Sheng-Nan Lu

Chronic Hepatitis C Virus Infection Increases Mortality From Hepatic and Extrahepatic Diseases: A Community-Based Long-Term Prospective Study

BACKGROUND The study aimed to evaluate the risk of hepatitis C virus (HCV) infection on hepatic and extrahepatic deaths. METHODS A cohort of 23 820 adults aged 30-65 years old were enrolled during 1991-1992. The seromarkers hepatitis B surface antigen (HBsAg), anti-HCV, and serum HCV RNA levels at study entry were tested. The vital status was ascertained through computerized linkage with national death certification profiles from 1991 to 2008. RESULTS There were 19,636 HBsAg-seronegatives, including 18,541 anti-HCV seronegatives and 1095 anti-HCV seropositives. Among anti-HCV seropositives, 69.4% had detectable serum HCV RNA levels. There were 2394 deaths that occurred during an average follow-up period of 16.2 years. Compared with anti-HCV seronegatives, anti-HCV seropositives had higher mortality from both hepatic and extrahepatic diseases, showing multivariate-adjusted hazard ratio (95% confidence interval) of 1.89 (1.66-2.15) for all causes of death; 12.48 (9.34-16.66) for hepatic diseases; 1.35 (1.15-1.57) for extrahepatic diseases; 1.50 (1.10-2.03) for circulatory diseases; 2.77 (1.49-5.15) for nephritis, nephrotic syndrome, and nephrosis; 4.08 (1.38-12.08) for esophageal cancer; 4.19 (1.18-14.94) for prostate cancer; and 8.22 (1.36-49.66) for thyroid cancer. Anti-HCV seropositives with detectable HCV RNA levels had significantly higher mortality from hepatic and extrahepatic diseases than anti-HCV seropositives with undetectable HCV RNA. CONCLUSIONS Monitoring HCV RNA in anti-HCV seropositives is essential for the prediction of mortality associated with hepatitis C.

Aflatoxin exposure and risk of hepatocellular carcinoma in Taiwan

To investigate the carcinogenic effect of environmental aflatoxin exposure, 56 cases of hepatocellular carcinoma (HCC) diagnosed between 1991 and 1995 were identified and individually matched by age, sex, residence and date of recruitment to 220 healthy controls from the same large cohort in Taiwan. Blood samples were analyzed for hepatitis B and C viral markers and for aflatoxin‐albumin adducts; urine was tested for aflatoxin metabolites. We obtained information about socio‐demographic characteristics, habitual alcohol drinking, cigarette smoking and diet in a structured interview. Hepatitis B virus surface antigen (HBsAg) carriers had a significantly increased risk for HCC. After adjustment for HBsAg serostatus, the matched odds ratio (ORm) was significantly elevated for subjects with high levels of urinary aflatoxin metabolites. When stratified into tertiles, a dose‐response relationship with HCC was observed. The ORm for detectable aflatoxin‐albumin adducts was not significant after adjustment for HBsAg serostatus. HBsAg‐seropositive subjects with high aflatoxin exposure had a higher risk than subjects with high aflatoxin exposure only or HBsAg seropositivity only. In male HBsAg‐seropositive subjects, adjusted ORs were 2.8 (95% confidence interval [Cl] = 0.9–9.1) for detectable compared with non‐detectable aflatoxin‐albumin adducts and 5.5 (Cl = 1.3–23.4) for high compared with low urinary aflatoxin metabolite levels. Our results suggest that environmental aflatoxin exposure may enhance the hepatic carcinogenic potential of hepatitis B virus. A large‐scale study will be needed to evaluate the effect of aflatoxin exposure on HBsAg non‐carriers.

Correlation between ultrasonographic and pathologic diagnoses of hepatitis B and C virus-related cirrhosis

Background. We aimed to evaluate the validity of ultrasonography (US) in the diagnosis of cirrhosis in patients with chronic hepatitis B virus (HBV) or C virus (HCV) infection. Methods: A total of 210 patients, 67 with chronic HBV and 143 with HCV infection, were evaluated for the cirrhotic status of liver by both needle biopsy and US. According to the pathological findings, a fibrosis score 4 on the histology activity index was the gold standard for the diagnosis of cirrhosis. A US scoring system consisting of liver surface, parenchyma, vascular structure, and splenic size was used to describe the severity of hepatic parenchymal damage. Results: Cirrhosis was found in 27 (40%) of the 67 HBV patients and in 51 (36%) of the 143 HCV patients pathologically. The mean fibrosis scores were 0.95, 1.24, 2.35, 2.95, 3.8 and 3.7 in patients with US scores of 4, 5, 6, 7, 8, and 9 or more, respectively. The US scores were significantly correlated with the hepatic fibrosis scores (P < 0.05). Based on the receiver operating characteristic (ROC) curve, a US score of 7 was the best cutoff point for the prediction of HBV-related cirrhosis, with sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 77.8%, 92.5%, 87.5%, 86.0%, and 86.6%, respectively. In HCV-related cirrhosis, a US score of 6 provided results of 82.4%, 70.7%, 60.9%, 87.8%, and 74.8%, respectively. The specificity, positive predictive value, and accuracy were significantly higher in patients with HBV than in those with HCV infection (P = 0.012, P = 0.032, and P = 0.079, respectively). Conclusions: Cirrhosis can be predicted well by US, especially in patients with HBV infection.

Survival comparison between surgical resection and radiofrequency ablation for patients in BCLC very early/early stage hepatocellular carcinoma

BACKGROUND & AIMS To compare the survival between surgical resection (SR) and radiofrequency ablation (RFA) in patients with hepatocellular carcinoma (HCC) in Barcelona Clinic Liver Cancer (BCLC) very early/early stage. METHODS Between 2002 and 2009, patients with newly diagnosed BCLC very early/early stage HCC who received SR or RFA were enrolled. Medical records were reviewed. The cumulative overall survival (OS) and disease-free survival (DFS) were compared. RESULTS A total of 605 patients, including 143 very early (SR: 52; RFA: 91) and 462 early stages (SR: 208; RFA: 254) were enrolled. For very early stage, the 3- and 5-year OS rates were 98% and 91.5% for SR, and 80.3% and 72% for RFA, respectively (p=0.073). The 3- and 5-year DFS rates were 62.1% and 40.7% for SR, and 39.8% and 29.3% for RFA, respectively (p=0.006). Either multiple adjustment by Cox model or match analysis based on propensity score showed no significant difference in OS between the two groups. For early stage, the 3- and 5-year OS rates were 87.8% and 77.2% for SR, and 73.5% and 57.4% for RFA, respectively (p=0.001). The 3- and 5-year DFS rates were 59.9% and 50.8% for SR, and 28.3% and 14.1% for RFA, respectively (p<0.001). After adjusting covariates, there was no significant difference in OS between the two groups. However, SR was superior to RFA in DFS. CONCLUSIONS For HCC patients in BCLC very early/early stage, there was no significant difference in OS between SR and RFA. However, SR yielded better DFS than RFA.

The efficacy of treatment schedules according to Barcelona Clinic Liver Cancer staging for hepatocellular carcinoma – Survival analysis of 3892 patients

The Barcelona Clinic Liver Cancer (BCLC) staging offers prognostic stratification and treatment allocation for hepatocellular carcinoma (HCC). We conducted this retrospective study to assess the efficacy of different treatment options for patients with initial HCC diagnosis. Survival rate and median survival times associated with different treatment options in each stage of BCLC classification were compared using the Kaplan-Meier method and log-rank test. A total of 3892 patients were enrolled. Overall survival rates were 46.2% at 1 year and 16.6% at 5 years. The median survival times decreased from 57.7 months in very early stage to 1.6 months in terminal stage. Surgical resection offered the best survival benefit for patients in very early, early and even intermediate stages. Transarterial embolisation and conformal radiotherapy offered survival benefits for selected patients in advanced and terminal stages. In conclusion, following the treatment schedules allocated by BCLC staging had survival benefits for HCC patients.

Age, gender, and local geographic variations of viral etiology of hepatocellular carcinoma in a hyperendemic area for hepatitis B virus infection

There are etiologic variations of hepatocellular carcinoma (HCC) in different geographic areas. Taiwan is a hyperendemic area for hepatitis B virus (HBV) infection. Hepatitis C virus (HCV) infection also plays an important role in HCC development in Taiwan. Identification of local HCV‐endemic areas is important to keep HCV from spreading. This study investigated the etiologic variations of HCC in different geographic areas of Taiwan.

Thrombocytopenia as a surrogate for cirrhosis and a marker for the identification of patients at high-risk for hepatocellular carcinoma.

The objective of this study was to examine the usefulness of platelet counts in the diagnosis of cirrhosis and for identifying high‐risk individuals in a community‐based hepatocellular carcinoma (HCC) screening program.

The role of hepatitis B and C viruses in hepatocellular carcinoma in a hepatitis B endemic area. A case‐control study

To investigate the role of hepatitis B (HBV) and C viruses (HCV) in hepatocellular carcinoma (HCC) in an HBV endemic area and elucidate the interaction of these two viruses, a case‐control study of 128 patients with HCC and 384 age‐matched and sex‐matched control subjects was done. The positive rates of hepatitis B surface antigen (HBsAg, 77.3%, 99 of 128) and anti‐HCV (19.5%, 25 of 128) in patients with HCC were significantly higher than in control subjects (P < 0.001). Both HBsAg and anti‐HCV were important risk factors for HCC (relative risks, 13.96 and 27.12, respectively), and the risk for HCC was elevated significantly to 40.05 (95% confidence interval, 12.57 to 127.6) when HBsAg and anti‐HCV were considered simultaneously. These results suggested that HBV and HCV were associated highly with HCC in an HBV endemic area and that these two viruses might contribute independent but synergistic effects to the pathogenesis of HCC.

Long‐term effect of interferon alpha‐2b plus ribavirin therapy on incidence of hepatocellular carcinoma in patients with hepatitis C virus‐related cirrhosis

Summary.  We assessed the efficacy of interferon (IFN) alpha‐2b plus ribavirin therapy in patients with hepatitis C virus (HCV)‐related cirrhosis, and elucidated the risk factors for the development of hepatocellular carcinoma (HCC) to determine whether these therapies might reduce the incidence of HCC. One hundred and thirty‐two HCV‐cirrhotic patients receiving IFN alpha‐2b (3 or 5 MU thrice weekly) and oral ribavirin (1000–1200 mg/day) for 24 or 48 weeks were analysed. Cumulative incidence of HCC was estimated by the Kaplan–Meier method. The prognostic relevance of clinical variables and HCC occurrence was evaluated by univariate analysis with the log‐rank test and by multivariate Coxs regression analysis. A total of 116 patients completed the treatment and 73 (55%) achieved a sustained virological response (SVR). Stepwise logistic regression analysis showed that nongenotype 1b (P < 0.001) and low viral load (P = 0.018) were independent variables of SVR. During a median follow‐up period of 37 (12–63) months, HCC developed in 11 patients with non‐SVR and five with SVR (P = 0.0178), whereas there was no difference between those with transient biochemical response and nonresponse (P = 0.5970). The Kaplan–Meier method also showed that old age (≥60 years) (P = 0.0034) and genotype 1b (P = 0.0104) were associated with HCC occurrence. Using Coxs regression analysis, non‐SVR (odds ratio = 3.521, P = 0.036), male (odds ratio = 6.269, P = 0.011) and old age (odds ratio = 3.076, P = 0.049) were independent significant risk factors contributing to HCC development. Our results suggest that achieving SVR by IFN alpha‐2b plus ribavirin therapy may decrease the incidence of HCC in patients with HCV‐related cirrhosis.

A randomised phase II study of pegylated arginine deiminase (ADI-PEG 20) in Asian advanced hepatocellular carcinoma patients

Background:Human hepatocellular carcinoma (HCC) cells are largely deficient of argininosuccinate synthetase and thus auxotrophic for arginine. This study aims to investigate the efficacy and pharmacodynamics of pegylated arginine deiminase (ADI-PEG 20), a systemic arginine deprivation agent, in Asian HCC patients.Methods:Patients with advanced HCC who were not candidates for local therapy were eligible and randomly assigned to receive weekly intramuscular injections of ADI-PEG 20 at doses of 160 or 320 IU m−2. The primary end point was disease-control rate (DCR).Results:Of the 71 accruals, 43.6% had failed previous systemic treatment. There were no objective responders. The DCR and the median overall survival (OS) of the intent-to-treat population were 31.0% (95% confidence interval (CI): 20.5–43.1) and 7.3 (95% CI: 4.7–9.9) months respectively. Both efficacy parameters were comparable between the two study arms. The median OS of patients with undetectable circulating arginine for more than or equal to and <4 weeks was 10.0 (95% CI: 2.1–17.9) and 5.8 (95% CI: 1.4–10.1) months respectively (P=0.251, log-rank test). The major treatment-related adverse events were grades 1–2 local and/or allergic reactions.Conclusions:ADI-PEG 20 is safe and efficacious in stabilising the progression of heavily pretreated advanced HCC in an Asian population, and deserves further exploration.