Therapeutic Monitoring and Variability of Atazanavir in HIV-Infected Patients, With and Without HCV Coinfection, Receiving Boosted or Unboosted Regimens

Abstract

Background: Adequate plasma trough concentrations (C trough ) of protease inhibitors are required to maintain antiviral activity throughout the dosing interval. Therapeutic drug monitoring is used in clinical practice to optimize dosage and avoid toxic or subtherapeutic drug exposure. The pharmacokinetic variability of Atazanavir (ATV) can be relatively large, as a result of several factors. One of the affecting factors may be hepatic impairment due to hepatitis C virus (HCV) coinfection. Methods:We collected trough plasma samples from human immunodeficiency virus (HIV)-1-infected outpatients, with and without HCV coinfection and/or cirrhosis, receiving stable highly active antiretroviral therapy containing ATV. In the total population, we mainly compared the 2 regimens: 300ATV + 100RTV OD [ritonavir (RTV), once daily (OD)] versus 400ATV OD. We used a threshold value of 0.15 mg/mL, based on the proposed therapeutic range (0.15-0.85 mg/mL). Plasma concentrations of ATV were determined by a validated assay using high-performance liquid chromatography with ultraviolet detection. A total of 214 HIV-infected outpatients were included. For each regimen, we compared 3 groups of subjects: HIV+/HCV2, HIV+/HCV+, and HIV+/HCV+ with cirrhosis.Results: In the whole study population, we observed a large variability and found suboptimal C trough levels (,0.15 mg/mL) in 23 subjects (2 belonging to the 300/100 OD group and 21 to the 400 OD group). For the standard dosage regimen of 300ATV + 100RTV OD, we did not find a statistical difference between HIV-infected patients without HCV coinfection versus HIV-infected patients with HCV coinfection: median 0.85 (interquartile range 0.53-1.34) and 0.95 (0.70-1.36) mg/mL, respectively. In HIV+/HCV+-infected patients with cirrhosis, we found a median C trough of 0.70 (0.43-1.0) mg/mL, with no statistical difference when compared with HIV+/HCV2 infected patients. For the 400ATV OD (n = 90) dosage regimen, the total median ATV C trough was 0.40 (0.23-1.0) mg/mL. In this group, we found a statistically significant difference between HIV+/HCV2 and HIV+/HCV+-infected patients: median C trough was 0.23 (0.11-0.42) and 0.52 (0.20-1.0) mg/mL, respectively. In HIV+/HCV+ subjects with cirrhosis, the C trough median value was 0.42 (0.13-0.75) mg/mL, and there was a significant difference when compared with HIV patients without coinfection.Conclusions: Therapeutic drug monitoring of ATV in patients receiving unboosted regimen may be useful to identify those HIVinfected subjects, with or without HCV coinfection, who may benefit from adding low RTV doses, or the subset of patients in whom removal of RTV could be attempted without the risk of suboptimal plasma ATV exposure.

Liver Toxicity of Current Antiretroviral Regimens in HIV-Infected Patients with Chronic Viral Hepatitis in a Real-Life Setting: The HEPAVIR SEG-HEP Cohort

“…However, various cohort studies published afterwards failed to confirm a relationship between the fibrosis stage and liver enzyme elevations in patients treated with various regimens [ 14 – 16 , 19 , 20 ] and an impact of advanced liver damage on grade 3 or 4 TE is therefore unlikely. Nevertheless, especially cirrhotic patients may have plasma levels of antiretrovirals that are above the safety concentration and HCV infection itself may have an impact on plasma levels of ART components such as ritonavir-boosted atazanavir, efavirenz and etravirine [ 33 – 35 ]. In the present study, a considerably high number of patients were administered the antiretroviral drugs susceptible to suffer plasma level elevations due to advanced liver disease.…”

The Advantages of Therapeutic Drug Monitoring in Patients Receiving Antiretroviral Treatment and Experiencing Medication-Related Problems

“…In the case of atazanavir, the situation may be complicated by the use of boosted and unboosted regimens. 37 In this study, almost all the patients received boosted treatments of atazanavir, and those that did not received an initial TDM at the request of attending physicians. In this study, 92% of the TDM-based recommendations were implemented.…”

Stable Virologic Suppression during Raltegravir plus Atazanavir Dual-Therapy Taken Every other Day: A Case Report

“…ATV is a protease inhibitor metabolized by the cytochrome P450 system [18]. A possible effect of substance use and hepatitis virus co-infection on ATV PK has been analyzed in previous studies, finding limited impact of these factors on plasma ATV trough levels [19,20]. However, several co-factors associated with variation in ATV concentrations have been indentified, including concurrent methadone use, cigarette smoking, and substance use status [21].…”