Elsevier

The Lancet HIV

Volume 5, Issue 6, June 2018, Pages e291-e300
The Lancet HIV

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

https://doi.org/10.1016/S2352-3018(18)30043-2Get rights and content

Summary

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.

Introduction

Improvements to antiretroviral treatment, which is used to control HIV, have substantially reduced the incidence of drug-related adverse events.1 However, a 2014 study2 suggested that the risk of cardiovascular disease is increasing among people living with HIV because of increased frequency and severity of cardiovascvular disease risk factors such as hypertension, diabetes, dyslipidaemia, and chronic kidney disease. With an ageing population of people living with HIV, at growing risk of cardiovascular disease, antiretroviral treatment tailored to fit individuals' risk profiles are increasingly needed.3 Earlier studies,4, 5, 6, 7 including previous analyses from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study, have shown longer cumulative use of the older protease inhibitors indinavir and ritonavir-boosted lopinavir is associated with cardiovascular disease. The mechanism of this association is believed to be at least partly mediated by dyslipidaemia, and different protease inhibitors are associated with different metabolic profiles.8

Research in context

Evidence before this study

Several first-generation protease inhibitors used in HIV treatment have been associated with an increased risk of cardiovascular disease. We used PubMed to identify all clinical trials and observational studies that reported associations between protease inhibitors and cardiovascular disease endpoints. The search terms that we used were “myocardial infarction”, “MI”, “stroke”, “cerebrovascular”, “cardiovascular disease”, “CVD”, with “AND HIV” or “AND antiretroviral treatment”, “protease inhibitors”, “indinavir”, “lopinavir”, “saquinavir”, “atazanavir”, and “darunavir”. We also searched for “adverse effects” with “AND protease inhibitors”, “indinavir”, “lopinavir”, “saquinavir”, “atazanavir”, and “darunavir”. The search included studies from the beginning of time until Aug 6–8, 2016, with no language restrictions. Evidence from observational and mechanistic studies suggest that an underlying mechanism between longer cumulative use of indinavir and ritonavir-boosted lopinavir and cardiovascular disease risk could, at least partly, be mediated by dyslipidaemia, and drugs within the protease inhibitor drug class have different metabolic profiles. Whether use of more contemporary protease inhibitors such as ritonavir-boosted darunavir and atazanavir are also associated with an increased risk of cardiovascular disease is unknown.

Added value of this study

After a median follow-up of 7 years, 1157 of 35 711 study participants developed a centrally validated cardiovascular disease event. After adjustment for potential confounders, ritonavir-boosted darunavir was associated with a 59% increased risk of cardiovascular disease per 5 years of additional use, whereas use of ritonavir-boosted atazanavir was not associated with cardiovascular disease. Several sensitivity analyses confirmed the robustness of this association, including adjustment for several factors on the potentially causal pathway between protease inhibitor use and cardiovascular disease. These analyses also separated cardiovascular disease into myocardial infarction and stroke; adjusted for plasma bilirubin concentration, which may be cardioprotective and is associated with ritonavir-boosted atazanavir use; and stratified by participants for whom ritonavir-boosted darunavir use was their first ever protease inhibitor, by use of this drug in combination with a non-nucleoside reverse transcriptase inhibitor, by history of virological failure, and by participants at high risk of cardiovascular disease.

Implications of all the available evidence

With an ageing population of people living with HIV at increasing risk of cardiovascular disease, tailoring of antiretroviral treatment to fit the individuals' risk profiles is increasingly important. Ritonavir-boosted darunavir is currently recommended as part of first-line treatment regimens in several international guidelines. In this prospective multicohort study with rigorously defined cardiovascular disease endpoints and relatively long follow-up, we identified a progressively increasing risk of cardiovascular disease with longer ritonavir-boosted darunavir use. Although the strength of the association between ritonavir-boosted darunavir and cardiovascular disease is similar to that reported for the first-generation protease inhibitors, the ritonavir-boosted darunavir association does not seem to be moderated by dyslipidaemia. These findings should prompt evaluation of whether other antiretrovirals that do not impart a risk of cardiovascular disease are available as part of individual care, particularly for people with HIV who are at high risk of cardiovascular disease.

The two most commonly used protease inhibitors presently are darunavir and atazanavir, both boosted with ritonavir.1, 9 Ritonavir-boosted darunavir and atazanavir are part of the recommended first-line treatment combinations for treatment-naive adults with HIV in several guidelines, including guidelines by the European AIDS Clinical Society, the British HIV Association, and the US Department of Health and Human Services.1, 9, 10

Whether contemporary protease inhibitors, such as darunavir and atazanavir, pose a similar risk of cardiovascular disease as previous protease inhibitors is unknown. A previous analysis11 of the D:A:D cohort showed no association between ritonavir-boosted atazanavir and increased risk of cardiovascular disease; however, the follow-up duration of that analysis was relatively short.

We therefore aimed to assess whether cumulative use of ritonavir-boosted atazanavir and ritonavir-boosted darunavir was associated with increased incidence of cardiovascular disease in people living with HIV in the D:A:D study.

Section snippets

Study design and participants

The D:A:D study is a prospective cohort collaboration that was established in 1999. This study monitored more than 49 000 adults (aged ≥16 years) with an HIV-1 infection from 11 cohorts in Australia, Europe, and the USA who were receiving routine clinical care; details of the D:A:D cohort have been published previously.4

All participating cohorts followed local or national guidelines or regulations regarding patient consent and ethical review. Of the countries with participating cohorts, only

Results

The full D:A:D cohorts consisted of 49 709 participants, of whom 35 711 (71·8%) had prospective follow-up data after Jan 1, 2009, including data on CD4 cell count and viral load. 13 998 (28·2%) participants did not have prospective follow-up data after 2009, CD4 cell count data, or data on viral load at the 2009 baseline, and so were not included in the current analysis (figure 1). During a median follow-up of 6·96 years (IQR 6·28–7·08), 1157 (3·2%) of 35 711 participants had a cardiovascular

Discussion

In this large heterogeneous cohort of people with HIV, cumulative use of ritonavir-boosted darunavir, but not ritonavir-boosted atazanavir, was independently associated with a small, but progressively increasing risk of centrally validated cardiovascular disease events. For individuals at high risk of cardiovascular disease (ie, with an absolute 5 year cardiovascular disease risk of 10%), use of ritonavir-boosted darunavir for 5 years would increase the absolute cardiovascular disease risk to

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    D:A:D study group members are listed in the appendix

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