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      Clinical use of cobicistat as a pharmacoenhancer of human immunodeficiency virus therapy

      review-article

      HIV/AIDS (Auckland, N.Z.)

      Dove Medical Press

      human immunodeficiency virus, fixed-dose combinations, pharmacoenhancers, drug safety

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          Abstract

          The pharmacoenhancement of plasma concentrations of protease inhibitors by coadministration of so-called boosters has been an integral part of antiretroviral therapy for human immunodeficiency virus (HIV) for 1.5 decades. Nearly all HIV protease inhibitors are combined with low-dose ritonavir or cobicistat, which are able to effectively inhibit the cytochrome-mediated metabolism of HIV protease inhibitors in the liver and thus enhance the plasma concentration and prolong the dosing interval of the antiretrovirally active combination partners. Therapies created in this way are clinically effective regimens, being convenient for patients and showing a high genetic barrier to viral resistance. In addition to ritonavir, which has been in use since 1996, cobicistat, a new pharmacoenhancer, has been approved and is widely used now. The outstanding property of cobicistat is its cytochrome P450 3A-selective inhibition of hepatic metabolism of antiretroviral drugs, in contrast with ritonavir, which not only inhibits but also induces a number of cytochrome P450 enzymes, UDP-glucuronosyltransferase, P-glycoprotein, and other cellular transporters. This article reviews the current literature, and compares the pharmacokinetics, pharmacodynamics, and safety of both pharmacoenhancers and discusses the clinical utility of cobicistat in up-to-date and future HIV therapy.

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          Most cited references 76

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          Fixed-dose combinations improve medication compliance: a meta-analysis.

          Compliance with treatment is a sine qua non for successful treatment of chronic conditions like hypertension. Fixed-dose combinations are designed to simplify the medication regimen and potentially improve compliance. However the data on comparison of fixed-dose combination with free-drug regimen to improve patient's medication compliance is limited. We conducted a MEDLINE search of studies using the words fixed-dose combinations, compliance and/or adherence. The inclusion criteria were studies which involved fixed-dose combination versus free-drug components of the regimen given separately. Only studies which reported patient's compliance were included. Of the 68 studies on fixed-dose combinations, only 9 studies fulfilled the inclusion criteria. Two studies were in patients with tuberculosis, 4 in the hypertensive population, 1 in patients with human immunodeficiency virus (HIV) disease and 2 in the diabetic population. A total of 11,925 patients on fixed-dose combination were compared against 8317 patients on free-drug component regimen. Fixed-dose combination resulted in a 26% decrease in the risk of non-compliance compared with free-drug component regimen (pooled relative risk [RR] 0.74; 95% confidence interval [CI], 0.69-0.80; P <.0001). There was no evidence of heterogeneity in this analysis (chi(2)=14.49, df=8; P=.07). A subgroup analysis of the 4 studies on hypertension showed that fixed-dose combination (pooled RR 0.76; 95% CI, 0.71-0.81; P <.0001) decreased the risk of medication non-compliance by 24% compared with free-drug combination regimen. Fixed-dose combination decreases the risk of medication non-compliance and should be considered in patients with chronic conditions like hypertension for improving medication compliance which can translate into better clinical outcomes.
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            Decline in the AIDS and death rates in the EuroSIDA study: an observational study.

             O Kirk,  A Mocroft,  B Knysz (2003)
            Since the introduction of highly active antiretroviral therapy (HAART), little is known about whether changes in HIV-1 mortality and morbidity rates have been sustained. We aimed to assess possible changes in these rates across Europe. We analysed data for 9803 patients in 70 European HIV centres including ones in Israel and Argentina. Incidence rates of AIDS or death were calculated for overall and most recent CD4 count in 6-monthly periods and in three treatment eras (pre-HAART, 1994-1995; early-HAART, 1996-1997; and late-HAART, 1998-2002). The incidence of AIDS or death fell after September, 1998, by 8% per 6-month period (rate ratio 0.92, 95% CI 0.88-0.95, p<0.0001). When AIDS and death were analysed separately, the incidence of all deaths during the late-HAART era was significantly lower than that during the early-HAART era in patients whose latest CD4 count was 20 cells/microL or less (0.43, 0.35-0.53, p<0.0001), but at higher CD4 counts, did not differ between early-HAART and late-HAART. Incidence of AIDS was about 50% lower in late-HAART than in early-HAART, irrespective of latest CD4 count (p<0.0001). In multivariate Cox's models, with early-HAART as the reference, there was an increased risk of AIDS (relative hazard 1.39; 95% CI 1.16-1.67, p=0.0004) and all deaths (1.29; 1.08-1.56, p=0.0065) in the pre-HAART era, and a reduced risk of AIDS (0.62; 0.50-0.77, p<0.0001) and all deaths (0.66; 0.53-0.82, p=0.0002) in the late-HAART era. The initial drop in mortality and morbidity after the introduction of HAART has been sustained. Potential long-term adverse effects associated with HAART have not altered its effectiveness in treating AIDS.
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              Rational design of peptide-based HIV proteinase inhibitors.

              A series of peptide derivatives based on the transition-state mimetic concept has been designed that inhibit the proteinase from the human immunodeficiency virus (HIV). The more active compounds inhibit both HIV-1 and HIV-2 proteinases in the nanomolar range with little effect at 10 micromolar against the structurally related human aspartic proteinases. Proteolytic cleavage of the HIV-1 gag polyprotein (p55) to the viral structural protein p24 was inhibited in chronically infected CEM cells. Antiviral activity was observed in the nanomolar range (with one compound active below 10 nanomolar) in three different cell systems, as assessed by p24 antigen and syncytium formation. Cytotoxicity was not detected at 10 and 5 micromolar in C8166 and JM cells, respectively, indicating a high therapeutic index for this new class of HIV proteinase inhibitors.
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                Author and article information

                Journal
                HIV AIDS (Auckl)
                HIV AIDS (Auckl)
                HIV/AIDS - Research and Palliative Care
                HIV/AIDS (Auckland, N.Z.)
                Dove Medical Press
                1179-1373
                2016
                22 December 2015
                : 8
                : 1-16
                Affiliations
                HIV Center, Medical Department II, Hospital of the JW Goethe-University, Frankfurt, BAG Darab-Kaboly/von Hentig, General Medicine and HIV Care, Frankfurt am Main, Germany
                Author notes
                Correspondence: Nils von Hentig, Department of Internal Medicine II, HIV Center, Johann Wolfgang Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany, BAG Darab-Kaboly/von Hentig, Ziegelhüttenweg 1-3, 60598, Frankfurt am Main, Germany, Tel +49 6961 4031, Fax +49 69 6032 5884, Email hentig@ 123456em.uni-frankfurt.de
                Article
                hiv-8-001
                10.2147/HIV.S70836
                4694690
                26730211
                c50aae7f-c3bf-4c6a-8812-f4882719b536
                © 2016 von Hentig. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License.

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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