Jui-Ting Hu

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)

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.

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.)

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.

Vitamin D receptor gene polymorphisms and distinct clinical phenotypes of hepatitis B carriers in Taiwan

Vitamin D exhibits immunomodulatory and antiproliferative effects through vitamin D receptor (VDR) in chronic infections and cancers. We genotyped the BsmI (rs1544410), ApaI (rs7975232) and TaqI (rs731236) polymorphisms of VDR gene in 250 Taiwanese chronic hepatitis B virus (HBV) carriers who were categorized into six phenotypes. After adjustment for age and sex, the frequencies of the VDR B/b, B/a, B/T, B/a/T in patients with hepatitis flare(s) were lower than those without (7 vs 20%, P=0.009; 1 vs 9%, P=0.004; 3 vs 10%, P=0.007; 1 vs 9%, P=0.005, respectively); in contrast, T/t, A/T, A/t, b/A/t were higher in flare(s) (8 vs 3%, P=0.003; 49 vs 34%, P=0.027; 2 vs 1%, P=0.004; 0.5 vs 0%, P=0.001, respectively). In addition, B/b, B/B, T/t, b/A, B/a, B/A, B/T, B/t, A/t, b/A/T, B/a/T, B/A/T, B/A/t, b/A/t were higher in patients positive for HBeAg. The distribution of VDR genotypes was comparable between patients with and without hepatocellular carcinoma (HCC). VDR gene polymorphisms are associated with distinct clinical phenotypes in Taiwanese HBV carriers but not with HCC development.

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.

Increased risk of hepatocellular carcinoma in chronic hepatitis C patients with new onset diabetes: a nation‐wide cohort study

The impact of diabetes for hepatocellular carcinoma (HCC) development in chronic hepatitis C (CHC) patients remains controversial.

On-treatment low serum HBV RNA level predicts initial virological response in chronic hepatitis B patients receiving nucleoside analogue therapy.

BACKGROUND Serum HBV RNA is detectable during nucleoside/nucleotide analogue therapy as a result of unaffected RNA replicative intermediates or interrupted reverse transcription. We studied the predictive value of serum HBV RNA for initial virological response during nucleoside analogue therapy. METHODS Serum HBV RNA was quantified before and at 12 and 24 weeks of lamivudine or entecavir therapy. Serum HBV DNA was measured every 4-12 weeks during treatment to define initial virological response. RESULTS Serum HBV RNA was detectable in 21 of 52 (40%) consecutive patients with a mean of 5.2 log copies/ml (male/female 35/17, mean age of 60 years with a range of 31-82, 44% HBeAg-positive, and 26 with lamivudine and 26 with entecavir) before treatment. Serum HBV RNA level at week 12 in patients with an interval from detectable to undetectable serum HBV DNA level <16 weeks was significantly lower than those with an interval ≥16 weeks (3.8 ±3.8 versus 6.6 ±3.5 log copies/ml, P=0.013). After adjustment for serum HBV DNA level at week 12, serum quantatitive HBsAg level at week 12 and pretreatment ALT level, low serum HBV RNA level at week 12 predicted a shorter interval to undetectable serum HBV DNA level (adjusted hazard ratio =0.908, 95% CI 0.829, 0.993, P=0.035). CONCLUSIONS Low serum HBV RNA level at week 12 of nucleoside analogue therapy independently predicts initial virological response in treated chronic hepatitis B patients. Serum HBV RNA levels may thus be useful for optimizing treatment of chronic hepatitis B.

Reduced Toll-like receptor 9 expression on peripheral CD14(+) monocytes of chronic hepatitis B patients and its restoration by effective therapy

BACKGROUND Chronic hepatitis B (CHB) patients display Toll-like receptor 9 (TLR9)-dependent defective immune responses. We aimed to study TLR9 expression on CHB patients and its alteration during therapy. METHODS We compared TLR9 expression on fresh peripheral CD14+ monocytes from a cohort of 97 CHB patients and 35 HBsAg-negative, anti-HCV-negative controls, during pegylated interferon or entecavir therapy. TLR9 expression on liver tissue was also investigated. RESULTS Compared with controls, peripheral CD14+ monocytes of CHB patients displayed reduced expression of TLR9 mean fluorescence intensity (MFI; 9.90 ±3.64 versus 7.95 ±3.61; P=0.007) independent of age, gender and alanine aminotransferase (ALT; -2.09, 95% CI -3.568, -0.613; P=0.006). Furthermore, age, gender, ALT, HBeAg status, quantitative HBsAg (qHBsAg) or HBV DNA did not predict the TLR9 expression (P=0.863). Hepatic TLR9 messenger RNA (mRNA) was significantly reduced in 54 patients compared with 3 controls (0.45 ±0.32 versus 1-fold). Using response-guided therapy by qHBsAg levels and pretreatment TLR9 MFI as a reference, TLR9 MFI restored to a mean of 1.7- to 2.7-fold in pegylated interferon responders and reduced to a mean of 0.6- to 0.7-fold in non-responders starting from treatment week 12. Among 10 entecavir-treated patients, TLR9 MFI gradually restored to a mean of 1.2- to 2.1-fold starting from treatment week 48. CONCLUSIONS CHB patients display reduced TLR9 expression on peripheral CD14+ monocytes, which is independent of host and viral markers, and on liver tissue. Responders to pegylated interferon and those under entecavir demonstrate restoration of TLR9 expression. On-treatment TLR9 expression on peripheral monocytes might predict response to pegylated interferon therapy.