Fulminant hepatitis and the new G/GBV-C flavivirus.
Academic Department of Medicine, Hippokration General Hospital, Athens, Greece.
A new virus within the family Flaviviridae. 'hepatitis' G/GBV-C, has been incriminated by several authors as a causative factor of idiopathic or cryptogenic fulminant hepatitis, a syndrome of presumed viral aetiology. Review of worldwide data from 22 studies on 364 cases indicates that G/GBV-C infection is present in approximately 20% of idiopathic cases but a similar or even higher prevalence is detected in fulminant hepatitis of viral B, D or C aetiology, reflecting a high rate of parenteral viral exposure rather than a specific aetiology of fulminant hepatic failure. An aetiopathogenic role of G/GBV-C in fulminant hepatitis seems to be further refuted by the analysis of other data in the literature. The presence of G/GBV-C infection in fulminant hepatic failure is largely a result of secondary infection or coinfection. The aetiopathogenetic mystery of cryptogenic or idiopathic fulminant hepatitis remains unsolved.
Expression and characterization of the hepatitis G virus helicase.
Laxton CD. McMillan D. Sullivan V. Ackrill AM.
Department of Virology, Roche Discovery Welwyn, Welwyn Garden City, Hertfordshire, UK.
The hepatitis G virus (HGV) is a new member of the Flaviviridae family and has a genomic organization similar to that of hepatitis C virus (HCV). Protein sequence motifs are present suggesting that HGV encodes a serine proteinase, an RNA-dependent RNA polymerase and a helicase. We have cloned and expressed the putative helicase of HGV and have shown that it contains a poly (U)-stimulated NTPase activity and is able to function as a DNA helicase. Preliminary characterization of the HGV helicase activity reveals similarities with other members of the Flaviviridae, but especially with HCV, raising the possibility that HGV could be used as a surrogate virus for the development of therapies against HCV.
Quantitative assessment of hepatitis C virus RNA in peripheral blood mononuclear cells during therapy with interferon-alpha2a.
Moonka DK. Henzel BS. Gutekunst K. O'Brien CB.
University of Pennsylvania, Division of Gastroenterology, Philadelphia 19104, USA.
A significant number of patients with hepatitis C (HCV) treated with interferon (IFN) will initially clear their serum of HCV RNA, but will then have recurrence of viraemia either during or after therapy. One proposed mechanism for relapse is that HCV may persist in peripheral blood mononuclear cells (PBMCs) and that the PBMCs serve as a 'viral reservoir' that is resistant to IFN. To address this hypothesis, we performed serial, quantitative polymerase chain reaction (PCR) of HCV RNA in serum and PBMCs from 26 consecutive patients treated with IFN-alpha2a. Of the 26 patients, 11 (42%) did not clear virus from their serum during therapy and were termed non-responders. Five patients (19%) had sustained clearance of virus from serum and were termed complete responders. The remaining 10 patients (39%) initially eliminated HCV RNA from their serum, but had relapse of viraemia. They were termed partial responders. In all 10 partial responders HCV RNA was undetectable in PBMCs at the same time that it was undetectable in serum. When virus recurred in serum, it was preceded by or occurred at the same time as the return of virus in PBMCs. The results of our study indicate that PBMCs did not serve as an IFN-resistant 'viral reservoir' during therapy. Partial responders who transiently cleared virus from serum also cleared virus from PBMCs and the presence or titre of HCV RNA in PBMCs at the initiation of therapy did not predict response to therapy.
Hepatitis G virus does not cause significant liver disease after liver transplantation.
Karayiannis P. Brind AM. Pickering J. Mathew J. Burt AD. Hess G. Bassendine MF. Thomas HC.
Department of Medicine, Imperial College School of Medicine at St. Mary's, London, UK.
The aim of this study was to determine the prevalence of infection with the newly described hepatitis G virus (HGV) in a liver transplant cohort, and to establish the frequency and nature of hepatitis in those with and without HGV infection. A reverse transcriptase-polymerase chain reaction technique was employed to determine viraemia in the patients, and liver biopsies taken at different times after transplantation were assessed histologically. Hepatitis G virus RNA was detected in 47% of the liver transplant recipients investigated. Those positive for HGV had received significantly more blood or blood products than the HGV-negative patients. The frequency of abnormal liver function tests was similar in HGV-positive and HGV-negative recipients. Bile duct epithelial cell damage was more frequently seen in those with HGV viraemia. This study indicates that almost half of the liver transplant recipients in Northern England are positive for HGV, and that infection is associated with exposure to blood and blood products. It appears that, in the immunosuppressed patient, HGV does not cause clinically significant liver disease, at least up to 2 years after transplantation. If HGV infection is associated with hepatitis outside this clinical setting, it is likely that the liver damage is immunopathologically mediated rather than as a result of direct viral cytotoxicity.
Factors associated with cirrhosis development in chronic hepatitis C patients from an area of low prevalence.
Verbaan H. Widell A. Bondeson L. Andersson K. Eriksson S.
Department of Medicine, University of Lund, University Hospital, Malmo, Sweden.
The aim of this study was to evaluate the importance of different endogenous and exogenous factors associated with cirrhosis development among hepatitis C virus (HCV)-positive individuals from an area of low prevalence. We studied 106 consecutive HCV RNA positive patients who had undergone liver biopsy. Each patient was assessed with special attention to risk factors for hepatitis C infection, average daily alcohol consumption and analysis of plasma levels of alpha1-antitrypsin (alpha1AT) and alpha1-antichymotrypsin (alpha1ACT). Viral RNA, amplified from serum with the polymerase chain reaction (PCR) technique, was used for genotyping. Liver biopsies were assessed according to conventional histopathological criteria, and for necroinflammatory activity (grade) and fibrosis (stage) according to a numerical scoring system. The presence of cirrhosis (stage 4) was used as the dependent variable in multivariate logistic regression analysis. Alcohol abuse (P = 0.007), age at entry (P < 0.001), immigrant status (P = 0.017) and a low alpha1ACT level (P = 0.008) were all independent determinants of progression to cirrhosis whereas HCV genotype 1, estimated duration of HCV infection and positivity for antibodies to hepatitis B core antigen (HBcAb) were not. Cirrhosis occurred at a significantly younger age (P = 0.00(5) among alcohol abusers. Hence, both endogenous and exogenous factors such as subnormal alpha1ACT levels and alcohol appear to contribute to the rate of progression to cirrhosis among HCV-positive patients.
Comparison of high initial and fixed-dose regimens of interferon-alpha2a in chronic hepatitis C: a randomized controlled trial. French Multicenter Interferon Study Group.
Ouzan D. Babany G. Valla D. Opolon P.
Institut Arnault-Tzanck, Saint-Laurent-du-Var, France.
The efficacy of a high-dose de-escalating treatment regimen versus the standard, fixed-treatment regimen of interferon-alpha2a (IFN; Roferon-A) in chronic hepatitis C was evaluated in 291 patients who had elevated alanine aminotransferase (ALT) levels, for at least 6 months prior to the study, and histologically proven chronic hepatitis. Patients were randomized into two groups: 142 patients received IFN at a fixed dose (3 million international units (MIU) three times a week for 6 months) and 149 patients received 6 MIU three times a week for 3 months followed by 3 MIU three times a week for the next 3 months. The groups did not differ significantly with respect to age, gender or percentage of patients with cirrhosis. Response was evaluated by monitoring ALT levels monthly during treatment and during the 6 months post-treatment follow-up. Sixty-one per cent and 66% of the patients in the fixed and de-escalating treatment groups had a primary response (serum ALT normalization) during the treatment period; sustained-response rates at the end of follow-up were 20% and 29%, respectively (not significant). In non-cirrhotic patients, a primary response was recorded in 65% and 70% of the patients in the fixed and de-escalating groups; sustained-response rates were 22% and 33%, respectively. Overall, 62% of patients with a sustained response showed histological improvement. In univariate analysis, patients with sustained response tended to be non-cirrhotic and had lower initial serum gamma-glutamyl transpeptidase and ferritin levels. Multivariate analysis indicated that only ALT activity assessed at month 1 (P < 0.01) was a significant predictor of sustained response. These findings suggest that although the difference in the response rates between the de-escalating (6 MIU three times a week for 3 months; 3 MIU three times a week for 3 months) and fixed (3 MIU three times a week for 6 months) treatment regimens did not reach statistical significance, there was a clear trend towards higher response with the 6 MIU induction dose in patients without cirrhosis.
Interferon treatment in hepatitis B surface antigen-positive hepatitis B e antibody-positive chronic hepatitis B: role of hepatitis B core antibody IgM titre in patient selection and treatment monitoring.
Lobello S. Lorenzoni U. Vian A. Floreani A. Brunetto MR. Chiaramonte M.
Department of Gastroenterology, University of Padova, Italy.
Chronic hepatitis B infection with the hepatitis B e antigen (HBeAg)-negative variant is associated with a severe clinical course and a low response rate to interferon (IFN). In an attempt to improve the chances of sustained response to interferon we designed a pilot study, using titres of IgM antibodies to hepatitis B core antigen (HBcAb IgM) to guide treatment initiation. Eighteen adults who were HBeAg-negative with biopsy-proven chronic active hepatitis (seven with cirrhosis) entered the study. They were followed-up bimonthly with routine liver function tests, and HBcAb IgM titres were also determined. Treatment (lymphoblastoid IFN 5 million units (MU) m(-2) three times weekly for 6 months) was started when the HBcAb IgM titre was increasing. Fifteen (83.3%) patients had normal alanine aminotransferase (ALT) levels and undetectable HBV DNA at the end of treatment. HBcAb IgM decreased in all responders. We observed a relapse in four patients (three with cirrhosis), in the first year after treatment, with an increase in ALT, HBV DNA and titre of HBcAb IgM. Eleven patients (61.1%) had a sustained response and eight of these 11 patients were followed-up for more than 18 months; two responders cleared hepatitis B surface antigen (HBsAg). Hence, the rate of sustained response to IFN in HBeAb-positive patients with chronic hepatitis is improved if treatment is started when HBcAb IgM levels are increasing.
Spread of hepatitis C virus infection within families. Investigators of an Italian Multicenter Group.
Caporaso N. Ascione A. Stroffolini T.
Dipartimento di Internistica Clinica e Sperimentale F. Magrassi, II Universita di Napoli, Italy.
In 1995, the intrafamilial spread of hepatitis C virus (HCV) was evaluated among 1379 household contacts of 585 HCV antibody-positive HCV RNA-positive subjects (index cases) in Italy. All index cases were patients with histologically proven chronic liver disease. The presence of antibodies to HCV (anti-HCV) was assessed by third-generation enzyme-linked immunosorbent assay (ELISA); the polymerase chain reaction (PCR) was used to test for HCV RNA. The overall anti-HCV prevalence among household contacts of index cases was 7.3% (101/1379); it was 15.6% in spouses and 3.2% in other relatives (P < 0.05; odds ratio (OR), 6.5; 95% confidence interval (CI), 3.5-8.6). Spouses married to index cases for longer than 20 years had a significantly higher anti-HCV prevalence than those married 20 years or less (19.8% vs 8.0%; P< 0.05; OR, 2.8; 95% CI, 1.5-5.3). Parenteral risk factors were more likely to be reported in anti-HCV positive than in anti-HCV negative household contacts. After adjustment for confounders by multiple logistic regression analysis, age greater than 4 5 years (OR, 3.1; 95% CI, 1.6-5.3) and any parenteral exposure (OR, 3.7; 95% CI, 1.7-8.1), were the only independent predictors of the likelihood of anti-HCV positivity among household contacts. Spouses versus other relatives and length of marriage were both no longer associated. These findings suggest that sexual transmission does not seem to play a role in the intrafamilial spread of HCV infection.
Management of hepatitis C.
Moussalli J. Opolon P. Poynard T.
Service d'Hepato-gastroenterologie, Groupe hospitalier Pitie-Salpetriere, Paris, France.
Chronic hepatitis C is a major health care problem throughout the world. The disease may progress to cirrhosis, with complications such as hepatocellular carcinoma. The usual primary goal of therapy is viral eradication, as patients with long-term remission are generally regarded as unlikely to develop cirrhosis or hepatocellular carcinoma. Another primary goal should be the reduction in liver fibrosis progression. Interferon-alpha (IFN-alpha) is the only drug approved for the treatment of hepatitis C in Europe and North America. Its effectiveness appears to be related to dose and duration of therapy. The best efficacy/risk ratio seems to be in favour of 3 million units (MU) IFN-alpha three times per week on a 12-month schedule. With this regimen, a sustained alanine aminotransferase (ALT) response is achieved in nearly 35% of patients. Ribavirin has emerged as potentially the second most effective drug. While it appears unsatisfactory when given alone, it seems much more effective in combination with IFN. Combining them seems to exert a synergistic effect between the two drugs and sustained remission might be achieved in nearly 50% of patients with combination therapy. Controversy persists concerning the long-term benefit of therapy in transient responders and non-responders. It is possible that IFN therapy, in comparison to natural history, might reduce liver fibrosis progression and prevent hepatocellular carcinoma, even in non-responders, and have greater efficacy if used in long-term treatment. Whatever the treatment schedule, prolonged viral eradication may not be achieved in all patients and new drugs should be sought to improve the results of therapy.
Composition of peripheral blood lymphocyte populations during different stages of chronic infection with hepatitis B virus.
Sing G. Butterworth L. Chen X. Bryant A. Cooksley G.
Clinical Research Centre, Royal Brisbane Hospital Research Foundation, Herston, Australia.
To characterize the immunological populations associated with different stages of chronic infection with hepatitis B virus (HBV), we performed flow cytometric analyses on the peripheral blood leucocytes of 29 patients with various forms of chronic hepatitis B. The clinical spectrum of the patients ranged from asymptomatic infections, in the presence of high virus production, to intermittent or recurrent exacerbations of liver injury alternating with relatively normal liver function. Patients with partial resolution of disease who experienced an initial acute flare followed by prolonged seroconversion showed decreased percentages of CD3+ cells during the seroconversion phase when levels of serum alanine transferase (ALT) had normalized. These CD3+ cells were predominantly CD4+ cells bearing the alpha beta+ T-cell receptor (TCR). In addition, we saw an increase in CD4+ and CD8+ cells bearing the gamma delta TCR in those patients who had seroconverted. No significant differences were seen between any of the groups with respect to percentage of cells with a naive (CD45RA) or memory (CD45RO) phenotype, or of cells displaying the activation markers CD38, HLA-DR or CD57. Longitudinal analyses of 15 patients failed to show any consistent pattern of changes in the immunophenotypic profile during acute flares and their resolution. Our results indicate that the turnover of circulating T lymphocytes during the apparent quiescent phase of chronic infections is higher than that during acute exacerbations, suggesting an active immunosurveillance role of T-cell subpopulations in maintaining low virus levels during seroconversion.
Statistical models for predicting a beneficial response to interferon-alpha in patients with chronic hepatitis B.
Lau DT. Comanor L. Minor JM. Everhart JE. Wuestehube LJ. Hoofnagle JH.
Liver Diseases Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Therapy with interferon-alpha has been reported to induce remissions in 35% of patients with chronic hepatitis B. The ability to identify patients likely to respond would be helpful in making recommendations for treatment. In this statistical analysis we included 82 patients with chronic hepatitis B who received interferon-alpha in clinical trials at the National Institutes of Health between 1984 and 1991. A response was defined as the loss of hepatitis B virus (HBV) DNA and hepatitis B e antigen (HBeAg) within 1 year of therapy. Multiple clinical parameters measured at pretreatment (month 0) and after the first month (month 1) of therapy were selected by stepwise regression to support the development of the prognostic models: the two-stage logistic regression model and a neural network that utilized higher-order non-linear interactions between variables. Among the 82 patients, 24 (29%) were responders. The two-stage logistic model using pretreatment variables: sex, hepatic fibrosis and alanine aminotransferase (ALT) levels correctly identified 61% of responders and 76% of non-responders. When HBV DNA at month 1 along with sex, initial ALT and fibrosis was included, the resultant model correctly identified 69% of responders and 77% of non-responders. The neural network, by incorporating interactions between variables, correctly identified 77% and 86% of responders, and 87% and 92% of non-responders, using pretreatment factors alone and the combination of pretreatment and month 1 factors respectively. Hence, the neural network was more accurate than the simple logistic regression model in predicting a response to interferon-alpha in chronic hepatitis B. The universality of these models needs to be further verified.
Prospective virological follow-up of hepatitis C infection in a haemodialysis unit.
Halfon P. Khiri H. Feryn JM. Sayada C. Chanas M. Ouzan D.
Laboratoire Alphabio, Marseille, France.
Hepatitis C virus (HCV) is of major concern in the management of patients on maintenance haemodialysis. Many studies have reported a high prevalence of HCV infection in dialysis centres. The objective of our study was first, to perform a prospective follow-up of the evolution of HCV infection in a haemodialysis centre, and second, to assess the rate of viral clearance in patients on dialysis. For this, genotypes, HCV antibodies (anti-HCV) and HCV RNA were evaluated initially and 9 months later. HCV RNA quantification was also performed. Of 136 patients, 62 (45.6%) were anti-HCV positive by third-generation enzyme immunoassay (EIA 3) in the first survey and 64 of 136 (47.1%) were anti-HCV positive by EIA 3 in the second survey. The rate of new HCV infection, estimated from the two seroconversions between the surveys, was 1.9% per year. One of the two patients was initially HCV RNA positive, with a titre of 0.6 x 10(6) eq ml-1. The viral load measured in the dialysis patients was low and does not seem to be influenced by dialysis. No significant difference was observed in viral load between the two periods nor were there any gender-related differences in viral load. In conclusion, detection of antibodies to HCV, together with HCV RNA, seems to be relevant in haemodialysis patients, but this strategy is not suitable for use in all haemodialysis centres because of its high cost.
Hepatitis G virus infection in hepatitis C virus-positive patients co-infected or not with hepatitis B virus and/or human immunodeficiency virus.
Thiers V. Pol S. Persico T. Carnot F. Zylberberg H. Berthelot P. Brechot C. Nalpas B.
Centre de Biologie Moleculaire Specialisee, Institut Pasteur, Paris, France.
This was a retrospective study to evaluate the prevalence and impact of hepatitis G virus (HGV) infection in hepatitis C virus (HCV)-positive drug addicts, according to the serological status of hepatitis B virus (HBV) and human immunodeficiency virus (HIV) coinfection. Two hundred and thirty-five randomly selected intravenous drug addicted patients (147 French, 88 Italian) were studied. All patients were positive for antibodies to HCV (anti-HCV). HGV RNA positivity was measured by reverse transcriptase-polymerase chain reaction (RT-PCR). Comparisons of HCV RNA positivity rate, and biological and histopathological variables, were made between HGV RNA-positive and negative patients, according to their HBV and HIV status. HGV prevalence was around 30% in both French and Italian groups. No clear association between HGV infection and a particular HCV genotype was observed. The rate of HCV RNA positivity did not differ between HGV-positive and HGV-negative patients after stratification for hepatitis B surface antigen (HBsAg) and HIV positivity. Histological severity of the underlying chronic hepatitis did not differ according to the HGV status; however, in HIV-positive HBsAg-negative patients, the hepatitis activity was moderately increased in HGV-positive patients. A striking negative influence of HBsAg positivity on HCV replication was observed in HIV-negative patients; an HCV RNA-positive rate of 25% was found in HBsAg-positive patients vs 86% in HBsAg-negative patients; similar significant results were observed in HIV-positive patients, although to a lesser extent. The underlying chronic hepatitis was significantly more severe in HBsAg-positive than in HBsAg-negative HIV-negative patients. Hence, HGV infection is highly prevalent in anti-HCV positive drug addicts but the co-infection with HCV does not seem to influence HCV replication nor to worsen the underlying chronic hepatitis, in HIV-negative patients at least. Reciprocal influence between HBV, HCV and HIV appears rather complex, HBsAg carriage seeming to exert per se a negative effect on HCV replication, particularly in HIV-negative patients, suggesting that interactions between hepatitis viruses should always be analysed in the light of HIV status.
Medical practices regarding hepatitis C virus infection in Europe.
Nalpas B. Delaroques-Astagneau E. Bihan CL. Drucker J. Desenclos JC.
Reseau National de Sante Publique, St Maurice, France.
Six hundred and ninety-three European Association for the Study of the Liver (EASL) members, belonging to one of the 15 European Union (EU) member-states, were surveyed, through a standardized 45-item questionnaire, on their medical practices regarding hepatitis C virus (HCV) infection. The response rate was 45%, roughly similar in all the countries concerned. Responders were classified into three groups according to their geographical origin: North, Centre and South. A consensus existed with regard to the necessity of HCV screening in well-defined situations, such as history of blood transfusion, haemodialysis, haemophilia or intravenous drug addiction (90% of positive answers) while opinions substantially differed for vertical and nosocomial transmission of HCV. For the prevention of sexual and vertical transmission, opinions differed greatly: 22% were in favour of barrier methods for HCV-positive subjects while 34% were against; 49% allowed breast-feeding for babies born to HCV-positive mothers while 14% were against. Conversely, there was relative homogeneity in the issue of domestic prevention (70% in favour of precautions). Algorithms for prescription of virological tests were inhomogeneous (recombinant immunoblot assay was used by 60%; polymerase chain reaction was requested by 77% when alanine amino-transferase (ALT) was elevated vs 89% when normal): medical evaluation varied according to ALT values: liver biopsy and liver ultrasonography were carried out in 90 and 91% vs 40 and 70% for increased and normal ALT, respectively. Thirty per cent of respondents advised patients to stop alcohol consumption and 60% advised moderation. Two-thirds of the responders did not take into account histological severity and virological parameters before initiating antiviral therapy. Eighty per cent of the participants claimed that they administered interferon (IFN) for 12 months. For most of the items studied, there was a large variation, not only between the three groups, but also within each group. Ninety-two per cent of the responders claimed that they were well trained on HCV but they were rather critical of the quality of the information diffused (satisfaction rate: 45%). Altogether, our survey demonstrates that preventive and medical practices towards HCV are not homogeneous throughout the EU; this suggests the need for a European consensus conference in this regard.