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Cardiovascular Risk as Great With Darunavir as With Indinavir or Lopinavir
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Conference on Retroviruses and Opportunistic Infections (CROI), February 13-16, 2017, Seattle
Mark Mascolini
Analysis based on 7 years of follow-up linked cumulative use of darunavir/ritonavir to a small but gradually increasing risk of cardiovascular disease (CVD) in HIV-positive D:A:D study members [1]. CVD incidence with cumulative darunavir proved similar to that seen with the older protease inhibitors (PIs) indinavir and lopinavir/ritonavir. In the same population, atazanavir/ritonavir use could not be tied to CVD risk.
Research linked older PIs to CVD risk, partly because of their negative impact on lipids. Indinavir use was associated with a CVD incidence rate ratio (IRR) of 1.47 events per 5 years, while lopinavir/ritonavir was linked to an IRR of 1.54 events per 5 years. To determine whether cumulative use of two contemporary PIs--ritonavir boosted darunavir and atazanavir--affects CVD risk, D:A:D investigators conducted this study.
As in previous studies, the D:A:D team defined CVD as a composite endpoint of centrally assessed events including myocardial infarction, stroke, sudden cardiac death, and invasive cardiovascular procedures. The analysis focused on D:A:D participants in follow-up after January 1, 2009; follow-up continued to the earliest CVD event, the last study visit plus 6 months, or February 1, 2016. The researchers used Poisson regression models adjusted for potential confounders to assess associations between CVD and the two PIs.
Through a median 7 years of follow-up, 35,711 D:A:D members had 1157 CVD events (3.2%) for an incidence of 5.3 per 1000 person-years. The study group had a median baseline age of 44 and a median baseline CD4 count of 501. Almost three quarters of participants were men, and 5.3% had a D:A:D CVD risk above 10%.
Crude CVD incidence rose from 5.03 per 1000 person-years in people never exposed to atazanavir/ritonavir to only 6.68 per 1000 in those exposed for more than 6 years. The rise in CVD incidence was much steeper with darunavir/ritonavir, from 4.91 per 1000 person-years in people who never took this PI to 13.67 per 1000 in those who took it for more than 6 years.
After baseline adjustment for factors that may drive CVD with PIs (like abnormal lipids), cumulative atazanavir use was not associated with CVD risk (IRR 1.03 per 5 years, 95% confidence interval [CI] 0.90 to 1.18) but cumulative darunavir use was (IRR 1.59 per 5 years, 95% CI 1.33 to 1.91). Additional time-updated adjustment for potential PI-related causal factors (CD4 count, body mass index, chronic kidney disease, abnormal lipids, diabetes) did not affect the CVD incidence rate ratios with darunavir (IRR 1.53 per 5 years, 95% CI 1.28 to 1.84) or atazanavir (IRR 1.01 per 5 years, 95% CI 0.88 to 1.16).
Further adjustment for bilirubin (a potentially protective factor) had little impact on CVD incidence with darunavir; neither did stratification for whether darunavir was the first PI used or whether darunavir was used with a nonnucleoside. Further analyses found significant associations between cumulative darunavir use and myocardial infarction alone (IRR 1.51 per 5 years, 95% CI 1.13 to 2.02) or stroke alone (IRR 1.49 per 5 years, 95% CI 1.08 to 2.07).
The D:A:D investigators conclude that the strength of the association between darunavir and CVD risk is similar to that of the older PIs indinavir or lopinavir/ritonavir. But unlike those PIs, abnormal lipids do not appear to modify the CVD risk with darunavir/ritonavir. The researchers call for further study to uncover potential mechanisms explaining the CVD impact of darunavir.
Reference
1. Ryom L, Lundgren JD, El-Sadr WM, et al. Association between cardiovascular disease and contemporarily used protease inhibitors. Conference on Retroviruses and Opportunistic Infections (CROI), February 13-16, 2017, Seattle. Abstract 128LB.
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