Nevirapine and Efavirenz Elicit Different Changes in Lipid Profiles in Antiretroviral- Therapy-Naive Patients Infected with HIV-1

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ABSTRACT

Background

Patients infected with HIV-1 initiating antiretroviral therapy (ART) containing a non-nucleoside reverse transcriptase inhibitor (NNRTI) show presumably fewer atherogenic lipid changes than those initiating most ARTs containing a protease inhibitor. We analysed whether lipid changes differed between the two most commonly used NNRTIs, nevirapine (NVP) and efavirenz (EFV).

Methods and Findings

Prospective analysis of lipids and lipoproteins was performed in patients enrolled in the NVP and EFV treatment groups of the 2NN study who remained on allocated treatment during 48 wk of follow-up. Patients were allocated to NVP ( n = 417), or EFV ( n = 289) in combination with stavudine and lamivudine. The primary endpoint was percentage change over 48 wk in high-density lipoprotein cholesterol (HDL-c), total cholesterol (TC), TC:HDL-c ratio, non-HDL-c, low-density lipoprotein cholesterol, and triglycerides. The increase of HDL-c was significantly larger for patients receiving NVP (42.5%) than for patients receiving EFV (33.7%; p = 0.036), while the increase in TC was lower (26.9% and 31.1%, respectively; p = 0.073), resulting in a decrease of the TC:HDL-c ratio for patients receiving NVP (−4.1%) and an increase for patients receiving EFV (+5.9%; p < 0.001). The increase of non-HDL-c was smaller for patients receiving NVP (24.7%) than for patients receiving EFV (33.6%; p = 0.007), as were the increases of triglycerides (20.1% and 49.0%, respectively; p < 0.001) and low-density lipoprotein cholesterol (35.0% and 40.0%, respectively; p = 0.378). These differences remained, or even increased, after adjusting for changes in HIV-1 RNA and CD4+ cell levels, indicating an effect of the drugs on lipids over and above that which may be explained by suppression of HIV-1 infection. The increases in HDL-c were of the same order of magnitude as those seen with the use of the investigational HDL-c-increasing drugs.

Conclusion

NVP-containing ART shows larger increases in HDL-c and decreases in TC:HDL-c ratio than an EFV-containing regimen. Based on these findings, protease-inhibitor-sparing regimens based on non-nucleoside reverse transcriptase inhibitor, particularly those containing NVP, may be expected to result in a reduced risk of coronary heart disease.

Abstract

Comparison of two commonly prescribed non-nucleoside reverse transcriptase inhibitors shows that patients on nevirapine have better blood lipid profiles

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Most cited references 54

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Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study.

J Downs, M Clearfield, S. Weis … (1998)

Although cholesterol-reducing treatment has been shown to reduce fatal and nonfatal coronary disease in patients with coronary heart disease (CHD), it is unknown whether benefit from the reduction of low-density lipoprotein cholesterol (LDL-C) in patients without CHD extends to individuals with average serum cholesterol levels, women, and older persons. To compare lovastatin with placebo for prevention of the first acute major coronary event in men and women without clinically evident atherosclerotic cardiovascular disease with average total cholesterol (TC) and LDL-C levels and below-average high-density lipoprotein cholesterol (HDL-C) levels. A randomized, double-blind, placebo-controlled trial. Outpatient clinics in Texas. A total of 5608 men and 997 women with average TC and LDL-C and below-average HDL-C (as characterized by lipid percentiles for an age- and sex-matched cohort without cardiovascular disease from the National Health and Nutrition Examination Survey [NHANES] III). Mean (SD) TC level was 5.71 (0.54) mmol/L (221 [21] mg/dL) (51 st percentile), mean (SD) LDL-C level was 3.89 (0.43) mmol/L (150 [17] mg/dL) (60th percentile), mean (SD) HDL-C level was 0.94 (0.14) mmol/L (36 [5] mg/dL) for men and 1.03 (0.14) mmol/L (40 [5] mg/dL) for women (25th and 16th percentiles, respectively), and median (SD) triglyceride levels were 1.78 (0.86) mmol/L (158 [76] mg/dL) (63rd percentile). Lovastatin (20-40 mg daily) or placebo in addition to a low-saturated fat, low-cholesterol diet. First acute major coronary event defined as fatal or nonfatal myocardial infarction, unstable angina, or sudden cardiac death. After an average follow-up of 5.2 years, lovastatin reduced the incidence of first acute major coronary events (1 83 vs 116 first events; relative risk [RR], 0.63; 95% confidence interval [CI], 0.50-0.79; P<.001), myocardial infarction (95 vs 57 myocardial infarctions; RR, 0.60; 95% CI, 0.43-0.83; P=.002), unstable angina (87 vs 60 first unstable angina events; RR, 0.68; 95% CI, 0.49-0.95; P=.02), coronary revascularization procedures (157 vs 106 procedures; RR, 0.67; 95% CI, 0.52-0.85; P=.001), coronary events (215 vs 163 coronary events; RR, 0.75; 95% CI, 0.61-0.92; P =.006), and cardiovascular events (255 vs 194 cardiovascular events; RR, 0.75; 95% CI, 0.62-0.91; P = .003). Lovastatin (20-40 mg daily) reduced LDL-C by 25% to 2.96 mmol/L (115 mg/dL) and increased HDL-C by 6% to 1.02 mmol/L (39 mg/dL). There were no clinically relevant differences in safety parameters between treatment groups. Lovastatin reduces the risk for the first acute major coronary event in men and women with average TC and LDL-C levels and below-average HDL-C levels. These findings support the inclusion of HDL-C in risk-factor assessment, confirm the benefit of LDL-C reduction to a target goal, and suggest the need for reassessment of the National Cholesterol Education Program guidelines regarding pharmacological intervention.

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Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor-associated lipodystrophy, hyperlipidaemia, and diabetes mellitus: a cohort study.

A. Carr, K Samaras, A Thorisdottir … (1999)

The prevalence and severity of lipodystrophy syndrome with long-term therapy for HIV-1 infection that includes a protease inhibitor is unknown. We studied the natural course of the syndrome to develop diagnostic criteria and identifying markers that predict its severity. We assessed 113 patients who were receiving HIV-1 protease inhibitors (mean 21 months) and 45 HIV-1-infected patients (28 with follow-up) never treated with a protease inhibitor. Lipodystrophy was assessed by questionnaire (including patients' rating of severity), physical examination, and dual-energy x-ray absorptiometry. Body composition and fasting lipid and glycaemic variables were compared with data obtained 8 months previously. Oral glucose tolerance was investigated. There was 98% concordance between patients' reports of the presence or absence of lipodystrophy (reported by 83% of protease-inhibitor recipients and 4% of treatment-naïve patients; p=0.0001) and physical examination. Patients' ratings of lipodystrophy were significantly associated with declining total body fat (p=0.02). Lower body fat was independently associated with longer duration of protease-inhibitor therapy and lower bodyweight before therapy, and more severe lipodystrophy was associated with higher previous (p < 0.03) and current (p < or = 0.01) triglyceride and C-peptide concentrations, and less peripheral and greater central fat (p=0.005 and 0.09, respectively). Body fat declined a mean 1.2 kg over 8 months in protease-inhibitor recipients (p=0.05). The prevalence of hyperlipidaemia remained stable over time (74% of treated patients vs 28% of naïve patients; p=0.0001). Impaired glucose tolerance occurred in 16% of protease-inhibitor recipients and diabetes mellitus in 7%; in all but three patients these abnormalities were detected on 2 h post-glucose load values. Diagnosis and rating severity of lipodystrophy is aided by the combination of physical examination, patient's rating, and measurement of body fat, fasting triglycerides, and C-peptide. Weight before therapy, fasting triglyceride, and C-peptide concentrations early in therapy, and therapy duration seem to predict lipodystrophy severity. Lipodystrophy was common and progressive after almost 2 years of protease inhibitor therapy, but was not usually severe. Hyperlipidaemia and impaired glucose tolerance were also common.

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Impact of HIV infection and HAART on serum lipids in men.

Jane R. Evans, L Kingsley, Adrian Dobs … (2003)

Alterations in serum lipid values have been widely reported among persons infected with human immunodeficiency virus (HIV) type 1 treated with highly active antiretroviral therapy (HAART), but no data have yet been reported on changes from preseroconversion lipid values. To describe changes in serum cholesterol levels associated with HIV infection and antiretroviral medication exposure, and 1-time assessment of triglyceride levels post-HAART initiation. The Multicenter AIDS Cohort Study, a prospective study in which homosexual and bisexual men were enrolled and from which 50 of 517 HIV seroconverters were drawn for the analysis herein, who later initiated HAART, involving measurements of stored serum samples obtained between 1984 and 2002. Changes in levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) at 6 time points during an average of 12 years; 1-time assessment of triglyceride levels from the third post-HAART clinic visit. Among the 50 men, notable declines in mean serum TC (-30 mg/dL [-0.78 mmol/L]), HDL-C (-12 mg/dL [-0.31 mmol/L]), and LDL-C values (-22 mg/dL [-0.57 mmol/L]) were observed after HIV infection. Following HAART initiation, there were large increases in mean TC and LDL-C values (50 and 21 mg/dL [1.30 and 0.54 mmol/L], respectively); however, the mean changes from the preseroconversion values were 20 mg/dL (0.52 mmol/L) (95% confidence interval [CI], -1 to 41) and -1 mg/dL (-0.03 mmol/L) (95% CI, -25 to 22), respectively. Mean HDL-C remained below baseline levels throughout follow-up. The median value (interquartile range) of triglycerides was 225 mg/dL (2.54 mmol/L) (147-331 mg/dL). Before treatment, HIV infection results in substantial decreases in serum TC, HDL-C, and LDL-C levels. Subsequent HAART initiation is associated with increases in TC and LDL-C but little change in HDL-C. Increases in TC and LDL-C observed after about 3 years of HAART possibly represent a return to preinfection serum lipid levels after accounting for expected age-related changes.

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Author and article information

Contributors

: Role: Academic Editor

Journal

Journal ID (nlm-ta): PLoS Med

Journal ID (publisher-id): pmed

Title: PLoS Medicine

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Print): 1549-1277

ISSN (Electronic): 1549-1676

Publication date (Print): October 2004

Publication date (Electronic): 19 October 2004

Volume: 1

Issue: 1

Electronic Location Identifier: e19

Affiliations

[1] 1International Antiviral Therapy Evaluation Center, Division of Infectious Diseases, Tropical Medicine, and AIDS, Department of Internal Medicine, Academic Medical Center, University of Amsterdam The Netherlands

[2] 2Thai Red Cross AIDS Research Center BangkokThailand

[3] 3Department of Vascular Medicine, Academic Medical Center, University of Amsterdam The Netherlands

[4] 4Chelsea and Westminster Hospital LondonUnited Kingdom

[5] 5Fundacion Huesped Buenos AiresArgentina

[6] 6University Hospital NantesFrance

[7] 7Sommerset Hospital CapetownSouth Africa

[8] 8University of Capetown South Africa

[9] 9Holdsworth House General Practice DarlinghurstAustralia

[10] 10Hospital Pitie-Salpetriere ParisFrance

[11] 11Hospital Sao Francisco de Assis Rio de JaneiroBrazil

[12] 12Hospital University Clementino Fraga Filoho Rio de JaneiroBrazil

[13] 13Northwestern University Chicago, IllinoisUnited States of America

[14] 14Wojewodzki Szpital Zakazny WarsawaPoland

[15] 15Boehringer Ingelheim, Ridgefield ConnecticutUnited States of America

[16]St. Vincent's Hospital Australia

Author notes

Competing Interests: FvL has received travel grants and honoraria for presentations from Boehringer Ingelheim and travel grants from GlaxoSmithKline. PP has received research grants and honoraria for speaking from GlaxoSmithKline, Bristol-Myers Squibb, Roche, Merck Sharp and Dohme, and Boerhinger Ingleheim. BG has received grants and honoraria from Abbott Pharmaceuticals, GlaxoSmithKline, Bristol-Myers Squibb, Gilead, and Boehringer Ingleheim. FR has received research grants and honoraria from GlaxoSmithKline, Roche, Bristol-Myers Squibb, Abbott, and Boehringer Ingleheim. RW is conducting clinical research supported by GlaxoSmithKline, Boehringer Ingelheim, Pfizer, and Bristol-Myers Squibb. MB is currently conducting clinical studies supported by Boehringer Ingelheim, Bristol-Myers Squibb, and Merck. CK has received grants and honoraria for speaking from Bristol-Myers Squibb, GlaxoSmithKline, Boehringer Ingelheim, Bayer, and Roche. MS has received research grants, travel grants, and honoraria for speaking from Abbott, Bristol-Myers Squibb, Boehringer Ingelheim, GlaxoSmithKline, Gilead, Merck, and Roche. RLM has received honoraria for consultancies from Boehringer Ingelheim and Bristol-Myers Squibb. AH has received honoraria for presentations from Boehringer Ingleheim. DBH is employed by Boehringer Ingelheim, the manufacturer of one of the trial medications. JMAL has received honoraria as an advisor for GlaxoSmithKline, Boehringer Ingelheim, Bristol-Myers Squibb, Roche, Merck Sharp and Dohme, Schering-Plough, Bayer, Shire Pharmaceuticals, Agouron/Pfizer, and Virco/Tibotec. PR, in the last five years, has received honoraria for speaking engagements from Boehringer Ingelheim.

JMAL is a member of the editorial board of PLoS Medicine.

Author Contributions: FvL, ES, DBH, JMAL, and PR designed the study. FvL and DBH analysed the data. PP, BG, PC, FR, RW, MB, CK, MS, RLM, and AH enrolled patients. FvL wrote the first draft of the paper. All authors contributed to the writing of the final version of the manuscript.

*To whom correspondence should be addressed. E-mail: f.vanleth@ 123456iatec.com

Article

DOI: 10.1371/journal.pmed.0010019

PMC ID: 523838

PubMed ID: 15526045

SO-VID: 2b69ed5e-d7ba-408f-ae74-8a9d6ed14798

Copyright © Copyright: © 2004 van Leth et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Nevirapine and Efavirenz Elicit Different Changes in Lipid Profiles in Antiretroviral- Therapy-Naive Patients Infected with HIV-1

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ABSTRACT

Background

Methods and Findings

Conclusion

Abstract

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Annual Reviews HIV/AIDS: Public Health and Society

Most cited references 54

Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study.

Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor-associated lipodystrophy, hyperlipidaemia, and diabetes mellitus: a cohort study.

Impact of HIV infection and HAART on serum lipids in men.

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