Department of Infectious Diseases, Centre of Excellence for Health, Immunity and Infections, Section 2100, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
Department of Infectious Diseases, Centre of Excellence for Health, Immunity and Infections, Section 2100, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
Lancet HIV. 2018 Jun;5(6):e291-e300. doi: 10.1016/S2352-3018(18)30043-2. Epub 2018 May 3.
Although earlier protease inhibitors have been associated with increased risk of cardiovascular disease, whether this increased risk also applies to more contemporary protease inhibitors is unknown. We aimed to assess whether cumulative use of ritonavir-boosted atazanavir and ritonavir-boosted darunavir were associated with increased incidence of cardiovascular disease in people living with HIV.
The prospective Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study consists of people living with HIV-1 from 11 cohorts in Australia, Europe, and the USA. Participants were monitored from Jan 1, 2009, until the earliest of a cardiovascular event, 6 months after the last visit, or until Feb 1, 2016. The outcome of interest was the incidence of cardiovascular disease in adults (aged ≥16 years) living with HIV who were being treated with contemporary treatments. We defined cardiovascular disease as centrally validated myocardial infarction, stroke, sudden cardiac death, or use of invasive cardiovascular procedures, including coronary bypass, coronary angioplasty, and carotid endarterectomy. We used Poisson regression models to assess the associations between cardiovascular disease and the contempoary protease inhibitors atazanavir and darunavir (both boosted with ritonavir).
49 709 participants were enrolled in the original cohort from 1999 onwards; 35 711 (71·8%) participants with available data on CD4 cell count and viral load at the 2009 baseline were included in the current analysis, and 13 998 (28·2%) participants had insufficent follow-up data after 2009. During a median 6·96 years of follow-up (IQR 6·28-7·08), 1157 people developed cardiovascular disease (incidence rate 5·34 events per 1000 person-years; 95% CI 5·03-5·65). The incidence rate of cardiovascular disease progressively increased from 4·91 events per 1000 person-years (4·59-5·23) in individuals unexposed to ritonavir-boosted darunavir to 13·67 events per 1000 person-years (8·51-18·82) in those exposed to the drug for more than 6 years. The changes associated with ritonavir-boosted atazanavir were less pronounced, showing an incidence rate of 5·03 cardiovascular events per 1000 person-years (4·69-5·37) in unexposed individuals to 6·68 events per 1000 person-years (5·02-8·35) in participants exposed for more than 6 years. After adjustment, keeping factors on the potential causal pathway from boosted protease inhibitor use to cardiovascular disease fixed at baseline, ritonavir-boosted darunavir use was associated with increased risk of cardiovascular disease (incidence rate ratio 1·59; 95% CI 1·33-1·91 per 5 years additional use), but use of ritonavir-boosted atazanavir was not (1·03; 0·90-1·18). This association remained after adjustment for time-updated factors on the potential causal pathway; myocardial infarction and stroke separately; plasma bilirubin concentration; and after stratification by use of ritonavir-boosted darunavir as the first ever protease inhibitor, used in combination with a non-nucleoside reverse transcriptase inhibitor, by previous virological failure, and by those at high risk of cardiovascular disease.
Cumulative use of ritonavir-boosted darunavir, but not of ritonavir-boosted atazanavir, is associated with progressively increasing risk of cardiovascular disease. Causal inference is limited by the observational nature of the D:A:D study. Our findings should prompt investigation into the possible underlying mechanisms of this finding.
The Highly Active Antiretroviral Therapy Oversight Committee.
虽然早期的蛋白酶抑制剂与心血管疾病风险增加有关，但这种风险增加是否也适用于更现代的蛋白酶抑制剂尚不清楚。我们旨在评估累积使用利托那韦增强的阿扎那韦和利托那韦增强的达芦那韦是否与艾滋病毒感染者心血管疾病的发生率增加有关。
前瞻性的抗 HIV 药物不良反应数据收集（D:A:D）研究包括来自澳大利亚、欧洲和美国的 11 个队列中的艾滋病毒 1 型感染者。参与者从 2009 年 1 月 1 日开始监测，直到发生心血管事件，最后一次就诊后 6 个月，或 2016 年 2 月 1 日。主要结局是接受当代治疗的艾滋病毒感染者中成年人（年龄≥16 岁）心血管疾病的发生率。我们将心血管疾病定义为中心验证的心肌梗死、中风、心源性猝死或使用有创心血管程序，包括冠状动脉旁路移植术、冠状动脉血管成形术和颈动脉内膜切除术。我们使用泊松回归模型评估心血管疾病与当代蛋白酶抑制剂阿扎那韦和达芦那韦（均与利托那韦联合增强）之间的关联。
从 1999 年开始，49709 名参与者被纳入原始队列；在 2009 年基线时具有可用的 CD4 细胞计数和病毒载量数据的 35711 名（71.8%）参与者被纳入当前分析，13998 名（28.2%）参与者在 2009 年后随访数据不足。在中位 6.96 年的随访期间（IQR 6.28-7.08），1157 人发生了心血管疾病（发生率为 5.34 例/1000 人年；95%CI 5.03-5.65）。心血管疾病的发生率从未暴露于利托那韦增强的达芦那韦的个体的每 1000 人年 4.91 例（4.59-5.23）逐渐增加到暴露于该药物超过 6 年的个体的每 1000 人年 13.67 例（8.51-18.82）。与利托那韦增强的阿扎那韦相关的变化不太明显，未暴露个体的心血管事件发生率为每 1000 人年 5.03 例（4.69-5.37），暴露个体超过 6 年的心血管事件发生率为每 1000 人年 6.68 例（5.02-8.35）。调整后，将增强蛋白酶抑制剂使用与心血管疾病之间的潜在因果途径的因素固定在基线水平，利托那韦增强的达芦那韦的使用与心血管疾病风险增加相关（发生率比 1.59；95%CI 每 5 年额外使用 1.33-1.91），但利托那韦增强的阿扎那韦的使用则没有（1.03；95%CI 0.90-1.18）。这种关联在调整潜在因果途径的时间更新因素、心肌梗死和中风单独、血浆胆红素浓度以及根据利托那韦增强的达芦那韦首次作为蛋白酶抑制剂使用、与非核苷逆转录酶抑制剂联合使用、以前的病毒学失败以及心血管疾病高危患者进行分层后仍然存在。
累积使用利托那韦增强的达芦那韦与心血管疾病风险的逐渐增加有关，但与利托那韦增强的阿扎那韦无关。D:A:D 研究的观察性质限制了因果推断。我们的发现应该促使人们对这一发现的潜在机制进行调查。
高效抗逆转录病毒治疗监督委员会。
