Gunnar Norkrans

Randomised, double-blind, placebo-controlled trial of interferon α-2b with and without ribavirin for chronic hepatitis C

Summary Background Pilot studies suggested that more patients with chronic hepatitis C virus (HCV) infection had a sustained virological response when treated with the combination of interferon α-2b and ribavirin than with interferon α-2b alone. We investigated the biochemical and virological responses and safety of treatment with interferon α-2b and ribavirin compared with interferon α-2b alone. Methods In this double-blind trial 100 patients were randomly assigned to treatment with interferon α-2b (3 MU three times a week) in combination with ribavirin (1000 or 1200 mg per day) or placebo for 24 weeks and then followed up for a further 24 weeks. A further follow-up was done 1 year after active treatment stopped. The primary endpoint was the sustained virological response, defined as no detectable HCV RNA by PCR at both week 24 and week 48. Retrospectively, the baseline HCV-RNA load was analysed as a predictor of a sustained virological response. Data were analysed by intention to treat. Findings 18 (36%) of the 50 patients in the interferon α-2b and ribavirin group had a sustained virological response compared with nine (18%) of the 50 patients in the interferon α-2b and placebo group (p=0·047). At the 1 year follow-up the proportion of patients with a virological response was greater in the interferon α-2b and ribavirin group than the interferon α-2b and placebo group (42 vs 20%, p=0·03), respectively. More patients with baseline HCV-RNA concentrations greater than 3×10 6 genome equivalents (Eq) per ml had a sustained response with interferon α-2b and ribavirin than with interferon α-2b and placebo (12/29 vs 1/26, p=0·009), whereas the sustained response did not differ between the two treatment groups for HCV-RNA amounts less than 3×10 6 Eq per ml (6/21 vs 8/24, p=0·67), respectively. Interpretation More patients with chronic hepatitis C have a sustained virological response with interferon α-2b and ribavirin than with only interferon α-2b treatment. We suggest that patients with high HCV-RNA loads should be treated with interferon α-2b and ribavirin.

Ribavirin treatment for patients with chronic hepatitis C: results of a placebo-controlled study

BACKGROUND/AIMS Small, uncontrolled studies of ribavirin for patients with chronic hepatitis C have reported efficacy in chronic hepatitis C. We have evaluated the efficacy and safety of a 24-week course of oral ribavirin in patients with chronic hepatitis C, compared to placebo. METHODS A total of 114 patients were randomised to ribavirin or placebo. Ribavirin was administered in doses of 1000 or 1200 mg/day for 24 weeks. Efficacy was determined in the intention-to-treat population: 76 received ribavirin and 38 placebo. RESULTS Ribavirin was significantly more effective than placebo in reducing and normalising serum ALT levels: 42/76 (55%) of ribavirin-treated patients vs 2/38 (5%) placebo recipients had either normalisation of the ALT levels or a reduction from baseline of at least 50% (p < 0.001). ALT levels were normal in 22/76 (29%) of ribavirin-treated patients vs 0/38 placebo recipients (p < 0.001). Twenty-four weeks after stopping ribavirin, the majority of patients had abnormal ALT levels. There was no difference between the treatment groups in reduction or disappearance of HCV-RNA levels. HCV RNA disappeared during treatment in 3% of ribavirin-treated patients and 3% of placebo recipients. More ribavirin than placebo patients showed improvement in total Knodell score (45% vs 31%), but these differences were not statistically significant. Analysis of each component of a histology activity index revealed no statistically significant differences between treatment groups. Ribavirin patients had fewer lymphoid aggregates than did placebo recipients at the post-treatment assessment (p = 0.05). Ribavirin was associated with reversible haemolytic anaemia: a fall in haemoglobin occurred in 3% of placebo- and 32% (25/78) of ribavirin-treated patients, respectively (p < 0.001). CONCLUSIONS These data indicate that ribavirin was no more effective than placebo in reducing or eliminating HCV-RNA levels, and was not significantly more effective than placebo in improving hepatic histology after 6 months of treatment. The role of a 6-month treatment of chronic hepatitis C with ribavirin alone, without a significant effect on HCV RNA, is therefore limited.

Core Promoter Mutations and Genotypes in Relation to Viral Replication and Liver Damage in East Asian Hepatitis B Virus Carriers

Virus load and liver damage, as measured by quantitative polymerase chain reaction and histology activity index, were related to genotype and core promoter mutations in 43 chronic hepatitis B virus (HBV) carriers of East Asian origin. T-1762 mutants were more frequent in genotype C strains and were associated with more inflammation (P=.0036) and fibrosis (P=.0088) of the liver but not with hepatitis B e antigen (HBeAg) status or virus load. Conversely, precore mutations were associated with less liver inflammation (P=. 08), which was linked to HBeAg negativity and lower viral replication. Carriers with genotype C were more often HBeAg positive (P=.03) with precore wild type strains and more-severe liver inflammation (P=.009) than were those with genotype B. These findings suggest that pathogenic differences between genotypes may exist and that the T-1762 mutation may be useful as a marker for progressive liver damage but seem to contradict that down-regulation of HBeAg production is the major effect of this mutation.

Steatosis accelerates fibrosis development over time in hepatitis C virus genotype 3 infected patients

BACKGROUND/AIMS Steatosis is common in patients with hepatitis C virus (HCV) infection. Its influence on disease progression is only partially understood. The aim of this study was to evaluate the impact of steatosis on fibrosis progression over time in relation to HCV genotype. METHODS We retrospectively analyzed 98 patients who underwent dual liver biopsies prior to antiviral treatment. The median follow-up time was 5.8 years. Biopsy specimens were assessed for necroinflammatory activity, fibrosis and steatosis. RESULTS The prevalence and grade of steatosis were strongly associated with HCV genotype 3, independent of sex, age, body mass index and alcohol consumption. Progressive fibrosis was more prevalent in patients whose initial biopsy showed steatosis, an effect seen mainly in genotype 3 infected patients. Low-grade steatosis was observed in overweight patients, but high-grade steatosis was associated with genotype 3, independent of body mass index. CONCLUSIONS Our data confirm the association between HCV genotype 3 and steatosis. Furthermore, we showed that steatosis in genotype 3 infected patients is a risk factor for progression of fibrosis. Therefore, patients with genotype 3 and steatosis ought to be recommended for early therapeutic intervention.

IP-10 predicts viral response and therapeutic outcome in difficult-to-treat patients with HCV genotype 1 infection

Plasma from 173 patients with HCV genotype 1 infection was analyzed for IP‐10 levels prior to treatment with pegylated interferon‐α‐2a and ribavirin. Significantly lower IP‐10 levels were observed in patients achieving a rapid viral response (RVR) (P < .0001), even in those with body mass index (BMI) ≥ 25 kg/m2 (P = .004) and with baseline viral load ≥ 2 million IU/mL (P = .001). Similarly, significantly lower IP‐10 levels were observed in patients obtaining a sustained viral response (SVR) (P = .0002), including those having higher BMI (P < .05), higher viral load (P = .0005), and both higher BMI and viral load (P < .03). In multivariate logistic regression analyses, a low IP‐10 value was independently predictive of both RVR and SVR. A baseline cutoff IP‐10 value of 600 pg/mL yielded a negative predictive value (NPV) of 79% (19/24) for all genotype 1–infected patients, which was comparable with that observed using a reduction in HCV‐RNA by at least 2 logs after 12 weeks of therapy (NPV 86%; 19/22); by combining the two, 30 of 38 patients (NPV 79%) potentially could have been spared unnecessary therapy. In patients having both higher BMI and viral load, cut‐off levels of 150 and 600 pg/mL yielded a positive predictive value (PPV) of 71% and NPV of 100%, respectively. In conclusion, pretreatment IP‐10 levels predict RVR and SVR in patients infected with HCV genotype 1, even in those with higher BMI and viral load. A substantial proportion of the latter patients may achieve SVR in spite of unfavorable baseline characteristics if their pretreatment IP‐10 level is low. Thus, pretreatment IP‐10 analysis may prove helpful in decision‐making regarding pharmaceutical intervention. (HEPATOLOGY 2006;44:1617–1625.)

Randomized comparison of 12 or 24 weeks of peginterferon α‐2a and ribavirin in chronic hepatitis C virus genotype 2/3 infection

Previous trials investigating the efficacy of treatment durations shorter than the standard of 24 weeks for chronic hepatitis C virus (HCV) genotype 2/3 infections have yielded discordant results. The aims of this investigator‐initiated phase III study were to compare the efficacy of 12 or 24 weeks of treatment and to identify patients suitable for short‐term therapy. Three hundred eighty‐two genotype 2/3–infected patients [intention‐to‐treat (ITT) population] at 31 centers in Denmark, Finland, Norway, and Sweden were randomized to 12 or 24 weeks of peginterferon α‐2a (180 μg/week) plus ribavirin (800 mg/day). Twelve weeks of therapy was inferior to 24 weeks in the ITT population (sustained viral response [SVR] rates: 59% versus 78%, P < 0.0001) and in the subgroups of patients infected with genotype 2 (56% versus 82%, P = 0.006) or 3 (58% versus 78%, P = 0.0015). These differences were observed regardless of the fibrosis stage. Age and HCV‐RNA levels on days 7 and 29 were independent predictors of SVR. Short‐term treatment was useful in patients < 40 years old, especially if HCV‐RNA was undetectable on day 29, and also in patients ≥ 40 years old, provided that HCV‐RNA was below 1000 IU/mL on day 7 in addition to being undetectable on day 29. If neither of these two criteria were met for patients ≥ 40 years old, 24 weeks of therapy was superior (P < 0.0001). Conclusion: Peginterferon/ribavirin treatment for 12 weeks in HCV genotype 2/3 infection is overall inferior to 24 weeks of treatment but may be useful in some patients with a rapid initial clearance of virus. (HEPATOLOGY 2008.)

Mother-to-infant transmission of hepatitis C virus

OBJECTIVE To describe the rate of perinatal transmission of hepatitis C virus (HCV). DESIGN Follow-up study of newborn children of mothers with chronic HCV infection. SETTING A university hospital in Sweden. PARTICIPANTS Fourteen women with chronic HCV infection and their 21 newly born children. MAIN OUTCOME MEASURES Detection of HCV RNA in serum by the polymerase chain reaction and detection of anti-HCV antibody by second generation assays. RESULTS All mothers were found to be positive for anti-HCV antibody both by second-generation enzyme-linked immunosorbent assay (ELISA) and by second-generation recombinant immunoblot assay (RIBA-2); all also had detectable serum HCV RNA. Two children had long-lasting alanine aminotransferase (ALT) elevations, and one of them became HCV RNA positive. None of the other children developed biochemical hepatitis. However, two additional children had temporary viremia. Only the child with biochemical and biopsy-proven hepatitis and detectable HCV RNA in multiple blood samples actively produced anti-HCV antibody. CONCLUSIONS Mother-to-infant transmission of HCV infection from chronically infected women without human immunodeficiency virus (HIV) infection seems to be uncommon.

Moderate alcohol intake increases fibrosis progression in untreated patients with hepatitis C virus infection

Although excessive alcohol consumption in combination with hepatitis C virus (HCV) infection is known to increase the risk of liver cirrhosis, the effect of moderate alcohol intake remains to be elucidated. The aim of this study was to evaluate the effect of moderate alcohol consumption on fibrosis progression in HCV infection. A group of 78 patients with HCV infection and moderate alcohol consumption were analysed retrospectively. All patients had undergone two liver biopsies, with a median time between biopsies of 6.3 years, and had not received any antiviral therapy. Their lifetime drinking history was recorded. All patients except one had daily alcohol consumption below 40 g of ethanol (median 4.8 g/day, interquartile range 1.1–11.6 g/day) during the period between the biopsies. The patients whose liver fibrosis had deteriorated had a higher total alcohol consumption and higher drinking frequency between the biopsies. The degree of fibrosis progression was greater in patients with a total alcohol intake and drinking frequency above the median level for the group. A multiple logistic regression analysis showed that drinking frequency and time between biopsies were independently associated with fibrosis progression. Hence, even moderate alcohol intake seems to increase fibrosis progression in HCV‐infected patients. From that point of view, total abstention ought to be recommended. If this is not achieved, occasional use of alcohol is probably less harmful than daily drinking for patients with low or moderate alcohol consumption.

Genotyping of hepatitis B virus by restriction pattern analysis of a pre-S amplicon

A method is described for genotyping of hepatitis B virus (HBV), based on the restriction fragment length polymorphism (RFLP) created by Ava2 and Dpn2 action on an amplified segment of the pre-S region. Analysing 51 database sequences by phylogenetic tree construction and RFLP prediction, the method was shown to be capable of detecting all known genotypes (A-F). The method was applied to 99 serum samples from hepatitis B e antigen (HBeAg)-positive chronic carriers, comparing observed agarose gel patterns with the RFLP predicted from the database sequences. In 95 typable samples the following genotypes were observed; 23 A, 20 B, 20 C, 22 D, 5 E and 5 F. Phylogenetic grouping of the 51 database sequences and RFLP genotyping of the 99 patient samples were compared with typing based on S gene analysis, showing disagreement in only one case, a database sequence of ayw subtype which was classified as genotype D by pre-S region and genotype A by S region analysis. This method should be useful for epidemiological investigations and for studying the potential influence of genotype on the course of infection.

Systemic and intrahepatic interferon-gamma-inducible protein 10 kDa predicts the first-phase decline in hepatitis C virus RNA and overall viral response to therapy in chronic hepatitis C†

High systemic levels of interferon‐gamma‐inducible protein 10 kDa (IP‐10) at onset of combination therapy for chronic hepatitis C virus (HCV) infection predict poor outcome, but details regarding the impact of IP‐10 on the reduction of HCV RNA during therapy remain unclear. In the present study, we correlated pretreatment levels of IP‐10 in liver biopsies (n = 73) and plasma (n = 265) with HCV RNA throughout therapy within a phase III treatment trial (DITTO‐HCV). Low levels of plasma or intrahepatic IP‐10 were strongly associated with a pronounced reduction of HCV RNA during the first 24 hours of treatment in all patients (P < 0.0001 and P = 0.002, respectively) as well as when patients were grouped as genotype 1 or 4 (P = 0.0008 and P = 0.01) and 2 or 3 (P = 0.002, and P = 0.02). Low plasma levels of IP‐10 also were predictive of the absolute reduction of HCV RNA (P < 0.0001) and the maximum reduction of HCV RNA in the first 4 days of treatment (P < 0.0001) as well as sustained virological response (genotype 1/4; P < 0.0001). To corroborate the relationship between early viral decline and IP‐10, pretreatment plasma samples from an independent phase IV trial for HCV genotypes 2/3 (NORDynamIC trial; n = 382) were analyzed. The results confirmed an association between IP‐10 and the immediate reduction of HCV RNA in response to therapy (P = 0.006). In contrast, pretreatment levels of IP‐10 in liver or in plasma did not affect the decline of HCV RNA between days 8 and 29, i.e., the second‐phase decline, or later time points in any of these cohorts. Conclusion: In patients with chronic hepatitis C, low levels of intrahepatic and systemic IP‐10 predict a favorable first‐phase decline of HCV RNA during therapy with pegylated interferon and ribavirin for genotypes of HCV. (HEPATOLOGY 2010.)