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Atazanavir

A Review of its Use in the Management of HIV-1 Infection

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Summary

Abstract

Atazanavir (Reyataz®), a protease inhibitor (PI), is approved in many countries for use as a component of antiretroviral therapy (ART) regimens for the treatment of adult, and in some countries in paediatric, patients with HIV-1 infection. ART regimens containing ritonavir-boosted atazanavir improved virological and immunological markers in adult patients with HIV-1 infection, and had similar efficacy to regimens containing lopinavir/ritonavir in treatment-naive and treatment-experienced patients. In addition, unboosted atazanavir was noninferior to ritonavir-boosted atazanavir in treatment-naive patients. Atazanavir is administered once daily and has a low capsule burden. Atazanavir, whether unboosted or boosted, was generally well tolerated and appeared to be associated with less marked metabolic effects, including less alteration of lipid levels, than other PIs. These properties mean that boosted atazanavir, and unboosted atazanavir in patients unable to tolerate ritonavir, continues to have a role as a component of ART regimens in patients with HIV-1 infection.

Pharmacological Properties

Atazanavir is a potent, HIV-1-specific PI that prevents the formation of mature virions in HIV-1-infected cells by inhibiting the cleavage of gag and gag-pol polyproteins. At the highest concentrations evaluated, there was no antagonistic antiretroviral activity, or enhanced cytotoxicity, in two-drug combinations of atazanavir with several nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), PIs, non-nucleoside reverse transcriptase inhibitors, an HIV-1 fusion inhibitor, or agents used for the treatment of viral hepatitis.

The signature resistance mutation for atazanavir has been identified as an isoleucine to leucine substitution at residue 50 (I50L). This mutation conferred resistance to atazanavir, but increased susceptibility to other PIs. Nonetheless, when the I50L substitution developed in isolates with other PI-associated mutations already present, these isolates were cross-resistant to other PIs. Virological response to atazanavir in ART-experienced patients was affected by the type and number of PI mutations present at baseline.

The absorption parameters of orally administered atazanavir were nonlinear after multiple doses. Steady-state was reached after approximately 6 days. Boosting with low-dose ritonavir increased plasma concentrations of atazanavir. Atazanavir was metabolized by cytochrome P450 isozyme 3A4 to inactive metabolites, and eliminated primarily via the biliary route. The elimination profile of atazanavir allows for once-daily administration. Pharmacokinetic drug interactions have been demonstrated between atazanavir and several drugs. For example, in treatment-experienced patients, concomitant administration with efavirenz is not recommended and proton-pump inhibitors should not be used.

Therapeutic Efficacy

The efficacy of ART regimens containing unboosted or boosted atazanavir has been assessed in a number of well designed trials in ART-naive and ART-experienced adults with HIV-1 infection. Patients also received dual-NRTI therapy, and virological efficacy was generally assessed using the mean change in viral load and/or the proportion of patients with viral load below the limit of quantification after 48–96 weeks of treatment.

In ART-naive patients receiving dual-NRTI backbone therapy, the virological efficacy of unboosted atazanavir 400 mg once daily was similar to that of unboosted nelfinavir and was noninferior to that of efavirenz in three 48-week trials. A 24-week extension of one study showed that viral suppression was maintained at 72 weeks with unboosted atazanavir. Similarly, the virological efficacy of once-daily atazanavir 300 mg boosted with ritonavir 100 mg was noninferior to that of lopinavir/ritonavir in ART-naive patients receiving dual-NRTI backbone therapy in a 96-week trial. In these studies, outcomes were similar for immunological response, as assessed by change in CD4+ cell count.

In ART-experienced patients with a history of virological failure on PI-containing regimens, the efficacy of boosted atazanavir was noninferior to that of lopinavir/ritonavir in terms of viral suppression, when both regimens were coadministered with dual-NRTI therapy for 48 weeks. The effect with boosted atazanavir was maintained in the longer term, with noninferiority to lopinavir/ritonavir also demonstrated after 96 weeks. However, unboosted atazanavir provided less viral suppression than a regimen containing lopinavir/ritonavir in similar patients.

In ART-experienced patients with prolonged virological suppression on a PI-containing ART regimen, a switch to an atazanavir-based regimen was non-inferior or similar to remaining on the original regimen in terms of maintaining suppression in three 48-week trials. In one of these trials (SWAN), the rate of virological failure was significantly reduced and the time to virological failure significantly increased in patients switching to atazanavir-based regimens, compared with patients who continued with the original PI-containing regimens.

Tolerability

In clinical trials, the most common adverse events reported with atazanavir (administered in combination with NRTI therapy) were nausea, jaundice and diarrhoea. The most common laboratory abnormality was elevated total bilirubin, which was generally due to elevated indirect (unconjugated) bilirubin, related to inhibition of uridine-glucuronosyl transferase 1A1. The tolerability profiles of unboosted and boosted atazanavir were generally similar, with the exception that jaundice and hyperbilirubinaemia were more common with boosted atazanavir. The overall incidence of adverse events was generally similar for atazanavir-based therapy and comparators, but jaundice and elevated bilirubin levels were more common with atazanavir than with nelfinavir, lopinavir/ritonavir, fosamprenavir plus ritonavir and efavirenz, and diarrhoea was less common with atazanavir than with nelfinavir, lopinavir/ritonavir and fosamprenavir plus ritonavir. Rash, mostly mild to moderate in severity, was reported in ≈20% of atazanavir recipients in clinical trials. PR interval prolongation may occur in some patients receiving atazanavir, and patients with chronic hepatitis B or C may be at risk of increased transaminases or hepatic decompensation during atazanavir therapy.

In clinical trials, unboosted atazanavir had a lower propensity to alter total cholesterol, low-density lipoprotein cholesterol and triglyceride levels than nelfinavir, lopinavir/ritonavir or efavirenz in antiretroviral-naive patients, and boosted atazanavir had a lower propensity to alter total cholesterol, non-high-density lipoprotein cholesterol and triglyceride levels compared with lopinavir/ritonavir in ART-naive or -experienced patients. Like other antiretroviral regimens, atazanavir-based regimens can be associated with fat accumulation, generally around the trunk, and some limb fat loss in the longer term, but there were no differences in fat accumulation or distribution for atazanavir compared with efavirenz or lopinavir/ritonavir. Atazanavir had no significant effect on blood glucose or insulin levels.

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Authors and Affiliations

  1. Wolters Kluwer Health ¦ Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, North Shore, Auckland, 0754, New Zealand

    Katherine F. Croom, Sohita Dhillon & Susan J. Keam

  2. Wolters Kluwer Health, Philadelphia, Pennsylvania, USA

    Katherine F. Croom, Sohita Dhillon & Susan J. Keam

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  1. Katherine F. Croom
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  2. Sohita Dhillon
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  3. Susan J. Keam
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Correspondence to Sohita Dhillon.

Additional information

Various sections of the manuscript reviewed by: F. Cainelli, School of Medicine, Faculty of Health Sciences, University of Botswana, Gaborone, Botswana; F. Gutiérrez, Infectious Diseases & HIV-1 Unit, Hospital General Universitario de Elche, Elche, Spain; K.A. Lichtenstein, School of Medicine, Division of Infectious Diseases, University of Colorado Health Sciences Center, Denver, Colorado, USA; J.D. Scott, Pharmacy Practice and Administration, Western University of Health Sciences, Pomona, California, USA; E. Seminari, Clinical Epidemiology and Biometric Unit, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo Pavia, Pavia, Italy; R. ter Heine, Department of Pharmacy and Pharmacology, Slotervaart Hospital, Amsterdam, the Netherlands.

Data Selection

Sources: Medical literature published in any language since 1980 on ‘atazanavir’, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Wolters Kluwer Health ∣ Adis). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: MEDLINE, EMBASE and AdisBase search terms were ‘atazanavir’ and ‘HIV-1 infections’. Searches were last updated 22 May 2009.

Selection: Studies in patients with HIV-1 infection who received atazanavir. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Atazanavir, HIV-1 infection, protease inhibitors, antiretroviral therapy, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability.

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Croom, K.F., Dhillon, S. & Keam, S.J. Atazanavir. Drugs 69, 1107–1140 (2009). https://doi.org/10.2165/00003495-200969080-00009

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