Drug susceptibility to etravirine and darunavir among Human Immunodeficiency Virus Type 1-derived pseudoviruses in treatment-experienced patients with HIV/AIDS in South Korea.

BACKGROUND: In South Korea, about 20 types of antiretroviral drugs are used in the treatment of patients with human immunodeficiency virus/acquired immune deficiency syndrome. Since 2010, raltegravir, etravirine, and darunavir have been spotlighted as new drugs for highly active antiretroviral therapy (HAART)-experienced adults with resistant HIV-1 in South Korea. In this study, we investigated potential susceptibility of pseudoviruses derived from treatment-experienced Korean patients to etravirine vs efavirenz and to darunavir vs amprenavir and indinavir using a modified single-round assay. METHODS: Pseudoviruses derived from nine treatment-experienced patients infected with HIV-1 were investigated by comparison with the wild-type strain pNL4-3. The 50% inhibitory concentration (IC50) values were calculated and drug susceptibility was compared. The intensity of genotypic drug resistance was classified based on the 'SIR' interpretation of the Stanford data base. RESULTS: Drug susceptibility was generally higher for etravirine and darunavir compared with efavirenz, amprenavir, and indinavir in pseudoviruses derived from treatment-experienced patients. Pseudoviruses derived from patients KRB4025 and KRB8014, who exhibited long-term use of protease inhibitors, showed an outside of tested drug concentration, especially for amprenavir and indinavir. However, they exhibited a lower fold-change in resistance to darunavir. CONCLUSIONS: Etravirine and darunavir have been used in HAART since 2010 in South Korea. Therefore, these antiretroviral drugs together with other newly introduced antiretroviral drugs are interesting for the optimal treatment of patients with treatment failure. This study may help to find a more effective HAART in the case of HIV-1 infected patients that have difficulty being treated.

Circadian and seasonal variations of ventricular tachyarrhythmias in patients with early repolarization syndrome and Brugada syndrome: analysis of patients with implantable cardioverter defibrillator.

INTRODUCTION: The circadian and seasonal patterns of ventricular tachyarrhythmia (VTA) in patients with early repolarization syndrome (ERS) have not been determined. We compared the timing of VTAs in patients with ERS and Brugada syndrome (BS). METHODS AND RESULTS: We enrolled patients with ERS (n = 14) and BS (n = 53) who underwent implantable cardioverter defibrillator (ICD) implantation. The timing of VTAs, including cardiac arrest and appropriate shocks, was determined. During follow up of 6.4 ± 3.6 years in the ERS group and 5.0 ± 3.3 years in the BS group, 5 of 14 (36%) ERS and 10 of 53 (19%) BS patients experienced appropriate shocks (P = 0.37). Cardiac arrest showed a trend of nocturnal distribution peaking from midnight to early morning (P = 0.14 in ERS, P = 0.16 in BS). Circadian distribution of appropriate shocks showed a significant nocturnal peak in patients with ERS (P < 0.0001) but a trend toward a nocturnal peak in patients with BS (P = 0.08). There were no seasonal differences in cardiac arrest in patients with ERS and BS. However, patients with ERS showed a seasonal peak in appropriate shocks from spring to summer (P < 0.0001). There was no significant seasonal peak in patients with BS. The timing of VTAs (cardiac arrest plus appropriate shock) showed significant nocturnal distributions in patients with ERS and BS (P < 0.01, respectively). A significant clustering of VTAs was noted from spring to summer (P < 0.01) in patients with ERS, but not in patients with BS (P = 0.42). CONCLUSIONS: Incidence of VTAs showed marked circadian variations with night-time peaks in patients with ERS and BS.

Drug susceptibility of human immunodeficiency virus type 1-derived pseudoviruses from treatment-experienced patients to protease inhibitors and reverse transcriptase inhibitors, using a modified single-round assay.

BACKGROUND: Genotypic drug resistance assay has been the only method available to provide information related to drug resistance in South Korea since 1999. Phenotypic assay is also a useful method to predict a patient's state related to antiretroviral drug resistance. However, commercial systems and methods for phenotyping have not been introduced into South Korea. OBJECTIVES: To establish and apply modified phenotypic drug susceptibility assay using treatment-experienced patients' derived HIV-1 in South Korea. STUDY DESIGN: The genotypic drug resistance and phenotypic drug susceptibility of two different methods, Stanford HIV Drug Resistance Database (Stanford DB) and modified phenotypic drug susceptibility assay were compared especially focused on the HIV-1 protease (PR) and reverse transcriptase (RT) sequences. RESULTS: There was some discordance in comparing drug susceptibility results (a modified drug susceptibility assay) with the predicted genotypic drug resistance (Stanford DB). Phenotypic drug resistance showed the following order for pseudoviruses from treatment-experienced patients infected with HIV/AIDS: Efavirenz (EFV, 21 to 1,319-fold change), Lamivudine (3TC, 31 to >189-fold change), Indinavir sulfate (IDV, 26 to 63-fold change), Amprenavir (APV, 4 to 35-fold change) and Zidovudine (AZT, 20 to 634-fold change). For patient KRC3221, the AZT-related phenotypic drug resistance was the greatest, with 634-fold change compared with the wild type. CONCLUSIONS: Application of this modified phenotypic drug susceptibility assay is expected to help in predicting drug resistance as a guideline for clinicians to obtain a combined interpretation among genotyping, phenotyping and effective clinical treatments.

High plasma concentrations of transforming growth factor-ß and tissue inhibitor of metalloproteinase-1: potential non-invasive predictors for electroanatomical remodeling of atrium in patients with non-valvular atrial fibrillation.

BACKGROUND: The degree of electroanatomical remodeling of the left atrial (LA) affects the clinical outcome after rhythm control of atrial fibrillation (AF). Our hypothesis was that plasma concentrations of transforming growth factor (TGF)-ß and tissue inhibitor of metalloproteinase (TIMP)-1 reflect LA voltage and structural remodeling in patients with non-valvular AF. METHODS AND RESULTS: In the study, 242 patients (male 79.4%, 55.1 ± 11.0 years old) with AF (155 paroxysmal AF, 87 persistent AF) underwent catheter ablation. Pre-ablation plasma concentrations of TGF-ß and TIMP-1 and the degree of electroanatomical remodeling quantified by LA voltage map (NavX) and 3D-CT were evaluated. The mean LA voltage and volume were compared in patients with high TGF-ß (≥10.0 ng/ml, H-TGF) vs. low TGF-ß (<10.0 ng/ml, L-TGF) and high TIMP-1 (≥1.1 ng/ml, H-TIMP) vs. low TIMP-1 (<1.1 ng/ml, L-TIMP). Patients with H-TGF had lower mean LA voltage (P=0.014) and greater LA volume (P=0.022), particularly, posterior venous LA volume (P=0.005) than those with L-TGF. In patients with H-TIMP, the mean LA voltage (P=0.019) was lower than those with L-TIMP. LA volume was significantly higher (P<0.001) in patients with ejection fraction ≤58% than those with >58%. CONCLUSIONS: In patients with non-valvular AF, high plasma concentrations TGF-ß and TIMP-1 and low ejection fraction were closely related with electroanatomical remodeling of LA.

Characteristics of complex fractionated atrial electrogram in the electroanatomically remodeled left atrium of patients with atrial fibrillation.

BACKGROUND: Complex fractionated atrial electrogram (CFAE) guided ablation is effective in some patients with persistent atrial fibrillation (PeAF), but the pattern of CFAE may be different in the remodeled left atrium (LA). METHODS AND RESULTS: In 100 AF patients (83 males, 55.0+/-10.6 years old) with AF (51 paroxysmal AF (PAF), 49 PeAF) who underwent catheter ablation, CFAE cycle length (CL) and distribution (NavX 3D map) were compared according to the LA volume (3D-CT) and endocardial voltage (during high right atrial pacing 500-ms (Vol(PACE)) and AF (Vol(AF); NavX). The mean CFAE-CL was longer (P=0.003) and the % area CFAE was smaller (P=0.006) in patients with LA >or=125 ml than those with <125 ml. The mean CFAE-CL was longer in patients with Vol(PACE) <1.7 mV than those with >or=1.7 mV (P=0.002) and in Vol(AF) <0.7 mV than >or=0.7 mV (P<0.001). The % area CFAE was smaller in patients with Vol(PACE) <1.7 mV than those with >or=1.7 mV (P=0.006). The incidence of septal CFAE was consistently high, regardless of the degree of LA remodeling. CONCLUSIONS: In the AF patients with an electroanatomically remodeled LA, the % area of CFAE was smaller and mean CFAE-CL was longer than in those with a less remodeled LA. However, the majority of CFAE are consistently positioned on the septum in the remodeled LA.