Population pharmacokinetic analysis of lamivudine, stavudine and zidovudine in controlled HIV-infected patients on HAART.

OBJECTIVE: This work aimed at building a population pharmacokinetic (PK) model for lamivudine (LMV), stavudine (STV) and zidovudine (ZDV), estimating their inter and intraindividual PK variability and investigating the influence of different covariates. METHODS: Population PK of LMV, STV and ZDV was separately evaluated from plasma concentrations obtained in 54, 39 and 27 HIV1-infected patients, respectively, enrolled in the COPHAR1-ANRS102 trial. The primary objective of this trial was to study the pharmacokinetics of indinavir (IDV) and nelfinavir (NFV) in treated patients with a sustained virological response. Concentrations of nucleoside analogs (NA) were measured in plasma as a secondary objective. A one-compartment model with first-order elimination was used, with zero-order absorption for LMV and first-order absorption for STV and ZDV. RESULTS: Mean parameters [interpatient variability in coefficient of variation (CV%)] of LMV, STV and ZDV were: oral volume of distribution (V/F) 145 l (52%), 24 l (81%) and 248 l (80%), oral clearance (Cl/F) 32 l/h, 16 l/h (74%) and 124 l/h (51%), respectively. For LMV, absorption duration (Ta) was 1.46 h (64%). For STV and ZDV, ka was 0.46 h(-1) and 2.9 h(-1), respectively. We found a systematic effect of combination with NFV vs. IDV. We found that intrapatient variability was greater than interpatient variability (except for STV) and greater than 55% for the three drugs. CONCLUSION: This trial enabled the estimation of the population PK parameters of three NA in patients with a sustained virological response, and the median curves could be used as references for concentration-controlled strategies. We observed, as for the protease inhibitors, a great variability of PK parameters.

High variability of indinavir and nelfinavir pharmacokinetics in HIV-infected patients with a sustained virological response on highly active antiretroviral therapy.

OBJECTIVES: To describe plasma concentrations of indinavir alone or combined with ritonavir, and of nelfinavir and its active metabolite M8, and to measure their variabilities in HIV-infected patients treated with a stable antiretroviral regimen and experiencing a sustained virological response for at least 12 months. PATIENTS AND METHODS: In this prospective trial, blood samples were drawn during a 6-hour time interval between two doses at enrolment to assess protease inhibitor (PI) pharmacokinetic parameters, and 4 months later to assess plasma trough and peak concentrations. Safety and adherence assessments and laboratory data were collected during an 8-month period. PI pharmacokinetic characteristics were analysed using a non-compartmental approach. Inter- and intrapatient variabilities were estimated using a linear mixed-effect model. The impact of different covariates on plasma trough concentrations was investigated. Eighty-eight patients were analysed: 42 treated with indinavir and 46 with nelfinavir. RESULTS: The interquartile range (IQR) of the plasma trough concentration corrected for the sampling time (Ccalc) was 116-374 microg/L for indinavir alone and 163-508 microg/L for indinavir/ritonavir. Ritonavir significantly increased indinavir elimination half-life and plasma exposure. For nelfinavir, the IQR of Ccalc was 896-2059 microg/L for three-times-daily administration and 998-2124 microg/L for twice-daily administration. Variabilities were high for both PIs. Intrapatient variability for indinavir alone (and indinavir + ritonavir) was 76% (107%) and interpatient variability was 58% (10%) in adherent patients. Intrapatient variability for nelfinavir three times daily (and twice daily) was 41% (74%) and interpatient variability was 62% (50%). Intrapatient variability was lowered in patients with a high adherence level. CONCLUSION: Although performed in a homogeneous population, this study documented a high interpatient but also intrapatient variability of indinavir and nelfinavir pharmacokinetics, which should be taken into account when interpreting therapeutic drug monitoring. Once patients have reached a sustained virological response, plasma PI monitoring may have a limited impact.

Virological and pharmacological factors associated with virological response to salvage therapy after an 8-week of treatment interruption in a context of very advanced HIV disease (GigHAART ANRS 097).

Both highly potent antiretroviral drug rescue multi therapy and treatment interruption (TI) have been suggested to be effective in HIV-1 infected-patients with multiple treatment failure. GigHAART-ANRS 097 was the only randomized trial during which an 8-week TI was beneficial in heavily pre-treated patients with multi-drug resistant virus on resuming a multiple-drug salvage regimen. The aim of this study was to analyze virological and pharmacological factors associated with a virological response. Clonal resistance analysis showed that although the viral population was highly mutated and nearly monoclonal at baseline, the 8-week interruption therapy allowed the re-emergence of more susceptible quasispecies to the subsequent salvage therapy, which were not detected by classical genotypic resistance testing. The fact that not every viral clone harbored all resistance viral mutations could explain a part of the virological response to a six to eight drug regimen for patients enrolled in the TI group. This phenomenon was associated with a transient virological response after the use of a GigHAART therapy, but was followed by the re-emergence of baseline resistance pattern and acquisition of additional mutations in patients failing this strategy. A combined factor of protease inhibitor (PI) concentration and genotypic score, expressed as a genotypic inhibitory quotient (GIQ), was used to assess the importance of genotypic resistance and plasma drug levels in the rate of response to multiple PI combination. The GIQ of each PI used in the regimen was not associated with virological success. However, the sum of PI GIQs was predictive of a virological response. These results suggest that pharmacological enhancement might overcome viral resistance and that there is some benefit in adding the activity of several boosted-PIs to improve the response to a salvage regimen.

Population pharmacokinetic analysis of indinavir in HIV-infected patient treated with a stable antiretroviral therapy.

The objectives of this study were to build a population pharmacokinetic model that describe plasma concentrations of indinavir in human immunodeficiency virus (HIV)-infected patients with sustained virological response under a stable antiretroviral combination, and to characterize the effect of covariates and co-medications on indinavir pharmacokinetics. Data were obtained from 45 patients who received different dosages of indinavir: either indinavir alone t.i.d. (mostly 800 mg), either indinavir b.i.d. (mostly 800 mg) with a booster dose of 100 mg of ritonavir. Patients were required to have a baseline plasma HIV RNA <200 copies/mL and to have unchanged antiretroviral treatment for 6 months. Indinavir concentrations were measured at a first visit (one sample before drug administration and five after) and at a second visit 3 months later (before and 1 or 3 h after drug administration). A one-compartment model with first-order absorption and first-order elimination best described indinavir pharmacokinetics. For patients treated with indinavir alone, absorption rate constant was estimated to be 0.43/h, and oral clearance Cl/F was 33 L/h. For patients treated with indinavir plus ritonavir these estimates were 0.25/h and 19 L/h, respectively. Cl/F was found to increase by 1.45-fold in men and by 1.18-fold in patients also receiving zidovudine. Oral volume of distribution (V/F) was 24 L. The inter-individual and intra-individual variability were 117 and 205% for V/F, 42 and 58% for Cl/F, respectively. This population analysis in patients with sustained virological response, quantified the effect of ritonavir on the absorption rate constant and on the clearance of indinavir, showed an increase of Cl/F in men and can be used to draw reference curve for therapeutic drug monitoring.

Benefit of treatment interruption in HIV-infected patients with multiple therapeutic failures: a randomized controlled trial (ANRS 097).

BACKGROUND: Both highly potent antiretroviral drug rescue therapy and treatment interruption have been suggested to be effective in patients with multiple treatment failure. OBJECTIVE: To assess both the benefits and risks of an 8-week treatment interruption associated with a six to nine-drug rescue regimen in patients with multiple treatment failures. DESIGN: A randomized comparative controlled trial in 19 university hospitals in France. PATIENTS: Sixty-eight HIV-infected patients with multiple previous treatment failures and CD4 cell counts less than 200 x 10(6) cells/l and plasma HIV-1-RNA levels of 50,000 copies/ml or greater. MEASUREMENTS: The primary efficacy outcome was the proportion of patients with at least a 1 log10 decrease (copies/ml) in the plasma HIV-1-RNA level after 12 weeks of therapy. RESULTS: Treatment interruption followed by multidrug salvage therapy led to a greater proportion of patients achieving virological success (i.e. 1 log10 decrease) at 12 weeks compared with patients receiving multidrug therapy alone (62 versus 26%, intent-to-treat analysis; P = 0.007). The median decrease in the HIV-1-RNA level was -1.91 and -0.37 log10 copies/ml (P = 0.008), respectively. Treatment interruption led to an increase in the number of sensitive drugs of the multidrug regimen (71 versus 35% of regimen with at least two sensitive drugs; P = 0.004). Factors associated with virological success were treatment interruption, the reversion of at least one mutation to wild type, adequate plasma drug concentration, and the use of lopinavir. CONCLUSION: Treatment interruption was beneficial for treatment-experienced HIV-infected patients with advanced HIV disease and multidrug-resistant virus.

Interruption of nonnucleoside reverse transcriptase inhibitor (NNRTI) therapy for 2 months has no effect on levels of human immunodeficiency virus type 1 in plasma of patients harboring viruses with mutations associated with resistance to NNRTIs.

A 2-month interruption of only nonnucleoside reverse transcriptase inhibitors (NNRTIs) for patients carrying mutations associated with resistance to NNRTIs was followed by no change in either viral load or CD4 cell counts. These data suggest that these compounds have lost all of their in vivo antiviral activity in such cases.