Early versus delayed initiation of highly active antiretroviral therapy for HIV-positive adults with newly diagnosed pulmonary tuberculosis (TB-HAART): a prospective, international, randomised, placebo-controlled trial
Early versus delayed initiation of highly active antiretroviral therapy for HIV-positive adults with newly diagnosed pulmonary tuberculosis (TB-HAART): a prospective, international, randomised, placebo-controlled trial
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DOI：
10.1016/s1473-3099(14)70733-9
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发表时间：
2014-07-01
影响因子：
56.3
通讯作者：
Onyebujoh, Philip
中科院分区：
文献类型：
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作者：
Mfinanga, Sayoki G.;Kirenga, Bruce J.;Onyebujoh, Philip
背景世卫组织指南建议对所有同时感染艾滋病毒的结核病患者及早开始抗逆转录病毒治疗(ART)，而不考虑CD4细胞计数，但支持这一方法的证据质量较低。方法2008年1月1日至2013年4月31日，我们在南非、坦桑尼亚、乌干达和赞比亚的26个治疗中心进行了这项随机、安慰剂对照试验，以评估开始抗逆转录病毒治疗的时机对CD4220个/亩L或更多的HIV阳性患者治疗结果的影响。我们招募了HIV阳性和培养确认的肺结核患者，他们已经耐受了2周的结核病短程化疗。参与者被随机分配(1：1)接受早期ART(在结核病治疗2周后开始)或延迟ART(安慰剂，然后在6个月的结核病治疗结束时开始ART)。随机分组由计算机生成，有8个大小的排列区块，并按CD_4计数分层(L每亩220-349个细胞，L每亩350个细胞)。患者和研究人员被屏蔽进行治疗分配，直到完成6个月的结核病治疗，之后该研究被公开标记。主要终点是在改良的意向治疗人群中，结核病治疗失败、结核病复发和在开始结核病治疗12个月内死亡的复合因素。次要终点包括死亡率。这项研究注册在对照试验网站(ISRCTN77861053)上。结果我们筛选了13588名患者，纳入了1675：834名分配早期ART的患者，841名延迟ART患者。早期ART组767名患者中有65名(8.5%)达到主要终点，而延迟ART组771名患者中有71名(9.2%)达到主要终点(相对风险[RR]0.91，95%可信区间0.64-1.30；p=0.9)。在CD_4细胞数为220~349个/亩的患者中，L，331例患者中有26例(7.9%)达到了主要终点，而342例患者中有33例(9.6%)达到了主要终点(相对危险度0.80，95%可信区间0.46~1.39；p=0.6)。对于L或更多的人，436人中的39人(8.9%)达到了主要终点，而429人中的38人(8.9%)达到了主要终点(RR1.01，95%CI 063-1.62；p=0.4)。治疗组之间的死亡率没有显著差异(RR 1.4，95%可信区间。0.8-2.3；p=0.23)。早期分配的834名患者中有149名(18%)发生了3级和4级的不良事件，而延迟分配的841名患者中有174名(21%)发生了不良反应(p=0.37)。834例中有87例(10%)有免疫重建炎症综合征，841例中有84例(10%)有免疫重建炎症综合征(p=0.56)。对于CD4细胞计数超过220个/亩L的HIV阳性肺结核患者，解释ART可以推迟到6个月结核病治疗结束后再进行，WHO指南应该相应更新。
Background WHO guidelines recommend early initiation of antiretroviral therapy (ART) irrespective of CD4 cell count for all patients with tuberculosis who also have HIV, but evidence supporting this approach is poor quality. We assessed the effect of timing of ART initiation on tuberculosis treatment outcomes for HIV-positive patients with CD4 counts of 220 cells per mu L or more.Methods We did this randomised, placebo-controlled trial between Jan 1, 2008, and April 31, 2013 at 26 treatment centres in South Africa, Tanzania, Uganda, and Zambia. We enrolled HIV-positive patients with culture-confirmed tuberculosis who had tolerated 2 weeks of tuberculosis short course chemotherapy. Participants were randomly allocated (1:1) to early ART (starting after 2 weeks of tuberculosis treatment) or delayed ART (placebo, then starting ART at the end of 6 months of tuberculosis treatment). Randomisation was computer generated, with permuted blocks of size eight, and stratified by CD4 count (220-349 cells per mu L vs >= 350 cells per mu L). Patients and investigators were masked to treatment allocation until completion of 6-months' tuberculosis treatment, after which the study was open label. The primary endpoint was a composite of failure of tuberculosis treatment, tuberculosis recurrence, and death within 12 months of starting tuberculosis treatment in the modified intention-to-treat population. Secondary endpoints included mortality. The study is registered with controlled-trials.com (ISRCTN77861053).Findings We screened 13 588 patients and enrolled 1675: 834 assigned early ART, 841 delayed ART. The primary endpoint was reached by 65 (8.5%) of 767 patients in the early ART group versus 71 (9.2%) of 771 in the delayed ART group (relative risk [RR] 0.91, 95% CI 0.64-1.30; p=0.9). Of patients with a CD4 cell count of 220-349 cells per mu L, 26 (7.9%) of 331 patients versus 33 (9.6%) of 342 reached the primary endpoint (RR 0.80, 95% CI 0.46-1.39; p=0.6). For those with 350 cells per mu L or more, 39 (8.9%) of 436 versus 38 (8.9%) of 429 reached the primary endpoint (RR 1.01, 95% CI 0 63-1.62; p=0.4). Mortality did not differ significantly between treatment groups (RR 1.4, 95% CI. 0.8-2.3; p=0.23). Grade 3 and 4 adverse events occurred in 149 (18%) of 834 patients assigned early ART versus 174 (21%) of 841 assigned delayed ART (p=0.37). 87 (10%) of 834 versus 84 (10%) of 841 had immune reconstitution inflammatory syndrome (p=0.56).Interpretation ART can be delayed until after completion of 6 months of tuberculosis treatment for HIV-positive patients with tuberculosis who have CD4 cell counts greater than 220 cells per mu L. WHO guidelines should be updated accordingly.