Unexpected high incidence of hepatocellular carcinoma in cirrhotic patients with sustained virologic response following interferon-free direct-acting antiviral treatment (2016)

Unexpected high incidence of hepatocellular carcinoma in patients with hepatitis C in the era of DAAs: Too alarming?Journal of HepatologyVol. 65Issue 5PreviewAs a terminator of hepatitis C virus (HCV) infection, sofosbuvir-based direct-acting antiviral agent (DAA) regimens have achieved great success in the eradication of HCV in patients with hepatitis C and related end stage liver diseases [1,2]. Recently, we read with interest the studies by Reig et al. [3] and Kozbial et al. [4] on the surprisingly high incidence of hepatocellular carcinoma (HCC) recurrence and occurrence in patients with advanced liver diseases during interferon (IFN)-free therapy and after sustained virologic response (SVR), respectively. Full-Text PDF Like the investigators from Barcelona [[1]Reig M. Mariño Z. Perelló C. Iñarrairaegui M. Ribeiro A. Lens S. et al.Unexpected early tumor recurrence in patients with hepatitis C virus -related hepatocellular carcinoma undergoing interferon-free therapy: a note of caution.J Hepatol. 2016; 65: 719-726Abstract Full Text Full Text PDF PubMed Scopus (736) Google Scholar] we also observed the occurrence of hepatocellular carcinoma (HCC) in patients with advanced liver disease shortly after interferon (IFN)-free direct-acting antiviral (DAA) combination therapy; in 16 without and in 3 with previous HCC. Fifteen patients were treated without (AURIC: Austrian ribavirin/interferon-free cohort; ClinicalTrials.gov, NCT02628717) and 4 with ribavirin (RBV). 14 of them achieved sustained virologic response (SVR), 5 relapsed. Before treatment all patients had an imaging method at the discretion of their physician to exclude HCC. The time interval between the last imaging examinations (by ultrasound in 11, each 4 by MRI or CT scan) without evidence of HCC and the start of treatment was 2 months (SD ± 2.1) (see Supplementary Table 1). At baseline, alpha-fetoprotein (AFP) was either within the normal range (<5.8 IU/ml) or minimally increased. Only two patients had a high AFP at baseline, which became normal in one at end of treatment (EOT). For details of these 19 patients with HCC see Table 1.Table 1Patients who developed HCC on or after treatment with DAA combinations.+Not part of AURIC; ∗patients with previous HCC, who were successfully treated and were in complete remission for >3 years; &mixed hepatocellular/cholangiocellular carcinoma.BL, baseline; CPS, Child-Pugh Score; CR, complete remission; DCV, daclatasvir; EoT, end of treatment; GT, genotype; HCC, hepatocellular carcinoma; LDV, ledipasvir; n.d., not done; RBV, ribavirin; SMV, simeprevir; SOF, sofosbuvir; 3D, paritaprevir/ombitasvir/dasabuvir. Open table in a new tab +Not part of AURIC; ∗patients with previous HCC, who were successfully treated and were in complete remission for >3 years; &mixed hepatocellular/cholangiocellular carcinoma. BL, baseline; CPS, Child-Pugh Score; CR, complete remission; DCV, daclatasvir; EoT, end of treatment; GT, genotype; HCC, hepatocellular carcinoma; LDV, ledipasvir; n.d., not done; RBV, ribavirin; SMV, simeprevir; SOF, sofosbuvir; 3D, paritaprevir/ombitasvir/dasabuvir. The patients with HCC can be classified in three groups. Eleven of the 14 cirrhotic patients (#1 to #9, #18, #19) without evidence of HCC in their past history had a SVR 48. Their tumors were relatively small at diagnosis. At EOT, 5 had normal serum AFP levels, and was increased in nine (data missing in 5). At diagnosis of HCC, AFP increased markedly in four, and was stable or normal in seven (AFP in #2, #4, and #9 is missing). The second group consisted of three patients (#10–12) with complete remission after treatment for preexistent HCC (surgical resection in one, radiofrequency ablation in 2). One of them had cirrhosis (#10), and 2 had no evidence of cirrhosis at biopsy. All three had a SVR 48 but developed a HCC during follow up. The third group consisted of 5 patients (#13–17) with relapse at or shortly after EOT. In patient #14, bone metastasis was documented at EOT, and hepatitis C virus (HCV) became detectable again. Further workup showed a HCC. Patient #15 relapsed 1 month after EOT, an ultrasound showed no evidence of a lesion. On retreatment with paritaprevir/ombitasvir/dasabuvir + RBV, AFP levels increased at week 8 of retreatment and HCC was finally diagnosed by magnetic resonance tomography (MRT) one month after EOT. Similar observations were made in patients with complete remission after treatment for HCC treated with IFN-free combination regimens (1) and in Italian patients with cirrhosis without or with previous HCC [[2]Buonfiglioli F, Conti F, Andreone P, Crespi C, Foschi FG, Marco Lenzi, et al. Development of hepatocellular carcinoma in HCV cirrhotic patients treated with direct acting antivirals. Late Breaker Abstract, 51. Annual Meeting of EASL, Barcelona, 2016.Google Scholar]. There is no clear explanation for these observations, but this high number raises the suspicion of a possible relation of HCC with IFN-free DAA therapy. Obviously, patients with advanced liver disease are at high risk for HCC and possibly HCC occurred just by chance in temporal relation to antiviral therapy. Three patients had a HCC in their previous history, but had a documented disease free period of many years and had no evidence for a recurrent HCC by imaging methods. Pretreatment, even the best imaging methods cannot exclude a small HCC with certainty [[3]Park M.S. Kim S. Patel J. Hajdu C.H. Do R.K. Mannelli L. et al.Hepatocellular carcinoma: detection with diffusion-weighted versus contrast-enhanced magnetic resonance imaging in pretransplant patients.Hepatology. 2012; 56: 140-148Crossref PubMed Scopus (94) Google Scholar]. The two-fold increase in HCC rates in Japanese patients treated with IFN-free regimens as compared to IFN/RBV therapy [[4]Toyoda H. Kumada T. Tada T. Changes in patient backgrounds may increase the incidence of HCC after SVR in the era of IFN-free therapy for HCV.Hepatology. 2016; (e-pub)https://doi.org/10.1002/hep.28632Crossref PubMed Scopus (30) Google Scholar] was explained by the higher age and more advanced stage of liver disease. In the present study only 4 of the 19 patients with HCC had Child-Pugh B and one Child-Pugh C. Calculating the frequency of HCC in our patients is difficult. Using the 182 AURIC patients completing 48 weeks of follow-up without developing HCC and the 16 with HCC as denominator, the HCC rate was 8.1% (16/198). By a more conservative estimate (by excluding the 3 patients with the history of HCC) it would be 6.6% overall (13/195) and 5.2% (10/192 in patients with SVR). We hope that the real frequency will be lower when all AURIC patients completed 48 weeks of follow-up. Whatever number is used, it is higher than the estimated 1%/year frequency of HCC in patients with SVR treated with IFN/RBV dual therapy [5van der Meer A.J. Wedemeyer H. Feld J.J. Dufour J.F. Zeuzem S. Hansen B.E. et al.Life expectancy in patients with chronic HCV infection and cirrhosis compared with a general population.JAMA. 2014; 312: 1927-1928Crossref PubMed Scopus (78) Google Scholar, 6Rutter K. Stättermayer A.F. Beinhardt S. Scherzer T.M. Steindl-Munda P. Trauner M. et al.Successful antiviral treatment improves survival of patients with advanced liver disease due to chronic hepatitis C.Aliment Pharmacol Ther. 2015; 41: 521-531Crossref PubMed Scopus (34) Google Scholar, 7Di Marco V. Calvaruso V. Ferraro D. Bavetta M.G. Cabibbo G. Conte E. et al.Effects of viral eradication in patients with HCV and cirrhosis differ with stage of portal hypertension.Gastroenterology. 2016; (pii: S0016-5085(16)30049-X. [Epub ahead of print])https://doi.org/10.1053/j.gastro.2016.03.036Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar, 8Lu M. Li J. Rupp L.B. Holmberg S.D. Moorman A.C. Spradling P.R. et al.CHeCS InvestigatorsHepatitis C treatment failure is associated with increased risk of hepatocellular carcinoma.J Viral Hepat. 2016; ([Epub ahead of print])https://doi.org/10.1111/jvh.12538Crossref Scopus (29) Google Scholar]. Of the 94 Austrian cirrhotic patients with SVR treated with IFN/RBV 10 developed a HCC within a mean follow-up of 7.8 years (see Fig. 1) [[8]Lu M. Li J. Rupp L.B. Holmberg S.D. Moorman A.C. Spradling P.R. et al.CHeCS InvestigatorsHepatitis C treatment failure is associated with increased risk of hepatocellular carcinoma.J Viral Hepat. 2016; ([Epub ahead of print])https://doi.org/10.1111/jvh.12538Crossref Scopus (29) Google Scholar]. Further explanations are that major mechanisms for regeneration are stimulated by curing inflammation, and the changed immunologic environment compared to treatment with IFN-containing treatments leading to growth of precancerous lesions or of small malignant cell clones [[9]Bruix J. Gores G.J. Mazzaferro V. Hepatocellular carcinoma: clinical frontiers and perspectives.Gut. 2014; 63: 844-855Crossref PubMed Scopus (1073) Google Scholar]. Interferon is an immune modulator with anti-proliferative properties. With IFN-free treatments, it has been shown that the rapid disappearance of HCV leads to reconstitution of innate immunity [[10]Serti E. Chepa-Lotrea X. Kim Y.J. Keane M. Fryzek N. Liang T.J. et al.Successful interferon-free therapy of chronic hepatitis C virus infection normalizes natural killer cell function.Gastroenterology. 2015; 149: 190-200Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar] and downregulation of type II and III IFNs, their receptors, and interferon stimulated genes [11Meissner E.G. Wu D. Osinusi A. Bon D. Virtaneva K. Sturdevant D. et al.Endogenous intrahepatic IFNs and association with IFN-free HCV treatment outcome.J Clin Invest. 2014; 124: 3352-3363Crossref PubMed Scopus (166) Google Scholar, 12Meissner E.G. Kohli A. Virtaneva K. Sturdevant D. Martens C. Porcella S.F. et al.Achieving sustained virologic response after interferon-free hepatitis C virus treatment correlates with hepatic interferon gene expression changes independent of cirrhosis.J Viral Hepat. 2016; https://doi.org/10.1111/jvh.12510Crossref PubMed Scopus (32) Google Scholar]. The lack of interferon activation may allow growth of malignant cells. Another factor involved may be miR-122, which plays a central role in suppressing viral replication and controlling hepatocarcinogenesis [13Harouaka D. Engle R.E. Wollenberg K. Diaz G. Tice A.B. Zamboni F. et al.Diminished viral replication and compartmentalization of hepatitis C virus in hepatocellular carcinoma tissue.Proc Natl Acad Sci U S A. 2016; 113: 1375-1380Crossref PubMed Scopus (44) Google Scholar, 14Tsai W.C. Hsu P.W. Lai T.C. Chau G.Y. Lin C.W. Chen C.M. et al.MicroRNA-122, a tumor suppressor microRNA that regulates intrahepatic metastasis of hepatocellular carcinoma.Hepatology. 2009; 49: 1571-1582Crossref PubMed Scopus (511) Google Scholar, 15Li C. Deng M. Hu J. Li X. Chen L. Ju Y. et al.Chronic inflammation contributes to the development of hepatocellular carcinoma by decreasing miR-122 levels.Oncotarget. 2016; ([Epub ahead of print])https://doi.org/10.18632/oncotarget.7740Crossref Google Scholar, 16Jialin H. Kai Z. Lu Z. Xu Zhizhen Wei G. Shan C. et al.Upregulation of microRNA-122 by farnesoid X receptor suppresses the growth of hepatocellular carcinoma cells.Infect Agent Cancer. 2016; 11 ([eCollection]): 9https://doi.org/10.1186/s13027-016-0056-yCrossref PubMed Scopus (4) Google Scholar]. miR-122 concentrations decrease on IFN-free DAA therapy, in serum levels [[17]Waring J.F. Dumas E.O. Abel S. Coakley E. Cohen D.E. Davis J.W. et al.Serum miR-122 may serve as a biomarker for response to direct acting antivirals: effect of paritaprevir/R with dasabuvir or ombitasvir on miR-122 in HCV-infected subjects.Oncotarget. 2016; ([Epub ahead of print])https://doi.org/10.18632/oncotarget.7740Crossref PubMed Scopus (52) Google Scholar]. If confirmed, these observations may have an important implication. Patients with cirrhosis should undergo regular HCC screening after achieving SVR. In patients on the orthotopic liver transplantation (OLT) waiting list the risk of developing a HCC could be argument for treating them only after successful transplantation. In contrast, treating non-cirrhotic patients as early as possible may prevent the development of HCC. Karin Kozbial, Stephan Moser, Remy Schwarzer, Hermann Laferl, Ramona El-Zoairy, Sandra Beinhardt, Clarissa Freissmuth, Michael Strasser: nothing to disclose. Albert F. Stättermayer received honoraria for consulting from Gilead, payments for lectures from Boehringer Ingelheim, Janssen, and Roche, as well as travel support from Bristol-Myerss Squibb, Gilead, Janssen, and Roche. Rudolf Stauber: received lecture fees from AbbVie, BMS, Gilead, and Merz; advisory board member of: AbbVie, BMS, Gilead, and MSD, unrestricted research grant: Abbvie, MSD. Ivo Graziadei: received lecture fees from AbbVie, MSD, Bristol Myers-Squibb, Gilead, and Janssen. Andreas Maieron: received lecture fees from AbbVie, MSD, Bristol Myers-Squibb, Gilead, and Janssen; advisory board member of: AbbVie, MSD, Bristol Myers-Squibb, Gilead, and Janssen. Michael Gschwantler: received lecture fees from AbbVie, MSD, Bristol Myers-Squibb, Gilead, and Janssen; advisory board member of: AbbVie, MSD, Bristol Myers-Squibb, Gilead, and Janssen. Markus Peck-Radosalvjevic: received grants from Gilead, MSD and Roche, honoraria for board membership and consulting from AbbVie, Boehringer Ingelheim, Bristol-Myerss Squibb, Gilead, Janssen and MSD, as well as payments for lectures from AbbVie, Boehringer Ingelheim, Bristol-Myerss Squibb, Gilead, Janssen, MSD and Roche. Michael Trauner: received grants from Albireo, Falk, Intercept, MSD, Takeda, honoraria for consulting from Albireo, AbbVie, Falk, Gilead, Janssen, MSD, Phenex, and Novartis, payments for lectures from BMS, Falk, Gilead, MSD and Roche. Harald Hofer: received lecture fees from AbbVie, MSD, Bristol Myers-Squibb, Gilead, and Janssen; advisory board member of: AbbVie, MSD, Bristol Myers-Squibb, Gilead, and Janssen; unrestricted research grant from AbbVie. Peter Ferenci: Advisory board: Merck, AbbVie, BMS, Gilead, Roche, Wilson Therapeutics, Speaker bureau: Abbvie, Gilead, MSD, BMS, unrestricted research grant: Roche, Gilead; received lecture fees from AbbVie, MSD, Bristol Myers-Squibb, Gilead, and Janssen. Karin Kozbial collected the data, maintained and updated the central database, data analysis. Stefan Moser, Remy Schwarzer, Hermann Laferl, Ramona Al-Zoairy, Rudolf Stauber, Sandra Beinhardt, Ivo Graziadei, Clarissa Freissmuth, Michael Strasser, Andreas Maieron: acquisition of data. Albert F. Stättermayer: data analysis, Michael Gschwantler, Markus Peck-Radosalvjevic, Michael Trauner, Harald Hofer: critical revision of the manuscript for important intellectual content. Peter Ferenci: study concept and design, analysis and interpretation of data, writing of the manuscript. Download .pdf (.04 MB) Help with pdf files Supplementary Table 1