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Polyunsaturated Ethyl Esters of n-3 Fatty Acids in HIV-Infected Patients With Moderate Hypertriglyceridemia: Comparison With Dietary and Lifestyle Changes, and Fibrate Therapy
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JAIDS Journal of Acquired Immune Deficiency Syndromes: Volume 36(3) 1 July 2004
Manfredi, Roberto MD; Calza, Leonardo MD; Chiodo, Francesco MD
From the Department of Clinical and Experimental Medicine, Division of Infectious Diseases, University of Bologna Alma Mater Studiorum, S. Orsola Hospital, Bologna, Italy
To the Editor:
Serum lipid anomalies have been emerging as a problem in the management of HIV-infected patients since the introduction of highly active antiretroviral therapy (HAART). Investigation is greatly needed into the management of dyslipidemia, which may prompt accelerated atherogenesis and cardiovascular complications. Although recommendations regarding HIV-associated dyslipidemia have existed since 2000, only a reduced number of observational studies and controlled trials is available, and most problems regarding the long-term management of this untoward event remain unsolved. The aim of our study was a prospective, open-label assessment of the efficacy and safety profile of polyunsaturated ethyl esters of n-3 fatty acids (PEEs) in the control of moderate hypertriglyceridemia complicating antiretroviral-treated HIV disease, compared with diet and exercise and with fibrate therapy.
All patients with stable HIV disease who developed moderate hypertriglyceridemia (expressed by serum levels of 200-500 mg/dL in at least 2 consecutive quarterly examinations) while on HAART, despite modified diet and increased physical exercise, entered our study since January 2002. Familial hypertriglyceridemia/dyslipidemia, concurrent alterations of serum cholesterol and glucose levels >10% compared with normal upper limits, administration of antilipidemic drugs in the prior 6 months, and change of antiretroviral therapy based on withdrawal of protease inhibitors or efavirenz (due to treatment failure or toxicity) were exclusion criteria, as well as an estimated adherence to prescribed medications of <90%. A total of 156 patients aged 36-62 years (97 men) treated with anti-HIV regimens including 2 nucleoside analogues plus a protease inhibitor in 103 cases (lopinavir/ritonavir in 61 patients), or a non-nucleoside reverse transcriptase inhibitor in 41 cases (efavirenz in 38 patients), and other triple-quadruple combinations in the remaining 12 subjects were evaluable. After giving informed consent, 54 patients received PEE at 1 g twice daily; 53 subjects were treated with standard doses of either bezafibrate (21 cases), fenofibrate (19 cases), or gemfibrozil (13 cases); and the remaining 49 patients continued a diet-exercise program and served as controls. All 156 patients were followed at least quarterly, and triglyceridemia was compared with baseline levels (mean 303.2 ± 40.7 mg/dL). An interim analysis shows data available until 18 months of observation.
Continued PEE administration led to a significant decrease of mean triglyceridemia of 5.6, 15.8, 13.3, 16, 15.3, and 11.6 after 3, 6, 9, 12, 15, and 18 months, respectively (P < 0.0001 vs. baseline levels), while negligible changes occurred in serum cholesterolemia. Both PEE and fibrate administration achieved a significant (P < 0.0001) amelioration of triglyceridemia compared with diet-exercise only, although fibrates showed a better efficacy profile vs. PEE (P < 0.0001); these significance levels were maintained throughout the entire 18-month observation period. When comparing the efficacy of PEE with that of a diet-exercise program, a significant difference was reached at the 6th month (P = 0.001) and was maintained until the 18th month (P = 0.005-P < 0.0001). Normal serum triglyceride levels (<172 mg/dL) were reached any time during the 18-month study period by 14 patients in the PEE group (25.9%), compared with 18 patients treated with fibrates (34%; no significant difference vs. PEE-treated subjects) and only 4 patients in the diet-exercise group (8.2%; P < 0.0001 vs. other study groups).
Mild and transient gastrointestinal disturbances (possibly attributable to concurrent medications) were referred by 10, 19, and 8 patients given, respectively, PEE, fibrates, and diet-exercise (P < 0.03 and P < 0.05 between patients given fibrates and those on diet-exercise program and PEE, respectively), but no treatment discontinuation became necessary. During the 18-month follow-up, treatment with either PEE or fibrates prevented changes of antiretroviral regimen, directly caused by persisting dyslipidemia.
Together with a broad spectrum of metabolic abnormalities, dyslipidemia is a mounting problem in long-term management of HIV infection. Hypertriglyceridemia is particularly related to the administration of the protease inhibitors lopinavir and ritonavir (up to two-thirds of patients are involved), compared with other protease inhibitors, while the possible role of efavirenz (among non-nucleoside reverse transcriptase inhibitors) is also emerging. In our previous experiences, all administered fibrates and statins showed a similar efficacy in the therapy for HIV-associated mixed dyslipidemia, with no significant difference among the available fibrates (beza-fibrate, fenofibrate, and gemfibrozil) against hypertriglyceridemia. However, possible side effects and drug-drug interactions of antilipidemic drugs have to be taken into careful account, especially when antiretroviral drugs and other underlying pharmacologic therapies are of concern. Unfortunately, dietary interventions seem to have a minor role in the management of elevated and prolonged HIV- and antiretroviral-associated dyslipidemia, so pharmacologic therapy is recommended. However, some investigations suggested appreciable advantages from a strict dietary regimen, and a role for very-low-fat diets has been recently hypothesized; also, our data confirm a nonnegligible effect of diet-exercise on long-term control of moderate hypertriglyceridemia. When considering the role of PEE in the setting of HIV disease, the adjunct of n-3 fatty acids was first attempted to correct HIV-related malnutrition and wasting and was also claimed to improve immunologic parameters, by acting on the cytokine network. Later, after the emergence of HAART-associated lipodystrophy and metabolic abnormalities, PEEs were proposed as a mode to favorably modify the body lipid composition: a single 6-month double-blind study with PEEs published in 1998 showed a reduction of triglyceridemia and cholesterolemia, but no comparison with other pharmacologic strategies was made. Encouraging results come from animal models, where adiponectin and leptin administration appeared to ameliorate dyslipidemia induced by protease inhibitors, maybe with a greater efficacy compared with PEE. Since very limited data regarding the possible role of PEEs during HIV disease are available, updated expert opinions and guidelines do not mention these compounds. As a consequence, our experience is the only available study evaluating the long-term efficacy and safety of PEEs compared with pharmacologic and nonpharmacologic strategies in HIV-infected patients with moderately elevated serum triglyceride levels. In the present investigation, although limited by its open-label observational design, we carried out a prospective comparison confirming that pharmacologic treatment of an isolated-predominant hypertriglyceridemia proves effective in HIV-infected patients undergoing selected HAART regimens, and a diet-exercise program is of limited value. When comparing fibrate and PEE therapy, a significant difference was confirmed in favor of fibrates, but PEE also acted remarkably during a quite prolonged follow-up and showed a better tolerability profile. When HIV-associated predominant hypertriglyceridemia is of concern, PEE may represent an effective and safe alternative to fibrates or statins, to be confirmed in enlarged, randomized, dose-finding trials.
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