Elbasvir-Grazoprevir (Zepatier)

Testing for HBV Infection

Test all patients for evidence of current or prior HBV infection by measuring hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) before initiating HCV treatment with ZEPATIER [see Warnings and Precautions (5.1)].

NS5A Resistance Testing in HCV Genotype 1a-Infected Patients

Testing patients with HCV genotype 1a infection for the presence of virus with NS5A resistance-associated polymorphisms is recommended prior to initiation of treatment with ZEPATIER to determine dosage regimen and duration [see Dosage and Administration (2.2), Table 1]. In subjects receiving ZEPATIER for 12 weeks, sustained virologic response (SVR12) rates were lower in genotype 1a-infected patients with one or more baseline NS5A resistance-associated polymorphisms at amino acid positions 28, 30, 31, or 93 [see Microbiology (12.4), Table 12].

Hepatic Laboratory Testing

Obtain hepatic laboratory testing prior to and during treatment with ZEPATIER [see Warnings and Precautions (5.2, 5.3)].

Treatment Regimen and Duration of Therapy

Relapse rates are affected by baseline host and viral factors and differ between treatment regimens and durations for certain subgroups [see Clinical Studies (14)].

Table 1 below provides the recommended ZEPATIER treatment regimen and duration based on the patient population and genotype in HCV mono-infected and HCV/HIV-1 co-infected patients with or without cirrhosis and with or without renal impairment including patients receiving hemodialysis.

Adverse Reactions with ZEPATIER in Treatment-Naïve Subjects

C-EDGE TN was a Phase 3 randomized, double-blind, placebo-controlled trial in 421 treatment-naïve (TN) subjects with HCV infection who received ZEPATIER or placebo one tablet once daily for 12 weeks. Adverse reactions (all intensity) occurring in C-EDGE TN in at least 5% of subjects treated with ZEPATIER for 12 weeks are presented in Table 3. In subjects treated with ZEPATIER who reported an adverse reaction, 73% had adverse reactions of mild severity. The type and severity of adverse reactions in subjects with compensated cirrhosis were comparable to those seen in subjects without cirrhosis. No subjects treated with ZEPATIER or placebo had serious adverse reactions. The proportion of subjects treated with ZEPATIER or placebo who permanently discontinued treatment due to adverse reactions was 1% in each group.

C-EDGE COINFECTION was a Phase 3 open-label trial in 218 treatment-naïve HCV/HIV co-infected subjects who received ZEPATIER one tablet once daily for 12 weeks. Adverse reactions (all intensity) reported in C-EDGE COINFECTION in at least 5% of subjects treated with ZEPATIER for 12 weeks were fatigue (7%), headache (7%), nausea (5%), insomnia (5%), and diarrhea (5%). No subjects reported serious adverse reactions or discontinued treatment due to adverse reactions. No subjects switched their antiretroviral therapy regimen due to loss of plasma HIV-1 RNA suppression. Median increase in CD4+ T-cell counts of 31 cells per mm³ was observed at the end of 12 weeks of treatment.

Adverse Reactions with ZEPATIER with or without Ribavirin in Treatment-Experienced Subjects

C-EDGE TE was a Phase 3 randomized, open-label trial in treatment-experienced (TE) subjects. Adverse reactions of moderate or severe intensity reported in C-EDGE TE in at least 2% of subjects treated with ZEPATIER one tablet once daily for 12 weeks or ZEPATIER one tablet once daily with ribavirin for 16 weeks are presented in Table 4. No subjects treated with ZEPATIER without ribavirin for 12 weeks reported serious adverse reactions or discontinued treatment due to adverse reactions. The proportion of subjects treated with ZEPATIER with ribavirin for 16 weeks with serious adverse reactions was 1%. The proportion of subjects treated with ZEPATIER with ribavirin for 16 weeks who permanently discontinued treatment due to adverse reactions was 3%. The type and severity of adverse reactions in subjects with cirrhosis were comparable to those seen in subjects without cirrhosis.

The type and severity of adverse reactions with ZEPATIER with or without ribavirin in 10 treatment-experienced subjects with HCV/HIV co-infection were comparable to those reported in subjects without HIV co-infection. Median increase in CD4+ T-cell counts of 32 cells/mm³ was observed at the end of 12 weeks of treatment with ZEPATIER alone. In subjects treated with ZEPATIER with ribavirin for 16 weeks, CD4+ T-cell counts decreased a median of 135 cells per mm³ at the end of treatment. No subjects switched their antiretroviral therapy regimen due to loss of plasma HIV-1 RNA suppression. No subject experienced an AIDS-related opportunistic infection.

C-SALVAGE was a Phase 2 open-label trial in 79 PegIFN/RBV/PI-experienced subjects. Adverse reactions of moderate or severe intensity reported in C-SALVAGE in at least 2% of subjects treated with ZEPATIER once daily with ribavirin for 12 weeks were fatigue (3%) and insomnia (3%). No subjects reported serious adverse reactions or discontinued treatment due to adverse reactions.

Adverse Reactions with ZEPATIER in Subjects with Severe Renal Impairment including Subjects on Hemodialysis

The safety of elbasvir and grazoprevir in comparison to placebo in subjects with severe renal impairment (Stage 4 or Stage 5 chronic kidney disease, including subjects on hemodialysis) and chronic hepatitis C virus infection with compensated liver disease (with or without cirrhosis) was assessed in 235 subjects (C-SURFER) [see Clinical Studies (14.4)]. The adverse reactions (all intensity) occurring in at least 5% of subjects treated with ZEPATIER for 12 weeks are presented in Table 5. In subjects treated with ZEPATIER who reported an adverse reaction, 76% had adverse reactions of mild severity. The proportion of subjects treated with ZEPATIER or placebo with serious adverse reactions was less than 1% in each treatment arm, and less than 1% and 3% of subjects, respectively, permanently discontinued treatment due to adverse reactions in each treatment arm.

Laboratory Abnormalities in Subjects Receiving ZEPATIER with or without Ribavirin

Skin and Subcutaneous Tissue Disorders

Angioedema

Hepatobiliary Disorders

Hepatic decompensation, hepatic failure [see Warnings and Precautions (5.3)]

Risk Summary

No adequate human data are available to establish whether or not ZEPATIER poses a risk to pregnancy outcomes. In animal reproduction studies, no evidence of adverse developmental outcomes was observed with the components of ZEPATIER (elbasvir or grazoprevir) at exposures greater than those in humans at the recommended human dose (RHD) (see Data). During organogenesis in the rat and rabbit, systemic exposures (AUC) were approximately 10 and 18 times (for elbasvir) and 117 and 41 times (for grazoprevir), respectively, the exposure in humans at the RHD. In rat pre/postnatal developmental studies, maternal systemic exposures (AUC) to elbasvir and grazoprevir were approximately 10 and 78 times, respectively, the exposure in humans at the RHD.

The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

If ZEPATIER is administered with ribavirin, the combination regimen is contraindicated in pregnant women and in men whose female partners are pregnant. Refer to the ribavirin prescribing information for more information on use in pregnancy.

Data

Risk Summary

It is not known whether ZEPATIER is present in human breast milk, affects human milk production, or has effects on the breastfed infant. When administered to lactating rats, the components of ZEPATIER (elbasvir and grazoprevir) were present in milk, without effects on growth and development observed in nursing pups (see Data).

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ZEPATIER and any potential adverse effects on the breastfed child from ZEPATIER or from the underlying maternal condition.

If ZEPATIER is administered with ribavirin, the information for ribavirin with regard to nursing mothers also applies to this combination regimen. Refer to the ribavirin prescribing information for information on use during lactation.

Data

Cardiac Electrophysiology

Thorough QT studies have been conducted for elbasvir and grazoprevir.

The effect of elbasvir 700 mg on QTc interval was evaluated in a randomized, single-dose, placebo- and active-controlled (moxifloxacin 400 mg) 3-period crossover thorough QT trial in 42 healthy subjects. At a concentration 3 to 4 times the therapeutic concentration, elbasvir does not prolong QTc to any clinically relevant extent.

The effect of grazoprevir 1600 mg (16 times the approved dose) on QTc interval was evaluated in a randomized, single-dose, placebo- and active-controlled (moxifloxacin 400 mg) 3-period crossover thorough QT trial in 41 healthy subjects. At a concentration 40 times the therapeutic concentration, grazoprevir does not prolong QTc to any clinically relevant extent.

Absorption

Following administration of ZEPATIER to HCV-infected subjects, elbasvir peak concentrations occur at a median T_max of 3 hours (range of 3 to 6 hours); grazoprevir peak concentrations occur at a median T_max of 2 hours (range of 30 minutes to 3 hours). The absolute bioavailability of elbasvir is estimated to be 32%, and grazoprevir is estimated to be 27%.

Distribution

Elbasvir and grazoprevir are extensively bound (greater than 99.9% and 98.8%, respectively) to human plasma proteins. Both elbasvir and grazoprevir bind to human serum albumin and α1-acid glycoprotein. Estimated apparent volume of distribution values of elbasvir and grazoprevir are approximately 680 L and 1250 L, respectively, based on population pharmacokinetic modeling.

In preclinical distribution studies, elbasvir distributes into most tissues including the liver; whereas grazoprevir distributes predominantly to the liver likely facilitated by the active transport through the OATP1B1/3 liver uptake transporter.

Elimination

The geometric mean apparent terminal half-life for elbasvir (50 mg) and grazoprevir (100 mg) is approximately 24 and 31 hours, respectively, in HCV-infected subjects.

Specific Populations

Drug Interaction Studies

Drug interaction studies were performed in healthy adults with elbasvir, grazoprevir, or co-administered elbasvir and grazoprevir and drugs likely to be co-administered or drugs commonly used as probes for pharmacokinetic interactions. Table 9 summarizes the effects of co-administered drugs on the exposures of the individual components of ZEPATIER (elbasvir and grazoprevir). Table 10 summarizes the effects of the individual components of ZEPATIER on the exposures of the co-administered drugs. For information regarding clinical recommendations, [see Contraindications (4), Warnings and Precautions (5) , and Drug Interactions (7)].

Elbasvir and grazoprevir are substrates of CYP3A and P-gp, but the role of intestinal P-gp in the absorption of elbasvir and grazoprevir appears to be minimal. Co-administration of moderate and strong CYP3A inducers with ZEPATIER may decrease elbasvir and grazoprevir plasma concentrations, leading to reduced therapeutic effect of ZEPATIER. Co-administration of strong CYP3A4 inhibitors with ZEPATIER may increase elbasvir and grazoprevir plasma concentrations.

Grazoprevir is a substrate of OATP1B1/3. Co-administration of ZEPATIER with drugs that inhibit OATP1B1/3 transporters may result in a clinically relevant increase in grazoprevir plasma concentrations.

Elbasvir is not a CYP3A inhibitor in vitro and grazoprevir is a weak CYP3A inhibitor in humans. Co-administration with grazoprevir resulted in a 34% increase in plasma exposure of midazolam and a 43% increase in plasma exposure of tacrolimus (see Tables 6 and 10). Elbasvir inhibited P-gp in vitro, but no clinically relevant increases in concentrations of digoxin (a P-gp substrate; see Table 10) were observed by co-administration of elbasvir. Grazoprevir is not a P-gp inhibitor in vitro. Elbasvir and grazoprevir are inhibitors of the drug transporter breast cancer resistance protein (BCRP) at the intestinal level in humans and may increase plasma concentrations of co-administered BCRP substrates.

Clinically significant drug interactions with ZEPATIER as an inhibitor of other CYP enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6), UGT1A1, esterases (CES1, CES2, and CatA), organic anion transporters (OAT)1 and OAT3, and organic cation transporter (OCT)2, are not expected, and multiple-dose administration of elbasvir or grazoprevir is unlikely to induce the metabolism of drugs metabolized by CYP1A2, CYP2B6, or CYP3A based on in vitro data.

Mechanism of Action

ZEPATIER combines two direct-acting antiviral agents with distinct mechanisms of action and non-overlapping resistance profiles to target HCV at multiple steps in the viral lifecycle.

Elbasvir is an inhibitor of HCV NS5A, which is essential for viral RNA replication and virion assembly. The mechanism of action of elbasvir has been characterized based on cell culture antiviral activity and drug resistance mapping studies.

Grazoprevir is an inhibitor of the HCV NS3/4A protease which is necessary for the proteolytic cleavage of the HCV encoded polyprotein (into mature forms of the NS3, NS4A, NS4B, NS5A, and NS5B proteins) and is essential for viral replication. In a biochemical assay, grazoprevir inhibited the proteolytic activity of the recombinant HCV genotype 1a, 1b, and 4a NS3/4A protease enzymes with IC₅₀ values of 7 pM, 4 pM, and 62 pM, respectively.

Antiviral Activity

In HCV replicon assays, the EC₅₀ values of elbasvir against full-length replicons from genotypes 1a, 1b, and 4, were 4 pM, 3 pM, and 0.3 pM, respectively. The median EC₅₀ values of elbasvir against chimeric replicons encoding NS5A sequences from clinical isolates were 5 pM for genotype 1a (range 3-9 pM; N=5), 9 pM for genotype 1b (range 5-10 pM; N=4), 0.2 pM for genotype 4a (range 0.2-0.2 pM; N=2), 3,600 pM for genotype 4b (range 17 pM-34,000 pM; N=3), 0.45 pM for genotype 4d (range 0.4-0.5 pM; N=2), 1.9 pM for genotype 4f (N=1), 36.3 pM for genotype 4g (range 0.6-72 pM; N=2), 0.6 pM for genotype 4m (range 0.4-0.7 pM; N=2), 2.2 pM for genotype 4o (N=1), and 0.5 pM for genotype 4q (N=1).

In HCV replicon assays, the EC₅₀ values of grazoprevir against full-length replicons from genotypes 1a, 1b, and 4, were 0.4 nM, 0.5 nM, and 0.3 nM, respectively. The median EC₅₀ values of grazoprevir against chimeric replicons encoding NS3/4A sequences from clinical isolates were 0.8 nM for genotype 1a (range 0.4-5.1 nM; N=10), 0.3 nM for genotype 1b (range 0.2-5.9 nM; N=9), 0.3 nM for genotype 4a (N=1), 0.16 nM for genotype 4b (range 0.11-0.2 nM; N=2), and 0.24 nM for genotype 4g (range 0.15-0.33 nM; N=2).

Combination Antiviral Activity

Evaluation of elbasvir in combination with grazoprevir or ribavirin showed no antagonistic effect in reducing HCV RNA levels in replicon cells. Evaluation of grazoprevir in combination with ribavirin showed no antagonistic effect in reducing HCV RNA levels in replicon cells.

Resistance

Persistence of Resistance-Associated Substitutions

The persistence of elbasvir and grazoprevir treatment-emergent amino acid substitutions in NS5A, and NS3, respectively, was assessed in HCV genotype 1-infected subjects in Phase 2 and 3 trials whose virus had treatment-emergent resistance-associated substitutions in the drug target, and with available data through at least 24 weeks post-treatment using population nucleotide sequence analysis.

Viral populations with treatment-emergent NS5A resistance-associated substitutions were generally more persistent than those with NS3 resistance-associated substitutions. Among genotype 1a-infected subjects, NS5A resistance-associated substitutions persisted at detectable levels at follow-up week 12 in 95% (35/37) of subjects and in 100% (9/9) of subjects with follow-up week 24 data. Among genotype 1b-infected subjects, NS5A resistance-associated substitutions persisted at detectable levels in 100% (7/7) of subjects at follow-up week 12 and in 100% (3/3) of subjects with follow-up week 24 data.

Among genotype 1a-infected subjects, NS3 resistance-associated substitutions persisted at detectable levels at follow-up week 24 in 31% (4/13) of subjects. Among genotype 1b-infected subjects, NS3 resistance-associated substitutions persisted at detectable levels at follow-up week 24 in 50% (1/2) of subjects.

Due to the limited number of genotype 4-infected subjects with treatment-emergent NS5A and NS3 resistance-associated substitutions, trends in persistence of treatment-emergent substitutions in this genotype could not be established.

The lack of detection of a virus containing a resistance-associated substitution does not necessarily indicate that viral populations carrying that substitution have declined to a background level that may have existed prior to treatment. The long-term clinical impact of the emergence or persistence of virus containing ZEPATIER-resistance-associated substitutions is unknown.

Effect of Baseline HCV Amino Acid Polymorphisms on Treatment Response in Genotype 1-Infected Subjects

Analyses using population nucleotide sequencing were conducted to explore the association between NS5A or NS3 amino acid polymorphisms and treatment response among treatment-naïve and treatment-experienced genotype 1-infected subjects. Baseline NS5A polymorphisms at resistance-associated positions (focusing on any change from subtype reference at NS5A amino acid positions 28, 30, 31, or 93) were evaluated. Baseline NS3 polymorphisms at positions 36, 54, 55, 56, 80, 107, 122, 132, 155, 156, 158, 168, 170, or 175 were evaluated. Analyses of SVR12 rates pooled data from subjects naïve to direct-acting antivirals and who received ZEPATIER with or without ribavirin in Phase 3 clinical trials, and censored subjects who did not achieve SVR12 for reasons unrelated to virologic failure.

Protocol 095

In Protocol 095, a sub-study of a prospective, observational comparative study, effectiveness of treatment with ZEPATIER plus ribavirin for 16 weeks was assessed in 29 HCV genotype 1a-infected patients with 1 or more baseline NS5A polymorphisms at amino acid positions M28, Q30, L31, and/or Y93. Overall, the SVR12 rate for patients with 1 or more baseline NS5A polymorphisms at any of the 4 amino acid positions was 93% (27/29). 23 patients had a NS5A polymorphism at a single amino acid position at baseline. The SVR12 rates for patients with a single polymorphism at amino acid position M28, Q30, L31, or Y93 were 100% (14/14), 100% (1/1), 33% (1/3), and 100% (5/5), respectively. Six patients had NS5A polymorphisms at more than 1 amino acid position (M28, Q30, L31, and/or Y93) at baseline. The SVR12 rate for these patients was 100% (6/6).

VA NS5A Cohort Study

In a retrospective Veterans Administration (VA) NS5A cohort study, effectiveness of treatment with ZEPATIER plus ribavirin for 16 weeks was assessed in 93 HCV genotype 1a-infected patients with 1 or more baseline NS5A polymorphisms at amino acid positions M28, Q30, L31, and/or Y93. Overall, the SVR12 rate for patients with 1 or more baseline NS5A polymorphisms at any of the 4 amino acid positions was 81% (75/93). 65 patients had a NS5A polymorphism at a single amino acid position at baseline. The SVR12 rates for patients with a single polymorphism at amino acid position M28, Q30, L31, or Y93 were 94% (16/17), 100% (8/8), 84% (16/19), and 81% (17/21), respectively. 28 patients had NS5A polymorphisms at more than 1 amino acid position (M28, Q30, L31, and/or Y93) at baseline. The SVR12 rate for these patients was 64% (18/28).

Effect of Baseline HCV Polymorphisms on Treatment Response in Genotype 4-Infected Subjects

Phylogenetic analysis of HCV sequences from genotype 4-infected subjects (n=71) in the pooled analyses of subjects (non-virologic failure-censored) treated with regimens containing ZEPATIER or elbasvir + grazoprevir with or without ribavirin in Phase 2 and 3 clinical trials identified 4 HCV genotype 4 subtypes (4a, 4d, 4k, 4o). Most subjects were infected with either subtype 4a (42%) or 4d (51%); 1 to 2 subjects were infected with each of the other genotype 4 subtypes. Among subjects enrolled at U.S. study sites, 11/13 (85%) were infected with HCV subtype 4a. There were two subjects infected with HCV subtype 4d who experienced virologic failure with the regimen containing grazoprevir and elbasvir.

In genotype 4-infected subjects, SVR12 rates for subjects with baseline NS5A polymorphisms (any change from reference at NS5A amino acid positions 28, 30, 31, 58, and 93 by population nucleotide sequencing) were 100% (28/28) and for subjects without baseline NS5A polymorphisms were 95% (41/43).

In genotype 4-infected subjects, SVR12 rates for subjects with baseline NS3 polymorphisms (any change from reference at NS3 amino acid positions 36, 54, 55, 56, 80, 107, 122, 132, 155, 156, 158, 168, 170, and 175 by population nucleotide sequencing) were 100% (18/18) and for subjects without baseline NS3 polymorphisms were 96% (51/53).

Cross Resistance

Cross resistance is possible among NS5A inhibitors and NS3/4A protease inhibitors by class. Elbasvir and grazoprevir are fully active against viral populations with substitutions conferring resistance to NS5B inhibitors.

In the C-SALVAGE trial, subjects with genotype 1 infection who had failed prior treatment with boceprevir (n=28), simeprevir (n=8), or telaprevir (n=43) in combination with PegIFN + RBV received EBR 50 mg once daily + GZR 100 mg once daily + RBV for 12 weeks. There are limited data to determine the impact of HCV NS3 resistance-associated substitutions detected at baseline in treatment-experienced subjects who failed prior PegIFN + RBV + HCV protease inhibitor therapy and received ZEPATIER with ribavirin. SVR was achieved in 88% (21/24) of genotype 1a and genotype 1b infected subjects with NS3 resistance-associated substitutions detected at baseline. Specific NS3 substitutions observed at baseline included one or more of the following: V36L/M (n=8), T54S (n=4), S122G/T (n=9), R155K/T (n=9), A156S/T (n=1), and D168E/N (n=3). SVR was 100% (55/55) in subjects without baseline NS3 resistance substitutions. The 3 virologic failure subjects had the following NS3 or NS5A substitutions/polymorphisms at baseline: NS3 R155T/D168N, NS3 R155K plus NS5A H58D, and NS3 T54S plus NS5A L31M.

The efficacy of ZEPATIER has not been established in patients who have previously failed treatment with other regimens that included an NS5A inhibitor.

Carcinogenesis and Mutagenesis

Elbasvir and grazoprevir were not genotoxic in a battery of in vitro or in vivo assays, including microbial mutagenesis, chromosomal aberration in Chinese Hamster Ovary cells, and in in vivo rat micronucleus assays.

Carcinogenicity studies with elbasvir or grazoprevir have not been conducted.

If ZEPATIER is administered in a regimen containing ribavirin, the information for ribavirin on carcinogenesis and mutagenesis also applies to this combination regimen. Refer to the ribavirin prescribing information for information on carcinogenesis and mutagenesis.

Impairment of Fertility

No effects on mating, female or male fertility, or early embryonic development were observed in rats at up to the highest dose tested. Systemic exposures (AUC) to elbasvir and grazoprevir were approximately 8 and 114 times, respectively, the exposure in humans at the recommended human dose.

If ZEPATIER is administered with ribavirin, the information for ribavirin on impairment of fertility also applies to this combination regimen. Refer to the ribavirin prescribing information for information on impairment of fertility.

Treatment-Experienced Subjects who Failed Prior PegIFN with RBV Therapy (C-EDGE TE)

C-EDGE TE was a randomized, open-label comparative trial in subjects with genotype 1 or 4 infection, with or without cirrhosis, with or without HCV/HIV-1 co-infection, who had failed prior therapy with PegIFN + RBV therapy. Subjects were randomized in a 1:1:1:1 ratio to one of the following treatment groups: ZEPATIER for 12 weeks, ZEPATIER + RBV for 12 weeks, ZEPATIER for 16 weeks, or ZEPATIER + RBV for 16 weeks. Among subjects with genotype 1 infection, the median age was 57 years (range: 19 to 77); 64% of the subjects were male; 67% were White; 18% were Black or African American; 9% were Hispanic or Latino; mean body mass index was 28 kg/m²; 78% had baseline HCV RNA levels greater than 800,000 IU/mL; 34% had cirrhosis; 79% had non-C/C IL28B alleles (CT or TT); and 60% had genotype 1a, 39% had genotype 1b, and 1% had genotype 1-Other chronic HCV infection.

Treatment outcomes in genotype 1 subjects treated with ZEPATIER for 12 weeks or ZEPATIER with RBV for 16 weeks are presented in Table 15. Treatment outcomes with ZEPATIER with RBV for 12 weeks or without RBV for 16 weeks are not shown because these regimens are not recommended in PegIFN/RBV-experienced genotype 1 patients. For treatment outcomes for ZEPATIER in genotype 4 infection, [see Clinical Studies (14.5)].

Treatment-Experienced Subjects who Failed Prior PegIFN + RBV + HCV Protease Inhibitor Therapy (C-SALVAGE)

C-SALVAGE was an open-label single-arm trial in subjects with genotype 1 infection, with or without cirrhosis, who had failed prior treatment with boceprevir, simeprevir, or telaprevir in combination with PegIFN + RBV. Subjects received EBR 50 mg once daily + GZR 100 mg once daily + RBV for 12 weeks. Subjects had a median age of 55 years (range: 23 to 75); 58% of the subjects were male; 97% were White; 3% were Black or African American; 15% were Hispanic or Latino; mean body mass index was 28 kg/m²; 63% had baseline HCV RNA levels greater than 800,000 IU/mL; 43% had cirrhosis; and 97% had non-C/C IL28B alleles (CT or TT); 46% had baseline NS3 resistance-associated substitutions.

Overall SVR was achieved in 96% (76/79) of subjects receiving EBR + GZR + RBV for 12 weeks. Four percent (3/79) of subjects did not achieve SVR due to relapse. Treatment outcomes were consistent in genotype 1a and genotype 1b subjects, in subjects with different response to previous HCV therapy, and in subjects with or without cirrhosis. Treatment outcomes were generally consistent in subjects with or without NS3 resistance-associated substitutions at baseline, although limited data are available for subjects with specific NS3 resistance-associated substitutions [see Microbiology (12.4)].