Highlights in Hepatitis C Virus From the 2018 AASLD Liver Meeting
A Review of Selected Presentations From the 2018 AASLD
Liver Meeting • November 9-13, 2018 • San Francisco, CA
Preliminary Efficacy and Safety of 8-Week Glecaprevir/Pibrentasvir in Patients With HCV Genotype 1-6 Infection and Compensated Cirrhosis: The EXPEDITION-8 Study
The fixed-dose combination of glecaprevir plus pibrentasvir administered for 8 weeks is approved as therapy for treatment-naive patients with hepatitis C virus (HCV) genotypes 1 to 6, without cirrhosis.1-3 This treatment has demonstrated high rates of sustained virologic response at week 12 (SVR12).1-3 The 2-drug combination inhibits the activity of 2 nonstructural proteins—the NS3/4A protease and the NS5A protein—thus interfering with viral replication. In registrational clinical trials, an 8-week regimen of glecaprevir plus pibrentasvir was associated with an SVR12 rate of 98% in treatment-naive patients without cirrhosis.4 In patients with cirrhosis, a 12-week regimen yielded an SVR12 rate of 99%.5,6
EXPEDITION-8 is an ongoing, single-arm, open-label, multicenter, phase 3b study evaluating the efficacy and safety of an 8-week regimen of glecaprevir plus pibrentasvir in treatment-naive patients with HCV infection and compensated cirrhosis.7 Enrolled patients were adults with treatment-naive, chronic HCV genotype 1, 2, 4, 5, or 6, with cirrhosis and a Child-Pugh score of 6 or less. Patients with HCV genotype 3 were enrolled as part of a protocol amendment, and data from this cohort will be presented at a later date. Primary endpoint 1, based on per-protocol analysis, excluded patients in the intention-to-treat (ITT) population who experienced virologic breakthrough or treatment discontinuation prior to week 8 and those without data for the SVR12 analysis. The SVR12 rate for primary endpoint 1 was compared with a historical SVR12 rate of 100%, with a noninferiority margin of 6% and a lower bound of the 95% CI of greater than 94%. Primary endpoint 2, based on ITT analysis, included all patients who received at least 1 dose of the study drug. The SVR12 rate of primary endpoint 2 was compared with a historical SVR12 rate of 99%, with a noninferiority margin of 6% and a lower bound of the 95% CI of greater than 93%.
Among the 280 enrolled patients, the median age was 60 years (range, 34-88 years), and 60% were male. Most patients (83%) had HCV genotype 1 infection. The median concentration of HCV RNA at baseline was 6.3 log10 IU/mL (range, 3.4-7.5 log10 IU/mL), and the mean transient elastography score at baseline was 23.7 (standard deviation, 11.1). Nearly all patients (99%) had a Child-Pugh score of 5 or 6, and 26% had a history of injection drug use. Baseline polymorphisms included NS5A-only in 36% and NS3-only in 1%.
After 8 weeks of treatment with glecaprevir plus pibrentasvir, there were no virologic failures. Both primary endpoints were met, with SVR12 rates of 100% for the per-protocol analysis and 98% for the ITT analysis (Figure 1). The ITT analysis excluded 6 patients. One patient discontinued treatment prior to completing the 8-week regimen, but nonetheless achieved SVR12. Among the 5 patients who were lost to follow-up, all had no detectable viral load at their most recent visit. The per-protocol analysis excluded 6 patients from the ITT population who failed to respond and 1 patient who achieved SVR12 after less than 8 weeks of study treatment. The 2-drug combination was generally well-tolerated, and no new safety signals were observed.
An adverse event (AE) of any grade occurred in 48% of patients, and a serious AE occurred in 2%. No patient discontinued treatment owing to an AE. No laboratory abnormalities were reported. Enrollment of patients with HCV genotype 3 infection is ongoing.
References
1. Mavyret [package insert]. North Chicago, IL: AbbVie, Inc; 2018.
2. Berg T, Naumann U, Stoehr A, et al. First real-world data on safety and effectiveness of glecaprevir/pibrentasvir for the treatment of patients with chronic hepatitis C virus infection: data from the German Hepatitis C-Registry [EASL abstract GS-007]. J Hepatol. 2018;68(suppl 1).
3. D’Ambrosio R, Pasulo L, Puoti M, et al. Real-life effectiveness and safety of glecaprevir/pibrentasvir among 723 Italian patients with chronic hepatitis C: the NAVIGATOR-II study [EASL abstract GS-013]. J Hepatol. 2018;68(suppl 1).
4. Puoti M, Foster GR, Wang S, et al. High SVR12 with 8-week and 12-week glecaprevir/pibrentasvir therapy: an integrated analysis of HCV genotype 1-6 patients without cirrhosis. J Hepatol. 2018;69(2):293-300.
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.
6. Wyles D, Poordad F, Wang S, et al. Glecaprevir/pibrentasvir for hepatitis C virus genotype 3 patients with cirrhosis and/or prior treatment experience: a partially randomized phase 3 clinical trial. Hepatology. 2017;67(2):514-523.
7. Brown RS Jr, Hezode C, Wang S, et al. Preliminary efficacy and safety of 8-week glecaprevir/pibrentasvir in patients with HCV genotype 1-6 infection and compensated cirrhosis: the EXPEDITION-8 study [AASLD abstract LB-7]. Hepatology. 2018;68(suppl 1).
Real-World Effectiveness of Sofosbuvir/Velpatasvir/Voxilaprevir in 573 Treatment-Experienced Patients With Hepatitis C
Few options are available for patients with HCV who require additional treatment after direct-acting antiviral agents. In clinical trials of this patient group, treatment with the combination of sofosbuvir, velpatasvir, and voxilaprevir yielded SVR12 rates of 95% to 100%.1,2 The United States Department of Veterans Affairs conducted a study to evaluate the real-world efficacy of sofosbuvir, velpatasvir, and voxilaprevir in veterans with HCV who had received previous treatment.3 The observational study included patients in the Veterans Affairs National HCV Clinical Case Registry. The primary endpoint was SVR assessed at least 12 weeks after the end of treatment, based on ITT analysis. Enrolled patients had HCV genotypes 1 to 4 and began treatment with sofosbuvir, velpatasvir, and voxilaprevir at any US Veterans Affairs facility, with treatment concluded by March 31, 2018. Among patients in the final SVR cohort, 490 had genotype 1, 20 had genotype 2, 51 had genotype 3, and 12 had genotype 4. Across the genotype cohorts, the patients’ mean age was approximately 60 to 65 years. The proportion of patients with cirrhosis ranged from 30.0% to 58.3%. Treatment duration of 12 weeks was reported for 91.2% to 100% of patients; the remainder of patients were treated for less than 12 weeks. All of the patients had received prior treatment with an NS5A or NS5B inhibitor, and the most common prior treatment was ledipasvir plus sofosbuvir, with or without ribavirin.
The overall SVR rate was 90.7% for HCV genotype 1, 90.0% for genotype 2, 91.3% for genotype 3, and 100.0% for genotype 4. Similar SVR rates were observed regardless of race, the presence of cirrhosis, the level of fibrosis, and any history of decompensation. Among patients whose treatment duration lasted less than 12 weeks, SVR rates were 46.5% (20/43) for genotype 1, 100.0% (1/1) for genotype 2, and 0% (0/1) for genotype 3. Among patients who received the full 12 weeks of treatment, SVR rates were approximately 95% (409/430) for genotype 1, 90% (17/19) for genotype 2, and 93% (42/45) for genotype 3 (Figure 2). The SVR rate was 100.0% (12/12) for genotype 4. SVR rates of approximately 88% to 92% were observed in cohorts with more than 10 patients based on prior treatment class and HCV genotype. Among patients with HCV genotype 1 infection, most had received prior treatment with ledipasvir and sofosbuvir, with or without ribavirin. These patients had an SVR rate of 91% after treatment with sofosbuvir, velpatasvir, and voxilaprevir. In patients who received 12 weeks of treatment with the 3 drugs, subgroup analyses generally yielded high SVR rates for HCV genotypes 1, 2, and 3, regardless of race, cirrhosis, and fibrosis score.
References
1. 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.
2. Jacobson IM, Lawitz E, Gane EJ, et al. Efficacy of 8 weeks of sofosbuvir, velpatasvir, and voxilaprevir in patients with chronic HCV infection: 2 phase 3 randomized trials. Gastroenterology. 2017;153(1):113-122.
3. Belperio P, Bakckus L, Shahoumian T, Loomis T, Mole L. Real-world effectiveness of sofosbuvir/velpatasvir/voxilaprevir in 573 treatment-experienced patients with hepatitis C [AASLD abstract 227]. Hepatology. 2018;68(suppl 1).
High Efficacy of Glecaprevir/Pibrentasvir in Patients With Chronic HCV GT1 Infection Who Failed Prior Treatment With NS5A-Inhibitor Plus Sofosbuvir Regimens
Sixteen weeks of therapy with the combination of glecaprevir plus pibrentasvir is approved by the US Food and Drug Administration (FDA) for the treatment of HCV genotype 1–infected patients with prior exposure to an NS5A inhibitor and without prior exposure to inhibitors of NS3/4A.1 The drug approval was based on results from the phase 2 MAGELLAN-1 study, an open-label, randomized trial that demonstrated high rates of SVR12 in HCV patients with prior exposure to an inhibitor of NS5A.2 The 16-week regimen is recommended as an alternative treatment option in guidelines from the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America.3
In an effort to reduce the required treatment period, an open-label, multicenter, phase 3b trial compared 12 weeks vs 16 weeks of treatment with glecaprevir plus pibrentasvir in patients with chronic HCV genotype 1 infection.4 Eligible patients had experienced treatment failure after at least 4 weeks of treatment with sofosbuvir plus an NS5A inhibitor, with or without ribavirin. Patients with decompensated cirrhosis and those with active hepatitis B virus were excluded from enrollment. Enrollment included patients who had undergone prior liver transplant and those infected with the human immunodeficiency virus (HIV) who were receiving antiretroviral therapy. Patients without cirrhosis (n=130) were randomly assigned in a 2:1 design to receive therapy for 12 weeks (arm A) or 16 weeks (arm B). Patients with cirrhosis (n=50) were randomly assigned in a 1:1 manner to receive 12 weeks of therapy with weight-based ribavirin (arm C) or 16 weeks of therapy without ribavirin (arm D). The primary endpoint was the SVR12 rate.
Among 86 noncirrhotic patients in arm A, 3 withdrew consent prior to receiving treatment. After the FDA approval of glecaprevir plus pibrentasvir, the study protocol was amended. Five patients in arm A and 1 patient in arm C had received a protease inhibitor prior to their treatment with sofosbuvir plus an NS5A inhibitor. These patients were treated for 16 weeks, and included in the analysis of the 16-week treatment cohorts. The final cohorts included 78 patients in arm A, 49 in arm B, 21 in arm C, and 29 in arm D. Across the 4 arms, 76% to 82% of patients were male, and 38% to 51% were black. The median age ranged from 60 to 64 years. HCV genotype 1a was reported in 78% to 90% of patients. HIV infection was noted in 3% to 6%. Prior liver transplant was reported in 6% of arm A and 20% of arm B. The median number of days since exposure to an NS5A inhibitor was 505 in arm A, 355 in arm B, 499 in arm C, and 482 in arm D.
The SVR12 rates were 90% in arm A (70/78), 94% in arm B (46/49), 86% in arm C (18/21), and 97% in arm D (28/29; Figure 3). All 8 patients with early exposure to sofosbuvir plus an NS5A inhibitor achieved SVR12. In arm A, 4 patients relapsed, 2 experienced a virologic breakthrough, 1 was reinfected, and 1 patient died. In arm B, 2 patients relapsed and 1 patient had a virologic breakthrough. Three patients in arm C had a virologic breakthrough, and 1 patient in arm D relapsed. The difference in SVR12 rates for 12 vs 16 weeks of treatment was –4.1% for arm A vs arm B (95% CI, –13.7% to 7.4%) and –10.8% for arm C vs arm D (95% CI, –31.4% to 5.8%). Among the cohort of patients treated for 12 weeks, the overall SVR12 rate was 89% (88/99), with a higher rate observed in patients with HCV genotype 1b infection vs 1a infection (95% vs 87%; Figure 4). Among the cohort of patients treated for 16 weeks, the SVR12 rate was 95%, with rates of 100% (13/13) in patients with HCV genotype 1b infection vs 94% (61/65) in those with HCV genotype 1a infection. Baseline polymorphisms observed across the 4 arms included NS5A (76%-81%), NS3 residue 80 (33%-48%), and NS3 residues 155, 156, and 168 (0% to 14%). Among the 6 patients who developed virologic failure while on treatment, all had HCV genotype 1a infection. None of these patients had baseline resistance-associated substitutions (RAS) in NS3 at baseline, and 5 of these patients had RAS observed after virologic failure. All of these patients had RAS in NS5A at baseline, and 4 of the 6 patients had additional treatment-emergent RAS after virologic failure. One patient who developed reinfection had no RAS in either NS3 or NS5A at baseline or
at failure.
Across the 4 arms, the proportion of patients with any AE ranged from 55% in arm D to 81% in arm C. The most commonly observed AEs were fatigue, headache, and nausea. Serious AEs were observed in 0% to 6% of patients, but no events were related to treatment with a direct-acting antiviral agent. No patient discontinued study treatment owing to an AE related to treatment with glecaprevir plus pibrentasvir. AEs during treatment with ribavirin led 7 patients (33%) to reduce the dose and 1 patient (5%) to discontinue treatment. One patient in arm A who received 11.5 weeks of study treatment later presented with advanced hepatocellular carcinoma and subsequently died. Laboratory abnormalities were observed in 6% of patients in arm A, 10% in arm B, 10% in arm C, and 8% in arm D.
References
1. Mavyret [package insert]. North Chicago, IL: AbbVie, Inc; 2018.
2. Poordad F, Pol S, Asatryan A, et al. Glecaprevir/pibrentasvir in patients with hepatitis C virus genotype 1 or 4 and past direct-acting antiviral treatment failure. Hepatology. 2018;67(4):1253-1260.
3. American Association for the Study of Liver Disease, Infectious Disease Society of America. HCV guidance: recommendations for testing, managing, and treating hepatitis C. www.hcvguidelines.org. Updated September 21, 2017. Accessed November 23, 2018.
4. Sulkowski MS, Lok AS, Willner I, et al. High efficacy of glecaprevir/pibrentasvir in patients with chronic HCV GT1 infection who failed prior treatment with NS5A-inhibitor plus sofosbuvir regimens [AASLD abstract 226]. Hepatology. 2018;68(suppl 1).
Hepatitis C Virus Reinfection and Injecting Risk Behavior Following Elbasvir/Grazoprevir Treatment in Participants on Opiate Agonist Therapy: C-EDGE CO-STAR Part B
The combination of elbasvir plus grazoprevir is available as a once-daily, fixed-dose combination tablet for the treatment of HCV genotypes 1 and 4.1 The therapy has shown in vitro activity against many clinically relevant RAS, and efficacy has been demonstrated in various patient settings.2,3 The phase 3 CO-STAR trial compared 12 weeks of elbasvir plus grazoprevir vs placebo in patients with HCV genotype 1, 4, or 6 infection who had been receiving opioid agonist therapy for at least 3 months. In part A of the trial, the SVR12 rate was 90.9% in the full analysis set and 95.8% in the modified full analysis set.4 Adherence to treatment was high, with 97% of patients demonstrating adherence exceeding 95%.
CO-STAR Part B was a 3-year observational trial that was open to all participants who received at least 1 dose of elbasvir plus grazoprevir in CO-STAR Part A.5 Every 6 months, patients underwent assessment for HCV RNA levels and urine drug screening, and they completed a behavioral questionnaire about drug use. If HCV RNA was detected, DNA sequencing was performed. Among the 301 patients who enrolled in part A of the study, 199 enrolled in part B. Follow-up visits were completed by 192 patients at 6 months, 179 at 12 months, 173 at 18 months, 155 at 24 months, and 148 at 30 months. Baseline characteristics were generally similar in patients who enrolled in part B vs those who participated only in part A. In part B, the patients’ median age was 48.6 years (range, 24-66 years), and 76% were male. Eight percent were HCV/HIV coinfected. Opioid agonist treatment included methadone (80%) and buprenorphine (20%). Ninety-two percent of patients had HCV genotype 1a or 1b infection. Among patients in part B, 59% had a positive urine drug test upon enrollment in part A. Positive results were observed for the use of benzodiazepines (24%), cannabinoids (23%), opiates (22%), cocaine (10%), and amphetamines (7%). The proportion of positive urine drug test results remained fairly constant, ranging from 53% to 62% throughout the 30 months of follow-up.
Self-reported drug use also remained fairly steady during follow-up. At any time point throughout 6 to 30 months of follow-up, the proportion of patients reporting noninjecting drug use during the previous 6 months ranged from 39% to 45% (Figure 5). Noninjecting drug use during the previous month was reported by 36% to 42%. Injecting drug use during the previous 6 months occurred in 20% to 26%. Injecting drug use during the previous month ranged from 15% to 21%.
Reinfections were observed in 6 patients during CO-STAR part A and in 4 patients during part B, consistent with a rate of 1.8 reinfections per 100 person-years. In part B, the reinfection rate was higher in patients who reported injecting drug use (2.8 reinfections per 100 person-years [95% CI, 1.0-6.2]) compared with those who did not report injecting drug use (0.3 reinfections per 100 person-years [95% CI, 0.0-1.8]).
Two study participants had recurrent viremia followed by spontaneous clearance. The first patient had HCV genotype 1a at baseline. After treatment with elbasvir plus grazoprevir, the patient was found to be reinfected with HCV genotype 6a at follow-up week 8. The reinfection spontaneously cleared and remained undetectable for approximately 2 years, but the patient was reinfected at week 170 with HCV genotype 2a. This patient’s urine drug tests were positive for benzodiazepines and opiates at several time points. The second patient was infected with HCV genotype 6a at baseline. After successful viral clearance with elbasvir plus grazoprevir, the patient was reinfected with HCV genotype 1a. This patient did not enroll in part B of the study. Among the 10 patients who were reinfected, 8 had persistent reinfection. Four of the latter patients were successfully treated outside of the clinical trial.
References
1. Morikawa K, Nakamura A, Shimazaki T, Sakamoto N. Safety and efficacy of elbasvir/grazoprevir for the treatment of chronic hepatitis C: current evidence. Drug Des Devel Ther. 2018;12:2749-2756.
2. 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.
3. Coburn CA, Meinke PT, Chang W, et al. Discovery of MK-8742: an HCV NS5A inhibitor with broad genotype activity. ChemMedChem. 2013;8(12):1930-1940.
4. Dore GJ, Altice F, Litwin AH, et al; C-EDGE CO-STAR Study Group. Elbasvir-grazoprevir to treat hepatitis C virus infection in persons receiving opioid agonist therapy: a randomized trial. Ann Intern Med. 2016;165(9):625-634.
5. Grebely J, Litwin AH, Dalgard O, et al. Hepatitis C virus reinfection and injecting risk behavior following elbasvir/grazoprevir treatment in participants on opiate agonist therapy: C-EDGE CO-STAR Part B [AASLD abstract 52]. Hepatology. 2018;68(suppl 1).
Pharmacokinetics, Safety, and Efficacy of Glecaprevir/Pibrentasvir in Pediatric Patients With Genotypes 1-6 Chronic HCV Infection: Part 1 of the DORA Study
Worldwide, approximately 13.2 million children ages 1 to 15 years are chronically infected with HCV.1 For children older than 12 years, the combinations of sofosbuvir plus ledipasvir and sofosbuvir plus ribavirin are the only approved, interferon-free, direct-acting antiviral agents. The phase 2/3 DORA trial (A Study to Evaluate the Pharmacokinetics, Safety, and Efficacy of Glecaprevir/Pibrentasvir in Pediatric Subjects With Genotypes 1-6 Chronic Hepatitis C Virus [HCV] Infection) is an ongoing study evaluating the pharmacokinetics, safety, and efficacy of glecaprevir plus pibrentasvir in pediatric patients with chronic HCV infection.2 Part 1 of the study was conducted in adolescents ages 12 to 17 years, all of whom received the adult formulation of the 2-drug combination. Part 2 of the study is evaluating a pediatric formulation of glecaprevir plus pibrentasvir in children ages 3 to 11 years.
DORA Part 1 enrolled patients ages 12 through 17 years. Patients had chronic infection with any HCV genotype, including mixed genotypes. HIV-1 coinfection was allowed with stable, concomitant antiretroviral therapy compatible with study treatment. Patients with compensated cirrhosis were permitted to enroll. The treatment duration was 8 weeks in 44 treatment-naive patients, including 2 with HIV coinfection. Three treatment-experienced patients with HCV genotype 3 infection received 16 weeks of study drug. The primary endpoint was the steady-state area under the curve values for each study drug.
Among 47 patients, 21 (45%) were male and 35 (74%) were white. The median age was 14 years (range, 12-17 years), and patients had a median weight of 58 kg (range, 32-109 kg). The majority of patients (79%) were infected with HCV genotype 1a or 1b, and the remaining patients were infected with genotype 2 (6%), 3 (9%), or 4 (6%). The median level of HCV RNA was 6.2 log10 IU/mL (range, 4.6-7.2 log10 IU/mL). None of the patients had cirrhosis, 23% were treatment-experienced, and 4% were coinfected with HIV. Among 44 patients with available data, 25% had baseline polymorphisms in NS5A only, and the remaining patients had no polymorphisms in NS3 or NS5A.
Based on the area under the curve at 24 hours, the steady-state exposures of glecaprevir and pibrentasvir observed in HCV-infected adolescents were similar to those observed in HCV-infected adults. Specifically, levels of glecaprevir were 4380 ng·h/mL in adolescents vs 4800 ng·h/mL in adults, and levels of pibrentasvir were 1440 ng·h/mL vs 1430 ng·h/mL, respectively. Neither patient weight nor patient age appeared to have a clinically meaningful relationship with study drug exposure. The study yielded an SVR12 rate of 100%. Viral remissions were seen across all genotypes and in the 2 patients coinfected with HIV (Figure 6).
Among the 47 patients in both treatment arms, 87% had an AE of any grade, with no serious AEs and no AEs leading to discontinuation of the study drug. The most common AEs of any grade were nasopharyngitis (26%), upper respiratory tract infection (19%), and headache (17%). Most AEs were mild and unrelated to treatment with glecaprevir plus pibrentasvir. There were no reports of clinically significant laboratory abnormalities, liver-related toxicities, or drug-induced liver injury. In both patients with HIV-1 coinfection, the infection remained suppressed during treatment.
References
1. Indolfi G, Hierro L, Dezsofi A, et al. Treatment of chronic hepatitis C virus infection in children: a position paper by the Hepatology Committee of European Society of Paediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr. 2018;66(3):505-515.
2. Jonas MM, Squires RH, Rhee SM, et al. Pharmacokinetics, safety, and efficacy of glecaprevir/pibrentasvir in pediatric patients with genotypes 1-6 chronic HCV infection: part 1 of the DORA study [AASLD abstract 2379]. Hepatology. 2018;68(suppl 1).
Sustained Virologic Response Reduces the Incidence of Extrahepatic Manifestations in Chronic Hepatitis C Infection
Cirrhosis and liver cancer are commonly observed in patients with chronic HCV infection. In addition, a large proportion of HCV patients experience extrahepatic manifestations (EHMs), such as diabetes and chronic kidney disease, which are associated with substantial cost and use of health care resources.1 A longitudinal cohort study evaluated the relationship between SVR10 and the incidence of EHMs among patients in the British Columbia Hepatitis Testers Cohort.2 Eligible patients had initiated interferon-based treatment for their HCV infection between January 1999 and July 2014 and had a documented treatment response. EHM outcomes included diabetes, chronic kidney disease/end-stage renal disease, ischemic heart disease, mood and anxiety disorders, and rheumatoid arthritis. The follow-up duration extended from the SVR testing date until the development of a specific EHM, death, retreatment or reinfection, or December 31, 2015 (whichever occurred first). All hazard ratio (HR) analyses were adjusted for factors such as age, sex, and injection drug use.
Among the 10,823 patients who received interferon-based treatment, 1352 had no measurement of HCV RNA at 10 or more weeks after cessation of HCV treatment. After exclusion of prevalent EHMs, the sample sizes for each EHM were 9413 for stroke, 9261 for rheumatoid arthritis, 9241 for chronic kidney disease, 9084 for diabetes, 8981 for heart disease, and 3777 for mood and anxiety disorders. Among the initial study population of 9471 patients, 5930 achieved an SVR. Baseline patient characteristics for the 2 cohorts were generally similar. The median age was 50 to 51 years (range, 42-56 years), and 66% to 70% of patients were male. Injection drug use was reported by 21% to 22% of patients, and 18% to 20% had problematic alcohol use. One-fourth of the patients in each cohort had a major mental illness. Rates of hypertension were 18% to 20%, and diabetes was noted in 3% to 6% of patients.
For each EHM, the crude incidence rate per 1000 person-years was lower in the cohort of patients who achieved SVR. The difference was significant for diabetes, chronic kidney disease/end-stage renal disease, hemorrhagic or ischemic stroke, and mood and anxiety disorders (Table). However, the difference was not significant for ischemic heart disease (P=.3523; adjusted HR, 1.06; 95% CI, 0.88-1.28) or rheumatoid arthritis (P=.98; adjusted HR, 0.83; 95% CI, 0.54-1.27). The study also identified a significant relationship between SVR24 and diabetes (adjusted HR, 0.51; 95% CI, 0.43-0.61), chronic kidney disease or end-stage renal disease (adjusted HR, 0.48; 95% CI, 0.37-0.61), and mood or anxiety disorders (adjusted HR, 0.70; 95% CI, 0.60-0.81). However, there was no significant relationship between SVR24 and ischemic heart disease (adjusted HR, 1.09; 95% CI, 0.90-1.32) or rheumatoid arthritis (adjusted HR, 0.82; 95% CI, 0.53-1.26). The findings are consistent with those observed in studies from Japan, Taiwan, and a US veterans cohort.
References
1. Zignego AL, Ramos-Casals M, Ferri C, et al; ISG-EHCV. International therapeutic guidelines for patients with HCV-related extrahepatic disorders. A multidisciplinary expert statement. Autoimmun Rev. 2017;16(5):523-541.
2. Rossi C, Butt ZA, Chapinal N, et al. Sustained virologic response reduces the incidence of extrahepatic manifestations in chronic hepatitis C infection [AASLD abstract 148]. Hepatology. 2018;68(suppl 1).
Quality of Life in Patients With Psychiatric Disorders: Pooled Analysis From Glecaprevir/Pibrentasvir Registrational Studies
Psychiatric disorders are common among patients with chronic HCV infection, affecting as many as half of these patients.1 In a study of 168 HCV patients, achievement of SVR with interferon-based treatment led to long-term improvements in neurocognitive performance.2 However, psychiatric comorbidities are associated with a lower likelihood of receiving treatment for HCV infection. A retrospective study evaluated the relationship between HCV treatment and quality of life in patients with or without psychiatric comorbidities.3 Data were pooled from 8 clinical trials: SURVEYOR -I and -II; ENDURANCE -2, -3, and -4; and EXPEDITION -1, -2, and -4. The study enrolled patients who were infected with chronic HCV, genotypes 1 to 6. Patients did not have cirrhosis or had compensated liver disease. Patients in the trials received daily glecaprevir plus pibrentasvir for 8, 12, or 16 weeks. Patients with psychiatric disorders were identified by medical history or concomitant use of antidepressants or antipsychotics. Patient-reported outcomes were collected by means of the Short Form 36 Health Survey (SF-36), the EuroQOL 5D questionnaire (EQ-5D), and the Fatigue Severity Scale (FSS). Patient-reported outcomes were recorded at baseline, end of treatment, and posttreatment week 12. Meaningful change was defined as one-half of the pooled standard deviation at baseline, and this measurement was then used to indicate whether the outcome was improved, stable, or deteriorated.
Among 2570 patients, 809 (31%) had a psychiatric disorder, including depression (65.4%), anxiety (27.8%), cognitive disorder (10.4%), and bipolar disorder (7.4%). Overall, patients with psychiatric disorders had a greater benefit from treatment as assessed by quality-of-life questionnaires. All domain scores from SF-36 showed a greater improvement in patients with psychiatric disorders compared with those without (Figure 7).
Patients with psychiatric disorders also demonstrated a greater mean change in improvement from baseline based on the EQ-5D health state index (0.03 vs 0.02), the EQ-5D visual analog scale (8.21 vs 5.14), and the FSS (–0.50 vs –0.29; Figure 8). For each domain in the SF-36 questionnaire, patients with psychiatric disorders were more likely to show improvement than those without psychiatric disorders, including for physical function; role, physical; bodily pain; general health; vitality; social function; role, emotional; and mental health (P<.0001 for each). The proportions of patients with an improvement in the FSS score were similar in both cohorts (P=.4356). However, patients with psychiatric disorders were again more likely to show improvement in the EQ-5D health state index (24% vs 19%; P=.0049) and the EQ-5D visual analog scale (40% vs 30%; P<.0001).
The study is limited by the fact that the analyses were not prespecified in the respective trials. In the cohort with psychiatric disorders, 81 patients were included based on concomitant medication use, which may have led to an overestimation of the number of patients with psychiatric disorders. The pooled analysis included data from registrational clinical studies; therefore, the findings may not reflect real-world outcomes.
References
1. Adinolfi LE, Nevola R, Lus G, et al. Chronic hepatitis C virus infection and neurological and psychiatric disorders: an overview. World J Gastroenterol. 2015;21(8):2269-2280.
2. Kraus MR, Schäfer A, Teuber G, et al. Improvement of neurocognitive function in responders to an antiviral therapy for chronic hepatitis C. Hepatology. 2013;58(2):497-504.
3. Cacoub P, Pinsky B, Bondin M, Hayes O, Negro F. Quality of life in patients with psychiatric disorders: pooled analysis from glecaprevir/pibrentasvir registrational studies [AASLD abstract 150]. Hepatology. 2018;68(suppl 1).
High SVR in People Who Inject Drugs With HCV Despite Imperfect Medication Adherence: Data From the ANCHOR Study
High rates of HCV acquisition and transmission have been observed among people who inject drugs.1 These people may be denied treatment with direct-acting antiviral agents, based in part on concerns regarding lack of adherence to treatment regimens. The single-center ANCHOR study (Hepatitis C Treatment to Prevent HIV, Initiate Opioid Substitution Therapy, and Reduce Risky Behavior) evaluated the use of direct-acting antiviral agents in patients with opioid use disorder and chronic HCV infection.2 The study evaluated adherence to treatment and the impact on SVR. Enrolled patients received sofosbuvir plus velpatasvir for 12 weeks, with medication dispensed monthly. Patients also received buprenorphine and medication to prevent possible infection with HIV. All study participants were treated at a harm reduction drop-in center in Washington, DC. They reported injection of an opioid within the prior 3 months. Exclusion criteria included decompensated cirrhosis and contraindicated drug-drug interactions. Adherence to treatment was assessed at weeks 4, 8, and 12 after initiation.
The study screened 160 people and enrolled 100 for the data analysis. Patients who were not enrolled were not eligible for the study (53%), lost to follow-up (35%), or excluded for another reason (12%). Patients had a median age of 57 years (range, 53-62 years), and 76% were male. Ninety-three percent of patients were black, one-third had cirrhosis, and half had unstable housing. More than 90% of patients had previously been incarcerated. The mean age at first intravenous drug use was 21 years (range, 17-30.5 years), and 58% injected opioids daily or more frequently. One-third had received medication-assisted treatment, 40% reported a hazardous level of alcohol consumption, and 29% had shared drug injection equipment within the prior 3 months.
Medication was dispensed to 97% of participants at week 4 and 92% at week 8. Visit adherence was 88% at week 4, 83% at week 8, 70% at week 12, and 88% at week 24. Among 95 patients, 89% had an HCV viral load of less than 200 IU/mL, and 11% had a higher HCV level. Treatment interruptions were reported for 13 patients, owing to stolen medication (n=3), failure to take medication (n=3), hospitalization (n=2), inpatient drug treatment (n=2), incarceration (n= 2), or lost medication (n=1). Eighty-seven patients completed 12 weeks of anti-HCV treatment, represented by 3 bottles of 28 pills each. Seven patients completed 2 to 3 bottles, 5 patients completed 1 to 2 bottles, and 1 patient completed less than 1 bottle. Among 80 patients with known end-of-treatment timing, 46 patients finished after 12 weeks, 21 patients finished on time, and 13 patients did not complete treatment.
Among 93 patients in the ITT population, 78% achieved SVR, 10% experienced virologic failure, 9% were lost to follow-up, and 3% died. In the per-protocol population of 82 patients, 89% achieved SVR and 11% had a virologic failure (Figure 9). No baseline factor, including daily injection, unstable housing, or hazardous drinking, was associated with SVR. HCV viral load of less than 200 IU/mL at week 4 was associated with SVR (P<.001). Among 76 patients without treatment interruption, the SVR rate was 86%, whereas 12 patients with treatment interruption had an SVR rate of 67%. Completion of at least 8 weeks of treatment was strongly associated with SVR (P<.001), whereas completing treatment on time did not affect the SVR rate (P=.65).
References
1. Larney S, Peacock A, Leung J, et al. Global, regional, and country-level coverage of interventions to prevent and manage HIV and hepatitis C among people who inject drugs: a systematic review. Lancet Glob Health. 2017;5(12):e1208-e1220.
2. Kattakuzhy S, Mathur P, Gross C, et al. High SVR in PWID with HCV despite imperfect medication adherence: data from the ANCHOR study [AASLD abstract 18]. Hepatology. 2018;68(suppl 1).
Highlights in Hepatitis C Virus From the 2018 AASLD Liver Meeting: Commentary
Fred Poordad, MD
Professor of Medicine
Chief, Hepatology
University Transplant Center
The University of Texas Health, San Antonio
San Antonio, Texas
Studies presented at the 2018 American Association for the Study of Liver Diseases (AASLD) Liver Meeting provided interesting new data regarding the treatment of patients with hepatitis C virus (HCV). One late-breaking abstract, and several other presentations, focused on glecaprevir and pibrentasvir. New data were also presented on the sofosbuvir, velpatasvir, and voxilaprevir regimen. Studies examined outcomes among patients who use drugs, and the use of deceased donor grafts was also evaluated.
Glecaprevir and Pibrentasvir
Dr Robert S. Brown Jr. and colleagues presented a late-breaking abstract on the EXPEDITION-8 study, which evaluated glecaprevir and pibrentasvir given for 8 weeks to treatment-naive patients with compensated cirrhosis.1 Patients with cirrhosis typically receive 12 weeks of treatment, and this duration was used in the registration trial for glecaprevir and pibrentasvir.2 The current analysis aimed to determine whether patients with compensated cirrhosis could receive treatment for a shorter duration. The analysis provided data for 280 patients with HCV genotype 1, 2, 4, 5, or 6; most patients had genotype 1. There were no reports of virologic failure, and 98% of patients in the intention-to-treat population achieved a sustained virologic response (SVR). This outcome is consistent with the SVR data for the 12-week regimen. It therefore appears that 8 weeks of glecaprevir plus pibrentasvir among treatment-naive patients with non–genotype 3 HCV and compensated cirrhosis is comparable with 12 weeks.
Patients with HCV genotype 3 were introduced into the study at a later date. Data for these patients were not presented at the AASLD meeting, and they are eagerly awaited. It should be noted that the approval of glecaprevir plus pibrentasvir by the US Food and Drug Administration does not include patients with decompensated cirrhosis. All of the patients in the EXPEDITION-8 trial had well-compensated disease.
Dr Mark S. Sulkowski and colleagues from the Hepatitis C Target Network presented results of a study that evaluated glecaprevir and pibrentasvir in patients with HCV genotype 1 who had failed prior treatment with an NS5A inhibitor plus sofosbuvir.3 The study included regimens of 12 and 16 weeks; ribavirin was added to the 12-week regimen in patients with cirrhosis. The analysis provided data for 127 patients without cirrhosis and 50 patients with compensated disease. The study found that 16 weeks of treatment was better than 12 weeks, with SVR rates of 95% vs 89%, respectively. The addition of ribavirin to the 12-week regimen did not improve efficacy. The data therefore support the use of 16 weeks of glecaprevir and pibrentasvir for patients without cirrhosis or with compensated cirrhosis who require further treatment after receiving an NS5A inhibitor and sofosbuvir.
Dr Franco Felizarta and colleagues provided long-term follow-up data for 377 patients who had been treated in phase 2 or 3 studies of glecaprevir plus pibrentasvir.4 After a mean follow-up of 792 days, the SVR rate was 99.5%. Therefore, there were very few reports of late relapses, even among the 90 patients who had been treated with the 8-week regimen.
A study from the German Hepatitis C Registry evaluated real-world data for glecaprevir and pibrentasvir.5 The analysis showed an SVR rate of 99%. Similarly, a study by Dr Steven L. Flamm and colleagues examined data from the Trio Health Network.6 Among 478 treatment-naive, noncirrhotic patients with HCV genotypes 1 to 6, treatment with glecaprevir and pibrentasvir for 8 weeks was associated with an SVR rate of 100%.
Dr Maureen M. Jonas and colleagues presented results from the DORA study, which focused on children with HCV.7 Worldwide, approximately 13 million children ages 1 through 15 years are infected with HCV.8 Two regimens—sofosbuvir plus ledipasvir and sofosbuvir plus ribavirin—are now approved for children older than 12 years. The DORA study evaluated the use of glecaprevir plus pibrentasvir in children ages 12 to 17 years. Most patients received 8 weeks of treatment; 16 weeks were given to treatment-experienced patients with genotype 3. The SVR rate was 100%.
Sofosbuvir, Velpatasvir, and Voxilaprevir
Dr Pamela Belperio and colleagues evaluated treatment of HCV among patients in the US Department of Veterans Affairs HCV clinical case registry.9 The study examined data for 573 treatment-experienced patients, genotypes 1 through 4. Most of the patients had genotype 1 and had received prior treatment with an NS5A inhibitor. They were treated with sofosbuvir, velpatasvir, and voxilaprevir. Among patients with genotype 1 who completed therapy, the SVR rate was 95.1%. In contrast, the SVR rate was 46.5% among patients with genotype 1 who did not complete therapy. This study underscores the fact that adherence is absolutely necessary during treatment with the triple regimen of sofosbuvir, velpatasvir, and voxilaprevir.
Patients With Hepatitis C Virus Who Use Drugs
Dr Jason Grebely and colleagues presented results from the C-EDGE CO-STAR Part B study.10 Part A of this study assessed 12 weeks of elbasvir and grazoprevir in patients with HCV genotypes 1 through 6 who had received opioid agonist therapy for more than 3 months.11 This treatment was associated with a good SVR rate of 96%. The Part B analysis showed that high-risk behavior continued in spite of the SVR. In approximately 60% of patients, drug screening was positive for amphetamines, cocaine, opioids, benzodiazepines, or cannabinoids over a 30-month follow-up period. In addition, up to 26% of patients reported injection drug use in the previous 6 months. Interestingly, the reinfection rate throughout the 30-month follow-up period was 1.8 per 100 person-years in the overall population. This rate was somewhat higher, 2.8 per 100 person-years, among patients who reported intravenous drug use. Overall, the analysis shows that the majority of these patients will remain virus-free in spite of ongoing high-risk behavior.
A study by Dr Sarah Kattakuzhy and coworkers also evaluated outcome among patients with HCV who inject drugs.12 In the per-protocol group, treatment with 12 weeks of sofosbuvir and velpatasvir yielded an SVR12 rate of 89%. In spite of missing doses, problems with housing, issues with adherence, and interruptions in treatment, these patients still were able to achieve high rates of SVR, particularly if they completed all 12 weeks of therapy. This study shows that it is necessary to treat the population of patients who inject drugs in order to eradicate HCV. These patients still achieve very respectable SVR rates, even if some have poor adherence to treatment.
Donor Grafts
Dr Thomas G. Cotter and colleagues evaluated whether the advent of direct-acting antiviral (DAA) therapy has impacted graft survival after liver transplant.13 The study addressed the question of whether deceased donor grafts placed into patients with HCV would lead to reasonable survival outcomes. It found that HCV-positive recipients had better outcomes in the post-DAA era than before. In fact, their outcomes were similar to non-HCV recipients of deceased organ grafts. Based on this finding, the study authors concluded that it is viable to use organ grafts from deceased donors in patients with or without HCV.
Disclosure
Dr Poordad is on the speakers bureaus/advisory boards of and receives educational and research grants from Gilead Sciences, Merck, Bristol-Myers Squibb, AbbVie, and Intercept Pharmaceuticals.
References
1. Brown RS Jr, Hezode C, Wang S, et al. Preliminary efficacy and safety of 8-week glecaprevir/pibrentasvir in patients with HCV genotype 1-6 infection and compensated cirrhosis: the EXPEDITION-8 study [AASLD abstract LB-7]. Hepatology. 2018;68(suppl 1).
2. Wyles D, Poordad F, Wang S, et al. Glecaprevir/pibrentasvir for hepatitis C virus genotype 3 patients with cirrhosis and/or prior treatment experience: a partially randomized phase 3 clinical trial. Hepatology. 2017;67(2):514-523.
3. Sulkowski MS, Lok AS, Willner I, et al. High efficacy of glecaprevir/pibrentasvir in patients with chronic HCV GT1 infection who failed prior treatment with NS5A-inhibitor plus sofosbuvir regimens [AASLD abstract 226]. Hepatology. 2018;68(suppl 1).
4. Felizarta F, Asatryan A, Aguilar HI, et al. Durability of sustained virologic response and liver safety in patients treated with glecaprevir/pibrentasvir: a long-term follow-up study [AASLD abstract 602]. Hepatology. 2018;68(suppl 1).
5. Wiegand J, Naumann U, Stoehr A, et al. Glecaprevir/pibrentasvir for the treatment of patients with chronic hepatitis C virus infection: updated real-world data from the German Hepatitis C Registry [AASLD abstract 611]. Hepatology. 2018;68(suppl 1).
6. Flamm SL, Kort J, Marx S, et al. Effectiveness of 8-week glecaprevir/pibrentasvir for treatment-naive, non-cirrhotic patients with HCV infection in the Trio Health Network [AASLD abstract 632]. Hepatology. 2018;68(suppl 1).
7. Jonas MM, Squires RH, Rhee SM, et al. Pharmacokinetics, safety, and efficacy of glecaprevir/pibrentasvir in pediatric patients with genotypes 1-6 chronic HCV infection: part 1 of the DORA study [AASLD abstract 2379]. Hepatology. 2018;68(suppl 1).
8. Indolfi G, Hierro L, Dezsofi A, et al. Treatment of Chronic Hepatitis C Virus Infection in Children: A Position Paper by the Hepatology Committee of European Society of Paediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr. 2018;66(3):505-515.
9. Belperio P, Bakckus L, Shahoumian T, Loomis T, Mole L. Real-world effectiveness of sofosbuvir/velpatasvir/voxilaprevir in 573 treatment-experienced patients with hepatitis C genotypes 1 through 4 [AASLD abstract 227]. Hepatology. 2018;68(suppl 1).
10. Grebely J, Litwin AH, Dalgard O, et al. HCV reinfection and injecting risk behavior following elbasvir/grazoprevir treatment in patients on opioid agonist therapy: CO-STAR Part B [AASLD abstract 52]. Hepatology. 2018;68(suppl 1).
11. Dore GJ, Altice F, Litwin AH, et al; C-EDGE CO-STAR Study Group. Elbasvir-grazoprevir to treat hepatitis C virus infection in persons receiving opioid agonist therapy: a randomized trial. Ann Intern Med. 2016;165(9):625-634.
12. Kattakuzhy S, Mathur P, Gross C, et al. High SVR in PWID with HCV despite imperfect medication adherence: data from the ANCHOR study [AASLD abstract 18]. Hepatology. 2018;68(suppl 1).
13. Cotter TG, Paul S, Sandikçi B, et al. Improved graft survival after liver transplantation for recipients with hepatitis C in the direct-acting antiviral era [AASLD abstract 228]. Hepatology. 2018;68(suppl 1).