Safety, adherence, and HIV-1 seroconversion among women using the dapivirine vaginal ring (DREAM): an open-label, extension study
Safety, adherence, and HIV-1 seroconversion among women using the dapivirine vaginal ring (DREAM): an open-label, extension study
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DOI：
10.1016/s2352-3018(20)30300-3
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发表时间：
2021-02-01
期刊：
影响因子：
16.1
通讯作者：
Rosenberg, Zeda
中科院分区：
文献类型：
--
作者：
Nel, Annalene;van Niekerk, Neliette;Rosenberg, Zeda
Ring研究是一项在1959名性活跃女性中进行的III期试验（随机化2：1），与安慰剂环相比，含有25 mg dapivirine的阴道环显示出有利的安全性特征和31%的HIV-1感染风险降低。我们在这里报告的梦想研究，其目的是评估安全性，坚持，和HIV-1的发病率在那些使用dapivirine阴道环（DVR）在开放标签use.Methods的梦想研究是一个开放标签的扩展环研究，在南非的五个研究中心和乌干达的一个研究中心。The Ring研究的前参与者，如果艾滋病毒呈阴性，并且没有因被认为与研究产品相关的不良事件或安全问题而停止研究，则符合资格。在DREAM筛查时怀孕、计划怀孕或哺乳的女性被排除在外。所有受试者在入组访视时均接受DVR植入。参与者参加了1个月的随访访视，可以每3个月进行一次访视，也可以参加每月一次的访视，直至第3个月，然后继续每3个月进行一次访视。在每次访视时，进行HIV检测和安全性评价，并测量使用过的环中的残留达匹韦林（持续使用28天后，DVR释放约4 mg）。将HIV-1发病率与模拟发病率进行了连续比较，模拟发病率是从环形研究安慰剂组受试者的Bootstrap抽样中获得的，与研究中心、年龄和入组时存在性传播感染相匹配。该研究在ClinicalTrials.gov注册，NCT 02862171。结果在2016年7月12日至2019年1月11日期间，筛选了1034名来自The Ring Study的前参与者，941人入组，848人完成了试验。941名参与者中有616名（65.5%）报告了治疗后出现的不良事件。其中，6例（0.6%）事件被认为与治疗相关。未报告治疗相关严重不良事件。两项试验中参与者每月环残留量的测量结果显示，DREAM的平均值始终低于环研究。入组DREAM的The Ring Study DVR组参与者的算术平均环残留量比The Ring Study中这些参与者的平均环残留量低0.25 mg（95% CI 0.03-0.47; p=0.027）。18（1.9%）在DVR使用期间确认HIV-1感染，导致发病率为1.8（95%CI 1.1-2.6）每100人-年，比模拟安慰剂率低62%。解释虽然疗效估计受到缺乏安慰剂组的限制，在DREAM中观察到的低HIV-1发病率和改善的依从性支持了这样的假设，即当妇女知道DVR的已证实的安全性和有效性时，由于改善的依从性而发生功效增加。显示了每3个月一次访视计划的可行性，表明DVR可用于常规临床实践中的真实情况。版权所有（C）2021作者。爱思唯尔有限公司出版
Background The Ring Study, a phase 3 trial in 1959 sexually active women (randomised 2:1), showed a favourable safety profile and a 31% HIV-1 infection risk reduction for a vaginal ring containing 25 mg of dapivirine, compared with a placebo ring. We report here the DREAM study, which aimed to evaluate safety, adherence, and HIV-1 incidence in those using the dapivirine vaginal ring (DVR) in open-label use.Methods The DREAM study is an open-label extension of The Ring Study, done at five research centres in South Africa and one research centre in Uganda. Former participants from The Ring Study, who remained HIV-negative and who did not discontinue the study due to an adverse event or safety concern that was considered to be related to the investigational product, were eligible. Women who were pregnant, planning to become pregnant, or breastfeeding at screening for DREAM were excluded. All participants received the DVR for insertion at the enrolment visit. Participants attended a 1-month follow-up visit and could either proceed with visits once every 3 months or attend monthly visits up to month 3 and then continue with visits once every 3 months. At each visit, HIV testing and safety evaluations were done, and residual dapivirine measured in used rings (approximately 4 mg is released from the DVR over 28 days of consistent use). HIV-1 incidence was compared descriptively with the simulated incidence rate obtained from bootstrap sampling of participants in the placebo group of The Ring Study, matched for research centre, age, and presence of sexually transmitted infections at enrolment. This study is registered with ClinicalTrials.gov, NCT02862171.Findings Between July 12, 2016, and Jan 11, 2019, 1034 former participants from The Ring Study were screened, 941 were enrolled and 848 completed the trial. 616 (65.5%) of 941 participants reported treatment-emergent adverse events. Of these, six (0.6%) had events considered to be treatment-related. No treatment-related serious adverse events were reported. Measurements of monthly ring residual amounts in participants enrolled in both trials showed consistently lower mean values in DREAM than in The Ring Study. Arithmetic mean ring residual amounts of participants in The Ring Study DVR group who enrolled in DREAM were 0.25 mg lower (95% CI 0.03-0.47; p=0.027) than the mean ring residual amounts of these participants in The Ring Study. 18 (1.9%) HIV-1 infections were confirmed during DVR use, resulting in an incidence of 1.8 (95% CI 1.1-2.6) per 100 person-years, 62% lower than the simulated placebo rate.Interpretation Although efficacy estimation is limited by the absence of a placebo group, the observed low HIV-1 incidence and improved adherence observed in DREAM support the hypothesis that increased efficacy due to improved adherence occurs when women know the demonstrated safety and efficacy of the DVR. The feasibility of a visit schedule of once every 3 months was shown, indicating that the DVR can be used in a real-world situation in usual clinical practice. Copyright (C) 2021 The Author(s). Published by Elsevier Ltd.