Cumulative Ritonavir-Boosted Darunavir Use May Be Associated With Increased CVD Risk

In patients infected with HIV, the cumulative use for ritonavir-boosted darunavir was associated with a progressively increasing risk for cardiovascular disease, according to research published in The Lancet HIV.

Data from the prospective Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study was used to investigate the incidence of cardiovascular disease in people age ≥16 infected with HIV being treated with contemporary treatments. The associations between cardiovascular disease and the contemporary protease inhibitors atazanavir and darunavir (both boosted with ritonavir) were also assessed.

A total of 49,709 participants were originally enrolled starting in 1999, and 71.8% of these had data on CD4 cell count and viral load available at the 2009 baseline and were therefore included in the study.

Median follow-up time was 6.96 years (interquartile range, 6.28-7.08), during which 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 patients unexposed to ritonavir-boosted darunavir to 13.67 events per 1000 person-years (8.51–18.82) in patients who were exposed to the drug for >6 years.

The changes in incidence rate in unexposed and exposed patients was not as large when ritonavir-boosted atazanavir was considered. The rate in unexposed individuals was 5.03 events per 1000 person-years (4.69–5.37) and grew to 6.68 events per 1000 person-years (5.02–8.35) in participants exposed for more than 6 years.

Investigators also performed adjustments to keep factors on the potential causal pathway from boosted protease inhibitor use to cardiovascular disease fixed at baseline, after which ritonavir-boosted darunavir use was associated with increased risk for 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).

The study was limited by the observational nature of the data. Specifically, investigators were unable to exclude potential unmeasured confounders and could not draw any causal inferences from the findings. The associations between drug doses and cardiovascular disease were also uncalculatable due to a lack of dosage data. 

The investigators concluded, however, that due to ritonavir-boosted darunavir being part of recommended first-line treatment their data “create[d] an impetus for other studies to investigate possible mechanisms by which the increased risk of cardiovascular events might occur,” and encouraged other large studies “to do analyses of the association between ritonavir-boosted darunavir and cardiovascular disease to investigate the reproducibility of our findings.”

Reference

Ryom L, Lundgren JD, El-Sadr W, et al. Cardiovascular disease and use of contemporary protease inhibitors: the D:A:D international prospective multicohort study [published online May 3 2018]. Lancet HIV. doi:10.1016/S2352-3018(18)30043-2