Cell disposition of raltegravir and newer antiretrovirals in HIV-infected patients: high inter-individual variability in raltegravir cellular penetration

Objectives The site of pharmacological activity of raltegravir is intracellular. Our aim was to determine the extent of raltegravir cellular penetration and whether raltegravir total plasma concentration (Ctot) predicts cellular concentration (Ccell). Methods Open-label, prospective, pharmacokinetic study on HIV-infected patients on a stable raltegravir-containing regimen. Plasma and peripheral blood mononuclear cells were simultaneously collected during a 12 h dosing interval after drug intake. Ctot and Ccell of raltegravir, darunavir, etravirine, maraviroc and ritonavir were measured by liquid chromatography coupled to tandem mass spectrometry after protein precipitation. Longitudinal mixed effects analysis was applied to the Ccell/Ctot ratio. Results Ten HIV-infected patients were included. The geometric mean (GM) raltegravir total plasma maximum concentration (Cmax), minimum concentration (Cmin) and area under the time-concentration curve from 0-12 h (AUC0-12) were 1068 ng/mL, 51.1 ng/mL and 4171 ng·h/mL, respectively. GM raltegravir cellular Cmax, Cmin and AUC0-12 were 27.5 ng/mL, 2.9 ng/mL and 165 ng·h/mL, respectively. Raltegravir Ccell corresponded to 5.3% of Ctot measured simultaneously. Both concentrations fluctuate in parallel, with Ccell/Ctot ratios remaining fairly constant for each patient without a significant time-related trend over the dosing interval. The AUCcell/AUCtot GM ratios for raltegravir, darunavir and etravirine were 0.039, 0.14 and 1.55, respectively. Conclusions Raltegravir Ccell correlated with Ctot (r = 0.86). Raltegravir penetration into cells is low overall (∼5% of plasma levels), with distinct raltegravir cellular penetration varying by as much as 15-fold between patients. The importance of this finding in the context of development of resistance to integrase inhibitors needs to be further investigate

Population pharmacokinetic modelling and evaluation of different dosage regimens for darunavir and ritonavir in HIV-infected individuals.

OBJECTIVES: Darunavir is a protease inhibitor that is administered with low-dose ritonavir to enhance its bioavailability. It is prescribed at standard dosage regimens of 600/100 mg twice daily in treatment-experienced patients and 800/100 mg once daily in naive patients. A population pharmacokinetic approach was used to characterize the pharmacokinetics of both drugs and their interaction in a cohort of unselected patients and to compare darunavir exposure expected under alternative dosage regimens. METHODS: The study population included 105 HIV-infected individuals who provided darunavir and ritonavir plasma concentrations. Firstly, a population pharmacokinetic analysis for darunavir and ritonavir was conducted, with inclusion of patients' demographic, clinical and genetic characteristics as potential covariates (NONMEM(®)). Then, the interaction between darunavir and ritonavir was studied while incorporating levels of both drugs into different inhibitory models. Finally, model-based simulations were performed to compare trough concentrations (Cmin) between the recommended dosage regimen and alternative combinations of darunavir and ritonavir. RESULTS: A one-compartment model with first-order absorption adequately characterized darunavir and ritonavir pharmacokinetics. The between-subject variability in both compounds was important [coefficient of variation (CV%) 34% and 47% for darunavir and ritonavir clearance, respectively]. Lopinavir and ritonavir exposure (AUC) affected darunavir clearance, while body weight and darunavir AUC influenced ritonavir elimination. None of the tested genetic variants showed any influence on darunavir or ritonavir pharmacokinetics. The simulations predicted darunavir Cmin much higher than the IC50 thresholds for wild-type and protease inhibitor-resistant HIV-1 strains (55 and 550 ng/mL, respectively) under standard dosing in >98% of experienced and naive patients. Alternative regimens of darunavir/ritonavir 1200/100 or 1200/200 mg once daily also had predicted adequate Cmin (>550 ng/mL) in 84% and 93% of patients, respectively. Reduction of darunavir/ritonavir dosage to 600/50 mg twice daily led to a 23% reduction in average Cmin, still with only 3.8% of patients having concentrations below the IC50 for resistant strains. CONCLUSIONS: The important variability in darunavir and ritonavir pharmacokinetics is poorly explained by clinical covariates and genetic influences. In experienced patients, treatment simplification strategies guided by drug level measurements and adherence monitoring could be proposed

Population pharmacokinetic modelling and evaluation of different dosage regimens for darunavir and ritonavir in HIV-infected individuals

Objectives Darunavir is a protease inhibitor that is administered with low-dose ritonavir to enhance its bioavailability. It is prescribed at standard dosage regimens of 600/100 mg twice daily in treatment-experienced patients and 800/100 mg once daily in naive patients. A population pharmacokinetic approach was used to characterize the pharmacokinetics of both drugs and their interaction in a cohort of unselected patients and to compare darunavir exposure expected under alternative dosage regimens. Methods The study population included 105 HIV-infected individuals who provided darunavir and ritonavir plasma concentrations. Firstly, a population pharmacokinetic analysis for darunavir and ritonavir was conducted, with inclusion of patients' demographic, clinical and genetic characteristics as potential covariates (NONMEM®). Then, the interaction between darunavir and ritonavir was studied while incorporating levels of both drugs into different inhibitory models. Finally, model-based simulations were performed to compare trough concentrations (Cmin) between the recommended dosage regimen and alternative combinations of darunavir and ritonavir. Results A one-compartment model with first-order absorption adequately characterized darunavir and ritonavir pharmacokinetics. The between-subject variability in both compounds was important [coefficient of variation (CV%) 34% and 47% for darunavir and ritonavir clearance, respectively]. Lopinavir and ritonavir exposure (AUC) affected darunavir clearance, while body weight and darunavir AUC influenced ritonavir elimination. None of the tested genetic variants showed any influence on darunavir or ritonavir pharmacokinetics. The simulations predicted darunavir Cmin much higher than the IC50 thresholds for wild-type and protease inhibitor-resistant HIV-1 strains (55 and 550 ng/mL, respectively) under standard dosing in >98% of experienced and naive patients. Alternative regimens of darunavir/ritonavir 1200/100 or 1200/200 mg once daily also had predicted adequate Cmin (>550 ng/mL) in 84% and 93% of patients, respectively. Reduction of darunavir/ritonavir dosage to 600/50 mg twice daily led to a 23% reduction in average Cmin, still with only 3.8% of patients having concentrations below the IC50 for resistant strains. Conclusions The important variability in darunavir and ritonavir pharmacokinetics is poorly explained by clinical covariates and genetic influences. In experienced patients, treatment simplification strategies guided by drug level measurements and adherence monitoring could be propose

Switching from a two-tablet regimen of tenofovir/emtricitabine and efavirenz to a one-tablet regimen may affect patients' perceptions and drug management.

Simplification of antiretroviral therapy enhances a patient's adherence but a new formulation could also lead to new adverse events and changes in daily routine. This study compared medication adherence, tolerance and satisfaction among subjects switching from a two-tablet tenofovir/emtricitabine/efavirenz regimen to a one-tablet regimen. Clinical and sociodemographic data were collected and three surveys were administered at month 0 (=switch), and then 1 and 4-6 months after the switch: the Beliefs about Medicines Questionnaire, the HIV-symptom index questionnaire, the Short HIV Treatment Satisfaction Questionnaire, the Swiss HIV Cohort Study (SHCS) two-item adherence questionnaire, and a questionnaire on daily combination antiretroviral therapy (cART) management. Medication adherence of a subgroup of subjects was routinely monitored using an electronic device (MEMS(™) ). Eighty-eight subjects gave informed consent to participate in the study. The subjects' back-switch rate was 7% (six of 88). Subjects who did not back-switch preferred the one-tablet regimen (median = 2; IQR = 1.3-2.5; on a -3 to 3 scale), but no change in adherence was found (10 of 46 nonadherent subjects; P = 1.00). The perception of treatment necessity score decreased (P = 0.004), the efavirenz blood level increased (14%; P = 0.04), and association/dissociation of cART with food intake evolved (P = 0.01) after the switch. Subjects listed equivalent numbers of symptoms during the three visits. The one-tablet regimen was preferred but the number of back-switches was not negligible. The perception of treatment necessity score decreased with the simplification of the regimen from a two-tablet to a one-tablet formulation, which could negatively impact adherence. Switching is a sensitive time in a patient's treatment life and professionals should pay particular attention to patient's perceptions of treatment during such a transition

[Drug-drug interactions with HIV treatments]

We develop a differential diagnosis and diagnostic approach to a possible drug-drug interaction between a cART based on boosted atazanavir and newly given drugs. History taking should not only encompass prescribed but also over-the-counter medication. Exchange of information between attending physicians as to therapeutic changes, documented side effects and adherence, therapeutic drug monitoring of cART and evaluation by pharmacologist in complex situations are the diagnostic tools at hand

Medikamenteninteraktion bei HIV-Therapie; Drug-drug interactions with HIV treatments

We develop a differential diagnosis and diagnostic approach to a possible drug-drug interaction between a cART based on boosted atazanavir and newly given drugs. History taking should not only encompass prescribed but also over-the-counter medication. Exchange of information between attending physicians as to therapeutic changes, documented side effects and adherence, therapeutic drug monitoring of cART and evaluation by pharmacologist in complex situations are the diagnostic tools at hand

Rivastigmine for HIV-associated neurocognitive disorders A randomized crossover pilot study

Objective: To assess the efficacy and safety of rivastigmine for the treatment of HIV-associated neurocognitive disorders (HAND) in a cohort of long-lasting aviremic HIV+ patients.Methods: Seventeen aviremic HIV+ patients with HAND were enrolled in a randomized, double-blind, placebo-controlled, crossover study to receive either oral rivastigmine (up to 12 mg/day for 20 weeks) followed by placebo (20 weeks) or placebo followed by rivastigmine. Efficacy endpoints were improvement on rivastigmine in the Alzheimer's Disease Assessment Scale–Cognitive subscale (ADAS-Cog) and individual neuropsychological scores of information processing speed, attention/working memory, executive functioning, and motor skills. Measures of safety included frequency and nature of adverse events and abnormalities on laboratory tests and on plasma concentrations of antiretroviral drugs. Analyses of variance with repeated measures were computed to look for treatment effects.Results: There was no change on the primary outcome ADAS-Cog on drug. For secondary outcomes, processing speed improved on rivastigmine (Trail Making Test A: F1,13 = 5.57, p = 0.03). One measure of executive functioning just failed to reach significance (CANTAB Spatial Working Memory [strategy]: F1,13 = 3.94, p = 0.069). No other change was observed. Adverse events were frequent, but not different from those observed in other populations treated with rivastigmine. No safety issues were recorded.Conclusions: Rivastigmine in aviremic HIV+ patients with HAND seemed to improve psychomotor speed. A larger trial with the better tolerated transdermal form of rivastigmine is warranted.Classification of evidence: This study provides Class III evidence that rivastigmine is ineffective for improving ADAS-Cog scores, but is effective in improving some secondary outcome measures in aviremic HIV+ patients with HAND

Rivastigmine for HIV-associated neurocognitive disorders: A randomized crossover pilot study.

OBJECTIVE: To assess the efficacy and safety of rivastigmine for the treatment of HIV-associated neurocognitive disorders (HAND) in a cohort of long-lasting aviremic HIV+ patients. METHODS: Seventeen aviremic HIV+ patients with HAND were enrolled in a randomized, double-blind, placebo-controlled, crossover study to receive either oral rivastigmine (up to 12 mg/day for 20 weeks) followed by placebo (20 weeks) or placebo followed by rivastigmine. Efficacy endpoints were improvement on rivastigmine in the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and individual neuropsychological scores of information processing speed, attention/working memory, executive functioning, and motor skills. Measures of safety included frequency and nature of adverse events and abnormalities on laboratory tests and on plasma concentrations of antiretroviral drugs. Analyses of variance with repeated measures were computed to look for treatment effects. RESULTS: There was no change on the primary outcome ADAS-Cog on drug. For secondary outcomes, processing speed improved on rivastigmine (Trail Making Test A: F(1,13) = 5.57, p = 0.03). One measure of executive functioning just failed to reach significance (CANTAB Spatial Working Memory [strategy]: F(1,13) = 3.94, p = 0.069). No other change was observed. Adverse events were frequent, but not different from those observed in other populations treated with rivastigmine. No safety issues were recorded. CONCLUSIONS: Rivastigmine in aviremic HIV+ patients with HAND seemed to improve psychomotor speed. A larger trial with the better tolerated transdermal form of rivastigmine is warranted. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that rivastigmine is ineffective for improving ADAS-Cog scores, but is effective in improving some secondary outcome measures in aviremic HIV+ patients with HAND

Successful efavirenz dose reduction guided by therapeutic drug monitoring

Background: There are potential benefits to individualizing dosage in patients treated with efavirenz (EFV). We tested a simplified algorithm based on a Bayesian pharmacokinetic approach for guiding dose reduction in patients with EFV concentrations above the 75th percentile (P75) with documented virological efficacy. Methods: We designed a prospective, open-label, multicentre study. All consenting participants with EFV concentrations above P75 on standard dosage were included in a dose-reduction cycle. Primary end point was the number of patients who reached plasma concentrations within target (1,000-4,000 ng/ml) after, at most, two cycles of dose reduction at 3 and 6 months. CYP2B6 genetic characterization was performed. Results: Seventy-two patients were screened and 13 fulfilled selection criteria. These patients, with undetectable viraemia on a stable 600 mg EFV-based regimen, had a median (interquartile range) EFV plasma level of 8,112 ng/ml (5,993-10,278) at baseline; 38% (between P75 and P95) qualified for a 400 mg EFV dose, and 62% (above P95) qualified for a 200 mg EFV dose. After one to two dose-reduction cycles, all patients reached targets for EFV plasma concentration at 24 weeks. The predictive dose reduction based on genetic profile differed from dose reduction according to therapeutic drug monitoring (TDM) in three patients. All patients maintained viral suppression at 6 months. Conclusions: A standardized TDM-guided EFV dose-reduction strategy over a 24-week period was successful, safe and yielded EFV plasma concentrations within the recommended therapeutic range. In addition to improving neuropsychiatric tolerability, EFV dose reduction has the potential to substantially decrease treatment cost.</p