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      Evidence-based review of statin use in patients with HIV on antiretroviral therapy

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          Highlights

          • Cardiovascular disease is up to two times more prevalent in patient with HIV.

          • Based on pharmacokinetic and clinical data, atorvastatin and pravastatin are generally considered safe for HIV patients receiving ART.

          • Rosuavstatin is generally safe if started at a low dose and a maximum 20 mg per day.

          • Fluvastatin, lovastatin, and simvastatin should be avoided in patients with HIV receiving ART.

          Abstract

          Introduction

          As a result of improved safe and effective therapeutic options for human immunodeficiency virus (HIV), life expectancy of those living with HIV is increasing leading to new challenges (e.g., management of chronic diseases). Some chronic diseases (e.g., cardiovascular disease [CVD]), are up to two times more prevalent in patients with HIV. Statins are a mainstay of therapy for prevention of CVD; but, clinicians should be aware that not all statins are appropriate for use in the HIV population, especially those receiving antiretroviral therapy (ART). The purpose of this article is to review the pharmacokinetic and clinical data for statin therapy in HIV-infected patients receiving ART.

          Methods

          A systematic literature search using PubMed and MEDLINE databases was performed using each statin drug name combined with HIV, pharmacokinetics, AIDS, and/or human immunodeficiency virus. English language trials published from 1946 to November 2016 were considered, and results were limited to clinical efficacy trials.

          Results

          In general, atorvastatin and pravastatin are safe and effective for patients treated with protease-inhibitor (PI) or non-nucleoside reverse transcriptase inhibitor-based ART. Rosuvastatin is generally considered safe if started at a low dose, but should be avoided if possible in patients receiving PI-based ART. Pitavastatin has limited supporting evidence, but appears safe for use based on its pharmacokinetic properties and low number of drug interactions. Fluvastatin, lovastatin, and simvastatin should be avoided in patients receiving ART due to drug interactions, adverse events, and/or limited clinical data.

          Conclusion

          Clinicians need to be familiar with the intricacies of statin selection for the prevention of CVD in patients with HIV on ART.

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          Most cited references71

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          Preclinical atherosclerosis due to HIV infection: carotid intima-medial thickness measurements from the FRAM study.

          Cardiovascular disease (CVD) is an increasing cause of morbidity and mortality in HIV-infected patients. However, it is controversial whether HIV infection contributes to accelerated atherosclerosis independent of traditional CVD risk factors. Cross-sectional study of HIV-infected participants and controls without pre-existing CVD from the study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM) and the Multi-Ethnic Study of Atherosclerosis (MESA). Preclinical atherosclerosis was assessed by carotid intima-medial thickness (cIMT) measurements in the internal/bulb and common regions in HIV-infected participants and controls after adjusting for traditional CVD risk factors. For internal carotid, mean IMT was 1.17 +/- 0.50 mm for HIV-infected participants and 1.06 +/- 0.58 mm for controls (P < 0.0001). After multivariable adjustment for demographic characteristics, the mean difference of HIV-infected participants vs. controls was 0.188 mm [95% confidence interval (CI) 0.113-0.263, P < 0.0001]. Further adjustment for traditional CVD risk factors modestly attenuated the HIV association (0.148 mm, 95% CI 0.072-0.224, P = 0.0001). For the common carotid, HIV infection was independently associated with greater IMT (0.033 mm, 95% CI 0.010-0.056, P = 0.005). The association of HIV infection with IMT was similar to that of smoking, which was also associated with greater IMT (internal 0.173 mm, common 0.020 mm). Even after adjustment for traditional CVD risk factors, HIV infection was accompanied by more extensive atherosclerosis measured by IMT. The stronger association of HIV infection with IMT in the internal/bulb region compared with the common carotid may explain previous discrepancies in the literature. The association of HIV infection with IMT was similar to that of traditional CVD risk factors, such as smoking. 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins
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            Ritonavir. Clinical pharmacokinetics and interactions with other anti-HIV agents.

            Ritonavir is 1 of the 4 potent synthetic HIV protease inhibitors, approved by the US Food and Drug Administration (FDA) between 1995 and 1997, that have revolutionised HIV therapy. The extent of oral absorption is high and is not affected by food. Within the clinical concentration range, ritonavir is approximately 98 to 99% bound to plasma proteins, including albumin and alpha 1-acid glycoprotein. Cerebrospinal fluid (CSF) drug concentrations are low in relation to total plasma concentration. However, parallel decreases in the viral burden have been observed in the plasma, CSF and other tissues. Ritonavir is primarily metabolised by cytochrome P450 (CYP) 3A isozymes and, to a lesser extent, by CYP2D6. Four major oxidative metabolites have been identified in humans, but are unlikely to contribute to the antiviral effect. About 34% and 3.5% of a 600 mg dose is excreted as unchanged drug in the faeces and urine, respectively. The clinically relevant t1/2 beta is about 3 to 5 hours. Because of autoinduction, plasma concentrations generally reach steady state 2 weeks after the start of administration. The pharmacokinetics of ritonavir are relatively linear after multiple doses, with apparent oral clearance averaging 7 to 9 L/h. In vitro, ritonavir is a potent inhibitor of CYP3A. In vivo, ritonavir significantly increases the AUC of drugs primarily eliminated by CYP3A metabolism (e.g. clarithromycin, ketoconazole, rifabutin, and other HIV protease inhibitors, including indinavir, saquinavir and nelfinavir) with effects ranging from an increase of 77% to 20-fold in humans. It also inhibits CYP2D6-mediated metabolism, but to a significantly lesser extent (145% increase in desipramine AUC). Since ritonavir is also an inducer of several metabolising enzymes [CYP1A4, glucuronosyl transferase (GT), and possibly CYP2C9 and CYP2C19], the magnitude of drug interactions is difficult to predict, particularly for drugs that are metabolised by multiple enzymes or have low intrinsic clearance by CYP3A. For example, the AUC of CYP3A substrate methadone was slightly decreased and alprazolam was unaffected. Ritonavir is minimally affected by other CYP3A inhibitors, including ketoconazole. Rifampicin (rifampin), a potent CYP3A inducer, decreased the AUC of ritonavir by only 35%. The degree and duration of suppression of HIV replication is significantly correlated with the plasma concentrations. Thus, the large increase in the plasma concentrations of other protease inhibitors when coadministered with ritonavir forms the basis of rational dual protease inhibitor regimens, providing patients with 2 potent drugs at significantly reduced doses and less frequent dosage intervals. Combination treatment of ritonavir with saquinavir and indinavir results in potent and sustained clinical activity. Other important factors with combination regimens include reduced interpatient variability for high clearance agents, and elimination of the food effect on the bioavailibility of indinavir.
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              Effects of statin therapy on coronary artery plaque volume and high-risk plaque morphology in HIV-infected patients with subclinical atherosclerosis: a randomised, double-blind, placebo-controlled trial.

              HIV-infected patients have a high risk of myocardial infarction. We aimed to assess the ability of statin treatment to reduce arterial inflammation and achieve regression of coronary atherosclerosis in this population.
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                Author and article information

                Contributors
                Journal
                J Clin Transl Endocrinol
                J Clin Transl Endocrinol
                Journal of Clinical & Translational Endocrinology
                Elsevier
                2214-6237
                22 February 2017
                June 2017
                22 February 2017
                : 8
                : 6-14
                Affiliations
                [a ]University of Georgia College of Pharmacy, Albany, GA, USA
                [b ]Phoebe Putney Memorial Hospital, Department of Pharmacy, Albany, GA, USA
                [c ]The University of Mississippi School of Pharmacy, Jackson, MS, USA
                [d ]The University of Mississippi School of Medicine, Jackson, MS, USA
                Author notes
                [* ]Corresponding author at: The University of Mississippi School of Pharmacy, Jackson, MS, USAThe University of Mississippi School of PharmacyJacksonMSUSA driche@ 123456umc.edu
                Article
                S2214-6237(17)30014-5
                10.1016/j.jcte.2017.01.004
                5651339
                bd3dc382-f16d-4590-bfc9-f31d4df14f3b
                © 2017 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 3 December 2016
                : 27 January 2017
                : 29 January 2017
                Categories
                Review

                antiretroviral therapy,hiv,statins,lipids,cvd
                antiretroviral therapy, hiv, statins, lipids, cvd

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