Fish oil and fenofibrate for the treatment of hypertriglyceridemia in HIV-infected subjects on antiretroviral therapy: results of ACTG A5186.

Before the introduction of highly active antiretroviral therapy (HAART), HIV-infected persons were noted to have elevated triglyceride (TG) levels with low total cholesterol and low high-density lipoprotein cholesterol (HDL-C), presumably attributable to a persistent inflammatory state. Furthermore, elevation of serum lipids is a frequent and serious complication associated with the use of HAART.1-4 The most common lipid elevation observed is with the serum TG level.5 Although ritonavir is the antiretroviral drug (ARV) most commonly associated with this lipid change, other ARVs have also been associated with serum TG perturbations.6-8 There is mounting evidence that the observed metabolic syndrome characterized by elevated TGs, low HDL-C, glucose intolerance, and body fat changes may accelerate the development of atherosclerosis, leading to higher rates of cerebrovascular and coronary heart disease (CHD).9,10 HIV-infected patients with HAART-induced hypertriglyceridemia have been observed to have atherogenic dyslipidemia. Although there is not universal consensus, hypertriglyceridemia is increasingly being recognized as an independent risk factor in the development of CHD and is a secondary target for intervention in the most recent National Cholesterol Education Project (NCEP) Adult Treatment Panel III guidelines.11-14 In addition to increased CHD risks, high serum TG is associated with the development of pancreatitis. Thus, the identification of effective therapy for drug-induced hypertriglyceridemia is an important clinical concern. Presently, the recommended approaches to the treatment of serum hypertriglyceridemia consist of diet, exercise, and the use of drugs like fibrates or niacin.15 Neither diet nor exercise is consistently effective because of the difficulty in adhering to these lifestyle changes. Pharmacotherapy is somewhat effective, but in a large clinical trial in HIV-infected subjects with lipid abnormalities, fenofibrate alone reduced serum TG level to <200 mg/dL (the NCEP Treatment Panel III guidelines’ suggested target level) in only 48% of the subjects, with a median baseline serum TG level of 336 mg/dL.16 Fish oil has been shown to reduce serum TGs in disparate populations, including those with congenital hypertriglyceridemia and drug-induced hypertriglyceridemia.17-19 Two trials evaluating lower doses of fish oil than we used decreased the serum TG concentration by 25% to 30% in HIV-infected individuals on ARVs.20,21 These studies were not designed to reduce serum TG to ≤200 mg/dL, however. Fish oil is an attractive compound because of its described effect in reducing atherogenic cardiovascular disease risk by means of a combination of anti-inflammatory and antiplatelet effects.22 Epidemiologic studies have suggested that a diet rich in omega-3 fatty acids is associated with a low incidence of CHD.23 In addition, the American Heart Association’s dietary guidelines have recommended that healthy adults eat at least 2 servings of fish per week and that people who have elevated TGs need 2 to 4 g of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) per day as a dietary supplement. AIDS Clinical Trials Group (ACTG) A5186 was designed to test the hypothesis that we could reach a TG goal <200 mg/dL in a significant proportion of subjects using fenofibrate plus fish oil in those failing either agent alone. At the time this study was designed, these agents had not been used in combination in this population. Further, we proposed using fish oil containing higher doses of EPA and DHA than previously studied in persons with HIV. Thus, the study was designed as a phase 2 study that, if successful, would merit a larger randomized controlled trial. The primary objectives of ACTG A5186 were (1) to evaluate whether the combination of fish oil supplement and fenofibrate would decrease fasting serum TGs to ≤200 mg/dL in subjects not responding to either agent alone and (2) to evaluate the safety and tolerability of fish oil supplement alone and in combination with fenofibrate in an HIV-infected population with elevated fasting serum TGs. The secondary objectives were (1) to evaluate the change in serum TG and low-density lipoprotein cholesterol (LDL-C) with the combination of fish oil supplement and fenofibrate and with each agent alone, (2) to describe the effect of fish oil supplement on lymphocyte proliferative responses to Candida and cytomegalovirus (CMV) antigens, (3) to describe the effect of fish oil supplement on C-reactive protein (CRP) concentrations, and (4) to describe the effect of fish oil supplement on the pharmacokinetics of concomitantly administered HIV protease inhibitors (PIs).