A Review of Selected Presentations From the 2017 AASLD Liver Meeting • October 20-24, 2017 • Washington, DC
Efficacy, Safety, and Pharmacokinetics of Glecaprevir/Pibrentasvir in Adults With Chronic Genotype 1-6 Hepatitis C Virus Infection and Compensated Cirrhosis: An Integrated Analysis
Dr Edward Gane and colleagues presented results from an integrated analysis of the efficacy, safety, and pharmacokinetics of the newly approved fixed-dose oral combination agent glecaprevir/pibrentasvir.1 Both agents are direct-acting antivirals (DAAs) targeting nonstructural (NS) proteins. Glecaprevir is a pangenotypic NS3/4A protease inhibitor, and pibrentasvir is a pangenotypic NS5A inhibitor.2 The glecaprevir/pibrentasvir combination is potent against several common polymorphisms found in hepatitis C virus (HCV), including Y93H in NS5A and Q80K in NS3.3,4 In 2017, the US Food and Drug Administration (FDA) approved glecaprevir/pibrentasvir for treatment-naive adult patients with HCV genotype 1 to 6 infection.2 An 8-week duration is approved for patients without cirrhosis, and a 12-week duration is approved for those with compensated cirrhosis
In phase 2 and 3 clinical trials, glecaprevir/pibrentasvir demonstrated an overall rate of sustained virologic response at 12 weeks (SVR12) of 98% in patients with HCV genotype 1 to 6.2 The safety profile in these studies indicated that glecaprevir/pibrentasvir was well-tolerated regardless of baseline factors, such as the presence of compensated cirrhosis or advanced renal disease.
The phase 3 EXPEDITION-1 trial was part of a clinical development program that evaluated a 12-week duration of treatment with glecaprevir/pibrentasvir in patients with HCV genotype 1, 2, 4, 5, or 6 infection and compensated cirrhosis. (Patients with genotype 3 HCV infection and compensated cirrhosis were enrolled in a separate trial.) This study demonstrated an SVR12 rate of 99%.5
The integrated analysis presented by Dr Gane evaluated the efficacy, safety, and pharmacokinetic profiles of treatment with glecaprevir/pibren-tasvir in patients with chronic HCV genotype 1 to 6 infection and compensated cirrhosis. The analysis included 308 patients enrolled in 4 open-label, phase 2 and 3 trials: EXPEDITION-1, EXPEDITION-4, SURVEYOR-II, and MAGELLAN-1. Glecaprevir/pibrentasvir was administered for 12 weeks in 245 patients and for 16 weeks in 63 patients. The primary efficacy endpoint was SVR12, which was assessed in the intent-to-treat population. An additional efficacy assessment was SVR12 in the modified intent-to-treat population, which excluded nonvirologic treatment failures.
Most patients were male (65%) and white (85%). The median age was 58.5 years (range, 26-88 years). All 6 HCV genotypes were represented; 40% of patients had genotype 1, 12% had genotype 2, 38% had genotype 3, 7% had genotype 4, 1% had genotype 5, and 2% had genotype 6. All patients were required to have compensated cirrhosis. The analysis excluded patients coinfected with HIV-1 or hepatitis B virus. Patients were either treatment-naive (59%) or had previously received antiviral therapy. Previous treatments could include interferon or pegylated interferon with or without ribavirin, sofosbuvir plus ribavirin with or without pegylated interferon, and HCV NS5A or protease inhibitors. Cirrhosis was confirmed at screening by 1 of 3 methods: a FibroTest score of 0.75 or higher plus a ratio of aspartate aminotransferase (AST) to platelets exceeding 2, a FibroScan score of 14.6 kPa or higher, or a liver biopsy. Most patients had a Child-Pugh score of 5 (86%) or 6 (13%), with no current or past clinical evidence of liver decompensation. The median HCV RNA level at baseline was 6.2 IU/mL. Approximately one-quarter of patients (23%) had low platelet counts (<100 × 109/L), and 7% had a low albumin level of less than 3.5 g/dL.
The rate of SVR12 in the intent-to-treat population was 96% across all HCV genotypes. Rates were 94% in patients with genotype 1, 97% in genotype 3, and 100% in genotype 2, 4, 5, and 6 (Figure 1). Treatment failed in 11 patients, owing to breakthrough (n=5), relapse (n=3), or treatment discontinuation (n=1). (The data were missing for the remaining 2 patients.) Five cases of treatment failure were attributed to viral breakthrough. Four of these patients had HCV genotype 1
and had been treated unsuccessfully with an NS5A regimen (2 of these patients had also received a protease inhibitor). The remaining case of treatment failure owing to viral breakthrough occurred in a patient with HCV genotype 3 who had previously failed treatment with pegylated interferon plus ribavirin.
The SVR12 rate in the modi-fied intent-to-treat population (which exclu-ded cases of nonvirologic treatment failures) was 97% overall. These rates were 96% in patients with genotype 1, 97% in patients with genotype 3, and 100% across the other genotypes (Figure 2).
A treatment-emergent adverse event was reported in 76% of patients overall; the majority of these events were mild or moderate. The most frequent adverse events were fatigue (19%), headache (16%), and nausea (10%). Serious adverse events occurred in 9% of patients; however, none were considered related to the study drug. Two patients discontinued treatment owing to adverse events: 1 patient with pruritus and 1 patient with diarrhea.
Two patients died after treatment, and both cases were deemed unrelated to the study drug. Additionally, 2 cases of treatment-emergent hepatocellular carcinoma (HCC) were reported, and 1 patient experienced adverse events that were consistent with hepatic decompensation.
There were no cases of alanine transaminase (ALT) or AST elevations that reached grade 3 or higher in severity. An elevation of total bilirubin reached grade 3 or higher in 3 patients (1%). These elevations were characterized as transient, asymptomatic, and predominantly indirect. The study investigators also noted that the elevations in total bilirubin levels were consistent with the known inhibition of bilirubin metabolism and/or transporters attributed to glecaprevir. Bilirubin elevations were not associated with ALT elevation or a worsening of hepatic function or hepatic failure, and they resolved without discontinuation of treatment.
An analysis of pharmacokinetic parameters showed that cirrhosis status impacted expo-sure to glecaprevir/pibrentasvir. Among the 308 patients with com-pensated cirrhosis included in this integrated analysis, glecaprevir exposure was approximately 2.2-fold higher than in 2056 patients without cirrhosis enrolled in other clinical trials. Despite this increased exposure, the frequency and severity of adverse events were similar in patients with or without cirrhosis. In contrast, pibrentasvir exposure was similar between the 2 patient groups.
The authors of this integrated analysis concluded that the results supported a high efficacy and favorable safety profile for glecaprevir/pibrentasvir in HCV patients with genotype 1 to 6 and compensated cirrhosis. They noted that the glecaprevir/pibrentasvir fixed-dose combination was well-tolerated, with no serious adverse events related to the study drug.
1. Gane EJ, Poordad F, Zadeikis N, et al. Efficacy, safety, and pharmacokinetics of glecaprevir/pibrentasvir in adults with chronic genotype 1-6 hepatitis C virus infection and compensated cirrhosis: an integrated analysis [AASLD Liver Meeting abstract 74]. Hepatology. 2017;66(S1).
2. Mavyret [package insert]. North Chicago, IL: AbbVie, Inc; 2017.
3. Ng TI, Krishnan P, Pilot-Matias T, et al. In vitro antiviral activity and resistance profile of the next-generation hepatitis C virus NS5A inhibitor pibrentasvir. Antimicrob Agents Chemother. 2017;61(5):e02558-e16.
4. Ng T, Reisch T, Middleton T, et al. ABT-493, a potent HCV NS3/4A protease inhibitor with broad genotypic coverage. Abstract presented at: the 21st Annual Conference on Retroviruses and Opportunistic Infections; March 3-6, 2014; Boston, MA.
5. Forns X, Lee SS, Valdes J, et al. Glecaprevir plus pibrentasvir for chronic hepatitis C virus genotype 1, 2, 4, 5, or 6 infection in adults with compensated cirrhosis (EXPEDITION-1): a single-arm, open-label, multicentre phase 3 trial. Lancet Infect Dis. 2017;17(10):1062-1068.
Hepatitis C Virus Reinfection and Injecting Risk Behavior Following Elbasvir/Grazoprevir Treatment in Participants on Opiate Agonist Therapy: Co-STAR Part B
Dr Gregory Dore and coworkers reported data from the Co-STAR Part B study, which evaluated HCV reinfection and injecting risk behavior after treatment with elbasvir/grazopre-vir among patients receiving opiate agonist therapy.1 Elbasvir/grazoprevir is a fixed-dose combination tablet administered orally once daily. It is approved by the FDA for the treatment of adults infected with HCV genotype 1 or 4.2
Elbasvir is an inhibitor of NS5A, and grazoprevir is an NS3/4A protease inhibitor.2 In vitro studies have previously demonstrated that this treatment has activity against multiple clinically relevant resistance-associated substitutions, including first-generation protease inhibitor variants and variants associated with daclatasvir and ledipasvir treatment failures.3-5 In clinical studies, elbasvir/grazoprevir was shown to be efficacious in both treatment-naive and previously treated patients, regardless of whether they had concomitant cirrhosis or HIV coinfection.6-10 The safety and efficacy of elbasvir/grazoprevir have been demonstrated in special populations of HCV-infected patients, including those with stage 4 or 5 chronic kidney disease or inherited blood disorders.7,10
The phase 3 randomized Co-STAR study evaluated the efficacy and safety of a 12-week regimen of elbasvir/grazoprevir among patients who inject drugs and were receiving opiate agonist therapy. The study recruited participants infected with HCV genotype 1, 4, or 6, and who had been receiving opiate agonist therapy for at least 3 months. Coinfection with HIV was allowed.
In the first phase of the study (part A), 301 patients were randomly assigned to 1 of 2 arms: an immediate-treatment arm (n=201), in which patients received elbasvir/grazoprevir for the first 12 weeks of the study; and a deferred-treatment arm (n=100), in which patients received placebo for the first 12 weeks. After week 12, the treatments in each arm were unblinded for 4 weeks. Participants in the deferred-treatment arm then went on to receive 12 weeks of elbasvir/grazoprevir. The full analysis set included data for patients who experienced nonvirologic failures of treatment, and it categorized cases of reinfection as failures. The SVR12 rate was 90.9% in the
combined treatment arms. The modified analysis set, which excluded 10 nonvirologic failures and categorized cases of reinfection as successes, showed an SVR12 of 95.8% in the combined treatment arms.
The report from Dr Dore provided interim results from part B of the study, which is ongoing. The analysis included a 3-year observational follow-up portion open to all participants who had received at least 1 dose of elbasvir/grazoprevir in part A. Assessments were performed every 6 months and included HCV RNA levels and urine drug screens. A behavioral questionnaire that included questions about drug use was administered to patients at each assessment. A total of 199 patients participated in Co-STAR part B. At the time of the interim analysis, follow-up was 6 months in 192 patients, 12 months in 179, 18 months in 173, and 24 months in 118.
The median age of the patients in part B was 48.6 years (range, 24-66 years) vs 44.1 years (range, 23-64 years) in the patients who did not enroll. In part B, most patients had HCV genotype 1, with 72% having 1a and 20% having 1b. Among participants who did not enroll in part B, genotype 1a accounted for 84% and genotype 1b for 5%. The remaining baseline characteristics were similar between the 2 groups. Most patients were male (76%) and white (79%). The rate of HIV-1 coinfection was 8%, and cirrhosis was present in 22%.
The incidence of ongoing risky behavior remained stable throughout part B. At the time of enrollment into part A, 59% of patients had a positive urine drug screen. The rate of positive drug screening at the time of enrollment into part B was 60%, and remained steady during follow-up at 6 months (59%), 12 months (62%), 18 months (59%), and 24 months (60%). Throughout follow-up, most positive urine drug screens were caused by the use of opioids (21% to 27%), benzodiazepines (21% to 24%), and cannabinoids (28% to 32%). Cocaine use (11% to 20%) and amphetamine use (2% to 8%) were less prevalent. Noninjecting drug use accounted for the majority of reported drug use throughout the follow-up period, with 39% of participants reporting noninjecting drug use during the previous month at the 6-month follow-up, and 40% reporting the same at the 24-month follow-up (Figure 3). Fewer participants reported injecting drug use during the previous month (21% at the 6-month follow-up, decreasing to 12% by the 24-month follow-up).
Ten cases of reinfection were reported from the end of treatment through 24 months of follow-up, which equated to 2.3 reinfections per 100 person-years (95% CI, 1.1-4.3). Among these, only 7 cases were found to be persistent, equating to 1.6 reinfections per 100 person-years (95% CI, 0.7-3.4). HCV RNA levels became detectable in these 7 participants during a wide range of follow-up periods, from week 9 to week 124, and subsequently persisted. Spontaneous clearance of reinfection was observed in the other 3 cases. HCV RNA levels became detectable at week 21 in 2 participants and at week 20 in 1 participant. Subsequently, HCV RNA levels became undetectable again at week 36 for 1 participant and at week 24 for the other 2 participants.
The use of injected drugs during follow-up seemed to be associated with an increased risk of reinfection. For example, among the 74 participants (37%) who self-reported injection drug use at any time during follow-up, the rate of reinfection was 4.2 per 100 person-years (95% CI, 1.5-9.2). In contrast, among the 125 participants (63%) who did not self-report injection drug use at any time during the follow-up, the rate of reinfection was 0.4 per 100 person-years (95% CI, 0-2.3).
Dr Dore and colleagues concluded that HCV reinfection was uncommon after treatment with elbasvir/grazoprevir among patients receiving opiate agonist therapy. Results from an interim analysis suggested that ongoing injection drug use may be a risk factor for reinfection. However, even among patients who self-reported injection drug use, reinfection rates remained low.
1. Dore G, Grebely J, Altice F, et al. Hepatitis C virus (HCV) reinfection and injecting risk behavior following elbasvir (EBR)/grazoprevir (GZR) treatment in participants on opiate agonist therapy (OAT): Co-STAR part B [AASLD Liver Meeting abstract 195]. Hepatology. 2017;66(S1).
2. Zepatier [package insert]. Whitehouse Station, NJ: Merck & Co, Inc; 2017.
3. Summa V, Ludmerer SW, McCauley JA, et al. MK-5172, a selective inhibitor of hepatitis C virus NS3/4a protease with broad activity across genotypes and resistant variants. Antimicrob Agents Chemother. 2012;56(8):4161-4167.
4. Coburn CA, Meinke PT, Chang W, et al. Discovery of MK-8742: an HCV NS5A inhibitor with broad genotype activity. ChemMedChem. 2013;8:1930-1940.
5. Lahser F, Liu R, Bystol K, et al. A combination containing MK-5172 (HCV NS3 protease inhibitor) and MK-8742 (HCV NS5A inhibitor) demonstrates high barrier to resistance in vitro in HCV replicons [AASLD Liver Meeting abstract 236A]. Hepatology. 2012;56(suppl S1).
6. Kwo P, Gane EJ, Peng CY, et al. Effectiveness of elbasvir and grazoprevir combination, with or without ribavirin, for treatment-experienced patients with chronic hepatitis C infection. Gastroenterology. 2017;152(1):164-175.e4.
7. Roth D, Nelson DR, Bruchfeld A, et al. Grazoprevir plus elbasvir in treatment-naive and treatment-experienced patients with hepatitis C virus genotype 1
infection and stage 4-5 chronic kidney disease (the C-SURFER study): a combination phase 3 study. Lancet. 2015;386(10003):1537-1545.
8. Rockstroh JK, Nelson M, Katlama C, et al. Efficacy and safety of grazoprevir (MK-5172) and elbasvir (MK-8742) in patients with hepatitis C virus and HIV co-infection (C-EDGE CO-INFECTION): a non-randomised, open-label trial. Lancet HIV. 2015;2(8):e319-e327.
9. Zeuzem S, Ghalib R, Reddy KR, et al. Grazoprevir-elbasvir combination therapy for treatment-naïve cirrhotic and noncirrhotic patients with chronic hepatitis C virus genotype 1, 4, or 6 infection: a randomized trial. Ann Intern Med. 2015;163:1-13.
10. Hézode C, Colombo M, Bourlière M, et al; C-EDGE IBLD Study Investigators. Elbasvir/grazoprevir for patients with hepatitis C virus infection and inherited blood disorders: a phase III study. Hepatology. 2017;66(3):736-745.
Efficacy and Safety of Glecaprevir/Pibrentasvir for 8 or 12 Weeks in Treatment-Naive Patients With Chronic HCV Genotype 3: An Integrated Phase 2/3 Analysis
Dr Steven Flamm and colleagues reported the results of an integrated analysis of glecaprevir/pibrentasvir.1 This study focused on the efficacy and safety of glecaprevir/pibrentasvir in treatment-naive patients infected with HCV genotype 3 who had compensated liver disease (with or without cirrhosis).
HCV genotype 3 is more difficult to treat than the other genotypes. DAA therapies have reduced rates of SVR in patients infected with this genotype. Until recently, guidelines from the American Association for the Study of Liver Diseases (AASLD) recommended regimens of sofosbuvir plus daclatasvir for 24 or 12 weeks (for patients with or without cirrhosis, respectively) or sofosbuvir/velpatasvir for 12 weeks (regardless of cirrhosis status) for treatment-naive patients with HCV genotype 3. These guidelines were updated to reflect the 2017 FDA approval of glecaprevir/pibrentasvir, which is indicated in treatment-naive patients infected with HCV genotype 1 to 6.2 Guidelines from the AASLD recommend an 8-week regimen of glecaprevir/pibrentasvir for patients without cirrhosis, and a 12-week regimen for patients with compensated cirrhosis. The guidelines also state that patients treated with glecaprevir/pibrentasvir can forgo testing for resistance-associated substitutions and skip concomitant administration with ribavirin.3
The integrated analysis included 571 patients enrolled in 7 phase 2 and 3 clinical trials. Among the 502 patients without cirrhosis, 208 were treated with glecaprevir/pibrentasvir for 8 weeks, and 294 were treated for 12 weeks. A total of 69 patients with cirrhosis received treatment with glecaprevir/pibrentasvir for 12 weeks.
Eligibility criteria for the analysis included chronic HCV infection with genotype 3. Coinfection with hepatitis B, but not HIV-1, was permitted. Patients were required to be treatment-naive, either with or without compensated cirrhosis (Child-Pugh class A). The analysis also included patients with chronic kidney disease (stage 4 or 5) or who had previously received a liver or kidney transplant.
The primary efficacy endpoint, SVR12, was assessed in the intent-to-treat population, which included all patients who had received at least 1 dose of the study drug. Additional efficacy assessments were SVR12, both overall and by patient subgroup, in the modified intent-to-treat population (which excluded nonvirologic treatment failures), and rates of on-treatment virologic failure and virologic relapse.
Overall, baseline characteristics were similar in the different treatment groups. Among the 208 patients without cirrhosis who received 8 weeks of gle-caprevir/pibrentasvir treatment, 59% were male and 87% were white. The median age was 46 years (range, 20-76 years). Among the 294 patients without cirrhosis who were treated with 12 weeks of glecaprevir/pibrentasvir, 57% were male and 88% were white. The median age was 49 years (range, 22-71 years). Although 11% of the 8-week treatment group had HIV-1 coinfection, none of the patients in the 12-week treatment group were co-infected with HIV-1. None of the patients in the 8-week group had chronic kidney disease or were post-transplant; in contrast, 4% of the 12-week group had chronic kidney disease and 8% were post-transplant. In the group of 69 patients with cirrhosis, 59% were male, 93% were white, and the median patient age was slightly older (56 years; range, 35-70 years). In this group, 6% were coinfected with HIV-1, 2% had chronic kidney disease, and none had undergone transplant.
Polymorphisms at baseline were found primarily in NS5A. Among patients without cirrhosis who were treated for 8 weeks, no patients had an NS3-only polymorphism, 28% had an NS5A-only polymorphism (10% with A30K and 6% with Y93H mutations), and 1% had polymorphisms in both. Among patients without cirrhosis who were treated for 12 weeks, 1% had an NS3-only polymorphism, 17% had an NS5A-only polymorphism (7% with A30K and 7% with Y93H mutations), and 1% had polymorphisms in both. In the group of patients with cirrhosis, 4% had an NS3-only polymorphism, and 19% had an NS5A-only polymorphism (3% with A30K and 10% with Y93H mutations). No patients had both polymorphisms.
In the intent-to-treat analysis of all patients who had received at least 1 dose of glecaprevir/pibrentasvir, the SVR12 rates were 95% in patients without cirrhosis (treated for 8 or 12 weeks) and 97% in patients with cirrhosis. The modified intent-to-treat analysis, which excluded patients with nonvirologic treatment failures, showed an SVR12 rate of 98% for patients without cirrhosis treated for 8 weeks, 99% for patients without cirrhosis treated for 12 weeks, and 100% for patients with cirrhosis treated for 12 weeks.
When the modified intent-to-treat analysis was performed according to patient characteristics in the non-cirrhosis arm, no statistically significant differences were noted between the 8-week and 12-week treatment groups for any subgroup (Figure 4). The SVR12 rate was 100% for patients of black race in both the 8-week and 12-week treatment groups. The degree of fibrosis did not significantly affect the SVR12 rate. Among patients with F0 to F2 fibrosis, 98% achieved SVR12 in both the 8-week and 12-week treatment groups. Among patients with F3 fibrosis, 94% achieved SVR12 in the 8-week group and 100% achieved SVR12 in the 12-week group. For patients receiving opioid substitution therapy, SVR12 was reported in 100% of the 8-week group and 98% of the 12-week group. Recent drug use did not affect the SVR12 rate in the 8-week group (100%) or the 12-week group (94%), nor did history of intravenous drug use (SVR12 of 98% in both the 8-week and 12-week groups).
Viral characteristics also did not significantly impact the SVR12 rates in the 8-week vs 12-week treatment groups for patients without cirrhosis. A similar SVR12 rate was achieved in the 8-week and 12-week treatment groups for patients with a baseline HCV RNA level of less than 800,000 IU/mL (99% vs 100%) or 800,000 IU/mL or higher (97% vs 98%). Additionally, the presence or absence of polymorphisms at baseline had no effect. Among patients with no baseline polymorphisms, the SVR12 rate was 99%, regardless of treatment duration. The SVR12 rates in the 8-week vs 12-week treatment groups were 95% vs 94% for those with a baseline NS5A polymorphism, 84% vs 94% for those with the A30K mutation, and 100% vs 90% for those with the Y93H mutation.
Overall, adverse events were sim-ilar in the different patient groups treated with glecaprevir/pibrentasvir. Among patients without cirrhosis, an adverse event occurred in 65% of the 8-week treatment group and 77% of the 12-week treatment group. Among patients with cirrhosis, 84% experienced an adverse event. In the 3 groups (8-week noncirrhotic group, 12-week non-cirrhotic group, and 12-week group with cirrhosis), the most commonly reported adverse events were headache (19%, 24%, and 19%, respectively), fatigue (14%, 19%, and 10%), and nausea (12%, 13%, and 10%).
Serious adverse events were reported by 1% of patients in the 8-week noncirrhotic group and 3% in the other groups. However, none of these serious adverse events were deemed related to the study drug. Three patients without cirrhosis who were treated with 12 weeks of glecaprevir/pibrentasvir dis-continued treatment owing to an adverse event; only 1 of these cases was deemed by the investigator to be rel-ated to the study drug.
No grade 3 or higher elevations in ALT were reported. A grade 3 or higher AST elevation occurred in 1 patient (who did not have cirrhosis and who was treated with 12 weeks of glecaprevir/pibrentasvir). Additionally, 1 patient in each of the treatment groups experienced a grade 3 or higher increase in total bilirubin level.
The study investigators concluded that the results of this integrated analysis showed high efficacy of glecaprevir/pibrentasvir in treatment-naive patients with chronic HCV genotype 3 infection, regardless of cirrhosis status. Glecaprevir/pibrentasvir was associated with high rates of SVR12. In most cases where SVR12 was not achieved, nonvirologic failure was the reason. Subgroup analyses demonstrated no significant difference in efficacy between 8 weeks and 12 weeks of treatment with glecaprevir/pibrentasvir among these patients with HCV genotype 3 infection.
1. Flamm SL, Wyles DL, Wang S, et al. Efficacy and safety of glecaprevir/pibrentasvir for 8 or 12 weeks in treatment-naive patients with chronic HCV genotype 3: an integrated phase 2/3 analysis [AASLD Liver Meeting abstract 62]. Hepatology. 2017;66(S1).
2. Mavyret [package insert]. North Chicago, IL: AbbVie, Inc; 2017.
3. HCV guidance: recommendations for testing, managing, and treating hepatitis C. The American Association for the Study of Liver Diseases and the Infectious Diseases Society of America. https://www.hcvguidelines.org/sites/default/files/full-guidance-pdf/HCVGuidance_September_21_2017_e.pdf. Updated September 21, 2017. Accessed November 15, 2017.
SOF/VEL/VOX for 12 Weeks in NS5A-Inhibitor–Experienced HCV-Infected Patients: Results of the Deferred Treatment Group in the Phase 3 POLARIS-1 Study
In a poster presentation, Dr Marc Bourlière and colleagues reported on a POLARIS-1 substudy that evaluated treatment with sofosbuvir/velpatasvir/vox-ilaprevir.1 This once-daily, oral single-tablet regimen is indicated for the treatment of adult patients with chronic HCV infection with or without compensated cirrhosis. It was approved by the FDA in November 2017 for patients with HCV genotype 1 to 6 who had previously been treated with an HCV regimen containing an NS5A inhibitor, and in patients with HCV genotype 1a or 3 infection who had previously been treated with an HCV regimen containing sofosbuvir without an NS5A inhibitor.2 This approval was based, in part, on results from the randomized, double-blind POLARIS-1 study, which demonstrated an SVR12 rate of 96% among patients who had previously been treated with an NS5A inhibitor.3 In POLARIS-1, patients infected with HCV genotype 1 at screening were randomly assigned to treatment with sofosbuvir/velpatasvir/voxilaprevir or placebo. Patients with all other HCV genotypes were treated with sofosbuvir/velpatasvir/voxilaprevir. Patients in the placebo arm were then eligible for a deferred treatment substudy, in which they could receive 12 weeks of open-label treatment with sofosbuvir/velpatasvir/voxilaprevir.
A total of 147 patients were enrolled into the substudy, and all completed deferred treatment. In these patients, the mean age was 59 years (range, 29-80 years), 79% were male, and 82% were white. One-third (33%) had cirrhosis. Most patients had HCV genotype 1a (77%) or 1b (20%), and 4 patients had a different HCV genotype. Approximately half of patients (52%) had prior treatment experience with NS5A and NS5B inhibitors; 41% had prior treatment experience with NS5A and NS3 inhibitors (with or without an NS5B inhibitor). At baseline, 41% of patients showed an NS5A-only polymorphism, 41% had both NS3 and NS5A polymorphisms, and 7% had an NS3-only polymorphism. No polymorphisms at baseline were reported in 10% of patients.
The SVR12 rate was 97%. High SVR12 rates were achieved regardless of the HCV genotype. SVR12 rates were 97% in patients with HCV genotype 1 overall, 95% in those with HCV genotype 1a, and 100% in those with HCV genotype 1b. Additionally, SVR12 rates were high regardless of the patient’s prior DAA regimen. SVR12 was 96% in patients with prior exposure to NS5A plus NS5B inhibitors, and 98% in patients with prior exposure to NS5A plus NS3, with or without NS5B inhibitors (Figure 5). SVR12 rates were not affected by baseline polymorphisms; they were 100% in patients with no resistance-associated substitutions vs 97% in patients with any. Among 4 patients who showed virologic failure, 2 had developed treatment-emergent resistance mutations.
An adverse event occurred in 76% of patients. The most common adverse events were fatigue (21%), headache (20%), diarrhea (19%), and nausea (14%). Grade 3 or 4 adverse events occurred in 5% of patients. No patients discontinued treatment because of an adverse event.
1. Bourlière M, Gordon SC, Schiff ER, et al. SOF/VEL/VOX for 12 weeks in NS5A-inhibitor experienced HCV-infected patients: results of the deferred treatment group in the phase 3 POLARIS-1 study [AASLD Liver Meeting abstract 1178]. Hepatology. 2017;66(S1).
2. Vosevi [package insert]. Foster City, CA; Gilead Sciences, Inc; 2017.
3. Bourlière M, Gordon SC, Flamm SL, et al; POLARIS-1 and POLARIS-4 Investigators. Sofosbuvir, velpatasvir, and voxilaprevir for previously treated HCV infection. N Engl J Med. 2017;376(22):2134-2146.
Adherence to Pangenotypic Glecaprevir/Pibrentasvir Treatment and SVR12 in HCV-Infected Patients: An Integrated Analysis of the Phase 2/3 Clinical Trial Program
Dr Ashley Brown and colleagues presented data from an integrated analysis of glecaprevir/pibrentasvir.1 This analysis examined the factors associated with nonadherence to glecaprevir/pibrentasvir, and their impact on SVR12 rates. Previous studies of anti-HCV regimens suggested that adherence to DAA regimens was good overall. There is an association between lower treatment adherence and reduced SVR rates.2 Therefore, this analysis aimed to assess the factors associated with nonadherence to glecaprevir/pibrentasvir.
Data from 2091 patients were pooled from 8 phase 3 clinical trials (ENDURANCE-1, ENDURANCE-2, ENDURANCE-3, ENDURANCE-4, EXPEDITION-1, EXPEDITION-4, SURVEYOR-II, and MAGELLAN-1). All patients were treated with glecaprevir/pibrentasvir. The treatment durations were 8 weeks (n=711), 12 weeks (n=1264), and 18 weeks (n=116). Patients had chronic HCV infection with genotype 1 to 6, either with or without compensated cirrhosis. (Patients with decompensated cirrhosis were excluded.) Patients with HIV-1 coinfection were permitted to enroll in the study, but patients with hepatitis B coinfection were excluded. Both treatment-naive and treatment-experienced patients were enrolled. Previously treated patients had prior exposure to interferon or pegylated interferon with or without ribavirin, or to sofosbuvir plus ribavirin with or without pegylated interferon. Prior treatment experience with protease inhibitors and/or NS5A inhibitors was allowed for patients enrolled in the MAGELLAN-1 study.
The primary study endpoint was SVR12 assessed in the intent-to-treat population. Other efficacy endpoints included SVR12 in the modified intent-to-treat population (this group excluded cases of nonvirologic failures). A multivariable logistic regression model was used to assess the interaction of nonadherence with treatment outcome, controlling for baseline demographic and clinical characteristics. Adherence was measured via pill count. Adherent patients were those who took between 80% to 120% of the assigned pills given at each treatment visit. Accordingly, nonadherent patients were those who took less than 80%, or more than 120%, of the assigned pills in at least 1 of the study visits.
Overall, 89% of patients (1851 of 2091) were adherent to glecaprevir/pibrentasvir at all consecutive treatment intervals. Nonadherence to treatment was reported in 240 patients. Nearly all of these patients (98%) were considered nonadherent because they took less than 80% of the assigned pill count.
Baseline characteristics did not markedly differ between the adherent vs nonadherent groups. In the adherent population, 54% were male and 79% were white. The median age was 54 years (range, 19-84 years). In the nonadherent population, 66% were male and 82% were white. The median age was 53 years (range, 20-88 years). All 6 HCV genotypes were represented in both the adherent and nonadherent groups. In the adherent group, 47% of patients had genotype 1, 19% had genotype 2, 23% had genotype 3, 8% had genotype 4, 1% had genotype 5, and 2% had genotype 6. In the nonadherent group, these rates were 33%, 12%, 44%, 8%, 2%, and 3%, respectively. Most patients were treatment-naive (68% in the adherent group and 72% in the nonadherent group). Approximately three-quarters of patients had fibrosis stage F0 to F2 (77% in the adherent group and 71% in the nonadherent group). Fibrosis stage F3 was reported in 10% of the adherent group and 9% of the nonadherent group.
More patients in the nonadherent group than in the adherent group had compensated cirrhosis (20% vs 13%, respectively), had severe renal impairment or end-stage renal disease (9% vs 4%), or were on opiate substitution therapy (13% vs 6%).
Polypharmacy was reported in 38% of the nonadherent group and 31% of the adherent group. Tobacco use was more common in the nonadherent group vs the adherent group (50% vs 35%). Similar trends were also apparent for current alcohol drinkers (38% vs 32%) and former alcohol drinkers (44% vs 32%). In the nonadherent group, 18% of patients were nondrinkers vs 35% in the adherent group. Among patients in the adherent group, the duration of treatment was 8 weeks in 34%, 12 weeks in 61%, and 16 weeks in 5%. These rates were 34%, 56%, and 10% in the nonadherent group.
Adherence was found to be high at all treatment intervals. It was slightly lower during weeks 0 to 4 (93%) and weeks 12 to 16 (91%; Figure 6). Among 23 independent variables assessed using the multivariable logistic regression model, 6 were significantly associated with nonadherence: alcohol use in drinkers vs nondrinkers (odds ratio [OR], 2.0; 95% CI, 1.3-3.0; P=.002), alcohol use in former drinkers vs nondrinkers (OR, 1.9; 95% CI, 1.2-2.9; P=.005), compensated cirrhosis (OR, 1.6; 95% CI, 1.1-2.3; P=.026), HCV genotype 3 vs genotype 1 (OR, 2.2; 95% CI, 1.5-3.0; P<.001), severe renal impairment (OR, 2.8; 95% CI, 1.6-5.0; P<.001), and tobacco use (OR, 1.5; 95% CI, 1.0-2.2; P=.037; Table 1).
Adherence had no significant impact on SVR12 rates. Adherence rates as low as 50% still correlated with at least a 90% chance of achieving SVR12. In the intent-to-treat population, 98% of patients in the adherent group and 95% of patients in the nonadherent group achieved SVR12. In the modified intent-to-treat population, the SVR12 rate was 99% regardless of whether patients were in the adherent or nonadherent group.
The adverse event profile was similar in patients who were adherent vs nonadherent (overall adverse events reported: 66% vs 73%, respectively). An adverse event leading to discontinuation of treatment was slightly more common in the nonadherent group (2%) vs the adherent group (0.4%).
The study authors concluded that in this integrated analysis of HCV-infected patients treated with the glecaprevir/pibrentasvir regimen for 8, 12, or 16 weeks, overall adherence was high. Importantly, nonadherence did not correlate with lower SVR12 rates, and patients retained an excellent chance (>90%) of achieving SVR12 even with 50% adherence to their prescribed regimen. The investigators noted that these data provide further support for the high SVR rates, regardless of patient characteristics, observed in clinical studies of glecaprevir/pibrentasvir.
1. Brown AS, Welzel TM, Conway B, et al. Adherence to pangenotypic glecaprevir/pibrentasvir treatment and SVR12 in HCV-infected patients: an integrated analysis of the phase 2/3 clinical trial program [AASLD Liver Meeting abstract 198]. Hepatology. 2017;66(S1).
2. Bernstein D, Marinho RT, Cohen DE, et al. Adherence to prescribed doses of ABT-450/r/ombitasvir, dasabuvir, and ribavirin in the phase 3 PEARL-II, PEARL-III, and PEARL-IV trials [AASLD Liver Meeting abstract 1953]. Hepatology. 2014;60(S1).
The C-BREEZE 1 and 2 Studies: Efficacy and Safety of Ruzasvir Plus Uprifosbuvir for 12 Weeks in Adults With Chronic Hepatitis C Virus Genotype 1, 2, 3, 4, or 6 Infection
Dr Eric Lawitz and coworkers reported on data from the C-BREEZE 1 and 2 studies, which evaluated a 2-drug combination of ruzasvir plus uprifosbuvir.1,2 Ruzasvir is a pangenotypic NS5A inhibitor that has shown in vitro activity against resistance-associated substitutions sel-ected by other first-generation NS5A inhibitors. Uprifosbuvir is a pangenotypic NS5B inhibitor shown to have a high barrier to resistance in in vitro studies.
The phase 2 C-BREEZE 1 trial found that uprifosbuvir (450 mg) coadministered with a lower dose of ruzasvir (60 mg) had suboptimal efficacy in patients infected with HCV genotype 3.1 This 12-week, open-label, single-arm study enrolled 160 patients infected with genotype 1 to 6. SVR12 rates were highest in patients with genotype 1, 2, and 4, and efficacy was lowest in patients with genotype 3 and 1a. Prior treatment history did not seem to impact the efficacy of the 2-drug combination. Baseline mutation status, particularly Y93, may have affected the efficacy rate.
The aim of C-BREEZE 2 was to assess the efficacy and safety of uprifosbuvir (450 mg) coadministered with a higher dose of ruzasvir (180 mg).2 C-BREEZE 2 was an open-label, single-arm study with 2 cohorts of patients. The initial cohort consisted of 50 patients who began treatment. After safety was confirmed, a second cohort of 200 patients was enrolled. In both cohorts, treatment was administered for 12 weeks, after which patients underwent a 24-week follow-up period.
The study enrolled patients with HCV genotype 1 to 6. They could be treatment-naive or treatment-experienced. However, the only prior treatment could be interferon; patients with prior DAA exposure were not eligible. Other key eligibility criteria included HCV monoinfection or HIV-1 coinfection. (Hepatitis B coinfection was not allowed.) The HCV RNA viral load was at least 10,000 IU/L. Patients with or without compensated cirrhosis were enrolled, but decompensated liver disease or evidence of HCC was exclusionary. Patients with significant laboratory abnormalities (eg, low platelet levels or a low estimated glomerular filtration rate) were also excluded from the study.
Most patients were male (55%) and white (78%). The mean patient age was 49.5 years. A total of 21% of patients had cirrhosis, and 56% of patients had a baseline viral HCV load exceeding 2,000,000 IU/mL. A small number of patients (16%) had received previous treatment with interferon. All HCV genotypes were represented; 17% of patients had genotype 1a, 11% had genotype 1b, 17% had genotype 2, 22% had genotype 3, 21% had genotype 4, 6% had genotype 5, and 8% had genotype 6.
The primary study endpoint was SVR12. It was assessed in both the full analysis set (all patients who received a minimum of 1 dose of the study drug) and in the modified full analysis set (which excluded patients with nonvirologic failures). The SVR12 rate in the full analysis set reached 90%. This rate improved to 92% in the modified full analysis set. The SVR12 rate was relatively similar across most HCV genotypes, with the exception of genotype 3, in which the SVR12 decreased to 76% in the modified full analysis set (Figure 7). The SVR12 rates (in the modified full analysis set) across the remainder of the HCV genotypes were 91% in genotype 6, 93% in genotype 1a, 96% in genotype 2, and 100% in genotype 1b, 4, and 5.
In the group of patients with genotype 3 infection, the SVR12 rate (in the modified full analysis set) was affected by the presence of cirrhosis (80% in patients without cirrhosis vs 68% in patients with cirrhosis). Additionally, among the genotype 3 patients, the combination treatment showed lower efficacy in those who had resistance-associated substitutions at baseline. SVR12 was 86% among patients without mutations vs 74% in patients with a mutation at any of the 7 analyzed positions. This observation held true when the SVR12 rate was assessed at each particular mutation site, such as A30 (SVR12 of 79% vs 57% in patients without vs with a mutation), S62 (SVR12 of 82% vs 69% in patients without vs with a mutation), and Y93 (SVR12 of 80% vs 40% in patients without vs with a mutation).
Accordingly, a total of 19 patients showed virologic failure; 14 of these had HCV genotype 3 and the rest had genotype 1 (n=3), genotype 2 (n=1), or genotype 6 (n=1). Among the 14 patients with HCV genotype 3, all the virologic failures were caused by relapsed disease. Of these, 8 occurred in patients without cirrhosis and 6 occurred in patients with cirrhosis. Among the 3 patients with HCV genotype 1, all treatment failures were caused by relapse as well. Notably, 2 of these relapses occurred in patients with a mutation at Y93. In contrast, neither cirrhosis nor baseline mutation status impacted efficacy in patients with HCV genotype 1b, 2, 4, 5, or 6.
An adverse event occurred in 61% of patients. In 33.3% of patients, the adverse events were deemed related to the study treatment. The most common adverse events related to study treatment were fatigue (7.8%) and headache (7.4%). Two patients discontinued the study treatment owing to adverse events. Serious adverse events were reported in 2.5% of patients.
The C-BREEZE 2 study investigators concluded that uprifosbuvir at 450 mg coadministered with a higher dose of ruzasvir, 180 mg, remained suboptimal as a pangenotypic regimen. This conclusion was supported by the low SVR12 rate reported in patients infected with HCV genotype 3, several of whom showed virologic relapse.
1. Lawitz E, Poordad F, Anderson LJ, et al. C-BREEZE 1: efficacy and safety of ruzasvir 60 mg plus uprifosbuvir 450 mg for 12 weeks in adults with chronic hepatitis C virus (HCV) genotype (GT) 1, 2, 3, 4, or 6 infection. [AASLD Liver Meeting abstract 1175]. Hepatology. 2017;66(S1).
2. Lawitz E, Gane EJ, Feld JJ, et al. C-BREEZE 2: efficacy and safety of a two-drug direct-acting antiviral agent (DAA) regimen ruzasvir 180 mg and uprifosbuvir 450 mg for 12 weeks in adults with chronic hepatitis C virus (HCV) genotype (GT) 1, 2, 3, 4, or 6 [AASLD Liver Meeting abstract 61]. Hepatology. 2017;66(S1).
100% SVR With 8 Weeks of Ledipasvir/Sofosbuvir in HIV-Infected Men With Acute HCV Infection: Results From the SWIFT-C Trial (Sofosbuvir-Containing Regimens Without Interferon for Treatment of Acute HCV in HIV-1–Infected Individuals)
A shortened duration of treatment with ledipasvir/sofosbuvir was evaluated in the SWIFT-C trials.1 Ledipasvir/sofosbuvir is FDA-app-roved as a once-daily fixed-dose com-bination regimen indicated for the treatment of adult patients with chronic HCV infection in several
settings: for patients with genotype 1, 4, 5, or 6 without cirrhosis or with compensated cirrhosis; those with genotype 1 with decompensated cirrhosis (in combination with ribavirin); and those with genotype 1 or 4 who are liver transplant recipients without cirrhosis or with compensated cirrhosis (in combination with ribavirin).2
Historically, early identification and treatment during the acute phase of HCV infection has been shown to result in higher response rates with a shortened course of pegylated interferon-based antiviral therapies. Guidelines from the European Association for the Study of the Liver (EASL) recommend 8 weeks of DAA therapy for acute-phase HCV infection, with certain caveats (including no coinfection
with HIV-1 and a baseline HCV RNA level <1 million IU/mL).3
Ledipasvir/sofosbuvir is approved for a 12-week treatment duration, but there is potential that a shorter duration regimen may be used in certain cases. Two studies have examined a 6-week regimen of ledipasvir/sofosbuvir for the treatment of patients in the acute phase of HCV infection. The HepNet Acute HCV IV study included 20 patients, of whom 55% had genotype 1a and 45% had genotype 1b. Coinfection with hepatitis B or HIV-1 was not allowed. The acute phase was defined as 4 months. The median HCV viral load in these patients was 4 log10 IU/mL, and 60% had the IL28B CC genotype. In this study, the SVR12 rate was 100%.4 The HIV/HCV cohort study included 26 patients, all of whom were coinfected with HIV-1; 69% had HCV genotype 1a and 31% had genotype 4. The acute phase was defined as 6 months. The mean viral load was 5.4 log10 IU/mL, and 46% had the IL28B CC genotype. In this study, the SVR12 rate was 77%.5
SWIFT-C is a single-arm, multi-center trial investigating the use of shortened, interferon-sparing regimens to treat acute HCV infection. The patients described here (n=27) were treated with a shortened 8-week ledipasvir/sofosbuvir regimen and evaluated for the potential to achieve noninferior SVR12 rates and an improved safety profile vs the standard of care (as assessed by historical control) for the treatment of acute HCV in patients with HCV/HIV coinfection. Acute HCV was defined as the first 24 weeks of HCV infection after diagnosis.
Key eligibility criteria included HIV-1 coinfection (hepatitis B coinfection was not permitted), infection with HCV genotype 1 or 4, and study enrollment between 12 and 24 weeks from the first laboratory evidence of HCV infection. The primary endpoint was SVR12.
All 27 patients were male, and 67% were white. Their median age was 46 years (range, 38-50 years). All but 1 patient (96%) had genotype 1 HCV infection, and the median HCV RNA level was 6.17 log10 IU/mL. Just over half (59%) had the IL28B CC genotype. At screening, all patients were receiving HIV-directed therapy, including boosted protease inhibitors (26%), non-nucleoside reverse transcription inhibitors (30%), integrase inhibitors (52%), and nucleoside reverse transcription inhibitors (100%).
All patients achieved an SVR12 (100%). This 100% SVR12 rate was superior to the control rate of 60%, which was drawn from historical studies of interferon-based regimens. The level of viral load at baseline was associated with the time it took to achieve an undetectable HCV RNA level; the higher the viral load, the longer it took to achieve undetectable levels (Figure 8). Ledipasvir/sofosbuvir was well-tolerated, with no treatment-related serious adverse events.
1. Naggie S, Fierer DS, Hughes M, et al. 100% SVR with 8 weeks of ledipasvir/sofosbuvir in HIV-infected men with acute HCV infection: results from the SWIFT-C trial (sofosbuvir-containing regimens without interferon for treatment of acute HCV in HIV-1 infected individuals) [AASLD Liver Meeting abstract 196]. Hepatology. 2017;66(S1).
2. Harvoni [package insert]. Foster City, CA: Gilead Sciences, Inc; 2017.
3. European Association for the Study of the Liver. EASL recommendations on treatment of hepatitis C 2016. J Hepatol. 2017;66(1):153-194.
4. Deterding K, Spinner CD, Schott E, et al; HepNet Acute HCV IV Study Group. Ledipasvir plus sofosbuvir fixed-dose combination for 6 weeks in patients with acute hepatitis C virus genotype 1 monoinfection (HepNet Acute HCV IV): an open-label, single-arm, phase 2 study. Lancet Infect Dis. 2017;17(2):215-222.
5. Rockstroh JK, Bhagani S, Hyland RH, et al. Ledipasvir-sofosbuvir for 6 weeks to treat acute hepatitis C virus genotype 1 or 4 infection in patients with HIV coinfection: an open-label, single-arm trial. Lancet Gastroenterol Hepatol. 2017;2(5):347-353.
Highlights in Hepatitis C Virus From the 2017 AASLD Liver Meeting: Commentary
Fred Poordad, MD
University Transplant Center
Clinical Professor of Medicine
The University of Texas Health, San Antonio
San Antonio, Texas
Presentations at the American Association for the Study of Liver Diseases (AASLD) 2017 Liver Meeting provided new insight into the optimal management of patients with hepatitis C virus. Data were presented for regimens such as glecaprevir/pibrentasvir; the triplet combination of AL-335, odalasvir, and simeprevir; ruzasvir plus uprifosbuvir; and sofosbuvir/velpatasvir/voxilaprevir. An analysis also evaluated the risk of hepatocellular carcinoma among patients treated with direct-acting antiviral (DAA) agents.
Dr Steven Flamm presented data from an integrated analysis of glecaprevir/pibrentasvir in treatment-naive patients with hepatitis C virus (HCV) genotype 3, with or without cirrhosis.1 The analysis showed that 8 weeks was as effective as 12 weeks in treatment-naive, genotype 3 patients without cirrhosis. The modified intent-to-treat analysis showed rates of sustained virologic response at 12 weeks (SVR12) of 98% in patients without cirrhosis treated for 8 weeks, 99% in patients without cirrhosis treated for 12 weeks, and 100% in patients with cirrhosis treated for 12 weeks. The one potential caveat may be that patients with baseline A30K variants had a lower SVR12 rate at 8 weeks (84%) compared with 12 weeks (94%). However, the number of patients in these subsets was small. Larger, real-world data sets will be needed to validate these data.
A study from Dr Edward Gane and colleagues evaluated glecaprevir/pibrentasvir in patients with cirrhosis, across all genotypes.2 Patients were treatment-naive or had received treatment with interferon or pegylated interferon, with or without ribavirin; or with sofosbuvir plus ribavirin, with or without pegylated interferon. Treatment was administered for 12 weeks. The overall SVR12 rate was 96%, with the lowest SVR12, 94%, reported in patients with genotype 1. This study hints that 12 weeks, and not 8 weeks, is most likely the appropriate duration of glecaprevir/pibrentasvir for patients with cirrhosis. An 8-week regimen of glecaprevir/pibrentasvir in cirrhotic patients will have to be prospectively assessed to determine if all patients need 12 weeks of therapy.
AL-335, Odalasvir, and Simeprevir
The OMEGA-1 trial evaluated the nucleotide analogue AL-335, odalasvir, and simeprevir given for 6 or 8 weeks.3 The study showed excellent results with both durations, yielding SVR12 rates of 99% and 98%, respectively. Patients with genotype 2C had SVR12 rates of only 75% with 8 weeks of treatment and 83% with 6 weeks, indicating a chink in the armor of this regimen. SVR12 rates were particularly low among patients who had baseline F28C resistance-associated substitutions and simeprevir resistance-associated substitutions. Unfortunately, this triplet combination will not undergo further assessment. However, a proof-of-concept finding is that 6 weeks of treatment worked for most patients, at least those with minimal fibrosis.
Ruzasvir and Uprifosbuvir
The C-BREEZE studies evaluated ruzasvir and uprifosbuvir given for 12 weeks in patients with genotype 1 to 6. Dr Eric Lawitz presented data for the modified full analysis set.4,5 The regimen did well in patients with genotype 1, 2, and 4, but it faltered in patients with genotype 3. Rates of SVR12 were 100% in patients with genotype 1b, 4, or 5; 96% in genotype 2; 93% in genotype 1a; 91% in genotype 6; and 76% in genotype 3. This 2-drug combination will not be competitive in today’s market, where there are several effective pangenotypic regimens.
Dr Marc Bourlière and colleagues analyzed data from the deferred treatment group of the POLARIS-1 study, which assessed the regimen of sofosbuvir/velpatasvir/voxilaprevir in patients with HCV genotype 1 to 6 who had received previous treatment with a nonstructural protein 5A (NS5A) inhibitor.6 The new analysis included patients who had received placebo during the initial study. These patients were treated with sofosbuvir/velpatasvir/voxilaprevir for 12 weeks. Overall SVR12 rates ranged from 96% to 100% across all genotypes. The presence of baseline resistance-associated substitutions had no impact. Sofosbuvir/velpatasvir/voxilaprevir is the salvage regimen of choice for patients who need further treatment after DAA therapy, and it does not require testing of baseline-resistance. In the United States, this regimen is currently approved as a salvage therapy for patients who require treatment after failing a DAA regimen. Interestingly, the European Union indication allows this regimen to be used as first-line therapy.
Previous data have shown the efficacy of glecaprevir/pibrentasvir in patients with HCV genotype 1 infection. The phase 2 MAGELLAN-1 trial evaluated a 12-week regimen in patients with genotype 1 without cirrhosis, who required retreatment after failing a DAA regimen.7 An SVR12 was reported in 100% of patients treated with 200-mg glecaprevir plus 80-mg pibrentasvir, 95% of patients treated with 300-mg glecaprevir plus 120-mg pibrentasvir with 800-mg once-daily ribavirin, and 86% of patients treated with 300-mg glecaprevir plus 120-mg pibrentasvir without ribavirin.
Risk of Hepatocellular Carcinoma
Dr George Ioannou and coworkers analyzed data from the National Veterans Affairs Healthcare System for more than 62,000 patients with HCV, with or without cirrhosis, who were treated with interferon-based and DAA-based therapies.8 The analysis evaluated the incidence of de novo cases of hepatocellular carcinoma. Importantly, there was no signal that DAA therapy led to a higher rate of de novo hepatocellular carcinoma compared with interferon-based therapies. In fact, an SVR with DAA therapy led to a 71% reduction in overall HCC risk. This analysis suggests that clinicians should treat patients with cirrhosis, and continue to check them for liver cancer every 6 months with imaging and measurement of the serum marker alpha-fetoprotein (AFP). Although the risk of liver cancer decreases in these patients, it does not reach zero, and indefinite surveillance for hepatocellular carcinoma is recommended.
Dr Poordad is on the speaker bureaus/advisory boards of and receives educational and research grants from Gilead Sciences, Merck, Bristol-Myers Squibb, AbbVie, and Janssen.
1. Flamm S, Wyles D, Asatryan A, et al. Efficacy and safety of glecaprevir/pibrentasvir for 8 or 12 weeks in treatment-naïve patients with chronic HCV genotype 3: an integrated phase 2/3 analysis [AASLD Liver Meeting abstract 62]. Hepatology. 2017;66(S1).
2. Gane E, Poordad F, Zadeikis N, et al. Efficacy, safety, and pharmacokinetics of glecaprevir/pibrentasvir in adults with chronic genotype 1-6 hepatitis C virus infection and compensated cirrhosis: an integrated analysis [AASLD Liver Meeting abstract 74]. Hepatology. 2017;66(S1).
3. Zeuzem S, Bourgeois S, Greenbloom S, et al. Evaluation of the efficacy and tolerability of JNJ-4178 (AL-335, odalasvir, and simeprevir) in hepatitis C virus-infected patients without cirrhosis: the phase IIb OMEGA-1 study [AASLD Liver Meeting abstract 65]. Hepatology. 2017;66(S1).
4. Lawitz E, Gane EJ, Feld JJ, et al. C-BREEZE 1: efficacy and safety of ruzasvir 60 mg plus uprifosbuvir 450 mg for 12 weeks in adults with chronic hepatitis C virus (HCV) genotype (GT) 1, 2, 3, 4, or 6 infection [AASLD Liver Meeting abstract 61]. Hepatology. 2017;66(S1).
5. Lawitz E, Poordad F, Anderson LJ, et al. C-BREEZE 2: efficacy and safety of a two-drug direct-acting antiviral agent (DAA) regimen ruzasvir 180 mg and uprifosbuvir 450 mg for 12 weeks in adults with chronic hepatitis C virus (HCV) genotype (GT) 1, 2, 3, 4, or 6 [AASLD Liver Meeting abstract 1175]. Hepatology. 2017;66(S1).
6. Bourlière M, Gordon SC, Schiff ER, et al. SOF/VEL/VOX for 12 weeks in NS5A-inhibitor experienced HCV-infected patients: results of the deferred treatment group in the phase 3 POLARIS-1 study [AASLD Liver Meeting abstract 1178]. Hepatology. 2017;66(S1).
7. Poordad F, Felizarta F, Asatryan A, et al. Glecaprevir and pibrentasvir for 12 weeks for hepatitis C virus genotype 1 infection and prior direct-acting antiviral treatment. Hepatology. 2017;66(2):389-397.
8. Ioannou GN, Green P, Berry K. Eradication of HCV induced by direct-acting antivirals is associated with a 79% reduction in HCC risk [AASLD Liver Meeting abstract 142]. Hepatology. 2017;66(S1).