Rune Wejstål

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.

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.

Long-term follow-up of chronic hepatitis C patients with sustained virological response to alpha-interferon

BACKGROUND/AIMS This study aimed to determine the long-term outcome of hepatitis C virus (HCV)-infected patients who respond to interferon treatment with clearance of serum HCV RNA. METHODS We performed a long-term biochemical, virological, and histological follow-up of all sustained virological responders, defined as those who became HCV RNA negative at follow-up 6 months after the end of treatment, from 3 controlled interferon trials performed in Sweden between 1988 and 1994. RESULTS At biochemical and virological long-term follow-up performed in 26 sustained virological responders 3.5-8.8 years (mean +/- SD, 5.4+/-1.6 years) after the end of IFN therapy, 22 patients (85%) had normal serum ALT levels, and 24 patients (92%) were HCV RNA negative in serum. Liver biopsies performed in 23 patients 2.1-8.7 years (mean +/- SD, 5.0+/-1.8 years) after end of treatment showed no or minimal inflammation, whereas mild and probably irreversible fibrosis was seen in a few patients. CONCLUSION In this well-defined material of sustained responders to IFN therapy, the long-term prognosis was excellent. Nearly all had a durable response, not only biochemically and virologically, but more importantly also histologically with normalisation or near normalisation of previous histological lesions.

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.

Sexual transmission of hepatitis C virus

Sexual transmission of hepatitis C virus (HCV) occurs; however, to what extent is still unclear. In this presentation relevant data from the literature concerning the following key issues will be presented: presence of HCV in the seminal fluid and vaginal secretions; presence of HCV infection in sexually promiscuous individuals; presence of HCV infection among sexual partners to HCV-infected individuals; and molecular biology evidence of sexual transmission. An anti-HCV prevalence of 2-12% is seen in sexually promiscuous individuals, which is higher than that usually seen among blood donors. In case-control studies, HCV infection is associated with sexual promiscuity and sex with a partner who has a past history of hepatitis. In most studies, HCV infection is common among sexual partners of HCV-infected subjects. Genotyping and genome sequencing provide further evidence for intraspousal transmission of HCV Despite these findings, stable sexual partners of hemophiliacs or recipients of HCV-contaminated immunoglobulin preparations rarely become infected. These discrepancies are not fully understood. Other sexual behaviours or confounding non-sexual transmission routes could play a part.

A Randomized Controlled Open Study of Interferon Alpha-2b Treatment of Chronic Non-A, Non-B Posttransfusion Hepatitis: No Correlation of Outcome to Presence of Hepatitis C Virus Antibodies

33 patients with biopsy-proven chronic non-A, non-B posttransfusion hepatitis (NANB PTH) were randomized 2:1 to treatment with interferon alpha-2b (Introna) or to controls. The treatment group received 3 MU interferon 3 times weekly subcutaneously for 36 weeks. 22/33 (67%) patients were reactive for antibodies against hepatitis C virus (anti-HCV). 11/19 (58%) treated patients versus none of the 12 controls had a complete response with normalization of serum alanine aminotransferase levels (p less than 0.001). Another 4/29 (21%) treated patients had a partial response which was also seen in 4/12 (33%) controls; 4 treated patients were nonresponders, all with chronic active hepatitis. Nonresponders had a significantly higher mean weight than responders (p less than 0.05) and tended to have a longer duration of their disease before therapy. During the 6-month follow-up period post treatment 4/11 (36%) complete responders had a sustained response and 7/11 (64%) relapsed. All who were retreated responded again. We conclude that a majority of patients with chronic NANB PTH will respond to 9 months interferon alpha-2b treatment, but that only 1 out of 3 will have a sustained response 6 months post treatment, and that the reactivity for anti-HCV was not correlated to the outcome of therapy.

IL28B polymorphisms determine early viral kinetics and treatment outcome in patients receiving peginterferon/ribavirin for chronic hepatitis C genotype 1.

Summary.  Single nucleotide polymorphisms (SNPs) upstream of IL28B predict the outcome of treatment in chronic hepatitis C virus (HCV) infection, but their impact on viral kinetics and relation to other predictors are not well known. Here, two SNPs, rs12979860 and rs8099917, were analysed and related to early viral kinetics during treatment in 110 patients with HCV genotype 1 infection. The reduction of HCV RNA after 7 days of therapy was more pronounced (P < 0.0001) in patients with CCrs12979860 or TTrs8099917 than in patients carrying TTrs12979860 or GGrs8099917, respectively. The two SNPs were in linkage disequilibrium (d’ = 1, r2 = 0.44), but CCrs12979860 was less common (43%vs 71%) than TTrs8099917. Patients carrying both CCrs12979860 and TTrs8099917 genotypes achieved lower levels of HCV RNA at week 4 than those with CT or TT at rs12979860 and TTrs8099917 (P = 0.0004). The viral elimination was significantly influenced by rs12979860 independently of baseline viral load, age or fibrosis. This translated into high rates of sustained viral response (SVR) among patients carrying CCrs12979860 despite the presence of high viral load at baseline (SVR 74%), high age (SVR 79%) or severe liver fibrosis (SVR 83%). We conclude that the IL28B variability influences the antiviral efficiency of interferon/ribavirin therapy and has a strong impact on SVR, independently of traditional response predictors. A combined assessment of these SNPs in conjunction with other response predictors may better predict outcome in difficult‐to‐treat patients.

Perinatal transmission of hepatitis G virus (GB virus type C) and hepatitis C virus infections--a comparison.

Hepatitis G virus (HGV) infection is more common than hepatitis C virus (HCV) infection and is frequently found in healthy individuals. Although parenteral spread of HGV is well recognized, other routes of transmission probably occur as well. In a prospective study of mother-to-infant transmission of hepatitis viruses, 69 pregnant women with antibodies to HCV and their 81 newborn children were included. Serum levels of HCV RNA and HGV RNA were detected by polymerase chain reaction (PCR) assays, and antibodies to HCV and HGV envelope protein E2 were detected by enzyme-linked immunosorbent assay. Fifty-nine of the mothers had HCV viremia, whereas 16 had HGV viremia. HCV transmission from viremic mothers occurred in 2.8%-4.2% of the cases, whereas HGV transmission from viremic mothers occurred in 75.0%-80.0% of the cases (P < .001). Sequencing of the PCR products of HGV from the mother-infant serum pairs showed minor differences in most cases but sequence homology in each pair. Although the rate of perinatal HGV transmission highly exceeded that of perinatal HCV transmission, HGV did not seem to induce hepatitis in the children.

Chronic Hepatitis C in Sweden: Genotype Distribution Over Time in Different Epidemiological Settings

Hepatitis C virus (HCV) strains are divided into 6 genotypes and several subtypes. Recent studies reported a change in the relative frequency of genotypes within certain regions. We studied the HCV genotype in 312 Swedish patients with chronic hepatitis C, using a core region primer-specific PCR, and grouped the patients according to parenteral risk factors. The date of infection could be estimated in 127 cases. Genotypes 1a (35%) and 3 (31%) were the most common genotypes, followed by genotype 2 (17%), while only 6% had genotype 1b. Genotype 3 was relatively more frequent among subjects infected sexually or by intravenous drug use. The genotype distribution was different from that in studies from other parts of the world, with a lower frequency of genotype 1 (especially 1b) and a higher frequency of genotype 3. The frequency of genotype 1b has decreased and genotype 3 increased over time. The reasons for a different distribution of genotypes in Sweden, compared with other countries, might be a relatively recent introduction of HCV into the population, or a different pattern of transmission.

Core mutations, IL28B polymorphisms and response to peginterferon/ribavirin treatment in Swedish patients with hepatitis C virus genotype 1 infection

BackgroundPatients infected with hepatitis C virus (HCV) genotype 1 respond poorly to standard treatment with 50% or less achieving sustained virologic response. Predicting outcome is essential and could help avoid unnecessary treatment and reduce health cost. Recently, an association of amino acid substitutions in the core region and treatment outcome was observed in Japanese patients. In the present study, the impact of these mutations on response kinetics and treatment outcome was explored in Caucasian patients.MethodsThe core region of HCV pre-treatment samples obtained from 50 patients treated with peginterferon/ribavirin in a previous Swedish clinical trial with genotype 1 infection were sequenced. The alleles at rs12979860, a single nucleotide polymorphism (SNP), were assessed in order to identify any co-association with this strong response predictor.ResultsNo association between treatment response and substitutions of core residue 91 was found. In contrast, substitutions of core residue 70 were observed in 6/21 (29%) non-responders, but only in one of 29 responders (p = 0.03), and were more common in subgenotype 1b (R70Q in 6 of 13 strains) than in 1a (R70P in 1 of 37 strains, p = 0.004). The rs12979860 SNP upstream of the IL28B gene was overall the strongest response predictor (p = 0.0001). Core 70 substitutions were associated with poorer response kinetics in patients carrying the CT genotype at rs12979860.ConclusionsThe results indicate that substitutions of core residue 70 are related to treatment response in Caucasian patients with HCV-1b infection, but are of less importance than IL28B polymorphism.