Metabolic Effects of Protease Inhibitor-Sparing Antiretroviral Regimens Given as Initial Treatment of HIV-1 Infection (AIDS Clinical Trials Group Study A5095)

Objective:To assess metabolic changes after initiation of protease inhibitor (PI)-sparing regimens in antiretroviral-naive patients. Methods:Metabolic changes were analyzed within the triple-nucleoside (zidovudine [ZDV]/lamivudine [3TC]/abacavir [ABC])-containing, 3-drug efavirenz (EFV) [ZDV/3TC + EFV]-containing, and 4-drug EFV [ZDV/3TC/ABC + EFV]-containing arms of the AIDS Clinical Trials Group multicenter trial A5095. Metabolic values were compared with published US general population norms. Results:From week 0 to week 24, all arms exhibited similar mild median increases in glucose and decreases in insulin sensitivity, whereas changes in lipids were greater in the ZDV/3TC + EFV and ZDV/3TC/ABC + EFV arms than in the ZDV/3TC/ABC arm: triglyceride (TG; 7, 18, and −1 mg/dL, respectively), total cholesterol (TC; 23, 28, and 5 mg/dL, respectively), low-density lipoprotein cholesterol (LDL-C; 9, 14, and 1 mg/dL, respectively), and high-density lipoprotein cholesterol (HDL-C; 10, 10, and 5 mg/dL, respectively). Adjusted mean study lipid values of all study participants at week 0 and week 96 compared with those of the National Health and Nutrition Examination Survey (NHANES) 1999 through 2002 values were: TG (148, 187, and 123 mg/dL, respectively), TC (164, 195, and 203 mg/dL, respectively), HDL-C (35, 47, and 51 mg/dL, respectively), and LDL-C (101, 117, and 123 mg/dL, respectively) (P ≤ 0.005 for each value vs. NHANES values). Conclusions:Similar mild increases in glucose and decreases in insulin sensitivity were observed in all regimens, whereas lipids were modestly higher in the EFV-containing arms. Compared with general population norms, the metabolic dysfunctions of concern after these PI-sparing therapies were increasingly abnormal TC and lower (but improved relative to baseline) HDL-C levels.

[1]  A. Malarcher,et al.  Cigarette Smoking Among Adults in the United States , 2008 .

[2]  Christopher D Pilcher,et al.  Three- vs four-drug antiretroviral regimens for the initial treatment of HIV-1 infection: a randomized controlled trial. , 2006, JAMA.

[3]  U. Caixas,et al.  Long-term and concentration-dependent beneficial effect of efavirenz on HDL-cholesterol in HIV-infected patients. , 2006, British journal of clinical pharmacology.

[4]  K. Tashima,et al.  A prospective, 96‐week study of the impact of Trizivir®, Combivir®/nelfinavir, and lamivudine/stavudine/nelfinavir on lipids, metabolic parameters and efficacy in antiretroviral‐naive patients: effect of sex and ethnicity , 2006, HIV medicine.

[5]  M. Noor,et al.  Body fat and other metabolic effects of atazanavir and efavirenz, each administered in combination with zidovudine plus lamivudine, in antiretroviral-naive HIV-infected patients. , 2006, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[6]  M. Busby,et al.  Randomized study of the safety and efficacy of fish oil (omega-3 fatty acid) supplementation with dietary and exercise counseling for the treatment of antiretroviral therapy-associated hypertriglyceridemia. , 2005, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[7]  R. Shafer,et al.  Glucose metabolism, lipid, and body fat changes in antiretroviral-naive subjects randomized to nelfinavir or efavirenz plus dual nucleosides , 2005, AIDS.

[8]  Jeffrey N. Martin,et al.  The relationship between nucleoside analogue treatment duration, insulin resistance, and fasting arterialized lactate level in patients with HIV infection. , 2005, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[9]  P. Sorlie,et al.  Trends in serum lipids and lipoproteins of adults, 1960-2002. , 2005, JAMA.

[10]  W. K. Henry,et al.  A randomized trial of the efficacy and safety of fenofibrate versus pravastatin in HIV-infected subjects with lipid abnormalities: AIDS Clinical Trials Group Study 5087. , 2005, AIDS research and human retroviruses.

[11]  D. Pereg,et al.  Normal fasting plasma glucose levels and type 2 diabetes in young men. , 2005, The New England journal of medicine.

[12]  R. Weber,et al.  Lipid Profiles for Antiretroviral-Naive Patients Starting Pi- and Nnrti-Based Therapy in the Swiss HIV Cohort Study , 2005, Antiviral therapy.

[13]  W. El-Sadr,et al.  Effects of HIV disease on lipid, glucose and insulin levels: results from a large antiretroviral‐naïve cohort , 2005, HIV medicine.

[14]  W. Lewis.  Nucleoside Reverse Transcriptase Inhibitors, Mitochondrial Dna and Aids Therapy , 2005, Antiviral therapy.

[15]  Ali H Mokdad,et al.  Increasing prevalence of the metabolic syndrome among u.s. Adults. , 2004, Diabetes care.

[16]  B. Gazzard,et al.  Nevirapine and Efavirenz Elicit Different Changes in Lipid Profiles in Antiretroviral- Therapy-Naive Patients Infected with HIV-1 , 2004, PLoS medicine.

[17]  K. Yarasheski,et al.  Niacin in HIV-infected individuals with hyperlipidemia receiving potent antiretroviral therapy. , 2004, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[18]  Christopher D Pilcher,et al.  Triple-nucleoside regimens versus efavirenz-containing regimens for the initial treatment of HIV-1 infection. , 2004, The New England journal of medicine.

[19]  J. Ribalta,et al.  Efavirenz induces a striking and generalized increase of HDL-cholesterol in HIV-infected patients , 2004, AIDS.

[20]  O. Kirk,et al.  Lipid profiles in HIV-infected patients receiving combination antiretroviral therapy: are different antiretroviral drugs associated with different lipid profiles? , 2004, The Journal of infectious diseases.

[21]  M. Schambelan,et al.  The metabolic effects of lopinavir/ritonavir in HIV-negative men , 2004, AIDS.

[22]  K. Petersen,et al.  Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. , 2004, The New England journal of medicine.

[23]  H. Pownall,et al.  Pathophysiology of dyslipidemia and increased cardiovascular risk in HIV lipodystrophy: a model of ‘systemic steatosis’ , 2004, Current opinion in lipidology.

[24]  D. Arveiler,et al.  Risk factors for coronary heart disease in patients treated for human immunodeficiency virus infection compared with the general population. , 2003, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[25]  S. Cole,et al.  Impact of HIV infection and HAART on serum lipids in men. , 2003, JAMA.

[26]  K. Tashima,et al.  Lipid Changes in Patients Initiating Efavirenz- and Indinavir-Based Antiretroviral Regimens , 2003, HIV clinical trials.

[27]  P. Reiss,et al.  Lipid profiles associated with antiretroviral drug choices , 2003, Current opinion in infectious diseases.

[28]  I. Weller,et al.  Lactic acidosis in HIV infected patients: a systematic review of published cases , 2002, Sexually transmitted infections.

[29]  S. Grinspoon,et al.  Increased rates of lipolysis among human immunodeficiency virus-infected men receiving highly active antiretroviral therapy. , 2002, Metabolism: clinical and experimental.

[30]  H. Pownall,et al.  Metabolic basis of HIV-lipodystrophy syndrome. , 2002, American journal of physiology. Endocrinology and metabolism.

[31]  M. Schambelan,et al.  Management of Metabolic Complications Associated With Antiretroviral Therapy for HIV‐1 Infection: Recommendations of an International AIDS Society‐USA Panel , 2002, Journal of acquired immune deficiency syndromes.

[32]  B Clotet,et al.  Nevirapine-containing antiretroviral therapy in HIV-1 infected patients results in an anti-atherogenic lipid profile , 2001, AIDS.

[33]  M. Dubé.  Disorders of glucose metabolism in patients infected with human immunodeficiency virus. , 2000, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[34]  P. Morlat,et al.  Increase of atherogenic plasma profile in HIV-infected patients treated with protease inhibitor-containing regimens. , 2000, Journal of acquired immune deficiency syndromes.

[35]  L. Duvillard,et al.  HIV-1 protease inhibitors induce an increase of triglyceride level in HIV-infected men without modification of insulin sensitivity: a longitudinal study. , 2000, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[36]  M. Schambelan,et al.  Hyperlipidemia and Insulin Resistance Are Induced by Protease Inhibitors Independent of Changes in Body Composition in Patients With HIV Infection , 2000, Journal of acquired immune deficiency syndromes.

[37]  S M Marcovina,et al.  Atherogenic dyslipidemia in HIV-infected individuals treated with protease inhibitors. The Swiss HIV Cohort Study. , 1999, Circulation.

[38]  B. Gazzard,et al.  The acute-phase protein response to human immunodeficiency virus infection in human subjects. , 1999, The American journal of physiology.

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

[40]  J. Hokanson,et al.  Hypertriglyceridemia as a cardiovascular risk factor. , 1998, The American journal of cardiology.

[41]  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.

[42]  M. King,et al.  Atherogenic lipoprotein phenotype. A proposed genetic marker for coronary heart disease risk. , 1990, Circulation.

[43]  R. Turner,et al.  Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man , 1985, Diabetologia.

[44]  D. Sviridov,et al.  HIV infection and high-density lipoprotein: the effect of the disease vs the effect of treatment. , 2006, Metabolism: clinical and experimental.

[45]  W. Howard.  Trends in Serum Lipids and Lipoproteins of Adults, 1960–2002Carroll MD, Lacher DA, Sorlie PD, et al (Centers for Disease Control and Prevention, Hyattsville, Md; NIH, Bethesda, Md; Univ of Texas, Dallas) JAMA 294:1773–1781, 2005§ , 2006 .

[46]  S. Grundy,et al.  National Cholesterol Education Program Third Report of the National Cholesterol Education Program ( NCEP ) Expert Panel on Detection , Evaluation , and Treatment of High Blood Cholesterol in Adults ( Adult Treatment Panel III ) Final Report , 2022 .

[47]  M. Taskinen.  Diabetic dyslipidemia. , 2002, Atherosclerosis. Supplements.

[48]  J. Mckenney,et al.  Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). , 2001, JAMA.

[49]  Treatment of Obesity in Adults.  Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults--The Evidence Report. National Institutes of Health. , 1998, Obesity research.

[50]  A. von Eckardstein,et al.  The emergence of triglycerides as a significant independent risk factor in coronary artery disease. , 1998, European heart journal.