JAIDS Journal of Acquired Immune Deficiency Syndromes:
Letters to the Editor
Calcagno, Andrea MD*; Bonora, Stefano MD*; Tettoni, Maria Cristina MD*; D'Avolio, Antonio BSc, MSc*; Di Perri, Giovanni MD, PhD*; Lanzafame, Massimiliano MD†; Penco, Giovanni MD‡
*Department of Infectious Diseases, University of Torino, Torino, Italy, †Unit of Infectious Diseases, University of Verona, Verona, Italy, ‡Unit of Infectious Diseases, Galliera Hospital, Genova, Italy
To the Editors:
Use of unboosted atazanavir (ATV) in selected patients is an attractive option due to its convenience and favorable metabolic profile. In Induction-Maintenance With Atazanavir in HIV Naive Patients (INDUMA) study,1 switching from 300 mg boosted by 100 mg of ritonavir to unboosted 400 mg ATV-containing regimen was recently shown to be virologically equivalent as compared with continuation of ATV/ritonavir as a first-line regimen. However, lower plasma concentrations and higher interindividual variability associated with unboosted dosing could lead to inadequate ATV plasma exposure and increased risk of virological failure.2,3 Coadministration of tenofovir (TDF) with unboosted ATV is contraindicated by current guidelines4 because the former has been shown to further decrease ATV plasma exposure (area under the curve and minimum concentration by 25% and 40%, respectively).5 However, it is not clear at which stage this interaction occurs, and there are no data on the impact of the latter in the clinical setting, considering that this association was not allowed in any trials. Nevertheless, some observational studies pointed out a good clinical outcome, and ATV plasmatic levels above the minimum effective concentration (150 ng/mL) in patients switching from a fully suppressive boosted ATV-containing regimen regardless of TDF use.6 In such context, off-label use of such association is not infrequent among Italian prescribers due to convenience and excellent tolerability along with limited alternatives to a TDF-containing backbone. In a proportion of patients, moreover, staggered doses of TDF and unboosted ATV have been administered, to avoid a possible interference on absorption of the latter, previously assumed as a possible mechanism of such drug interaction.7
Therefore, our aim was to evaluate the impact of coadministration of TDF on unboosted ATV plasma exposure in the clinical setting. We analyzed our therapeutic drug monitoring (TDM) registry (collecting samples from various HIV facilities in Italy) to evaluate ATV plasmatic concentrations in patients taking 400 mg once daily. Main exclusion criteria were age below 18 years, concomitant administration of interacting drugs (excluding TDF), pregnancy, severe hepatic impairment, self-reported adherence below 80%. Samples collected 24 ± 3 hours after ATV administration were considered. Measurements of ATV plasma concentration were performed by a validated high-performance liquid chromatography method.
One hundred three patients were included (males 57.3%). Mean age and body mass index were 46 years and 23.6, respectively. Each patient had a mean of 1.6 samples analyzed. Median (interquartile range) ATV Ctrough was 110 (52-229) ng/mL, and 59 patients (57.3%) had a value below the minimum effective concentration. Nucleoside/nucleotide reverse transcriptase inhibitors-based backbone contained TDF in most cases [74 (71.8%) patients], followed by emtricitabine [48 patients (46.6%)], lamivudine [28 patients (27.2%)], and abacavir [22 patients (21.4%)]. Patients in the TDF group were considered separately if they were taking TDF and ATV simultaneously or with a delay of at least 9 hours [42 of 74 patients (56.7%)]. TDF coadministration did not result in a significant reduction of plasmatic concentrations of ATV [119.6 (51.8-286) ng/mL without TDF vs. 108.9 (51-227.8) ng/mL with TDF; P = 0.8, Mann-Whitney Test] and no significant effect of the different timing strategies on ATV plasmatic levels was shown [179.3 (64-262) ng/mL when coadministered vs. 107 (34.5-199) ng/mL when staggered, P = 0.16]. Neither significant difference was found in the proportion of patients below the 150 ng/mL cutoff in the group without TDF [17 (58.6%)] vs. the TDF group [42 (56.7%)] (P = 0.86) nor if TDF administration was concomitant [15 (46.8%)] or staggered [27 (64.3%)] (P = 0.13).
Even with the limits that a TDM registry analysis embodies, 2 issues raise by our data. First of all, timing strategies seeking avoidance of interaction between TDF and ATV did not result in any significant difference of ATV exposure, supporting an interaction mechanism not related to the drug absorption.8 Second, a sizeable proportion of patients showed ATV Ctrough below the threshold of clinical efficacy, but TDF was not associated with lower ATV plasma concentration. These findings suggest that a very high interindividual variability may influence ATV plasma exposure to a greater extent than the interaction with TDF. Pharmacogenetic studies9,10 reported a clear effect of specific mutated alleles on ATV exposure, whose magnitude (65%-78%) was higher as compared with that known of TDF interaction. On the other hand, this implies that a not negligible proportion of patients (43.2 % in our study) can benefit from such coadministration, keeping an adequate ATV plasma exposure. In other words, unboosted ATV and TDF concomitant use could not be considered a priori contraindicated as generally reported in guidelines, but it could be feasible with TDM of ATV. Further clinical investigation is warranted to assess individual factors predicting the feasibility of unboosted ATV and TDF coadministration.
Andrea Calcagno, MD*
Stefano Bonora, MD*
Maria Cristina Tettoni, MD*
Antonio D'Avolio, BSc, MSc*
Giovanni Di Perri, MD, PhD*
Massimiliano Lanzafame, MD†
Giovanni Penco, MD‡
*Department of Infectious Diseases, University of Torino, Torino, Italy
†Unit of Infectious Diseases, University of Verona, Verona, Italy
‡Unit of Infectious Diseases, Galliera Hospital, Genova, Italy
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2. Malan DR, Krantz E, David N, et al, and 089 Study Group. Efficacy and safety of atazanavir, with or without ritonavir, as part of once-daily highly active antiretroviral therapy regimens in antiretroviral-naive patients. J Acquir Immune Defic Syndr
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8. Dailly E, Tribut O, Tattevin P, et al. Influence of tenofovir, nevirapine and efavirenz on ritonavir-boosted atazanavir pharmacokinetics in HIV-infected patients. Eur J Clin Pharmacol
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9. Rodriguez-Novoa S, Barreiro P, Rendon A, et al. Plasma levels of atazanavir and the risk of hyperbilirubinemia are predicted by the 3435 C->T polymorphism at the multidrug resistance gene 1. Clin Infect Dis
10. Siccardi M, D'Avolio A, Baietto, L, et al. Association of a single-nucleotide polymorphism in the pregnane X receptor (PXR 63396C -->T) with reduced concentrations of unboosted atazanavir. Clin Infect Dis
© 2009 Lippincott Williams & Wilkins, Inc.