Effect of antiretroviral therapy use and adherence on the risk of hyperlipidemia among HIV-infected patients, in the highly active antiretroviral therapy era

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Abstract

HIV-infected patients exposed to antiretroviral therapy (ART) have an increased risk for hyperlipidemia and cardiovascular disease. We performed a longitudinal, comprehensive, and population-based study to investigate the cumulative effect of different types of ART regimens on hyperlipidemia risk in the Taiwanese HIV/ART cohort. A total of 13,370 HIV-infected patients (2,674 hyperlipidemia and 10,696 non-hyperlipidemia patients) were recruited after matching for age, gender, and the first diagnosis date of HIV infection by using the National Health Insurance Research Database in Taiwan. Hyperlipidemia risk associated with cumulative ART use, ART adherence, and their combination was assessed. The matched hyperlipidemia group had a larger number of patients using ART and a higher incidence of comorbidities, specifically, respiratory disease and diabetes. Patients with high ART dosage and dose-dependent manner adherence, respectively, demonstrated an increased risk of hyperlipidemia. For single ART regimens, patients receiving nucleoside reverse-transcriptase inhibitors (NRTI/NRTI)- containing regimen had the highest hyperlipidemia risk, followed by protease inhibitor (PI)- containing and non-NRTI- containing regimens. For combination ART regimens, patients receiving a NRTI/NRTI + PI regimen had the highest hyperlipidemia risk. An increased cumulative drug dose was observed in patients who received the PI, NRTI/NRTI, NRTI, and NNRTI regimens in the hyperlipidemia group, when compared to the non-hyperlipidemia group. In conclusion, ART cumulative use, adherence, and regimen may affect hyperlipidemia risk among HIV-infected patients in a dose-dependent manner.

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A review of the toxicity of HIV medications.

Asa M Margolis, Harry Heverling, Paul A Pham … (2014)

Antiretroviral therapy has changed human immunodeficiency virus (HIV) infection from a near-certainly fatal illness to one that can be managed chronically. More patients are taking antiretroviral drugs (ARVs) for longer periods of time, which naturally results in more observed toxicity. Overdose with ARVs is not commonly reported. The most serious overdose outcomes have been reported in neonates who were inadvertently administered supratherapeutic doses of HIV prophylaxis medications. Typical ARV regimens include a "backbone" of two nucleoside reverse transcriptase inhibitors (NRTI) and a "base" of either a protease inhibitor (PI) or nonnucleoside reverse transcriptase inhibitor. New classes of drugs called entry inhibitors and integrase inhibitors have also emerged. Older NRTIs were associated with mitochondrial toxicity, but this is less common in the newer drugs, emtricitabine, lamivudine, and tenofovir. Mitochondrial toxicity results from NRTI inhibition of a mitochondrial DNA polymerase. Mitochondrial toxicity manifests as myopathy, neuropathy, hepatic failure, and lactic acidosis. Routine lactate assessment in asymptomatic patients is not indicated. Lactate concentration should be obtained in patients taking NRTIs who have fatigue, nausea, vomiting, or vague abdominal pain. Mitochondrial toxicity can be fatal and is treated by supportive care and discontinuing NRTIs. Metabolic cofactors like thiamine, carnitine, and riboflavin may be helpful in managing mitochondrial toxicity. Lipodystrophy describes changes in fat distribution and lipid metabolism that have been attributed to both PIs and NRTIs. Lipodystrophy consists of loss of fat around the face (lipoatrophy), increase in truncal fat, and hypertriglyceridemia. There is no specific treatment of lipodystrophy. Clinicians should be able to recognize effects of chronic toxicity of ARVs, especially mitochondrial toxicity.

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HIV infection and the risk of diabetes mellitus.

Debra Butt, Matthew Bidwell Goetz, David Leaf … (2009)

The influence of HIV infection on the risk of diabetes is unclear. We determined the association and predictors of prevalent diabetes mellitus in HIV infected and uninfected veterans. We determined baseline prevalence and risk factors for diabetes between HIV infected and uninfected veterans in the Veterans Aging Cohort Study. Logistic regression was used to determine the odds of diabetes in HIV infected and uninfected persons. We studied 3227 HIV-infected and 3240 HIV-uninfected individuals. HIV-infected individuals were younger, more likely to be black males, have HCV coinfection and a lower BMI. HIV-infected individuals had a lower prevalence of diabetes at baseline (14.9 vs. 21.4%, P < 0.0001). After adjustment for known risk factors, HIV-infected individuals had a lower risk of diabetes (odds ratio = 0.84, 95% confidence interval = 0.72-0.97). Increasing age, male sex, minority race, and BMI were associated with an increased risk. The odds ratio for diabetes associated with increasing age, minority race and BMI were greater among HIV-infected veterans. HCV coinfection and nucleoside and nonnucleoside reverse transcriptase inhibitor therapy were associated with a higher risk of diabetes in HIV-infected veterans. Although HIV infection itself is not associated with increased risk of diabetes, increasing age; HCV coinfection and BMI have a more profound effect upon the risk of diabetes among HIV-infected persons. Further, long-term ARV treatment also increases risk. Future studies will need to determine whether incidence of diabetes mellitus differs by HIV status.

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Pathogenesis of HIV-1-protease inhibitor-associated peripheral lipodystrophy, hyperlipidaemia, and insulin resistance.

Andrew G. Carr, Katherine Samaras, Donald J. Chisholm … (1998)

HIV-1 protease-inhibitor treatments are associated with a syndrome of peripheral lipodystrophy, central adiposity, breast hypertrophy in women, hyperlipidaemia, and insulin resistance. The catalytic region of HIV-1 protease, to which protease inhibitors bind, has approximately 60% homology to regions within two proteins that regulate lipid metabolism: cytoplasmic retinoic-acid binding protein type 1 (CRABP-1) and low density lipoprotein-receptor-related protein (LRP). We hypothesise that protease inhibitors inhibit CRABP-1-modified, and cytochrome P450 3A-mediated synthesis of cis-9-retinoic acid, a key activator of the retinoid X receptor; and peroxisome proliferator activated receptor type gamma (PPAR-gamma) heterodimer, an adipocyte receptor that regulates peripheral adipocyte differentiation and apoptosis. Protease-inhibitor binding to LRP would impair hepatic chylomicron uptake and triglyceride clearance by the endothelial LRP-lipoprotein lipase complex. The resulting hyperlipidaemia contributes to central fat deposition (and in the breasts in the presence of oestrogen), insulin resistance, and, in susceptible individuals, type 2 diabetes. Understanding the syndrome's pathogenesis should lead to treatment strategies and to the design of protease inhibitors that do not cause this syndrome.

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Author and article information

Journal

Journal ID (nlm-ta): Oncotarget

Journal ID (iso-abbrev): Oncotarget

Journal ID (publisher-id): Oncotarget

Journal ID (publisher-id): ImpactJ

Title: Oncotarget

Publisher: Impact Journals LLC

ISSN (Electronic): 1949-2553

Publication date Collection: 5 December 2017

Publication date (Electronic): 15 November 2017

Volume: 8

Issue: 63

Pages: 106369-106381

Affiliations

¹ School of Chinese Medicine, China Medical University, Taichung, Taiwan

² Genetic Center, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan

³ Asia University, Taichung, Taiwan

⁴ Graduate Institute of Biostatistics, School of Public Health, China Medical University, Taichung, Taiwan

⁵ Department of Microbiology and Immunology, Chang Gung University, Taoyuan, Taiwan

⁶ Section of Infectious Diseases, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan

⁷ Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan

⁸ National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA

⁹ Rheumatism Research Center, China Medical University Hospital, Taichung, Taiwan

¹⁰ School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan

¹¹ Department of Cosmetic Science, Providence University, Taichung, Taiwan

¹² Biostatistics Center, College of Management, Taipei Medical University, Taipei, Taiwan

¹³ School of Health Care Administration, College of Management, Taipei Medical University, Taipei, Taiwan

Author notes

Correspondence to: Ying-Ju Lin, yjlin.kath@ 123456gmail.com

Wen-Miin Liang, wmliang@ 123456mail.cmu.edu.tw

[*]

These authors contributed equally to this work

Article

Publisher ID: 22465

DOI: 10.18632/oncotarget.22465

PMC ID: 5739740

PubMed ID: 29290955

SO-VID: 7e828a3d-5bc6-4f84-bd4d-4581a5550b55

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Effect of antiretroviral therapy use and adherence on the risk of hyperlipidemia among HIV-infected patients, in the highly active antiretroviral therapy era

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Karger: Oncology

Most cited references 55

A review of the toxicity of HIV medications.

HIV infection and the risk of diabetes mellitus.

Pathogenesis of HIV-1-protease inhibitor-associated peripheral lipodystrophy, hyperlipidaemia, and insulin resistance.

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