NEJM：多替拉韦或达芦那韦联合齐多夫定或替诺福韦治疗HIV感染的比较的析因研究（NADIA研究）

世界卫生组织推荐将多替拉韦联合两种核苷逆转录酶抑制剂（NRTI）用于人类免疫缺陷病毒1型（HIV-1）感染的二线治疗。该治疗方案对于以下情况的疗效证据有限：因耐药而预计NRTI缺乏抗病毒活性时，以及推荐的将NRTI从替诺福韦换成齐多夫定。

方法

在一项2×2析因、开放标签、非劣效性试验中，我们将一线治疗失败（HIV-1病毒载量，≥1000 copies/mL）的患者随机分组，分别接受多替拉韦或利托那韦增强达芦那韦治疗，并且接受替诺福韦或齐多夫定治疗；所有患者均接受了拉米夫定治疗。主要结局是按照美国食品药品管理局快照算法，第48周的病毒载量<400 copies/mL（对于发生主要结局的患者百分比的组间差异，非劣效性界值为12个百分点）。

结果

我们在撒哈拉以南非洲地区的7个研究中心纳入了464例患者。在多替拉韦组90.2%的患者（212/235）和达芦那韦组91.7%的患者（210/229）（差异，-1.5%；95%置信区间[CI]，-6.7~3.7；P=0.58；证明了多替拉韦的非劣效性，但未证明优效性）中，以及在替诺福韦组92.3%的患者（215/233）和齐多夫定组89.6%的患者（207/231）（差异，2.7%；95% CI，-2.6~7.9；P=0.32；证明了替诺福韦的非劣效性，但未证明优效性）中，我们观察到第48周的病毒载量<400 copies/mL。在预计NRTI缺乏抗病毒活性的患者亚组中，我们在多替拉韦组和达芦那韦组90%以上的患者中观察到病毒载量<400 copies/mL。在任何一项析因比较分析中，不良事件发生率均无显著组间差异。

结论

多替拉韦联合NRTI可有效治疗HIV-1感染患者，包括预计NRTI缺乏抗病毒活性的广泛NRTI耐药患者。作为二线治疗，替诺福韦不劣于齐多夫定。（由杨森公司资助；NADIA在ClinicalTrials.gov注册号为NCT03988452。）

In a two-by-two factorial, open-label, noninferiority trial, we randomly assigned patients for whom first-line therapy was failing (HIV-1 viral load, ≥1000 copies per milliliter) to receive dolutegravir or ritonavir-boosted darunavir and to receive tenofovir or zidovudine; all patients received lamivudine. The primary outcome was a week 48 viral load of less than 400 copies per milliliter, assessed with the Food and Drug Administration snapshot algorithm (noninferiority margin for the between-group difference in the percentage of patients with the primary outcome, 12 percentage points).

Result

We enrolled 464 patients at seven sub-Saharan African sites. A week 48 viral load of less than 400 copies per milliliter was observed in 90.2% of the patients in the dolutegravir group (212 of 235) and in 91.7% of those in the darunavir group (210 of 229) (difference, −1.5 percentage points; 95% confidence interval [CI], −6.7 to 3.7; P=0.58; indicating noninferiority of dolutegravir, without superiority) and in 92.3% of the patients in the tenofovir group (215 of 233) and in 89.6% of those in the zidovudine group (207 of 231) (difference, 2.7 percentage points; 95% CI, −2.6 to 7.9; P=0.32; indicating noninferiority of tenofovir, without superiority). In the subgroup of patients with no NRTIs that were predicted to have activity, a viral load of less than 400 copies per milliliter was observed in more than 90% of the patients in the dolutegravir group and the darunavir group. The incidence of adverse events did not differ substantially between the groups in either factorial comparison.

Conclusions