Miriam T. Levy

Hepatitis B surface antigen levels during the natural history of chronic hepatitis B: A perspective on Asia

BACKGROUND & AIMS Data from clinical trials suggest a potential role for on-treatment monitoring of serum HBsAg titres during interferon-alpha (pegIFN) therapy in predicting virological responses. However, baseline HBsAg titres during the natural history of chronic hepatitis B (CHB) have not been well-characterized. We aimed to define the serum HBsAg titres during the different phases of CHB in a cohort of Asian patients infected with either genotype B or C HBV. METHODS Two-hundred and twenty patients were classified into immune-tolerant (IT), immune-clearance (IC), non/low-replicative (LR) or hepatitis B e antigen negative hepatitis (ENH) phases. Serum HBsAg was quantified using the ARCHITECT platform (Abbott Laboratories, Chicago, USA). Correlation of HBsAg titre with HBV DNA and serum ALT within each phase of infection was performed. RESULTS Median HBsAg titres were different between each phase of CHB (p=0.001): IT (4.53 log(10)IU/ml), IC (4.03 log(10)IU/ml), LR (2.86 log(10)IU/ml), and ENH (3.35 log(10)IU/ml). HBsAg titres were highest in the IT phase, and lowest in the LR phase. In general, median HBsAg titres were similar between genotypes B and C HBV. Serum HBsAg titres only correlated with HBV viral load in the IC phase. No correlation between the serum HBsAg level and ALT was observed. CONCLUSIONS This study demonstrated significant differences in median baseline serum HBsAg titres across the different phases of CHB. These results provide further insight into the HBV viral life cycle in the setting of the various phases of CHB. Baseline HBsAg quantification may help refine future treatment algorithms for both immune-modulator therapy and oral nucleos(t)ide analogue therapy.

Efficacy and safety of tenofovir disoproxil fumarate in pregnancy to prevent perinatal transmission of hepatitis B virus

BACKGROUND & AIMS Perinatal transmission of hepatitis B virus still occurs despite immunoprophylaxis in approximately 9% of children from highly viraemic mothers. Antiviral therapy in this setting has been suggested, however with limited evidence to direct agent choice. METHODS We conducted a multi-centre, prospective, opt-in observational study of antiviral safety and efficacy in pregnant women with high viral load (>7 log IU/ml); lamivudine was used from 2007 to 2010 and tenofovir disoproxil fumarate (TDF) from late 2010. Outcomes of treated and untreated cohorts were compared. RESULTS 120 women with 130 pregnancies used TDF (58), lamivudine (52 including four who switched due to TDF intolerance) and no therapy (20). 96% were HBeAg positive, with baseline viral load mean 7.8 log IU/ml (±0.72) and ALT median 25 U/L (18.75-33). Duration of antiviral theraphy before birth was mean 58 days (±19) TDF and 53 (±14) lamivudine. Viral load declined by 3.64 log IU/ml (±0.9) TDF and 2.81 log IU/ml (±1.33) lamivudine. Virologic failure (birth viral load >7 IU/ml) occurred in 3% and 18% respectively. Congenital abnormality rate and neonatal growth centiles were similar across cohorts. Perinatal transmission reduced significantly to 2% and 0% in TDF and lamivudine cohorts, compared with 20% in untreated. CONCLUSIONS TDF in this setting is safe, effective and more potent than lamivudine. Antiviral therapy did not adversely impact obstetric or infant parameters. More TDF intolerance occurred than expected. Perinatal transmission was significantly reduced in antiviral therapy cohorts.

Adverse impact of hepatitis C virus infection on renal replacement therapy and renal transplant patients in Australia and New Zealand.

Background. Understanding the impact of hepatitis C virus (HCV) infection in patients with end-stage renal disease before and after renal transplantation requires more data. We examined the outcomes of HCV antibody positive (HCVAb+) dialysis and renal transplant patients using the Australian and New Zealand Dialysis and Transplant registry. Methods. Two cohorts of dialysis (n=23,046) and transplant (n=7572) patients were identified. Survival outcomes, causes of mortality, and causes of graft failure were examined. Results. Dialysis Cohort: 362 (1.6%) were HCVAb+ve. The cause of end-stage renal disease in the HCVAb+ve group was more likely to be glomerulonephritis or diabetes. Survival figures were similar at 5 years (48% vs. 47%) and 10 years (22% and 20%) for HCVAb+ve and HCVAb negative (HCVAb−ve) groups; however, the adjusted hazard ratio (aHR) for mortality was increased, 1.25 (95% confidence interval [CI], 1.07–1.46), for the HCVAb+ve cohort. Liver failure was more likely. Renal Transplantation Cohort: 140 (1.8%) were HCVAb+ve. Patient survival among HCVAb+ve and HCVAb−ve groups was 77% vs. 90% and 50% vs. 79% at 5 and 10 years, respectively. The aHR for patient death was 2.38 (95%CI, 1.69–3.37). Higher rates of death due to cardiovascular disease (aHR=2.74), malignancy (aHR=2.52), and hepatic failure (aHR=22.1) were observed. The aHR for graft loss was 1.71 (95%CI, 1.28–2.29) for HCVAb+ve patients; and glomerulonephritis, chronic allograft neuropathy, and death were more frequent causes of graft failure. Conclusion. On dialysis, HCVAb+ve patients had a slightly worse outcome. After renal transplantation, the HCVAb+ve cohort had a markedly worse patient and graft outcome. The impact of viral eradication on these outcomes is unknown.

Reversal of activation of human myofibroblast-like cells by culture on a basement membrane-like substrate

BACKGROUND Liver injury transforms hepatic stellate cells into myofibroblast (MFB)-like cells. With recovery from injury, MFBs undergo apoptosis, but it is unknown whether they can also revert to quiescence. AIM To determine whether human (h)MFBs become quiescent if cultured on a basement membrane-like substrate (Matrigel). METHODS hMFBs obtained from cirrhotic liver were re-cultured on plastic or Matrigel. Expression of genes of collagen metabolism was assayed before and after transforming growth factor beta (TGFbeta) and Oncostatin M (OSM) stimulation. RESULTS hMFBs had typical MFB-like morphology, with abundant alpha-smooth muscle actin (SMA) but no cytoplasmic lipid droplets. hMFBs re-cultured on Matrigel reverted to alphaSMA-negative, lipid droplet-positive quiescent morphology. alphaSMA, collagen alpha1(1) (COL1A1) and collagen alpha2(1) (COL1A2) messages were upregulated in hMFBs cultured on plastic, but suppressed by Matrigel. The opposite was true for metalloproteinase-1 mRNA. OSM but not TGFbeta reduced alphaSMA mRNA by 30% while TGFbeta but not OSM upregulated COL1A1 mRNA by 48%, in hMFBs on plastic. TGFbeta and OSM stimulated COL1A1 gene expression in Matrigel by 50 and 60%, respectively. CONCLUSIONS Matrigel culture de-activates hMFBs yet collagen gene expression still responds to fibrogenic cytokines. The responses of hMFB gene expression to TGFbeta and OSM, are regulated differently by the extracellular matrix.

Molecular pathogenesis of liver disease: an approach to hepatic inflammation, cirrhosis and liver transplant tolerance

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Short duration of lamivudine for the prevention of hepatitis B virus transmission in pregnancy: lack of potency and selection of resistance mutations

This study sought to assess the antiviral efficacy of lamivudine (LMV) administered during third trimester to reduce maternal viraemia and to identify the emergence of LMV resistance. A prospective observational analysis was performed on 26 mothers with high viral load (>107 IU/mL). Twenty‐one women received LMV (treated group) for an average of 53 days (range 22–88 days), and the remaining five formed the untreated control group. Serum samples from two time points were used to measure HBV DNA levels and antiviral drug resistance. The LMV‐treated women achieved a median HBV DNA reduction of 2.6‐log10 IU/mL. Although end‐of‐treatment (EOT) HBV DNA in four (18%) LMV‐treated women remained at >107 IU/mL (±0.5 log IU/mL), no mother‐to‐baby transmission was observed. In contrast, a baby from the untreated mother was HBsAg positive at 9 months postpartum. Four technologies were used for drug resistance testing. Only ultra‐deep pyrosequencing (UDPS) was sufficiently sensitive to detect minor viral variants down to <1%. UDPS showed that LMV therapy resulted in increased viral quasispecies diversity and positive selection of HBV variants with reverse transcriptase amino acid substitutions at sites associated with primary LMV resistance (rtM204I/V and rtA181T) in four (19%) women. These viral variants were detected mostly at low frequencies (0.63–5.92%) at EOT, but one LMV‐treated mother had an rtA181T variant that increased from 2.2% pretherapy to 25.59% at EOT. This mother was also infected with the vaccine escape variant (sG145R), which was inhibited by LMV treatment. LMV therapy during late pregnancy only reduced maternal viraemia moderately, and drug‐resistant viral variants emerged.

Oncostatin M: a cytokine upregulated in human cirrhosis, increases collagen production by human hepatic stellate cells

BACKGROUND/AIMS Hepatic stellate cells are predominantly responsible for the increased extracellular matrix seen in cirrhosis. The cytokine oncostatin M has been implicated in fibrogenesis in vitro in other cell types and in vivo in other tissues, although its effect on hepatic stellate cells or in cirrhosis is unknown. METHODS To examine the effect of oncostatin M on collagen production by human hepatic stellate cells in culture, collagen protein was measured and collagen alpha2(1) mRNA was quantified by Northern analysis. Tissue inhibitor of metalloproteinase-1 (an inhibitor of collagen degradation) mRNA was measured in response to oncostation M stimulation. To explore the potential biological significance of this work to human liver disease, oncostatin M messenger RNA in normal and cirrhotic human liver was measured. RESULTS Oncostatin M induced in a 2-fold increase in collagen secretion. The potency of induction of collagen protein secretion was equal to that observed after transforming growth factor beta stimulation. An increase in endogenous collagen alpha2(1) mRNA could not be detected. This suggested a post-transcriptional mechanism for the increase in collagen protein. In response to oncostatin M stimulation, there was a 2-fold increase in the tissue inhibitor or metalloproteinase-1 mRNA. Oncostatin M mRNA was detected in 6/6 cirrhotic livers and 1/7 normal livers after 28 PCR cycles. CONCLUSION These results suggest that oncostatin M expression is upregulated in cirrhosis where it may have a role as a profibrogenic cytokine in hepatic stellate cells.

Anti-viral therapy for prevention of perinatal HBV transmission: extending therapy beyond birth does not protect against post-partum flare

Antepartum anti‐viral therapy (AVT) is often administered to prevent perinatal transmission of hepatitis B virus (HBV) infection. Little is known about the effect of AVT on post‐partum flare rates and severity.

Antiviral therapy for hepatitis B-related liver cancer prevention is more cost-effective than cancer screening

BACKGROUND/AIMS In Australia, Asian-born populations are 6-12 times more likely to develop hepatocellular cancer (HCC) than Australian-born individuals. We therefore, modelled the consequences of different management strategies for chronic hepatitis B (CHB) in Asian-born adults aged > or = 35 years. METHODS A Markov model compared (1) enhanced surveillance for HCC alone (HCC surveillance), or (2) enhanced HCC surveillance coupled with CHB treatment (HCC prevention) to the current practice, of low CHB treatment uptake. Patients were stratified and managed according to risk categories, based upon hepatitis B virus (HBV) viral load and alanine aminotransferase (ALT) levels. We measured costs, health outcomes [cases of HCC and deaths averted, quality-adjusted life-years (QALYs) gained] and incremental cost-effectiveness ratios (ICERs). RESULTS HCC surveillance would cost on average AU

Case Report: Delayed resolution of severe pulmonary hypertension after isolated liver transplantation in a patient with cirrhosis

8479 per person, compared to AU