HIV-1 infection is associated with decreased high-density lipoprotein cholesterol (HDL-c) concentration and increased risk of cardiovascular disease (CVD) [1,2]. Traditional CVD risk calculators stratify risk around specific low-density lipoprotein cholesterol (LDL-c) targets as the primary focus for intervention. However, as there is a high prevalence of low HDL-c in HIV-infected patients [present in more than 60% of patients prior to antiretroviral therapy (ART)] , we aimed to determine the relevant contribution of HDL-c to CVD risk in a contemporary cohort of HIV-infected patients and postulated that HDL-c is an important contributor to cardiovascular risk in this patient population.
We performed a cross-sectional study of HIV-infected patients attending the Infectious Diseases Outpatient Clinic at the Mater Misericordiae University Hospital from February 2008 to February 2010. Patients provided their written, informed consent and ethical approval was obtained. Information on demographics, HIV infection and treatment history, together with clinical assessments and laboratory investigations were gathered.
Ten-year risk of CVD was estimated using the Framingham equation [low (<10%), moderate (10–20%) and high (>20%) risk] . The contribution of each known CVD risk factor [age, sex, current smoking, total and HDL-c, systolic blood pressure (SBP) and diabetes mellitus] to the predicted risk at a cohort level was assessed by fitting a multiple linear regression model with 10-year predicted risk as the outcome and each of the seven CVD risk factors as covariates. We excluded each factor in turn to calculate the proportion of the variation in the predicted risk that was explained by each factor alone. We also estimated the degree of reclassification of CVD risk and number of CVD events averted if HDL-c concentration was increased in all patients in the cohort by 20 and 40%, respectively.
Of 134 patients recruited, 127 patients had sufficient CVD risk information for inclusion in the analyses; among this subgroup, the median age was 37 years (range 21–62), 65% of patients were male and 58% Caucasian. Acquisition risk groups were all represented: heterosexual acquisition (55%); men who have sex with men (21%); and injection drug users (21%). The median CD4+ T-cell count was 378 cells/μl (interquartile range 263). Two thirds (n = 83, 65%) of patients were on ART, of whom 86% were virologically suppressed (HIV-RNA < 50 copies/ml). Of the 83 patients, 95% were on ART regimens including nucleoside or nucleotide reverse transcriptase inhibitors, 43% were on nonnucleoside reverse transcriptase inhibitors and 57% were on ritonavir-boosted protease inhibitors. Thirty-eight percent of patients were smokers, 20% had a family history of cardiovascular disease, 11% were hypertensive and only 1% had a diagnosis of diabetes mellitus. One hundred and ten patients had low CVD risk, 12 had moderate risk and five were classified as high risk. As per National Cholesterol Education Programme (NCEP) guidelines, 3% had elevated total cholesterol, 53% had low HDL-c and 5% had elevated LDL-c .
Among the CVD risk factors considered, HDL-c ranked second, after age, as the factor that contributed most to overall CVD risk (Fig. 1), above both smoking and total-cholesterol. Increasing HDL-c by 20% and 40% led to reclassification of six and 12 patients to a lower CVD risk group, respectively. Increasing HDL-c concentration by 20% would result in the reclassification of one patient from high to moderate CVD risk and five patients from moderate to low risk. This would potentially avert 1.26 CVD events over 10 years. Increasing HDL-c concentration by 40% would result in the reclassification of two patients from high to moderate risk and 10 patients from moderate to low risk, potentially averting 2.14 CVD events over 10 years.
Our data highlight the important contribution of low HDL-c to CVD risk in HIV-infected patients, with HDL-c contributing more to 10-year cardiovascular risk than smoking, total cholesterol, SBP or sex. Although our study is limited by a relatively small sample size, our cohort is sufficiently representative of a contemporary HIV-infected population. While in-vitro studies suggest a role for viral proteins in inhibiting cholesterol efflux from cells, thereby contributing to low HDL-c [6,7], little is known of the underlying mechanisms for persistent low HDL-c in patients on ART. In addition, existing therapeutic options to raise HDL-c are limited. Both 3-hydroxy 3-methylglutaryl CoA reductase inhibitors and niacin have little appreciable effect on HDL-c [8,9], although newer agents are under development . Results from this study demonstrate the importance of further research into the causes of low HDL-c in HIV-infected patients and the effect of ART on low HDL-c. Furthermore, validation of these results in larger epidemiological studies, such as the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Study, is necessary to determine the impact of low HDL-c on CVD events in HIV-infected patients.
In summary, in a cohort of HIV-infected patients, HDL-c contributed more to CVD risk than smoking, total cholesterol, SBP and sex. Further research is warranted, in order to explain why HDL-c is low in HIV-infected patients and identify potential therapeutic targets.
This work was supported by the Irish Health Research Board who fund A.G.C. (award HRA_POR/2010/66).
We would like to that the patients who participated in the Cardiac Monitoring Program Study and the nursing staff.
A.G.C. and E.R.F have received support, in the form of sponsorship to attend meetings, from Gilead Sciences Ltd, GlaxoSmithKline (Ireland Ltd) and Bristol-Myers Squibb Pharmaceuticals. C.S.S. has received honoraria from Gilead Sciences Ltd. J.A.O'H and C.A.S. have no conflicts of interest. P.W.G.M. has received support from the following: Molecular Medicine Ireland, Science Foundation Ireland, ViiV Healthcare, Gilead Sciences Ltd., GlaxoSmithKline (Ireland Ltd), Abbott, MSD and Janssen-Cilag.
This study was presented as a poster presentation (P20) at the 12th International Workshop on Adverse Drug Reactions and Co-morbidities in HIV, London, UK on 4–5 November 2010.
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