Léčba chronické hepatitidy typu C kombinací přímo působících perorálních virostatik (directly acting antivirals, DAA) má vysokou účinnost (až 100 %), minimum kontraindikací a mimořádně příznivý bezpečnostní profil. Fixní kombinace elbasviru s grazoprevirem (Zepatier) představuje nově dostupnou, vysoce účinnou variantu této léčby určenou pro pacienty infikované virem hepatitidy typu C (HCV) genotypu 1 nebo 4. Elbasvir (EBR) je inhibitor NS5A (nestrukturálního proteinu 5A) druhé vlny 1. generace, grazoprevir (GZR) proteázový inhibitor 2. generace. Léčivý přípravek Zepatier obsahuje 50 mg EBR a 100 mg GZR. Standardní dávkování představuje jedna tableta denně.

Chronic hepatitis C therapy using directly acting antivirals (DAA) has high efficacy (up to 100%), minimum contraindications plus an extraordinarily favorable safety profile. Fixed combination of elbasvir and grazoprevir represents a newly available, highly effective variant of this therapy, indicated for patients infected with hepatitis C virus (HCV), genotypes 1 or 4. Elbasvir (EBR) is a NS5A inhibitor of the second wave of the 1st generation; grazoprevir (GZR) is a protease inhibitor of the 2nd generation. The preparation Zepatier includes 50 mg of EBR and 100 mg of GZR. The standard dose is one tablet daily.

• Klíčová slova
• elbasvir, grazoprevir,
• MeSH
• antivirové látky farmakologie   metabolismus   terapeutické užití   MeSH
• benzofurany farmakologie   metabolismus   terapeutické užití   MeSH
• chinoxaliny farmakologie   metabolismus   terapeutické užití   MeSH
• chronická hepatitida C * farmakoterapie   MeSH
• fixní kombinace léků MeSH
• imidazoly farmakologie   metabolismus   terapeutické užití   MeSH
• inhibitory proteas farmakologie   metabolismus   terapeutické užití   MeSH
• klinická studie jako téma MeSH
• kvantitativní vztahy mezi strukturou a aktivitou MeSH
• lidé MeSH
• nežádoucí účinky léčiv MeSH
• virové nestrukturální proteiny farmakologie   metabolismus   terapeutické užití   MeSH
• Check Tag
• lidé MeSH

• Klíčová slova
• Zepatier, grazoprevir, elbasvir,
• MeSH
• antivirové látky * terapeutické užití   MeSH
• benzofurany terapeutické užití   MeSH
• chinoxaliny terapeutické užití   MeSH
• chronická hepatitida C * farmakoterapie   MeSH
• dospělí MeSH
• fixní kombinace léků MeSH
• Hepacivirus účinky léků   MeSH
• hodnocení léčiv MeSH
• imidazoly terapeutické užití   MeSH
• klinická studie jako téma MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• práce podpořená grantem 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).

• 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
• dospělí MeSH
• genotyp MeSH
• Hepacivirus genetika   MeSH
• HIV infekce komplikace   MeSH
• imidazoly škodlivé účinky   terapeutické užití   MeSH
• jaterní cirhóza patofyziologie   virologie   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
• 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

BACKGROUND & AIMS: Direct-acting antiviral agents have improved treatment outcomes for patients with hepatitis C virus (HCV) infection; however, head-to-head comparisons are limited. The C-EDGE Head-2-Head Study compared the safety and efficacy of elbasvir/grazoprevir (EBR/GZR) with sofosbuvir plus pegylated interferon/ribavirin (SOF/PR) in patients with HCV infection. METHODS: This was a randomized, open-label, phase III trial. Two hundred fifty-seven patients with HCV genotype (GT)1 or 4 infection and baseline viral load >10,000IU/ml were randomized to receive 12weeks of EBR/GZR 50mg/100mg once daily (n=129) or sofosbuvir (400mg once daily) plus PR (n=128). Primary efficacy objective was sustained virologic response 12weeks after the end of therapy (SVR12, HCV RNA <15IU/ml). The primary safety objective was the proportion of patients experiencing a tier 1 safety event. RESULTS: The majority of patients were non-cirrhotic (83.1%), treatment-naïve (74.9%) and had HCV GT1b infection (82.0%). SVR12 rates were 99.2% (128/129) and 90.5% (114/126) in the EBR/GZR and SOF/PR groups, respectively. The estimated adjusted difference in SVR12 was 8.8% (95% confidence interval [CI], 3.6-15.3%). Because the lower bound of the 1-sided 1-sample exact test was greater than -10% and greater than zero, both non-inferiority and superiority of EBR/GZR vs. SOF/PR were established. The frequency of tier 1 safety events was lower among patients receiving EBR/GZR than SOF/PR (0.8% vs. 27.8%, between group difference, 27.0% [95% CI, -35.5% to -19.6%; p<0.001]). CONCLUSIONS: EBR/GZR has a superior efficacy and safety profile in patients with HCV GT1 or 4 infection compared with SOF/PR. LAY SUMMARY: The combination of elbasvir/grazoprevir for 12weeks was highly effective in treating patients with chronic hepatitis C, genotypes 1 or 4 infection. This regimen was more effective than sofosbuvir/pegylated interferon/ribavirin for 12weeks, and was notably superior in patients regarded as difficult to treat, including those with previous treatment failure, cirrhosis, or a high baseline viral load. The combination of elbasvir/grazoprevir also demonstrated a superior safety and tolerability profile based on fewer serious adverse events, no serious drug-related adverse events, and no treatment discontinuations. CLINICAL TRIAL REGISTRATION: Clinical trials.gov Identifier: NCT02358044.

• MeSH
• antivirové látky MeSH
• benzofurany MeSH
• chinoxaliny MeSH
• chronická hepatitida C * MeSH
• genotyp MeSH
• Hepacivirus MeSH
• imidazoly MeSH
• interferony MeSH
• kombinovaná farmakoterapie MeSH
• lidé MeSH
• ribavirin MeSH
• RNA virová MeSH
• sofosbuvir MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• randomizované kontrolované studie MeSH

• Klíčová slova
• Zepatier,
• MeSH
• antivirové látky terapeutické užití   MeSH
• benzofurany aplikace a dávkování   MeSH
• chinoxaliny aplikace a dávkování   MeSH
• chronická hepatitida C farmakoterapie   genetika   MeSH
• fixní kombinace léků MeSH
• Hepacivirus účinky léků   MeSH
• hepatitida C * farmakoterapie   genetika   MeSH
• imidazoly aplikace a dávkování   MeSH
• lidé MeSH
• ribavirin aplikace a dávkování   MeSH
• virová nálož účinky léků   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• klinická studie MeSH

• Klíčová slova
• Zepatier, přímo působící antivirotika,
• MeSH
• antivirové látky terapeutické užití   MeSH
• chronická hepatitida C * farmakoterapie   MeSH
• fixní kombinace léků MeSH
• interferon alfa terapeutické užití   MeSH
• klinické zkoušky jako téma MeSH
• lidé MeSH
• Check Tag
• lidé MeSH

• MeSH
• antivirové látky terapeutické užití   MeSH
• benzofurany aplikace a dávkování   MeSH
• chronická hepatitida C epidemiologie   farmakoterapie   komplikace   MeSH
• chronická renální insuficience farmakoterapie   MeSH
• fixní kombinace léků MeSH
• HIV infekce farmakoterapie   MeSH
• jaterní cirhóza farmakoterapie   MeSH
• koinfekce farmakoterapie   MeSH
• komorbidita MeSH
• lidé MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• klinická studie MeSH

Purpose: People chronically infected with hepatitis C virus (HCV) have diminished patient-reported outcomes (PROs). This study aimed to compare the impact of elbasvir/grazoprevir (EBR/GZR) treatment versus sofosbuvir with pegylated interferon and ribavirin (SOF/PR) on changes in PROs: 1) during the treatment period and 2) at posttreatment follow-up. Patients and methods: PRO data collected during the Phase III C-EDGE Head-2-Head (H2H) open-label study was analyzed. In this trial, patients infected with HCV were randomized 1:1 to receive either EBR/GZR or SOF/PR for 12 weeks. Patients self-administered the Short Form-36 version 2 (SF-36v2®) Health Survey Acute (1-week recall) Form and the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Scale at baseline, during treatment, and posttreatment. Between-group differences in mean change of PRO scores from baseline were estimated during the treatment period and also at the posttreatment follow-up. Effect sizes were calculated to evaluate if the detected change in mean PRO scores is clinically meaningful between groups. Results: There were 255 patients (99.2% White, 54.1% female, 74.9% treatment naïve) included in the analysis. During the treatment period, significant declines in SF-36v2 scores were observed across all domains for the SOF/PR group. Compared to the SOF/PR group, the EBR/GZR group reported more improvement in scores across all SF-36v2 domain scores at the end of the treatment period. At treatment week 12, the between-group differences for 6 out of the 8 domain scores for these patients reflected at least moderate effects (effect sizes >0.5). No significant between-group differences in change in SF-36v2 scores from baseline were detected posttreatment. The decline in SF-36v2 scores observed during the treatment period for the SOF/PR group returned to near baseline scores or above posttreatment. Treatment with EBR/GZR did not impact fatigue scores, but treatment with SOF/PR led to increased fatigue scores during treatment which resolved by posttreatment follow-up week 12. Conclusion: This study demonstrated that HCV treatment with EBR/GZR resulted in a significantly better PRO profile as compared to SOF/PR. PROs are an important consideration as worsening PROs experienced during treatment may negatively influence adherence and ultimately contribute to an unfavorable clinical outcome. Clinicaltrialsgov Identifier: NCT02358044.

• Publikační typ
• časopisecké články MeSH

Introduction: Some direct-acting antiviral regimens for hepatitis C virus (HCV) infection pose safety or efficacy concerns if coadministered with drugs containing ethinyl estradiol. The present analysis was conducted to examine the impact of concomitant oral contraceptive pills (OCP) or hormone replacement therapy (HRT) during treatment with elbasvir (EBR)/grazoprevir (GZR) in women with HCV genotype (GT)1 or GT4 infection. Methods: This is a post hoc, integrated retrospective analysis of female participants with HCV GT1 or GT4 infection who received EBR 50 mg/GZR 100 mg once daily for 12 weeks in phase 2/3 clinical trials. The primary end point was sustained virologic response at 12 weeks after therapy completion (SVR12). For this analysis, participants were stratified according to whether they received OCP or HRT during the original treatment study. Results: A total of 1,022 women with HCV GT1 or GT4 infection were included (receiving OCP/HRT, n=81; not receiving OCP/HRT, n=941). Most participants receiving OCP/HRT were treatment-naive (79%), noncirrhotic (91.4%), and aged >35 years (71.6%). SVR12 rates were similar in women receiving OCP/HRT and those not receiving OCP/HRT (95.1% vs 96.3%). SVR12 rates remained high across all subgroups within the population receiving OCP/HRT: SVR12 rates were 94.6%, 100%, and 100% in participants with GT1a, GT1b, and GT4 infection, and all women aged 18-35 years achieved SVR (21/21). Treatment-related adverse events occurred in 40.7% (33/81) and 30.1% (283/941) of women receiving and those not receiving OCP/HRT, respectively. Conclusion: The efficacy and safety of EBR/GZR administered for 12 weeks was similar in women receiving OCP/HRT and those not on OCP/HRT. These data indicate that EBR/GZR can be safely used for the treatment of HCV GT1 or GT4 infection in women receiving concomitant OCP/HRT.

• Publikační typ
• časopisecké články MeSH