Relationship between antiretroviral plasma concentration and emergence of HIV-1 resistance mutations at treatment failure.
ABSTRACT The relationship between antiretroviral pharmacokinetic exposure and acquisition of human immunodeficency virus-1 (HIV-1) drug resistance mutations (DRM) is not fully understood. The aim of this study was to investigate whether antiretroviral plasma concentration could predict the emergence of DRM at treatment failure.
The study cohort comprised retrospectively selected patients with failing antiretroviral regimens for whom a protease inhibitor (PI) or non-nucleoside reverse transcriptase inhibitor (NNRTI) trough concentration measurement (TDM) had been obtained before failure, a genotypic resistance test (GRT1) had been performed before the TDM, and a genotypic resistance test (GRT2) had been performed at therapeutic failure. Drug levels were classified as undetectable/detectable or subtherapeutic/therapeutic according to limits of quantification of a high-performance liquid chromatography-ultraviolet assay or pre-defined efficacy thresholds, respectively. The number of DRM acquired at treatment failure was evaluated by comparing the results of the GRT2 and GRT1.
A total of ten and 57 failure episodes occurred among our patients on NNRTI-based and PI-based regimens, respectively, and included in the evaluation. PI concentration was subtherapeutic in 28.1% of patients, among which the levels were undetectable in 21.1%. Twenty-five (43.9%) patients acquired at least one new PI-DRM according to the GRT2. Patients with undetectable PI levels showed a lower emergence of PI-DRM (minor + major) than those with detectable levels (8.3 vs. 53.3%, p = 0.007). Multivariate analysis confirmed that undetectable PI levels were independent negative predictors of DRM selection. NNRTI measurements were subtherapeutic in 2/10 (20%) patients. NNRTI-DRM were acquired by all patients regardless of NNRTI levels.
A PI measurement showing undetectable drug levels prior to treatment failure predicted the lack of emergence of PI-DRM at failure. These results suggest that PI levels can help clinicians interpret the reasons for treatment failure and guide the type of interventions needed.
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ABSTRACT: Sub-therapeutic and supra-therapeutic plasma concentrations of antriretrovirals are the significant causes of treatment failure and toxicity respectively among HIV-infected patients. We conducted this study to determine the pattern of efavirenz and nevirapine plasma drug concentrations among adult HIV-infected patients with immunological failure attending at a tertiary hospital in North-western Tanzania. A cross-sectional study was conducted among adult HIV-infected patients with immunological failure who have been on either efavirenz or nevirapine based antiretroviral regimen for more than 6 months. Patients were serially enrolled through routine Care and Treatment Clinic (CTC) activities. Plasma drug concentrations for efavirenz and nevirapine were determined by high performance liquid chromatography (HPLC) and Gas Chromatography (GC) respectively. Demographic, clinical and laboratory data such as viral load and CD4 counts were collected. Data analysis was done using STATA 12. Of the 152 patients with immunological failure enrolled, the sub-therapeutic, therapeutic and supra-therapeutic plasma antiretroviral drug concentrations were found in 43/152 (28.3%), 76/152 (50.0%) and 33/152 (21.7%) respectively. Half of the patients were outside therapeutic window with either sub-therapeutic or supra-therapeutic plasma ARV drug concentrations. There was a significant difference in distribution of ARV adherence (p-value<0.001), NRTI backbone (p-value = 0.039), HIV stage (p-value = 0.026) and viral load (p-value = 0.007) within sub-therapeutic, therapeutic and supra-therapeutic ARV plasma drug concentrations. There is a wide inter-individual variability of plasma ARV concentrations among HIV patients with immunological failure, with a large proportion of patients being outside therapeutic window. This variability is significant based on ARV adherence, NRTI backbone, viral load and HIV stage. Routine therapeutic drug monitoring (TDM) could assist identifying these patients early and making timely correction to avoid virological failure, poor immunological outcome and prevent associated drug toxicities. Nonetheless, ARV adherence should be strictly emphasized on HIV patients with immunological failure.PLoS ONE 01/2013; 8(9):e75118. · 3.53 Impact Factor
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ABSTRACT: Human immunodeficiency virus type 1 (HIV-1) infections with a plasma efavirenz concentration of <1,000 ng/mL appear to have a high risk for the emergence of drug resistance. In the present study, we assessed the influence of the CYP2B6 polymorphism on the plasma efavirenz level. CYP2B6 T18492C (rs2279345) in 149 HIV-infected Thai adults were genotyped. Plasma efavirenz concentrations 12 h after dosing were measured using a validated high-performance liquid chromatography. The relationship between the plasma efavirenz level and the CYP2B6 T18492C polymorphism were analysed. Among the 149 patients, the frequency of T18492C heterozygous (T/C) and homozygous mutant (C/C) was 38.26 % (n = 57) and 6.04 % (n = 9), respectively. In the entire cohort, the median efavirenz plasma concentration was 2,410 ng/mL [interquartile range (IQR) 1,460-4,120 ng/mL]. The plasma efavirenz concentration for patients with 18492CC (1,200 ng/mL, IQR 1,050-1,990 ng/mL) or 18492TC (1,900 ng/mL, IQR 1,320-2,510 ng/mL) genotypes were significantly lower than those with homozygous wild type (3,380 ng/mL, IQR 2,040-5,660 ng/mL), P-value < 0.001. The CYP2B6 T18492C polymorphism was significantly associated with lower efavirenz concentrations compared to those with homozygous wild type in HIV-1 infections. The genetic polymorphism CYP2B6 T18492C may be useful for the optimised efavirenz dose. Further studies in the clinical setting will need to be conducted before such an approach can be recommended for widespread use.Infection 11/2013; · 2.44 Impact Factor
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ABSTRACT: Data regarding the effect of CYP2B6 18492T>C polymorphism on plasma efavirenz concentration and 48-week virologic response in HIV and tuberculosis (TB) co-infected patients is still unknown. A total of 139 antiretroviral-naive HIV-infected adults with active TB were prospectively enrolled to receive efavirenz 600 mg/tenofovir/lamivudine. Eight single nucleotide polymorphisms (SNPs) within CYP2B6 were genotyped. Seven SNPs, including 64C>T, 499C>G, 516G>T, 785A>G, 1375A>G, 1459C>T, and 21563C>T, were included for CYP2B6 haplotype determination. CYP2B6 18492T>C was studied in 48 patients who carried haplotype *1/*1. At 12 and 24 weeks after ART, plasma efavirenz concentrations at 12 hours after dosing were measured. Plasma HIV-RNA was monitored every 12 weeks for 96 weeks. Of 48 patients, mean±SD body weight was 56±10 kilograms and 77% received rifampicin-containing anti-TB regimen. No drug resistance-associated mutation was detected at baseline. The frequencies of wild type (18492TT), heterozygous (18492TC), and homozygous (18492CC) mutant of CYP2B6 18492T>C were 39%, 42%, and 19%, respectively. At 12 weeks, mean±SD efavirenz concentrations of patients who carried 18492TT, 18492TC, and 18492CC were 2.8±1.6, 1.7±0.9, and 1.4±0.5 mg/L, respectively (P=0.005). At 24 weeks, efavirenz concentrations of corresponding groups were 2.4±0.8, 1.7±0.8, and 1.2±0.4 mg/L, respectively (P=0.003). Low efavirenz concentration was independently associated with 18492T>C (β=-0.937, P=0.004) and high body weight (β=-0.032, P=0.046). At 96 weeks, 19%, 17%, and 28% of patients carrying 18492TT, 18492TC, and 18492CC had plasma HIV-RNA >40 copies/mL and developed efavirenz-associated mutations (P=0.254). In summary, CYP2B6 18492T>C polymorphism compromises efavirenz concentrations in co-infected HIV and tuberculosis patients with CYP2B6 haplotype *1/*1.Antimicrobial Agents and Chemotherapy 02/2014; · 4.57 Impact Factor