Evaluation of efficacy and safety of interferon-free “3D” regimen among patients with non-compensated cirrhosis caused by HCV genotype 1b infection
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Moscow Regional Research Clinical Institute named after M.F. Vladimirsky, Moscow, Russia
First Moscow State Medical University named after I. M. Sechenov, Moscow, Russia
Online publish date: 2018-03-16
Publish date: 2018-03-16
Submission date: 2018-02-02
Acceptance date: 2018-02-02
Electron J Gen Med 2018;15(4):em37
The first interferon-free regimen became available in Russia in 2015. It brought hope to HCV Gt1 patients with cirrhosis for whom interferon-based schemes found to be non-effective or contraindicated. 3D therapy was the only available etiotropic option for them. New safety data published after the start of our study significantly limited usage of this regimen among patients with non-compensated cirrhosis. The aim of this study was to evaluate efficacy and safety of the 3D interferon-free regimen among HCV Gt1b patients with non-compensated cirrhosis.

66 patients (26 males and 40 females) with HCV Gt1b and non-compensated cirrhosis were enrolled. All of them were treated with ombitasvir/paritaprevir/ritonavir, dasabuvir and ribavirin for 12 weeks. Ribavirin was discontinued after 4 weeks of therapy due to onset of new data on the efficacy of 3D regimen without ribavirin in Turquoise III study published in September 2015 before the change of package insert. Child-Pugh score was assessed before the start of antiviral therapy as follows: 21 patients (31,8%) – 9 points, 11 patients (16,7%) – 8 points, 34 patients (51,5%) – 7 points. The key method used to evaluate study results was modified intent-to-treat (mITT) analysis because number of analyzed patients within treatment period changed after withdrawal caused by safety reasons but followed by assessment of efficacy among patients who discontinued treatment. Per protocol (PP) method was also used in addition to mITT.

Aviremia after 14 days of treatment was reached among 35 out of 65 patients (53,8%), rapid virologic response – among 79,7% patients (51/64). Each patient who received full 12-week course of treatment (n=60) including those who discontinued due to safety reasons (n=3) between 14th and 30th days of therapy reached SVR12 and SVR24. Assessment of Child-Pugh score in 6 months after EOT demonstrated decrease by 3-4 points among 21 patients (33,9%) and by 1-2 points among 35 patients. 66,1% patients reached clinical improvement in MELD score. Treatment discontinuation was caused by progression of hepatic encephalopathy and/or jaundice (4 cases). Those adverse events regressed among majority of patients after discontinuation of therapy. 3 deaths were reported (bacterial endocarditis, progression of hepatic encephalopathy and bleeding from gastric ulcers) during treatment period and 1 death in follow-up period due to progression of hepatocellular carcinoma.

3D therapy was effective in 100% patients (mITT) with HCV GT1b and non-compensated cirrhosis both among those who completed full therapy course and those who discontinued the therapy due to safety reasons. Safety analysis demonstrated that the rate of severe adverse events was comparable with natural course of HCV-infection in patients on non-compensated cirrhotic stage without antiviral treatment.

1. D'Amico G, Morabito A, D'Amico M, Pasta L, Malizia G, Rebora P, Valsecchi MG. Clinical states of cirrhosis and competing risks. J Hepatol. 2017 Oct 27;68(3):563-76. pii: S0168-8278(17)32399-1 https://doi.org/10.1016/j.jhep... [Epub ahead of print].
2. Keane MG, Hensher C, Pereira SP. Improving the identification and monitoring of cirrhosis. Practitioner. 2016 Nov;260(1798):25-9.
3. Poordad FF. Presentation and complications associated with cirrhosis of the liver. Curr Med Res Opin. 2015 May;31(5):925-37. https://doi.org/10.1185/030079....
4. Tapper EB, Kanwal F, Asrani SK, Ho C, Ovchinsky N, Poterucha J, Flores A, Smith JE, Ankoma-Sey V, Luxon B, Volk M. Patient Reported Outcomes in Cirrhosis: A Scoping Review of the Literature. Hepatology. 2017 Dec 22. https://doi.org/10.1002/hep.29... [Epub ahead of print].
5. Jacobson IM, Lim JK, Fried MW. American Gastroenterological Association Institute Clinical Practice Update-Expert Review: Care of Patients Who Have Achieved a Sustained Virologic Response After Antiviral Therapy for Chronic Hepatitis C Infection. Gastroenterology. 2017 May;152(6):1578-1587. https://doi.org/10.1053/j.gast... Epub 2017 Mar 23.
6. Petta S, Di Marco V, Bruno S, Enea M, Calvaruso V, Boccaccio V, Rossi S, Craxì A, Cammà C. Impact of virus eradication in patients with compensated hepatitis C virus-related cirrhosis: competing risks and multistate model. Liver Int. 2016 Dec;36(12):1765-1773. https://doi.org/10.1111/liv.13... Epub 2016 Oct 19.
7. Chen Yi Mei SLG, Thompson AJ, Christensen B, Cunningham G, McDonald L, Bell S, Iser D, Nguyen T, Desmond PV. Sustained virological response halts fibrosis progression: A long-term follow-up study of people with chronic hepatitis C infection. PLoS One. 2017 Oct 24;12(10):e0185609. https://doi.org/10.1371/journa... eCollection 2017.
8. Butt AA, Yan P, Lo Re V. 3rd, Rimland D, Goetz MB, Leaf D. et al. Liver fibrosis progres sion in hepatitis C virus infection after seroconversion. JAMA Intern Med. 2015; 175: 178–185.
9. Rogal SS, Yan P, Rimland D, Lo Re V 3rd, Al-Rowais H, Fried L, Butt AA; Electronically Retrieved Cohort of HCV Infected Veterans Study Group. Incidence and Progression of Chronic Kidney Disease After Hepatitis C Seroconversion: Results from ERCHIVES. Dig Dis Sci. 2016 Mar;61(3):930-6. https://doi.org/10.1007/s10620... Epub 2015 Nov.
10. Rogal SS, Udawatta V, Akpan I, Moghe A, Chidi A, Shetty A, Szigethy E, Bielefeldt K, DiMartini A. Risk factors for hospitalizations among patients with cirrhosis: A prospective cohort study. PLoS One. 2017 Nov 17;12(11):e0187176. https://doi.org/10.1371/journa... eCollection 2017.
11. Kartoun U, Corey KE, Simon TG, Zheng H, Aggarwal R, Ng K, Shaw SY. The MELD-Plus: A generalizable prediction risk score in cirrhosis. PLoS One. 2017 Oct 25;12(10):e0186301. https://doi.org/10.1371/journa... eCollection 2017.
12. Nasta P. "Immune activation, aging and gender" and progression of liver disease. Acta Biomed. 2011 Aug;82(2):115-23.
13. Grannan S. Understanding patient perceptions and risk for hepatitis C screening. J Viral Hepat. 2017 Aug;24(8):631-635. https://doi.org/10.1111/jvh.12... Epub 2017 Apr 5.
14. Waziry R, Grebely J, Amin J., Alavi M, Hajarizadeh B, George J., Matthews GV, Law M, Dore GJ. Trends in hepatocellular carcinoma among people with HBV or HCV notification in Australia (2000-2014). J Hepatol. 2016 Aug 26. pii: S0168-8278(16)30442-1. https://doi.org/10.1016/j.jhep....
15. Budny A, Kozłowski P, Kamińska M, Jankiewicz M, Kolak A, Budny B, Budny W, Niemunis-Sawicka J, Szczypiór G, Kurniawka B, Burdan F.Epidemiology and risk factors of hepatocellular carcinoma. Pol Merkur Lekarski. 2017 Sep 29;43(255):133-39.
16. Kanwal F, Hoang T, Kramer JR., Asch SM, Goetz MB., Zeringue A. et al. Increasing prevalence of HCC and cirrhosis in patients with chronic hepatitis C virus infection. Gastroenterology. 2011;140:1182–88.
17. Taniguchi M. Liver transplantation in the MELD era-analysis of the OPTN/UNOS registry. Clin Transpl. 2012:41-65.
18. Fagiuoli S, Ravasio R, Lucà MG, Baldan A, Pecere S, Vitale A, Pasulo L. Management of hepatitis C infection before and after liver transplantation. World J Gastroenterol. 2015 Apr 21;21(15):4447-56. https://doi.org/10.3748/wjg.v2....
19. Xu Y, Qi W, Wang X, Zhao P, Zhang Y, Zhang Q, Qin S, Wang J. Pegylated interferon α-2a plus ribavirin for decompensated hepatitis C virus-related cirrhosis: relationship between efficacy and cumulative dose. Liver Int. 2014 Nov;34(10):1522-31.
20. Hézode C, Fontaine H, Dorival C et al. CUPIC Study Group. Effectiveness of telaprevir or boceprevir in treatment-experienced patients with HCV genotype 1 infection and cirrhosis. Gastroenterology. 2014;147(1):132-42.
21. Ferenci P. Treatment of hepatitis C in difficult-to-treat patients. Nat Rev Gastroenterol Hepatol. 2015 May;12(5):284-92.
22. Feld JJ, Moreno C, Trinh R, Tam E, Bourgeois S, Horsmans Y, Elkhashab M, Bernstein DE, Younes Z, Reindollar RW, Larsen L, Fu B, Howieson K, Polepally AR, Pangerl A, Shulman NS, Poordad F. Sustained virologic response of 100% in HCV genotype 1b patients with cirrhosis receiving ombitasvir/paritaprevir/r and dasabuvir for 12weeks. J Hepatol. 2016 Feb;64(2):301-7. https://doi.org/10.1016/j.jhep... Epub 2015 Oct 22.
23. Ferenci P, Bernstein D, Lalezari J, Cohen D, Luo Y, Cooper C, et al. PEARL-III Study; PEARL-IV Study.ABT-450/r-ombitasvir and dasabuvir with or without ribavirin for HCV. N Engl J Med. 2014 May 22;370(21):1983-92.
24. Zeuzem S, Jacobson IM, Baykal T, Marinho RT, Poordad F, Bourlière M, Sulkowski MS, Wedemeyer H, Tam E, Desmond P, Jensen DM, Di Bisceglie AM, Varunok P, Hassanein T, Xiong J, Pilot-Matias T, DaSilva-Tillmann B, Larsen L, Podsadecki T, Bernstein B. Retreatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med. 2014 Apr 24;370(17):1604-14. https://doi.org/10.1056/NEJMoa... Epub 2014 Apr 10.
25. Poordad F, Hezode C, Trinh R, Kowdley KV, Zeuzem S, Agarwal K, Shiffman ML, Wedemeyer H, Berg T, Yoshida EM, Forns X, Lovell SS, Da Silva-Tillmann B, Collins CA, Campbell AL, Podsadecki T, Bernstein B. ABT-450/r-ombitasvir & dasabuvir with ribavirin for hepatitis C with cirrhosis. N Engl J Med. 2014 May 22;370(21):1973-82. https://doi.org/10.1056/NEJMoa... Epub 2014 Apr 11.
26. US Food and Drug Administration FDA Drug Safety Communication: FDA warns of serious liver injury risk with hepatitis C treatments Viekira Pak and Technivie. Available at http://www.fda.gov/Drugs/DrugS... (accessed 17 April 2016).