Heart disease in people with HIV

11 February 2006. Related: Conference reports, EACS 10 Dublin 2005.

Mike Youle and Jules Levin for NATAP.org

With so many ominous links between antiretrovirals and cardiovascular disease making recent headlines, one can be excused for assuming that researchers have closed the book on ties between therapy and a threatened heart. But nothing could be further from the truth, according to results of two randomised antiretroviral trials unveiled at EACS.

Meanwhile, mortality studies in two vast HIV cohorts confirmed some suspicions and rendered more than one surprise.

Antiretrovirals improve arterial function

Work reported four years ago linked protease inhibitors (PIs) to dangerously impaired endothelial function [1]. In this study James Stein used ultrasound to gauge flow-mediated vasodilation of the brachial artery—a standard technique to estimate arterial elasticity—in 37 people taking antiretrovirals. The 15 people using a non-PI regimen had relatively good flow-mediated vasodilation (8.1 + 6.7%), while the 22 PI-treated people had stiff arteries signaled by a vasodilation score of 2.6 + 4.6% (P = 0.005). But the study was small and checked people at a single time point, so Stein couldn’t tell how good—or bad—artery walls looked before these people started antiretrovirals or as treatment continued.

An AIDS Clinical Trials Group (ACTG) team will try to plug this research gap in an ongoing study of 82 antiretroviral-naive people randomised to one of three regimens—efavirenz plus two nucleoside reverse transcriptase inhibitors (NRTIs), lopinavir/ritonavir plus two NRTIs, or lopinavir/ritonavir plus efavirenz [2]. Francesca Torriani from the University of California, San Diego reported that the study group’s median age stood at 35 years (young for an HIV cohort in the US), their median CD4 count measured 244 cells/mm³, and their median viral load was 4.82 log copies/mL.

Torriani and colleagues at six ACTG sites excluded people with a history of cerebrovascular disease or diabetes and anyone taking antilipid drugs, antioxidants, or steroids. Like Stein, they used high-resolution ultrasonography to grade flow-mediated vasodilation of the brachial artery—an artery in the upper arm. Unlike Stein, they found that everyone had dangerously low flow-mediated vasodilation before they even started antiretrovirals (Table 1; normal is 11%). Yet that metric improved significantly after only 4 weeks of therapy, and the improvement continued through 24 weeks of follow-up.

Table 1: Average flow-mediated vasodilation in people starting antiretrovirals

Antiretroviral assignment had not been disclosed at week 24, but Torriani reported that vasodilation improved significantly with all three regimens tested, designated Arms X, Y, and Z. Although she offered no opinion on between-arm vasodilation differences, it appears that people in Arm Z are improving most. Lipid improvements did differ significantly from arm to arm, but Torriani didn’t say whether Arm Z surpassed the others by lipid measures.

The ACTG 5152S team suggested that improved endothelial function in this study may signify a lower short-term risk of cardiovascular disease.

Concerns that years of antiretroviral therapy will kill more and more people with heart attacks rest mainly on results from the multicohort D:A:D study, which reckoned a 17% jump in myocardial infarction risk for every extra year of treatment [3]. It’s easy to forget that a similarly massive cohort study, this one involving the US Veterans Administration (VA), charted dwindling hospital admission rates for cardiovascular or cerebrovascular disease among people taking antiretrovirals from 1995 to 2001 [4]. In a review lecture at EACS, Düsseldorf HIV clinician Stefan Mauss noted that an additional 3 years of follow-up in the VA cohort still failed to turn up any hint that prolonged antiretroviral therapy poses a serious threat of heart disease. The VA update will probably get aired at a big HIV meeting soon.

References:

1. Stein JH, Klein MA, Bellehumeur JL, et al. Use of human immunodeficiency virus-1 protease inhibitors is associated with atherogenic lipoprotein changes and endothelial dysfunction. Circulation 2001;104:257-262.
2. Torriani FJ, Parker RA, Murphy FL, et al. Antiretroviral therapy improves endothelial function in treatment-naive HIV-infected subjects: a prospective, randomised multicenter trial (A5152S). 10th European AIDS Conference. November 17-20, 2005. Dublin. Abstract PS5/3.
3. El-Sadr W, Reiss P, De Wit S, et al. Relationship between prolonged exposure to combination ART and myocardial infarction: effect of sex, age, and lipid changes. 12th Conference on Retroviruses and Opportunistic Infections. Feb 22-25, 2005. Boston. Abstract 42.
4. Bozzette SA, Ake CF et al. Cardiovascular and cerebrovascular events in patients treated for human immunodeficiency virus infection. N Engl J Med 2003;348:702-710.