Background

Although associations between older antiretroviral drug classes and cardiovascular disease in people living with HIV are well described, there is a paucity of data regarding a possible association with integrase strand-transfer inhibitors (INSTIs). We investigated whether exposure to INSTIs was associated with an increased incidence of cardiovascular disease.

Methods

RESPOND is a prospective, multicentre, collaboration study between 17 pre-existing European and Australian cohorts and includes more than 32 000 adults living with HIV in clinical care after Jan 1, 2012. Individuals were eligible for inclusion in these analyses if they were older than 18 years, had CD4 cell counts and HIV viral load measurements in the 12 months before or within 3 months after baseline (latest of cohort enrolment or Jan 1, 2012), and had no exposure to INSTIs before baseline. These individuals were subsequently followed up to the earliest of the first cardiovascular disease event (ie, myocardial infarction, stroke, or invasive cardiovascular procedure), last follow-up, or Dec 31, 2019. We used multivariable negative binomial regression to assess associations between cardiovascular disease and INSTI exposure (0 months [no exposure] vs >0 to 6 months, >6 to 12 months, >12 to 24 months, >24 to 36 months, and >36 months), adjusted for cardiovascular risk factors. RESPOND is registered with ClinicalTrials.gov, NCT04090151, and is ongoing.

Findings

29 340 people living with HIV were included in these analyses, of whom 7478 (25·5%) were female, 21 818 (74·4%) were male, and 44 (<1%) were transgender, with a median age of 44·3 years (IQR 36·2–51·3) at baseline. As of Dec 31, 2019, 14 000 (47·7%) of 29 340 participants had been exposed to an INSTI. During a median follow-up of 6·16 years (IQR 3·87–7·52; 160 252 person-years), 748 (2·5%) individuals had a cardiovascular disease event (incidence rate of 4·67 events [95% CI 4·34–5·01] per 1000 person-years of follow-up). The crude cardiovascular disease incidence rate was 4·19 events (3·83–4·57) per 1000 person-years in those with no INSTI exposure, which increased to 8·46 events (6·58–10·71) per 1000 person-years in those with more than 0 months to 6 months of exposure, and gradually decreased with increasing length of exposure, until it decreased to similar levels of no exposure at more than 24 months of exposure (4·25 events [2·89–6·04] per 1000 person-years among those with >24 to 36 months of exposure). Compared with those with no INSTI exposure, the risk of cardiovascular disease was increased in the first 24 months of INSTI exposure and thereafter decreased to levels similar to those never exposed (>0 to 6 months of exposure: adjusted incidence rate ratio of 1·85 [1·44–2·39]; >6 to 12 months of exposure: 1·19 [0·84–1·68]; >12 to 24 months of exposure: 1·46 [1·13–1·88]; >24 to 36 months of exposure: 0·89 [0·62–1·29]; and >36 months of exposure: 0·96 [0·69–1·33]; p<0·0001).

Interpretation

Although the potential for unmeasured confounding and channelling bias cannot fully be excluded, INSTIs initiation was associated with an early onset, excess incidence of cardiovascular disease in the first 2 years of exposure, after accounting for known cardiovascular disease risk factors. These early findings call for analyses in other large studies, and the potential underlying mechanisms explored further.

Funding

The CHU St Pierre Brussels HIV Cohort, The Austrian HIV Cohort Study, The Australian HIV Observational Database, The AIDS Therapy Evaluation in the Netherlands National Observational HIV cohort, The EuroSIDA cohort, The Frankfurt HIV Cohort Study, The Georgian National AIDS Health Information System, The Nice HIV Cohort, The ICONA Foundation, The Modena HIV Cohort, The PISCIS Cohort Study, The Swiss HIV Cohort Study, The Swedish InfCare HIV Cohort, The Royal Free HIV Cohort Study, The San Raffaele Scientific Institute, The University Hospital Bonn HIV Cohort and The University of Cologne HIV Cohorts, ViiV Healthcare, and Gilead Sciences.

中文翻译：

---

整合酶链转移抑制剂与 HIV 感染者心血管疾病之间的关联：来自 RESPOND 队列联盟的多中心前瞻性研究

背景

尽管较早的抗逆转录病毒药物类别与 HIV 感染者的心血管疾病之间的关联得到了很好的描述，但关于与整合酶链转移抑制剂 (INSTI) 可能关联的数据却很少。我们调查了暴露于 INSTIs 是否与心血管疾病发病率增加有关。

方法

RESPOND 是一项前瞻性、多中心、合作研究，由 17 个先前存在的欧洲和澳大利亚队列组成，包括 2012 年 1 月 1 日之后接受临床护理的 32,000 多名 HIV 感染者。如果年龄超过18 岁，在基线前 12 个月内或基线后 3 个月内进行过 CD4 细胞计数和 HIV 病毒载量测量（队列登记的最新时间或 2012 年 1 月 1 日），并且在基线前未接触过 INSTI。随后对这些个体进行随访，直至最早的第一次心血管疾病事件（即心肌梗死、中风或侵入性心血管手术）、最后一次随访或 2019 年 12 月 31 日。我们使用多变量负二项回归来评估两者之间的关联心血管疾病和 INSTI 暴露（0 个月 [无暴露]vs >0 至 6 个月、>6 至 12 个月、>12 至 24 个月、>24 至 36 个月和 >36 个月），针对心血管危险因素进行了调整。RESPOND 已在 ClinicalTrials.gov 注册，NCT04090151，并且正在进行中。

发现

29340 名 HIV 感染者被纳入这些分析，其中女性 7478 人（25·5%），男性 21818 人（74·4%），跨性别者 44 人（<1%），中位年龄为基线时 44·3 岁 (IQR 36·2–51·3)。截至 2019 年 12 月 31 日，29 340 名参与者中有 14 000 人（47·7%）接触过 INSTI。在 6·16 年的中位随访期间（IQR 3·87–7·52；160252 人年），748 (2·5%) 人发生心血管疾病事件（4·67 事件的发生率 [ 95% CI 4·34–5·01] 每 1000 人年的随访）。在未接触 INSTI 的人群中，心血管疾病的粗发病率为每 1000 人年 4·19 次事件（3·83–4·57），增加到每 1000 人年 8·46 次事件（6·58–10·71）暴露时间超过 0 个月至 6 个月的人年，并随着暴露时间的增加而逐渐减少，直到它在暴露超过 24 个月后下降到与无暴露相似的水平（在暴露超过 24 至 36 个月的人群中，每 1000 人年发生 4·25 起事件 [2·89–6·04]）。与未暴露 INSTI 者相比，暴露于 INSTI 的前 24 个月心血管疾病风险增加，此后降低至与从未暴露者相似的水平（>0 至 6 个月暴露：调整后的发病率比为 1·85 [1·44–2·39]；>6 至 12 个月的暴露：1·19 [0·84–1·68]；>12 至 24 个月的暴露：1·46 [1·13–1·88 ]；>24 至 36 个月的暴露：0·89 [0·62–1·29]；>36 个月的暴露：0·96 [0·69–1·33]；p<0·0001）。1·46 [1·13–1·88]；>24 至 36 个月的暴露：0·89 [0·62–1·29]；和 >36 个月的暴露：0·96 [0·69–1·33]；p<0·0001)。1·46 [1·13–1·88]；>24 至 36 个月的暴露：0·89 [0·62–1·29]；和 >36 个月的暴露：0·96 [0·69–1·33]；p<0·0001)。

解释

尽管不能完全排除未测量的混杂和通道偏倚的可能性，但在考虑已知的心血管疾病风险因素后，INSTIs 的启动与暴露的头 2 年内心血管疾病的早发、高发病率有关。这些早期发现需要在其他大型研究中进行分析，并进一步探索潜在的潜在机制。

资金

CHU St Pierre Brussels HIV 队列、奥地利 HIV 队列研究、澳大利亚 HIV 观察数据库、荷兰艾滋病治疗评估国家 HIV 观察队列、EuroSIDA 队列、法兰克福 HIV 队列研究、格鲁吉亚国家艾滋病健康信息系统、尼斯 HIV 队列、ICONA 基金会、摩德纳 HIV 队列、PISCIS 队列研究、瑞士 HIV 队列研究、瑞典 InfCare HIV 队列、皇家免费 HIV 队列研究、圣拉斐尔科学研究所、波恩大学医院 HIV 队列以及科隆大学 HIV 队列、ViiV Healthcare 和 Gilead Sciences。