Dolutegravir-based maintenance monotherapy versus dual therapy with lamivudine: a planned 24 week analysis of the DOLAM randomized clinical trial
Dolutegravir-based maintenance monotherapy versus dual therapy with lamivudine: a planned 24 week analysis of the DOLAM randomized clinical trial
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DOI：
10.1093/jac/dky093
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发表时间：
2018-07-01
影响因子：
5.2
通讯作者：
Martinez, Esteban
中科院分区：
文献类型：
--
作者：
Blanco, Jose L.;Rojas, Jhon;Martinez, Esteban
背景：多替拉韦/拉米夫定或多替拉韦维持治疗之间尚未进行对照比较。我们假设这些方案与三联抗逆转录病毒疗法（ART）具有相似的疗效。
方法：我们采用了一项开放标签的非劣效性随机对照试验，包括两个阶段：A阶段旨在测试试验组的失败率不会不可接受（≥5%）；B阶段计划纳入完整数量的患者并随访48周。接受治疗的HIV - 1感染成人，病毒载量＜50拷贝/毫升持续≥12个月，既往无病毒学失败或对研究药物无耐药突变，最低CD4细胞计数≥200个/立方毫米，且乙肝病毒表面抗原阴性，按1∶1∶1的比例随机分配至继续三联疗法（对照组），或转换为多替拉韦/拉米夫定，或转换为多替拉韦单药治疗，并根据基础用药分层。如果因病毒学失败或由于不良事件、并发疾病、方案偏离或患者意愿导致治疗中断，则视为提前停药。记录病毒载量短暂升高情况。在此报告计划的A阶段24周结果。该研究在欧盟临床试验注册中心（EudraCT）注册：201500027435。
结果：91名患者（对照组，n = 31；双联疗法组，n = 29；单药治疗组，n = 31）被随机分组。3名患者（之前均未使用过整合酶抑制剂）因病毒学失败提前停止治疗：多替拉韦/拉米夫定（n = 1），无耐药突变（患者A）；多替拉韦（n = 2），出现N155H、S147G和Q148R耐药突变（患者B），以及E138K、G140S和N155H耐药突变（患者C）。无因其他原因停药的情况。1名患者（多替拉韦/拉米夫定）出现病毒载量短暂升高。数据安全监测委员会建议停止多替拉韦单药治疗组。
结论：与多替拉韦/拉米夫定不同，多替拉韦维持单药治疗出现病毒学失败且产生交叉耐药整合酶突变的风险高于预期。
Background: No controlled comparisons between dolutegravir/lamivudine or dolutegravir maintenance therapy have been done. We hypothesized that these options would have similar efficacy to triple ART.Methods: We used an open-label non-inferiority randomized controlled trial comprising two phases: phase A was established to test that experimental arms did not have an unacceptable (>= 5%) failure rate; phase B was intended to include the full number of patients followed for 48 weeks. Treated HIV-1-infected adults with viral load,50 copies/mL for >= 12months, no prior viral failure or resistance mutations to study drugs, nadir CD4.200 cells/mm(3), and hepatitis B virus surface antigen negative were randomized 1: 1: 1 to maintain triple therapy (control arm), or to switch to dolutegravir/lamivudine, or to dolutegravir monotherapy stratifying by anchor drug. Premature discontinuation was considered if viral failure or therapy interruption due to adverse events, concurrent illness, protocol deviation or patient's wish occurred. Blips were registered. Planned phase A results at 24 weeks are reported here. The study is registered at EudraCT: 201500027435.Results: Ninety-one (control, n = 31; dual therapy, n = 29; monotherapy, n = 31) patients were randomized. Three patients (none previously exposed to integrase inhibitors) prematurely discontinued treatment due to viral failure: dolutegravir/lamivudine (n = 1), no resistance mutations (subject A); dolutegravir (n = 2), N155H, S147G and Q148R resistance mutations (subject B), and E138K, G140S and N155H resistance mutations (subject C). There were no discontinuations for other reasons. One patient (dolutegravir/lamivudine) experienced a blip in viral load. The Data Safety Monitoring Board recommended stopping the dolutegravir monotherapy arm.Conclusions: In contrast to dolutegravir/lamivudine, a higher than expected risk of viral failure with development of cross-resistance integrase mutations occurred with dolutegravir maintenance monotherapy.