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Background and Aim: The introduction of highly effective direct-acting antiviral (DAA) therapy has revolutionized hepatitis C virus (HCV) treatment. However, some patients, most often those with genotype (Gt) 3 infection and cirrhosis, do not respond to first-line DAA therapy. In clinical trials, salvage therapy including sofosbuvir-velpatasvir- voxilaprevir (SOF/VEL/VOX) achieved a rate of sustained virological response at 12 weeks (SVR12) of 96% in NS5A-experienced participants. An extended access program (EAP) for SOF/VEL/VOX was sponsored by Gilead Pharmaceuticals for Australian patients with advanced liver disease or prior liver transplantation who had relapsed. We determined the real-world efficacy and safety of this regimen in this cohort. Method(s): In this Australian multicenter EAP study, adult patients with chronic HCV infection Gt1-6 with prior failure on a DAA NS5A inhibitor-containing regimen were eligible to access 12 weeks of SOF/VEL/VOX 400 mg/100 mg/100 mg. Other eligibility criteria included estimated glomerular filtration rate of > 30 mL/min/1.73 m2 and compensated liver disease with at least one of the following: Child-Pugh (CP) A cirrhosis with clinically significant portal hypertension or platelets of < 100 x 109/L; prior liver transplantation; or severe extrahepatic manifestations. Hospitals with more than one EAP recipient were invited to participate. Clinical characteristics and treatment outcomes were recorded at baseline, end of treatment (EOT), and SVR12. HCV NS5A resistanceassociated substitution testing was performed before retreatment, where serum was available. The primary outcome was SVR12 rate. Secondary outcomes included frequency of adverse events. Result(s): A total of 114 patients have been identified as eligible. Data collection is ongoing. To date, baseline data have been collected for 56 participants, 44 have reached EOT, and 31 have reached the SVR12 time point. The median age is 60 years. Gt3 infection was most common (42

Background and Aim: The introduction of highly effective direct-acting antiviral (DAA) therapy has revolutionized hepatitis C virus (HCV) treatment. However, some patients, most often those with genotype (Gt) 3 infection and cirrhosis, do not respond to first-line DAA therapy. In clinical trials, salvage therapy including sofosbuvir-velpatasvir- voxilaprevir (SOF/VEL/VOX) achieved a rate of sustained virological response at 12 weeks (SVR12) of 96% in NS5A-experienced participants. An extended access program (EAP) for SOF/VEL/VOX was sponsored by Gilead Pharmaceuticals for Australian patients with advanced liver disease or prior liver transplantation who had relapsed. We determined the real-world efficacy and safety of this regimen in this cohort. Method(s): In this Australian multicenter EAP study, adult patients with chronic HCV infection Gt1-6 with prior failure on a DAA NS5A inhibitor-containing regimen were eligible to access 12 weeks of SOF/VEL/VOX 400 mg/100 mg/100 mg. Other eligibility criteria included estimated glomerular filtration rate of > 30 mL/min/1.73 m2 and compensated liver disease with at least one of the following: Child-Pugh (CP) A cirrhosis with clinically significant portal hypertension or platelets of < 100 x 109/L; prior liver transplantation; or severe extrahepatic manifestations. Hospitals with more than one EAP recipient were invited to participate. Clinical characteristics and treatment outcomes were recorded at baseline, end of treatment (EOT), and SVR12. HCV NS5A resistanceassociated substitution testing was performed before retreatment, where serum was available. The primary outcome was SVR12 rate. Secondary outcomes included frequency of adverse events. Result(s): A total of 114 patients have been identified as eligible. Data collection is ongoing. To date, baseline data have been collected for 56 participants, 44 have reached EOT, and 31 have reached the SVR12 time point. The median age is 60 years. Gt3 infection was most common (42

Background & Aims: Protease inhibitors (PIs) are of central importance in the treatment of patients with chronic hepatitis C virus (HCV) infection. HCV NS3 protease (NS3P) position 80 displays polymorphisms associated with resistance to the PI simeprevir for HCV genotype 1a. We investigated the effects of position-80-substitutions on fitness and PI-resistance for HCV genotypes 1-6, and analyzed evolutionary mechanisms underlying viral escape mediated by pre-existing Q80K. Methods: The fitness of infectious NS3P recombinants of HCV genotypes 1-6, with engineered position-80-substitutions, was studied by comparison of viral spread kinetics in Huh-7.5 cells in culture. Median effective concentration (EC50) and fold resistance for PIs simeprevir, asunaprevir, paritaprevir, grazoprevir, glecaprevir and voxilaprevir were determined in short-term treatment assays. Viral escape was studied by long-term treatment of genotype 1a recombinants with simeprevir, grazoprevir, glecaprevir and voxilaprevir and of genotype 3a recombinants with glecaprevir and voxilaprevir, next generation sequencing, NS3P substitution linkage and haplotype analysis. Results: Among tested PIs, only glecaprevir and voxilaprevir showed pan-genotypic activity against the original genotype 1-6 culture viruses. Variants with position-80-substitutions were all viable, but fitness depended on the specific substitution and the HCV isolate. Q80K conferred resistance to simeprevir across genotypes but had only minor effects on the activity of the remaining PIs. For genotype 1a, pre-existing Q80K mediated accelerated escape from simeprevir, grazoprevir and to a lesser extent glecaprevir, but not voxilaprevir. For genotype 3a, Q80K mediated accelerated escape from glecaprevir and voxilaprevir. Escape was mediated by rapid and genotype-, PI- and PI-concentration-dependent co-selection of clinically relevant resistance associated substitutions. Conclusions: Position-80-substitutions had relatively low fitnes

PURPOSE/BACKGROUND: To evaluate the safety and efficacy of all-oral therapy for HCV using combinations of 3 direct-acting antiviral drugs: grazoprevir, an NS3/4A protease inhibitor; MK-3682, an NS5B polymerase inhibitor, and either elbasvir or MK-8408, which are NS5A inhibitors. METHOD(S): In Part A of 2 ongoing randomized, dose-ranging, parallel-group, multicenter, open-label Phase 2 trials, 93 GT1 (46 GT1a, 47 GT1b), 61 GT2, and 86 GT3-infected treatment-naive, non-cirrhotic patients with chronic HCV infection were dosed once-daily for 8 weeks duration with one of 4 regimens including grazoprevir (100 mg), MK-3682 (300 mg or 450 mg), and either elbasvir (50 mg) or MK-8408 (60 mg). RESULT(S): GT1: Across treatment arms, 45/46 (98%) GT1a and 46/47 (98%) GT1b patients achieved sustained virologic response 12 weeks after end of study therapy (SVR12). In the 2 relapsers, population sequencing did not detect NS3, NS5B, or NS5A resistance associated variants (RAVs) conferring >=5-fold potency shifts at baseline or following relapse. GT2: The grazoprevir/ MK-3682 (450 mg)/MK-8408 regimen was highly effective, with SVR12 among 15/16 (94%) of GT2-infected patients, but regimens containing the 300 mg dose of MK-3682 and/or elbasvir resulted in lower efficacy (SVR12 in 29/45 (64%) GT2 patients; 60-71% across the 3 arms). Relapses were more common among patients who harbored an L31M/I NS5A variant at baseline. No treatment-emergent RAVs were observed. GT3: Across arms, SVR12 was achieved among 78/86 (91%) of GT3-infected patients; response was comparable across arms (86-95%). Eight GT3 patients relapsed. SVR12 was lower among GT3-infected patients who harbored an NS5A A30K, L31M, or Y93H RAV at baseline compared with patients without these RAVs at baseline (5/11 [45%] vs 72/74 [97%], respectively). Two of 8 GT3 relapsers acquired NS5A Y93H. All 240 patients completed the full 8 weeks of dosing. All regimens were generally well tolerated, and no cardiac or renal safety signals

Background and Aims: To evaluate a retreatment regimen for patients who had virologic relapse following 8 weeks of a 3-drug direct-acting antiviral (DAA) combination: MK-3682 (an NS5B polymerase nucleotide inhibitor), grazoprevir (GZR, an NS3/4A protease inhibitor), and either elbasvir (EBR) or ruzasvir (RZR, MK- 8408) which are NS5A inhibitors. Method(s): Genotype (GT)1-, 2-, and 3-infected, non-cirrhotic patients with chronic HCV infection who relapsed after 8 weeks of therapy with one of 4 regimens that included a 3-DAA combination of MK- 3682 (300 mg or 450 mg), GZR (100 mg), and either EBR (50 mg) or RZR (60 mg) were offered open-label retreatment with 16 weeks of a fixed-dose combination (FDC) of once-daily MK3 [MK-3682 (450 mg)/GZR (100 mg)/RZR (60 mg)] + ribavirin (RBV). Next-generation sequencing with a 15% thresholdwas used to test for resistanceassociated substitutions (RASs). Result(s): Twenty-four of 26 eligible patients were enrolled, 2 with GT1, 14 with GT2, and 8 with GT3 infection. All RASs observed at time of failure of initial therapy were also detected at initiation of retreatment. Overall, 21/24 (88%) patients had RASs in >1 class. High-impact NS5A RASs (>5-fold reduction in susceptibility to RZR) were detected in 11/14 (79%) of GT2-infected patients (L31M/I). Among GT3-infected patients, 2/8 (25%) had one (A30K or Y93H), 4/8 (50%) had two (A30K, L31M, S62L or Y93H) high-impact NS5A RASs; 1/8 (13%) had both Y93H and a high-impact NS3 RAS (Q168R) that resulted in >5-fold reduction in susceptibility to GZR. 1/8 (13%) GT3- infected and 2/2 (100%) GT1 infected patients had no high-impact RASs detected. Of all patients who received at least one dose of study drug (full analysis set), the SVR24 rates were 2/2 (100%) in GT1 patients, 13/14 (93%) in GT2 patients, and 8/8 (100%) in GT3 patients. The only patient who did not achieve SVR24 was a GT2-infected patient who withdrew after a single dose because of adverse events (AEs) of vomiting and tachycardi

PURPOSE/BACKGROUND: To evaluate the safety and efficacy of all-oral therapy for HCV using combinations of 3 direct-acting antiviral drugs: grazoprevir, an NS3/4A protease inhibitor; MK-3682, an NS5B polymerase inhibitor, and either elbasvir or MK-8408, which are NS5A inhibitors. METHOD(S): In Part A of 2 ongoing randomized, dose-ranging, parallel-group, multicenter, open-label Phase 2 trials, 93 GT1 (46 GT1a, 47 GT1b), 61 GT2, and 86 GT3-infected treatment-naive, non-cirrhotic patients with chronic HCV infection were dosed once-daily for 8 weeks duration with one of 4 regimens including grazoprevir (100 mg), MK-3682 (300 mg or 450 mg), and either elbasvir (50 mg) or MK-8408 (60 mg). RESULT(S): GT1: Across treatment arms, 45/46 (98%) GT1a and 46/47 (98%) GT1b patients achieved sustained virologic response 12 weeks after end of study therapy (SVR12). In the 2 relapsers, population sequencing did not detect NS3, NS5B, or NS5A resistance associated variants (RAVs) conferring >=5-fold potency shifts at baseline or following relapse. GT2: The grazoprevir/ MK-3682 (450 mg)/MK-8408 regimen was highly effective, with SVR12 among 15/16 (94%) of GT2-infected patients, but regimens containing the 300 mg dose of MK-3682 and/or elbasvir resulted in lower efficacy (SVR12 in 29/45 (64%) GT2 patients; 60-71% across the 3 arms). Relapses were more common among patients who harbored an L31M/I NS5A variant at baseline. No treatment-emergent RAVs were observed. GT3: Across arms, SVR12 was achieved among 78/86 (91%) of GT3-infected patients; response was comparable across arms (86-95%). Eight GT3 patients relapsed. SVR12 was lower among GT3-infected patients who harbored an NS5A A30K, L31M, or Y93H RAV at baseline compared with patients without these RAVs at baseline (5/11 [45%] vs 72/74 [97%], respectively). Two of 8 GT3 relapsers acquired NS5A Y93H. All 240 patients completed the full 8 weeks of dosing. All regimens were generally well tolerated, and no cardiac or renal safety signals

Background and Aims: To evaluate a retreatment regimen for patients who had virologic relapse following 8 weeks of a 3-drug direct-acting antiviral (DAA) combination: MK-3682 (an NS5B polymerase nucleotide inhibitor), grazoprevir (GZR, an NS3/4A protease inhibitor), and either elbasvir (EBR) or ruzasvir (RZR, MK- 8408) which are NS5A inhibitors. Method(s): Genotype (GT)1-, 2-, and 3-infected, non-cirrhotic patients with chronic HCV infection who relapsed after 8 weeks of therapy with one of 4 regimens that included a 3-DAA combination of MK- 3682 (300 mg or 450 mg), GZR (100 mg), and either EBR (50 mg) or RZR (60 mg) were offered open-label retreatment with 16 weeks of a fixed-dose combination (FDC) of once-daily MK3 [MK-3682 (450 mg)/GZR (100 mg)/RZR (60 mg)] + ribavirin (RBV). Next-generation sequencing with a 15% thresholdwas used to test for resistanceassociated substitutions (RASs). Result(s): Twenty-four of 26 eligible patients were enrolled, 2 with GT1, 14 with GT2, and 8 with GT3 infection. All RASs observed at time of failure of initial therapy were also detected at initiation of retreatment. Overall, 21/24 (88%) patients had RASs in >1 class. High-impact NS5A RASs (>5-fold reduction in susceptibility to RZR) were detected in 11/14 (79%) of GT2-infected patients (L31M/I). Among GT3-infected patients, 2/8 (25%) had one (A30K or Y93H), 4/8 (50%) had two (A30K, L31M, S62L or Y93H) high-impact NS5A RASs; 1/8 (13%) had both Y93H and a high-impact NS3 RAS (Q168R) that resulted in >5-fold reduction in susceptibility to GZR. 1/8 (13%) GT3- infected and 2/2 (100%) GT1 infected patients had no high-impact RASs detected. Of all patients who received at least one dose of study drug (full analysis set), the SVR24 rates were 2/2 (100%) in GT1 patients, 13/14 (93%) in GT2 patients, and 8/8 (100%) in GT3 patients. The only patient who did not achieve SVR24 was a GT2-infected patient who withdrew after a single dose because of adverse events (AEs) of vomiting and tachycardi

A simple, Accurate and precise method was developed for the simultaneous estimation of the Grazoprevir and Elbasvir in Tablet dosage form. Chromatogram was run through Kromosil C18 (250 x 4.6 mm), 5m. Mobile phase containing Buffer: Acetonitrile taken in the ratio 45:55 was pumped through column at a flow rate of 1 ml/min. Buffer used in this method was Di Potassium Hydrogen ortho Phosphate. Temperature was maintained at 30°C. Optimized wavelength selected was 215 nm. Retention time of Elbasvir and Grazoprevir and were found to be 2.503 min and 3.004. %RSD of the Elbasvir and Grazoprevir were and found to be 0.3 and 0.4 respectively. %Recovery was obtained as 98.17% and 99.83% for Grazoprevir and Elbasvir respectively. LOD, LOQ values obtained from regression equations of Grazoprevir and Elbasvir were 0.24, 0.73 and 0.06, 0.19 respectively. Retention times were decreased and run time was decreased, so the method developed was simple and economical that can be adopted in regular Quality control test in Industries.

A simple, Accurate and precise method was developed for the simultaneous estimation of the Grazoprevir and Elbasvir in Tablet dosage form. Chromatogram was run through Kromosil C18 (250 x 4.6 mm), 5m. Mobile phase containing Buffer: Acetonitrile taken in the ratio 45:55 was pumped through column at a flow rate of 1 ml/min. Buffer used in this method was Di Potassium Hydrogen ortho Phosphate. Temperature was maintained at 30°C. Optimized wavelength selected was 215 nm. Retention time of Elbasvir and Grazoprevir and were found to be 2.503 min and 3.004. %RSD of the Elbasvir and Grazoprevir were and found to be 0.3 and 0.4 respectively. %Recovery was obtained as 98.17% and 99.83% for Grazoprevir and Elbasvir respectively. LOD, LOQ values obtained from regression equations of Grazoprevir and Elbasvir were 0.24, 0.73 and 0.06, 0.19 respectively. Retention times were decreased and run time was decreased, so the method developed was simple and economical that can be adopted in regular Quality control test in Industries.

Background and Aims: Hepatitis C virus (HCV) regimens that contain 3 potent direct-acting antiviral agents, each targeting different steps in the viral life cycle, may prevent the emergence of resistance increase antiviral efficacy, and permit a shorter duration of therapy. The aim of Part A of the C-CREST 1 and 2 studies was to evaluate the safety and efficacy of once-daily 3-drug regimens for 8 weeks, including grazoprevir (GZR), an NS3/4A protease inhibitor; elbasvir (EBR) or MK-8408, NS5A inhibitors; and MK-3682, an NS5B polymerase inhibitor. Method(s): These were randomized, open-label, dose-ranging Phase 2 studies in treatment-naive, noncirrhotic patients with HCV genotype (GT)1, 2 (C-CREST-1) or 3 (C-CREST-2) infection. Patients received EBR 50 mg/MK-3682 300 mg or 450 mg/GZR 100 mg or GZR 100 mg/MK- 8408 60 mg/MK-3682 300 mg or 450 mg. All patients were treated for 8 weeks and followed for 24 weeks after completion of therapy. The primary efficacy endpoint was sustained virologic response at follow-up week (FUW) 12 (SVR12); the secondary efficacy outcome was SVR24. Analysis of HCV resistance-associated variants (RAVs)was performed at baseline in all patients, and at failure and during followup in those with virologic failure. Result(s): 240 patients were enrolled (GT1a, n = 46; GT1b, n = 47; GT2, n = 61; GT3, n = 86). All patients completed the full 8 weeks of dosing and have FUW12 data. Across treatment arms, 98% (45/46) of GT1a and 98% (46/47) GT1b patients achieved SVR12. The GZR/MK-8408/ MK-3682 (450 mg) regimen achieved SVR12 in 94% (15/16) of GT2 patients and 91% (20/22) of GT3 patients. To date, there have been no relapses between FUW12 and FUW24. Based on population sequencing, high rates of SVR were maintained in patients with NS5A RAVs at baseline. Data for the NS3, NS5A and NS5B loci by nextgeneration sequencing will be presented. Treatments were generally safe and well tolerated, with no discontinuations due to adverse events and no cardiac or re

PURPOSE/BACKGROUND: To evaluate a retreatment regimen for patients who had failed therapy with a 3-drug direct-acting antiviral (DAA) combination: MK-3682, an NS5B polymerase inhibitor, grazoprevir, an NS3/4A protease inhibitor, and either elbasvir or MK-8408, which are NS5A inhibitors. METHOD(S): GT1-, 2-, and 3-infected treatment-naive, non-cirrhotic patients with chronic HCV infection who relapsed after 8 weeks of therapy with one of 4 regimens including grazoprevir (100 mg), MK-3682 (300 mg or 450 mg), and either elbasvir (50 mg) or MK-8408 (60 mg) were offered retreatment with 16 weeks of a fixed-dose combination of MK-3682 (450 mg)/ grazoprevir/MK-8408 plus ribavirin (RBV). RESULT(S): Twenty- four of 26 eligible patients were enrolled, 2 with GT1, 14 with GT2, and 8 with GT3 infection. At the time of relapse following initial therapy, NS5A RAVs were detected in 0% (0/2) GT1, 93% (13/14) GT2 and 88% (7/8) GT3 patients. NS3 RAVs were detected in 50% (1/2) GT1, 100% (14/14) GT2, and 100% (8/8) GT3 patients. NS5B RAVs were detected in 50% (1/2) GT1, 0% (0/14) GT2, and 0% (0/8) GT3 patients. 88% (21/24) patients had RAVs in >1 class. One GT2-infected patient withdrew after a single dose with adverse events (AEs) of vomiting and tachycardia. The remaining 23 patients completed the full 16 weeks of dosing. All patients had undetectable HCV RNA at the end of treatment. All 23 patients (2 GT1, 13 GT2, and 8 GT3) have reached at least follow-up week 4; 100% have achieved SVR4. Treatment was generally well tolerated, and no cardiac or renal safety signals were identified. The most frequent study drug-related AEs in >10% of all patients were headache, fatigue, nausea, rash, pruritus, insomnia, decreased hemoglobin and cough. CONCLUSION(S): A 16-week regimen of the fixed-dose combination of MK-3682 (450 mg)/grazoprevir/MK-8408 plus RBV was highly effective and well-tolerated in GT1-, 2-, and 3-infected treatment-naive, non-cirrhotic patients who had previously failed 8 wee

Background and Aims: Hepatitis C virus (HCV) regimens that contain 3 potent direct-acting antiviral agents, each targeting different steps in the viral life cycle, may prevent the emergence of resistance increase antiviral efficacy, and permit a shorter duration of therapy. The aim of Part A of the C-CREST 1 and 2 studies was to evaluate the safety and efficacy of once-daily 3-drug regimens for 8 weeks, including grazoprevir (GZR), an NS3/4A protease inhibitor; elbasvir (EBR) or MK-8408, NS5A inhibitors; and MK-3682, an NS5B polymerase inhibitor. Method(s): These were randomized, open-label, dose-ranging Phase 2 studies in treatment-naive, noncirrhotic patients with HCV genotype (GT)1, 2 (C-CREST-1) or 3 (C-CREST-2) infection. Patients received EBR 50 mg/MK-3682 300 mg or 450 mg/GZR 100 mg or GZR 100 mg/MK- 8408 60 mg/MK-3682 300 mg or 450 mg. All patients were treated for 8 weeks and followed for 24 weeks after completion of therapy. The primary efficacy endpoint was sustained virologic response at follow-up week (FUW) 12 (SVR12); the secondary efficacy outcome was SVR24. Analysis of HCV resistance-associated variants (RAVs)was performed at baseline in all patients, and at failure and during followup in those with virologic failure. Result(s): 240 patients were enrolled (GT1a, n = 46; GT1b, n = 47; GT2, n = 61; GT3, n = 86). All patients completed the full 8 weeks of dosing and have FUW12 data. Across treatment arms, 98% (45/46) of GT1a and 98% (46/47) GT1b patients achieved SVR12. The GZR/MK-8408/ MK-3682 (450 mg) regimen achieved SVR12 in 94% (15/16) of GT2 patients and 91% (20/22) of GT3 patients. To date, there have been no relapses between FUW12 and FUW24. Based on population sequencing, high rates of SVR were maintained in patients with NS5A RAVs at baseline. Data for the NS3, NS5A and NS5B loci by nextgeneration sequencing will be presented. Treatments were generally safe and well tolerated, with no discontinuations due to adverse events and no cardiac or re

PURPOSE/BACKGROUND: To evaluate a retreatment regimen for patients who had failed therapy with a 3-drug direct-acting antiviral (DAA) combination: MK-3682, an NS5B polymerase inhibitor, grazoprevir, an NS3/4A protease inhibitor, and either elbasvir or MK-8408, which are NS5A inhibitors. METHOD(S): GT1-, 2-, and 3-infected treatment-naive, non-cirrhotic patients with chronic HCV infection who relapsed after 8 weeks of therapy with one of 4 regimens including grazoprevir (100 mg), MK-3682 (300 mg or 450 mg), and either elbasvir (50 mg) or MK-8408 (60 mg) were offered retreatment with 16 weeks of a fixed-dose combination of MK-3682 (450 mg)/ grazoprevir/MK-8408 plus ribavirin (RBV). RESULT(S): Twenty- four of 26 eligible patients were enrolled, 2 with GT1, 14 with GT2, and 8 with GT3 infection. At the time of relapse following initial therapy, NS5A RAVs were detected in 0% (0/2) GT1, 93% (13/14) GT2 and 88% (7/8) GT3 patients. NS3 RAVs were detected in 50% (1/2) GT1, 100% (14/14) GT2, and 100% (8/8) GT3 patients. NS5B RAVs were detected in 50% (1/2) GT1, 0% (0/14) GT2, and 0% (0/8) GT3 patients. 88% (21/24) patients had RAVs in >1 class. One GT2-infected patient withdrew after a single dose with adverse events (AEs) of vomiting and tachycardia. The remaining 23 patients completed the full 16 weeks of dosing. All patients had undetectable HCV RNA at the end of treatment. All 23 patients (2 GT1, 13 GT2, and 8 GT3) have reached at least follow-up week 4; 100% have achieved SVR4. Treatment was generally well tolerated, and no cardiac or renal safety signals were identified. The most frequent study drug-related AEs in >10% of all patients were headache, fatigue, nausea, rash, pruritus, insomnia, decreased hemoglobin and cough. CONCLUSION(S): A 16-week regimen of the fixed-dose combination of MK-3682 (450 mg)/grazoprevir/MK-8408 plus RBV was highly effective and well-tolerated in GT1-, 2-, and 3-infected treatment-naive, non-cirrhotic patients who had previously failed 8 wee

Purpose: Elbasvir (MK-8742) and grazoprevir (MK-5172; Merck & Co, Inc, Kenilworth, New Jersey) are hepatitis C virus (HCV)-specific inhibitors of the nonstructural protein 5A phosphoprotein and the nonstructural protein 3/4A protease, respectively. The aims of these studies were to evaluate the antiviral activity and safety of different doses of elbasvir or grazoprevir each administered as monotherapy to participants infected with either HCV genotype (GT) 1 or GT3. Methods: These 2 double-blind, randomized, placebo-controlled, sequential-panel, multiple ascending dose studies were conducted to assess the safety and pharmacodynamics of 5 days of once-daily elbasvir or 7 days of once-daily grazoprevir in adult male participants chronically infected with either HCV GT1 or GT3. Findings: Oral administration of elbasvir or grazoprevir once daily exhibited potent antiviral activity in participants with chronic GT1 or GT3 HCV infections. HCV RNA levels declined rapidly (within 1 day for elbasvir and 2 days for grazoprevir). At 50 mg of elbasvir once daily, the mean maximum reductions in HCV RNA from baseline were 5.21, 4.17, and 3.12 log10 IU/mL for GT1b-, GT1a-, and GT3-infected participants, respectively. At 100 mg of grazoprevir once daily, the mean maximum reductions in HCV RNA from baseline were 4.74 and 2.64 log10 IU/mL for GT1- and GT3-infected participants. Implications: The results in the elbasvir monotherapy study showed that 10 to 50 mg of elbasvir was associated with a rapid decline in HCV viral load; the results in the grazoprevir monotherapy study suggest that doses of 50 mg of grazoprevir and higher are on the maximum response plateau of the dose–response curve for GT1-infected participants. The results of these proof-of-concept studies provided preliminary data for the selection of the dosages of elbasvir and grazoprevir to test in Phase II and III clinical studies. ClinicalTrials.gov identifiers: NCT00998985 (Protocol 5172-004) and NCT01532973 (Protoco