Influence of ABCC2 and ABCC4 Polymorphisms on Tenofovir Plasma Concentrations in Thai HIV-Infected Patients

Contains fulltext : 153170.pdf (publisher's version ) (Open Access)Tenofovir (TFV) is eliminated by renal excretion, which is mediated through multidrug-resistant protein 2 (MRP2) and MRP4, encoded by ABCC2 and ABCC4, respectively. Genetic polymorphisms of these transporters may affect the plasma concentrations of tenofovir. Therefore, the aim of this study was to investigate the influence of genetic and nongenetic factors on tenofovir plasma concentrations. A cross-sectional study was performed in Thai HIV-infected patients aged >/=18 years who had been receiving tenofovir disoproxil fumarate at 300 mg once daily for at least 6 months. A middose tenofovir plasma concentration was obtained. Multivariate analysis was performed to investigate whether there was an association between tenofovir plasma concentrations and demographic data, including age, sex, body weight, estimated glomerular filtration rate (eGFR), hepatitis B virus coinfection, hepatitis C virus coinfection, duration of tenofovir treatment, concomitant use of ritonavir-boosted protease inhibitors, and polymorphisms of ABCC2 and ABCC4. A total of 150 Thai HIV-infected patients were included. The mean age of the patients was 43.9 +/- 7.2 years. The mean tenofovir plasma concentration was 100.3 +/- 52.7 ng/ml. In multivariate analysis, a low body weight, a low eGFR, the concomitant use of ritonavir-boosted protease inhibitors, and the ABCC4 4131T --> G variation (genotype TG or GG) were independently associated with higher tenofovir plasma concentrations. After adjusting for weight, eGFR, and the concomitant use of ritonavir-boosted protease inhibitors, a 30% increase in the mean tenofovir plasma concentration was observed in patients having the ABCC4 4131 TG or GG genotype. Both genetic and nongenetic factors affect tenofovir plasma concentrations. These factors should be considered when adjusting tenofovir dosage regimens to ensure the efficacy and safety of a drug. (This study has been registered at ClinicalTrials.gov under registration no. NCT01138241.)

Therapeutic drug monitoring of antiretroviral drugs in HIV-infected patients

Item does not contain fulltextINTRODUCTION: Therapeutic drug monitoring (TDM) may be beneficial when applied to antiretroviral (ARV). Even though TDM can be a valuable strategy in HIV management, its role remains controversial. Areas covered: This review provides a comprehensive update on important issues relating to TDM of ARV drugs in HIV-infected patients. Articles from PubMed with keywords relevant to each topic section were reviewed. Search strategies limited to articles published in English. Expert commentary: There is evidence supporting the use of TDM in HIV treatment. However, some limitations need to be considered. The evidence supporting the use of routine TDM for all patients is limited, as it is not clear that this strategy offers any advantages over TDM for selected indications. Selected groups of patients including patients with physiological changes, patients with drug-drug interactions or toxicity, and the elderly could potentially benefit from TDM, as optimized dosing is challenging in these populations

Le développement de la motivation dans le but d'acquérir les compétences dans le cadre du cours d'éducation physique

Rencontrer la motivation des élèves en EP, grâce à la technique induite, à l'organisation de situations compétitives, ou à la coopération

Pharmacogenetics-based population pharmacokinetic analysis of tenofovir in Thai HIV-infected patients

AIM: To develop a population pharmacokinetic model and identify sources of variability, genetic and nongenetic factors, of tenofovir. METHODS: The ABCC2 and ABCC4 polymorphisms were genotyped in 342 patients. A nonlinear mixed effects model was used to develop the population pharmacokinetic model and investigate the influence of these polymorphisms and other patient specific covariates on the pharmacokinetics of tenofovir. RESULTS: The estimated glomerular filtration rate calculated by the Cockcroft and Gault equation, concomitant use of lopinavir/ritonavir and ABCC4 3463A>G polymorphism were associated with tenofovir apparent oral clearance (CL/F). The use of lopinavir/ritonavir decreased tenofovir CL/F by 25%. Patients carrying ABCC4 3463 AG or GG had a tenofovir CL/F 11% higher than those with genotype AA. CONCLUSION: Renal function, co-medication and genetic variation impact the pharmacokinetics of tenofovir. These factors should be taken into consideration to guide the individual tenofovir disoproxil fumarate dosage regimen in Thai HIV-infected patients

Efficacy and safety of a once-daily single-tablet regimen of tenofovir, lamivudine, and efavirenz assessed at 144 weeks among antiretroviral-naive and experienced HIV-1-infected Thai adults

OBJECTIVE: To assess the efficacy and safety of a new single-tablet regimen (STR) of tenofovir disoproxil fumarate (TDF) 300mg, lamivudine (3TC) 300mg, and efavirenz (EFV) 600mg in HIV-infected Thai patients. METHODS: This was a prospective study performed for 144 weeks among 51 treatment-naive patients and 49 experienced patients on separate tablets of TDF, 3TC, and EFV with HIV RNA<50 copies/ml. CD4, HIV RNA, liver and renal function, and lipid profiles were assessed at baseline, weeks 12, 24, and 48, and then every 24 weeks. RESULTS: The median baseline CD4 cell count was 512 cells/mul for treatment-experienced patients and 230 cells/mul for treatment-naive patients. Median baseline log10 HIV-1 RNA for treatment-naive subjects was 4.9 copies/ml. From the intention-to-treat (ITT) analysis, the proportion of subjects with HIV RNA <50 copies/ml at week 48, 96, and 144 was 95%, 94%, and 94%, respectively, for antiretroviral-experienced patients and 88%, 90%, and 80%, respectively, for antiretroviral-naive patients. One virological failure at week 12 had primary drug resistance of K70R, T69D, V75L. Three serious adverse events occurred (tension headache, infective endocarditis, and cervical dysplasia) and another three discontinued the study drug due to EFV intolerance. CONCLUSIONS: This generic STR TDF/3TC/EFV is effective and well-tolerated. These findings lend support to the use of this generic STR as first-line antiretroviral therapy in resource-limited settings

Pharmacokinetics of rilpivirine and 24-week outcomes after switching from efavirenz in virologically suppressed HIV-1-infected adolescents

Contains fulltext : 196253.pdf (publisher's version ) (Closed access)BACKGROUND: Rilpivirine (RPV), a non-nucleoside reverse transcriptase inhibitor drug, could be a favourable drug for maintenance therapy in HIV-infected adolescents because it has few long-term side effects. However, data among adolescents switching from efavirenz (EFV) to RPV are limited. This study investigated the pharmacokinetics (PK), safety and efficacy of RPV in virologically suppressed HIV-1-infected adolescents after switching from EFV. METHODS: Adolescents aged 12-18 years on EFV-based antiretroviral therapy (ART) were switched from EFV to RPV (25 mg, once daily). Intensive 24-h blood samplings at 0 (pre-dose), 1, 2, 4, 5, 6, 9, 12 and 24 h were performed 4 weeks after switching. PK parameters were calculated using a non-compartmental method and compared with published data from the PAINT and pooled ECHO/THRIVE substudies. HIV RNA level was measured at weeks 12 and 24. Biochemical profiles were measured at baseline and week 24. RESULTS: From January to June 2016, 20 adolescents (12 male) were enrolled. Median (IQR) age was 16 (15-17) years and weight was 49 (42-59) kg. Mean (sd) AUC24 h, C24 h and Cmax of RPV were 2,041 (745) ng*h/ml, 69 (29) ng/ml and 143 (65) ng/ml, respectively. Median (IQR) Tmax was 5 (2-9) h. Four adolescents had C24 h <40 ng/ml. All PK parameters were comparable with published data. All adolescents remained virologically suppressed at week 24. Significant decreases in fasting total cholesterol, triglyceride and low-density lipoprotein were observed (P-value <0.05). CONCLUSIONS: Virologically suppressed HIV-infected adolescents had adequate RPV exposure and remained virologically suppressed after switching from EFV. RPV can be used as long-term maintenance ART in HIV-infected adolescents

Factors associated with daily tenofovir exposure in Thai subjects taking combination antiretroviral therapy

Contains fulltext : 155259.pdf (publisher's version ) (Closed access)Tenofovir (TFV) exposure is associated with antiretroviral efficacy and risk of kidney disease. There is evidence of high interindividual variability of the pharmacokinetics of TFV. The effect of several clinical conditions on the pharmacokinetics of TFV has been observed and may partly explain its variability. We assessed factors influencing the pharmacokinetics of TFV in Thai patients. Thirty participants (50% female) taking efavirenz- or ritonavir-boosted protease inhibitor-based regimens were investigated. Intensive pharmacokinetic sampling was performed over 24 h. Multivariate geometric mean regression models adjusted for covariates with p</=0.2 in univariate analysis were developed. The median age was 41 years. Five participants [three taking a protease inhibitor (PI) and two taking efavirenz (EFV)] had mild renal dysfunction [estimated glomerular filtration rate (eGFR) 60-90 ml/min/1.73 m(2); range 72-89]. TFV AUC0-24 was 23% (95% CI 1-49%; p=0.04) higher in those taking PI vs. EFV, 39% (95% CI 5-84%; p=0.02) higher in those with mild renal dysfunction, and reduced by 16% (95% CI 5-26%; p=0.008) with each 10 kg body weight increase, after adjusting for sex and duration of TFV exposure. In PI-treated subjects TFV AUC0-24 increased by 3% (0.3-6%; p=0.03) for each mg.h/liter increase in ritonavir (RTV) AUC0-24 after adjusting for sex, weight, mild renal impairment, and proximal renal tubular dysfunction. Significantly higher TFV exposures were independently associated with PI regimens, mild renal impairment, lower body weight, and increasing RTV AUC0-24. Clinicians should be aware of the effect of these factors on TFV exposure when this drug is prescribed