Gastroenterology & Hepatology
December 2016, Volume 12, Issue 12, Supplement 6
A Review of Selected Presentations From the 2016 AASLD Liver Meeting • November 11-15, 2016 • Boston, Massachusetts
Special Reporting on:
• A Randomized Phase 3 Trial of Sofosbuvir/Velpatasvir/Voxilaprevir for 8 Weeks and Sofosbuvir/Velpatasvir for 12 Weeks for Patients With Genotype 3 HCV Infection and Cirrhosis: The POLARIS-3 Study
• SURVEYOR-II, Part 3: Efficacy and Safety of ABT-493/ABT-530 in Patients With Hepatitis C Virus Genotype 3 Infection With Prior Treatment Experience and/or Cirrhosis
• Sofosbuvir/Velpatasvir/Voxilaprevir for 12 Weeks as a Salvage Regimen in NS5A Inhibitor-Experienced Patients With Genotype 1-6 Infection: The Phase 3 POLARIS-1 Study
• The Fixed-Dose Combination Regimen of MK-3682/Grazoprevir/MK-8408 With or Without Ribavirin: Results From Parts B and C of C-CREST 1 & 2
• A Randomized, Controlled, Phase 3 Trial of Sofosbuvir/Velpatasvir/Voxilaprevir or Sofosbuvir/Velpatasvir for 12 Weeks in Direct Acting Antiviral Experienced Patients With Genotype 1-6 HCV Infection: The POLARIS-4 Study
• C-ISLE: Grazoprevir/Elbasvir Plus Sofosbuvir in Treatment-Naive and Treatment-Experienced HCV GT3 Cirrhotic Patients Treated for 8, 12 or 16 Weeks
• Eight Weeks Treatment Duration With Ledipasvir/Sofosbuvir (LDV/SOF) Is Effective for Appropriately Selected Patients With Genotype 1 Hepatitis C Virus (HCV) Infection: An Analysis of Multiple Real World Cohorts Totaling >6,500 Patients
PLUS Meeting Abstract Summaries
With Expert Commentary by:
Steven L. Flamm, MD
Chief, Liver Transplantation Program
Professor of Medicine and Surgery
Northwestern University Feinberg School of Medicine
Chicago, Illinois
A Randomized Phase 3 Trial of Sofosbuvir/Velpatasvir/Voxilaprevir for 8 Weeks and Sofosbuvir/Velpatasvir for 12 Weeks for Patients With Genotype 3 HCV Infection and Cirrhosis: The POLARIS-3 Study
Sofosbuvir is a nucleotide analogue inhibitor of NS5B polymerase with activity against hepatitis C virus (HCV) genotypes 1 through 6. Velpatasvir is a pangenotypic NS5A inhibitor. The 2 drugs are approved as a once-daily, fixed-dose combination administered for 12 weeks for the treatment of HCV genotype 3 infection in patients with cirrhosis who have not received prior treatment with direct-acting antiviral (DAA) agents.1 Voxilaprevir (GS-9857) is a pangenotypic NS3/4A protease inhibitor and has demonstrated activity against most resistance-associated substitutions (RASs). In phase 2 studies, the combin-ation of sofosbuvir/velpatasvir plus voxilaprevir administered daily for 8 weeks yielded high rates of sustained virologic response at 12 weeks posttreatment (SVR12) in patients with HCV genotype 3 infection, including those with cirrhosis.2 HCV genotype 3 accounts for approximately 30% of infections worldwide and is associated with high rates of hepatocellular carcinoma and rapid development of cirrhosis.3
Dr Graham Foster presented results of the international, open-label, randomized, phase 3 POLARIS-3 study (Safety and Efficacy of SOF/VEL/VOX FDC for 8 Weeks and SOF/VEL for 12 Weeks in Adults With Chronic Genotype 3 HCV Infection and Cirrhosis), which investigated 8 weeks of treatment with the once-daily, fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg)/voxilaprevir (100 mg) vs 12 weeks of sofosbuvir (400 mg)/velpatasvir (100 mg) in patients with HCV genotype 3 infection and compensated cirrhosis.4 Treatment-naive and treatment-experienced patients were eligible. Patients were stratified based on prior interferon exposure and were randomly assigned to the 2 treatment arms. HCV RNA levels were assessed by quantitative polymerase chain reaction with a lower limit of quantification of 15 IU/mL. Deep sequencing of HCV was performed using a 15% cutoff. Cirrhosis was determined by liver biopsy, blood biomarker testing, or transient elastography. The primary endpoint was SVR12, with additional safety and laboratory endpoints.
Sofosbuvir/velpatasvir/voxilaprevir was administered to 110 patients for 8 weeks. Sofosbuvir/velpatasvir was given to 109 patients for 12 weeks. Patients had a median age of 55 years (range, 25-75 years), and most were male. In the experimental vs the control arm, the mean platelet count was 140 × 103/µL (range, 37-351 × 103/µL) vs 130 × 103/µL (range, 51-292 × 103/µL). The proportion of patients with a platelet count below 100 × 103/µL was 29% vs 19%. The mean transient elastography score was 23 (range, 13-75) vs 22 (range, 13-75), reflecting a population with advanced cirrhosis. Approximately one-third of patients in each arm had received prior treatment with interferon, and the mean HCV RNA concentration was 6.0 log10 IU/mL (range, 1.6-7.6 log10 IU/mL) vs 6.3 log10 IU/mL (range, 4.1-7.5 log10 IU/mL). Patient compliance was 100% in the sofosbuvir/velpatasvir/voxilaprevir arm and 98% in the sofosbuvir/velpatasvir arm.
The SVR12 rate was 96% in both arms. In the sofosbuvir/velpatasvir/voxilaprevir arm, 2 patients relapsed, 1 patient withdrew consent, and 1 patient died. In the sofosbuvir/velpatasvir arm, 1 patient experienced on-treatment failure, 1 patient relapsed, 1 patient discontinued treatment owing to an adverse event (AE), and 1 patient was lost to follow-up. In treatment-naive patients, the SVR12 rate was 96% (72/75) with sofosbuvir/velpatasvir/voxilaprevir vs 99% (76/77) with sofosbuvir/velpatasvir (Figure 1). The addition of voxilaprevir improved the outcome in treatment-experienced patients, yielding an SVR12 rate of 97% (34/35) compared with 91% (29/32) in the treatment-experienced patients who received sofosbuvir/velpatasvir alone.
Baseline RASs were not associated with resistance to the combination of sofosbuvir/velpatasvir/voxilaprevir (Figure 2). The Y93H RAS was present in 6 patients in the voxilaprevir-containing arm and 4 patients in the sofosbuvir/velpatasvir arm, and all of these patients achieved SVR12. No treatment-emergent RASs were observed in the patients who received the voxilaprevir-containing regimen, and both patients with virologic failure in the sofosbuvir/velpatasvir arm had treatment-emergent Y93H mutations.
In the voxilaprevir-containing arm vs the control arm, the most common AEs included headache (25% vs 29%), fatigue (25% vs 28%), nausea (21% vs 9%), and diarrhea (15% vs 5%). Grade 3/4 AEs occurred in 3% and 4% of patients, and serious AEs occurred in 2% and 3%, respectively. No serious AEs were considered treatment-related.
References
1. Foster GR, Afdhal N, Roberts SK, et al; ASTRAL-2 Investigators; ASTRAL-3 Investigators. Sofosbuvir and velpatasvir for HCV genotype 2 and 3 infection. N Engl J Med. 2015;373(27):2608-2617.
2. Gane E, Kowdley KV, Pound D, et al. Efficacy of sofosbuvir, velpatasvir, and GS-9857 in patients with hepatitis C virus genotype 2, 3, 4, or 6 infections in an open-label, phase 2 trial. Gastroenterology. 2016;151(5):902-909.
3. Messina JP, Humphreys I, Flaxman A, et al. Global distribution and prevalence of hepatitis C virus genotypes. Hepatology. 2015;61(1):77-87.
4. Foster GR, Thompson A, Ruane PJ, et al. A randomized phase 3 trial of sofosbuvir/velpatasvir/voxilaprevir for 8 weeks and sofosbuvir/velpatasvir for 12 weeks for patients with genotype 3 HCV infection and cirrhosis: the POLARIS-3 study [AASLD abstract 258]. Hepatology. 2016;64(suppl 1):125A.
SURVEYOR-II, Part 3: Efficacy and Safety of ABT-493/ABT-530 in Patients With Hepatitis C Virus Genotype 3 Infection With Prior Treatment Experience and/or Cirrhosis
Current treatment recommendations from the American Association for the Study of Liver Diseases for patients with HCV genotype 3 infection include sofosbuvir plus daclatasvir or sofosbuvir plus velpatasvir, with the addition of ribavirin for patients with cirrhosis and/or prior treatment.1 The addition of ribavirin is also recommended for patients with either cirrhosis or prior treatment experience, as well as the baseline Y93H mutation. Ribavirin-free treatment regimens administered for the shortest possible duration are needed for these patient populations, which are the most difficult to treat. Glecaprevir (ABT-493) is a pangenotypic NS3/4A protease inhibitor that is being investigated in combination with pibrentasvir (ABT-530) for HCV treatment. The combination has demonstrated strong activity against HCV genotypes 1 to 6, including common NS3 and NS5A variants.2 The DAAs have been coformulated and are dosed once daily in 3 pills of glecaprevir (100 mg)/pibrentasvir (40 mg). The 2-drug combination has shown minimal metabolism and less than 1% renal excretion.
In a phase 2 study from 2015, glecaprevir (300 mg)/pibrentasvir (100 mg) administered for 12 weeks without ribavirin elicited an SVR12 rate of 100% in treatment-naive patients with HCV genotype 3 infection and compensated cirrhosis.3 In treatment-experienced patients with HCV genotype 3 infection and no cirrhosis, the SVR12 rate was 92%.
Part 3 of the phase 2 SURVEYOR-II trial (A Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Co-Administration of ABT-493 and ABT-530 With and Without RBV in Subjects With Chronic Hepatitis C Virus [HCV] Genotypes 2, 3, 4, 5 or 6 Infection) evaluated the efficacy and safety of glecaprevir (300 mg)/pibrentasvir (120 mg) administered for 12 or 16 weeks in patients with HCV genotype 3 infection.4 Eligible patients in part 3 of the study were adults with chronic HCV genotype 3 infection and an HCV RNA level of greater than 1000 IU/mL, without cirrhosis or with compensated cirrhosis. The study enrolled treatment-naive patients as well as patients whose prior treatment included interferon or pegylated interferon, with or without ribavirin, or sofosbuvir plus ribavirin with or without pegylated interferon. Key exclusion criteria included coinfection with hepatitis B virus or human immunodeficiency virus (HIV), previous DAA therapy (excepting sofosbuvir), or a history of hepatic decompensation. Patients with a level of alanine aminotransferase greater than 10 times the upper limit of normal and patients with inadequate levels of albumin (<2.9 g/dL) or platelets (<60 × 109/L) were excluded. The primary endpoint was SVR12 based on HCV RNA below the lower limit of quantification (25 IU/mL), with additional safety endpoints.
Forty-four treatment-experienced patients without cirrhosis were randomly assigned to receive glecaprevir/pibrentasvir for 12 or 16 weeks. The 2-drug combination was administered for 12 weeks in 40 treatment-naive patients with cirrhosis, and for 16 weeks in 47 treatment-experienced patients with cirrhosis. The median age in the 4 arms was 56 to 59 years (range, 29-70 years), and approximately two-thirds of patients were male. The median HCV RNA level across the 4 arms was 6.1 to 6.6 log10 IU/mL (range, 4.2-7.5 log10 IU/mL), and the proportion of patients with an HCV RNA level of at least 6 million IU/mL was 10% to 41%. The majority of patients did not have baseline NS3 or NS5A polymorphisms, and no patients exhibited concomitant NS3 and NS5A mutations. Two patients had NS3 polymorphisms, and 24 had NS5A polymorphisms. Of note, while these mutations are associated with resistance to earlier-generation NS3 or NS5A inhibitors, pibrentasvir has demonstrated activity against HCV mutants with established RASs.2
Among the treatment-experienced patients without cirrhosis, 12 or 16 weeks of treatment with glecaprevir/pibrentasvir yielded SVR12 rates of 91% and 96%, respectively (Figure 3). In treatment-naive patients with cirrhosis, 12 weeks of treatment yielded an SVR12 rate of 98%, including 1 patient who was lost to follow-up, and in treatment-experienced patients with cirrhosis, 16 weeks of treatment yielded an SVR12 rate of 96%. Across the 4 arms, 4 patients experienced relapse and 1 patient experienced breakthrough; all 5 patients were treatment-experienced, and all 5 had high baseline viral loads, ranging from 2.84 × 106 IU/mL to 18.9 × 106 IU/mL. The 1 patient who experienced virologic breakthrough had a body-mass index of approximately 42 and had previously failed sofosbuvir plus ribavirin. The patient had the NS3 variant A166S at baseline, and developed the additional A156G variant after breakthrough. This patient had no baseline NS5 variants, and had A30K plus Y93H after breakthrough. One patient who experienced relapse had no baseline NS3 RASs and had the combination of Y56H and Q168R after relapse. The 3 other patients who experienced relapse had no NS3 RASs at baseline or after virologic failure (Table 1). NS5A baseline variants were observed in 3 of the 4 patients who relapsed, including 1 patient with Y93H and 2 patients with A30K. At failure, both patients with baseline A30K had acquired a second mutation of Y93H. The patient with no baseline RASs had the combination of L31F plus Y93H after relapse.
AEs of any grade were observed in at least half of patients in each of the 4 arms. Serious AEs occurred in 3% to 7% of patients in the 4 arms, but no serious AEs were considered related to study drug, and no patients discontinued treatment owing to an AE. AEs occurring in at least 10% of patients included fatigue and headache.
References
1. HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. American Association for the Study of Liver Diseases/Infectious Diseases Society of America. http://www.hcvguidelines.org. Accessed December 5, 2016.
2. Ng T, Pilot-Matias T, Lu L, et al. A next generation HCV DAA combination: potent, pangenotypic inhibitors ABT-493 and ABT-530 with high barriers to resistance [AASLD abstract 1946]. Hepatology. 2014;60(suppl 1):1142A.
3. Kwo PY, Wyles DL, Wang S, et al. 100% SVR12 with ABT-493 and ABT-530 with or without ribavirin in treatment-naive HCV genotype 3-infected patients with cirrhosis [EASL abstract LB01]. J Hepatol. 2015;64(suppl 2).
4. Wyles DL, Poordad F, Wang S, et al. SURVEYOR-II, part 3: efficacy and safety of ABT-493/ABT-530 in patients with hepatitis C virus genotype 3 infection with prior treatment experience and/or cirrhosis [AASLD abstract 113]. Hepatology. 2016;64(suppl 1):62A.
Sofosbuvir/Velpatasvir/Voxilaprevir for 12 Weeks as a Salvage Regimen in NS5A Inhibitor-Experienced Patients With Genotype 1-6 Infection: The Phase 3 POLARIS-1 Study
In phase 2 studies, sofosbuvir, velpatasvir, and voxilaprevir yielded high rates of SVR12 in patients who had received prior treatment with DAA-containing regimens, including patients with cirrhosis.1,2 The double-blind, randomized, placebo-controlled phase 3 POLARIS-1 study (Safety and Efficacy of Sofosbuvir/Velpatasvir/Voxilaprevir in Adults With Chronic HCV Infection Who Have Previously Received Treatment With Direct-Acting Antiviral Therapy) evaluated sofosbuvir/velpatasvir/voxilaprevir in patients with HCV genotype 1 to 6 infection who failed prior treatment with an NS5A inhibitor.3 Patients with HCV genotype 1 infection were stratified based on cirrhosis and randomly assigned to receive 12 weeks of treatment with the once-daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg)/voxilaprevir (100 mg) or placebo. Patients with all other HCV genotypes were enrolled into the active treatment arm. HCV RNA levels were measured by quantitative polymerase chain reaction with a lower limit of quantification of 15 IU/mL. Deep sequencing was performed using a 15% cutoff, and cirrhosis was determined by liver biopsy, blood biomarker testing, or transient elastography. The primary endpoint was SVR12. Other endpoints included AEs, discontinuations, and laboratory abnormalities.
There were 263 patients in the sofosbuvir/velpatasvir/voxilaprevir arm and 152 patients in the placebo arm. The mean age was 58 years (range, 27-84 years), and more than three-fourths of patients were male. Patients had a mean HCV RNA level of 6.3 log10 IU/mL (range, 1.6-7.7 log10 IU/mL). In the active treatment arm, 57% of patients had HCV genotype 1, 2% had genotype 2, 30% had genotype 3, 8% had genotype 4, and the remainder had genotype 5, 6, or an unknown genotype. In the active treatment arm, 46% of patients had cirrhosis vs 34% in the placebo arm. Previous use of NS5A inhibitors included ledipasvir in 51%, daclatasvir in 27%, and ombitasvir in 11%. In the active treatment arm, 2 patients discontinued treatment: one experienced an AE on day 12, and one was lost to follow-up after week 8 of treatment. In the placebo arm, 3 patients discontinued treatment owing to an AE.
The combination of sofosbuvir/velpatasvir/voxilaprevir administered for 12 weeks yielded an SVR12 rate of 96% (253/263). Six patients relapsed, and 2 withdrew consent. One patient experienced on-treatment failure and had drug exposure levels consistent with nonadherence. One patient was lost to follow-up. No patients in the placebo arm achieved SVR12 (P<.001 for superiority compared with the prespecified performance goal of 85% for the triple-combination therapy). The 3-drug combination yielded an SVR12 rate of 99% (140/142) in the group of patients without cirrhosis. Among the 2 patients who did not achieve SVR12, 1 withdrew consent and 1 was lost to follow-up. The SVR12 rate was 93% (113/121) in the patients with cirrhosis, and included 6 patients who relapsed, 1 with on-treatment failure, and 1 who withdrew consent. SVR12 rates were high across all genotypes, with SVR12 rates of 100% observed for genotype 1b (n=45), 2 (n=5), 5 (n=1), and 6 (n=6; Figure 4). In genotypes 1, 1a, 3, and 4, SVR12 rates were 97%, 96%, 95%, and 91%, respectively. Eighty-three percent of patients had baseline RASs, with the majority in NS5A. SVR12 rates in the patients without vs with baselines RASs were 98% and 96%, respectively. Among the patients with baseline RASs, SVR12 rates were 100% (9/9) in those with variants in NS3 only, 94% (120/127) in those with NS5A only, and 97% (70/72) in those with both (Figure 5). None of the patients who relapsed had treatment-emergent mutations.
The fixed-dose combination of sofosbuvir/velpatasvir/voxilaprevir was generally well-tolerated. The proportion of patients with an AE of any grade was 78% in the active treatment arm, vs 70% in the placebo arm. Grade 3/4 AEs occurred in 2% vs 3% of patients, and serious AEs occurred in 2% vs 5%, respectively. No serious AEs were considered related to treatment.
References
1. Gane EJ, Schwabe C, Hyland RH, et al. Efficacy of the combination of sofosbuvir, velpatasvir, and the NS3/4A protease inhibitor GS-9857 in treatment-naive or previously treated patients with hepatitis C virus genotype 1 or 3 infections. Gastroenterology. 2016;151(3):448-456.e1.
2. Lawitz E, Reau N, Hinestrosa F, et al. Efficacy of sofosbuvir, velpatasvir, and GS-9857 in patients with genotype 1 hepatitis C virus infection in an open-label, phase 2 trial. Gastroenterology. 2016;151(5):893-901.
3. Bourlière M, Gordon SC, Ramji A, et al. Sofosbuvir/velpatasvir/voxilaprevir for 12 weeks as a salvage regimen in NS5A inhibitor-experienced patients with genotype 1-6 infection: the phase 3 POLARIS-1 study [AASLD abstract 194]. Hepatology. 2016;64(suppl 1):102A.
The Fixed-Dose Combination Regimen of MK-3682/Grazoprevir/MK-8408 With or Without Ribavirin: Results From Parts B and C of C-CREST 1 & 2
The fixed-dose combination of MK-3682 (225 mg)/grazoprevir (50 mg)/ruzasvir (30 mg) is dosed in 2 tablets administered once daily.1-3 These 3 pangenotypic DAAs have nonoverlapping resistance profiles and are inhibitors of NS5B, NS3/4A, and NS5A, respectively. The regimen is known as MK-3682B or MK3. The parallel-group, multicenter, open-label, randomized phase 2 CREST 1 and 2 trials investigated this regimen with or without ribavirin for 8, 12, or 16 weeks in patients with HCV genotypes 1, 2, and 3. The trials enrolled a total of 664 patients and included 3 arms with ribavirin and 3 arms without ribavirin.
Dr Eric Lawitz presented findings from C-CREST 1 and 2, part B.4 All enrolled patients had documented chronic HCV genotype 1, 2, or 3 infection. Patients with genotype 1 or 2 infection were required to be treatment-naive, whereas patients with genotype 3 infection could be treatment-naive or could have received prior treatment with pegylated interferon and ribavirin. An HCV RNA level of at least 10,000 IU/mL was required, and coinfection with HIV was allowed. Cirrhotic and noncirrhotic patients were enrolled. Key exclusion criteria were decompensated liver disease, coinfection with hepatitis B virus, evidence or suspicion of hepatocellular carcinoma, elevated transaminase levels, and low levels of hemoglobin or platelets. Patients with HCV genotype 1 were randomized to receive MK3 without ribavirin for 8 or 12 weeks. Patients with genotype 2 or 3 were randomized to receive MK3 with or without ribavirin for 8 or 12 weeks. The primary endpoint was SVR12.
Patient characteristics were well-balanced among the 3 arms. The 664 patients had a median age of 54 years (range, 19-85 years), and 59% were male. Thirty-eight percent of patients had cirrhosis, and 4% of patients were coinfected with HIV. Among the 176 patients with genotype 1 infection, SVR12 rates after 8 or 12 weeks of MK3 treatment were 93% and 98%, respectively, for patients with genotype 1a infection, and 98% and 100% for patients with genotype 1b infection (Figure 6). After 8, 12, or 16 weeks of MK3 treatment with or without ribavirin, patients with genotype 2 infection showed SVR12 rates of 86%, 97%, and 100%, respectively, and patients with genotype 3 infection had SVR12 rates of 95%, 97%, and 96%. The MK3 regimen was effective in patients with HCV genotype 1 infection with or without cirrhosis. After 8 weeks of MK3, SVR rates were 97% for genotype 1a patients without cirrhosis and 92% for those with cirrhosis. Among patients with genotype 1b infection, SVR12 was 96% for those without cirrhosis vs 100% for those with cirrhosis. After 12 weeks of MK3, all patients with HCV genotype 1a or 1b infection, with or without cirrhosis, achieved SVR12. In patients with HCV genotype 2 or 3 infection, the addition of ribavirin did not significantly or consistently improve outcomes compared with MK3 alone.
Baseline NS5A RASs did not reduce SVR12 rates in patients with HCV genotype 1 infection. In contrast, in patients with genotype 2 or 3 infection, the presence of baseline NS5A RASs generally reduced the SVR12 rate. In genotype 2 patients without vs with the NS5A L31M RAS at baseline, SVR12 rates were 94% vs 80% after 8 weeks of treatment. However, 12 weeks of treatment yielded SVR12 rates of 100% in all patients with or without the L31M baseline RAS. In genotype 3 patients without vs with Y93H at baseline, SVR12 rates were 98% vs 50% after 8 weeks of treatment and 99% vs 71% after 12 weeks of treatment.
AEs and treatment-related AEs were more common in patients who received treatment containing ribavirin. The most common AEs of any grade in patients receiving MK3 alone were headache (19%), fatigue (15%), and nausea (11.3%).
Dr Edward Gane presented res-ults from C-CREST part C, which evaluated retreatment of patients who relapsed in part A of the same trial.5 In part A, patients received a 3-DAA combination for 8 weeks. In part C, 24 patients with HCV genotype 1 (n=2), 2 (n=14), or 3 (n=8) who had relapsed in part A received MK3 plus ribavirin for 16 weeks. SVR12 rates for the patients with genotype 1, 2, or 3 were 100%, 93%, and 100%, respectively. The common AEs were headache (25%), fatigue (25%), nausea (25%), rash (21%), and insomnia (21%).
References
1. Tong L, Yu W, Chen L, et al. The discovery of ruzasvir (MK-8408): a potent, pan-genotype HCV NS5A inhibitor with optimized activity against common resistance-associated polymorphisms [published online November 3, 2016]. J Med Chem. 2016. doi:10.1021/acs.jmedchem.6b01310.
2. Gane EJ, Pianko S, Roberts SK, et al. High efficacy of an 8-week drug regimen of grazoprevir/MK-8408/MK-3682 in HCV genotype 1, 2 and 3-infected patients: SVR24 data from the phase 2 C-CREST 1 and 2 studies [EASL abstract SAT-139]. J Hepatol. 2016;64(suppl 2).
3. Gao W, Huang H, Fitzgerald B, et al. Phase 2, randomized, open-label clinical trials of the efficacy and safety of grazoprevir and MK-3682 (NS5B polymerase inhibitor) with either elbasvir or MK-8408 (NS5A inhibitor) in patients with chronic HCV GT1, 2, or 3 infection (part A of C-CREST-1 and 2) [AASLD abstract LB-15]. Hepatology. 2015;62(suppl 6):1389A.
4. Lawitz E, Yoshida EM, Buti M, et al. Safety and efficacy of the fixed-dose combination regimen of MK-3682/grazoprevir/MK-8408 with or without ribavirin in non-cirrhotic or cirrhotic patients with chronic HCV GT1, 2 or 3 infection (part B of C-CREST-1 & 2) [AASLD abstract 110]. Hepatology. 2016;64(suppl 1):60A.
5. Serfaty L, Pianko S, Ben Ari Z, et al. High sustained virologic response (SVR) rates in patients with chronic HCV GT1, 2 or 3 infection following 16 weeks of MK-3682/grazoprevir/MK-8408 plus ribavirin after failure of 8 weeks of therapy (part C of C-CREST-1 & 2) [AASLD abstract 112]. Hepatology. 2016;64(suppl 1):61A.
A Randomized, Controlled, Phase 3 Trial of Sofosbuvir/Velpatasvir/Voxilaprevir or Sofosbuvir/Velpatasvir for 12 Weeks in Direct Acting Antiviral Experienced Patients With Genotype 1-6 HCV Infection: The POLARIS-4 Study
Sofosbuvir (400 mg)/velpatasvir (100 mg) administered for 12 weeks is approved for treatment of HCV patients without prior exposure to DAAs. However, treatments for DAA-experienced patients are needed. Dr Stefan Zeuzem presented results of the open-label, randomized, phase 3 POLARIS-4 trial (Safety and Efficacy of SOF/VEL/VOX FDC for 12 Weeks and SOF/VEL for 12 Weeks in DAA-Experienced Adults With Chronic HCV Infection Who Have Not Received an NS5A Inhibitor), which investigated the fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg)/voxilaprevir (100 mg) in DAA-experienced patients with HCV genotypes 1 to 6 who had not received an NS5A inhibitor.1-3 Patients with HCV genotypes 1 to 3 were randomly assigned to receive 12 weeks of treatment with sofosbuvir/velpatasvir/voxilaprevir or sofosbuvir/velpatasvir, after stratification for cirrhosis. Patients with genotypes 4 to 6 were assigned to 12 weeks of treatment with sofosbuvir/velpatasvir/voxilaprevir.
The study enrolled 182 patients in the sofosbuvir/velpatasvir/voxila-previr arm and 151 patients in the sofosbuvir/velpatasvir arm. Patients had a median age of 57 years (range, 24-85 years), more than three-fourths were male, and 46% had cirrho-sis. The voxilaprevir-containing arm inclu-ded 19 patients (10%) with HCV genotype 4. Across the entire study cohort, SVR12 rates were 69% for patients with prior exposure to sofosbuvir and 4% for patients with exposure to an NS5B inhibitor other than sofosbuvir. Patients with prior exposure to sofosbuvir plus simeprevir achieved an SVR12 rate of 11%, whereas those with prior exposure to a different NS5B and NS3 inhibitor combination achieved an SVR12 rate of 14%. In patients with prior DAA exposure to other unspecified DAA regimens, the SVR12 rate was 2%. All patients treated with sofosbuvir/velpatasvir/voxilaprevir completed study treatment. In the comparator arm, 1 patient discontinued treatment owing to an AE and 1 patient discontinued owing to lack of efficacy. Treatment with sofosbuvir/velpatasvir/voxilaprevir yielded an SVR12 rate of 97% and a P value of <.001 for superiority compared with a prespecified 85% performance goal. One patient relapsed, 1 patient died, and 3 patients were lost to follow-up. Treatment with sofosbuvir/velpatasvir yielded an SVR12 rate of 90%, and a P value of .092 for superiority. One patient exhibited viral breakthrough, and 14 patients relapsed.
After 12 weeks of treatment, in pati-ents without cirrhosis, SVR12 rates were 98% with sofosbuvir/velpatasvir/vox-ilaprevir vs 94% with sofosbuvir/velpatasvir. In patients with cirrhosis, SVR12 rates were 96% vs 86%, respectively (Figure 7). After treatment with the 3-drug vs the 2-drug regimen, SVR12 rates were 98% vs 89% in gen-otype 1a–infected patients, 96% vs 95% in genotype 1b–infected patients, 100% vs 97% in genotype 2–infected patients, and 94% vs 85% in genotype 3–infected patients. In the 19 patients with genotype 4 infection, the 3-drug com-bination yielded an SVR12 rate of 100%.
In patients without baseline RASs, SVR12 was 94% with voxilaprevir vs 89% without. In patients with baseline RASs, SVR12 was 100% with voxilaprevir vs 90% without. The addition of voxilaprevir yielded SVR12 rates of 100% in patients with baseline RASs in NS3 only, NS5A only, or both NS3 and NS5A. Without voxilaprevir, these rates were 91%, 94%, and 50%, respectively. Twenty-two patients had baseline NS5B RASs, and all achieved SVR12. No treatment-emergent RASs were reported in the patient who relapsed after 3-drug treatment. In the cohort of patients treated with sofosbuvir/velpatasvir, 10 of the 15 patients who experienced virologic failure exhibited treatment-emergent Y93H or Y93C.
The triple-therapy treatment was generally well-tolerated. AEs of any grade were reported in approximately three-fourths of patients in either treatment cohort. Grade 3/4 AEs occurred in 2 patients (1%) in each cohort, and serious AEs occurred in 4 patients (2%-3%) in each cohort. No serious AEs were considered treatment-related. The most common AEs of any grade occurring in more than 10% of patients in the 3-drug vs the 2-drug cohort were headache (27% vs 28%), fatigue (24% vs 28%), diarrhea (20% vs 5%), and nausea (12% vs 8%).
References
1. Foster GR, Afdhal N, Roberts SK, et al; ASTRAL-2 Investigators; ASTRAL-3 Investigators. Sofosbuvir and velpatasvir for HCV genotype 2 and 3 infection. N Engl J Med. 2015;373(27):2608-2617.
2. Gane E, Kowdley KV, Pound D, et al. Efficacy of sofosbuvir, velpatasvir, and GS-9857 in patients with hepatitis C virus genotype 2, 3, 4, or 6 infections in an open-label, phase 2 trial. Gastroenterology. 2016;151(5):902-909.
3. Zeuzem S, Flamm SL, Tong M, et al. A randomized, controlled, phase 3 trial of sofosbuvir/velpatasvir/voxilaprevir or sofosbuvir/velpatasvir for 12 weeks in direct acting antiviral experienced patients with genotype 1-6 HCV infection: the POLARIS-4 study [AASLD abstract 109]. Hepatology. 2016;64(suppl 1):59A.
C-ISLE: Grazoprevir/Elbasvir Plus Sofosbuvir in Treatment-Naive and Treatment-Experienced HCV GT3 Cirrhotic Patients Treated for 8, 12 or 16 Weeks
Patients with HCV genotype 3 infection and cirrhosis remain a challenging population.1 Within this group, treatment-experienced patients and those with baseline NS5A RASs present an even greater treatment challenge. Dr Graham Foster presented findings from the C-ISLE trial (Elbasvir/Grazoprevir [EBR/GZR] and Sofosbuvir [SOF] With and Without Ribavirin [RBV] in Cirrhotic Subjects With Chronic HCV GT3 Infection), which evaluated the combination of daily sofosbuvir (400 mg) plus the fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg), with or without weight-based ribavirin, in patients with HCV genotype 3 infection and cirrhosis.2 The 3 drugs are already approved for HCV treatment and thus could be implemented immediately for this population. The study design included 5 treatment arms, with a planned enrollment of 25 patients per arm. Patients with or without prior treatment experience were eligible. Treatment-naive patients received 8 weeks of sofosbuvir plus elbasvir/grazoprevir with ribavirin or 12 weeks of this treatment without ribavirin. Treatment-experienced patients received 12 weeks of 3-drug therapy with or without ribavirin or 16 weeks of treatment without ribavirin. The primary endpoint was SVR12. Adult patients with chronic HCV genotype 3 infection were enrolled. Compensated cirrhosis was defined by biopsy or noninvasive testing. Patients could be treatment-naive or could have received treatment with pegylated interferon plus ribavirin. HIV coinfection was permitted. Next-generation sequencing of RASs was performed using a 15% threshold.
The 100 enrolled patients had a median age of 53 ± 8.7 years, and 68% were male. Cirrhosis was evaluated by transient elastography in 84% of patients, yielding a mean score of 25.4 ± 12.1 kPa. The mean HCV RNA level was 6.2 ± 0.7 log10 IU/mL. The mean platelet count was 148 × 103 cells/µL (range, 46-396 cells/µL), and 24 patients had a platelet count of less than 100 × 103 cells/µL.
In treatment-naive patients, 8 weeks of sofosbuvir plus elbasvir/grazoprevir with ribavirin yielded an SVR12 rate of 91%, including 2 relapses, and 12 weeks of 3-DAA therapy without ribavirin yielded an SVR12 rate of 96%, with 1 failure in a patient who did not complete the treatment course. In treatment-experienced patients, 12 weeks of 3-DAA therapy without ribavirin achieved an SVR12 rate of 100%, and the same treatment with ribavirin achieved an SVR12 rate of 94%, with 1 failure in a patient who did not complete treatment. The 16-week regimen of 3-DAAs without ribavirin also yielded an SVR12 rate of 94%, with 1 failure in a patient who did not complete treatment. Approximately half of the study patients had baseline NS5A RASs, and the SVR12 rate was 98% in patients with or without these mutations. One patient with a Y93 RAS in the 8-week treatment arm experienced virologic failure, and 3 patients harboring a Y93 RAS achieved SVR12 with a 12- or 16-week regimen.
No safety signals were raised in this population of cirrhotic patients with HCV genotype 3 infection. In the entire study population, 5 patients experienced a serious AE.
References
1. Lawitz E, Poordad F, Gutierrez JA, et al. Short-duration treatment with elbasvir/grazoprevir and sofosbuvir for hepatitis C: a randomized trial [published online October 22, 2016]. Hepatology. 2016. doi:10.1002/hep.28877.
2. Foster GR, Agarwal K, Cramp M, et al. C-ISLE: grazoprevir/elbasvir plus sofosbuvir in treatment-naïve and treatment-experienced HCV GT3 cirrhotic patients treated for 8, 12 or 16 weeks [AASLD abstract 74]. Hepatology. 2016;64(suppl 1):39A.
Eight Weeks Treatment Duration With Ledipasvir/Sofosbuvir (LDV/SOF) Is Effective for Appropriately Selected Patients With Genotype 1 Hepatitis C Virus (HCV) Infection: An Analysis of Multiple Real World Cohorts Totaling >6,500 Patients
Two studies investigated real-world treatment with ledipasvir/sofosbuvir, one in patients with HCV genotype 1 infection1 and the other in patients coinfected with HIV-1.2 Based on a post-hoc analysis of data from the ION-3 trial (Safety and Efficacy of Ledipasvir/Sofosbuvir Fixed-Dose Combination ± Ribavirin for the Treatment of HCV), ledipasvir/sofosbuvir for 8 weeks can be considered in treatment-naive patients with HCV genotype 1 infection, no cirrhosis, and a pretreatment HCV RNA level of less than 6,000,000 IU/mL.3 A study was conducted to evaluate the real-world effectiveness of 8 weeks vs 12 weeks of ledipasvir (90 mg)/sofosbuvir (400 mg) and to evaluate predictors of relapse.1 The primary analysis included pooled data from treatment-naive adults without cirrhosis identified in the HCV TRIO Health network. A secondary analysis consisted of a systematic review and a random effects meta-analysis of additional real-world cohorts from observational studies to identify any differences between 8 and 12 weeks of treatment. Among the 868 patients in the pooled analysis, virologic outcomes were available for 857, and 798 were considered eligible for 8 weeks of treatment with ledipasvir/sofosbuvir per the indication from the US Food and Drug Administration. Among the 798 patients eligible for 8 weeks of ledipasvir/sofosbuvir, the SVR12 rate was 98.5%. In white, African American, or Hispanic patients, SVR12 rates were 99.1%, 96.5%, and 98.8%, respectively. In patients with genotype 1a or 1b infection, SVR12 rates were 98.3% and 99.2%, respectively. Patients with fibrosis of stage 0, 1, 2, or 3 had SVR12 rates of 100%, 98.3%, 99.6%, and 95.2%, respectively. The SVR12 rate in 18 patients with HIV coinfection was 100%. Sixty-one patients with a viral load of greater than 6,000,000 IU/mL yielded an SVR12 rate of 100%. No variables were associated with relapse, including age, sex, and genotype. Based on the systematic review and meta-analysis of 6 studies, per-protocol SVR12 rates were 95.8% and 97.2% for 8 vs 12 weeks of treatment, respectively. The risk of relapse was similar for both cohorts.
A separate study evaluated the efficacy of ledipasvir/sofosbuvir in patients coinfected with HCV genotype 1 and HIV-1 based on a pooled analysis of patients from clinical trials vs the real world.2 For the clinical trial population, the pooled analysis included 353 patients from the phase 3 ION-4 study (Efficacy and Safety of Ledipasvir/Sofosbuvir Fixed-Dose Combination for 12 Weeks in Subjects With Chronic Genotype 1 or 4 HCV and HIV-1 Co-Infection), 50 patients from the phase 2b ERADICATE trial (Study of a Combination Pill With GS-7977 and GS-5885 for Hepatitis C in People With HIV), and 68 patients from the phase 2 Pilot Study to Assess Efficacy and Safety of Sofosbuvir/Ledipasvir Fixed-Dose Combination in Treatment Experienced Subjects With Hepatitis C Virus (HCV) Genotype 1 – HIV Co-Infection, conducted in France.4-6 For the real-world population, the pooled analysis included 150 patients from the TRIO network, 600 from the phase 4 ASCEND study (Study to Assess Community-Based Treatment of Chronic Hepatitis C Monoinfection and Coinfection With HIV in the District of Columbia), 270 from the US Veterans Health Administration, and 211 from the Portuguese Universal Coverage Program to Eradicate Hepatitis C.7-10 Approximately 20% to 30% of patients in each pooled population had cirrhosis. The pooled analysis yielded SVR12 rates of 97% (428/442) for patients in clinical trials and 94% (688/731) for real-world patients. Patients with negative predictive factors demonstrated high rates of SVR12 in the clinical trial and real-world cohorts. SVR12 rates were 98% vs 97% in treatment-experienced patients, 96% vs 94% in cirrhotic patients, and 93% vs 92% in black patients, respectively.
References
1. Sundaram V, Jeon CY, Qureshi K, et al. Eight weeks treatment duration with ledipasvir/sofosbuvir (LDV/SOF) is effective for appropriately selected patients with genotype 1 hepatitis C virus (HCV) infection: an analysis of multiple real world cohorts totaling >6,500 patients [AASLD abstract LB-16]. Hepatology. 2016;64(suppl 6):1129A.
2. Naggie S, Rosenthal E, Kattakuzhy S, et al. Real world effectiveness of ledipasvir/sofosbuvir in patients coinfected with HCV and HIV-1: a comparative analysis of clinical trials with four real world cohorts [AASLD abstract 892]. Hepatology. 2016;64(suppl 1):445A.
3. Kowdley KV, Gordon SC, Reddy KR, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med. 2014;370(20):1879-1888.
4. Naggie S, Cooper C, Saag M, et al; ION-4 Inves-tigators. Ledipasvir and sofosbuvir for HCV in pat-ients coinfected with HIV-1. N Engl J Med. 2015;373(8):705-713.
5. Osinusi A, Townsend K, Kohli A, et al. Virologic response following combined ledipasvir and sofosbuvir administration in patients with HCV genotype 1 and HIV co-infection. JAMA. 2015;313(12):1232-1239.
6. Rosenthal E, Fougerou-Leurent C, Renault A, et al. Ledipasvir/sofosbuvir in NS3/4A protease inhibitor-experienced subjects with HCV genotype 1 and HIV-co-infection. Final results of the ANRS HC31 SOFTRIH study [EASL abstract SAT-149]. J Hepatol. 2016;64(suppl 2).
7. Dieterich DT, Bacon B, Curry M, et al. Ledipasvir/sofosbuvir ± ribavirin in patients co-infected with HCV and HIV: real-world heterogeneous population from the TRIO network [EASL abstract SAT-134]. J Hepatol. 2016;64(suppl 2).
8. McGinnis J, McCombs, Mehta D, Fox S, Tonnu-Mihara I. Analysis of the impact of HIV co-infection on hepatitis C treatment effectiveness for patients using new direct-acting antivirals [EASL abstract LBP514]. J Hepatol. 2016;64(suppl 2).
9. Rodrigues J, Tato-Marinho R, Mota-Filipe H, et al. Evidence of impressive real world SVR from the Portuguese ledipasvir/sofosbuvir and sofosbuvir universal coverage program to eradicate (eliminate) hepatitis C [EASL abstract LBP523]. J Hepatol. 2016;64(suppl 2).
10. Kattakuzhy S, Gross C, Teferi G, et al. A novel task shifting model to expand the HCV care continuum: the ASCEND investigation [EASL abstract LBP524]. J Hepatol. 2016;64(suppl 2).
Highlights in the Treatment of Hepatitis C Virus From the 2016 AASLD Liver Meeting: Commentary
Steven L. Flamm, MD
Presentations at the 2016 American Association for the Study of Liver Diseases (AASLD) Liver Meeting provided data representing important advances in the treatment of hepatitis C virus (HCV). This may seem surprising since there are now very effective therapies for HCV. It is still possible, however, to improve in certain areas. Many of the studies presented at the meeting attempted to refine the current therapeutic regimens. Other studies evaluated new therapies, with several goals in mind. One goal is to shorten the treatment course to 8 weeks. Most current regimens are administered for 12 weeks, and some patients require 24 weeks. Only a specific group of patients can be cured with 8 weeks of direct-acting antiviral (DAA) therapy with sofosbuvir and ledipasvir.
Another goal of the new therapies is to limit or avoid the use of ribavirin. Ribavirin remains a component of several current therapeutic regimens. Although the use of ribavirin is not onerous for most patients, there are several disadvantages. Ribavirin can cause anemia, so the patient’s red blood cell count must be monitored during use. It has teratogenic effects, so pregnancy must be avoided. It is associated with several other side effects leading to poor tolerability in some patients. Regimens that do not require ribavirin are highly sought.
Some of the novel regimens aim to improve response rates in patients who respond poorly to the current DAA therapies. The available regimens have been effective in most patients; the exceptions, depending upon the regimen, include those with renal failure, those with genotype 3, and those who have failed previous treatment with a DAA regimen. For unclear reasons, the worst outcomes with the current regimens are seen in patients with genotype 3 who have cirrhosis or who have already failed interferon α–based regimens. New therapies are being sought to better achieve sustained virologic response (SVR) in these populations.
Lastly, other presentations at the meeting addressed the question of whether the positive results achieved in clinical trials for HCV will extend to real-life scenarios. Several abstracts at The Liver Meeting presented real-world data, with a focus on identifying factors that predict failure.
Special Populations
Genotype 3
Most of the regimens under evaluation in special populations have not yet been approved in the United States, but they should be within the next year or so. A study by Wyles and colleagues evaluated the combination of 2 new medications: glecaprevir, a protease inhibitor, and pibrentasvir, an NS5A inhibitor.1 Ribavirin was not a component of this regimen. The study population consisted of approximately 130 patients with genotype 3. For enrollment, treatment-naive patients were required to have cirrhosis. The presence of cirrhosis was not required for treatment-experienced patients. The study had 4 arms. Treatment-naive patients with cirrhosis received 12 weeks of glecaprevir/pibrentasvir. Treatment-experienced patients with cirrhosis received a longer course of 16 weeks. Patients without cirrhosis were randomly assigned to receive 12 or 16 weeks of this combination.
The cure rate with this regimen was 98% in patients who were treatment-naive with cirrhosis. In the population that had received previous treatment and had cirrhosis—those patients with 2 strikes against them—the 16-week regimen achieved an SVR12 of 96%. In the treatment-experienced patients without cirrhosis, SVR12 was 91% after 12 weeks of treatment. There were only 22 patients in that arm, and 2 patients failed. In the treatment-experienced, noncirrhotic patients who received 16 weeks of treatment, the SVR12 rate was 96%. One of the 21 patients in this group did not achieve an SVR12.
This study showed that a regimen of glecaprevir and pibrentasvir, without ribavirin, worked extremely well. A 12-week course of therapy achieved high rates of SVR12 in treatment-naive patients with cirrhosis and in treatment-experienced patients without cirrhosis. In treatment-experienced patients with cirrhosis, 16 weeks of therapy was effective.
Foster and coworkers presented results of the POLARIS-3 trial, which enrolled patients with genotype 3 and cirrhosis.2 The regimen consisted of sofosbuvir, a polymerase inhibitor; velpatasvir, the most recently approved NS5A inhibitor; and voxilaprevir, a new protease inhibitor. This triple regimen includes DAA agents from each of the 3 classes currently in use against HCV. The study enrolled both treatment-naive and treatment-experienced patients. Sofosbuvir/velpatasvir/voxilaprevir, administered for 8 weeks, was compared against the recently approved regimen of sofosbuvir/velpatasvir given for 12 weeks. Overall, the cure rate was 96% with both the short, 8-week course of triple therapy and the approved 12-week course of sofosbuvir/velpatasvir. With some regimens, patients with genotype 3 may have lower cure rates when they have baseline resistance-associated substitutions (RASs). In this study, however, the presence of RASs did not impact response rates. Treatment-naive genotype 3 patients with cirrhosis had a cure rate of 96% with sofosbuvir/velpatasvir/voxilaprevir vs 99% with the currently available sofosbuvir/velpatasvir regimen. Among treatment-experienced patients, SVR12 was 99% with the new 8-week regimen of sofosbuvir/velpatasvir/voxilaprevir, vs only 91% for the sofosbuvir/velpatasvir 12-week regimen. This study showed that this new 8-week, triple-therapy regimen is highly effective in genotype 3 patients with cirrhosis, regardless of whether they had received previous treatment.
Patients with HCV genotype 3 and cirrhosis, who were treatment-experienced or treatment-naive, were enrolled in the C-ISLE trial, also presented by Foster and colleagues.3 This study evaluated sofosbuvir (a polymerase inhibitor), grazoprevir (a protease inhibitor), and elbasvir (an NS5A inhibitor), with or without ribavirin. There were 5 treatment arms enrolling 100 patients. The treatment-naive patients received elbasvir/grazoprevir/sofosbuvir with or without ribavirin for 12 weeks. The cure rates were 96% without ribavirin and 91% with ribavirin. The treatment-experienced population, a more challenging group, was divided among the other 3 treatment arms. Elbasvir/grazoprevir/sofosbuvir administered without ribavirin for 12 weeks achie-ved an SVR12 rate of 100%. SVR12 was lower (94%) when this new regimen was administered with ribavirin for 12 weeks and without ribavirin for 16 weeks. Therefore, 12 weeks of this triple-therapy regimen, without ribavirin, in treatment-naive or treatment-experienced genotype 3 patients with cirrhosis was effective. However, it would be difficult to administer this regimen at present because it is not currently approved for this indication, and costs would be high.
Renal Impairment
Gane and colleagues evaluated patients with HCV and renal impairment in the EXPEDITION-IV trial.4 Treatment consisted of 12 weeks of
glecaprevir and pibrentasvir, without rib-avirin. The study enrolled 104 patients and included genotypes 1 through 6. Most patients had genotypes 1 (n=54), 2 (n=17), 3 (n=11), or 4 (n=20). Genotypes 5 and 6 were represented by 1 patient each. This open-label, single-arm study enrolled patients with severe renal insufficiency or who were on dialysis. Among the 88% of patients with stage 5 chronic kidney disease, most were receiving dialysis. The remaining 12% of patients had stage 4 chronic kidney disease. Cirrhosis was reported in 20% of patients, and 42% were treatment-experienced. In this challenging patient population, 98% achieved an SVR12. Among the 2 patients who did not, 1 patient died from massive intracerebral hemorrhage secondary to uncontrolled hypertension, and 1 patient discontinued treatment for nonvirologic reasons. The per-protocol SVR12 rate was 100%. This important study suggests that glecaprevir and pibrentasvir will be highly effective in patients with renal failure.
Patients Who Did Not Respond to Previous DAA Therapy
The POLARIS-1 trial evaluated the new combination of sofosbuvir/velpatasvir/voxilaprevir in patients who were not cured by previous treatment with a DAA regimen that included an NS5A inhibitor, such as sofosbuvir/ledipasvir, sofosbuvir/daclatasvir, or ombitasvir/paritaprevir/ritonavir with dasabuvir.5 Patients could have genotypes 1 through 6, with or without cirrhosis. There were 150 patients with genotype 1, 5 with genotype 2, 78 with genotype 3, 22 with genotype 4, 1 with genotype 5, and 6 with genotype 6. In 1 patient, the genotype was unknown. This large trial is one of few with a placebo arm. Patients with genotype 1 were randomly assigned to receive 12 weeks of sofosbuvir/velpatasvir/voxilaprevir (n=150) or 12 weeks of placebo (n=152). The other 113 non–genotype 1 patients were assigned to the open-label treatment arm. Overall, the SVR12 rate was 96% in the treatment group. Among the 10 patients who did not achieve an SVR12, 7 relapsed and 3 had nonvirologic reasons for the failure. SVR12 was 97% in genotype 1 patients and 95% in genotype 3 patients. Among patients without cirrhosis, SVR12 was 99% overall and 100% in the per-protocol analysis. In cirrhotic patients, SVR12 was 93% overall. These data are very encouraging for patients not cured by initial DAA therapy, and the regimen should be available in mid to late 2017.
The POLARIS-4 trial evaluated the same regimen, but in patients who had failed a DAA regimen that did not include an NS5A inhibitor.6 For example, patients could have received treatment with sofosbuvir and simeprevir (a protease inhibitor). Although patients with genotypes 1 through 6 were eligible, no patients with genotypes 5 or 6 enrolled. The study included 333 patients. They received treatment either with 12 weeks of sofosbuvir/velpatasvir/voxilaprevir or with the currently approved regimen sofosbuvir/velpatasvir. The SVR12 rate was 97% among the patients treated with sofosbuvir/velpatasvir/voxilaprevir (n=182) vs 90% in the patients treated with sofosbuvir/velpatasvir (n=151). Among patients with cirrhosis, SVR12 was 96% in those receiving sofosbuvir/velpatasvir/voxilaprevir (n=84) vs 86% in those receiving sofosbuvir/velpatasvir (n=69). These are promising data in patients who failed a DAA regimen without an NS5A inhibitor.
Wyles and coworkers evaluated another novel treatment in patients not cured by DAA therapy.7 The regimen consisted of grazoprevir plus 2 new therapies: an NS5A inhibitor known as ruzasvir and a polymerase inhibitor called MK-3682. This triple-therapy regimen has agents from each of the 3 classes of DAAs. Patients did or did not have cirrhosis. The 93 patients were assigned to 1 of 2 arms: triple therapy with ribavirin for 16 weeks or triple therapy without ribavirin for 24 weeks.
This preliminary report provided rates of SVR8, which was 98% in the 44 patients who received triple therapy plus ribavirin for 16 weeks vs 100% in the 30 patients who received triple therapy without ribavirin for 24 weeks. Therefore, the addition of ribavirin was not beneficial, and 16 weeks of treatment was no worse than 24 weeks. This study showed that this new triple-therapy regimen for 16 weeks, without ribavirin, was very effective in patients who have failed an initial course of DAA therapy.
New Regimens
Shorter Duration of Therapy
Zeuzem and colleagues presented results from the ENDURANCE-1 trial, which evaluated 8 weeks of glecaprevir and pibrentasvir in genotype 1 patients without cirrhosis.8 Patients could be treatment-naive or treatment-experienced. Patients with human immunodeficiency virus (HIV) coinfection were eligible. This large trial enrolled 703 patients, including 4% to 5% with HIV. Overall, slightly less than 10% had stage 2 fibrosis, and slightly less than 10% had stage 3 fibrosis. The study compared treatment durations of 8 weeks (n=352) vs 12 weeks (n=351). The cure rate was over 99%. Among the 4 patients who did not achieve an SVR12, 3 were lost to follow-up or discontinued for nonvirologic reasons. Only 1 patient (genotype 1a and treatment-experienced) of 703 was considered to have relapsed. The cure rates were over 99% in the intent-to-treat group and over 99% per protocol. This study, therefore, showed extremely impressive rates of SVR12 with only 8 weeks of therapy in noncirrhotic, genotype 1 patients, regardless of whether they had received previous treatment, had HIV coinfection, or had stage 2 or stage 3 fibrosis.
Jacobson and coworkers presented the POLARIS-2 trial, which compared 8 weeks of sofosbuvir/velpatasvir/voxilaprevir vs 12 weeks of sofosbuvir/velpatasvir in genotype 1 through 6 patients with or without cirrhosis.9 This study enrolled 941 patients to determine whether the new regimen was noninferior to the existing regimen. SVR12 was 95% with sofosbuvir/velpatasvir/voxilaprevir for 8 weeks vs 98% with sofosbuvir/velpatasvir for 12 weeks. Therefore, the new treatment was not noninferior to the existing treatment. The higher relapse rate in the sofosbuvir/velpatasvir/voxilaprevir arm was largely due to more relapses in genotype 1a patients. Among patients without cirrhosis, SVR12 was 96% for the 8-week arm vs 98% for the 12-week arm. The difference was large among patients with cirrhosis, at 91% in the 8-week arm and 99% in the 12-week arm.
It appears, therefore, that 8 weeks of sofosbuvir/velpatasvir/voxilaprevir cannot replace the current 12-week regimen of sofosbuvir/velpatasvir. In patients without cirrhosis, it may be possible to shorten therapy to 8 weeks. For patients with cirrhosis, however, the current treatment regimen of sofosbuvir/velpatasvir for 12 weeks is superior to the 8-week triple regimen.
A study presented by Lawitz and coworkers evaluated a triple regimen consisting of grazoprevir, the new NS5A inhibitor ruzasvir, and the new polymerase inhibitor MK-3682, with or without ribavirin.10 The study enrolled 664 patients with genotypes 1, 2, or 3. Genotype 1 and 2 patients were treatment-naive, and patients with genotype 3 could be treatment-naive or treatment-experienced. HCV genotype 1 patients were randomly assigned to receive triple therapy without ribavirin for 8 or 12 weeks. Patients with genotypes 2 or 3 were randomized to receive triple therapy with or without ribavirin for 8 or 12 weeks. The study found that the SVR rates for 12 weeks were 97% or higher. Ribavirin was unnecessary with this triple regimen. SVR12 for 8 weeks of treatment ranged from 86% to 98%. Among the patients who received 16 weeks of treatment, SVR12 was 100% for those with genotype 2 and 96% for those with genotype 3. The results from this study suggested that it is not possible to reduce treatment to 8 weeks; rather, 12 weeks is the optimal duration for this triple regimen.
Real-Life Analyses
There were several real-world analyses presented at The Liver Meeting, and the one by Sundaram and colleagues was among the most important.11 A major question for practitioners who care for patients with chronic HCV is whether the 8-week regimen of sofosbuvir/ledipasvir will be as efficacious in real-life as it was in the pivotal ION-3 trial.12 This clinical trial showed that 8 weeks of sofosbuvir/ledipasvir was effective in genotype 1 patients who were treatment-naive, did not have cirrhosis, and had a baseline viral load of less than 6,000,000 IU/mL. Some practitioners have worried, however, that perhaps 12 weeks is better than 8 weeks in real life. The study by Sundaram included 2 different analyses. The primary analysis was performed in 798 patients from various databases who had received 8 weeks of sofosbuvir and ledipasvir. The study confirmed that these patients were appropriate candidates for the 8-week therapy, and the cure rate was 98%; 786 of the 798 patients achieved an SVR12. These rates are similar to those observed in the ION-3 trial.12 The study was unable to identify any factors predictive of treatment failure, including characteristics such as genotype 1a or 1b, stage of fibrosis, HIV status, age, and race. The secondary analysis of the study examined a more robust number of databases, which included more than 5600 patients, to identify any differences in outcome for patients treated for 12 weeks vs 8 weeks. The study found no differences; SVR12 was 96% in the 8-week treatment arm and 97% in the 12-week treatment arm. The study suggests that 8 weeks of therapy should suffice in appropriately chosen patients.
Conclusion
The 2016 AASLD Liver Meeting featured HCV presentations confirming that an 8-week regimen of sofosbuvir and ledipasvir is effective in appropriately selected patients—those who are treatment-naive, without cirrhosis, and with a baseline viral load of less than 6,000,000 IU/mL—in a real-life setting. Furthermore, many studies presented data on new DAA regimens that seek to improve features of the current approaches. In particular, additional regimens are forthcoming that will not require ribavirin. Eight-week regimens may be available for an expanded group of patients. Encouraging data were also presented for new regimens administered to HCV patients with renal failure, those with genotype 3, and those who had previously failed DAA regimens. HCV therapy continues to be refined, and populations of patients that represent unmet medical needs are being addressed.
Disclosure
Dr Flamm has performed research for Gilead, AbbVie, and BMS. He is a consultant for Gilead, AbbVie, BMS, and Merck.
References
1. Wyles DL, Poordad F, Wang S, et al. SURVEYOR-II, part 3: efficacy and safety of ABT-493/ABT-530 in patients with hepatitis C virus genotype 3 infection with prior treatment experience and/or cirrhosis [AASLD abstract 113]. Hepatology. 2016;64(suppl 1):62A.
2. Foster GR, Thompson A, Ruane PJ, et al. A randomized phase 3 trial of sofosbuvir/velpatasvir/voxilaprevir for 8 weeks and sofosbuvir/velpatasvir for 12 weeks for patients with genotype 3 HCV infection and cirrhosis: the POLARIS-3 study [AASLD abstract 258]. Hepatology. 2016;64(suppl 1):125A.
3. Foster GR, Agarwal K, Cramp M, et al. C-ISLE: grazoprevir/elbasvir plus sofosbuvir in treatment-naïve and treatment-experienced HCV GT3 cirrhotic patients treated for 8, 12 or 16 weeks [AASLD abstract 74]. Hepatology. 2016;64(suppl 1):39A.
4. Gane E, Lawitz E, Pugatch D, et al. EXPEDITION-IV: safety and efficacy of GLE/PIB in adults with renal impairment and chronic hepatitis C virus genotype 1 – 6 infection [AASLD abstract LB-11]. Hepatology. 2016;64(suppl 1):1125A.
5. Bourlière M, Gordon SC, Ramji A, et al. Sofosbuvir/
velpatasvir/voxilaprevir for 12 weeks as a salvage regi-men in NS5A inhibitor-experienced patients with geno-type 1-6 infection: the phase 3 POLARIS-1 study [AASLD abstract 194]. Hepatology. 2016;64(suppl 1):102A.
6. Zeuzem S, Flamm SL, Tong M, et al. A randomized, controlled, phase 3 trial of sofosbuvir/velpatasvir/voxilaprevir or sofosbuvir/velpatasvir for 12 weeks in direct acting antiviral experienced patients with genotype 1-6 HCV infection: the POLARIS-4 study [AASLD abstract 109]. Hepatology. 2016;64(suppl 1):59A
7. Wyles D, Wedemeyer H, Reddy KR, et al. Safety and efficacy of the fixed-dose combination regimen of MK-3682/grazoprevir/MK-8408 in cirrhotic or non-cirrhotic patients with chronic HCV GT1 infection who previously failed a direct-acting antiviral regimen (C-SURGE) [AASLD abstract 193]. Hepatology. 2016;64(suppl 1):101A.
8. Zeuzem S, Feld J, Wang S, et al. ENDURANCE-1: efficacy and safety of 8- versus 12-week treatment with ABT-493/ABT-530 in patients with chronic HCV genotype 1 infection [AASLD abstract 253]. Hepatology. 2016;64(suppl 1).
9. Jacobson IM, Asselah T, Nahass R, et al. A randomized phase 3 trial of sofosbuvir/velpatasvir/voxilaprevir for 8 weeks compared to sofosbuvir/velpatasvir for 12 weeks in DAA-naive genotype 1-6 HCV-infected patients: the POLARIS-2 study [AASLD abstract LB-12]. Hepatology. 2016;64(suppl 1):1126A.
10. Lawitz E, Yoshida EM, Buti M, et al. Safety and efficacy of the fixed-dose combination regimen of MK-3682/grazoprevir/MK-8408 with or without ribavirin in non-cirrhotic or cirrhotic patients with chronic HCV GT1, 2 or 3 infection (part B of C-CREST-1 & 2) [AASLD abstract 110]. Hepatology. 2016;64(suppl 1):60A.
11. Sundaram V, Jeon CY, Qureshi K, et al. Eight weeks treatment duration with ledipasvir/sofosbuvir (LDV/SOF) is effective for appropriately selected patients with genotype 1 hepatitis C virus (HCV) infection: an analysis of multiple real world cohorts totaling >6,500 patients [AASLD abstract LB-16]. Hepatology. 2016;64(suppl 6):1129A.
12. Kowdley KV, Gordon SC, Reddy KR, et al; ION-3 Investigators. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med. 2014;370(20):1879-1888.