OVERVIEW

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Glecaprevir, Pibrentasvir – Mavyret®

DRUG CLASS

Hepatitis C Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULAS AND STRUCTURES

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DRUG	CAS REGISTRY NUMBER	MOLECULAR FORMULA	STRUCTURE
Glecaprevir	1365970-03-1	C38-H46-F4-N6-O9-S
Pibrentasvir	1353900-92-1	C57-H65-F5-N10-O8	SID:252163521

ANNOTATED BIBLIOGRAPHY

References updated: 07 February 2022

Abbreviations: HCV, hepatitis C virus; DAA, direct acting antiviral agent; SVR, sustained virological response; ULN, upper limit of the normal range.

• Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013.

  (Multi-authored textbook of hepatotoxicity published in 2013; does not discuss oral, direct acting antiviral agents used to treat hepatitis C).
• European Association for Study of Liver. EASL Recommendations on treatment of hepatitis C 2015. J Hepatol. 2015;63:199–236. [PubMed: 25911336]

  (Guidelines for the antiviral therapy of chronic hepatitis C from the European liver disease research and academic society).
• AASLD/IDSA HCV Guidance Panel. Hepatitis C guidance: AASLD-IDSA recommendations for testing, managing, and treating adults infected with hepatitis C virus. Hepatology. 2015;62:932–54. [PubMed: 26111063]

  (Guidelines for the antiviral therapy of chronic hepatitis C from the US liver and infectious diseases research and academic societies).
• Gane E, Poordad F, Wang S, Asatryan A, Kwo PY, Lalezari J, Wyles DL, et al. High Efficacy of ABT-493 and ABT-530 treatment in patients with HCV genotype 1 or 3 infection and compensated cirrhosis. Gastroenterology. 2016;151:651–659.e1. [PubMed: 27456384]

  (Among 82 cirrhotic patients with chronic HCV infection genotypes 1 or 3 who were treated with glecaprevir and pibrentasvir for 12 or 16 weeks with or without ribavirin, the overall SVR rate was 98% and no patient developed hepatic decompensation).
• Kwo PY, Poordad F, Asatryan A, Wang S, Wyles DL, Hassanein T, Felizarta F, et al. Glecaprevir and pibrentasvir yield high response rates in patients with HCV genotype 1-6 without cirrhosis. J Hepatol. 2017;67:263–71. [PubMed: 28412293]

  (Among 449 noncirrhotic patients with chronic HCV infection of all genotypes treated with glecaprevir and pibrentasvir with or without ribavirin for 8 or 12 weeks in 2 open label trials, SVR rates were excellent [97-100%], except in patients with genotype 3 [83-94%], and there were no ALT elevations after the initial decreases from baseline).
• Poordad F, Felizarta F, Asatryan A, Sulkowski MS, Reindollar RW, Landis CS, Gordon SC, et al. Glecaprevir and pibrentasvir for 12 weeks for hepatitis C virus genotype 1 infection and prior direct-acting antiviral treatment. Hepatology. 2017;66:389–97. [PMC free article: PMC5573922] [PubMed: 28128852]

  (Among 91 noncirrhotic patients with chronic HCV infection, genotype 1, previously treated with NS3/4 or NS5A inhibitors, who received glecaprevir and pibrentasvir, SVR rates were 86-100% and there were no liver related serious adverse events or ALT elevations above 3 times ULN).
• AASLD. http://www​.hcvguidelines.org/

  (Guidelines for therapy of hepatitis C maintained and regularly updated by the American Association for the Study of Liver Diseases [AASLD] and the Infectious Diseases Society of America [IDSA]).
• Gane E, Lawitz E, Pugatch D, Papatheodoridis G, Bräu N, Brown A, Pol S, et al. Glecaprevir and pibrentasvir in patients with HCV and severe renal impairment. N Engl J Med. 2017;377:1448–55. [PubMed: 29020583]

  (Among 104 patients with chronic hepatitis C [any genotype] and severe renal dysfunction [82% on dialysis] treated with glecaprevir and pibrentasvir for 12 weeks, the SVR rate was 98% and no patient developed hepatic decompensation or ALT elevations above 3 times ULN).
• Forns X, Lee SS, Valdes J, Lens S, Ghalib R, Aguilar H, Felizarta F, 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;17:1062–8. [PubMed: 28818546]

  (Among 146 patients with compensated cirrhosis due to chronic hepatitis C [genotypes 1, 2, 4, 5 and 6] treated with glecaprevir and pibrentasvir for 12 weeks, 99% had an SVR, while 11 patients [8%] had a serious adverse event, but none had late ALT elevations above 5 times ULN or hepatic decompensation).
• Mavyret and Vosevi--two new combinations for chronic HCV infection. Med Lett Drugs Ther. 2017;59(1531):166–70. [PubMed: 28977807]

  (Concise review of mechanism of action, clinical efficacy, safety and costs of Mavyret; mentions that common adverse effects are headache, fatigue and nausea and that the product label has a boxed warning of HBV reactivation).
• Asselah T, Kowdley KV, Zadeikis N, Wang S, Hassanein T, Horsmans Y, Colombo M, et al. Efficacy of glecaprevir/pibrentasvir for 8 or 12 Weeks in patients with hepatitis C virus genotype 2, 4, 5, or 6 infection without cirrhosis. Clin Gastroenterol Hepatol. 2018;16:417–26. [PubMed: 28951228]

  (Among 526 patients with chronic hepatitis C, genotypes 2, 4, 5 and 6, treated with Mavyret, SVR rates were 93-98% with 8 weeks and 99% with 12 weeks, ALT elevations above 5 times ULN occurred in 3 subjects, one becoming jaundiced at week 12, but resolving completely within 2 weeks of discontinuation and accompanied by an SVR).
• Chayama K, Suzuki F, Karino Y, Kawakami Y, Sato K, Atarashi T, Naganuma A, et al. Efficacy and safety of glecaprevir/pibrentasvir in Japanese patients with chronic genotype 1 hepatitis C virus infection with and without cirrhosis. J Gastroenterol. 2018;53:557–65. [PMC free article: PMC5866824] [PubMed: 28948366]

  (Among 129 Japanese noncirrhotic patients with chronic hepatitis C, genotype 1, treated with glecaprevir/pibrentasivir for 8 weeks, the SVR rate was 99%, while among 38 cirrhotic patients treated for 12 weeks the SVR rate was 100%).
• Zeuzem S, Foster GR, Wang S, Asatryan A, Gane E, Feld JJ, Asselah T, et al. Glecaprevir-pibrentasvir for 8 or 12 weeks in HCV genotype 1 or 3 infection. N Engl J Med. 2018;378:354–69. [PubMed: 29365309]

  (Among 1208 patients with chronic hepatitis C without cirrhosis who were treated with glecaprevir and pibrentasvir for 8 or 12 weeks, SVR rates were 99% with 8 weeks of therapy in genotype 1 and 95% with 8 or 12 weeks of therapy in genotype 3 infected patients and there were no ALT elevations above 5 times ULN, no instances of decompensated liver disease or early termination of therapy for hepatic adverse events).
• Poordad F, Pol S, Asatryan A, Buti M, Shaw D, Hézode C, Felizarta F, et al. Glecaprevir/pibrentasvir in patients with HCV genotype 1 or 4 and prior direct-acting antiviral treatment failure. Hepatology. 2018;67:1253–60. [PMC free article: PMC5901397] [PubMed: 29152781]

  (Among 91 patients with chronic hepatitis C, genotypes 1 and 4, who had failed previous DAA therapy and were treated with glecaprevir and pibrentasvir, SV rates were 89% with 12 weeks and 91% for 16 weeks, relapse occurring only in those with previous exposure to NS5A inhibitors; there were no ALT elevations above 5 times ULN during therapy, but 3 patients were found to have liver cancer within 12 weeks of completing treatment).
• Wyles D, Poordad F, Wang S, Alric L, Felizarta F, Kwo PY, Maliakkal B, 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. 2018;67:514–23. [PMC free article: PMC5817409] [PubMed: 28926120]

  (Among 131 patients with chronic hepatitis C, genotype 3, with cirrhosis or previous failure of antiviral therapy who received glecaprevir and pibrentasvir, the SVR rate was 91% with 12 weeks and 96% with 16 weeks of treatment, the differences being largely among those with previous therapy; no patient had a late increase in ALT levels or episode of hepatic decompensation).
• Rockstroh JK, Lacombe K, Viani RM, Orkin C, Wyles D, Luetkemeyer AF, Soto-Malave R, et al. Efficacy and safety of glecaprevir/pibrentasvir in patients co-infected with hepatitis C virus and human immunodeficiency virus-1: the EXPEDITION-2 Study. Clin Infect Dis. 2018;67:1010–7. [PMC free article: PMC6137115] [PubMed: 29566246]

  (Among 153 patients with chronic hepatitis C [genotype 1 to 6] who were coinfected with HIV and were treated with glecaprevir and pibrentasvir for 8 or 12 weeks, SVR rates were 98% with either duration of treatment, and there were no ALT or AST elevations above 3 times ULN or instances of decompensated liver disease).
• Garrison KL, German P, Mogalian E, Mathias A. The drug-drug interaction potential of antiviral agents for the treatment of chronic hepatitis C infection. Drug Metab Dispos. 2018;46:1212–1225. [PubMed: 29695614]

  (Extensive summary of drug-drug interactions of the drugs used to treat chronic hepatitis C; Glecaprevir and pibrentasvir are substrates of P-glycoprotein [Pgp] and weak inhibitors of Pgp, CYP3A, CYP1A2 and UGT1A1).
• Caroleo B, Caroleo MC, Cimellaro A, Colangelo L, Perticone M, Di Mizio G, De Sarro G, et al. Glecaprevir/ pibrentasvir induced cholestatic jaundice in a HCV patient with renal failure. a case presentation. Curr Drug Saf. 2019;14:67–71. [PubMed: 30444202]

  (86 year old man with chronic hepatitis C and possible cirrhosis developed jaundice within 4 weeks of starting Mavyret [bilirubin 5.8 mg/dL, ALT 43 U/L, GGT 34 U/L, INR and albumin normal], which resolved within 1 month of stopping and patient was HCV RNA negative in follow up).
• Hammami MB, Aboushaar R, Alsabbagh E. Glecaprevir/pibrentasvir-associated acute liver injury in non-cirrhotic, chronic HCV infection without HBV co-infection. BMJ Case Rep. 2019;12:e226622. [PMC free article: PMC6536190] [PubMed: 31129632]

  (A 53 year old woman with chronic hepatitis C without cirrhosis developed jaundice 2-3 weeks after starting Mavyret [bilirubin 6.8 mg/dL, ALT 974 U/L, Alk P 177 U/L, INR 1.2], symptoms resolving within a week of stopping and with normal liver tests and no detectable HCV RNA in serum in follow up).
• Yoon JH, Kim SM, Kang G, Kim HJ, Jun CH, Choi SK. A case report of glecaprevir/pibrentasvir-induced severe hyperbilirubinemia in a patient with compensated liver cirrhosis. Medicine (Baltimore). 2019;98:e17343. [PMC free article: PMC6775421] [PubMed: 31574875]

  (77 year old man with chronic hepatitis C, cirrhosis, a history of hepatocellular cancer and tuberculosis developed jaundice 3 weeks after starting Mavyret [bilirubin 21.6 mg/dL, ALT normal], which resolved within a few weeks of stopping therapy; in follow up he was HCV RNA negative and bilirubin fell to 1.2 mg/dL).
• Persico M, Aglitti A, Milella M, Coppola C, Messina V, Claar E, Gentile I, et al. Real-life glecaprevir/pibrentasvir in a large cohort of patients with hepatitis C virus infection: The MISTRAL study. Liver Int. 2019;39:1852–1859. [PubMed: 31175707]

  (Among 1177 patients with chronic hepatitis C enrolled in an observational study of therapy with Mavyret, the overall SVR was 99% and adverse event rate was 5.2% with 6 serious adverse events, two of which were jaundice).
• Gane E, Poordad F, Zadeikis N, Valdes J, Lin CW, Liu W, Asatryan A, et al. Safety and pharmacokinetics of glecaprevir/pibrentasvir in adults with chronic genotype 1-6 hepatitis C virus infections and compensated liver disease. Clin Infect Dis. 2019;69:1657–1664. [PMC free article: PMC6821220] [PubMed: 30923816]

  (Among 2369 patients with chronic hepatitis C treated with Mavyret for 8-16 weeks in 9 clinical trials, the 308 with cirrhosis compared to those without had similar rates of SVR [96% vs 97.5%], adverse events [74% vs 67%], serious adverse events [6% vs 2%], ALT elevations above 5 times ULN [0% vs <1%]; and one patient with cirrhosis and esophageal varices had a variceal bleed without evidence of hepatic worsening on day 22 and continued therapy and achieved an SVR).
• Brown RS Jr, Buti M, Rodrigues L, Chulanov V, Chuang WL, Aguilar H, Horváth G, et al. Glecaprevir/pibrentasvir for 8 weeks in treatment-naïve patients with chronic HCV genotypes 1-6 and compensated cirrhosis: The EXPEDITION-8 trial. J Hepatol. 2020;72:441–449. [PubMed: 31682879]

  (Among 343 patients with chronic hepatitis C and compensated cirrhosis treated with Mavyret for 8 weeks, the overall SVR rate was 98%, and 46% had adverse events, 2% serious, no patient developed hepatic decompensation, and only one had an isolated single elevation of ALT above 5 times ULN).
• Liu YC, Jeng WJ, Cheng YT, Hsieh YC, Teng W, Chen YC, Lin CY, et al. Incidence and predictors for abnormal liver function during direct-acting antiviral agents in chronic hepatitis C patients. Medicine (Baltimore). 2020;99:e21898. [PMC free article: PMC7489670] [PubMed: 32925725]

  (Among 1563 patients with chronic hepatitis C treated with direct acting antiviral agents between 2015 -2019 at a single referral center in Taiwan, the SVR rate was 98% and on treatment ALT elevations arose in 11%, with higher rates in those with cirrhosis, with elevated levels pre-treatment, and those receiving asunaprevir with daclatasvir [40%], compared to Zepatier [12.3%], sofosbuvir-based regimens [11.6%] and Mavyret [5.4%]; on treatment ALT elevations were not associated with a lower SVR rate).
• Aghemo A, Alberti A, Andreone P, Angelico M, Brunetto MR, Chessa L, Ciancio A, et al. MARS Study Group. Effectiveness and safety of glecaprevir/pibrentasvir in chronic hepatitis C patients: Results of the Italian cohort of a post-marketing observational study. Dig Liver Dis. 2021;53:612–619. [PubMed: 32917546]

  (Among 321 patients with chronic hepatitis C treated with Mavyret followed in a postmarketing observational study, the SVR rate in those with follow up was 99% and adverse event rate 9%, which were serious in 1.2%, one patient developing ascites).
• Wedemeyer H, Erren P, Naumann U, Rieke A, Stoehr A, Zimmermann T, Lohmann K, et al. Glecaprevir/pibrentasvir is safe and effective in hepatitis C patients with cirrhosis: Real-world data from the German Hepatitis C-Registry. Liver Int. 2021;41:949–955. [PubMed: 33592123]

  (Among 182 patients with chronic hepatitis C and cirrhosis who were treated with Mavyret and followed in a prospective observation study, the SVR rate was 100% in patients with follow up and serious adverse events arose in 4% including 1 patient with liver transplant, 1 with hepatic decompensation, and 4 with ALT elevations above 3 times ULN).
• Forns X, Feld JJ, Dylla DE, Pol S, Chayama K, Hou J, Heo J, et al. Safety of patients with hepatitis C virus treated with glecaprevir/pibrentasvir from clinical trials and real-world cohorts. Adv Ther. 2021;38:3409–3426. [PMC free article: PMC8189955] [PubMed: 34021887]

  (Among 5106 patients with chronic hepatitis C treated with Mavyret in clinical trials or postmarketing observational studies, the overall SVR rate was 97.5% and adverse event rate in clinical trials was 61%, scored as serious in 1.7%; ALT elevations above 5 times ULN arose in 0.2% and 2 patients developed jaundice with ALT elevations and 1 patient [with preexisting cirrhosis) had hepatic decompensation).
• Klinker H, Naumann U, Rössle M, Berg T, Bondin M, Lohmann K, Koenig B, et al. Glecaprevir/pibrentasvir for 8 weeks in patients with compensated cirrhosis: safety and effectiveness data from the German Hepatitis C-Registry. Liver Int. 2021;41:1518–1522. [PubMed: 33966349]

  (Among 148 patients with chronic hepatitis C and cirrhosis who were treated with Mavyret and enrolled in a German Registry, the SVR rate was 98% among those with follow up and no patient had a drug-related severe adverse event, although one developed jaundice which persisted after stopping and despite an SVR).
• Hara T, Ohara T, Taniguchi M, Sakai H, Oka K, Iwai N, Tsuji T, et al. Severe liver injury associated with glecaprevir plus pibrentasvir therapy in a patient with treatment-naïve hepatitis C virus infection. Intern Med. 2021;60:2437–2443. [PMC free article: PMC8381168] [PubMed: 33612683]

  (49 year old Japanese man with chronic hepatitis C, HBsAg carrier state and history of alcoholism developed jaundice 6 weeks after starting Mavyret [pre-treatment bilirubin 1.4 rising to 20.6 mg/dL, ALT 50 to 65 U/L, AST 100 to 205 U/L, Alk P 436 to 442 U/L, INR 1.2, HBV DNA remaining negative] and evidence of hepatic encephalopathy, but ultimately recovered and was HCV RNA negative).
• Torgersen J, Newcomb CW, Carbonari DM, Rentsch CT, Park LS, Mezochow A, Mehta RL, et al. Protease inhibitor-based direct-acting antivirals are associated with increased risk of aminotransferase elevations but not hepatic dysfunction or decompensation. J Hepatol. 2021;75:1312–1322. [PMC free article: PMC8604762] [PubMed: 34333102]

  (Among propensity matched subgroups of 71,391 adults with chronic hepatitis C treated in the Veterans Administration Medical system with oral, direct acting antiviral agents, patients with higher baseline fibrosis scores compared to those with lower scores were more likely to have serum ALT elevations [>200 U/L] [0.5% vs 0.3%] and hepatic decompensation [0.41% vs 0.03%], and ALT elevations were more frequent with Viekira Pak and Technive [1.1-1.2%] compared to Mavyret, Zepatier, Epclusa, and Harvoni [0.11-0.39%]).
• Huang CF, Kuo HT, Chang TS, Lo CC, Hung CH, Huang CW, Chong LW, et al. Nationwide registry of glecaprevir plus pibrentasvir in the treatment of HCV in Taiwan. Sci Rep. 2021;11:23473. [PMC free article: PMC8648748] [PubMed: 34873250]

  (Among 3144 patients with chronic hepatitis C treated with Mavyret and enrolled in a nationwide Taiwanese HCV registry, the SVR rate was 99% and adverse events included ALT elevations in 2%, but most were mild and transient, only 0.6% were above 5 times ULN, and no patient developed clinically apparent liver injury or hepatic decompensation).