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Fish Oil for Triglycerides Study
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The Safety and Efficacy of Fish Oil in Combination with Fenofibrate in Subjects on ART with Hypertriglyceridemia Who Had an Incomplete Response to Either Agent Alone: Results of ACTG A5186
13th CROI
Denver, Feb 5-8, 2006
....In HIV+ patients with hypertriglyceridemia receiving antiretroviral therapy (ART), fish oil reduced triglycerides and was well tolerated; patients who did not respond to either fish oil or fenofibrate alone, combining the 2 therapies resulted in greater reductions in triglycerides than either agent used alone....
John Gerber*1, D Kitch2, J Aberg3, R Zackin2, S Charles4, E Hogg5, E Acosta6, E Connick1, D Wohl7, C Fichtenbaum8, and ACTG A5186 Team
1Univ of Colorado Hlth Sci Ctr, Denver, US; 2Statistical and Data Analysis Ctr, Harvard Sch of Publ Hlth, Boston, MA, US; 3New York Univ, NY, US; 4Frontier Sci & Tech Res Fndn, Amherst, NY, US; 5Social & Sci Systems, Silver Spring, MD, US; 6Univ of Alabama at Birmingham, US; 7Univ of North Carolina at Chapel Hill, US; and 8Univ of Cincinnati Med Ctr, OH, US
Hypertriglyceridemia (HTG) is commonly encountered in HIV-infected subjects on ART. Currently fibrates and fish oil are 2 of the pharmacologic approaches used in therapy. The safety and efficacy of the combination of fish oil and fenofibrate in the therapy of ART-associated HTG is unknown.
A5186 was an open-labeled prospective study examining the efficacy (defined as serum TG <200 mg/dL) of fish oil 3g (1500 mg elcosapentaeonoic acid + 910 mg docosahexaenoic acid twice daily + fenofibrate 160 mg once daily in subjects with incomplete serum triglyceride-lowering response to fish oil or fenofibrate alone.
We randomized 100 patients on effective ART with fasting serum TG _400 mg/dL and normal LDL cholesterol 1:1 to fish oil or fenofibrate for 8 weeks (step 1). If serum TG was _200 mg/dL at week 8, the combination of fish oil + fenofibrate was administered from week 10 to week 18 (step 2). Using a 95% confidence interval (CI) with 90% power, the primary objective was to determine if step 2 response rates were _10%. Subjects on fish oil participated in an immunological study evaluating changes in antigen-specific lymphocyte proliferation assays (LPA). In addition subjects on fish oil and protease inhibitors (PI) participated in the pharmacologic study examining changes in PI trough concentrations due to fish oil.
Results
90% were men in study; median age 43 yrs; 58% white, 14% black; 28% Hispanic. Median CD4 count was 429-528. Median HIV RNA was 1.33 log. Median LDL was 73 & 86 mg/dL in the fish oil & fenofibrate arms, respectively. Median HDL was 28 & 32 mg/dl in fish oil & fenofibrate arms, respectively.
The median baseline serum TG was 662 mg/dL in fish oil arm and 694 mg/dL in fenofibrate arm. During step 1 both fish oil and fenofibrate decreased serum TG by a median of 46% and 58%, respectively (intent to treat, p = 0.039, Wilcoxon Rank Sum Test).
Of 47 subjects on fish oil, 4 (8.5%) and of 48 on fenofibrate, 8 (16.7%) achieved TG <200 mg/dL; 75 (90.4%) of the step 1 non-responders entered step 2.
The combination of fish oil + fenofibrate further decreased serum TG and the response rate increased to 22.7% (15% lower limit of CI; intent to treat, no difference between fish oil and fenofibrate arms). At week 10 fish oil + fenofibrate group median TG were: 369 mg/dL in the initial fish oil arm & 414 in the initial fenofibrate arm. At week 18, TG were 280 in the initial fish oil arm & 279 in the initial fenofibrate arm.
The median decrease in serum TG from baseline to week 18 was 65% for subjects participating in step 2 of the protocol.
Fish oil and fenofibrate were well tolerated and only 1 subject discontinued fish oil because of side effects and 3 subjects discontinued the fish oil + fenofibrate combination because of side effects.
Fish oil had no significant effect on CD4 count, CD4%, and LPA for cytomegalovirus, Candida, or PHA. Fish oil had no effect on the trough concentration of lopinavir, the most commonly used PI. Median LPV trough concentration was 6453 before fish oil 7 5881 ng/mL after fish oil.
Fish oil was well tolerated: no grade 4 events, 4 grade 3 events, 1 of which was related to fish oil. Fenofibrate had more lab abnormalities associated with its use: 1 grade 4 lipase elevation; 7 grade 3 events, 4 bilirubin elevations not requiring drug discontinuation. In the fishoil+fenofibrate combination therapy there were no grade 4 events & grade 3 lipase elevations.
LDL cholesterol was 86 & 73 mg/dl in the fish oil & fenofibrate arms, respectively, at baseline, and 108 & 110 at week 8.
The authors concluded that fish oil is an effective and safe agent in the treatment of ART-associated HTG even though the majority of subjects did not reach serum TG L200 mg/dL. When fish oil is combined with fenofibrate, further TG lowering is observed.
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