Effect of ritonavir on lipids and post-heparin lipase activities in normal subjects

BackgroundIntensive therapy of HIV infection with highly active antiretroviral therapy (HAART) dramatically reduces viral loads and improves immune status. Abnormalities of lipid levels, body fat distribution, and insulin resistance have been commonly reported after starting HAART. Whether the lipid abnormalities result from changes in metabolism after an improvement in HIV status or are partly attributable to the effects of protease inhibitor use is unknown. MethodsTwenty-one healthy volunteers participated in a 2 week double-blind, placebo-controlled study on the effect of the protease inhibitor ritonavir on total lipids, apolipoproteins, and post-heparin plasma lipase activities. ResultsThose taking ritonavir (n = 11) had significantly higher levels of plasma triglyceride, VLDL cholesterol, IDL cholesterol, apolipoprotein B, and lipoprotein (a) compared with placebo (n = 8). HDL cholesterol was lower with therapy as a result of a reduction in HDL3 cholesterol. Post-heparin lipoprotein lipase (LpL) activity did not change but hepatic lipase activity decreased 20% (P < 0.01) in those taking ritonavirrcompared with placebo. Although all lipoprotein subfractions became triglyceride enriched, most of the increase in triglyceride was in VLDL and not in IDL particles. ConclusionTreatment with ritonavir in the absence of HIV infection or changes in body composition results in hypertriglyceridemia that is apparently not mediated by impaired LpL activity or the defective removal of remnant lipoproteins, but could be caused by enhanced formation of VLDL. Long-term studies of patients with HIV infection receiving HAART will be necessary to determine the impact of these drugs and associated dyslipidemia on the risk of coronary artery disease.

[1]  J. Hokanson,et al.  Evidence for a new pathophysiological mechanism for coronary artery disease regression: hepatic lipase-mediated changes in LDL density. , 1999, Circulation.

[2]  F. Goebel,et al.  Treatment with protease inhibitors associated with peripheral insulin resistance and impaired oral glucose tolerance in HIV‐1‐infected patients , 1998, AIDS.

[3]  David A. Cooper,et al.  A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors , 1998, AIDS.

[4]  Morris Schambelan,et al.  “Buffalo hump” in men with HIV-1 infection , 1998, The Lancet.

[5]  K. Miller,et al.  Visceral abdominal-fat accumulation associated with use of indinavir , 1998, The Lancet.

[6]  R. Knopp,et al.  Multiple beneficial effects of estrogen on lipoprotein metabolism. , 1997, The Journal of clinical endocrinology and metabolism.

[7]  R. Krauss,et al.  A prospective study of triglyceride level, low-density lipoprotein particle diameter, and risk of myocardial infarction. , 1996, JAMA.

[8]  J. Després,et al.  The Dense LDL Phenotype: Association with plasma lipoprotein levels, visceral obesity, and hyperinsulinemia in men , 1996, Diabetes Care.

[9]  W. Ryu,et al.  Changes in Lp(a) lipoprotein and lipid levels after cessation of female sex hormone production and estrogen replacement therapy. , 1996, Archives of internal medicine.

[10]  Andrew Carr,et al.  HIV protease inhibitors , 1996, AIDS.

[11]  L. M. Lehman,et al.  A short-term study of the safety, pharmacokinetics, and efficacy of ritonavir, an inhibitor of HIV-1 protease. European-Australian Collaborative Ritonavir Study Group. , 1995, The New England journal of medicine.

[12]  M. Koschinsky,et al.  Effect of the number of apolipoprotein(a) kringle 4 domains on immunochemical measurements of lipoprotein(a). , 1995, Clinical chemistry.

[13]  M. Vilardell,et al.  Serum lipoprotein (a) levels in patients with chronic renal failure--evolution after renal transplantation and relationship with other parameters of lipoprotein metabolism: a prospective study. , 1995, Nephron.

[14]  R. Knopp,et al.  Sex Hormones and Lipid Interactions: Implications for Cardiovascular Disease in Women , 1994 .

[15]  J. Hokanson,et al.  The visceral adiposity syndrome in Japanese-American men. , 1994, Obesity research.

[16]  W. H. Hannon,et al.  International Federation of Clinical Chemistry standardization project for measurements of apolipoproteins A-I and B. III. Comparability of apolipoprotein A-I values by use of international reference material. , 1993 .

[17]  J. Hokanson,et al.  Epidemiology of triglycerides, small dense low-density lipoprotein, and lipoprotein(a) as risk factors for coronary heart disease. , 1994, The Medical clinics of North America.

[18]  W. Riesen,et al.  Effect of thyroid function on concentrations of lipoprotein(a) , 1993, Clinical chemistry.

[19]  R. Krauss,et al.  The hypertriglyceridemia of acquired immunodeficiency syndrome is associated with an increased prevalence of low density lipoprotein subclass pattern B. , 1993, The Journal of clinical endocrinology and metabolism.

[20]  J. Hokanson,et al.  Effect of hepatic lipase on LDL in normal men and those with coronary artery disease. , 1993, Arteriosclerosis and thrombosis : a journal of vascular biology.

[21]  K. Feingold,et al.  Lipids, lipoproteins, triglyceride clearance, and cytokines in human immunodeficiency virus infection and the acquired immunodeficiency syndrome. , 1992, The Journal of clinical endocrinology and metabolism.

[22]  C. Bouchard,et al.  Role of hepatic-triglyceride lipase activity in the association between intra-abdominal fat and plasma HDL cholesterol in obese women. , 1989, Arteriosclerosis.

[23]  J. Hokanson,et al.  Large Buoyant LDL‐like Particles in Hepatic Lipase Deficiency , 1989, Arteriosclerosis.

[24]  J. Wang,et al.  Hypertriglyceridemia in the acquired immunodeficiency syndrome. , 1989, The American journal of medicine.

[25]  S. Grundy,et al.  Plasma lipoproteins in familial combined hyperlipidemia and monogenic familial hypertriglyceridemia. , 1983, Journal of lipid research.

[26]  E. Nikkilä,et al.  High density lipoprotein-2 and hepatic lipase: reciprocal changes produced by estrogen and norgestrel. , 1982, The Journal of clinical endocrinology and metabolism.

[27]  K. Shirai,et al.  Hydrolysis of human plasma high density lipoprotein 2- phospholipids and triglycerides by hepatic lipase. , 1981, Biochemical and biophysical research communications.

[28]  A. Goldberg,et al.  Effect of estrogen on post-heparin lipolytic activity. Selective decline in hepatic triglyceride lipase. , 1977, The Journal of clinical investigation.