Concomitant nonalcoholic fatty liver disease does not alter the activity, severity or course of primary biliary cholangitis.

BACKGROUND & AIMS: The impact of nonalcoholic fatty liver disease (NAFLD) on the natural history of primary biliary cholangitis (PBC) has yet to be described. The aim of this study was to document the activity, severity and progression of PBC in patients with concomitant NAFLD and compare the findings to those with PBC alone. METHODS: Disease activity was assessed by serum liver enzyme levels; severity, by Fib-4 scores and percent of patients with APRI >1.5; and progression, by changes in Fib-4 and prevalence of APRI >1.5 during follow-up. RESULTS: The study populations consisted of 168 PBC alone and 68 PBC/NAFLD patients. The mean ages and gender distributions of the two cohorts were similar. At presentation, PBC alone patients had greater disease activity (higher serum ALP and GGT values, P = .003 and 0.01, respectively) and advanced disease (higher Fib-4 (P = .04) scores) than PBC/NAFLD patients. Although the prevalence of APRI >1.5 was also higher in PBC alone (11.1%) vs PBC/NAFLD (4.7%) patients, the difference was not significant (P = .16). During mean follow-up of 6.7 ± 5.5 (PBC alone) and 6.4 ± 4.4 (PBC/NAFLD) years (ranges: 0.5-21 years) annual increases in Fib-4 and prevalence of ≥ APRI 1.5 were greater in PBC alone patients but the differences did not reach statistical significance. CONCLUSIONS: The results of this retrospective, single centre study suggest that the activity, severity and progression of PBC are not adversely affected by concomitant NAFLD.

Safety and antiviral activity of albinterferon alfa-2b dosed every four weeks in genotype 2/3 chronic hepatitis C patients.

BACKGROUND & AIMS: A phase 2, randomized, multicenter, open-label study evaluated the safety and efficacy of albinterferon alfa-2b in interferon-alpha treatment-naïve patients with genotype 2/3, chronic hepatitis C virus infection. METHODS: Forty-three patients were randomly assigned in a 1:1 ratio to receive subcutaneous albinterferon alfa-2b 1500 microg every 4 weeks (q4wk) or every 2 weeks (q2wk) with oral ribavirin 800 mg/day for 24 weeks. Primary efficacy end point was sustained virologic response (undetectable hepatitis C virus RNA 24 weeks after completion of treatment). Insulin resistance was also assessed. RESULTS: The safety of albinterferon alfa-2b was acceptable, with a similar adverse event profile in both treatment arms. Discontinuation as a result of adverse events occurred in 4.5% and 14.3% of patients in the q4wk and q2wk arms, respectively. No dose reductions caused by adverse events were reported in the q4wk arm versus 9.5% in the q2wk arm. Rapid viral response rates at week 4 were 68.2% and 76.2% for the q4wk and q2wk arms, respectively; the corresponding sustained virologic response rates were 77.3% and 61.9%. Insulin resistance at baseline was significantly associated with lower sustained virologic response rates independent of body mass index. CONCLUSIONS: Albinterferon alfa-2b administered at 4-week intervals was safe and well-tolerated and demonstrated significant antiviral activity in patients with genotype 2/3, chronic hepatitis C virus. Insulin resistance appeared to have an independent effect on treatment response.

Dynamics of interferon-specific gene expression in peripheral blood of interferon alfa-naïve patients with genotype 1 chronic hepatitis C infection treated with albumin-interferon alfa.

Albumin-interferon alfa (alb-IFN) is a novel recombinant protein derived from IFNalpha-2b genetically fused to human albumin, which combines in a single polypeptide the antiviral properties of IFNalpha with the long serum half-life of albumin. Interferon alfa (IFNalpha) mediated biological responses stem from the engagement of IFNalpha with its target receptor and subsequent modulation of interferon-specific gene (ISG) expression. The dynamics of ISG expression were evaluated in a Phase 2a study conducted in IFNalpha naïve patients with genotype 1 chronic hepatitis C (CHC) treated with alb-IFN. Whole blood was obtained pre-dose and on days 7 and 28 from 47 patients enrolled to receive two subcutaneous injections of alb-IFN 14 days apart in five dose cohorts ranging from 200 to1200mug. Gene expression of nine candidate genes including four ISGs was determined by a TaqMan Real-time PCR assay. There was sustained >5-fold median induction on days 7 and 28 of the ISG's- OAS1, IRF7, IFI44 and IFI27. While all subjects showed a molecular response to alb-IFN, individual variability in pre-treatment gene expression levels and fold of modulation during treatment was observed. At days 7 and 28, induction of OAS1, IFI44 and IRF7 showed significant pair-wise correlation in individual patients (r>0.7 and P<0.001). There was no correlation of baseline expression or induction of gene expression with antiviral response. In conclusion, alb-IFN demonstrated robust induction of ISG that was consistent with the molecular response associated with an IFNalpha.

A phase 2 study to evaluate the antiviral activity, safety, and pharmacokinetics of recombinant human albumin-interferon alfa fusion protein in genotype 1 chronic hepatitis C patients.

BACKGROUND/AIMS: Recombinant human albumin-interferon alfa (alb-IFN) is a novel 85.7-kD recombinant protein consisting of interferon alfa-2b genetically fused to human serum albumin. METHODS: A phase 2, open-label, dose-ranging study was conducted in IFN-alfa-naïve patients with genotype 1 chronic hepatitis C to evaluate the antiviral activity, safety, and pharmacokinetics of alb-IFN. Fifty-six patients were enrolled to receive two subcutaneous injections of alb-IFN 14 days apart in five dose cohorts of 200, 450, 670, 900, and 1,200 microg. RESULTS: A 2 log(10) IU/mL or greater reduction in hepatitis C virus (HCV) RNA at Week 4 was observed in 69% (18/26) of patients who received the higher alb-IFN doses of 900 and 1,200 microg. The mean HCV RNA reduction at Week 4 in these two higher-dose cohorts was 3.2 log(10) IU/mL. Modeling of viral kinetics demonstrated a biphasic response that was dose dependent. Adverse events were mostly mild to moderate in severity. The most common adverse events were headache (73%), chills (63%), fatigue (61%), and arthralgia (55%). The median terminal half-life was 141 h consistent with previous alb-IFN data from IFN-alfa-experienced patients. CONCLUSIONS: Alb-IFN demonstrated significant antiviral activity and was well tolerated in patients with HCV genotype 1 infection.

Genomic analysis of a recently identified virus (SEN virus) and genotypes D and H by polymerase chain reaction.

BACKGROUND/AIMS: SEN virus (SENV) was discovered in 1999 as a DNA virus with hepatotropic properties. Nine genotypes (A-I) have been identified with genotypes D and H being more prevalent in cases of chronic hepatitis. Attempts to determine whether SENV causes liver disease have been hampered by limited diagnostic testing. METHODS: In the present study, we developed two PCR based assays; a general SENV screening and genotype-specific assay. RESULTS: By screening PCR, the specificity for all SENV genotypes and SENV-related sequences was 20/20 (100%) with confirmation of the results being provided by genomic sequencing. With the genotype-specific PCR, specificities for SENV-D and SENV-H were 7/7 (100%) and 7/11 (64%), respectively. All screening PCR products were cloned and sequenced. The results of sequencing showed high genetic diversity in representative SENV genotypes. Five of twenty patients (25%) had mixed infections with several SENV genotypes. CONCLUSIONS: The screening PCR was useful for identifying cases of SENV infection. However, because of high genetic divergence and mixed co-infection, it was difficult to establish a specific method for genotype distinction. Hence, sequencing is still required for further investigations of SENV as a potential cause of liver disease.

The absence of up-regulation of telomerase activity during regeneration after partial hepatectomy in hepatitis B virus X gene transgenic mice.

BACKGROUND/AIMS: Transgenic mice that express HBV X protein (HBx) have increased sensitivity to hepatocarcinogens. In the present study, we hypothesized that HBx interferes with the DNA protective increases in telomerase activity that occur in proliferating hepatocytes. METHODS: Male CD-1 mice (4-6/grp) were killed and hepatic telomerase activity measured at 0, 6, 12, 24, 36, 48 h post partial hepatectomy (PHx). Four HBx transgenic mice were killed at 12 h post-PHx when maximum telomerase activity was observed in CD-1 non-transgenic mice. mRNA of the telomerase catalytic subunit; murine telomerase reverse transcriptase (mTERT), was measured by reverse transcription-polymerase chain reaction. Telomerase activity and human TERT (hTERT) were also measured in Chang and PLC/PRF/5 cells following transient transfection with HBx cDNA. RESULTS: Telomerase activity peaked at 12 h post-PHx in normal mice, however, in HBx transgenic mice, telomerase activity was significantly lower, both at baseline (P<0.05) and 12 h post-PHx (P<0.01). Following PHx, mTERT mRNA expression remained constant in normal mice but decreased significantly (P<0.01) in HBx transgenic mice. Transfection of HBx in Chang and PLC/PRF/5 cells had no effect on telomerase activity or hTERT mRNA expression. CONCLUSIONS: The results of this study suggest that HBx expression may play a role in hepatocellular carcinogenesis by interfering with telomerase activity during hepatocyte proliferation.