Dynamic tailoring of treatment durations improves efficiency of hepatitis C treatment with pegylated interferon and ribavirin.

The treatment durations for hepatitis C are guided by the analysis of hepatitis C virus (HCV) RNA in blood at certain time points. This multicentre, randomized open label trial evaluated the utility and performance of individualized treatment durations guided by viral decline rates in 103 patients with HCV genotype 1 infection. Pegylated interferon 2a and ribavirin were given as standard of care (SOC) for 24, 48 or 72 weeks or as dynamic treatment (DT) for 24-72 weeks. The DT duration was based on the time point when log HCV RNA would reach 0 log copies/mL, as estimated by the second-phase decline. The rate of sustained virologic response was 63% for SOC and 54% for DT, but this difference was not significant in multiple regression analysis taking predictive factors such as interleukin-28B genotypes, age and baseline viremia into account (P = 0.45). The mean required treatment time per cured patient was 51 weeks for DT as compared with 58 weeks for SOC (P = 0.22) when given per protocol (n = 95) and was significantly shorter (42 vs 51 weeks) among patients who achieved undetectable HCV RNA (P = 0.01). We conclude that DT was feasible and increased efficiency. The estimated time point for 0 log viral copies/mL is a new and quantitative response variable, which may be used as a complement to the qualitative variable rapid virologic response. The outcome parameter treatment weeks per cured patient could become a useful tool for comparing treatment efficiency also in the era of directly acting antivirals.

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

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 CC(rs12979860) or TT(rs8099917) than in patients carrying TT(rs12979860) or GG(rs8099917), respectively. The two SNPs were in linkage disequilibrium (d' = 1, r2 = 0.44), but CC(rs12979860) was less common (43% vs. 71%) than TT(rs8099917). Patients carrying both CC(rs12979860) and TT(rs8099917) genotypes achieved lower levels of HCV RNA at week 4 than those with CT or TT at rs12979860 and TT(rs8099917) (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 CC(rs12979860) 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.

Hepatitis C treatment response kinetics and impact of baseline predictors.

The optimal duration of treatment for hepatitis C virus (HCV) infections is highly variable but critical for achieving cure (sustained virological response, SVR). We prospectively investigated the impact of age, fibrosis, baseline viraemia and genotype on the early viral kinetics and treatment outcome. Patients treated with peginterferon alfa-2a and ribavirin in standard dosing were included: 49 with genotype 1 treated for 48weeks and 139 with genotype 2 or 3 treated for 24weeks. The reduced SVR rates in patients older than 45years, with severe liver fibrosis or pretreatment viraemia above 400,000IU/mL were strongly associated with slower second phase declines of HCV RNA. Genotype 2/3 infections responded more rapidly than genotype 1, reaching week 4 negativity (RVR) in 59%vs 22%. We conclude that baseline response predictors such as age, fibrosis and viral load were well reflected by the early viral kinetics as assessed by repeated HCV RNA quantifications. The kinetic patterns and the high relapse rate in genotype 2/3 patients without RVR suggest that this group might benefit from treatment durations longer than 24weeks.

Histamine and the response to IFN-alpha in chronic hepatitis C.

Whole blood concentrations of histamine were examined in 20 patients with chronic hepatitis C after longterm treatment with interferon-alpha (IFN-alpha). In 13 of these patients, a transient (n = 5) or sustained (n = 8) normalization of liver enzymes and elimination of viral RNA were noted at the end of therapy. Seven patients did not respond to IFN-alpha. Nonresponding patients had significantly lower histamine levels in blood than transient (p = 0.0005) or sustained (p = 0.04) responders. Histamine levels were not different in patients with a sustained vs. a transient IFN response. Confounding factors, such as ongoing viral replication or liver cirrhosis, did not account for the differences in histamine levels. Our data suggest that hypohistaminism in peripheral blood may determine a poor response to IFN-alpha in chronic hepatitis C.

[Hepatitis G virus exists--but does hepatitis G?]. / Hepatit G-virus finns--men finns hepatit G?

Hepatitis G virus, or GB virus type C, is a recently discovered RNA virus, remotely related to hepatitis C virus. The infection is frequently found, and seems to be blood-borne, occurring among intravenous drug abusers and transmitted from mother to child. Although long-term viraemia is common, in most cases the infection resolves spontaneously. Whether the viral infection causes liver disease or has other manifestations remains unknown.

Immune-mediated liver damage in chronic hepatitis C.

Although the exact mechanisms inducing the hepatic injury in chronic hepatitis C infection are still not completely elucidated, the evidence of a direct cytopathic viral effect is sparse. The overall majority of experimental studies and clinical observations among patients instead favour immune-mediated hepatocellular damage. This does not exclude the possibility of direct cytopathic viral effects partly contributing to the cell injury. The immune reaction is not always harmful, however. Instead, an intact immune system is probably important for virus clearance in acute infection and after interferon treatment. The therapeutic possibilities are still not adequate, and attempts to understand the immunologic events and manipulate them could perhaps in the future give us more effective tools in the management of this disease.

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.

Chronic non-A, non-B hepatitis in pregnancy: outcome and possible transmission to the offspring.

11 women with chronic non-A, non-B hepatitis (NANBH) were studied during 14 pregnancies. All women remained well, without signs of deterioration of liver function. On the contrary, serum transaminase levels were significantly lower in the latter part of the pregnancy compared to before and after. 12 children were born at full term. One child was born preterm and 1 child was stillborn after 36 gestational weeks. During follow-up, 8 of the children had elevated alanine amino transferase (ALT) levels in serum at least at one sampling occasion. Four children had ALT elevation in consecutive blood samples, 2 of whom had a longlasting ALT elevation, probably due to mother-to-infant transmission of NANBH virus(es).

Chronic non-A, non-B, non-C hepatitis: is hepatitis G/GBV-C involved?

BACKGROUND: Hepatitis G virus/GBV-C is a recently discovered virus, and its relevance in chronic hepatitis is still debated. METHODS: We have previously described 127 long-term-studied and well-characterized patients with chronic non-A, non-B hepatitis (NANBH). Ninety-one (71.7%) were positive for hepatitis C virus antibodies (anti-HCV) in a first-generation anti-HCV enzyme-linked immunosorbent assay (ELISA). We now reanalyzed the same group of patients and added a third-generation anti-HCV ELISA and recombinant immunoblot assay and, in negative patients, also polymerase chain reactions for hepatitis C virus RNA, hepatitis GBV-C RNA, and hepatitis B virus DNA. Additional tests for autoimmune hepatitis types 2 and 3 were also included. RESULTS: Anti-HCV were detected in 114 of the 123 evaluable patients (92.7%). Of the remaining nine anti-HCV-negative patients one had misdiagnosed primary biliary cirrhosis, and two had autoimmune hepatitis type 3. None of the anti-HCV-negative patients were hepatitis GBV-C RNA-, HCV RNA-, or HBV DNA-positive. Thus, 114 of 120 NANBH patients (95.0%) had chronic hepatitis C. None of the remaining six patients had received blood transfusions or was a drug addict, and two of them were successfully treated with steroids. CONCLUSIONS: Hepatitis G/GBV-C as a single cause of chronic non-A, non-B hepatitis is uncommon, and in all patients with parenteral risk factors hepatitis C was detected.

Hepatitis C virus infection with progression to hepatocellular carcinoma: a report of five prospectively followed patients in Sweden.

Five Swedish patients with chronic hepatitis C were prospectively followed until hepatocellular carcinoma (HCC) developed. Hepatitis C virus (HCV) antibodies were analysed by a second generation anti-HCV ELISA and a recombinant immunoblot assay (RIBA-2) and viraemia by detection of serum HCV RNA by polymerase chain reaction. Four patients had post transfusion hepatitis and in one patient the source of infection was unknown. HCC developed after 8 to 23 years of mostly asymptomatic disease and all patients died. Four of them were repeatedly biopsied during follow-up and all had chronic active hepatitis. When HCC was diagnosed, cirrhosis was present in all 5. In 4 patients with available sera, anti-HCV was positive and confirmed with RIBA-2, whereof 2 were reactive only to the c-22 and c-33c epitopes. HCV-RNA was present in all sera when HCC was diagnosed. Thus, after prolonged disease duration these patients were still viraemic.

HCV-RNA levels increase during pregnancy in women with chronic hepatitis C.

Alanine aminotransferase (ALT) levels decline during pregnancy in women chronically infected with hepatitis C virus (HCV). In order to understand further the underlying mechanisms, we prospectively followed 10 chronically infected women before, during and after pregnancy. ALT levels were analysed together with quantification of serum HCV-RNA using the branched DNA technology. As anticipated, the ALT levels significantly declined late in pregnancy and increased again after delivery. HCV-RNA levels, conversely, significantly increased late in pregnancy and returned to baseline levels 1 y after delivery. These findings suggest the importance of immune mediated mechanisms in controlling the viral replication and contributing to the liver injury in chronic hepatitis C.

Long-term follow-up of chronic hepatitis non-A, non-B--with special reference to hepatitis C.

One hundred and twenty-seven patients with histologically verified chronic non-A, non-B hepatitis were followed for up to 23 years (mean 6.3 years). Thirty-nine were infected by blood transfusion, 58 were drug-addicts and 30 had no obvious source of infection. Chronic persistent hepatitis (CPH) was diagnosed in 84 (66%), while 43 patients (34%) had chronic active hepatitis (CAH) with or without cirrhosis. Patients with CPH were significantly younger (29.7 years vs 46.8 years; p less than 0.01), irrespective of the type of virus exposure. Antibodies to hepatitis C virus (anti-HCV) were detectable in 91 patients (72%) and 36 (28%) were anti-HCV negative. Fifteen patients with acute onset, and negative for anti-HCV at the start, became positive during follow-up; 12 of them within 4.5 months. We found no differences among anti-HCV positive and anti-HCV negative patients in liver function tests, resolving rate, morphological progression in serial biopsies or mortality rate. Five previously anti-HCV positive patients became negative during follow-up and in two of them this was accompanied by decreasing hepatic inflammation.

Hepatitis C: natural history of a unique infection.

In 1988 investigators defined the agent causing most cases of non-A, non-B hepatitis and named this agent hepatitis C virus (HCV). Assays for antibody to HCV and more specific diagnostic tests (immunoblot and polymerase chain reactions) were subsequently developed. Exposure to HCV seems to result in chronic infection in a majority of cases, with progressive chronic liver disease sometimes leading to hepatocellular carcinoma. This virus is spread mainly by parenteral routes; intravenous drug users are at high risk. Sexual and intrafamilial spread has also been documented but seems to occur to a limited extent. Perinatal transmission, which is prominent in infection with hepatitis B virus, does not play an important role in the spread of HCV. Antiviral therapy with interferon alpha is usually tried in chronic hepatitis C but permanently normalizes liver function in only one-fourth of patients. The failure to demonstrate protective immunity after single or multiple episodes of infection raises doubts about the existence of neutralizing antibodies and concerns about the potential for the development of a vaccine against HCV.

Persistent alanine aminotransferase elevation in healthy Swedish blood donors--mainly caused by obesity.

Five hundred consecutive healthy blood donors were tested for serum alanine aminotransferase (ALT) and 44 (8.8%) had increased levels. Donors with and without raised ALT were compared in several aspects but only weight (expressed as percentage of ideal body weight) and sex differed significantly (119.1 +/- 14.5 and 106.3 +/- 12.8%, respectively; p less than 0.001 and males 97.7 and 77.1%, respectively; p less than 0.01). The 44 donors with raised ALT were followed up and in 13 out of 15 donors with persistently raised ALT without obvious reason, a liver biopsy was performed. Ten donors had various degrees of liver steatosis, 2 had normal liver morphology and in 1 donor chronic hepatitis could not be ruled out. If ALT screening is introduced as a surrogate test for non-A, non-B hepatitis in Swedish blood donors, we suggest that a correction for overweight must be considered in order to minimize donor loss.

Chronic non-A, non-B hepatitis. A long-term follow-up study in 49 patients.

Forty-nine patients with biopsy-verified chronic non-A, non-B hepatitis (NANBH) of both percutaneously transmitted and sporadic types were followed up for up to 20 years (mean, 62 months +/- 44 months). Drug addicts were not included. Twenty-four patients had chronic persistent hepatitis (CPH), and 25 had chronic active hepatitis (CAH) or cirrhosis on the basis of the first biopsy. Patients with CPH were significantly younger than patients with CAH (mean age, 31 and 51 years, respectively; p less than 0.001). Standard laboratory data (means) correlated with histology, but great variations made liver biopsy essential for the diagnosis. Twenty-one patients were rebiopsied, and 24% had more severe lesions. In total, 16 patients (33%) had signs of cirrhosis. The disease seemed to resolve in eight patients (16%), whereas two patients died of it. Some patients with CPH might progress to CAH, and the frequent finding of cirrhosis in CAH implies the possibility of hepatic failure and fatality in chronic NANBH.

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.

Mother to infant transmission of hepatitis C virus infection.

Eight women with chronic hepatitis C virus (HCV) infection during pregnancy gave birth to 11 children. Five of these children had elevated ALT, but only two had increased levels in more than one sample. All children tested before 6 months of age were positive for anti-HCV at most up to 7 months of age and then became negative. One child with a maximum ALT level of 8.4 mukat/l however, regained anti-HCV positivity at 12 months of age, and a liver biopsy at 21 months of age showed resolving hepatitis. Passively acquired HCV antibodies are obviously found in newborns of anti-HCV-positive mothers with chronic hepatitis. In 1 of 11 children, active anti-HCV production and concomitant liver disease suggested mother to infant transmission of hepatitis C virus infection.

Chronic non-A, non-B hepatitis in drug addicts--a follow-up study.

Forty-seven drug addicts with histologically verified chronic non-A, non-B hepatitis were followed up for at least 12 months (mean 58 +/- 34.5 months). The patients were young, mean age 25 years and predominantly of the male sex. Forty patients (85%) had chronic persistent hepatitis (CPH) in the first biopsy and seven (15%) had chronic active hepatitis with or without cirrhosis (CAH/C). Except for bilirubin levels, standard biochemical tests at the time of the biopsy did not differ significantly between the two histologic groups. Ten patients had repeated biopsies performed and in four of them a histologic progression was observed. Six patients with CAH had evidence of cirrhosis. No patient developed hepatic failure or died because of the liver disease. Two patients seemed to resolve biochemically during follow-up. The rather benign liver morphology contrasts with chronic NANBH after blood transfusion where chronic active hepatitis and cirrhosis are much more common. Age-dependent immunologic factors might to some extent explain these differences.

Interferon alpha-2b treatment of chronic posttransfusion non-A, non-B hepatitis: interim results of a randomized controlled open study.

32 patients with biopsy-proven chronic non-A, non-B posttransfusion hepatitis and raised aminotransferase levels since more than 1 year were randomized 2:1 to treatment with interferon alpha-2b, Introna, or to controls. The interferon group received 3 MU interferon 3 times weekly subcutaneously. Interim results 12 weeks after randomization showed that 14/21 (67%) patients in the treatment group had normalized their serum alanine aminotransferase levels whereas none of 11 patients in the control group had (p less than 0.001). If interferon alpha-2b is only suppressive during ongoing therapy or curative will be shown later during continued follow-up.