsevier Ltd.