Factors predicting hepatocellular carcinoma in hepatitis C infection
Abstract
Hepatitis C virus (HCV) has emerged as a leading cause of hepatocellular carcinoma (HCC). In most cases, the virus causes HCC in the presence of chronic hepatic inflammation, advanced fibrosis, and cirrhosis. A combination of viral, environmental, and genetic factors are likely to determine the host immune response to the infection as well as the progression to HCC. Clinical and epidemiologic studies have identified many of the risk factors associated with HCC development in patients with chronic hepatitis C. Male sex and older age are considered as independent risk factors for HCC, while alcohol consumption accelerates fibrosis, increasing the risk for progression to HCC. Obesity, diabetes mellitus, nonalcoholic fatty liver disease, aflatoxin exposure and occult hepatitis B infection, all contribute to a higher HCC risk. HCV patients infected with HCV genotype 3 are also more likely to develop HCC and genetic variations such as single nucleotide polymorphisms, which may also alter the risk. Sustained virological response to the antiviral therapy results in significantly more favorable long-term outcomes. The incidence of HCC after HCV eradication is similar between patients treated with peginterferon plus ribavirin and direct-acting antiviral therapy.
Keywords
Introduction
Hepatocellular carcinoma (HCC) is the fifth most common cause of cancer in men and ranks seventh among women. It is also the third leading cause of cancer-related deaths in the world[1,2]. Hepatitis C virus (HCV) has emerged as the foremost cause of HCC in many countries and has surpassed hepatitis B virus (HBV) as a significant risk factor for the disease[3]. In the majority of cases, HCC in hepatitis C occurs following persistent liver insult in the form of chronic hepatic inflammation, advanced fibrosis and cirrhosis[4,5]. Recently, studies have also shown a direct role for HCV in cancer promotion with various HCV proteins demonstrating oncogenic properties[6]. Overall, a combination of viral, genetic, host and environmental factors likely influence HCC carcinogenesis[7]. Factors that thus affect or modify the likelihood of HCC development in patients with chronic hepatitis C, have been identified by clinical and epidemiologic studies. This review seeks to identify and analyze these diverse factors.
Age and gender
Male sex and older age are independent risk factors for HCC in chronic hepatitis C patients[1,8-12]. In one study investigating a Chinese cohort, age > 55, and male sex were associated with an increased risk of developing HCC[13]. Multivariate analyses of another study showed that older age, truncal obesity, and diabetes were significant predictors of advanced disease and HCC[14,15]. Furthermore, a study on patients with transfusion-acquired HCV infection concluded that age at transfusion > 36 affected the risk for hepatic decompensation and was an independent risk factor for HCC development, alongside gender[16].
Interestingly, multiple pregnancies may also increase the risk of HCV-related HCC. This raises questions about the role of estrogens and other pregnancy-related hormones in the modulation of HCV infection and its progression to HCC in female patients[17].
Alcohol abuse
Patients with a history of alcohol abuse have a significantly higher prevalence of HCV infection than the general population[18]. Furthermore, alcohol consumption in patients with chronic hepatitis C accelerates the process of fibrosis with an increased risk for progression to cirrhosis and HCC. Indeed, a study of 2235 patients with chronic hepatitis C, daily alcohol consumption of 50 g or greater was associated with a 34% increase in the rate of fibrosis progression[19]. A meta-analysis of 20 articles (published between 1995 and 2004), involving more than 15,000 HCV chronically infected persons, illustrated that the pooled relative risk of cirrhosis associated with heavy alcohol intake (defined in the range of at least 210-560 gram per week) was 2.33 [95% confidence interval (CI), 1.67-3.26][20].
Alcohol abuse has been shown to be a key independent predictor of progression to HCC[21,22]. The exact amount of alcohol that increases the risk of HCC in patients with HCV is unknown but it appears that even modest alcohol use can accelerate fibrosis and so the risk for HCC[23]. Indeed, a case-control study to evaluate the risk of HCC for HCV infection found that the odds ratio (OR) of HCC development in HCV RNA positive patients was 26.1 (95% CI: 12.6-54.0) among subjects with alcohol intake of 0-40 g/day and increased to 62.6 (23.3-168) and 126 (42.8-373) with an alcohol intake of 41-80 and greater than 80 g/day, respectively[24].
The progression to HCC may be the direct result of an increase in HCV replication and an attenuation of the antiviral action of interferon due to alcohol[25]. Impaired host cellular immunity (due to dendritic cell dysfunction)[26] and increased oxidative stress and mitochondrial injury[27] due to alcohol consumption, all contribute to the development of HCC.
Diabetes and non-alcoholic fatty liver disease
Hepatitis C patients with obesity, diabetes mellitus, and/or non-alcoholic fatty liver disease (NAFLD) have a higher risk of developing HCC[28,29]. In fact, five of seven studies analyzing diabetes demonstrated significantly increased HCC risk associated with concurrent diabetes with effect sizes ranging from HR 1.73 (95% CI: 1.30-2.30) to RR 3.52 (95% CI: 1.29-9.24). Additionally, insulin resistance, as measured by HOMA-IR, was also found to be significantly associated with HCV-related HCC[30]. Diabetes not only increases the risk of HCC in treatment-naïve chronic hepatitis C patients[31] but also in patients with eradicated HCV[1,9,12,32].
Meanwhile, one of three studies analyzing body mass index demonstrated a significant association with HCC risk (BMI ≥ 30.0 vs. BMI < 23; RR 4.13, 95% CI: 1.38-12.40) and two of the three studies analyzing steatosis demonstrated the significantly higher risk of HCC associated with steatosis[28]. Indeed, HCV patients in the US were found to progress more rapidly to HCC than their counterparts in China and the underlying fatty liver disease was found to be a major contributor to this difference[15].
Hepatitis B core antibody positivity
The risk of HCC increases in patients with hepatitis C who have occult hepatitis B infection or are hepatitis B core antibody positive[14,33]. In one study, the presence of hepatitis B core antigen was one of the independent predictors associated with the occurrence of HCC in HCV patients without advanced fibrosis[34]. On the other hand, HCV sero-status (positive vs. negative among patients with chronic hepatitis B may also increase the risk of HCC, independent of HBV viral load, with a HR of 2.5 (95% CI: 1.7-3.6)[35].
Aflatoxin
Significant contamination of food by aflatoxin is an additional risk factor for HCC in some parts of Asia[36,37]. While studies have shown synergism between aflatoxin and HBV in causing HCC, much less is known about whether aflatoxin and HCV synergize in a similar fashion. It is interesting to note that HCV prevalence itself is much higher in areas where aflatoxin exposure is also high[38].
Advanced fibrosis and cirrhosis
HCC develops in hepatitis C patients mostly in the setting of advanced fibrosis and liver cirrhosis[13]. For patients without pre-existing cirrhosis, a higher Fibrosis-4 (FIB-4) index translates to a higher risk of HCC[39]. Untreated patients with cirrhosis have a significantly higher HCC incidence rate (45.3 per 1000 person-years) compared to those treated with either IFN or DAAs[40,41]. Moreover, liver cirrhosis, high AST to platelet ratio index (APRI) levels, and IL28B rs12979860 at baseline are all associated with HCC development in patients without sustained virological response (SVR) after peg-IFN combination therapy[42]. Even with SVR, the absolute risk of HCC is high in patients with established cirrhosis[1,8,9,12,43-46].
HCV genotype
HCV patients infected with HCV genotype 3 are at higher risk for end-stage liver disease, HCC, and liver-related death compared to other genotypes[11,43]. This association is independent of patients' age, diabetes, body mass index, or antiviral treatment[43]. The risk of HCC remains high even after eradication of genotype 3 HCV[1,46-48]. This genotype may have a particular oncogenic mechanism, leading to HCC development even in non-cirrhotic patients[49]. Certain polymorphisms of the core, NS3, and NS5A proteins of HCV genotype 1b may be associated with the development of HCC[50].
Single nucleotide polymorphisms
Genetic variations, such as single nucleotide polymorphisms (SNPs), may alter disease risk and thus may be used as predictive markers of disease outcome. A genome-wide association study found a strong association between the SNP rs17047200, located within the intron of the tolloid-like 1 gene (TLL1) on chromosome 4, and the development of HCC in patients who achieved an SVR after treatment for chronic HCV infection[9]. Additionally, the association of variants in patatin-like phospholipase domain containing 3 (PNPLA3) and the unfolded protein response regulator GRP78, with the risk of developing HCC, has been described in Italian HCV patients[51]. Moreover, the reversion-inducing-cysteine-rich protein with Kazal motifs (RECK) gene, a novel transformation suppressor gene, has also been linked to HCC amongst several other malignancies. However, a study conducted on an Egyptian cohort concluded that the RECK gene rs10814325 TT genotype could not be considered a risk factor for HCC development in hepatitis C patients, but may be related to the disease progression and metastasis[52].
Furthermore, the GG and GG + GA genotypes of IL17A gene may also serve as a risk factor for HCC development by increasing IL17 and IgE levels[53]. WT IL-23R GG[54], transforming growth factor-β1 (TGF-β1)-509 and tumor necrosis factor-α (TNF-α)-308 genes polymorphisms may also serve as risk factors for cirrhosis and HCC in chronic hepatitis C patients[55].
Non-response to the therapy
Antiviral therapy reduces the development of HCC and complications of cirrhosis in patients with chronic hepatitis C[56]. A risk scoring system has been developed to predict HCC development for HCV patients following antiviral therapies. The system includes age, gender, platelets count, alpha-fetoprotein levels, fibrotic stage, HCV genotype and response to the antiviral therapy[10].
The cumulative risk of HCC development is higher in subjects with high HCV RNA titer than subjects with low titer[45]. SVR results in significantly more favorable long-term outcomes, and decreased risk of progression to cirrhosis and HCC[13,57]. Indeed, a meta-analysis showed that SVR after treatment at any stage of fibrosis is associated with reduced HCC risk[58]. The risk of developing HCC diminishes significantly 2 years after SVR[44].
The risk of HCC after HCV eradication, though considerably reduced, remains relatively high at 0.33% per year[47]. Compared to subjects with spontaneous viral clearance, subjects with antiviral treatment-induced HCV viral clearance are at higher risk for HCC development, especially if they have significant hepatic fibrosis[12].
Antiviral therapy for patients with normal ALT levels can also lower the HCC incidence in responders, particularly for elderly and male patients[59]. Moreover, even in patients who have developed HCC within the Milan criteria and have undergone curative treatment for HCC, elimination of HCV and SVR inhibits recurrence and contributes to a preferential prognosis[60].
Directly acting antiviral agents
The role of DAAs (used in the treatment of HCV) in the development of HCC is controversial, with several early studies demonstrating a tenuous link. However, a retrospective population-based cohort study of 17,836 patients treated with either an interferon-based regimen or DAA, showed that the risk of HCC was the same in both groups[40]. A meta-analysis of 41 studies further clarified the issue and concluded that the risks of HCC development after HCV eradication were similar between patients treated with peginterferon plus ribavirin and direct-acting antiviral therapy and that there was no evidence to suggest that DAAs promoted HCC[8,61]. The seemingly higher incidence of HCC following SVR with DAA therapy was related to baseline risk factors and patient selection, and not the use of interferon-free therapy per se. The cohort of patients treated with DAAs in earlier studies included older patients and patients with more advanced cirrhosis who were already predisposed to a higher risk for HCC at baseline. In a cohort study of 857 patients, individuals receiving interferon-free therapy were more likely to be older, of white ethnicity, Child-Turcotte-Pugh B/C vs. Child-Turcotte-Pugh A; thrombocytopenic, non-genotype 3, and treatment experienced. HCC occurrence was observed in 46 individuals during follow-up. In univariate analysis, IFN-free therapy was associated with a significantly increased risk of HCC (HR: 2.48; P = 0.021). However, after multivariate adjustment for baseline factors, no significant risk attributable to interferon-free therapy persisted[41].
Among patients treated with DAA, SVR is associated with a considerable reduction in the risk of HCC. However, in patients with SVR, the absolute risk of HCC remains high in patients with established cirrhosis[62].
Conclusion
Hepatitis C accounts for the majority of the cases of HCC in many parts of the world. HCC typically occurs in patients with advanced hepatic fibrosis or cirrhosis in the setting of chronic inflammatory state induced by HCV. Clinical and epidemiologic studies have identified host and viral factors associated with HCC development in patients with HCV infection. Direct-acting antiviral drugs do not increase the risk of developing HCC. Sustained virological response to the antiviral therapy results in significantly more favorable long-term outcomes.
Declarations
Authors’ contributionsBoth authors contributed by literature review and manuscript writing, editing and review.
Availability of data and materialsNot applicable.
Financial support and sponsorshipNone.
Conflicts of interestBoth authors declared that there are no conflicts of interest.
Ethical approval and consent to participateNot applicable.
Consent for publicationNot applicable.
Copyright© The Author(s) 2018.
REFERENCES
1. El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 2007;132:2557-76.
2. Mittal S, El-Serag HB. Epidemiology of hepatocellular carcinoma: consider the population. J Clin Gastroenterol 2013;47 Suppl:S2-6.
3. Kim MN, Kim BK, Han KH. Hepatocellular carcinoma in patients with chronic hepatitis C virus infection in the Asia-Pacific region. J Gastroenterol 2013;48:681-8.
4. Budhu A, Wang XW. The role of cytokines in hepatocellular carcinoma. J Leukoc Biol 2006;80:1197-213.
5. Maki A, Kono H, Gupta M, Asakawa M, Suzuki T, Matsuda M, Fujii H, Rusyn I. Predictive power of biomarkers of oxidative stress and inflammation in patients with hepatitis C virus-associated hepatocellular carcinoma. Ann Surg Oncol 2007;14:1182-90.
6. Moriya K, Fujie H, Shintani Y, Yotsuyanagi H, Tsutsumi T, Ishibashi K, Matsuura Y, Kimura S, Miyamura T, Koike K. The core protein of hepatitis C virus induces hepatocellular carcinoma in transgenic mice. Nat Med 1998;4:1065-7.
7. Mitchell JK, Lemon SM, McGivern DR. How do persistent infections with hepatitis C virus cause liver cancer? Curr Opin Virol 2015;14:101-8.
8. Nagaoki Y, Imamura M, Aikata H, Daijo K, Teraoka Y, Honda F, Nakamura Y, Hatooka M, Morio R, Morio K, Kan H, Fujino H, Kobayashi T, Masaki K, Ono A, Nakahara T, Kawaoka T, Tsuge M, Hiramatsu A, Kawakami Y, Hayes CN, Miki D, Ochi H, Chayama K. 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.
9. Matsuura K, Sawai H, Ikeo K, Ogawa S, Iio E, Isogawa M, Shimada N, Komori A, Toyoda H, Kumada T, Namisaki T, Yoshiji H, Sakamoto N, Nakagawa M, Asahina Y, Kurosaki M, Izumi N, Enomoto N, Kusakabe A, Kajiwara E, Itoh Y, Ide T, Tamori A, Matsubara M, Kawada N, Shirabe K, Tomita E, Honda M, Kaneko S, Nishina S, Suetsugu A, Hiasa Y, Watanabe H, Genda T, Sakaida I, Nishiguchi S, Takaguchi K, Tanaka E, Sugihara J, Shimada M, Kondo Y, Kawai Y, Kojima K, Nagasaki M, Tokunaga K, Tanaka Y; Japanese Genome-Wide Association Study Group for Viral Hepatitis. Genome-wide association study identifies TLL1 variant associated with development of hepatocellular carcinoma after eradication of hepatitis C virus infection. Gastroenterology 2017;152:1383-94.
10. Chang KC, Wu YY, Hung CH, Lu SN, Lee CM, Chiu KW, Tsai MC, Tseng PL, Huang CM, Cho CL, Chen HH, Hu TH. Clinical-guide risk prediction of hepatocellular carcinoma development in chronic hepatitis C patients after interferon-based therapy. Br J Cancer 2013;109:2481-8.
11. McMahon BJ, Bruden D, Townshend-Bulson L, Simons B, Spradling P, Livingston S, Gove J, Hewitt A, Plotnik J, Homan C, Espera H, Negus S, Snowball M, Barbour Y, Bruce M, Gounder P. Infection with hepatitis C virus genotype 3 is an independent risk factor for end-stage liver disease, hepatocellular carcinoma, and liver-related death. Clin Gastroenterol Hepatol 2017;15:431-7.
12. Huang CF, Yeh ML, Huang CI, Lin YJ, Tsai PC, Lin ZY, Chan SY, Chen SC, Yang HI, Huang JF, Lu SN, Dai CY, Jen CL, Yuan Y, L'Italien G, Wang LY, Lee MH, Yu ML, Chuang WL, Chen CJ. Risk of hepatitis C virus related hepatocellular carcinoma between subjects with spontaneous and treatment-induced viral clearance. Oncotarget 2017;8:43925-33.
13. Lee SH, Jin YJ, Shin JY, Lee JW. Assessment of hepatocellular carcinoma risk based on peg-interferon plus ribavirin treatment experience in this new era of highly effective oral antiviral drugs. Medicine (Baltimore) 2017;96:e5321.
14. Parikh ND, Fu S, Rao H, Yang M, Li Y, Powell C, Wu E, Lin A, Xing B, Wei L, Lok ASF. Risk assessment of hepatocellular carcinoma in patients with hepatitis C in China and the USA. Dig Dis Sci 2017;62:3243-53.
15. Rao H, Wu E, Fu S, Yang M, Feng B, Lin A, Fei R, Fontana RJ, Lok AS, Wei L. The higher prevalence of truncal obesity and diabetes in American than Chinese patients with chronic hepatitis C might contribute to more rapid progression to advanced liver disease. Aliment Pharmacol Ther 2017;46:731-40.
16. Zavaglia C, Silini E, Mangia A, Airoldi A, Piazzolla V, Vangeli M, Stigliano R, Foschi A, Mazzarelli C, Tinelli C. Prognostic factors of hepatic decompensation and hepatocellular carcinoma in patients with transfusion-acquired HCV infection. Liver Int 2014;34:e308-16.
17. Amr S, Iarocci EA, Nasr GR, Saleh D, Blancato J, Shetty K, Loffredo CA. Multiple pregnancies, hepatitis C, and risk for hepatocellular carcinoma in Egyptian women. BMC Cancer 2014;14:893.
18. Coelho-Little ME, Jeffers LJ, Bernstein DE, Goodman JJ, Reddy KR, de Medina M, Li X, Hill M, La Rue S, Schiff ER. Hepatitis C virus in alcoholic patients with and without clinically apparent liver disease. Alcohol Clin Exp Res 1995;19:1173-6.
19. Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet 1997;349:825-32.
20. Hutchinson SJ, Bird SM, Goldberg DJ. Influence of alcohol on the progression of hepatitis C virus infection: a meta-analysis. Clin Gastroenterol Hepatol 2005;3:1150-9.
21. Benvegnù L, Fattovich G, Noventa F, Tremolada F, Chemello L, Cecchetto A, Alberti A. Concurrent hepatitis B and C virus infection and risk of hepatocellular carcinoma in cirrhosis. A prospective study. Cancer 1994;74:2442-8.
22. Ikeda K, Saitoh S, Koida I, Arase Y, Tsubota A, Chayama K, Kumada H, Kawanishi M. A multivariate analysis of risk factors for hepatocellular carcinogenesis: a prospective observation of 795 patients with viral and alcoholic cirrhosis. Hepatology 1993;18:47-53.
23. Monto A, Patel K, Bostrom A, Pianko S, Pockros P, McHutchison JG, Wright TL. Risks of a range of alcohol intake on hepatitis C-related fibrosis. Hepatology 2004;39:826-34.
24. Tagger A, Donato F, Ribero ML, Chiesa R, Portera G, Gelatti U, Albertini A, Fasola M, Boffetta P, Nardi G. Case-control study on hepatitis C virus (HCV) as a risk factor for hepatocellular carcinoma: the role of HCV genotypes and the synergism with hepatitis B virus and alcohol. Brescia HCC Study. Int J Cancer 1999;81:695-9.
25. McCartney EM, Semendric L, Helbig KJ, Hinze S, Jones B, Weinman SA, Beard MR. Alcohol metabolism increases the replication of hepatitis C virus and attenuates the antiviral action of interferon. J Infect Dis 2008;198:1766-75.
26. Aloman C, Gehring S, Wintermeyer P, Kuzushita N, Wands JR. Chronic ethanol consumption impairs cellular immune responses against HCV NS5 protein due to dendritic cell dysfunction. Gastroenterology 2007;132:698-708.
27. Otani K, Korenaga M, Beard MR, Li K, Qian T, Showalter LA, Singh AK, Wang T, Weinman SA. Hepatitis C virus core protein, cytochrome P450 2E1, and alcohol produce combined mitochondrial injury and cytotoxicity in hepatoma cells. Gastroenterology 2005;128:96-107.
28. Dyal HK, Aguilar M, Bartos G, Holt EW, Bhuket T, Liu B, Cheung R, Wong RJ. Diabetes mellitus increases risk of hepatocellular carcinoma in chronic hepatitis c virus patients: a systematic review. Dig Dis Sci 2016;61:636-45.
29. Schlesinger S, Aleksandrova K, Pischon T, Jenab M, Fedirko V, Trepo E, Overvad K, Roswall N, Tjønneland A, Boutron-Ruault MC, Fagherazzi G, Racine A, Kaaks R, Grote VA, Boeing H, Trichopoulou A, Pantzalis M, Kritikou M, Mattiello A, Sieri S, Sacerdote C, Palli D, Tumino R, Peeters PH, Bueno-de-Mesquita HB, Weiderpass E, Quirós JR, Zamora-Ros R, Sánchez MJ, Arriola L, Ardanaz E, Tormo MJ, Nilsson P, Lindkvist B, Sund M, Rolandsson O, Khaw KT, Wareham N, Travis RC, Riboli E, Nöthlings U. Diabetes mellitus, insulin treatment, diabetes duration, and risk of biliary tract cancer and hepatocellular carcinoma in a European cohort. Ann Oncol 2013;24:2449-55.
30. Khattab MA, Eslam M, Mousa YI, Ela-adawy N, Fathy S, Shatat M, Abd-Aalhalim H, Kamal A, Sharawe MA. Association between metabolic abnormalities and hepatitis C-related hepatocellular carcinoma. Ann Hepatol 2012;11:487-94.
31. Li X, Xu H, Gao Y, Pan M, Wang L, Gao P. Diabetes mellitus increases the risk of hepatocellular carcinoma in treatment-naïve chronic hepatitis C patients in China. Medicine (Baltimore) 2017;96:e6508.
32. Toyoda H, Kumada T, Tada T, Kiriyama S, Tanikawa M, Hisanaga Y, Kanamori A, Kitabatake S, Ito T. Risk factors of hepatocellular carcinoma development in non-cirrhotic patients with sustained virologic response for chronic hepatitis C virus infection. J Gastroenterol Hepatol 2015;30:1183-9.
33. Kitab B, Ezzikouri S, Alaoui R, Nadir S, Badre W, Trepo C, Chemin I, Benjelloun S. Occult HBV infection in Morocco: from chronic hepatitis to hepatocellular carcinoma. Liver Int 2014;34:e144-50.
34. K-Kutala B, Bedossa P, Guedj J, Asselah T, Martinot-Peignoux M, Duval X, Marcellin P. Patients with chronic hepatitis C without advanced fibrosis and hepatocellular carcinoma: a retrospective clinical-pathological study. Dig Liver Dis 2015;47:296-302.
35. Huang YT, Yang HI, Liu J, Lee MH, Freeman JR, Chen CJ. Mediation analysis of hepatitis B and C in relation to hepatocellular carcinoma risk. Epidemiology 2016;27:14-20.
36. Goh GB, Chang PE, Tan CK. Changing epidemiology of hepatocellular carcinoma in Asia. Best Pract Res Clin Gastroenterol 2015;29:919-28.
38. Palliyaguru DL, Wu F. Global geographical overlap of aflatoxin and hepatitis C: controlling risk factors for liver cancer worldwide. Food Addit Contam Part A Chem Anal Control Expo Risk Assess 2013;30:534-40.
39. Huang CM, Hu TH, Chang KC, Tseng PL, Lu SN, Chen CH, Wang JH, Lee CM, Tsai MC, Lin MT, Yen YH, Hung CH, Cho CL, Wu CK. Dynamic noninvasive markers predict hepatocellular carcinoma in chronic hepatitis C patients without sustained virological response after interferon-based therapy: prioritize who needs urgent direct-acting antiviral agents. Medicine (Baltimore) 2017;96:e8696.
40. Li DK, Ren Y, Fierer DS, Rutledge S, Shaikh OS, Lo Re V 3rd, Simon T, Abou-Samra AB, Chung RT, Butt AA. The short-term incidence of hepatocellular carcinoma is not increased after hepatitis C treatment with direct-acting antivirals: an ERCHIVES study. Hepatology 2018;67:2244-53.
41. Innes H, Barclay ST, Hayes PC, Fraser A, Dillon JF, Stanley A, Bathgate A, McDonald SA, Goldberg D, Valerio H, Fox R(8), Kennedy N, Bramley P, Hutchinson SJ. The risk of hepatocellular carcinoma in cirrhotic patients with hepatitis C and sustained viral response: role of the treatment regimen. J Hepatol 2017; doi: 10.1016/j.jhep.2017.10.033.
42. Chang KC, Ye YH, Wu CK, Lin MT, Tsai MC, Tseng PL, Hu TH. Risk factors for development of hepatocellular carcinoma in patients with chronic hepatitis C without sustained response to combination therapy. J Formos Med Assos 2017; doi: 10.1016/j.jfma.2017.11.008.
43. Kanwal F, Kramer JR, Ilyas J, Duan Z, El-Serag HB. HCV genotype 3 is associated with an increased risk of cirrhosis and hepatocellular cancer in a national sample of U.S. Veterans with HCV. Hepatology 2014;60:98-105.
44. Hedenstierna M, Nangarhari A, Weiland O, Aleman S. Diabetes and cirrhosis are risk factors for hepatocellular carcinoma after successful treatment of chronic hepatitis C. Clin Infect Dis 2016;63:723-9.
45. Noh R, Lee DH, Kwon BW, Kim YH, Kim SB, Song IH. Clinical impact of viral load on the development of hepatocellular carcinoma and liver-related mortality in patients with hepatitis C virus infection. Gastroenterol Res Pract 2016; doi: 10.1155/2016/7476231.
46. Baumert TF, Jühling F, Ono A, Hoshida Y. Hepatitis C-related hepatocellular carcinoma in the era of new generation antivirals. BMC Med 2017;15:52.
47. El-Serag HB, Kanwal F, Richardson P, Kramer J. Risk of hepatocellular carcinoma after sustained virological response in Veterans with hepatitis C virus infection. Hepatology 2016;64:130-7.
48. Janjua NZ, Chong M, Kuo M, Woods R, Wong J, Yoshida EM, Sherman M, Butt ZA, Samji H, Cook D, Yu A, Alvarez M, Tyndall M, Krajden M. Long-term effect of sustained virological response on hepatocellular carcinoma in patients with hepatitis C in Canada. J Hepatol 2017;66:504-13.
49. Mattos AA, Marcon Pdos S, Araújo FS, Coral GP, Tovo CV. Hepatocellular carcinoma in a non-cirrhotic patient with sustained virological response after hepatitis C treatment. Rev Inst Med Trop Sao Paulo 2015;57:519-22.
50. El-Shamy A, Shindo M, Shoji I, Deng L, Okuno T, Hotta H. Polymorphisms of the core, NS3, and NS5A proteins of hepatitis C virus genotype 1b associate with development of hepatocellular carcinoma. Hepatology 2013;58:555-63.
51. Balasus D, Way M, Fusilli C, Mazza T, Morgan MY, Cervello M, Giannitrapani L, Soresi M, Agliastro R, Vinciguerra M, Montalto G. The association of variants in PNPLA3 and GRP78 and the risk of developing hepatocellular carcinoma in an Italian population. Oncotarget 2016;7:86791-802.
52. Fakhry AB, Ahmed AI, AbdelAlim MA, Ramadan DI. RECK gene promoter rs10814325 polymorphism in Egyptian patients with hepatocellular carcinoma on top of chronic hepatitis C viral infection. Asian Pac J Cancer Prev 2016;17:2383-8.
53. ELBassuoni MA, Abd El Fatah G, Zaghla H. IL17A gene polymorphism, serum IL17 and total IgE in Egyptian population with chronic HCV and hepatocellular carcinoma. Immunol Lett 2015;168:240-5.
54. Labib HA, Ahmed HS, Shalaby SM, Wahab EA, Hamed EF. Genetic polymorphism of IL-23R influences susceptibility to HCV-related hepatocellular carcinoma. Cell Immunol 2015;294:21-4.
55. Radwan MI, Pasha HF, Mohamed RH, Hussien HI, El-Khshab MN. Influence of transforming growth factor-β1 and tumor necrosis factor-α genes polymorphisms on the development of cirrhosis and hepatocellular carcinoma in chronic hepatitis C patients. Cytokine 2012;60:271-6.
56. Hsu CS, Huang CJ, Kao JH, Lin HH, Chao YC, Fan YC, Tsai PS. Interferon-based therapy decreases risks of hepatocellular carcinoma and complications of cirrhosis in chronic hepatitis C patients. PLoS One 2013;8:e70458.
57. Moon C, Jung KS, Kim DY, Baatarkhuu O, Park JY, Kim BK, Kim SU, Ahn SH, Han KH. Lower incidence of hepatocellular carcinoma and cirrhosis in hepatitis C patients with sustained virological response by pegylated interferon and ribavirin. Dig Dis Sci 2015;60:573-81.
58. Morgan RL, Baack B, Smith BD, Yartel A, Pitasi M, Falck-Ytter Y. Eradication of hepatitis C virus infection and the development of hepatocellular carcinoma: a meta-analysis of observational studies. Ann Intern Med 2013;158:329-37.
59. Harada N, Hiramatsu N, Oze T, Morishita N, Yamada R, Hikita H, Miyazaki M, Yakushijin T, Miyagi T, Yoshida Y, Tatsumi T, Kanto T, Kasahara A, Oshita M, Mita E, Hagiwara H, Inui Y, Katayama K, Tamura S, Yoshihara H, Imai Y, Inoue A, Hayashi N, Takehara T. Risk factors for hepatocellular carcinoma in hepatitis C patients with normal alanine aminotransferase treated with pegylated interferon and ribavirin. J Viral Hepat 2014;21:357-65.
60. Kanogawa N, Ogasawara S, Chiba T, Saito T, Motoyama T, Suzuki E, Ooka Y, Tawada A, Kanda T, Mikami S, Azemoto R, Kaiho T, Shinozaki M, Ohtsuka M, Miyazaki M, Yokosuka O. Sustained virologic response achieved after curative treatment of hepatitis C virus-related hepatocellular carcinoma as an independent prognostic factor. J Gastroenterol Hepatol 2015;30:1197-204.
61. Waziry R, Hajarizadeh B, Grebely J, Amin J, Law M, Danta M, George J, Dore GJ. Hepatocellular carcinoma risk following direct-acting antiviral HCV therapy: a systematic review, meta-analyses, and meta-regression. J Hepatol 2017;67:1204-12.
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Abbas, Z.; Abbas M. Factors predicting hepatocellular carcinoma in hepatitis C infection. Hepatoma. Res. 2018, 4, 43. http://dx.doi.org/10.20517/2394-5079.2018.26
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