感染HIV婴儿早期限时抗逆转录病毒疗法的临床和免疫学预后较好

感染HIV婴儿早期限时抗逆转录病毒疗法的临床和免疫学预后较好。发表于Lancet最新的研究发现，HIV 感染患儿的早期抗逆转录病毒 (CHER) 试验的中期结果显示，早期抗逆转录病毒疗法 (ART) 可以拯救感染 HIV 的婴儿的生命。 早期限时 ART 的临床及免疫学预后优于延期 ART，无证据表明在后续的治疗中断期间存在过度的疾病进展，且其总体 ART 暴露也少于延期 ART。 较长时间的初步 ART 可实现较长的后续中断期，其预后也略好。 

背景

HIV 感染患儿的早期抗逆转录病毒 (CHER) 试验的中期结果显示，早期抗逆转录病毒疗法 (ART) 可以拯救感染 HIV 的婴儿的生命。

鉴于治疗方案很少以及终身 ART 相关的潜在毒性，在 CHER 试验中，我们对早期限时 ART 与延期 ART 进行了比较。

方法

CHER 是一项开放标签随机对照试验，受试者为在两个南非试验站点感染 HIV 的无症状婴儿，他们均未满 12 周，且 CD4 阳性 T 淋巴细胞百分比 (CD4%) 不低于 25%。

377 名婴儿随机分配入三组之一：延期 ART (ART-Def)、为期 40 周的即时 ART (ART-40W) 或为期 96 周的即时 ART (ART-96W) 后中断治疗。

根据临床站点对随机化时间表进行分层，并重新排列随机区组的大小，以平衡各组婴儿的数量。

在 ART-Def 组中开始 ART 以及在其他组中中断治疗后重新开始 ART 的标准为婴儿期 CD4% 低于 25%；否则，该标准为 CD4% 低于 20% 或疾病预防控制中心定义的重度 B 期或 C 期疾病。

洛匹那韦—利托那韦、齐多夫定和拉米夫定联合疗法是开始和重新开始 ART 的一线治疗方案。

主要终点为至一线 ART 失败（免疫学、临床或病毒学）或死亡的时间。

使用时间-事件法，通过意向性治疗分析完成比较。 本试验已在 ClinicalTrials.gov 登记，编号为 NCT00102960。

结果

我们招募了 377 名婴儿，其中位年龄为 7·4 周，CD4% 为 35%，HIV RNA 为 log 5·7 拷贝/mL。 中位随访时间为 4·8 年；34 名婴儿 (9%) 在随访中失访。

ART-Def 组的中位时间至 ART 开始时间为 20 周 (IQR 16-25)。 ART-40W 组和 ART-96W 组的中断后至重新开始 ART 时间分别为 33 (26-45) 周和 70 (35-109) 周；在试验结束时，ART-40W 组和 ART-96W 组中分别有 19% 和 32% 的患者无需再接受 ART。

ART-Def 组、ART-40W 组和 ART-96W 组中用于 ART 的随访时间比例分别为 81%、70% 和 69%。 ART-Def 组、ART-40W 组和 ART-96W 组中分别有 48/125 (38%)、32/126 (25%) 和 26/126 (21%) 的儿童达到主要终点。

与 ART-Def 组相比，ART-40W 组和 ART-96W 组的危险比分别为 0·59 (95% CI 0·38-0·93, p=0·02) 和 0·47 (0·27—0·76, p=0·002)。 ART-Def 组、ART-40W 组和 ART-96W 组中转为接受二线 ART 的人数分别为 3、3 和 1。

结果解读

早期限时 ART 的临床及免疫学预后优于延期 ART，无证据表明在后续的治疗中断期间存在过度的疾病进展，且其总体 ART 暴露也少于延期 ART。

较长时间的初步 ART 可实现较长的后续中断期，其预后也略好。

Background

Interim results from the children with HIV early antiretroviral (CHER) trial showed that early antiretroviral therapy (ART) was life-saving for infants infected with HIV. In view of the few treatment options and the potential toxicity associated with lifelong ART, in the CHER trial we compared early time-limited ART with deferred ART.

Methods

CHER was an open-label randomised controlled trial of HIV-infected asymptomatic infants younger than 12 weeks in two South African trial sites with a percentage of CD4-positive T lymphocytes (CD4%) of 25% or higher. 377 infants were randomly allocated to one of three groups: deferred ART (ART-Def), immediate ART for 40 weeks (ART-40W), or immediate ART for 96 weeks (ART-96W), with subsequent treatment interruption. The randomisation schedule was stratified by clinical site with permuted blocks of random sizes to balance the numbers of infants allocated to each group. Criteria for ART initiation in the ART-Def group and re-initiation after interruption in the other groups were CD4% less than 25% in infancy; otherwise, the criteria were CD4% less than 20% or Centers for Disease Control and Prevention severe stage B or stage C disease. Combination therapy of lopinavir—ritonavir, zidovudine, and lamivudine was the first-line treatment regimen at ART initiation and re-initiation. The primary endpoint was time to failure of first-line ART (immunological, clinical, or virological) or death. Comparisons were done by intention-to-treat analysis, with use of time-to-event methods. This trial is registered with ClinicalTrials.gov, number NCT00102960.

Findings

377 infants were enrolled, with a median age of 7·4 weeks, CD4% of 35%, and HIV RNA log 5·7 copies per mL. Median follow-up was 4·8 years; 34 infants (9%) were lost to follow-up. Median time to ART initiation in the ART-Def group was 20 weeks (IQR 16-25). Time to restarting of ART after interruption was 33 weeks (26-45) in ART-40W and 70 weeks (35—109) in ART-96W; at the end of the trial, 19% of patients in ART-40W and 32% of patients in ART-96W remained off ART. Proportions of follow-up time spent on ART were 81% in the ART-Def group, 70% in the ART-40W group, and 69% in the ART-96W group. 48 (38%) of 125 children in the ART-Def group, 32 (25%) of 126 in the ART-40W group, and 26 (21%) of 126 in the ART-96W group reached the primary endpoint. The hazard ratio, relative to ART-Def, was 0·59 (95% CI 0·38-0·93, p=0·02) for ART-40W and 0·47 (0·27-0·76, p=0·002) for ART-96W. Three children in ART-Def, three in ART-40W, and one in ART-96W switched to second-line ART.

Interpretation

Early time-limited ART had better clinical and immunological outcomes than deferred ART, with no evidence of excess disease progression during subsequent treatment interruption and less overall ART exposure than deferred ART. Longer time on primary ART permits longer subsequent interruption, with marginally better outcomes.

 

参考文献：Mark F Cotton MMed et.al. Early time-limited antiretroviral therapy versus deferred therapy in South African infants infected with HIV: results from the children with HIV early antiretroviral (CHER) randomised trial. Lancet, 22 August 2013