Hepatocellular carcinoma accounts for 5% of. Hepatitis B Viral Load Predicts Survival of HCC Patients Undergoing Systemic Chemotherapy

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1 Hepatitis B Viral Load Predicts Survival of HCC Patients Undergoing Systemic Chemotherapy Winnie Yeo, 1 Frankie K. F. Mo, 1 Stephen L. Chan, 1 Nancy W. Y. Leung, 2 Pun Hui, 1 Wai-Yip Lam, 3 Tony S. K. Mok, 1 Kowk C. Lam, 1 Wing M. Ho, 1 Jane Koh, 1 Julian W. Tang, 3 Anthony T. Chan, 1 and Paul K. S. Chan 3,4 HCC is a common cause of morbidity and mortality. For patients who are not candidates for curative surgery, systemic chemotherapy is one of the standard treatments. In parts of China and the Far East, over 80% of HCC patients have chronic HBV infection. In this study, we aimed to assess the relationship between pre-chemotherapy HBV viral load and the survival of HCC patients. HBV infection status was determined prior to chemotherapy in 188 patients, 170 of whom had evidence of HBV chronic infection/exposure (160 hepatitis B surface antigen [HBsAg]-positive, 10 HBsAg-negative/hepatitis B core antibody positive). Of these, 125 had pretreatment HBV DNA levels determined via real-time PCR. Virological data were analyzed using conventional clinical variables to identify factors that influenced survival. Multivariate analysis revealed that high total bilirubin (P ; hazard ratio per 1 M increase; 95% CI ), HCV infection (P ; hazard ratio 6.955; 95% CI ), and high HBV DNA level (P ; hazard ratio 1.650; 95% CI ) affected survival significantly. Exploratory analysis revealed that high levels of pretreatment HBV DNA had a significantly higher incidence of severe hepatitis during chemotherapy. Conclusion: For HCC patients with HBV chronic infection/exposure, a high viral load prior to treatment is an adverse factor for survival and may be associated with a higher incidence of severe hepatitis during chemotherapy. Future strategies to improve the prognosis of HCC patients undergoing chemotherapy should consider supportive therapy that incorporates antiviral therapies to reduce HBV viral load. (HEPATOLOGY 2007;45: ) Hepatocellular carcinoma accounts for 5% of cancer incidence worldwide. It is one of the most common causes of cancer morbidity and mortality in Southeast Asia and China, 1,2 and in the United States its incidence has increased by more than 90% in the past 3 decades. 3 It is a highly aggressive cancer with a rapid progression, and only 10%-20% of patients are candidates for curative surgery. 4,5 For the remaining Abbreviations: anti-hbc, hepatitis B core antibody; HBsAg, hepatitis B surface antigen. From the Departments of 1 Clinical Oncology and 3 Microbiology, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China; the 2 Department of Medicine, Alice Ho Mui Ling Nethersole Hospital, Tai Po, Hong Kong, China; and the 4 Centre for Emerging Infectious Diseases, School of Public Health, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China. Received July 13, 2006; accepted January 4, Address reprint requests to: Winnie Yeo, Department of Clinical Oncology, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong. winnieyeo@cuhk.edu.hk; fax: (852) Copyright 2007 by the American Association for the Study of Liver Diseases. Published online in Wiley InterScience ( DOI /hep Potential conflict of interest: Nothing to report. 80% who have unresectable tumors, the prognosis is poor. Apart from large primary lesions, multifocal disease, invasion and thrombosis of major blood vessels, and extrahepatic metastases, one of the major reasons that worsens the prognosis of these patients is the coexistence of advanced cirrhosis with poor hepatic reserve; in Southeast Asia and China, this is associated with chronic HBV infection in 85% of patients, 6,7 resulting in a median survival of only 4 months. 8,9 Patients with unresectable disease could be considered for some form of locoregional therapy such as transarterial chemoembolization, 10,11 percutaneous ethanol injection, 12,13 thermal ablation, 14,15 or internal radiotherapy. 16 However, it must be emphasized that these locoregional therapies are only effective in patients with small tumors, which represents a minor proportion of patients with unresectable disease. 17 For the majority of patients with unresectable HCC, systemic chemotherapy and supportive therapy especially for patients with poor liver function (i.e., Child- Turcotte-Pugh grade C cirrhosis) remain the only option of palliative management. 1382

2 HEPATOLOGY, Vol. 45, No. 6, 2007 YEO ET AL Several studies have investigated prognostic factors in patients with hepatocellular carcinoma and prognostic systems, including the CLIP, BCLC, French, Central European and Chinese systems, have been reported to enable differentiation of patients with favorable and adverse prognosis While most studies have been based on patient population associated with hepatitis C infection and alcoholic liver disease, there are limited data based on those associated with chronic hepatitis B infection. 23 Further, to date, there are no studies that assessed whether pre-chemotherapy hepatitis B viral load provides prognostic information in addition to conventional clinical factors for patients with unresectable disease. The goal of the present study was to assess the significance of pre-chemotherapy hepatitis B viral load (HBV DNA levels) in the survival of HCC patients who participated in our recently reported phase 3 prospective randomized chemotherapy study. 25 Patients and Methods The study population consisted of 188 patients participating a phase 3 randomized controlled trial comparing the efficacy and tolerability of 2 different thrice-weekly palliative chemotherapeutic regimens: (1) doxorubicin (60 mg/m 2 on day 1 every 3 weeks) and (2) combination chemotherapy (cisplatin 20 mg/m 2 day 1-4, IFN- 2b 5 MU/m 2 day 1-4, doxorubicin 40 mg/m 2 day 1, 5-fluorouracil 400 mg/m 2 day 1-4) from 1999 to Patients were eligible for the study if they had histologically confirmed unresectable or metastatic HCC and fulfilled other entry criteria, including: age years; Eastern Co-Operative Group performance score between 0-2; adequate hematological function (white cell count /l, platelet count /l); adequate hepatic function (total bilirubin 30 M); and adequate renal function (creatinine clearance 50 ml/min). None of the studied patients received interferon or antiviral therapy before starting chemotherapy. Surgical resectability was assessed jointly with hepatobiliary surgeons in the Joint Hepatoma Clinic; patients who had small surgically resectable tumors ( 3 cm) but who were medically unfit were offered intralesional ethanol injection and were not considered for systemic chemotherapy. For other patients, systemic chemotherapy was considered as the firstline treatment modality until Since 2002, HCC patients who were not amenable to surgery or ethanol injection in the absence of extrahepatic disease and major vessel involvement and with adequate liver functions were considered for locoregional therapy using transarterial chemoembolization as a first-line treatment based on its proven benefit in this subgroup of patients. 10,11 Investigations. Prior to chemotherapy, serum was collected from each patient for virological assessment. The presence of hepatitis B surface antigen (HBsAg) was screened with AXSYM HBsAg V2 and confirmed with the AXSYM HBsAg Confirmatory V2 (Abbott Laboratories, Abbott Park, IL). Total hepatitis B core antibody (anti-hbc) was detected with AXSYM CORE (Abbott Laboratories). All patients were tested for HCV antibody using the AXSYM HCV V3 (Abbott Laboratories) and for HCV RNA using reverse-transcription PCR with the primers 209, 211, 939, and 940, as described. 26 Patients who tested positive for HBsAg or anti-hbc were further tested for serum HBV DNA level using real-time PCR as described previously. 27 The real-time PCR assay has been shown to accurately detect samples ranging from 10 to 10 9 copies of HBV DNA per milliliter. During the course of chemotherapy, on day 1 and day 10 of each thrice-weekly cycle, complete blood picture, renal, and liver function tests were monitored with clinical signs and symptoms in all patients. Monitoring of these parameters was continued for 8 weeks after completion of chemotherapy. All toxicities were graded according to U.S. National Cancer Institute Common Toxicity Criteria recommendations on acute and subacute toxicity of cancer treatment using NCI CTC version 2.0 (National Cancer Institute, Bethesda, MD). The chemotherapy was planned for up to six cycles. Treatment was stopped in the event of progressive disease or intolerable side effects. Prognostic Clinical Variables. The following conventional clinical prognostic variables were included as potential clinical covariates: age, sex, Eastern Co-Operative Group performance score, total bilirubin, ALT and albumin levels, prothrombin time, hemoglobin level, alpha-fetoprotein, presence of cirrhosis (based on radiological or histological assessment via Child-Turcotte-Pugh classification), presence of ascites, vascular involvement (i.e., presence of vascular invasion of the portal veins, hepatic veins, or inferior vena cava on imaging), Okuda staging of HCC, 18 and tumor node metastasis staging of HCC. 28 Statistical Analysis. Survival time was measured from the date of randomization to the date of death or last contact. Survival differences were calculated using the Kaplan-Meier method. Virological data were analyzed with conventional clinical variables at the time of entry into the study to identify factors that influenced survival via the Cox proportional hazards model. Multivariate analysis was performed using a stepwise model-building procedure based on a significance value of P 0.05 for both inclusion and exclusion of prognostic factors. The

3 1384 YEO ET AL. HEPATOLOGY, June 2007 Fig. 1. Virological assessment of HCC patients undergoing chemotherapy. statistical analysis was performed using SAS version 8 software. Results Of the 188 patients in the study, 3 did not have serum available for analyses (although 2 were noted to have chronic HBV infection in their case notes) (Fig. 1). Of these 188 patients, 170 (91.9%) were found to have evidence of HBV infection; 160 (86.5%) were HBsAg-positive, and 10 (5.4%) were HBsAg-negative but anti-hbc positive. Seven patients (3.8%) had evidence of hepatitis C infection (positive for both HCV antibody and serum HCV RNA); including 4 (2.2%) who had HBV chronic infection/exposure. Twelve patients (6.5%) were negative for all viral analyses. None showed discrepant results between anti-hcv antibody and HCV RNA. Of the 170 patients with evidence of HBV chronic infection/exposure, 125 had sera available for determination of HBV DNA levels and were included in the study. The characteristics of the 125 patients with HBV chronic infection/exposure are illustrated in Table 1. The median age of the patients was 49 years (range, 19-72); 115 were males (92%). Ninety percent of the patients had an Eastern Co-Operative Group performance score of 0. One hundred nineteen were HBsAg-positive, and 6 were HBsAg-negative/anti-HBc positive (including 2 with HBV DNA levels of and copies/ml, respectively). Eighty patients (63.4%) had an HBV DNA level higher than copies/ml. Of the 45 patients who had viral load below this level, 41 were HBsAg-positive, while 4 were HBsAg-negative/anti-HBc positive. Thirty-one patients (24.8%) were hepatitis B e antigen positive. Two patients (1.6%) had HCV infection. The median ALT activity was 67 IU/l (range, ). The median values for other laboratory tests were as fol- Table 1. Patient Characteristics Characteristics No. (%) Values No. of patients 125 (100) Median age, years (range) 49 (19 72) Male 115 (92) ECOG performance score (90.3) 1 12 (10.0) 2 1 (0.7) HBsAg-positive:HBsAg-negative/ anti-hbc positive 119:6 (95.2:4.8) HBV DNA level ( copies/ml) 80 (63.4) HBeAg-positive 31 (24.8) HCV infection 2 (1.6) Median baseline biochemistry and hematology (range) Total bilirubilin, M 12 (4 46) Albumin, g/l 34 (22 46) ALT, IU/l 67 (13 346) Prothrombin time, s 11.4 ( ) Alpha-fetoprotein, ng/ml 3,375 (2 1,892,600) Hemoglobin, g/dl 13.6 ( ) Presence of cirrhosis 58 (46.4) Child-Turcotte-Pugh grade A 42 (33.6) B 16 (12.8) Presence of ascites 10 (8) Presence of vascular invasion 66 (52.8) Okuda stage I 6 (4.8) II 112 (89.6) III 7 (5.6) TNM stage I 16 (12.8) II 23 (18.4) III 66 (52.8) IV 20 (16.0) Combination versus singleagent chemotherapy 63:62 (50.4:49.6) Median survival, months (95% CI) 6.83 ( ) Abbreviations: ECOG, Eastern Co-Operative Group; TNM, tumor node metastasis.

4 HEPATOLOGY, Vol. 45, No. 6, 2007 YEO ET AL lows: albumin level, 34 g/l (range, 22-46); prothrombin time, 11.4 s (range, ); hemoglobin level, 13.6 g/dl (range, ); and alpha-fetoprotein level, 3,375 ng/ml (range, 2-1,892,600). The median total bilirubin level was 12 M (range, 4-46). There were 4 patients in the combination chemotherapy group and 3 in the doxorubicin group who had an initial bilirubin level at study entry above the exclusion level that did not normalize before the start of treatment but were included in the analysis of the randomized chemotherapy study. 25 Evidence of cirrhosis was found in 58 (46.4%) patients; 57 were HBsAg-positive, and 1 was HBsAg-negative/anti- HBc positive with HCV infection. Of these, 42 (33.6%) had Child-Turcotte-Pugh grade A cirrhosis; the other 16 (12.8%) had Child-Turcotte-Pugh grade B cirrhosis. Ten patients (8%) had ascites. Sixty-six of the 125 patients (52.8%) had vascular invasion. Most patients had extensive tumor involvement (95.2% Okuda stage II and above; 87.2% tumor node metastasis stage II and above). The number of patients Table 2. Factors Identified on Univariate and Multivariate Analyses that Influenced Survival in HCC Patients Undergoing Chemotherapy Factors P Value (Cox Regression) Hazard Ratio 95% CI Univariate analysis Age, years Sex (F:M) ECOG performance score HBsAg-positive HBeAg-positive HBV DNA level (cut at copies/ml) HCV infection Total bilirubilin ALT Albumin Prothrombin time Hemoglobin Alpha-fetoprotein Cirrhosis (Child- Turcotte-Pugh grade A vs. grade B vs. no cirrhosis) Presence of ascites Vascular invasion Okuda stage TNM stage (I II vs. III IV) Multivariate analysis Total bilirubin HCV infection HBV DNA level (cut at copies/ml) Abbreviations: ECOG, Eastern Co-Operative Group; TNM, tumor node metastasis. Fig. 2. Survival of patients with high and low HBV DNA load. who received combination versus single-agent chemotherapy was 63 and 62, respectively. The median survival of the patients was 6.83 months (95% CI ). Prognostic Effect of Virological and Clinical Variables on Survival. Univariate and multivariate analyses were performed to investigate the prognostic effect of virological and clinical variables simultaneously. The results are listed in Table 2. Univariate analysis revealed that the following pretreatment factors had a significant effect on survival: high HBV DNA level (defined as copies/ml), hepatitis B e antigen positivity, HCV infection, high serum total bilirubin, high serum ALT, prolonged prothrombin time, high serum alpha-fetoprotein, presence of ascites, and advanced Okuda staging of HCC. Multivariate analysis revealed that high serum total bilirubin (P ; hazard ratio per 1 M increase; 95% CI ), HCV infection (P ; hazard ratio 6.955; 95% CI ), and high HBV DNA level (P ; hazard ratio 1.650; 95% CI ) had a significant effect on survival. Figure 2 illustrates the survival of patients with high and low pre-chemotherapy viral load. Exploratory Analysis of Pretreatment HBV Viral Load and Occurrence of Hepatitis During Chemotherapy. Severe hepatitis during chemotherapy was defined by an elevated ALT level of grade 3 or more according to NCI CTC version 2.0 software, 26 which refers to an ALT level of more than 5 times the institutional upper limit of normal of 58 IU/l (i.e., 290 IU/l) during treatment irrespective of baseline level. Three patients had baseline ALT levels that exceeded 290 IU/l, though none developed severe hepatitis during chemotherapy. Twenty-one of the 119 HBsAg-positive patients but none of the HBsAg-negative/anti-HBc positive patients developed severe hepatitis. The mean serum level of pretreatment HBV DNA for patients who developed se-

5 1386 YEO ET AL. HEPATOLOGY, June 2007 Fig. 3. Survival of HCC patients who did and did not develop severe hepatitis during chemotherapy. vere hepatitis during chemotherapy was , and the corresponding level for those who had grade 0-2 toxicity was (P ). Although not statistically significant, there was a trend of poorer survival for patients who had developed severe hepatitis during chemotherapy (P 0.55) (Fig. 3). Discussion Our study confirmed chronic HBV infection as one of the main etiological factors (85.6%) of HCC in our geographical area, with another 5.4% having evidence of HBV exposure. Hepatitis C infection accounted for 3.8% of the study population, with 2.2% of patients being affected by HBV chronic infection/exposure. Chronic HBV infection is associated with a more than 200-fold increase in risk of HCC development compared with healthy individuals. 29 Serum HBV DNA levels in patients with chronic HBV infection have been shown to be significantly associated with disease activity and disease progression HBV is also recognized to have both direct and indirect roles in hepato-carcinogenesis More recent studies have demonstrated HBV viral load to be more sensitive in reflecting viral replication and predicting risk of HCC Using sensitive real-time PCR, a level of HBV DNA greater than 10 5 copies/ml has been associated with a 7-fold to 9-fold increase in risk of HCC. 40 On the other hand, the administration of antiviral agents suppresses HBV replication and has been shown to delay clinical progression of chronic HBV infection with advanced fibrosis or cirrhosis, with significant reduction in the incidence of hepatic decompensation and risk of HCC. 42 Although the role of HBV DNA in risk stratification and chemoprevention in HCC among patients with chronic HBV infection is increasingly recognized, its role in prognostication for patients with established HCC has not been defined. The present study, which was conducted before prophylactic antiviral therapy was widely practiced for patents who were planned for chemotherapy, 43,44 has allowed this issue to be addressed. Our previous study identified low bilirubin level, high albumin level, and low ALT level as favorable prognostic factors among HBV-related HCC patients receiving systemic chemotherapy. 25 By quantifying pre-chemotherapy HBV DNA level in the same patient population, the present study has shown that a pre-chemotherapy viral load higher than copies/ml is associated with poorer survival in HCC patients with chronic HBV infection, and this association is independent of an individual s hepatic reserve, tumor, and clinical factors. To the best of our knowledge, this is the first study addressing the prognostic value of HBV DNA in the survival of patients with inoperable HCC undergoing systemic chemotherapy. Patients with chronic hepatitis B infection undergoing immunosuppressive chemotherapy have been well recognized to be affected by HBV reactivation during treatment. 45 HCC patients who are treated with chemotherapy in our geographical area present a unique clinical entity. Apart from having the highest rate of chronic HBV infection and chronic liver disease, HCC is a male-predominant disease with a male/female ratio of 3.4:1, 1 and one of the most common components of the standard systemic chemotherapy for the disease has been doxorubicin. 46,47 Male sex and doxorubicin therapy have been reported to be associated with increased risk of developing HBV reactivation. 45,48 As a result, a subprotocol was developed in the randomized chemotherapy study, in which 88 HBsAg-seropositive patients were closely monitored for hepatitis and HBV reactivation during chemotherapy. 49 Patients entered into the subprotocol were followed up on day 1 and day 10 of each cycle of chemotherapy; after the last cycle of chemotherapy, they were followed-up 4-weekly for 8 weeks. Serum biochemistry, which included albumin, ALT, total bilirubin, and prothrombin time were checked, and serum for HBV DNA was collected at each visit. The results of this subprotocol revealed that 58% of these patients developed hepatitis, and that 60% of these cases were attributable to HBV reactivation. 49 The present study provides additional information on HBsAg-negative/anti-HBc positive patients undergoing systemic chemotherapy who, in the absence of antiviral prophylaxis, have a very low risk of developing severe hepatitis during chemotherapy. Other studies on patients with hepatitis B related HCC receiving anticancer therapy have suggested that the incidence of viral reactivation correlates with the level of immunosuppression of the

6 HEPATOLOGY, Vol. 45, No. 6, 2007 YEO ET AL administered therapy; viral reactivation was reported in 40%, 25%, and 2% of patients who underwent systemic chemotherapy, transarterial chemotherapy, and percutaneous ethanol injection or surgical resection, respectively, in descending order of immunosuppressive effects The association between viral load and risk of viral reactivation has been assessed. In our previous report on HCC patients receiving systemic chemotherapy, HBV DNA was not found to be a risk factor for HBV reactivation. 49 This was mostly likely due to the low sensitivity of the assay used. Different studies have applied different assays in measuring viral load, and the lack of standardization with variable range of detection may have limited the understanding of the disease. Using more sensitive assays, recent studies in patients undergoing systemic chemotherapy have shown that high pre-chemotherapy HBV DNA load, defined above as copies/ml, is associated with increased likelihood of developing reactivation. 48,52 The exploratory analysis in the present study supports the latter findings in that patients with high pre-chemotherapy viral load were found to have a significantly increased incidence of severe hepatitis when compared with those who had lower levels of HBV DNA; furthermore, patients who developed severe hepatitis appeared to have worse survival rates. Although this difference in clinical outcome was not found to be statistically significant, presumably due to the relatively small number studied, the results nonetheless support a causal relationship between HBV DNA load and viral reactivation, which as a consequence adversely affects outcome in HCC patients undergoing chemotherapy. Furthermore, the subgroup of patients with high HBV DNA levels (i.e., 63% of the study cohort who had HBV DNA levels higher than copies/ml) might represent an unfavorable subset with increased viral activity and hepatic necroinflammation, with HCC as the terminal event. This is supported by studies demonstrating the direct oncogenic role of HBV DNA in hepatocytes. 53 Other factors that were identified in this study to be of prognostic significance include high total bilirubin and HCV infection. In a study investigating factors predicting chemotherapeutic responses and survival in HCC patients treated with systemic chemotherapy, absence of cirrhosis and low bilirubin level were consistently associated with a better treatment outcome. 54 Another report showed that age under 60 years, low bilirubin level, high albumin level, and absence of ascites were related to longer survival after chemotherapy. 55 Adequate liver function, as reflected by high albumin coupled with low/ normal bilirubin and lower hepatic aminotransferase, may allow optimal cytotoxic delivery. 56 In a case control study of patients with advanced HCC, patients with HBV-related disease were reported to have significantly poorer prognosis than those with HCV-related HCC. 57 The molecular mechanisms of hepato-carcinogenesis according to viral etiology remain unclear. HBV-related HCCs have been reported to express variant -estrogen receptors more frequently than HCV-related tumors, and this has been suggested to account for a rapid growth rate. 58,59 In addition, HBV-related tumors have a distinct pattern of genetic mutation with greater chromosome instability than HCC with other etiologies, and a higher prevalence of loss of heterozygosity that has been correlated with tumor aggressiveness. 60,61 HBV genome integrates to the liver cells and may activate cellular genes directly to allow selective growth advantage, while production of HBV X protein can act as a transactivator on various cellular genes for tumor development. 62 HBV and HCV infections affect cell signaling pathways differently; however, the clinical relevance of HCV and occult HBV infections remains controversial. 63,64 The present data suggest that concurrent HBV and HCV infection have a deleterious effect on the prognosis of HCC patients. Although the expected incidence of HCV infection in our geographical area is low, determination of HCV status in HBV carriers provides additional information, especially when evaluating the effectiveness of potential biological agents in the treatment of virus-related HCCs. Interferon has immunodulatory, antiproliferative, and antiangiogenic effects on tumor cells. When used as a part of the combination chemotherapy regimen, conventional interferon did not seem to affect the HBV reactivation rate. 49 At a therapeutic dose of 5 MU/day or 10 MU 3 times a week for 4-6 months, conventional interferon has been shown to be effective in chronic HBV infection in Western countries, with a response rate of 30%. 65 The mean level of HBV DNA fell by 70% within the first 4 weeks, and clearance of HBV DNA occurred at 16 weeks of treatment in the responders. 66 However, the same dosage of interferon had been shown to be less effective in Asian chronic HBV infection, with a response rate of approximately 10%. 67 Furthermore, the dosage of interferon in the combination chemotherapy regimen was much lower (only 5 MU/m 2 /day for 4 d) than that used for the treatment of chronic HBV infection and is thus unlikely to have a therapeutic effect on the chronic HBV infection in our HCC population. Identification of a prognostic role of serum HBV DNA in HCC patients may have implications in both staging and therapeutics. Different clinical and laboratory parameters had been used for staging. In HBV-associated HCC, the significance of serum HBV DNA level as a factor incorporated into staging systems and prognostication needs to be confirmed in future clinical studies. The in-

7 1388 YEO ET AL. HEPATOLOGY, June 2007 corporation of antiviral therapies alongside anticancer treatment modalities needs to be considered as a therapeutic strategy to improve outcomes of HCC patients. This notion is supported by prospective studies showing that pre-emptive use of lamivudine can decrease morbidity due to HBV reactivation in patients receiving transarterial chemoembolization or systemic chemotherapy. 43,68 In conclusion, the present study demonstrated that a high HBV load prior to treatment has an adverse effect on survival for HCC patients with chronic HBV infection undergoing chemotherapy. With the advances in therapy for chronic HBV infection, oral antiviral agents with increasing potent efficacy in viral suppression should have a significant impact on improving the survival of these patients. Other poor prognostic factors include high total bilirubin level and hepatitis C infection. 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