Background

A low CD4/CD8 ratio during antiretroviral therapy (ART) identifies people with heightened immunosenescence and increased risk of mortality. We aimed to assess the effects of integrase strand transfer inhibitor (INSTI)-based, protease inhibitor-based, or non-nucleoside reverse transcriptase inhibitor (NNRTI)-based first-line ART on long-term CD4/CD8 ratio recovery.

Methods

This prospective cohort study included 13 026 individuals with HIV registered in the Spanish HIV Research Network (CoRIS) cohort recruited from 45 Spanish hospitals. We included HIV-positive people who started triple ART (two nucleoside reverse transcriptase inhibitors [NRTI] with a NNRTI, protease inhibitor, or INSTI) and had HIV RNA suppression within 48 weeks. We used piecewise linear mixed models adjusted for potential confounders to compare longitudinal changes in the CD4/CD8 ratio between people receiving three different types of ART. We used Cox proportional-hazard models to compare the times to CD4/CD8 normalisation between the treatment groups, using cutoff ratios of 0·4, 1·0, and 1·5.

Findings

6804 individuals contributing 37 149 persons-years and 37 680 observations were analysed; median follow-up was 49 months (IQR 22–89). INSTI-based ART was associated with greater CD4/CD8 gain (change per year compared with INSTI was coefficient −0·07 [95% CI −0·08 to −0·06] for NNRTI and was −0·08 [–0·09 to −0·08] for protease inhibitors). Differences were observed from the first year of therapy and were driven by changes in both CD4 and CD8 cell counts. Subanalyses at different time periods suggested that these differences were driven by changes during the first year of ART without significant differences in the adjusted CD4/CD8 ratio trajectories after the second year of ART (change per year compared with INSTI was coefficient −0·03 [95% CI −0·05 to −0·13] for NNRTI and was −0·06 [95% CI −0·08 to −0·04] for protease inhibitors). Although no differences in the time until CD4/CD8 normalisation at a cutoff ratio of no less than 0·4 were reported between any of the groups, compared with the INSTI group, both the NNRTI and protease inhibitor groups showed lower rates of normalisation at cutoff ratios of 1·0 or more (adjusted hazard ratio 0·80 [95% CI 0·72–0·89] for the NNRTI group and 0·79 [0·69–0·89] for the protease inhibitor group), and 1·5 or more (0·79 [0·65–0·95] for the NNRTI group and 0·78 [0·64–0·97] for the protease inhibitor group). No differences were found between the different integrases in the time until CD4/CD8 normalisation. Subanalyses adjusted for the backbone NRTIs and allowing observations after virological failure yielded similar results.

Interpretation

This study provides new evidence that reinforces the positioning of INSTI-based therapies as a first choice and underlines the importance of analysing the effects of therapeutic interventions on biomarkers linked with morbidity and mortality beyond the plasma HIV RNA and the CD4 cell counts.

Funding

Spanish AIDS Research Network (Instituto de Salud Carlos III), European Development Regional Fund “A way to achieve Europe”.

中文翻译：

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一线抗逆转录病毒疗法对CoRIS中CD4 / CD8比和CD8细胞计数的影响：一项前瞻性多中心队列研究。

背景

抗逆转录病毒疗法（ART）期间CD4 / CD8比率低可识别免疫衰老加剧和死亡风险增加的人。我们旨在评估基于整合酶链转移抑制剂（INSTI），基于蛋白酶抑制剂或基于非核苷逆转录酶抑制剂（NNRTI）的一线ART对长期CD4 / CD8比率恢复的影响。

方法

这项前瞻性队列研究包括从西班牙45家医院招募的13026例在HIV研究网络（CoRIS）中注册的HIV个体。我们纳入了HIV阳性患者，他们开始了三联抗逆转录病毒疗法（两种核苷类逆转录酶抑制剂[NRTI]和NNRTI，蛋白酶抑制剂或INSTI），并在48周内抑制了HIV RNA。我们使用针对潜在混杂因素进行调整的分段线性混合模型，比较了接受三种不同类型抗病毒治疗的人群之间CD4 / CD8比率的纵向变化。我们使用Cox比例风险模型比较了各治疗组之间CD4 / CD8归一化的时间，使用的截止率为0·4、1·0和1·5。

发现

分析了6804个人，贡献了37 149人年-年，观察了37 680次观察；中位随访时间为49个月（IQR 22-89）。基于INSTI的ART与更大的CD4 / CD8增益相关（与INSTI相比，每年的变化是NNRTI的系数−0·07 [95％CI −0·08至−0·06]，而−0·08 [–0 （对于蛋白酶抑制剂而言，[09至-0.08]）。从治疗的第一年开始观察到差异，这是由CD4和CD8细胞计数的变化所驱动的。在不同时间段的子分析表明，这些差异是由抗病毒药物治疗第一年的变化驱动的，而抗病毒治疗第二年之后调整后的CD4 / CD8比值轨迹没有显着差异（每年变化与INSTI相比为系数−0·03 [ NNRTI为95％CI -0·05至-0·13]，蛋白酶抑制剂为-0·06 [95％CI -0·08至-0·04]。尽管在任何一组之间没有报告截止到CD4 / CD8归一化的时间在不小于0·4的时间上的差异，但是与INSTI组相比，NNRTI和蛋白酶抑制剂组均显示出更低的归一化率比率大于或等于1·0（NNRTI组的危险比调整为0·80 [95％CI 0·72-0.89]，蛋白酶抑制剂组的危险比为0·79 [0·69-0.89]），和1·5或更高（NNRTI组为0·79 [0·65-0·95]，蛋白酶抑制剂组为0·78 [0·64-0·97]）。在CD4 / CD8归一化之前的时间内，不同积分之间未发现差异。子分析针对骨干NRTI进行了调整，并在病毒学失败后进行观察，得到了相似的结果。

解释

这项研究提供了新的证据，强化了将基于INSTI的疗法作为首选的定位，并强调了分析治疗性干预对生物标志物的影响的重要性，这些标志物与血浆HIV RNA和CD4细胞计数以外的发病率和死亡率有关。

资金

西班牙艾滋病研究网络（萨卢德·卡洛斯三世研究所），欧洲发展区域基金，“通往欧洲的道路”。