Sien-Sing Yang

Increased risk of cirrhosis and its decompensation in chronic hepatitis C patients with new‐onset diabetes: A nationwide cohort study

The effect of diabetes on cirrhosis, its decompensation, and their time relationship in chronic hepatitis C (CHC) patients remains unclear. We conducted a nation‐wide cohort study by using the Taiwanese National Health Insurance Research Database, which is comprised of data from >99% of the entire population. Among having randomly sampled 1 million enrollees, 6,251 adult CHC patients were identified from 1997 to 2009. Diabetes was defined as new onset in CHC patients who were given the diagnosis in the years 1999‐2003, but not in 1997‐1998. The cohorts of CHC with new‐onset diabetes (n = 424) and nondiabetes (n = 1,708) were followed up from inception point in diabetes and from year 1999 in the nondiabetes cohort until development of cirrhosis or its decompensation, withdrawal from insurance, or December 2009. Kaplan‐Meiers survival analysis showed a significantly higher cumulative incidence of cirrhosis (relative risk [RR] = 1.53; 95% confidence interval [CI] = 1.11‐2.11; log‐rank test; P < 0.001) and decompensated cirrhosis (RR = 2.01; 95% CI = 1.07‐3.79; log‐rank test; P < 0.001) among patients with new‐onset diabetes, as compared to those without. After adjustment for age, gender, CHC treatment, diabetes treatment, hepatocellular carcinoma, comorbidity index, hypertension, hyperlipidemia, and obesity by Coxs proportional hazard model, diabetes was still an independent predictor for cirrhosis (hazard ratio [HR] = 2.505; 95% CI = 1.609‐3.897; P < 0.001) and its decompensation (HR = 3.560; 95% CI = 1.526‐8.307; P = 0.003). Conclusion: CHC patients who develop diabetes are at an increased risk of liver cirrhosis and its decompensation over time. (Hepatology 2014;60:807–814)

Sustained hepatitis C virus clearance and increased hepatitis B surface antigen seroclearance in patients with dual chronic hepatitis C and B during posttreatment follow-up†‡§

Patients dually infected with hepatitis C virus (HCV)/hepatitis B virus (HBV) have a higher risk of developing advanced liver disease or hepatocellular carcinoma compared with monoinfected patients. Yet, there is a similar rate of sustained virologic response (SVR) after peginterferon alfa‐2a and ribavirin combination therapy in these patients compared with HCV‐monoinfected patients and a high hepatitis B surface antigen (HBsAg) seroclearance rate. The durability of hepatitis C and B clearance in coinfected patients was investigated in a 5‐year follow‐up study. Patients with active HCV genotype 1, both HBV‐coinfected (n = 97) and HBV‐monoinfected (n = 110), underwent 48‐week combination therapy with peginterferon alfa‐2a plus ribavirin. In patients with active HCV genotype 2 or 3, both HBV‐coinfected (n = 64) and monoinfected (n = 50) patients underwent 24‐week combination therapy. A total of 295 (91.9%) patients completed treatment and 24 weeks posttreatment follow‐up; 264 (89.5%) patients agreed to receive additional follow‐up for up to 5 years after the end of treatment. After a median follow‐up of 4.6 ± 1.0 years, six of the 232 patients achieving SVR developed HCV RNA reappearance, including five HCV genotype 1/HBV‐coinfected patients and one HCV genotype 2/3‐monoinfected patient. Subgenomic analysis of the HCV core gene indicated that five patients developed delayed recurrence of HCV infection. Overall, the cumulative recurrence rate of HCV infection was 2.3% (0.4%/year; 95% confidence interval [CI], 0.9%‐5.5%). The cumulative HBsAg seroclearance rate was 30.0% (95% CI, 21.5%‐42.0%); with 33.1% (95% CI, 21.8%‐50.1%) in the 48‐week combination therapy group and 24.3% (95% CI, 13.7%‐42.9%) in the 24‐week therapy group. Conclusion: Peginterferon alfa‐2a and ribavirin therapy provides good HCV SVR durability and a high accumulative HBsAg seroclearance rate in patients who are coinfected with HCV and HBV. (HEPATOLOGY 2013;)

Increased Risk of Cirrhosis and Its Decompensation in Chronic Hepatitis B Patients With Newly Diagnosed Diabetes: A Nationwide Cohort Study

BACKGROUND The impact of diabetes on cirrhosis, its decompensation, and their time relationship in patients with chronic hepatitis B (CHB) remain unclear. METHODS We conducted a nationwide cohort study by using the Taiwanese National Health Insurance Research Database, which was comprised of data from >99% of the entire population. Among 1 million randomly sampled enrollees, 14 523 adult CHB patients were identified from 1997 to 2009. Diabetes was defined as newly diagnosed in CHB patients who were given the diagnosis in the years 1998-2001 but not in 1996-1997 and with physician visits of at least twice per year. The cohorts of CHB with newly diagnosed diabetes (n = 351) and without diabetes (n = 7886) were followed up from the diagnosis of diabetes and from 2000 in the patients without diabetes until development of cirrhosis or its decompensation, withdrawal from insurance, or December 2009. RESULTS Kaplan-Meier survival analysis showed a significantly higher cumulative incidence of cirrhosis (relative risk [RR] = 3.43; 95% confidence interval [CI], 2.62-4.49; P < .001, log-rank test) and decompensated cirrhosis (RR = 4.11; 95% CI, 2.95-5.70; P < .001, log-rank test) among patients with newly developed diabetes compared with those without diabetes. After adjustment for age, sex, CHB treatment, hepatocellular carcinoma, and comorbidity index by Cox proportional hazards model, diabetes was still an independent predictor for cirrhosis (hazard ratio [HR] = 2.015; 95% CI, 1.393-2.915; P < .001) and its decompensation (HR = 1.792; 95% CI, 1.192-2.695; P = .005). CONCLUSIONS Patients with CHB who develop diabetes are at an increased risk of liver cirrhosis and its decompensation over time.

HBsAg Profiles in Patients Receiving Peginterferon Alfa-2a plus Ribavirin for the Treatment of Dual Chronic Infection with Hepatitis B and C Viruses

BACKGROUND With use of peginterferon alfa-2a and ribavirin combination therapy in patients with dual chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, 11.2% of patients achieved clearance of hepatitis B surface antigen (HBsAg) at 6 months after treatment; however, reactivation of HBV DNA was observed in 36.3%. We investigated the predictive potential of HBsAg quantification. METHODS HBsAg quantification was performed in 120 e antigen-negative patients dually infected with HBV and hepatitis C virus and treated with peginterferon alfa-2a/ribavirin for 48 weeks (HCV genotype 1; n = 74) or 24 weeks (HCV genotype 2/3; n = 46). HBsAg was quantified at baseline, week 4, week 12, end of treatment, and 24 weeks after treatment. RESULTS The baseline median serum HBsAg level was 120 IU/mL and decreased gradually during treatment. Low baseline HBsAg was significantly associated with HBsAg clearance (40% for HBsAg level 20 IU/mL vs 2.2% for HBsAg level >20 IU/mL; P < .05). A decrease in HBsAg level from baseline to week 12 of 50% was associated with a reduced likelihood of HBV DNA reactivation in patients with baseline undetectable serum HBV DNA (positive predictive value, 89.5%). CONCLUSIONS HBsAg quantification appears to be a useful indicator of posttreatment outcome in patients dually infected with HBV and hepatitis C virus.

Statins Reduce the Risk of Cirrhosis and Its Decompensation in Chronic Hepatitis B Patients: A Nationwide Cohort Study

OBJECTIVES:The protective effect of statins in cirrhosis and its decompensation in chronic hepatitis B (CHB) patients remains unknown.METHODS:We conducted a population-based cohort study using data from the Taiwanese National Health Insurance Research Database from 1997 to 2009. A total of 298,761 CHB patients were identified. CHB patients using statins (n=6,543; defined as ≥28 cumulative defined daily doses (cDDD)) and a 1:1 ratio propensity score and inception point (the date of first use of statins)-matched non-statins (<28 cDDD) were followed up from the inception point until the development of cirrhosis or its decompensation or until withdrawal from insurance or December 2009.RESULTS:After adjustment for competing mortality, CHB patients using statins had a significantly lower cumulative incidence of cirrhosis (relative risk)=0.433; 95% confidence interval (CI)=0.344–0.515; modified log-rank test, P<0.001) and decompensated cirrhosis (relative risk=0.468; 95% CI=0.344–0.637; P<0.001) compared with patients not using statins. After adjustment for age, gender, comorbidity index, hypertension, diabetes, hyperlipidemia, hepatocellular carcinoma, obesity, non-alcoholic fatty liver disease, aspirin use, diabetes medication, CHB treatment, non-statin lipid-lowering drugs, and triglyceride lipid-lowering drugs using the Cox proportional hazard model, statins were still an independent protector against cirrhosis (adjusted hazard ratio (AHR)=0.512; 95% CI=0.413–0.634; P<0.001) and its decompensation (AHR=0.534; 95% CI=0.433–0.659; P<0.001). The AHRs for cirrhosis were 0.467 and 0.200, and the AHRs for decompensated cirrhosis were 0.611 and 0.231 with 91–365 and >365 cDDD of statins, respectively.CONCLUSIONS:CHB patients who receive statin therapy have a dose-dependent reduction in the risk of cirrhosis and its decompensation.

Interferon α‐2b with and without ribavirin in the treatment of hepatitis B e antigen–positive chronic hepatitis B: A randomized study

To study whether interferon (IFN) α and ribavirin combination therapy has a beneficial effect for hepatitis B e antigen (HBeAg)‐positive chronic hepatitis B, we enrolled 119 such patients in a randomized study. Fifty‐nine patients received 5 million units of IFN‐α2b daily for 4 weeks followed by 5 million units three times a week for 28 weeks, plus 1,200 mg ribavirin daily. Sixty patients received the same dosage of IFN plus placebo. They were followed up for 24 weeks posttreatment, and 105 patients (88%) completed the entire course of 56 weeks. By intention‐to‐treat analysis, the rate of combined response (serum hepatitis B virus [HBV] DNA <2.5 pg/mL and HBeAg seroconversion) was 17% versus 25% between the IFN/ribavirin and IFN/placebo group, respectively, at the end of treatment (P = .35) and 25% vs. 20% at the end of follow‐up (P = .32). Using quantitative real‐time polymerase chain reaction assay, the log(10) reduction of serum HBV DNA was 1.05 ± 1.72 (mean ± SD) versus 1.29 ± 1.91 between the two groups at the end of treatment (P = .49) and was 2.15 ± 2.15 versus 1.21 ± 2.48 at the end of follow‐up (P = .04). Prolonged observations in 83 patients suggested that the combined response was 29% (n = 17) versus 20% (n = 12) at 48 weeks after the end of treatment, respectively (P = .17). The safety profile was similar, except that the IFN/ribavirin group had a higher risk of anemia (15% vs. 0%; P = .002). In conclusion, for the treatment of HBeAg‐positive chronic hepatitis B, adding ribavirin does not seem to increase the efficacy of IFN. (HEPATOLOGY 2006;43:742–749.)

Evoked potentials in liver diseases

Evoked potentials are objective and quantitative methods capable of evaluating functions of both peripheral and central nervous systems (PNS and CNS). During the past 8 years, we have been using somatosensory, brainstem auditory, and pattern‐reversal visual evoked potentials (SEP, BAEP, VEP) to study hepatic encephalopathy (HE) as well as functional status of the PNS and CNS in various liver diseases including viral hepatitis B, alcoholic liver disease and Wilsons disease (WD). In HE irrespective of its etiologies, there is a sequential prolongation and eventual disappearance of cortical components of the median nerve evoked SEP while there is no change in BAEP, suggesting that HE is primarily due to a disturbance in cerebral cortical function and that median SEP may be used for early detection of HE and for monitoring its clinical course. In addition, absence of the N20‐P25 component, or presence of only the N20 component of the wave complex in fulminant hepatic failure is associated with high mortality, whereas presence of late cortical components in HE is usually associated with reversibility of clinical course. Central conduction time (CCT) of the BAEP is prolonged in patients with WD, alcoholic liver disease and liver cirrhosis due to hepatitis B. Furthermore, BAEP abnormality is most severe in WD, followed by alcoholic liver disease, and finally hepatitis B. Peripheral nerve conduction as determined by the N9 latency of SEP is slowed in alcoholic liver disease and liver cirrhosis of chronic hepatitis B, but normal in WD. Our studies, therefore, suggest that evoked potentials may be useful in the evaluation of both CNS and PNS functions in various liver diseases and also in the diagnosis and monitoring of HE.

A hospital-based study on the use of alternative medicine in patients with chronic liver and gastrointestinal diseases.

To determine the extent to which Taiwanese patients use alternative medicine, we interviewed 500 consecutive patients with chronic liver and gastrointestinal disorders at an outpatient-service. Forty-two patients were excluded due to incomplete data. The percentages of patients with chronic liver (102/269, 37.9%) and gastrointestinal (74/189, 39.2%) diseases using alternative medicine were not significantly different (p = 0.70). The patients who used alternative medicine were not statistically different in gender (p = 0.37), age (p = 0.59), education level (p = 0.83), family income (p = 0.90), or occupation (p = 0.72). Only 36% (64/176) of patients informed their doctors of their use of alternative medicine. The kinds of alternative medicine used by the 176 patients included: Chinese/herbal medicine, 169 (96%); acupuncture, 31 (18%); nutritional supplements, 22 (13%); chiropractic, 17 (10%); scratching, 14 (8%); Qigong, 13 (7%); cupping, 13 (7%); and incense ash, 3 (2%). Sixty-six percent (111/169) of patients used Chinese/herbal medicine in addition to Western allopathic medicine. Only 11% (19/169) of them believed that Chinese/herbal medicine had side effects. Our study indicates the use of alternative medicine occurs across all demographic groups in one-third of patients with chronic liver and gastrointestinal diseases at a major general hospital in Taipei. We suggest that the doctors question all patients for history of alternative therapy use.

Reduced Toll-like receptor 3 expression in chronic hepatitis B patients and its restoration by interferon therapy.

BACKGROUND Toll-like receptor (TLR)3 gene variants may correlate with clinical significance of chronic viral infections including HBV. We aimed to investigate the expression of TLR3 in peripheral blood mononuclear cells (PBMCs) and liver cells of chronic hepatitis B (CHB) patients and its response to pegylated interferon or nucleoside analogue therapy. METHODS We consecutively enrolled 127 CHB patients and 64 hepatitis B surface antigen-negative, anti-HCV-negative healthy individuals as controls. We compared the TLR3 expressions on fresh PBMCs and liver cells from patients and controls, before and during pegylated interferon or nucleoside analogue therapy. RESULTS Compared to controls, patients had a lower TLR3 mean fluorescence intensity (MFI) on PBMCs (mean ± sd 14.61 ± 13.49 versus 9.70 ± 4.61; P < 0.001), independent of age, gender and alanine aminotransferase (ALT; -13.466, 95% CI -17.202, -9.730; P < 0.001). Patients had limited TLR3 stains on Kupffer cells, whereas controls had diffuse stains on Kupffer and hepatocytes. Hepatic TLR3 messenger RNA was lower in patients than controls (0.47 ± 0.30 versus 1-fold). Using pretreatment TLR3 MFI as a referent, among 5 of 12 pegylated-interferon-treated patients with sustained virological response (SVR), TLR3 MFI was restored to a mean of 1.5- to 1.7-folds immediately after treatment. Among seven non-responders or relapsers, TLR3 MFI reduced to a mean of 0.5- to 0.7-fold. Among 10 entecavir-treated patients with on-treatment virological response, TLR3 MFI gradually was restored to a mean of 1.2-folds during 48-week therapy. CONCLUSIONS CHB patients have reduced TLR3 expression on PBMCs, independent of age, gender and ALT, and on liver cells. Patients with pegylated-interferon-induced SVR have a more significant restoration of TLR3 expression than those under entecavir.

Differential effects of interferon and lamivudine on serum HBV RNA inhibition in patients with chronic hepatitis B.

BACKGROUND Lamivudine and interferon have been widely used for the treatment of patients with chronic HBV infection. Serum HBV RNA is detected during lamivudine therapy as a consequence of interrupted reverse transcription and because RNA replicative intermediates are unaffected by the drug. In this study, we aimed to determine the detectability of serum HBV RNA during sequential combination therapy of interferon and lamivudine. METHODS HBV DNA and RNA in serum samples were quantified by reverse transcription of HBV nucleic acid extract and real-time PCR. Samples were analysed every 2 weeks to 3 months from three groups of patients: 10 male patients treated with nucleoside analogue monotherapy for 44-48 weeks (5 with lamivudine and 5 with entecavir), 6 males on sequential interferon and lamivudine combination therapy, and 3 males on lamivudine monotherapy for 20-24 weeks. RESULTS HBV RNA was not detectable in any patients before treatment, but became detectable in 15 during antiviral treatment. Among the three groups, pre-treatment HBV DNA (8.1 +/-2.4 versus 7.7 +/-1.4 versus 5.1 +/-0.3 log(10) copies/ml; P=0.06), treatment and follow-up durations (45.5 +/-2.0 versus 49.7 +/-5.6 versus 48.7 +/-6.4 weeks; P=0.32) were comparable. HBV RNA was detectable at the end of treatment or follow-up in all patients with monotherapy, but in none of those with sequential combination therapy (100% versus 0%; P<0.001). CONCLUSIONS Compared with lamivudine therapy with detectable serum HBV RNA in patients with chronic HBV infection, interferon treatment might reduce HBV DNA replication through the inhibition of HBV RNA replicative intermediates, resulting in the loss of serum HBV RNA.