THE RISKS OF HEPATOCELLULAR CARCINOMA AND VARICEAL BLEEDING AFTER HCV ERADICATION WITH DIRECT-ACTING ANTIVIRAL THERAPY: A PROPENSITY SCORE ANALYSIS

https://www.doi.org/10.22551/MSJ.2021.01.08

  • TRIFAN Anca “Grigore T. Popa” University of Medicine and Pharmacy Iasi
  • STANCIU C. “Grigore T. Popa” University of Medicine and Pharmacy Iasi
  • GIRLEANU Irina “Grigore T. Popa” University of Medicine and Pharmacy Iasi
  • SINGEAP Ana Maria “Grigore T. Popa” University of Medicine and Pharmacy Iasi
  • COJOCARIU Camelia “Grigore T. Popa” University of Medicine and Pharmacy Iasi
  • CIJEVSCHI PRELIPCEAN Cristina “Grigore T. Popa” University of Medicine and Pharmacy Iasi
  • MIHAI Catalina “Grigore T. Popa” University of Medicine and Pharmacy Iasi
  • POP Corina “Carol Davila” University of Medicine and Pharmacy, Bucharest
  • STEFANESCU Gabriela “Grigore T. Popa” University of Medicine and Pharmacy Iasi
  • CIORTESCU Irina “Grigore T. Popa” University of Medicine and Pharmacy Iasi
  • DIMACHE Mihaela “Grigore T. Popa” University of Medicine and Pharmacy Iasi
  • MANOLACHE M. “Carol Davila” University of Medicine and Pharmacy, Bucharest
  • IACOB Speranta “Carol Davila” University of Medicine and Pharmacy, Bucharest
  • GHEORGHE Liana “Carol Davila” University of Medicine and Pharmacy, Bucharest
  • PREDA Carmen “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
  • CUCIUREANU T. “Grigore T. Popa” University of Medicine and Pharmacy Iasi
  • MUZICA Cristina Maria “Grigore T. Popa” University of Medicine and Pharmacy Iasi
  • HUIBAN Laura “Grigore T. Popa” University of Medicine and Pharmacy Iasi
  • MIFTODE Egidia “Grigore T. Popa” University of Medicine and Pharmacy Iasi
  • SFARTI C. “Grigore T. Popa” University of Medicine and Pharmacy Iasi

Abstract

The combination paritaprevir/ritonavir, ombitasvir, and dasabuvir (PrOD), which achieves a high sustained virologic response (SVR) rate and few side effects, has dramatically changed the outcome of hepatitis C virus (HCV) infection. The risk of hepatocellular carcinoma (HCC) and variceal bleeding in patients treated with interferon (IFN)-free direct-acting antivirals (DAAs) is unknown. The aim of this prospective study was to evaluate the rate of HCC and variceal bleeding and identify prognostic factors for decompensation/complications in HCV-1b-infected patients with compensated liver cirrhosis following treatment with PrOD with or without ribavirin. Material and methods: A total of 483 HCV patients received PrOD treatment. Patients with a history of HCC were excluded from the study. Prior antiviral therapy was identified in 59% of patients. Patient data were collected at baseline, at the end of treatment (EoT), at 3 months after EOT (SVR) and during an 18-month surveillance period. Patients were divided into two age groups: <60 years (233 patients) and ≥60 years (250 patients). Results: The median observation period was 540 days. During this period, HCC developed in 18 patients (3.7%) and variceal bleeding developed in 9 patients (1.9%). A Propensity score matching analysis found no significant difference in the incidence of HCC (p= 0.078) or variceal bleeding (p=0.426) between the two groups. The mean serum AFP levels decreased in the young group (baseline=19.44 ng/dL, SVR=4.57 ng/dL) and the elderly group (baseline=4.52 ng/dL, SVR=10.69 ng/dL). Edge of decompensation and previous esophageal varices were significantly associated with the risk of variceal bleeding. Conclusions: The risk of HCC (5.3%) and variceal bleeding (2%) development in elderly patients (≥60years) following viral eradication by IFN-free DAA therapy may follow a specific pattern.

Author Biographies

TRIFAN Anca, “Grigore T. Popa” University of Medicine and Pharmacy Iasi

“Sf. Spiridon” Country Clinical Emergency Hospital, Iasi
Institute of Gastroenterology and Hepatology

STANCIU C., “Grigore T. Popa” University of Medicine and Pharmacy Iasi

“Sf. Spiridon” Country Clinical Emergency Hospital, Iasi
Institute of Gastroenterology and Hepatology

GIRLEANU Irina, “Grigore T. Popa” University of Medicine and Pharmacy Iasi

Sf. Spiridon” Country Clinical Emergency Hospital, Iasi
Institute of Gastroenterology and Hepatology

SINGEAP Ana Maria, “Grigore T. Popa” University of Medicine and Pharmacy Iasi

Sf. Spiridon” Country Clinical Emergency Hospital, Iasi
Institute of Gastroenterology and Hepatology

COJOCARIU Camelia, “Grigore T. Popa” University of Medicine and Pharmacy Iasi

Sf. Spiridon” Country Clinical Emergency Hospital, Iasi
Institute of Gastroenterology and Hepatology

CIJEVSCHI PRELIPCEAN Cristina, “Grigore T. Popa” University of Medicine and Pharmacy Iasi

Sf. Spiridon” Country Clinical Emergency Hospital, Iasi
Institute of Gastroenterology and Hepatology

MIHAI Catalina, “Grigore T. Popa” University of Medicine and Pharmacy Iasi

Sf. Spiridon” Country Clinical Emergency Hospital, Iasi
Institute of Gastroenterology and Hepatology

POP Corina, “Carol Davila” University of Medicine and Pharmacy, Bucharest

Emergency Universitary Hospital, Bucharest
Internal Medicine & Gastroenterology Department

STEFANESCU Gabriela, “Grigore T. Popa” University of Medicine and Pharmacy Iasi

“Sf. Spiridon” Country Clinical Emergency Hospital, Iasi
Institute of Gastroenterology and Hepatology

CIORTESCU Irina, “Grigore T. Popa” University of Medicine and Pharmacy Iasi

“Sf. Spiridon” Country Clinical Emergency Hospital, Iasi
Institute of Gastroenterology and Hepatology

DIMACHE Mihaela, “Grigore T. Popa” University of Medicine and Pharmacy Iasi

“Sf. Spiridon” Country Clinical Emergency Hospital, Iasi
Institute of Gastroenterology and Hepatology

MANOLACHE M., “Carol Davila” University of Medicine and Pharmacy, Bucharest

CEBIS International SAGL – Switzerland

IACOB Speranta, “Carol Davila” University of Medicine and Pharmacy, Bucharest

“Fundeni” Clinical Institute, Gastroenterology and Hepatology Center, Bucharest

GHEORGHE Liana, “Carol Davila” University of Medicine and Pharmacy, Bucharest

“Fundeni” Clinical Institute, Gastroenterology and Hepatology Center, Bucharest

PREDA Carmen, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania

“Fundeni” Clinical Institute, Gastroenterology and Hepatology Center, Bucharest

CUCIUREANU T., “Grigore T. Popa” University of Medicine and Pharmacy Iasi

“Sf. Spiridon” Country Clinical Emergency Hospital, Iasi
Institute of Gastroenterology and Hepatology

MUZICA Cristina Maria, “Grigore T. Popa” University of Medicine and Pharmacy Iasi

“Sf. Spiridon” Country Clinical Emergency Hospital, Iasi
Institute of Gastroenterology and Hepatology

HUIBAN Laura, “Grigore T. Popa” University of Medicine and Pharmacy Iasi

“Sf. Spiridon” Country Clinical Emergency Hospital, Iasi
Institute of Gastroenterology and Hepatology

MIFTODE Egidia, “Grigore T. Popa” University of Medicine and Pharmacy Iasi

“Sf. Parascheva” Infectious Disease Clinical Hospital, Iasi

SFARTI C., “Grigore T. Popa” University of Medicine and Pharmacy Iasi

Sf. Spiridon” Country Clinical Emergency Hospital, Iasi
Institute of Gastroenterology and Hepatology

References

1. Guarino M, Sessa A, Cossiga V, Morando F, Caporaso N, Morisco F. Direct-acting antivirals and hepatocellular carcinoma in chronic hepatitis C: a few lights and many shadows. World J Gastroenterol 2018; 24: 2582-2595.
2. Hezode C, Fontaine H, Dorival C, et al. Triple therapy in treatment-experienced patients with HCV-cirrhosis in a multicentre cohort of the French early access programme (ANRS CO20-CUPIC) - NCT01514890. J Hepatol 2013; 59: 434-441.
3. Modi AA, Nazario H, Trotter JF, et al. Safety and efficacy of simeprevir plus sofosbuvir with or without ribavirin in patients with decompensated genotype 1 hepatitis C cirrhosis. Liver Transpl 2016; 22: 281-286.
4. Forns X, Poordad F, Pedrosa M, et al. Ombitasvir/paritaprevir/r, dasabuvir and ribavirin for cirrhotic HCV patients with thrombocytopenia and hypoalbuminaemia. Liver Int 2015; 35: 2358-2362.
5. Hilgenfeldt EG, Schlachterman A, Firpi RJ. Hepatitis C: treatment of difficult to treat patients. World J Hepatol 2015; 7: 1953-1963.
6. Afdhal NH. Hepatitis C viral infection in difficult-to-treat populations: an overview. Clin Liver Dis 2012; 1: 63-64.
7. Fattovich G, Giustina G, Degos F, et al. Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 patients. Gastroenterology 1997; 112: 463-472.
8. Kobayashi M, Suzuki F, Fujiyama S, et al. Sustained virologic response by direct antiviral agents reduces the incidence of hepatocellular carcinoma in patients with HCV infection. J Med Virol 2017; 89: 476-83.
9. Nagaoki Y, Imamura M, Aikata H, et al. The risks of hepatocellular carcinoma development after HCV eradication are similar between patients treated with peg-interferon plus ribavirin and direct-acting antiviral therapy. PLoS One 2017; 12: e0182710.
10. Ioannou GN, Green PK, Berry K. HCV eradication induced by direct-acting antiviral agents reduces the risk of hepatocellular carcinoma. J Hepatol 2017; 68: 25-32.
11. Castera L. Transient elastography and other noninvasive tests to assess hepatic fibrosis in patients with viral hepatitis. J Viral Hepat 2009; 16: 300-314.
12. Grattagliano I, Ubaldi E, Napoli L, et al. Utility of noninvasive methods for the characterization of nonalcoholic liver steatosis in the family practice. The "VARES" Italian multicenter study. Ann Hepatol 2013; 12: 70-77.
13. European Association for the Study of the Liver. EASL clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 2018; 69: 182-236.
14. deFranchis R. Expanding consensus in portal hypertension: report of the Baveno VI consensus work-shop: stratifying risk and individualizing care for portal hypertension. J Hepatol 2015; 63: 743-752.
15. Yoshida EM, Sulkowski MS, Gane EJ, et al. Concordance of sustained virological response 4-, 12-, and 24-weeks post-treatment with sofosbuvir-containing regimens for hepatitis C virus. Hepatology 2015; 61: 41-45.
16. Di Martino V, Crouzet J, Hillon P, Thevenot T, Minello A, Monnet E. Long-term outcome of chronic hepatitis C in a population-based cohort and impact of antiviral therapy: a propensity-adjusted analysis. J Viral Hepat 2011; 18: 493-505.
17. Preda C, Popescu C, Baicus C, et al. Real world efficacy and safety of ombitasvir, Paritaprevir/r+ Dasabuvir+Ribavirin IN genotype 1B patients with HCV liver cirrhosis. Liver Int 2018; 38(4): 602-610.
18. D'Agostino RB, Jr. Propensity score methods for bias reduction in the comparison of a treatment to a non-randomized control group. Stat Med 1998; 17: 2265-2281.
19. Reig M, Marino Z, Perello C, et al. Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing interferon-free therapy. J Hepatol 2016; 65: 719-726.
20. Yang JD, Aqel BA, Pungpapong S, Gores GJ, Roberts LR, Leise MD. Direct acting antiviral therapy and tumor recurrence after liver transplantation for hepatitis C-associated hepatocellular carcinoma. J Hepatol 2016; 65: 859-860.
21. Mettke F, Schlevogt B, Deterding K, et al. Interferon-free therapy of chronic hepatitis C with direct-acting antivirals does not change the short-term risk for de novo hepatocellular carcinoma in patients with liver cirrhosis. Aliment Pharmacol Ther 2018; 47: 516-525.
22. Asahina Y, Tsuchiya K, Nishimura T, et al. Alpha-fetoprotein levels after interferon therapy and risk of hepatocarcinogenesis in chronic hepatitis C. Hepatology 2013; 58: 1253-1262.
23. Ioannou GN, Splan MF, Weiss NS, McDonald GB, Beretta L, Lee SP. Incidence and predictors of hepatocellular carcinoma in patients with cirrhosis. Clin Gastroenterol Hepatol 2007; 5: 938-945.
24. Sangiovanni A, Prati GM, Fasani P, Ronchi G, Romeo R, Manini M, et al. The natural history of compensated cirrhosis due to hepatitis C virus: a 17-year cohort study of 214 patients. Hepatology 2006; 43: 1303-1310.
25. D'Ambrosio R, Aghemo A, Rumi MG, et al. The course of esophageal varices in patients with hepatitis C cirrhosis responding to interferon/ribavirin therapy. Antivir Ther 2011; 16: 677-684.
26. Trifan A, Stanciu C, Gheorghe L, et al. Efficacy and safety of paritaprevir/ritonavir, ombitasvir, and dasabuvir with ribavirin or the treatment of HCV genotype 1b compensated cirrhosis in patients aged 70 years or older. Medicine 2017; 96 (50): e9271.
27. Groszmann RJ, Garcia-Tsao G, Bosch J, et al. Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis. N Engl J Med 2005; 353 (21): 2254-2261.
28. Merli M, Nicolini G, Angeloni S, et al. Incidence and natural history of small esophageal varices in cirrhotic patients. J Hepatol 2003; 38 (3): 266-272.
Published
2021-03-30
Section
INTERNAL MEDICINE - PEDIATRICS