HBsAg loss in a New Zealand community study with 28-year follow-up: rates, predictors and long-term outcomes.

BACKGROUND AND AIMS: HBsAg seroclearance is the most desired endpoint in chronic hepatitis B (CHB) but occurs uncommonly. Recent studies have shown baseline HBsAg levels to be predictive of HBsAg loss up to 10 years. We report the 28-year rates of HBsAg loss and outcomes in the Kawerau study cohort from New Zealand, and assess the predictive value of baseline HBsAg levels to predict long-term HBsAg loss. METHODS: The 1984 Kawerau community study identified 572 CHB patients, followed up for 28 years (41 % HBeAg-positive, median age 17 years, range 1-71 years). In 2012, surviving individuals attended a local clinic for an interview, blood tests and transient elastography. RESULTS: 384/218 (74 %) surviving individuals attended the clinic in 2012. Spontaneous HBsAg loss occurred in 145 (33 %) after 12,702 person-years of follow-up (1.14 per 100 person-years). Liver stiffness measurements were significantly lower if HBsAg loss occurred <50 years (mean 6.1 kPa) versus >50 years (mean 11.6 kPa), p = 0.0002. No HCC occurred following HBsAg loss (median follow-up 72 months). Predictors of HBsAg loss were older age and lower baseline HBsAg level (HR for HBsAg loss at 28 years 2.7 (95 % CI 1.7-4.2), 6.7 (95 % CI 3.9-11.4) and 9.4 (95 % CI 5.2-16.9), respectively, for HBsAg 1000-9999, 100-999 and <100 IU/mL compared to HBsAg >10,000 IU/mL at baseline, (p < 0.0001). Baseline HBsAg was a superior predictor of HBsAg loss compared to HBV DNA at all time-points: AUROC at 15 years: 0.87 (95 % CI 0.82-0.93) versus 0.73 (95 % CI 0.66-0.80) (p < 0.0001) and AUROC at 28 years: 0.74 (95 % CI 0.69-0.79) versus 0.67 (95 % CI 0.62-0.72) (p = 0.0007). The optimal cut-off HBsAg level to predict HBsAg seroclearance at 28 years is HBsAg <10,000 IU/mL (sensitivity 72 %, specificity 64 %, NPV 88 %). CONCLUSIONS: Rates of HBsAg loss in our community cohort were high, and occurred earlier than previously reported. Earlier HBsAg loss was associated with less severe liver fibrosis. Baseline HBsAg level was a good predictor of long-term HBsAg loss up to 28 years and superior to HBV DNA.

Serological and clinical outcomes of horizontally transmitted chronic hepatitis B infection in New Zealand Maori: results from a 28-year follow-up study.

BACKGROUND: Chronic hepatitis B infection is endemic in New Zealand and has high prevalence in New Zealand Maori. Previous longitudinal studies in populations with predominantly vertically acquired chronic hepatitis B have shown low spontaneous hepatitis B surface-antigen (HBsAg) seroclearance rates: 0.5-1.4% annually (mean age of clearance 48 years). We report the 28-year follow-up data on clinical and serological outcomes in indigenous New Zealand Maori with early horizontally acquired HBV. METHODS: In 1984, community seroprevalence study identified 572 HBsAg-positive individuals, followed for 28 years. Liver-related mortality and hepatocellular carcinoma (HCC) incidence were compared between these 572 HBV carriers and 1140 HBsAg-negative matched case-controls. Surviving HBsAg-positive individuals have been followed up in 2012 with clinical assessment, blood tests and liver transient elastography. Rates of hepatitis B e-antigen (HBeAg) and HBsAg seroconversion were determined. RESULTS: After total 13 187.4 person-years follow-up, 15 HBsAg-positive patients have developed HCC compared with none of the HBsAg-negative controls (p<0.001). 12 HBsAg-positive patients died from liver-related causes compared with none in the controls (p<0.001). Spontaneous HBeAg-seroconversion occurred in 91% of HBeAg-positive patients. Spontaneous HBsAg loss occurred in 33% overall (annual clearance rate 1.34%), with higher rates at older ages (1.05% in patients<20 years at entry vs 4.3% per annum >40 years at entry, p<0.0001). Median ages of HBeAg loss and HBsAg loss were 23 years (range 6-66 years) and 40 years (range 4-80 years), respectively. CONCLUSIONS: Horizontally transmitted HBV in Maori is similarly associated with increased risk of liver-related mortality and HCC compared with Chinese, although absolute incidence rates are lower. The rates of HBeAg and HBsAg loss are high, and occur at an earlier age than previously reported.

Time trends, ethnicity and risk factors for eczema in New Zealand children: ISAAC Phase Three.

BACKGROUND: Eczema is a common chronic disease which has significant morbidity and costs for children and their families. Phase One (1993) of the International Study of Asthma and Allergies in Childhood (ISAAC) found a high prevalence of symptoms of eczema in New Zealand. OBJECTIVE: In Phase Three (2001-3) we aimed to answer these three questions: Is the prevalence of eczema changing over time?; Are there ethnic differences in prevalence?; and What are the risk factors for eczema? METHODS: Five New Zealand centres participated in ISAAC Phases One and Three using the same methodology. Questionnaires about ethnicity, symptoms of eczema and environmental factors were completed by parents of 6-7 year olds (children) and self-completed by 13-14 year olds (adolescents). Prevalence and change per year were calculated by centre, ethnicity and gender. Prevalence differences between centres and associations with environmental factors were examined using logistic regression. RESULTS: There was little change in prevalence over time for the children, and a decrease in prevalence for the adolescents. Prevalence was higher among Maori and even higher among Pacific participants than among European children. Positive associations with current eczema symptoms were found for both age groups for truck traffic in the street of residence, and current paracetamol consumption, and for children only, antibiotics or paracetamol in the 1st year of life. Inverse associations were found with residence in New Zealand less than 5 years, consumption of milk, seafood, and eggs, and presence of a dog in the home. CONCLUSION: Eczema remains a significant problem, particularly for young Maori and Pacific New Zealanders in whom less recognition of eczema and poorer access to effective, sustained eczema management may be contributing factors. Reverse causation may explain all the environmental findings apart from truck traffic which is increasing in New Zealand.

Time trends and risk factors for rhinoconjunctivitis in New Zealand children: an International Study of Asthma and Allergies in Childhood (ISAAC) survey.

AIM: To investigate prevalence, time trends and factors associated with rhinitis and rhinoconjunctivitis not related to acute infections in New Zealand. METHODS: The International Study of Asthma and Allergies in Childhood (ISAAC) surveyed children aged 6-7 and 13-14 years for symptoms of these conditions. Five New Zealand centres were surveyed on two occasions (Phase One and Phase Three) 8-10 years apart. In Phase Three, questions were included on environmental factors, which might be associated with rhinoconjunctivitis. We report findings related to symptoms of rhinoconjunctivitis among 24 190 New Zealand children. RESULTS: Symptoms of rhinoconjunctivitis in the past year were reported in 11.4% of 6- to 7-year-old children and 18% of 13- to 14-year-old adolescents in Phase Three compared with 9.5 and 19.1%, respectively, in Phase One. Severe symptoms of rhinoconjunctivitis were reported in 0.5% of children and 0.8% of adolescents. Current symptoms were more common in males at 6-7 years and in females of 13-14 years, and Maori and Pacific Island ethnic groups had higher prevalence compared with those of European descent, especially in the older age group. For immigrant children, there was a very strong positive relationship between symptoms and length of time resident in New Zealand, supporting the probable importance of environmental factors. A positive association was found between symptoms and use of paracetamol in infancy or in the last year, and weaker associations were noted for antibiotic use, exercise, and regular pasta ingestion. CONCLUSIONS: Further study of environmental factors is recommended.

Genomic analysis of hepatitis B virus reveals antigen state and genotype as sources of evolutionary rate variation.

Hepatitis B virus (HBV) genomes are small, semi-double-stranded DNA circular genomes that contain alternating overlapping reading frames and replicate through an RNA intermediary phase. This complex biology has presented a challenge to estimating an evolutionary rate for HBV, leading to difficulties resolving the evolutionary and epidemiological history of the virus. Here, we re-examine rates of HBV evolution using a novel data set of 112 within-host, transmission history (pedigree) and among-host genomes isolated over 20 years from the indigenous peoples of the South Pacific, combined with 313 previously published HBV genomes. We employ Bayesian phylogenetic approaches to examine several potential causes and consequences of evolutionary rate variation in HBV. Our results reveal rate variation both between genotypes and across the genome, as well as strikingly slower rates when genomes are sampled in the Hepatitis B e antigen positive state, compared to the e antigen negative state. This Hepatitis B e antigen rate variation was found to be largely attributable to changes during the course of infection in the preCore and Core genes and their regulatory elements.

Nuclear SIRT1 activity, but not protein content, regulates mitochondrial biogenesis in rat and human skeletal muscle.

Silent mating type information regulator 2 homolog 1 (SIRT1)-mediated peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) deacetylation is potentially key for activating mitochondrial biogenesis. Yet, at the whole muscle level, SIRT1 is not associated with mitochondrial biogenesis (Gurd, BJ, Yoshida Y, Lally J, Holloway GP, Bonen A. J Physiol 587: 1817-1828, 2009). Therefore, we examined nuclear SIRT1 protein and activity in muscle with varied mitochondrial content and in response to acute exercise. We also measured these parameters after stimulating mitochondrial biogenesis with chronic muscle contraction and 5-aminoimidazole-4-carboxamide-1-ß-d-ribofuranoside (AICAR) administration in rodents and exercise training in humans. In skeletal and heart muscles, nuclear SIRT1 protein was negatively correlated with indices of mitochondrial density (citrate synthase activity, CS; cytochrome oxidase IV, COX IV), but SIRT1 activity was positively correlated with these parameters (r > 0.98). Acute exercise did not alter nuclear SIRT1 protein but did induce a time-dependent increase in nuclear SIRT1 activity. This increase in SIRT1 activity was temporally related to increases in mRNA expression of genes activated by PGC-1α. Both chronic muscle stimulation and AICAR increased mitochondrial biogenesis and muscle PGC-1α, but not nuclear PGC-1α. Concomitantly, muscle and nuclear SIRT1 protein contents were reduced, but nuclear SIRT1 activity was increased. In human muscle, training-induced mitochondrial biogenesis did not alter muscle or nuclear SIRT1 protein content, but it did increase muscle and nuclear PGC-1α and SIRT1 activity. Thus, nuclear SIRT1 activity, but not muscle or nuclear SIRT1 protein content, is associated with contraction-stimulated mitochondrial biogenesis in rat and human muscle, possibly via AMPK activation.

Has the prevalence and severity of symptoms of asthma changed among children in New Zealand? ISAAC Phase Three.

AIM: To investigate time trends in prevalence of symptoms of asthma by repeating, during 2001-3 (Phase Three), the International Study of Asthma and Allergies in Childhood (ISAAC) Phase One study that was conducted in New Zealand in 1992-3. METHODS: ISAAC Phase Three involved repeating the cross-sectional questionnaire survey of two age groups of school children (6-7 years and 13-14 years, children and adolescents respectively) using the same methodology as Phase One. In New Zealand it was conducted in Auckland, Bay of Plenty, Christchurch, Nelson, and Wellington. RESULTS: After 9 years, reported asthma ever increased from 24.6% to 30.2% in children and from 24.1% to 32.4% in adolescents (p<0.001). Current wheeze (written questionnaire) significantly decreased in children from 23.6% to 22.2% (p=0.002) and in adolescents from 29.7% to 26.7% (p=0.047), and for the video questionnaire from 18.1% to 11.1% (p<0.001). There was a significant reduction in wheezing limiting speech from 5.0% to 3.7% in children, and 7.9% to 6.2% in adolescents. Little regional variation was found. A higher proportion of children with asthma symptoms now report having ever had asthma. CONCLUSIONS: The decrease in prevalence and severity of symptoms of asthma is encouraging, but the reasons for these trends are currently unclear. Increases in asthma labelling are likely to be due to greater awareness of asthma. A trend of decreasing prevalence of asthma symptoms, if maintained, has positive implications for lessened burden of disease among asthmatics and lowered cost of treatment.

The New Zealand Hepatitis B Screening Programme: screening coverage and prevalence of chronic hepatitis B infection.

AIM: To report on screening coverage and the distribution of HBsAg (a marker of chronic hepatitis B virus infection) among participants in the New Zealand Hepatitis B Screening Programme. METHOD: Coverage and crude and age-standardised prevalence rates of HBsAg by age group, sex, ethnic group, and region were calculated from data held by the two providers and the New Zealand 2001 Census. RESULTS: 177,000 people were tested for hepatitis B virus infection (51% of the programme targets and 27% of Census 2001 eligible population), with highest coverage among women (28.9%) and Pacific people (34.9%). Overall, 5.7% (10,176) of participants were HBsAg-positive and there were significant regional, ethnic group, and gender differences. 5.6% of Maori, 7.3% of Pacific people, and 6.2% of Asians were HBsAg-positive, and men were more likely to test HBsAg-positive (6.1%) than women (5.4%). CONCLUSIONS: Previous estimates of HBsAg prevalence among Maori and Pacific people from smaller surveys were confirmed and new information obtained about the distribution of hepatitis B virus infection among Pacific Islands and Asian populations in New Zealand. Opportunistic screening of adults in these populations should continue in order to identify others with (as yet undetected) infection. Regular follow-up of people with chronic hepatitis B virus infection should also continue. Ongoing outcome monitoring is now needed to judge whether this unique programme has been an effective component of New Zealand's hepatitis B control strategy and whether it is a worthwhile investment of resources.

Sequence mutations in teleost cardiac troponin C that are permissive of high Ca2+ affinity of site II.

Cardiac myofibrils isolated from trout heart have been demonstrated to have a higher sensitivity for Ca(2+) than mammalian cardiac myofibrils. Using cardiac troponin C (cTnC) cloned from trout and mammalian hearts, we have previously demonstrated that this comparatively high Ca(2+) sensitivity is due, in part, to trout cTnC (ScTnC) having twice the Ca(2+) affinity of mammalian cTnC (McTnC) over a broad range of temperatures. The amino acid sequence of ScTnC is 92% identical to McTnC. To determine the residues responsible for the high Ca(2+) affinity, the function of a number of ScTnC and McTnC mutants was characterized by monitoring an intrinsic fluorescent reporter that monitors Ca(2+) binding to site II (F27W). The removal of the COOH terminus (amino acids 90-161) from ScTnC and McTnC maintained the difference in Ca(2+) affinity between the truncated cTnC isoforms (ScNTnC and McNTnC). The replacement of Gln(29) and Asp(30) in ScNTnC with the corresponding residues from McNTnC, Leu and Gly, respectively, reduced Ca(2+) affinity to that of McNTnC. These results demonstrate that Gln(29) and Asp(30) in ScTnC are required for the high Ca(2+) affinity of site II.

Field evaluation of the efficacy and immunogenicity of recombinant hepatitis B vaccine without HBIG in newborn Vietnamese infants.

A study involving more than 2,000 infants was conducted in Vietnam to assess the field effectiveness and immunogenicity of recombinant hepatitis B vaccine given at birth, 1 month, 2 months, without concomitant hepatitis B immune globulin (HBIG). All received a 5 microg dose of H-B-VAX II at birth. Infants born to non-carrier mothers (Group 1; N = 1798) then received 2.5 microg doses at 1 and 2 months of age, while infants of HBeAg-negative (Group 2; N = 125) or HBeAg-positive (Group 3; N = 88) carrier mothers received 5 microg doses. No Group 1 or 2 vaccinees were infected. In Group 3, 12 (14.6%) of 82 infants did become infected (estimated efficacy 84%). 98.0-98.6% of uninfected infants who were tested for anti-HBs developed a seroprotective concentration > or = 10 IU/L. In hyperendemic Vietnam, where routine maternal screening and passive-active prophylaxis of high-risk infants with vaccine plus HBIG is not feasible, administration of vaccine alone to all newborns may control effectively HBV infection.