Baseline HBsAg and HBcrAg titres allow peginterferon-based 'precision medicine' in HBeAg-negative chronic hepatitis B patients.

Quantitative hepatitis B core-related antigen (qHBcrAg) has been proposed as an additional marker to quantitative HBsAg (qHBsAg), for management of chronic hepatitis B. Evaluate baseline combination of qHBsAg and qHBcrAg for identification of patients that could benefit from pegylated interferon-alpha-2a (PegIFN)-based therapy. Sixty-two HBeAg-negative patients treated with PegIFN or PegIFN plus tenofovir disoproxil fumarate (PegIFN+TDF). HBsAg and HBcrAg titres were evaluated at baseline. Thirty patients received PegIFN and 32 PegIFN+TDF. SR was 10 of 30 and 17 of 32 in PegIFN and PegIFN+TDF patients, respectively. Cut-offs determined by maximized Youden's index for identifying patients likely to respond to therapy were as follows: 3.141 log10 IU/mL and 3.450 log10 U/mL for HBsAg and HBcrAg, respectively. At the end of 3 years post-treatment follow-up, HBsAg loss was observed in 7 of 30 and 6 of 32 in PegIFN and PegIFN+TDF patients, respectively. The AUC was estimated to be 0.716 (95% CI [0.578, 0.855]) for HBsAg and 0.668 (95% CI [0.524, 0.811]) for HBcrAg (P=.5541). PPVs for AUCs(95%CI) were 0.762(0.590-0.947), 0.714(0.533-1.000) and 0.800(0.611-1.000), and NPVs for AUCs(95%CI) were 0.756(0.660-0.899), 0.718(0.630-0.857) and 0.765(0.675-0.889) for qHBsAg, qHBcrAg and the combination of both markers, respectively. Baseline qHBsAg 3.141 log10 IU/mL and qHBcrAg 3.450 log10 U/mL thresholds used separately or in combination allow prediction of response, prior to PegIFN-based therapy, with a PPV of 80.3% and NPV of 76.5%. Baseline qHBsAg is predictive of HBsAg loss. Both markers could be used, separately or in combination, for PegIFN-based 'precision therapy'. Our results emphasize that the combination of PegIFN alpha-2a plus TDF with 53% of SR might be an alternative to finite therapy.

IFNL3 (IL28B) polymorphism does not predict long-term response to interferon therapy in HBeAg-positive chronic hepatitis B patients.

UNLABELLED: The impact of IFNL3 (IL28B) polymorphism on response to interferon (IFN) treatment in patients infected with hepatitis B virus (HBV) is controversial. We aimed to investigate whether IFNL3 polymorphism (rs12979860) influences the long-term response of chronic hepatitis B (CHB) treatment to conventional IFN. DESIGN: Ninety-seven HBeAg-positive patients treated with IFN were evaluated in this study. Associations were investigated between IFNL3 genotypes and (i) HBeAg seroconversion at the end of treatment (EOT), (ii) sustained virological response (SVR) and (iii) HBsAg seroconversion through long-term follow-up (LTFU). Patients were followed for a median of 14 years. The majority of patients were infected with HBV genotype A (69.6%) and were Caucasian (77.9%). Ninety-five patients were genotyped at rs12979860. Similar IFNL3 distribution was observed among the different ethnicities (P = 0.62) or across HBV genotypes A through G (P = 0.70). Thirty-six patients experienced HBeAg seroconversion at EOT; HBeAg seroconversion rates were 37.0 and 35.5% in patients with CC and CT/TT genotypes, respectively (P = 0.82). Among the 44 patients (45%) who achieved a SVR, SVR rates were 48.9 and 39.6% in patients with CC and CT/TT IL28B genotypes, respectively (P = 0.80). HBsAg seroconversion occurred through LTFU in 28 patients. HBsAg seroconversion rates were 25.5 and 31.2% in patients with CC and CT/TT genotypes, respectively (P = 0.51). No significant relationship between IFNL3 rs12979860 and fibrosis stage was observed (P = 0.85). IFNL3 genotype was neither associated with SVR, nor with HBeAg seroconversion and long-term HBsAg seroconversion in HBeAg-positive CHB patients responding to IFN therapy.

Sequential therapy with adefovir dipivoxil and pegylated interferon alfa-2a for HBeAg-negative patients.

To assess the impact of sequential therapy with adefovir dipivoxil (ADV) and pegylated interferon alfa-2a (PEG-IFN) on virological (serum HBV-DNA) and serological (serum HBsAg) response in 20 consecutive HBeAg-negative patients. Patients received ADV for 20 weeks, then ADV and PEG-IFN for 4 weeks and lastly PEG-IFN for 44 weeks. Serum HBV-DNA and HBsAg were assessed at baseline, during therapy (weeks 20, 44 and 68) and follow-up (weeks 92 and 116). Sustained virological response (SVR) was defined as serum HBV-DNA <10 000 copies/mL (partial) or <70 copies/mL (complete) 24 weeks after stopping treatment. A serological response was defined as a serum HBsAg decrease ≥1 log(10) IU/mL at the end of treatment. Baseline median serum HBV-DNA and HBsAg levels were 7.6 log(10) copies/mL and 3.8 log(10) IU/mL, respectively. Ten patients (50%) achieved SVR, six of them had partial response and four complete response. Four patients (20%) achieved serological response. Complete SVRs showed a major and steep decline in HBsAg level with a median decrease of 0.5, 1.6 and 2.0 log(10) IU/mL at treatment week 20, 44 and 68, respectively. Partial SVRs showed a slight and slow decline in serum HBsAg level (0.1, 0.4, and 0.6 log IU/mL at weeks 20, 44 and 68, respectively). On-treatment serum HBsAg decrease had a high accuracy to predict SVR (AUROC = 0.88). Our results suggest that sequential therapy might be an interesting strategy for HBeAg-negative patients. Serum HBsAg kinetics seem to be an accurate tool to predict SVR. Large clinical trials are needed to explore this strategy with more potent analogues.

[HBsAg seroclearance: prognostic value for the response to treatment and the long-term outcome]. / Négativation de l'antigène HBs: valeur pronostique pour la réponse au traitement et l'évolution à long terme.

Chronic hepatitis B is a major cause of liver disease worldwide, ranking as the first cause of cirrhosis and hepatocellular carcinoma. Hepatitis B surface antigen (HBsAg) is usually used as a qualitative marker for the diagnosis of hepatitis B virus (HBV) infection. HBsAg clearance is the closest to cure outcome as one can expect to achieve in hepatitis B. Support for this comes from natural history studies demonstrating increased length of survival, lower rates of hepatic decompensation, reduction in the frequency of hepatocellular carcinoma, and regression of liver fibrosis in patients who clear HBsAg. HBsAg seroclearance may occur spontaneously at a yearly incidence of 1-2%, preceded usually by a long period of inactive disease. Interferon treatment enhanced HBsAg seroclearance by approximately three-fold in western studies and sixfold in Asian studies compared with non-treated patients. Pegylated interferon induced a 10-15% yearly rate of HBsAg seroclearance in patients who developed sustained virological response in clinical trials. By contrast, treatment with nucleos (t) ides analogues did not significantly affect the rate of HBsAg seroclearance, especially in patients with hepatitis B e antigen (HBeAg) - negative disease. Recently, serum HBsAg has been shown to be a surrogate marker of covalently closed circular DNA (cccDNA) concentration in the liver. Quantification of serum HBsAg has also been recently shown to be a promising tool for monitoring virologic response in HBeAg-negative patients treated with pegylated interferon.

Insulin resistance and geographical origin: major predictors of liver fibrosis and response to peginterferon and ribavirin in HCV-4.

BACKGROUND AND AIMS: Hepatitis C virus (HCV) genotype 4 (HCV-4) is increasing in prevalence in Western countries. However, little is known about the severity of the disease and response to treatment. The aim of this study was to assess the predictors (logistic regression) of severe fibrosis (METAVIR score F3-F4), and sustained virological response (SVR) to peginterferon and ribavirin in 226 consecutive HCV-4 patients (Egyptians 40%, Europeans 35% and Africans 24%). PATIENTS AND METHODS: Insulin resistance was assessed using the homeostasis model (HOMA-IR). Serum HCV-RNA level (bDNA) and subtypes of HCV (LiPA) were determined for all patients. RESULTS: Insulin resistance (HOMA-IR >3) was present in 105 patients (46%), and was associated with: age >45 years (OR, 2.614; 95% CI, 1.316 to 5.194), body mass index (BMI) >25 kg/m(2) (OR, 2.105; 95% CI, 1.048 to 4.229), serum HCV-RNA >800 000 IU/ml (OR, 3.143; 95% CI, 1.503 to 6.574), severe fibrosis (OR, 2.657; 95% CI, 1.214 to 5.818), and steatosis >30% (OR, 2.488; 95% CI, 1.105 to 5.602). Severe fibrosis was present in 67 patients (29%) and was associated with Egyptian origin (OR, 5.872; 95% CI, 2.747 to 12.553), excessive alcohol intake (OR, 5.311; 95% CI, 1.287 to 21.924), and HOMA-IR >3 (OR, 3.864; 95% CI, 1.859 to 8.034). 108 patients received a 48 week course of peginterferon plus ribavirin. SVR (undetectable serum HCV-RNA (TMA) 24 weeks after treatment stopping) was achieved in 59 patients (55%) and was associated with Egyptian origin (OR, 13.119; 95% CI, 3.089 to 55.706), HOMA-IR <2 (OR, 5.314; 95% CI, 1.953 to 14.459), and non-severe fibrosis (OR, 8.059; 95% CI, 2.512 to 25.855). CONCLUSION: Insulin resistance and geographical origin are major predictors of liver fibrosis and response to peginterferon and ribavirin in HCV-4 patients. Insulin resistance is frequently encountered in these patients, and correlated independently with serum HCV-RNA.

Hepatocellular carcinoma in Budd-Chiari syndrome: characteristics and risk factors.

BACKGROUND AND AIMS: To analyse the characteristics of and the factors associated with the development of hepatocellular carcinoma (HCC) in patients with Budd-Chiari syndrome (BCS). PATIENTS AND METHODS: 97 consecutive patients with BCS and a follow-up > or = 1 year were evaluated retrospectively. Liver nodules were evaluated using serum alpha-fetoprotein (AFP) level and imaging features (CT/MRI). Biopsy of nodules was obtained when one of the following criteria was met: number < or = 3, diameter > or = 3 cm, heterogeneity, washout on portal venous phase, increase in size on surveillance, or increase in AFP level. RESULTS: Patients were mainly Caucasian (69%) and female (66%). Mean age at the diagnosis of BCS was 35.8 (SE 1.2 years), and median follow-up 5 years (1-20 years). The inferior vena cava (IVC) was obstructed in 13 patients. Liver nodules were found in 43 patients, 11 of whom had HCC. Cumulative incidence of HCC during follow-up was 4%. Liver parenchyma adjacent to HCC showed cirrhosis in nine patients. HCC was associated with male sex (72.7% v 29.0%, p = 0.007); factor V Leiden (54.5% v 17.5%, p = 0.01); and IVC obstruction (81.8% v 4.6%, p < 0.001). Increased levels of serum AFP were highly accurate in distinguishing HCC from benign nodules: PPV = 100% and NPV = 91% for a cut-off level of 15 ng/ml. CONCLUSION: The incidence of HCC in this large cohort of BCS patients was similar to that reported for other chronic liver diseases. IVC obstruction was a major predictor for HCC development. Serum AFP appears to have a higher utility for HCC screening in patients with BCS than with other liver diseases.