Acceptance of antiviral treatment and enhanced service model for pregnant patients carrying hepatitis B.

INTRODUCTION: A service model was established for pregnant women with positive screening results for hepatitis B surface antigen (HBsAg) at Queen Mary Hospital in Hong Kong. All women were offered a blood test for hepatitis B virus (HBV) DNA level during the first antenatal visit. Women with HBV DNA levels of ≥200 000 IU/mL received counselling from hepatologists regarding treatment with antenatal tenofovir disoproxil fumarate (TDF) 300 mg daily. METHODS: This retrospective review included women attending our antenatal clinic who exhibited positive HBsAg screening results from 15 May 2017 to 31 December 2019. The proportions of women with positive HBsAg, DNA test acceptance, hepatological review, and TDF acceptance during pregnancy were reviewed. RESULTS: In total, 375 (2.9%) of 13 082 pregnant women had positive HBsAg screening results. Blood tests for HBV DNA and hepatological reviews were offered to 273 women who had not undergone hepatological review prior to pregnancy; the acceptance rate was 97.8%. Sixty (22.6%) pregnant women were hepatitis B carriers with high viral loads of ≥200 000 IU/mL. Among 58 women with high viral loads, 57 received antenatal counselling regarding TDF and 56 (96.6%) agreed to take the drug; 92.9% of these 56 women had commenced TDF at or before 32 weeks of gestation. CONCLUSIONS: This study indicated broad acceptance of HBV DNA tests by pregnant women. Triage allowed early review and commencement of antiviral medication. This service model serves as a framework for enhanced antenatal service to prevent mother-to-child-transmission in public maternity units.

Inverse relationship between hepatic steatosis and hepatitis B viremia: Results of a large case-control study.

The potential interaction between chronic hepatitis B (CHB) and nonalcoholic fatty liver disease (NAFLD), two of the most prevalent liver diseases worldwide, has not been well defined. We performed liver stiffness (LS) and controlled attenuation parameter (CAP) measurements using transient elastography in 1202 CHB patients. Of these, 601 steatotic patients were matched with nonsteatotic controls in a 1:1 ratio by age, gender, nucleoside analogue treatment status, and treatment duration. Severe fibrosis was defined according to EASL-ALEH criteria, and steatosis was defined as CAP ≥222 dB m-1 . Anthropometric measurements and metabolic-related parameters were recorded. The mean age of the 1202 patients (51.4% male) was 51.8 years. 696 patients (57.9%) were on nucleoside analogues for a median duration of 76.2 months. Among treatment-naïve patients, median serum HBV DNA was lower in steatotic individuals than in controls (3.0 vs 3.4 log IU mL-1 , P < .05), with this inverse relationship remaining significant in multivariate analysis (odds ratio 0.859, 95% CI 0.743-0.994, P < .05). With increased steatosis severity, there was a stepwise decrease in median HBV DNA levels (3.1 and 2.6 log IU mL-1 in no steatosis and severe steatosis, respectively, P = .032). Steatosis was associated with a higher median LS (5.4 kPa vs 5.0 kPa, P < .001). Severe steatosis, when compared to mild/moderate steatosis, was associated with an increased percentage of severe fibrosis (23.2% and 12.6%, respectively, P = .005). We conclude that severe steatosis was associated with increased fibrosis in CHB patients. Increasing steatosis was independently associated with lower serum HBV DNA levels, suggesting its potential negative effects on viral replication.

Relationship between HBsAg, HBcrAg and hepatocellular carcinoma in patients with undetectable HBV DNA under nucleos(t)ide therapy.

We examined the relationship between hepatitis B surface and core-related antigens (HBsAg, HBcrAg) and hepatocellular carcinoma (HCC) development in patients with undetectable serum HBV DNA receiving nucleos(t)ide analogue (NA). Seventy-six HBV carriers with undetectable HBV DNA (<20 IU/mL) who subsequently developed HCC were compared with 152 matched controls. Clinical and laboratory parameters (including novel assays to measure linearized HBsAg [HQ-HBsAg] and HBcrAg) were analysed. There were no significant differences in HBsAg/HQ-HBsAg levels between the two groups. There was a significant difference in the median values of both pre- and post-NA HBcrAg levels between the HCC and control groups (pre-treatment: 279.0 vs 35.4 kU/mL, P=.005; post-treatment: 10.2 vs 1.7 kU/mL, P=.005, respectively). For the whole HCC group, a cut-off value of post-treatment HBcrAg level ≥7.8 kU/mL yielded an area under receiver operating curve (AUROC) of 0.61 with a negative predictive value (NPV) of 77.0%. The OR of HCC development was 3.27. For noncirrhotic patients, the median values of post-treatment HBcrAg level of HCC group and controls were 10.2 and 1.0 kU/mL, respectively (P=.001). A cut-off value of HBcrAg level ≥7.9 kU/mL yielded an AUROC of 0.70 with a NPV of 80.6%. The OR of HCC development was 5.95. A higher pre- and post-NA treatment HBcrAg level (but not HBsAg) was associated with an increased risk of HCC development in patients achieving undetectable serum HBV DNA while on NA therapy. HBcrAg may serve as a novel risk marker for HCC in this group of patients.

NUDT15 gene polymorphism related to mercaptopurine intolerance in Taiwan Chinese children with acute lymphoblastic leukemia.

A recent study identified a variant of the NUDT15 gene (rs116855232 C>T) associated with intolerance to thiopurine in Korean patients with Crohn's disease. This study prompted us to substantiate the finding in a Taiwanese population. Four hundred and four children with acute lymphoblastic leukemia (ALL), and 100 adults with chronic immune thrombocytopenic purpura or localized lymphoma having normal bone marrow were examined. Two candidate gene approaches, pyrosequencing for NUDT15 and TaqMan assay for thiopurine methyltransferase (TPMT) genotyping (rs1142345 A>G), were performed. We showed a risk allele frequency of NUDT15 of 11.6% in children with ALL and 15.5% in adults. By contrast, the risk allele frequency of TPMT was only 1.6% in children with ALL and 0.5% in adults. The high frequency of risk variant for NUDT15, but not the very low frequency of risk variant for TPMT, was closely associated with the intolerance to mercaptopurine in children with ALL in Taiwan, contrast to that of European descent. In regard to NUDT15 polymorphism, the maximal tolerable daily doses of mercaptopurine in homozygotes, heterozygotes and wild-type groups were 9.4 mg m-2, 30.7 mg m-2 and 44.1 mg m-2, respectively. The outcomes did not differ significantly among the different genotypes.

The effectiveness of a computer reminder system for laboratory monitoring of metabolic syndrome in schizophrenic outpatients using second-generation antipsychotics.

INTRODUCTION: A computer reminder system (CRS) may help psychiatrists follow guidelines and monitor patients at risk of metabolic syndrome. This study explores the effectiveness of a CRS for outpatients with schizophrenia. METHODS: The study data were collected from July 2004 to July 2008. A CRS was implemented in July 2006. The intervention group was patients taking either clozapine, olanzapine, risperidone, or quetiapine with a CRS. The control group was patients taking either sulpiride or zotepine without a CRS. We defined a qualified patient visit (QPV) as a visit in which metabolic monitoring adhered to established guidelines when the patient visit was within 6 months of performing the recommended laboratory examinations. We compared the percentage difference in QPVs between the 2 study groups. RESULTS: The percentage of QPVs in the intervention group was significantly higher than the control group (OR=3.51, 95% CI=1.83~6.73, P=0.0002) after adjusting potential confounding factors. The intervention group was divided into a high metabolic risk (clozapine and olanzapine) subgroup and an intermediate metabolic risk (risperidone and quetiapine) subgroup and compared with the control group. The percentage of QPVs in the high risk subgroup was significantly higher than the intermediate risk subgroup (OR=4.27, 95% CI=2.71~6.75, p<0.0001) and control group (OR=6.99, 95% CI=3.48~14.07, p<0.0001). DISCUSSION: The percentage of QPVs in the intervention group was higher than the control group and the different metabolic risk of SGAs also influenced the performance of laboratory examinations. Further studies are needed to confirm the results of our studies.

Determinants of cerebral white matter changes in patients with stroke.

BACKGROUND/AIM: Cerebral white matter changes (WMC) are commonly observed in magnetic resonance imaging (MRI) scans of elderly people. Information about the prevalence of WMC is limited, and little is known about site-specific risk factors for the subcortical and periventricular regions in patients with ischaemic stroke. The study aims to analyse the prevalence and severity of WMC and investigate the risk factors of periventricular WMC (PVWMC) and deep WMC (DWMC) separately in patients with ischaemic stroke. METHODS: The data were collected between January and December 2013 from a medical centre in southern Taiwan. Every patient underwent a cerebral MRI scan, and WMC was separately rated as PVWMC and DWMC by using the modified Fazekas scale. RESULTS: In total, 527 patients who had experienced ischaemic stroke were included. The mean age of the patients was 67.0 ± 12.5 years (range: 31-94) and 62% of them were men. The mean age was significantly different among the four grades of severity in both the PVWMC (P < 0.001) and DWMC (P < 0.001) groups after adjustments for sex and vascular risk factors. Hypertension was independently correlated with severity of DWMC (P = 0.032) but not with PVWMC (P = 0.222). In multiple logistic regressions model, hypertension was a significant independent indicator of DWMC (odds ratio = 4.30; 95% confidence interval = 1.70-10.89). CONCLUSION: Our results suggest a region-specific pathogenesis of cerebral white matter in Asian patients with ischaemic stroke that may differ from those in the general population.

Role of IL28B and inosine triphosphatase polymorphisms in the treatment of chronic hepatitis C virus genotype 6 infection.

IL28B and inosine triphosphatase (ITPA) polymorphisms are able to predict treatment response and degree of ribavirin-related anaemia, respectively, in the treatment of chronic hepatitis C virus (HCV) infection. However, their roles in the treatment of chronic HCV genotype 6 remain undetermined. Sixty patients who were infected with HCV genotype 6 were commenced on 48 weeks of combination pegylated interferon and ribavirin therapy. Response to therapy, profiles of haemoglobin changes and platelet counts during therapy and their associations with IL28B rs8099917 and ITPA rs1127354 polymorphisms were analysed. The overall sustained virologic response (SVR) rate was 91.7%. 18 patients (30.0%) required a reduction in ribavirin dosage. The distribution of IL28B rs8099917 TT/TG genotypes and ITPA rs1127354 CC/CA genotypes were in Hardy-Weinberg equilibrium. IL28B rs8099917 TT genotype, when compared to TG genotype, was significantly associated with an increased SVR rate (96.2% and 62.5%, respectively) and was the only clinical parameter that predicted SVR (P = 0.014). The same significant association was observed when analysing allelic frequencies (T vs G, P = 0.001). ITPA rs1127354 CA genotype, when compared to CC genotype, was associated with lesser degree of anaemia throughout therapy (P < 0.05 for all time points). ITPA polymorphisms showed no association with changes in platelet count throughout therapy (P > 0.05 for all time points) and was not associated with SVR (P = 0.640). In chronic HCV genotype 6 infection, IL28B polymorphisms were associated with response to therapy. ITPA polymorphisms influenced the degree of anaemia but not thrombocytopenia during therapy.

Prognostic significance of liver stiffness for hepatocellular carcinoma and mortality in HBeAg-negative chronic hepatitis B.

The prognostic value of liver stiffness measurements for chronic hepatitis B (CHB) is not known. The present study aimed to investigate the use of transient elastography in predicting hepatocellular carcinoma (HCC) development and mortality in patients with CHB. Five hundred and twenty-eight patients with HBeAg-negative CHB underwent liver stiffness measurements and were prospectively followed up every 3-6 months for a median length of 35 months. The patients were divided into those with liver stiffness < 10 kPa (group 1) and ≥ 10 kPa (group 2). Of the 528 patients, 324 (61%) were men. The median age was 42 years. Compared with group 1, group 2 had a higher percentage of men, with higher median levels of age, liver biochemistry, and viral load. At the third year of follow-up, the cumulative incidence of HCC was higher in group 2 compared with group 1 (9%vs 0%, respectively, P < 0.001). The cumulative liver-related mortality was also higher in group 2 compared to group 1 (4%vs 0%, respectively, P < 0.001). After multivariate analysis, only liver stiffness measurement (LSM) was significantly associated with HCC development and mortality. There was also a higher cumulative incidence of hepatitis flares in group 2 compared to group 1 (46%vs 14%, respectively, P = 0.001) in patients with normal ALT, with higher LSM and AST being significantly associated with subsequent flares. In HBeAg-negative CHB patients, a liver stiffness measurement of ≥ 10 kPa was associated with a significantly increased risk of subsequent HCC development and mortality.

Significant changes in liver stiffness measurements in patients with chronic hepatitis B: 3-year follow-up study.

For patients with chronic hepatitis B (CHB) infection, changes in liver stiffness measurement (LSM) over time are not known. We examined changes longitudinally in a cohort of patients. Four hundred and twenty-six patients with CHB underwent transient elastography. Patients were followed regularly, and repeat elastography was performed at 3 years. Hepatitis serology, viral load and routine liver biochemistry were monitored. Of the 426 patients, 38 (9%) were hepatitis B e-antigen (HBeAg)-positive, 293 (69%) were HBeAg-negative and 95 (22%) were patients with prior hepatitis B surface antigen (HBsAg) seroclearance. A total of 110 patients received oral antiviral therapy. There was a significant decline of LSMs at the follow-up measurement compared to baseline (6.1 vs 7.8 kPa respectively, P = 0.002) in treated patients who had elevated alanine aminotransferase (ALT) at baseline and subsequent normalization after 3 years (normal ALT limit being 30 U/L for males and 19 U/L for females). In nontreated patients, only the patients with persistently normal ALT at both time points had significantly lower LSMs at the follow-up measurement compared to baseline: 4.9 vs 5.3 kPa, respectively, in patients who remained positive for HBsAg (P = 0.005) and 5.1 vs. 5.4 kPa, respectively, in patients who had HBsAg seroclearance (P = 0.026). In patients who remained positive for HBsAg, independent factors associated with a significant decline in LSM of ≥1 kPa included antiviral therapy (P = 0.011) and the ALT levels at the follow-up time point (P = 0.024). Thus, in patients with CHB, a significant decline in LSM after 3 years was observed in treated patients with ALT normalization and in untreated patients who had persistently normal ALT. Antiviral therapy and follow-up ALT levels were independent significant factors associated with a decline in LSM.

Loss of HBsAg antigen during treatment with entecavir or lamivudine in nucleoside-naïve HBeAg-positive patients with chronic hepatitis B.

This retrospective analysis was conducted to describe the characteristics of nucleoside-naïve hepatitis B e antigen (HBeAg)-positive patients with chronic hepatitis B, who achieved hepatitis B surface antigen (HBsAg) loss during entecavir or lamivudine therapy. HBeAg-positive adults with chronic hepatitis B, elevated serum alanine aminotransferase, and compensated liver disease were randomized to double-blind treatment for up to 96 weeks with entecavir 0.5 mg/day or lamivudine 100 mg/day. HBsAg and hepatitis B virus (HBV) DNA were measured at regular intervals during and off-treatment follow-up. Through a maximum duration of 96 weeks on-treatment and 24 weeks off-treatment, HBsAg loss was confirmed in 18/354 (5.1%) patients treated with entecavir and 10/355 (2.8%) patients treated with lamivudine. Among the 28 patients with confirmed HBsAg loss, 27 (96%) achieved HBV DNA <300 copies/mL, and 27 (96%) achieved confirmed HBeAg loss. All entecavir recipients with HBsAg loss had HBV DNA <300 copies/mL. Caucasian patients, and those infected with HBV genotype A or D, were significantly more likely to lose HBsAg. This retrospective analysis of data from a randomized, global phase three trial shows that confirmed loss of HBsAg occurred in 5% of nucleoside-naïve HBeAg-positive patients treated with entecavir, and that HBsAg loss is associated with sustained off-treatment suppression of HBV DNA.

Health-related quality of life of Southern Chinese with chronic hepatitis B infection.

BACKGROUND: Few studies have evaluated the health-related quality of life (HRQOL) of Southern Chinese with chronic hepatitis B (CHB) infection. AIM: To evaluate the HRQOL of Chinese patients at different stages of CHB infection and to find out factors associated with HRQOL. METHODS: 520 Chinese adult CHB patients of whom 156 were uncomplicated, 102 had impaired liver function, 139 had cirrhosis and 123 had hepatocellular carcinoma (HCC) were interviewed with a structured questionnaire, the SF-36 Health Survey version 2 (SF-36v2), and the Chronic Liver Disease Questionnaire (CLDQ). The differences in SF-6D health preference values and SF-36v2 scores between each CHB group and Hong Kong population norms were assessed by t-test. ANOVA was used to compare the mean SF-6D health preference, SF-36v2 scores, and CLDQ scores among CHB groups. Multiple linear regressions were performed to identify determinants of HRQOL. RESULTS: CHB patients had significantly lower SF-36v2 scores than the population norm. The SF-6D values of CHB patients with uncomplicated disease, impaired liver function, HCC and cirrhosis were 0.755, 0.745, 0.720 and 0.701, respectively, all significantly lower than the population norm of 0.787. Advanced stage of CHB illness, anti-viral treatment, bilirubin level, psychological co-morbidity, younger age and female were associated with poorer HRQOL. CONCLUSION: CHB infection had a negative impact on HRQOL. There was a progressive decrease in health preference values with CHB disease progression. The results can be used for the estimation of quality adjusted life years (QALYs) for CHB patients in cost effectiveness or cost utility studies. TRIAL REGISTRATION: http://www.hkclinicaltrials.com; HKCTR-151.

Risk for hepatocellular carcinoma with respect to hepatitis B virus genotypes B/C, specific mutations of enhancer II/core promoter/precore regions and HBV DNA levels.

BACKGROUND/AIM: To examine the risks for hepatocellular carcinoma (HCC) with respect to hepatitis B virus (HBV) genotypes, specific viral mutations (MT), serum HBV DNA levels, and cirrhosis. METHODS: HBV genotypes, 1653/1753/core promoter (CP)/precore MT and HBV DNA levels were determined in 248 HBV patients with HCC and 248 HBV controls. RESULTS: Genotype C, CP-MT, T1653, HBV DNA levels >or=4 log(10) copies/ml and cirrhosis had a higher risk for HCC compared to patients with genotype B (p = 0.001, OR 1.9), CP wild-type (WT) (p<0.001, OR 4.1), C1653 (p = 0.028, OR 2.4), HBV DNA <4 log(10) copies/ml (p = 0.003, OR 2.1) and without cirrhosis (p<0.001, OR 4.0) respectively. Multivariate analysis showed that CP-MT, T1653, HBV DNA >or=4 log(10) copies/ml and cirrhosis were independent factors for HCC (all p<0.05). A receiver operating characteristics curve showed no cut-off HBV DNA level associated with minimal chance of HCC. Patients with CP-MT and cirrhosis had a 22.2-fold increased risk of HCC compared to patients with CP-WT and without cirrhosis. Patients with CP-MT and HBV DNA levels >or=4 log(10) copies/ml had a 7.2-fold increased risk of HCC compared to patients with CP-WT and HBV DNA levels <4 log(10) copies/ml. Patients with CP-MT and T1653 had a 9.9-fold increased risk of HCC compared to patients with wild-type for both regions. CONCLUSIONS: CP-MT, T1653, HBV DNA levels >or=4 log(10) copies/ml and cirrhosis are independent factors for development of HCC. The risks increased substantially in patients having these factors in combination.

Androgen receptor CAG repeat polymorphisms in canine prostate cancer.

BACKGROUND: Relatively shorter lengths of the polymorphic polyglutamine repeat-1 of the androgen receptor (AR) have been associated with an increased risk of prostate cancer (PC) in humans. In the dog, there are 2 polymorphic CAG repeat (CAGr) regions. OBJECTIVE: To investigate the relationship of CAGr length of the canine AR-gene and the development of PC. ANIMALS: Thirty-two dogs with PC and 172 control dogs were used. METHODS: DNA was extracted from blood. Both CAG repeats were amplified by polymerase chain reaction (PCR) and PCR products were sequenced. RESULTS: In dogs with PC, CAG-1 repeat length was shorter (P = .001) by an increased proportion of 10 repeats (P = .011) and no 12 repeats (P = .0017) than in the control dogs. No significant changes were found in CAG-3 length distribution. CAG-1 and CAG-3 polymorphisms proved not to be in linkage disequilibrium. Breed difference in allelic distribution was found in the control group. Of the prostate-disease sensitive breeds, a high percentage (64.5%) of the shortest haplotype 10/11 was found in the Doberman, whereas Beagles and German Pointers had higher haplotype 12/11 (47.1 and 50%). Bernese Mountain dogs and Bouvier dogs both shared a high percentage of 11 CAG-1 repeats and 13 CAG-3 repeats. Differences in (combined) allelic distributions among breeds were not significant. CONCLUSIONS AND CLINICAL IMPORTANCE: In this preliminary study, short CAG-1 repeats in the AR-gene were associated with an increased risk of developing canine PC. Although breed-specific differences in allelic distribution of CAG-1 and CAG-3 repeats were found, these could not be related to PC risk.

Review article: hepatitis B core-related antigen (HBcrAg): an emerging marker for chronic hepatitis B virus infection.

BACKGROUND: Chronic hepatitis B (CHB) cannot be completely eradicated due to the presence of covalently closed circular DNA (cccDNA) in the nuclei of infected hepatocytes. While quantification of intrahepatic cccDNA requires liver biopsies, serological markers can be non-invasive alternatives to reflect intrahepatic viral replicative activity. Recently, hepatitis B core-related antigen (HBcrAg) has been advocated as a novel serum marker for disease monitoring and prognostication of CHB. AIM: To examine the virological aspect and clinical application of HBcrAg with respect to the natural history and treatment of CHB. METHODS: We reviewed all papers published in the PubMed journal list and abstracts from major international meetings that included the keyword "HBcrAg" or "hepatitis B core-related antigen" until March 2017. Selected studies were compared and summarised on the basis of existing theories, as well as the authors' experience. RESULTS: HBcrAg exhibited good correlation with intrahepatic (ih) cccDNA, ih total hepatitis B virus (HBV) DNA, serum HBV DNA and to a lesser extent HBV surface antigen (HBsAg). In situations where serum HBV DNA levels become undetectable or HBsAg loss is achieved, HBcrAg can still be detectable. This marker is helpful in differentiation of HBeAg-negative chronic hepatitis from HBeAg-negative chronic infection, predicting spontaneous or treatment-induced HBeAg seroconversion, sustained response to nucleos(t)ide analogue (NA), risk of HBV reactivation in occult HBV infection under immunosuppressive therapies, and risk of hepatocellular carcinoma (HCC) development as well as post-operative HCC recurrence. CONCLUSIONS: HBcrAg is a potential surrogate marker of cccDNA. It may soon become a useful marker for disease monitoring, predicting treatment response and disease outcome of chronic hepatitis B.