The Impact of Direct-Acting Antiviral Therapy on the Risk of Recurrence after Curative Resection in Patients with Hepatitis-C-Virus-Related Early Stage Hepatocellular Carcinoma
Abstract
:1. Introduction
2. Materials and Methods
2.1. Patients
2.2. HCC Diagnosis and Follow-Up
2.3. Antiviral Therapy
2.4. Statistical Analysis
3. Results
3.1. Characteristics of the Patients
3.2. Subgroup Analysis
3.3. Univariate and Multivariate Analyses of Independent Risk Factors
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- El-Serag, H.B. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology 2012, 142, 1264–1273.e1. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chapman, W.C.; Klintmalm, G.; Hemming, A.; Vachharajani, N.; Majella Doyle, M.B.; DeMatteo, R.; Zaydfudim, V.; Chung, H.; Cavaness, K.; Goldstein, R.; et al. Surgical treatment of hepatocellular carcinoma in North America: Can hepatic resection still be justified? J. Am. Coll. Surg. 2015, 220, 628–637. [Google Scholar] [CrossRef] [PubMed]
- Kudo, M.; Izumi, N.; Sakamoto, M.; Matsuyama, Y.; Ichida, T.; Nakashima, O.; Matsui, O.; Ku, Y.; Kokudo, N.; Makuuchi, M. Survival Analysis over 28 Years of 173,378 Patients with Hepatocellular Carcinoma in Japan. Liver Cancer 2016, 5, 190–197. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Shiina, S.; Tateishi, R.; Arano, T.; Uchino, K.; Enooku, K.; Nakagawa, H.; Asaoka, Y.; Sato, T.; Masuzaki, R.; Kondo, Y.; et al. Radiofrequency ablation for hepatocellular carcinoma: 10-year outcome and prognostic factors. Am. J. Gastroenterol. 2012, 107, 569–577; quiz 578. [Google Scholar] [CrossRef] [Green Version]
- Shim, J.H.; Jun, M.J.; Han, S.; Lee, Y.J.; Lee, S.G.; Kim, K.M.; Lim, Y.S.; Lee, H.C. Prognostic nomograms for prediction of recurrence and survival after curative liver resection for hepatocellular carcinoma. Ann. Surg. 2015, 261, 939–946. [Google Scholar] [CrossRef]
- Tabrizian, P.; Jibara, G.; Shrager, B.; Schwartz, M.; Roayaie, S. Recurrence of hepatocellular cancer after resection: Patterns, treatments, and prognosis. Ann. Surg. 2015, 261, 947–955. [Google Scholar] [CrossRef]
- Villanueva, A. Hepatocellular Carcinoma. N. Engl. J. Med. 2019, 380, 1450–1462. [Google Scholar] [CrossRef] [Green Version]
- Fried, M.W.; Shiffman, M.L.; Reddy, K.R.; Smith, C.; Marinos, G.; Gonçales, F.L., Jr.; Häussinger, D.; Diago, M.; Carosi, G.; Dhumeaux, D.; et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N. Engl. J. Med. 2002, 347, 975–982. [Google Scholar] [CrossRef] [Green Version]
- Innes, H.A.; McDonald, S.A.; Dillon, J.F.; Allen, S.; Hayes, P.C.; Goldberg, D.; Mills, P.R.; Barclay, S.T.; Wilks, D.; Valerio, H.; et al. Toward a more complete understanding of the association between a hepatitis C sustained viral response and cause-specific outcomes. Hepatology 2015, 62, 355–364. [Google Scholar] [CrossRef] [Green Version]
- van der Meer, A.J.; Veldt, B.J.; Feld, J.J.; Wedemeyer, H.; Dufour, J.F.; Lammert, F.; Duarte-Rojo, A.; Heathcote, E.J.; Manns, M.P.; Kuske, L.; et al. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA 2012, 308, 2584–2593. [Google Scholar] [CrossRef]
- Ogawa, E.; Furusyo, N.; Kajiwara, E.; Takahashi, K.; Nomura, H.; Maruyama, T.; Tanabe, Y.; Satoh, T.; Nakamuta, M.; Kotoh, K.; et al. Efficacy of pegylated interferon alpha-2b and ribavirin treatment on the risk of hepatocellular carcinoma in patients with chronic hepatitis C: A prospective, multicenter study. J. Hepatol. 2013, 58, 495–501. [Google Scholar] [CrossRef] [PubMed]
- Nahon, P.; Bourcier, V.; Layese, R.; Audureau, E.; Cagnot, C.; Marcellin, P.; Guyader, D.; Fontaine, H.; Larrey, D.; De Lédinghen, V.; et al. Eradication of Hepatitis C Virus Infection in Patients with Cirrhosis Reduces Risk of Liver and Non-Liver Complications. Gastroenterology 2017, 152, 142–156.e142. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- El-Serag, H.B.; Kanwal, F.; Richardson, P.; Kramer, J. Risk of hepatocellular carcinoma after sustained virological response in Veterans with hepatitis C virus infection. Hepatology 2016, 64, 130–137. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Fried, M.W. Side effects of therapy of hepatitis C and their management. Hepatology 2002, 36, S237–S244. [Google Scholar] [CrossRef]
- Afdhal, N.; Zeuzem, S.; Kwo, P.; Chojkier, M.; Gitlin, N.; Puoti, M.; Romero-Gomez, M.; Zarski, J.P.; Agarwal, K.; Buggisch, P.; et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N. Engl. J. Med. 2014, 370, 1889–1898. [Google Scholar] [CrossRef] [Green Version]
- Charlton, M.; Everson, G.T.; Flamm, S.L.; Kumar, P.; Landis, C.; Brown, R.S., Jr.; Fried, M.W.; Terrault, N.A.; O’Leary, J.G.; Vargas, H.E.; et al. Ledipasvir and Sofosbuvir Plus Ribavirin for Treatment of HCV Infection in Patients with Advanced Liver Disease. Gastroenterology 2015, 149, 649–659. [Google Scholar] [CrossRef] [Green Version]
- Leroy, V.; Angus, P.; Bronowicki, J.P.; Dore, G.J.; Hezode, C.; Pianko, S.; Pol, S.; Stuart, K.; Tse, E.; McPhee, F.; et al. Daclatasvir, sofosbuvir, and ribavirin for hepatitis C virus genotype 3 and advanced liver disease: A randomized phase III study (ALLY-3+). Hepatology 2016, 63, 1430–1441. [Google Scholar] [CrossRef]
- Abdelaziz, A.O.; Nabil, M.M.; Abdelmaksoud, A.H.; Shousha, H.I.; Cordie, A.A.; Hassan, E.M.; Omran, D.A.; Leithy, R.; Elbaz, T.M. De-novo versus recurrent hepatocellular carcinoma following direct-acting antiviral therapy for hepatitis C virus. Eur. J. Gastroenterol. Hepatol. 2018, 30, 39–43. [Google Scholar] [CrossRef]
- Conti, F.; Buonfiglioli, F.; Scuteri, A.; Crespi, C.; Bolondi, L.; Caraceni, P.; Foschi, F.G.; Lenzi, M.; Mazzella, G.; Verucchi, G.; et al. Early occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with direct-acting antivirals. J. Hepatol. 2016, 65, 727–733. [Google Scholar] [CrossRef]
- Alberti, A.; Piovesan, S. Increased incidence of liver cancer after successful DAA treatment of chronic hepatitis C: Fact or fiction? Liver Int. 2017, 37, 802–808. [Google Scholar] [CrossRef]
- Nishibatake Kinoshita, M.; Minami, T.; Tateishi, R.; Wake, T.; Nakagomi, R.; Fujiwara, N.; Sato, M.; Uchino, K.; Enooku, K.; Nakagawa, H.; et al. Impact of direct-acting antivirals on early recurrence of HCV-related HCC: Comparison with interferon-based therapy. J. Hepatol. 2019, 70, 78–86. [Google Scholar] [CrossRef] [PubMed]
- Waziry, R.; Hajarizadeh, B.; Grebely, J.; Amin, J.; Law, M.; Danta, M.; George, J.; Dore, G.J. Hepatocellular carcinoma risk following direct-acting antiviral HCV therapy: A systematic review, meta-analyses, and meta-regression. J. Hepatol. 2017, 67, 1204–1212. [Google Scholar] [CrossRef] [PubMed]
- Cabibbo, G.; Petta, S.; Barbàra, M.; Missale, G.; Virdone, R.; Caturelli, E.; Piscaglia, F.; Morisco, F.; Colecchia, A.; Farinati, F.; et al. A meta-analysis of single HCV-untreated arm of studies evaluating outcomes after curative treatments of HCV-related hepatocellular carcinoma. Liver Int. 2017, 37, 1157–1166. [Google Scholar] [CrossRef]
- Reig, M.; Boix, L.; Marino, Z.; Torres, F.; Forns, X.; Bruix, J. Liver Cancer Emergence Associated with Antiviral Treatment: An Immune Surveillance Failure? Semin. Liver Dis. 2017, 37, 109–118. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Giovannini, C.; Fornari, F.; Indio, V.; Trerè, D.; Renzulli, M.; Vasuri, F.; Cescon, M.; Ravaioli, M.; Perrucci, A.; Astolfi, A.; et al. Direct Antiviral Treatments for Hepatitis C Virus Have Off-Target Effects of Oncologic Relevance in Hepatocellular Carcinoma. Cancers 2020, 12, 2674. [Google Scholar] [CrossRef] [PubMed]
- Nagaoki, Y.; Imamura, M.; Nishida, Y.; Daijo, K.; Teraoka, Y.; Honda, F.; Nakamura, Y.; Morio, K.; Fujino, H.; Nakahara, T.; et al. The impact of interferon-free direct-acting antivirals on clinical outcome after curative treatment for hepatitis C virus-associated hepatocellular carcinoma: Comparison with interferon-based therapy. J. Med. Virol. 2019, 91, 650–658. [Google Scholar] [CrossRef]
- Cabibbo, G.; Celsa, C.; Calvaruso, V.; Petta, S.; Cacciola, I.; Cannavò, M.R.; Madonia, S.; Rossi, M.; Magro, B.; Rini, F.; et al. Direct-acting antivirals after successful treatment of early hepatocellular carcinoma improve survival in HCV-cirrhotic patients. J. Hepatol. 2019, 71, 265–273. [Google Scholar] [CrossRef]
- Ochi, H.; Hiraoka, A.; Hirooka, M.; Koizumi, Y.; Amano, M.; Azemoto, N.; Watanabe, T.; Yoshida, O.; Tokumoto, Y.; Mashiba, T.; et al. Direct-acting antivirals improve survival and recurrence rates after treatment of hepatocellular carcinoma within the Milan criteria. J. Gastroenterol. 2021, 56, 90–100. [Google Scholar] [CrossRef]
- Manthravadi, S.; Paleti, S.; Pandya, P. Impact of sustained viral response postcurative therapy of hepatitis C-related hepatocellular carcinoma: A systematic review and meta-analysis. Int. J. Cancer 2017, 140, 1042–1049. [Google Scholar] [CrossRef]
- He, S.; Lockart, I.; Alavi, M.; Danta, M.; Hajarizadeh, B.; Dore, G.J. Systematic review with meta-analysis: Effectiveness of direct-acting antiviral treatment for hepatitis C in patients with hepatocellular carcinoma. Aliment. Pharmacol. Ther. 2020, 51, 34–52. [Google Scholar] [CrossRef] [Green Version]
- Degasperi, E.; D’Ambrosio, R.; Iavarone, M.; Sangiovanni, A.; Aghemo, A.; Soffredini, R.; Borghi, M.; Lunghi, G.; Colombo, M.; Lampertico, P. Factors Associated with Increased Risk of De Novo or Recurrent Hepatocellular Carcinoma in Patients with Cirrhosis Treated with Direct-Acting Antivirals for HCV Infection. Clin. Gastroenterol. Hepatol. 2019, 17, 1183–1191.e1187. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ahn, Y.H.; Lee, H.; Kim, D.Y.; Lee, H.W.; Yu, S.J.; Cho, Y.Y.; Jang, J.W.; Jang, B.K.; Kim, C.W.; Kim, H.Y.; et al. Independent Risk Factors for Hepatocellular Carcinoma Recurrence after Direct-Acting Antiviral Therapy in Patients with Chronic Hepatitis C. Gut Liver 2021, 15, 410–419. [Google Scholar] [CrossRef] [PubMed]
- Kishta, S.; Tabll, A.; Omanovic Kolaric, T.; Smolic, R.; Smolic, M. Risk Factors Contributing to the Occurrence and Recurrence of Hepatocellular Carcinoma in Hepatitis C Virus Patients Treated with Direct-Acting Antivirals. Biomedicines 2020, 8, 175. [Google Scholar] [CrossRef] [PubMed]
No HCV Tx (n = 104) | DAA Tx (n = 48) | p-Value | |
---|---|---|---|
Age (years) | 66.1 ± 808 | 65.2 ± 8.7 | 0.561 |
Sex, male | 66 (63.5%) | 26 (54.2%) | 0.276 |
Diabetes mellitus | 35 (33.7%) | 13 (27.1%) | 0.418 |
Platelet (1000/μL) | 144.5 ± 57.7 | 129.8 ± 42.7 | 0.118 |
AST (U/L) | 63.1 ± 55.3 | 66.8 ± 50.8 | 0.695 |
ALT (U/L) | 61.1 ± 46.5 | 70.5 ± 51.8 | 0.270 |
Total bilirubin (mg/dL) | 0.8 ± 0.3 | 1.2 ± 2.8 | 0.282 |
Albumin (g/dL) | 3.5 ± 0.7 | 3.5 ± 06 | 0.814 |
Creatinine (mg/dL) | 1.1 ± 1.2 | 1.2 ± 1.7 | 0.953 |
AFP (>200 ng/mL) | 22 (22.4%) | 13 (27.1%) | 0.538 |
Child–Pugh A/B | 87/17 | 41/7 | 0.782 |
Liver cirrhosis | 48 (46.2%) | 26 (54.2%) | 0.358 |
DAA regimen | |||
ASV + DCV | 11 (22.9%) | ||
SOF + RBV | 7 (14.6%) | ||
SOF + LDV | 14 (29.2%) | ||
SOF + VEL | 5 (10.4%) | ||
ERB + GZR | 8 (16.7%) | ||
GLE + PIB | 3 (6.3%) | ||
DAA-surgery interval, months | |||
DAA before surgery | 0 | ||
DAA after surgery | 48 (100%) | ||
0–12 months after surgery | 10 (20.8%) | ||
12–24 months after surgery | 5 (10.4%) | ||
>24 months after surgery | 33 (68.8%) | ||
Tumors, multiple | 6 (4.8%) | 5 (10.4%) | 0.195 |
Tumor size max (cm) | 2.9 ± 0.9 | 2.8 ± 1.1 | 0.485 |
Histology grade (I/II/III) | 14/87/3 | 4/43/1 | 0.624 |
Microvascular invasion | 40 (38.5%) | 24 (50%) | 0.180 |
Recurrence | 62 (59.6%) | 5 (10.4%) | <0.001 |
Death | 39 (37.5%) | 3 (6.3%) | <0.001 |
Follow-up (months) | 62.8 ± 44.9 | 19.6 ± 11.3 | <0.001 |
Univariate | Multivariate | ||||
---|---|---|---|---|---|
HR (95%CI) | p | HR (95%CI) | p | ||
Age (years) | >60 vs. ≤60 | 1.093 (0.645–1.852) | 0.742 | ||
Gender | Male vs. Female | 1.063 (0.644–1.755) | 0.813 | ||
DM | Yes vs. No | 0.822 (0.478–1.414) | 0.479 | ||
Platelet (1000/μL) | <150 vs. ≥150 | 1.435 (0.854–2.413) | 0.173 | ||
AFP (ng/mL) | >15 vs. ≤15 | 1.764 (1.083–2.872) | 0.023 | 1.799 (1.089–2.970) | 0.022 |
Albumin (g/dL) | <3 vs. ≥3 | 1.708 (1.014–2.876) | 0.044 | ||
Child–Pugh | B vs. A | 0.951 (0.471–1.921) | 0.889 | ||
ALBI stage | II/III vs. I | 2.086 (1.147–3.796) | 0.016 | ||
BCLC stage | A vs. 0 | 1.704 (0.813–3.570) | 0.158 | ||
Tumor size (cm) | >2 vs. ≤2 | 1.715 (0.933–3.151) | 0.082 | ||
Tumor number | Multiple vs. Single | 1.375 (0.551–3.430) | 0.495 | ||
Liver cirrhosis | Yes vs. No | 1.954 (1.194–3.197) | 0.008 | 2.062 (1.247–3.410) | 0.005 |
Histology grade | Moderate + Poor vs. Well | 1.577 (0.711–3.494) | 0.262 | ||
Microvascular invasion | Present vs. Absent | 2.246 (1.370–3.683) | 0.001 | 2.331 (1.408–3.860) | 0.001 |
DAA treatment | No vs. Yes | 4.058 (1.615–10.199) | 0.003 | 4.978 (1.976–12.542) | 0.001 |
Univariate | Multivariate | ||||
---|---|---|---|---|---|
HR (95% CI) | p | HR (95%CI) | P | ||
Age (years) | >60 vs. ≤60 | 1.670 (0.798–3.494) | 0.174 | ||
Gender | Male vs. Female | 1.642 (0.839–3.214) | 0.148 | ||
DM | Yes vs. No | 1.883 (1.019–3.479) | 0.043 | ||
Platelet (1000/μL) | <150 vs. ≤150 | 1.718 (0.895–3.297) | 0.104 | ||
AFP (ng/mL) | >15 vs. ≤15 | 1.909 (1.034–3.525) | 0.039 | ||
Albumin (g/dL) | <3 vs. ≥3 | 1.985 (1.045–3.772) | 0.036 | ||
Child–Pugh | B vs. A | 1.571 (0.724–3.410) | 0.253 | ||
ALBI stage | II/III vs. I | 2.876 (1.262–6.553) | 0.012 | 3.249 (1.418–7.443) | 0.005 |
BCLC stage | A vs. 0 | 1.322 (0.556–3.143) | 0.527 | ||
Tumor size (cm) | >2 vs. ≤2 | 1.428 (0.681–2.992) | 0.345 | ||
Tumor number | Multiple vs. Single | 1.375 (0.551–3.430) | 0.495 | ||
Liver cirrhosis | Yes vs. No | 2.219 (1.187–4.149) | 0.013 | ||
Histology grade | Moderate + Poor vs. Well | 1.813 (1.641–5.124) | 0.262 | ||
Microvascular invasion | Present vs. Absent | 3.606 (1.890–6.879) | <0.001 | 4.037 (2.071–7.869) | <0.001 |
DAA treatment | No vs. Yes | 1.714 (0.496–5.925) | 0.394 |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Chen, Y.-S.; Huang, K.-H.; Wang, P.-M.; Chuang, C.-H.; Yong, C.-C.; Liu, Y.-W.; Huang, P.-Y.; Yao, C.-C.; Lin, Y.-P.; Tsai, M.-C. The Impact of Direct-Acting Antiviral Therapy on the Risk of Recurrence after Curative Resection in Patients with Hepatitis-C-Virus-Related Early Stage Hepatocellular Carcinoma. Medicina 2022, 58, 259. https://doi.org/10.3390/medicina58020259
Chen Y-S, Huang K-H, Wang P-M, Chuang C-H, Yong C-C, Liu Y-W, Huang P-Y, Yao C-C, Lin Y-P, Tsai M-C. The Impact of Direct-Acting Antiviral Therapy on the Risk of Recurrence after Curative Resection in Patients with Hepatitis-C-Virus-Related Early Stage Hepatocellular Carcinoma. Medicina. 2022; 58(2):259. https://doi.org/10.3390/medicina58020259
Chicago/Turabian StyleChen, Yu-Syuan, Kuo-Hsuan Huang, Pei-Ming Wang, Ching-Hui Chuang, Chee-Chien Yong, Yueh-Wei Liu, Pao-Yuan Huang, Chih-Chien Yao, Yen-Po Lin, and Ming-Chao Tsai. 2022. "The Impact of Direct-Acting Antiviral Therapy on the Risk of Recurrence after Curative Resection in Patients with Hepatitis-C-Virus-Related Early Stage Hepatocellular Carcinoma" Medicina 58, no. 2: 259. https://doi.org/10.3390/medicina58020259