A5027458645- HIV/AIDS drug development and treatment
- HIV Research and Treatment
- HIV/AIDS Research and Interventions
- Hepatitis C virus research
- Mosquito-borne diseases and control
- Malaria Research and Control
- Viral Infections and Vectors
- Pneumocystis jirovecii pneumonia detection and treatment
- Hepatitis B Virus Studies
- Dengue and Mosquito Control Research
- Liver Disease Diagnosis and Treatment
- Biochemical and Molecular Research
- DNA and Nucleic Acid Chemistry
- Pharmacological Effects and Toxicity Studies
- Viral Infections and Immunology Research
Janssen (Belgium)
2012-2023
Janssen (Switzerland)
2014
Abstract Dengue is a major health threat and the number of symptomatic infections caused by four dengue serotypes estimated to be 96 million 1 with annually around 10,000 deaths 2 . However, no antiviral drugs are available for treatment or prophylaxis dengue. We recently described interaction between non-structural proteins NS3 NS4B as promising target development pan-serotype virus (DENV) inhibitors 3 Here we present JNJ-1802—a highly potent DENV inhibitor that blocks NS3–NS4B within viral...
Objective: To refine the genotypic and phenotypic correlates of response to nonnucleoside reverse transcriptase inhibitor etravirine. Design: Initial analyses identified 13 etravirine resistance-associated mutations (RAMs) clinical cutoffs (CCOs) for A multivariate analysis was performed initial RAM list improve predictive value resistance testing with regard virologic relationship data. Methods: Week 24 data were pooled from phase III studies TMC125 Demonstrate Undetectable viral load in...
Background & AimsSimeprevir is an oral hepatitis C virus (HCV) NS3/4A protease inhibitor approved for treatment of chronic HCV infection. Baseline NS3 polymorphisms in all patients and emerging mutations who failed to achieve sustained virologic response (SVR) with simeprevir plus peginterferon/ribavirin (PR) Phase IIb/III studies are described.MethodsBaseline sequencing data were available 2007 genotype 1 (GT1)-infected patients. Post-baseline 197/245 simeprevir-treated did not SVR. In...
The contribution of E138 mutations to etravirine resistance was investigated. Amino acids at position after failure with in DUET were A (n = 1), G 5), K 3), P Q and V 2). At baseline, only E138A found 3.0% 2.5%, respectively. Virologic response (less than 50 copies/mL) observed six 12 eight 10 patients E138Q, Site-directed mutants harboring E138A/G/K/Q/R or S showed fold change values 2.9, 2.4, 2.6, 3.0, 3.6, 2.8, E138G, K, added the existing etravirine-weighted genotypic score including 17...
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are an important component of antiretroviral therapy for HIV type-1 (HIV-1)-infected patients. Development NNRTI resistance can lead to treatment failure and is conferred by the presence specific resistance-associated mutations (RAMs) in transcriptase. In addition widely used list RAMs provided International AIDS Society-USA HIV-1 Drug Resistance Mutation Group, which were identified on basis clinical experience with approved NNRTIs, a...
Background. Simeprevir is an oral, once-daily, hepatitis C virus (HCV) NS3/4A protease inhibitor for the treatment of chronic HCV genotype 1 infection. Human immunodeficiency (HIV) coinfection accelerates progression liver disease. This uncontrolled, open-label trial explored safety and efficacy simeprevir in patients with 1/HIV type (HIV-1) coinfection.
Dengue virus (DENV) infections are major causes of morbidity and mortality throughout the tropics subtropics. More than 400 million estimated to occur every year, resulting in nearly 100 symptomatic more 20,000 deaths. Early immune response kinetics infection remain unclear, large part due variable incubation period exhibited by DENVs after introduction into a susceptible host. To fill this knowledge gap, we performed comprehensive virologic immunologic analysis individuals experimentally...
The randomized, placebo-controlled Phase III DUET studies enrolled treatment-experienced, HIV-1-infected patients. We examined the genotypic and phenotypic changes at endpoint relative to baseline, including emergence of individual reverse transcriptase (RT) mutations, in patients who received non-nucleoside inhibitor (NNRTI) etravirine experienced virologic failure by rebound time Week 96 analysis. Patients 200 mg twice-daily combination with a background regimen containing...
ABSTRACT Connection domain mutations (CDMs) in HIV-1 reverse transcriptase (RT) alter susceptibility to some nucleoside/nonnucleoside RT inhibitors (NRTIs/NNRTIs). Their effects on and virologic responses etravirine were analyzed. Seventeen CDMs evaluated: L283I, E312Q, G333D, G333E, G335C, G335D, N348I, A360I, A360T, A360V, V365I, T369I, A371V, A376S, I393L, E399D, E399G. CDM prevalence analyzed retrospectively using clinical data. The assessed samples confirmed site-directed mutants. most...
Objectives PIANO ( P aediatric study of I ntelence A s an NNRTI O ption; TMC125‐C213 ; NCT00665847 ) assessed the safety/tolerability, antiviral activity and pharmacokinetics etravirine plus optimized background regimen OBR in treatment‐experienced, HIV ‐1‐infected children (≥ 6 to < 12 years) adolescents 18 over 48 weeks. Methods In a phase II , open‐label, single‐arm study, 101 treatment‐experienced patients (41 children; 60 adolescents) with screening viral load VL ≥ 500 ‐1 RNA...
This study investigated strategies that may increase the yield of drug resistance testing prior to starting antiretroviral therapy (ART), and whether transmitted polymorphic resistance-associated mutations (RAMs) correlated with virological outcomes. We carried out retrospective baseline samples from patients entering SENSE trial first-line ART in Europe, Russia Israel. Prior randomization etravirine or efavirenz plus two nucleos(t)ide reverse transcriptase inhibitors (NRTIs), plasma...
JNJ-54257099 (9) is a novel cyclic phosphate ester derivative that belongs to the class of 2'-deoxy-2'-spirooxetane uridine nucleotide prodrugs which are known as inhibitors HCV NS5B RNA-dependent RNA polymerase (RdRp). In Huh-7 genotype (GT) 1b replicon-containing cell line 9 devoid any anti-HCV activity, an observation attributable inefficient prodrug metabolism was found be CYP3A4-dependent. contrast, in vitro incubation primary human hepatocytes well pharmacokinetic evaluation thereof...
Abstract The prevalence of susceptibility to etravirine was investigated among clinical samples submitted for routine testing in the United States using two separate weighted genotypic scoring systems. presence mutations and by phenotype from HIV-1-infected patients, Monogram Biosciences resistance between June 2008 2009, were analyzed. Susceptibility genotype determined Tibotec etravirine-weighted systems, with scores ≤3 ≤2, respectively, indicating full susceptibility. PhenoSense HIV...
Etravirine is a recently approved nonnucleoside reverse transcriptase inhibitor. The ability of etravirine to limit the emergence resistance protease inhibitors, and specifically darunavir, was investigated in subset treatment-experienced patients with virologic rebound phase III DUET trials. Of those experiencing rebound, fewer etravirine-treated than placebo-treated developed mutations associated inhibitors general darunavir particular, more placebo-group maintained baseline susceptibility...
The aims of this study were to compare various genotypic scoring systems commonly used predict virological outcome etravirine, and examine their concordance with etravirine phenotypic susceptibility.Six assessed: Tibotec 2010 (based on 20 mutations; TBT 20), Monogram, Stanford HIVdb, ANRS, Rega 37, 30, 27 49 mutations, respectively) virco(®)TYPE HIV-1 (predicted fold change based genotype). Samples from treatment-experienced patients who participated in the DUET trials both data (n=403)...
Etravirine (ETR) has previously shown potent in vitro activity against different primary HIV-1 isolates and demonstrated durable efficacy treatment-experienced, HIV-1-infected patients the Phase III DUET studies. The antiviral of ETR subtypes B non-B were further investigated. effect subtype on fold change EC50 value (FC) was analyzed recombinant clinical from 673 treatment-naive enrolled other Tibotec Subgroup analyses studies proportion with viral load (VL) <50 RNA copies/ml also conducted...
This observational study in antiretroviral treatment-experienced, HIV-1-infected adults explored the efficacy of etravirine plus darunavir/ritonavir (DRV group; n = 999) vs. an alternative boosted protease inhibitor (other PI 116) using pooled European cohort data.Two international (EuroSIDA; EUResist Network) and five national (France, Italy, Spain, Switzerland UK) cohorts provided data (collected 2007-2012). Stratum-adjusted (for confounding factors) Mantel-Haenszel differences virological...
To describe the pharmacokinetics, safety, and efficacy of etravirine (ETR) in HIV-infected children 1 to less than 6 years age.Phase I/II, open-label, multicenter, dose-finding study.Antiretroviral therapy (ART)-experienced two age cohorts (I: 2 <6 years; II: years) received weight-based ETR, swallowed whole or dispersed liquid, with optimized ART including a ritonavir-boosted protease inhibitor. Intensive pharmacokinetics occurred 7-18 days after starting ETR. Participants ETR AUC12h 2350...
Objectives. TEACH (NCT00896051) was a randomized, open-label, two-arm Phase II trial to investigate the pharmacokinetic interaction between etravirine and atazanavir/ritonavir safety efficacy in treatment-experienced, HIV-1-infected patients. Methods. After two-week lead-in of two nucleoside reverse transcriptase inhibitors (NRTIs) 300/100 mg, 44 patients received 200 mg bid with one NRTI, plus or 400/100 qd (n = 22 each group) over 48 weeks. Results. At steady-state decreased atazanavir C...
We assessed etravirine resistance in treatment-experienced, HIV-1-infected children (n=41)/adolescents (n=60) who received twice-daily 5.2 mg/kg and a background regimen (boosted protease inhibitor plus nucleoside/nucleotide reverse transcriptase inhibitors, optional enfuvirtide/raltegravir) Phase II, open-label, multicentre trial (PIANO).In addition to phenotypes, viral genotypes were by population deep sequencing (PS DS) virological failures (VFs; baseline end point) responders (baseline)....
Introduction In DUET, etravirine (ETR) 200 mg bid had durable efficacy and a favourable safety profile versus placebo, both arms with an optimised background regimen (BR) including darunavir/ritonavir (DRV/r). TMC125IFD3002 (VIOLIN; NCT01422330) investigated ETR plus ARVs other than DRV/r. Materials Methods This was 48 week, Phase IV, open‐label, single‐arm, multicentre study. HIV‐1‐infected treatment‐experienced adult patients on=8 weeks ARV therapy prior to screening, switching either for...
Methods In this analysis, patients with a virologic rebound were defined as those who showed response at earlier time-points but rebounded to >50 copies/ml in the DUET week 48 dataset. Phenotyping and genotyping baseline end-point performed AntivirogramTM Virco® TYPE HIV-1 assays, respectively, if viral load (VL) was >1000 copies/ml. Emerging mutations present (i.e. last available resistance test on treatment) not baseline. Patients discontinued trial for non-virologic reasons excluded.
VIOLIN (TMC125IFD3002; NCT01422330) evaluated the safety, tolerability, and pharmacokinetics of etravirine with antiretrovirals other than darunavir/ritonavir in HIV-1-infected patients.In a 48-week, phase IV, single-arm, multicenter study, patients on prior antiretroviral therapy (⩾8 weeks) who needed to change regimen for virologic failure (viral load ⩾ 500 copies/mL) or simplification/adverse events < 50 received 200 mg bid ⩾1 active antiretroviral, excluding only nucleoside/tide reverse...