OBJECTIVES: The aim was to introduce a diagnostic method for detecting variants of hepatitis C virus (HCV) with protease NS3 resistance primarily to simeprevir (Q80K mutation in HCV genotype 1a) and its subsequent use in routine practice. MATERIAL AND METHODS: The detection of HCV resistance-associated variants in the NS3 protease gene by sequence analysis was introduced in the molecular biology laboratory of University Hospital Hradec Kralove in 2015. The primers were designed by sequence analysis software Custom Primers - OligoPerfect™ Designer. The method was optimized for HCV genotype 1a. The search for variants was performed using two programs. RESULTS: A total of 16 patients with genotype 1a chronic hepatitis C have been examined since 2015. In five of them, the Q80K variant was detected. CONCLUSION: The development of resistance to antiviral therapy for chronic hepatitis C gained importance after the introduction of direct-acting antivirals. Given the relatively high prevalence of the Q80K mutation in HCV genotype 1a, it is crucial to confirm its presence or absence before the therapy is initiated. The reported method enables clear and early detection of the Q80K mutation.

• MeSH
• Hepacivirus genetika   MeSH
• hepatitida C diagnóza   virologie   MeSH
• lidé MeSH
• mutace genetika   MeSH
• virologie metody   MeSH
• virová léková rezistence genetika   MeSH
• virové nestrukturální proteiny genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• NS3 protein, hepatitis C virus MeSH Prohlížeč
• virové nestrukturální proteiny MeSH

Since its discovery in 1988, the hepatitis C virus (HCV) has become a hot topic of research by many groups around the world. This globally spread infectious agent is responsible for a large proportion of chronic viral hepatitides. The clue to halting the hepatitis C pandemic may be the detailed understanding of the virus structure, its replication mechanism, and the exact functions of the various proteins. Such understanding could enable the development of new antivirals targeted against hepatitis C virus and possibly an effective vaccine. This review recaps the current knowledge about the HCV genome 15 years after its discovery. The structure and function of particular viral structural (core, E1, E2) and nonstructural (NS2, NS3, NS4, NS5) proteins and noncoding regions known to date are described. With respect to frequent conflicting reports from different research groups, results reproducibly demonstrated by independent investigators are emphasized. Owing to many obstacles and limitations inherent in doing research on this noteworthy virus, the current knowledge is incomplete and the answers to many important questions are to be expected in the future.

• MeSH
• 3' nepřekládaná oblast MeSH
• 5' nepřekládaná oblast MeSH
• genom virový MeSH
• Hepacivirus klasifikace   genetika   fyziologie   MeSH
• virové nestrukturální proteiny * chemie   genetika   fyziologie   MeSH
• virové strukturální proteiny * chemie   genetika   fyziologie   MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• 3' nepřekládaná oblast MeSH
• 5' nepřekládaná oblast MeSH
• virové nestrukturální proteiny * MeSH
• virové strukturální proteiny * MeSH

In this study we sought to evaluate narlaprevir (NVR) pharmacokinetics (PK) after a single dose with or without ritonavir (RTV) in cirrhotic versus healthy subjects. NVR at 200 mg was administered to 8 healthy and 8 cirrhotic subjects, and NVR at 100 mg with RTV at 100 mg was administered to 8 healthy and 8 cirrhotic subjects. PK analysis was performed. The geometric mean maximum concentration of a drug in serum (Cmax) and the area under the concentration-time curve from 0 to infinity (AUC0-∞) were 563.1 ng/ml and 4,701.8 ng · h/ml in cirrhotic patients versus 364.8 ng/ml and 1,917.1 ng · h/ml in healthy volunteers, respectively. The geometric mean ratios of the PK parameters of cirrhotic subjects to healthy volunteers were 1.54-fold (90% confidence interval [CI] = 1.05 to 2.27) for Cmax and 2.45-fold (90% CI = 1.56 to 3.85) for AUC0-∞ The geometric mean Cmax and AUC0-∞ in cirrhotic and healthy subjects were similar: 1,225.7 ng/ml for Cmax and 15,213.1 ng · h/ml for AUC0-∞ in cirrhotic subjects and 1,178.9 ng/ml for Cmax and 14,257.2 ng · h/ml for AUC0-∞ in healthy volunteers. The corresponding geometric mean ratios were 1.04 (90% CI = 0.67 to 1.62) for Cmax and 1.07 (90% CI = 0.72 to 1.58) for AUC0-∞ Higher exposures in cirrhotic subjects were safe and well tolerated. We found that NVR exposures after a 200-mg single dose were higher in cirrhotic subjects than in healthy subjects and that a 100-mg single dose of NVR boosted with RTV at 100 mg resulted in no significant PK differences between cirrhotic and healthy subjects.

• MeSH
• antivirové látky aplikace a dávkování   farmakokinetika   MeSH
• aplikace orální MeSH
• cyklopropany MeSH
• dipeptidy aplikace a dávkování   farmakokinetika   MeSH
• dospělí MeSH
• jaterní cirhóza farmakoterapie   MeSH
• leucin analogy a deriváty   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• močovina MeSH
• plocha pod křivkou MeSH
• prolin analogy a deriváty   MeSH
• ritonavir aplikace a dávkování   farmakokinetika   MeSH
• senioři MeSH
• sulfony aplikace a dávkování   farmakokinetika   MeSH
• virové nestrukturální proteiny antagonisté a inhibitory   MeSH
• zdraví dobrovolníci pro lékařské studie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky kontrolované MeSH
• klinické zkoušky, fáze I MeSH
• Názvy látek
• antivirové látky MeSH
• cyklopropany MeSH
• dipeptidy MeSH
• leucin MeSH
• močovina MeSH
• narlaprevir MeSH Prohlížeč
• NS3 protein, hepatitis C virus MeSH Prohlížeč
• prolin MeSH
• ritonavir MeSH
• sulfony MeSH
• virové nestrukturální proteiny MeSH

Changes in the specific CD4+ T-cell immunity against HCV in response to the treatment with alpha-interferon and ribavirin have been studied in 56 patients with chronic HCV infection. It was shown that after the treatment enhancement of the immune response to HCV infection was mainly due to the elevation of the numbers of NS3 and NS4 antigen-specific CD4+ T cells, which indicates that these cells play an important role in the development of the specific defense directed towards elimination of the virus from the human organism.

• MeSH
• antigeny CD4 analýza   MeSH
• antivirové látky aplikace a dávkování   MeSH
• chronická hepatitida C farmakoterapie   imunologie   MeSH
• dospělí MeSH
• interferon alfa-2 MeSH
• interferon alfa aplikace a dávkování   MeSH
• kombinovaná farmakoterapie MeSH
• lidé MeSH
• rekombinantní proteiny MeSH
• ribavirin aplikace a dávkování   MeSH
• T-lymfocyty pomocné-indukující imunologie   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antigeny CD4 MeSH
• antivirové látky MeSH
• interferon alfa-2 MeSH
• interferon alfa MeSH
• rekombinantní proteiny MeSH
• ribavirin MeSH

BACKGROUND & AIMS: Eight-week glecaprevir/pibrentasvir leads to high rates of sustained virological response at post-treatment week 12 (SVR12) across HCV genotypes (GT) 1-6 in treatment-naïve patients without cirrhosis. We evaluated glecaprevir/pibrentasvir once daily for 8 weeks in treatment-naïve patients with compensated cirrhosis. METHODS: EXPEDITION-8 was a single-arm, multicenter, phase IIIb trial. The primary and key secondary efficacy analyses were to compare the lower bound of the 95% CI of the SVR12 rate in i) patients with GT1,2,4-6 in the per protocol (PP) population, ii) patients with GT1,2,4-6 in the intention-to-treat (ITT) population, iii) patients with GT1-6 in the PP population, and iv) patients with GT1-6 in the ITT population, to pre-defined efficacy thresholds based on historical SVR12 rates for 12 weeks of glecaprevir/pibrentasvir in the same populations. Safety was also assessed. RESULTS: A total of 343 patients were enrolled. Most patients were male (63%), white (83%), and had GT1 (67%). The SVR12 rate in patients with GT1-6 was 99.7% (n/N = 334/335; 95%CI 98.3-99.9) in the PP population and 97.7% (n/N = 335/343; 95% CI 96.1-99.3) in the ITT population. All primary and key secondary efficacy analyses were achieved. One patient (GT3a) experienced relapse (0.3%) at post-treatment week 4. Common adverse events (≥5%) were fatigue (9%), pruritus (8%), headache (8%), and nausea (6%). Serious adverse events (none related) occurred in 2% of patients. No adverse event led to study drug discontinuation. Clinically significant laboratory abnormalities were infrequent. CONCLUSIONS: Eight-week glecaprevir/pibrentasvir was well tolerated and led to a similarly high SVR12 rate as the 12-week regimen in treatment-naïve patients with chronic HCV GT1-6 infection and compensated cirrhosis. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03089944. LAY SUMMARY: This study was the first to evaluate an 8-week direct-acting antiviral (DAA) regimen active against all major types of hepatitis C virus (HCV) in untreated patients with compensated cirrhosis. High virological cure rates were achieved with glecaprevir/pibrentasvir across HCV genotypes 1-6, and these high cure rates did not depend on any patient or viral characteristics present before treatment. This may simplify care and allow non-specialist healthcare professionals to treat these patients, contributing to global efforts to eliminate HCV.

• Klíčová slova
• Chronic HCV infection, Compensated cirrhosis, Direct-acting antiviral, Glecaprevir/pibrentasvir, HCV elimination, Hepatitis C virus, Pangenotypic, Short duration,
• MeSH
• antivirové látky aplikace a dávkování   škodlivé účinky   MeSH
• benzimidazoly aplikace a dávkování   škodlivé účinky   MeSH
• chinoxaliny aplikace a dávkování   škodlivé účinky   MeSH
• chronická hepatitida C krev   komplikace   farmakoterapie   virologie   MeSH
• cyklopropany aplikace a dávkování   škodlivé účinky   MeSH
• fixní kombinace léků MeSH
• genotyp * MeSH
• Hepacivirus enzymologie   genetika   MeSH
• jaterní cirhóza komplikace   farmakoterapie   MeSH
• kyseliny aminoisomáselné aplikace a dávkování   škodlivé účinky   MeSH
• leucin aplikace a dávkování   škodlivé účinky   analogy a deriváty   MeSH
• lidé středního věku MeSH
• lidé MeSH
• makrocyklické laktamy aplikace a dávkování   škodlivé účinky   MeSH
• polymorfismus genetický MeSH
• prolin aplikace a dávkování   škodlivé účinky   analogy a deriváty   MeSH
• pyrrolidiny aplikace a dávkování   škodlivé účinky   MeSH
• RNA virová krev   genetika   MeSH
• senioři MeSH
• setrvalá virologická odpověď MeSH
• sulfonamidy aplikace a dávkování   škodlivé účinky   MeSH
• virové nestrukturální proteiny genetika   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antivirové látky MeSH
• benzimidazoly MeSH
• chinoxaliny MeSH
• cyklopropany MeSH
• fixní kombinace léků MeSH
• glecaprevir MeSH Prohlížeč
• kyseliny aminoisomáselné MeSH
• leucin MeSH
• makrocyklické laktamy MeSH
• NS-5 protein, hepatitis C virus MeSH Prohlížeč
• NS3 protein, hepatitis C virus MeSH Prohlížeč
• pibrentasvir MeSH Prohlížeč
• prolin MeSH
• pyrrolidiny MeSH
• RNA virová MeSH
• sulfonamidy MeSH
• virové nestrukturální proteiny MeSH