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.

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.

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.

Effects of nucleoside analogue prescription for hepatitis B on the incidence of liver cancer in Hong Kong: a territory-wide ecological study.

BACKGROUND: The temporal relationship between nucleoside analogue therapy for chronic hepatitis B (CHB) and liver cancer development has not been evaluated at a population level. AIM: To investigate the impact of nucleoside analogue prescription on liver cancer incidence in a CHB-prevalent region. METHODS: We obtained territory-wide nucleoside analogue prescription data from 1999, when nucleoside analogue was first available in Hong Kong, to 2012 and the population-based liver cancer incidence data from 1990 to 2012. We compared the liver cancer incidences from 1990 to 1998 and 1999 to 2012 with adjustment for local hepatitis B surface antigen seroprevalence. RESULTS: Nucleoside analogue prescription patient headcount increased from 2006 per year in 1999 to 26 411 in 2012. Prescription volume in 2012 was highest among 55-64 years (30.3%), higher than 65-74 years (13.0%) and ≥75 years (5.8%). Age-standardised liver cancer incidence 1999-2012 decreased by 1.88%/year (95% CI 3.34% to 0.42%/year). NA therapy was associated with decline in age-adjusted liver cancer incidence (2.7 per 100 000 persons, P < 0.001, 95% CI 1.4-4.0 per 100 000 persons). Fifty-five to sixty-four years age group had the most significant decline (men: 24.0 per 100 000 persons, P = 0.001, 95% CI 11.4-36.6 per 100 000 persons; women: 8.5 per 100 000 persons, P = 0.009, 95% CI 2.3-14.6 per 100 000 persons). No significant association was noted in age groups 65-74 years and ≥75 years (both P > 0.05). CONCLUSIONS: Nucleoside analogue prescription was associated with a reduction of overall liver cancer incidence in a CHB-prevalent region. The lack of association among individuals of ≥65 years was consistent with the low nucleoside analogue prescription volume in elderly patients, mitigating the impact of CHB treatment on liver cancer.

Body-mass index is associated with fibrosis regression during long-term nucleoside analogue therapy in chronic hepatitis B.

BACKGROUND: Factors influencing changes in liver stiffness measurements during long-term nucleoside analogue therapy for chronic hepatitis B (CHB) have not been thoroughly investigated. AIM: To identify determinants of on-treatment fibrosis regression in CHB. METHODS: We performed follow-up liver stiffness and controlled attenuation parameter measurements on nucleoside analogue-treated CHB patients with severe liver fibrosis, according to EASL-ALEH criteria, diagnosed by transient elastography in 2006-2008. Anthropometric measurements and different metabolic parameters were recorded. RESULTS: Among 257 patients with severe liver fibrosis by initial transient elastography, 123 (47.9%) were recruited for reassessment. Median treatment duration was 87.5 (interquartile range 75.3-102.2) months; 97.5% had undetectable HBV DNA. There was a significant reduction in median liver stiffness from 14.6 to 8.3 kPa (P < 0.001). A total of 29.3% had fibrosis regression, with lower rates of 17.9%, 14.9% and 11.5% noted in patients with body-mass index (BMI) ≥25 kg/m2 , metabolic syndrome and diabetes, respectively. Absence of BMI ≥25 kg/m2 , diabetes and metabolic syndrome, when compared with presence of any one of these three factors, was associated with increased fibrosis regression (43.1% vs. 16.9%, P = 0.001). Multivariate analysis found a lower BMI to be the only factor independently associated with fibrosis regression (P = 0.034, odds ratio 0.68, 95% CI 0.48-0.97). No association was noted between controlled attenuation parameter measurements and fibrosis regression (P > 0.05). CONCLUSION: An increased BMI hindered fibrosis regression in patients with chronic hepatitis B during nucleoside analogue treatment, suggesting that control of metabolic risk factors, in addition to virologic suppression via antiviral therapy, might be needed to halt the fibrogenic process in chronic hepatitis B.

Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update.

Worldwide, some 240 million people have chronic hepatitis B virus (HBV), with the highest rates of infection in Africa and Asia. Our understanding of the natural history of HBV infection and the potential for therapy of the resultant disease is continuously improving. New data have become available since the previous APASL guidelines for management of HBV infection were published in 2012. The objective of this manuscript is to update the recommendations for the optimal management of chronic HBV infection. The 2015 guidelines were developed by a panel of Asian experts chosen by the APASL. The clinical practice guidelines are based on evidence from existing publications or, if evidence was unavailable, on the experts' personal experience and opinion after deliberations. Manuscripts and abstracts of important meetings published through January 2015 have been evaluated. This guideline covers the full spectrum of care of patients infected with hepatitis B, including new terminology, natural history, screening, vaccination, counseling, diagnosis, assessment of the stage of liver disease, the indications, timing, choice and duration of single or combination of antiviral drugs, screening for HCC, management in special situations like childhood, pregnancy, coinfections, renal impairment and pre- and post-liver transplant, and policy guidelines. However, areas of uncertainty still exist, and clinicians, patients, and public health authorities must therefore continue to make choices on the basis of the evolving evidence. The final clinical practice guidelines and recommendations are presented here, along with the relevant background information.

Sofosbuvir plus ribavirin for the treatment of patients with chronic genotype 1 or 6 hepatitis C virus infection in Hong Kong.

BACKGROUND: In Hong Kong, most patients with hepatitis C virus (HCV) have either genotype 6a or 1b infection. AIM: To evaluate the efficacy and safety of sofosbuvir with ribavirin in treatment-naïve patients in Hong Kong with HCV genotype 1 or 6. METHODS: In an open-label study, patients were randomised to sofosbuvir 400 mg once daily plus ribavirin 1000-1200 divided twice daily for 12 (n = 10), 16 (n = 11) or 24 (n = 10) weeks. The primary endpoint was the percentage of patients with HCV RNA < LLOQ (lower limit of quantification, 25 IU/mL) 12 weeks after cessation of therapy (SVR12). RESULTS: All 31 patients (20 HCV genotype 1 and 11 genotype 6) had HCV RNA < LLOQ by Week 4 of treatment and at their last on-treatment visit. SVR12 rates were high in all treatment groups: 100% (10/10) for 12 weeks, 100% (11/11) for 16 weeks and 90% (9/10) for 24 weeks of therapy. The only patient who did not reach SVR12 had genotype 1 HCV and relapsed at post-treatment Week 4. Sofosbuvir with ribavirin was generally well tolerated. The most common adverse events were malaise (13%) and upper respiratory tract infection (13%), followed by anaemia (10%). No patients experienced serious adverse events. One patient discontinued treatment at Week 16 because of an adverse event. The event, upper respiratory tract infection, was not considered treatment related by the investigator. This subject achieved SVR12. CONCLUSIONS: The all-oral regimen sofosbuvir plus ribavirin is effective in treatment-naïve patients in Hong Kong with genotype 1 or 6 HCV. TRIAL REGISTRATION NUMBER: NCT02021643.

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.

Intrahepatic hepatitis B virus replication and liver histology in subjects with occult hepatitis B infection.

We studied the intrahepatic hepatitis B virus (HBV) replicative status in 40 people with occult hepatitis B infection (OBI) and 40 patients with chronic hepatitis B (CHB). Intrahepatic HBV DNA, covalently closed circular DNA (cccDNA), and pre-genomic RNA (pgRNA) were quantified. Patients with OBI had median necroinflammation and fibrosis scores of 1 and 0, respectively. Intrahepatic total HBV DNA, cccDNA and pgRNA were detectable in 30 (77%), one (3%) and five (13%) of the participants with OBI, respectively. People with OBI had lower median intrahepatic total HBV DNA than the patients with CHB (p < 0.0001). They had nearly normal liver histology and low intrahepatic HBV replication.

Increased risk of pulmonary and extra-pulmonary tuberculosis in patients with rheumatic diseases.

SETTING: Impaired immunity in patients with rheumatic diseases can increase the risk of pulmonary tuberculosis (PTB). However, it is less clear whether rheumatic diseases affect the risk of extra-pulmonary tuberculosis (EPTB). OBJECTIVE: To investigate the risk of PTB and EPTB in patients with rheumatic diseases using a population-based database. DESIGN: From Taiwan's National Health Insurance Research Database, 8536 patients with tuberculosis (TB) were frequency-matched with 42,680 controls for sex, 10-year age group and index year. Subjects were retrospectively traced back for their first diagnosis of rheumatic diseases. The association between TB and rheumatic diseases was assessed using multivariate logistic regression analyses. RESULTS: The risk of developing PTB was significantly higher in patients with systemic lupus erythematosus (adjusted odds ratio [aOR] 4.90, P < 0.001), rheumatoid arthritis (RA) (aOR 2.00, P < 0.001) and Sjögren's syndrome (aOR 6.11, P < 0.001). In addition, the risks of developing EPTB were significantly higher in RA patients (aOR 4.67, P < 0.001), those with Sjögren's syndrome (aOR 5.94, P < 0.001), and the group comprising progressive systemic sclerosis, polymyositis or dermatomyositis (aOR 8.31, P = 0.021). CONCLUSION: Elevated risks of PTB and EPTB were associated with various rheumatic diseases. Rheumatologists should be vigilant to the possibility of TB, and particularly EPTB, in their patients.

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.

High prevalence of human herpesvirus type 8 infection in patients with pulmonary tuberculosis in Taiwan.

Blood samples were collected from 101 untreated pulmonary tuberculosis (TB) patients and 101 age- and sex-matched healthy control subjects. TB patients had lower lymphocyte and a higher monocyte counts than control subjects (p <0.0001 for both). The seropositive rate of human herpesvirus (HHV) type 8 antibody was higher in patients (30/101) than in control subjects (15/101) (p = 0.01). Antibody titres in patients also exceeded those in control subjects (p 0.006). Lymphocyte and monocyte counts between seronegative and seropositive subjects were not different. Four patients were positive for HHV-8 DNA. The study revealed a significantly higher HHV-8 seroprevalence in untreated pulmonary TB patients than in general population.

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.