Critical drug interaction between ritonavir-boosted atazanavir regimen and non-nucleoside reverse transcriptase inhibitors

Coadministration of atazanavir (ATV) and efavirenz (EFV) should be proposed with caution owing to a marked fall in ATV plasma concentrations observed in healthy volunteers receiving both drugs [1,2]. International consensus has not yet been established on coadministration of ritonavir (RTV)-boosted ATV and non-nucleoside reverse transcriptase inhibitors (NNRTI). The French pharmacological prospective cohort Pharmataz assessed drug interaction between ATV and NNRTI. This was a prospective open-label study compared plasma ATV trough concentrations (Cmin) in 186 HIV-infected patients receiving ATV/RTV (300 mg/100 mg) in group 1 (12 patients) and ATV/RTV (400 mg/100 mg) in group 2 (20 patients), with or without a NNRTI [EFV or nevirapine (NVP)], from June 2004 to October 2005 in two HIV clinics in Paris. Patients receiving more than two protease inhibitors or proton pump inhibitors were excluded from the study. The nurse who drew the blood samples asked the patients when they had taken their last dose of ATV/RTV. Only ATV measurements taken 24 ± 4 h after the last intake in patients receiving a stable ATV/RTV regimen for at least 2 weeks were utilized in the analyses. The ATV Cmin was determined with a validated high-performance liquid chromatography-based method with limit cut-offs of 10 ng/ml for ATV [3]. Data were analysed with the Mann–Whitney test. Median ATV and RTV Cmin values were 92 ng/ml (range, 24–415) and 0 ng/ml (range, 0–13), respectively, in group 1 and 290 ng/ml (range, 71–2069) and 0 ng/ml (range, 0–347), respectively, in group 2. This compared with 506 ng/ml (range, 26–2657) and 39 ng/ml (range, 0–621) for ATV and RTV, respectively, in patients not taking an NNRTI (Table 1).Table 1: Atazanavir concentrations with and without non-nucleoside reverse transcriptase inhibitors.Coadministration of an NNRTI (EFV in five and NVP in seven) with ATV/RTV 300/100 mg (group 1) resulted in a 5.5-fold decrease of ATV Cmin (P < 0.0001) and undetectable RTV Cmin (< 10 ng/ml; P < 0.0001). Coadministration of an NNRTI (EFV in 13 and NVP in seven) with the ATV/RTV 400/100 mg regimen (group 2) resulted in median ATV Cmin that was 1.7-fold lower than that observed in the other patients (P < 0.05). Among patients receiving a NNRTI, 8/12 patients in group 1 (67%) and 5/20 patients in group 2 (25%) had ATV Cmin < 150 ng/ml (P < 0.05). This proportion was significantly higher for group 1 and 2 (P < 0.0001 and P < 0.01, respectively) than for patients not receiving any NNRTI [ATV Cmin < 150 ng/ml in 11/154 (7%)]. In HIV-infected patients, ATV Cmin is not significantly modified by tenofovir [4–8]. Data for patients treated with tenofovir were, therefore, taken into the analyses. Compared with patients receiving the same dosing regimen without NNRTI, both ATV and RTV Cmin values were significantly reduced when a NNRTI was coadministered. Contrary to recently published data showing that reduced ATV Cmin values were only associated with NVP and not EFV coadministration, our results show that the inducer effects of EFV and NVP are similar on ATV metabolism in patients receiving boosted-ATV [8] At the 400/100 mg ATV/RTV dosing regimen currently recommended in Europe, ATV Cmin remained 1.7 fold lower when a NNRTI was coadministered than without one. Up to 25% of these patients taking ATV/RTV plus a NNRTI had ATV Cmin < 150 ng/ml, the lowest Cmin currently considered acceptable [9]. Therefore, increasing the ATV dosage up to 400 mg did not overcome the inducer effect of NNRTI on ATV metabolism in a RTV-boosted regimen (Table 1). The considerably higher proportion of patients with ATV Cmin < 150 ng/ml among patients receiving 300/100 mg ATV/RTV regimen combined with a NNRTI could indicate reduced antiviral efficacy at this dosage. In a previous study on 19 healthy volunteers, coadministration of EFV plus ATV/RTV 400/200 mg resulted in an 7.7-fold higher ATV Cmin than observed with ATV 400 mg alone [10]. However, in our HIV-infected patients, ATV Cmin was only three-fold higher in patients treated with 400/100 mg ATV/RTV plus EFV compared with patients receiving 400 mg ATV alone. Therefore, the significant decrease in ATV Cmin we observed in patients receiving 300/100 or 400/100 mg ATV/RTV plus a NNRTI may be partly explained by the low RTV dosing regimen (100 mg). In the presence of NNRTI, ATV Cmin was significantly reduced. Administration of once a day 400/100 mg ATV/RTV instead of 300/100 mg ATV/RTV did not overcome the inducer effect of NNRTI on ATV metabolism. These results should be taken into account when establishing drug regimens and it may be prudent to monitor ATV drug concentrations when a NNRTI is coadministration. Further investigations are needed to establish recommendations for ATV dosage in a regimens that includes a NNRTI.