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Lancet HIV. 2018 Jun;5(6):e291-e300. doi: 10.1016/S2352-3018(18)30043-2. Epub 2018 May 3.

Cardiovascular disease and use of contemporary protease inhibitors: the D:A:D international prospective multicohort study.

Author information

1
Department of Infectious Diseases, Centre of Excellence for Health, Immunity and Infections, Section 2100, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. Electronic address: lene.ryom.nielsen@regionh.dk.
2
Department of Infectious Diseases, Centre of Excellence for Health, Immunity and Infections, Section 2100, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
3
ICAP at Columbia University, New York, NY, USA; Harlem Hospital, New York, NY, USA.
4
Academic Medical Centre, Division of Infectious Diseases and Department of Global Health, University of Amsterdam, Amsterdam, Netherlands; HIV Monitoring Foundation, Amsterdam, Netherlands.
5
The Kirby Institute, University of New South Wales, Sydney, NSW, Australia.
6
Research Department of Infection and Population Health, University College London, London, UK.
7
Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
8
Public Health Department, Centre Hospitalier Universitaire (CHU) de Nice, Nice, France.
9
Department of Health Sciences, Infectious and Tropical Diseases Clinic, Azienda Ospedaliera, Milan, Italy.
10
Department of Infectious Diseases, CHU Saint-Pierre, Brussels, Belgium.
11
CHU de Bordeaux and INSERM U897, Bordeaux University, Bordeaux, France.

Abstract

BACKGROUND:

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.

METHODS:

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).

FINDINGS:

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.

INTERPRETATION:

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.

FUNDING:

The Highly Active Antiretroviral Therapy Oversight Committee.

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