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

BACKGROUND: Genotype 1b (GT1b) is the most common subtype of the hepatitis C virus (HCV). We present an integrated analysis of 1070 participants with HCV GT1b infection from 30 countries who received elbasvir/grazoprevir for 12 weeks. METHODS: This is a retrospective analysis of data from participants with chronic HCV GT1b infection enrolled in 11 phase II/III clinical trials. All participants received elbasvir 50 mg plus grazoprevir 100 mg once daily for 12 weeks. The primary end point of all studies was sustained virologic response 12 weeks after completion of therapy (SVR12, HCV RNA < 15 IU/ml). RESULTS: SVR12 was 97.2% (1040/1070). Of the 30 participants who failed to attain SVR12, 15 relapsed and 15 had nonvirologic failure. Among participant subgroups, SVR12 was high in those with compensated cirrhosis (188/189, 99.5%), HIV co-infection (51/54, 94.4%), and baseline viral load > 800,000 IU/ml (705/728, 96.8%). Resistance-associated substitutions (RASs) at NS5A positions 28, 30, 31, or 93 were present in 21.6% of participants at baseline. SVR12 was 99.6% (820/823) in participants without baseline NS5A RASs and 94.7% (215/227) in those with baseline NS5A RASs. Serious adverse events occurred in 3.2% (34/1070) of participants, nine of which occurred after study medication was completed. CONCLUSIONS: Elbasvir/grazoprevir for 12 weeks represents an effective treatment option for participants with HCV GT1b infection. SVR12 was high in all participant subgroups, including those with compensated cirrhosis, HIV co-infection, and high baseline viral load. CLINICALTRIALS. GOV IDENTIFIERS: The trials discussed in this paper were registered with Clinicaltrial.gov as the following: NCT02092350 (C-SURFER), NCT02105662 (C-EDGE Co-Infection), NCT02105467 (C-EDGE treatment-naive), NCT02105701 (C-EDGE treatment-experienced), NCT01717326 (C-WORTHy), NCT02251990 (C-CORAL), NCT02105688 (C-EDGE COSTAR), NCT02252016 (C-EDGE IBLD), NCT02115321 (C-SALT), NCT02203149 (Japan phase 2/3 study), NCT02358044 (C-EDGE Head-2-Head).

• Klíčová slova
• Hepatitis, Retrospective, Therapy,
• MeSH
• amidy MeSH
• antivirové látky škodlivé účinky   terapeutické užití   MeSH
• benzofurany škodlivé účinky   terapeutické užití   MeSH
• chinoxaliny škodlivé účinky   terapeutické užití   MeSH
• chronická hepatitida C komplikace   farmakoterapie   virologie   MeSH
• cyklopropany MeSH
• dospělí MeSH
• genotyp MeSH
• Hepacivirus genetika   MeSH
• HIV infekce komplikace   MeSH
• imidazoly škodlivé účinky   terapeutické užití   MeSH
• jaterní cirhóza patofyziologie   virologie   MeSH
• karbamáty MeSH
• klinické zkoušky, fáze II jako téma MeSH
• klinické zkoušky, fáze III jako téma MeSH
• koinfekce komplikace   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• retrospektivní studie MeSH
• senioři MeSH
• setrvalá virologická odpověď MeSH
• sulfonamidy MeSH
• virová léková rezistence genetika   MeSH
• virová nálož MeSH
• virové nestrukturální proteiny genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• amidy MeSH
• antivirové látky MeSH
• benzofurany MeSH
• chinoxaliny MeSH
• cyklopropany MeSH
• elbasvir MeSH Prohlížeč
• grazoprevir MeSH Prohlížeč
• imidazoly MeSH
• karbamáty MeSH
• NS-5 protein, hepatitis C virus MeSH Prohlížeč
• sulfonamidy MeSH
• virové nestrukturální proteiny MeSH

The effect of growth stimulators Carbadox and Cyadox was studied in laboratory rats and mice as exerted on their fertility, gravidity, embryo ontogenesis, and genetic efficacy of these drugs was also tested. In all tests one dose approaching the dose used in practice and multiple doses were administered. No antifertility effects were observed in either sex of rats, slight reduction in fertility was found in treated male mice. No teratogenic effect was observed, but both stimulators acted highly embryotoxically. Irrespective of the dose, genetic hazard occurred, influencing the first stages of spermatogenesis (spermatogony), and increasing the incidence ob abnormalities of spermatozoon heads after Carbadox treatment. In all tests Cyadox was less harmful than Carbadox. The results show that it is somewhat hazardous to use both growth stimulators in the period of animal reproduction.

• MeSH
• chinoxaliny škodlivé účinky   farmakologie   MeSH
• fertilita účinky léků   MeSH
• karbadox farmakologie   MeSH
• krysa rodu Rattus MeSH
• odumření plodu chemicky indukované   MeSH
• plod účinky léků   MeSH
• růstové látky škodlivé účinky   farmakologie   MeSH
• spermatogeneze účinky léků   MeSH
• těhotenství u zvířat účinky léků   MeSH
• těhotenství MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• Názvy látek
• chinoxaliny MeSH
• cyadox MeSH Prohlížeč
• karbadox MeSH
• růstové látky MeSH