Atazanavir plasma concentrations are impaired in HIV-1-infected adults simultaneously taking a methadone oral solution in a once-daily observed therapy setting.

OBJECTIVE: The human immundeficiency virus (HIV) protease inhibitor atazanavir is often used in once-daily observed therapy of methadone substituted former opiate drug users. We performed a matched-pairs analysis on 24 patients (12 men/women) taking atazanavir/ritonavir 300/100 mg daily plus reverse transcriptase inhibitors, with (n = 12) or without (n = 12) methadone co-administration. METHODS: Twenty-four-hour pharmacokinetic profiles of atazanavir/ritonavir were assessed at steady-state and measured by liquid chromatography-tandem mass spectrometry. The geometric mean (GM, t test) minimum and maximum plasma drug concentrations (C(min), C(max)), area under the concentration-time curve (AUC), and total clearance (CL(total)) were compared between the groups of pairs, which were matched for age, sex, weight, and ethnicity. RESULTS: The GM [90% confidence interval (CI)] of the atazanavir C(min), C(max), and AUC of patients taking the methadone oral solution at doses of 20-175 mg/day simultaneously with antiretroviral therapy were impaired compared to patients not taking methadone oral solution: C(min) = 315 (range 197-448) vs. 519 (279-793) ng/mL [GM ratio (GMR) = 0.61, p = 0.229]; C(max) = 1714 (1238-2262) vs. 3190 (2412-4076) ng/mL (GMR = 0.54, p = 0.018); AUC = 21,987 (15,870-29,327) vs. 35,572 (26,211-46,728) ng h/mL (GMR = 0.62, p = 0.074). Methadone dose, which is proportional to the amount of methadone oral solution (10 mg/mL), was significantly correlated to atazanavir C(max) (r (2) = 0.40, p = 0.001) and AUC (r (2) = 0.32, p = 0.006). Ritonavir pharmacokinetics was similar between the groups with C(min), C(max), and AUC GMR of 1.01, 0.80, and 0.96, respectively. CONCLUSION: The partial decrease in atazanavir plasma concentrations in patients concomitantly taking racemic methadone oral solution in this daily observed therapy setting deserves further attention, and therapeutic drug monitoring should be considered.

Evolution of resistance mutations during low-level viral replication in HIV-1-infected patients treated with zidovudine/lamivudine/abacavir as a first-line regimen.

OBJECTIVE: Long-term evaluation of viral evolution in patients who continued first-line therapy with zidovudine/lamivudine/abacavir (Trizivir [TZV]) in the presence of low-level viral replication and assessment of the impact of mutational patterns selected under TZV on viral load (VL), CD4+ T-cell count (CD4) and subsequent therapeutic options. DESIGN: Analysis of viral evolution based on genotypic resistance tests (GRT) from samples collected during non-suppressive first-line therapy with TZV. METHODS: Patients from the Frankfurt HIV cohort with at least 3 months uninterrupted first-line therapy with TZV in whom VL and CD4 measurements were performed at baseline and at follow up were identified. Criteria for virological failure (VF) were two consecutive VL >400 copies/ml. GRTs were required at baseline, VF and last visit (LV). RESULTS: Initially, 23/119 patients were classified as VF; 4/23 were lost to follow up. Median time to VF was 48 weeks. Because of the observed virological and immunological benefit, patients continued TZV for a median of 87 weeks despite detectable viraemia. Median CD4 increase and VL reduction at LV were 120 cells/mm3 and 317,100 copies/ml, respectively, compared to baseline. After 54 weeks of treatment with detectable VL, three mutational patterns were observed: Group A (n=4) characterized by M184V without further regimen-associated mutations, group B (n=9) by M184V accompanied by one to three thymidine analogue mutations (TAMs), and group C (n=6) by M184V and four to six TAMs. No virological or CD4 parameters correlated with these patterns. Group A remained unchanged, thus preserving activity of most nucleoside analogues (NA). However, in the majority of patients (groups B and C) accumulation of mutations at different rates was observed, leading to a sequential loss of NA options. CONCLUSIONS: Continuous treatment with TZV in the presence of viral replication is associated with a stepwise accumulation of resistance mutations. M184V was present in all cases, not followed by further selection of TAMs in a small, unpredictable subgroup of patients. However, in the majority of patients selection of M184V was associated with accumulation of TAMs at different rates leading to a substantial loss of active NAs, despite continuous virological and immunological benefit when compared with baseline.