From the Medical Research Council Clinical Trials Unit at University College London, London (N.I.P., A.H., J.B., J.T., A.S.W.); Yong Loo Lin School of Medicine, National University of Singapore, Singapore (N.I.P.); Joint Clinical Research Centre (JCRC) (C.K., D.T., P.M.), Infectious Diseases Institute (A.K., I.M., P.J.E.), and St. Francis of Nsambya Hospital (R.M.), Kampala, JCRC, Mbarara (A.L.), JCRC, Fort Portal (M.K.), JCRC, Mbale (M.A.), JCRC, Gulu (G.A.), JCRC, Kabale (H.A.), and JCRC, Kakira (D.A.) - all in Uganda; University of Zimbabwe Clinical Research Centre, Harare (A.R., E.C., J.H.); Malawi-Liverpool-Wellcome Trust Clinical Research Programme, University of Malawi College of Medicine, Blantyre (J.J.O.), Dignitas International, Zomba (J.J.O.), and Mzuzu Central Hospital, Mzuzu (R.N.) - all in Malawi; Moi University School of Medicine, Eldoret, Kenya (A.S.); University Teaching Hospital, Lusaka, Zambia (A.M.); and Hospital La Paz, Madrid (J.R.A.).
N Engl J Med. 2014 Jul 17;371(3):234-47. doi: 10.1056/NEJMoa1311274.
The efficacy and toxic effects of nucleoside reverse-transcriptase inhibitors (NRTIs) are uncertain when these agents are used with a protease inhibitor in second-line therapy for human immunodeficiency virus (HIV) infection in resource-limited settings. Removing the NRTIs or replacing them with raltegravir may provide a benefit.
In this open-label trial in sub-Saharan Africa, we randomly assigned 1277 adults and adolescents with HIV infection and first-line treatment failure to receive a ritonavir-boosted protease inhibitor (lopinavir-ritonavir) plus clinician-selected NRTIs (NRTI group, 426 patients), a protease inhibitor plus raltegravir in a superiority comparison (raltegravir group, 433 patients), or protease-inhibitor monotherapy after 12 weeks of induction therapy with raltegravir in a noninferiority comparison (monotherapy group, 418 patients). The primary composite end point, good HIV disease control, was defined as survival with no new World Health Organization stage 4 events, a CD4+ count of more than 250 cells per cubic millimeter, and a viral load of less than 10,000 copies per milliliter or 10,000 copies or more with no protease resistance mutations at week 96 and was analyzed with the use of imputation of data (≤4%).
Good HIV disease control was achieved in 60% of the patients (mean, 255 patients) in the NRTI group, 64% of the patients (mean, 277) in the raltegravir group (P=0.21 for the comparison with the NRTI group; superiority of raltegravir not shown), and 55% of the patients (mean, 232) in the monotherapy group (noninferiority of monotherapy not shown, based on a 10-percentage-point margin). There was no significant difference in rates of grade 3 or 4 adverse events among the three groups (P=0.82). The viral load was less than 400 copies per milliliter in 86% of patients in the NRTI group, 86% in the raltegravir group (P=0.97), and 61% in the monotherapy group (P<0.001).
When given with a protease inhibitor in second-line therapy, NRTIs retained substantial virologic activity without evidence of increased toxicity, and there was no advantage to replacing them with raltegravir. Virologic control was inferior with protease-inhibitor monotherapy. (Funded by European and Developing Countries Clinical Trials Partnership and others; EARNEST Current Controlled Trials number, ISRCTN37737787, and ClinicalTrials.gov number, NCT00988039.).
在资源有限的情况下，核苷类逆转录酶抑制剂（NRTIs）与蛋白酶抑制剂联合用于二线治疗人类免疫缺陷病毒（HIV）感染时，其疗效和毒副作用尚不确定。停用 NRTIs 或用拉替拉韦替代可能会带来益处。
在这项在撒哈拉以南非洲进行的开放性标签试验中，我们将 1277 名 HIV 感染且一线治疗失败的成人和青少年随机分配至接受利托那韦增强型蛋白酶抑制剂（洛匹那韦-利托那韦）加临床医生选择的 NRTIs 的治疗（NRTI 组，426 例）、接受蛋白酶抑制剂加拉替拉韦的治疗（头对头比较组，433 例），或接受拉替拉韦诱导治疗 12 周后进行蛋白酶抑制剂单药治疗（非劣效性比较组，418 例）。主要复合终点为良好的 HIV 疾病控制，定义为无新发世界卫生组织（WHO）第 4 阶段事件、CD4+计数超过 250 个细胞/立方毫米以及病毒载量＜10000 拷贝/ml 或病毒载量≥10000 拷贝/ml 但无蛋白酶耐药突变的存活，采用数据插补（≤4%）进行分析。
NRTI 组 60%（426 例中有 255 例）、拉替拉韦组 64%（433 例中有 277 例）（与 NRTI 组相比，P=0.21；未显示拉替拉韦的优势）和单药治疗组 55%（418 例中有 232 例）的患者达到良好的 HIV 疾病控制（单药治疗未显示非劣效性，基于 10 个百分点的边界）。三组患者的 3 级或 4 级不良事件发生率无显著差异（P=0.82）。NRTI 组 86%（426 例中有 366 例）、拉替拉韦组 86%（433 例中有 374 例）（P=0.97）和单药治疗组 61%（418 例中有 255 例）的患者病毒载量＜400 拷贝/ml（P＜0.001）。
在二线治疗中与蛋白酶抑制剂联合使用时，NRTIs 仍具有显著的病毒学活性，且无毒性增加的证据，用拉替拉韦替代 NRTIs 没有优势。蛋白酶抑制剂单药治疗的病毒学控制较差。（由欧洲和发展中国家临床试验合作组织和其他组织资助；EARNEST 正在进行的对照试验编号，ISRCTN37737787，和 ClinicalTrials.gov 编号，NCT00988039。）
