J.M. Sánchez-Tapias

The Prognostic Relevance of the Nonstructural 5A Gene Interferon Sensitivity Determining Region Is Different in Infections with Genotype 1b and 3a Isolates of Hepatitis C Virus

Hepatitis C virus (HCV) RNA serum concentration, quasispecies complexity, and sequence and phylogenetic analysis of the nonstructural 5A gene (NS5A) interferon sensitivity determining region (ISDR) were determined in pretreatment serum samples from 47 patients with chronic hepatitis C (36 infected by HCV genotype 1b and 11 by 3a). Among HCV genotype 1b-infected patients, virus load was lower (P = .003) and the number of NS5A-ISDR amino acid changes was higher (P = .001) in long-term responders than in non-long-term responders, but there were no differences in quasispecies complexity. Multivariate analysis showed a close association between response to interferon and NS5A-ISDR phenotype. Phylogenetic analysis showed that isolates from non-long-term responders clustered apart from the majority of isolates from long-term responders. There was no association between virologic features and therapeutic response in HCV genotype 3a-infected patients. In conclusion, low virus load and mutant NS5A-ISDR phenotype are closely associated with long-term response to interferon in HCV genotype 1b- but probably not in 3a-infected patients.

Systemic Autoimmune Diseases in Patients with Hepatitis C Virus Infection: Characterization of 1020 Cases (The HISPAMEC Registry)

Objective. To describe the clinical and immunologic characteristics of a large series of patients with systemic autoimmune diseases (SAD) associated with chronic hepatitis C virus (HCV) infection. Methods. The HISPAMEC Registry is a multicenter international study group dedicated to collecting data on patients diagnosed with SAD with serological evidence of chronic HCV infection. The information sources are cases reported by physicians of the HISPAMEC Study Group and periodic surveillance of reported cases by a Medline search updated up to December 31, 2007. Results. One thousand twenty HCV patients with SAD were included in the registry. Patients were reported from Southern Europe (60%), North America (15%), Asia (14%), Northern Europe (9%), South America (1%), and Australia (1%). Countries reporting the most cases were Spain (236 cases), France (222 cases), Italy (144 cases), USA (120 cases), and Japan (95 cases). The most frequently reported SAD were Sjögren’s syndrome (SS; 483 cases), rheumatoid arthritis (RA; 150 cases), systemic lupus erythematosus (SLE; 129 cases), polyarteritis nodosa (78 cases), antiphospholipid syndrome (59 cases), inflammatory myopathies (39 cases), and sarcoidosis (28 cases). Twenty patients had 2 or more SAD. Epidemiological data were available in 677 cases. Four hundred eighty-seven (72%) patients were female and 186 (28%) male, with a mean age of 49.5 ± 1.0 years at SAD diagnosis and 50.5 ± 1.1 years at diagnosis of HCV infection. The main immunologic features were antinuclear antibody (ANA) in 61% of patients, rheumatoid factor (RF) in 57%, hypocomplementemia in 52%, and cryoglobulins in 52%. The main differential aspect between primary and HCV-related SAD was the predominance of cryoglobulinemic-related markers (cryoglobulins, RF, hypocomplementemia) over specific SAD-related markers (anti-ENA antibodies, anti-dsDNA, anti-cyclic citrullinated peptide) in patients with HCV. Conclusion. In the selected cohort, the SAD most commonly reported in association with chronic HCV infection were SS (nearly half the cases), RA and SLE. Nearly two thirds of SAD-HCV cases were reported from the Mediterranean area. In these patients, ANA, RF and cryoglobulins are the predominant immunological features.

Consensus conference on chronic viral hepatitis and HIV infection: updated Spanish recommendations

Summary.  Chronic hepatitis B and C represent a leading cause of morbidity and mortality among human immunodeficiency virus (HIV)‐infected patients worldwide. New treatment options against both hepatitis B (HBV) and C (HCV) viruses have prompted us to update previous recommendations for the management of coinfected individuals. Fifteen topics (nine related to HCV, five to HBV and one to both viruses) were selected for this purpose. A panel of Spanish experts in the field was invited to review these areas and propose specific recommendations, which were scored according to the Infectious Disease Society of America (IDSA) grading system. These guidelines represent a comprehensive and updated overview on the management of hepatitis B and C in HIV‐infected patients.

Epidemiological, clinical and therapeutic associations of hepatitis C types in western European patients

BACKGROUND/AIMS Different variants of hepatitis C virus might show different susceptibility to interferon alpha treatment, but it is important to understand whether this difference in sensitivity reflects an association with other factors, such as cirrhosis or age. METHODS We have used an enzyme-linked immunosorbent hepatitis C virus typing assay based upon the detection of antibody in patients era to type-specific NS-4 antigens to investigate the effect of hepatitis C virus type in 610 patients with chronic hepatitis C virus infection. The influence of viral types and their interdependency with host factors were separately analyzed to establish which factors executed an independent effect on the probability of sustained response. RESULTS There was a marked difference in the distribution of hepatitis C virus types with age: infection with type 3 was more common in younger patients. The distribution of hepatitis C virus type with age is accounted for by differences in risk-factors for infection in different age groups. The frequency of cirrhosis increased markedly with age. Even after standardization for age, center and the presence of cirrhosis, viral type was strongly related to the outcome of infection. CONCLUSIONS Our data suggest that enzyme-linked immunosorbent hepatitis C virus typing could assist in patient selection for interferon treatment to improve sustained response rates. Together with measurement of viral load, hepatitis C virus typing may serve to indicate the probability of response in patients with chronic hepatitis C, and to elucidate antiviral mechanisms in the disease. The serotyping assay provides a relatively inexpensive screening method to determine the infecting hepatitis C virus type, which could facilitate therapeutic decisions and strategies in patients with chronic hepatitis C.

Infection with a novel human DNA virus (TTV) has no pathogenic significance in patients with liver diseases

BACKGROUND/AIMS A recently identified DNA virus, termed TT virus (TTV), has been associated with post-transfusional hepatitis, and a high prevalence of TTV infection in patients with acute or chronic liver disease of unknown etiology has been reported from Japan, but few data are available about TTV infection in other countries. METHODS Using hemi-nested-PCR amplification to detect TTV-DNA sequences in serum, we investigated TTV infection in blood donors and in patients with liver diseases of varied etiology. RESULTS The prevalence of TTV infection was 13.7% in blood donors (23/168), 18.6% in chronic hepatitis C (19/102), 28.6% in chronic hepatitis B (16/56), 29.9% in hepatocellular carcinoma (20/67), 9.1% in cryptogenic chronic liver disease (2/22) and 39.6% in fulminant hepatitis (19/48). The prevalence of TTV infection in patients with virus-induced or idiopathic fulminant hepatitis was similar. Comparison of TTV-infected and non-infected patients did not reveal significant differences concerning demographic, epidemiological or histopathological features. In patients with hepatitis C, response to interferon therapy was not related to TTV infection. Phylogenetic analysis of TTV isolates showed that at least three different types of TTV are present in Spain. CONCLUSIONS Our data suggest that TTV infection is frequent among blood donors and patients with acute liver disease. However, pathogenic effects associated with TTV infection were not observed.

Prevalence and route of transmission of infection with a novel DNA virus (TTV), hepatitis C virus, and hepatitis G virus in patients infected with HIV.

Objectives: To evaluate the prevalence, route of transmission and clinical significance that current co‐infection with TT virus (TTV), hepatitis C virus (HCV), and hepatitis G virus (HGV) have in HIV‐1‐infected patients. Design: Presence of TTV, HCV, and HGV was analyzed in plasma samples from 160 HIV‐1‐infected patients with parenteral (38 intravenous drug users [IVDUs] and 41 patients with hemophilia) or sexual (39 homosexuals and 42 heterosexuals) risk of exposure, and in 168 volunteer blood donors. Alanine aminotransferase (ALT) levels and CD4+ counts were also analyzed. Methods: HCV and HGV RNA were detected by specific reverse transcriptase (RT) nested polymerase chain reaction (PCR) and TTV DNA by specific heminested PCR. Results: TTV DNA was detected in 39% of the patients and in 14% of the volunteer blood donors. HCV and HGV infections were detected in 42% and in 14% of the patients, and in 0% and 3% of the blood donors, respectively. Prevalences of TTV and HCV infection were higher among patients with parenteral (62% and 68%) than in those with sexual (17% and 16%) risk of exposure. A higher prevalence of TTV infection (but not of HCV or HGV infection) was observed among patients with hemophilia (76%) than IVDUs (47%), and among homosexuals (26%) than among heterosexuals (10%). Abnormal ALT levels were related with the presence of HCV infection, independently of the detection of TTV DNA. TTV infection did not seem to alter the levels of CD4+ T cells. Conclusions: Prevalence of current TTV infection is high among HIV‐infected patients with parenteral risk of exposure, but TTV is also transmitted through sexual routes; detection of TTV does not seem to influence the clinical or immune status of HIV‐infected patients.

Prevalence and genotypes of GB virus C/hepatitis G virus (GBV-C/HGV) and hepatitis C virus among patients infected with human immunodeficiency virus : Evidence of GBV-C/HGV sexual transmission

The development of new antiretroviral agents may improve survival of HIV‐infected individuals, and therefore chronic viral hepatitis may become more relevant in these patients. The presence of GBV‐C/HGV and hepatitis C virus (HCV) RNA were investigated by reverse transcriptase‐nested polymerase chain reaction in plasma from 168 Spanish HIV‐infected patients belonging to four different risk groups: intravenous drug users (IVDUs), hemophiliacs, homosexuals, and heterosexuals. GBV‐C/HGV‐RNA and HCV‐RNA were detected in 18% and 43% of the patients, respectively. The prevalence of current infection with these viruses was notably high, 19% for GBV‐C/HGV and 69% for HCV, among individuals with parenteral risk of infection (intravenous drug abusers and hemophiliacs), but sexual transmission with GBV‐C/HGV was also suggested because 16.5% of patients with sexual risk, either homosexual or heterosexual, had GBV‐C/HGV‐RNA in plasma. Although investigation of GBV‐C/HGV‐RNA possibly underestimates the actual prevalence of infection with GBV‐C/HGV, the above data suggest that sexual contact may play a relevant role in the spread of this virus. Phylogenetic analysis showed no evidence for clustering of NS3 sequences into different genotypes or subtypes of GBV‐C/HGV. J. Med. Virol. 55:293–299, 1998.

Hepatitis G virus infection in chronic liver disease

Background—The hepatitis G virus (HGV), a recently identified member of the Flaviviridae family, can cause chronic infection in man but the role of this agent in chronic liver disease is poorly understood. Aims—To evaluate the prevalence and meaning of HGV infection in a large series of patients with chronic liver disease. Subjects—Two hundred volunteer blood donors, 179 patients with chronic hepatitis C, 111 with chronic hepatitis B, 104 with alcoholic liver disease, 136 with hepatocellular carcinoma, and 24 with cryptogenic chronic liver disease were studied. Methods—HGV RNA was investigated in serum samples by reverse transcription and polymerase chain reaction amplification of the 5′ non-coding region of HCV and hybridisation to a specific probe. The main features of HGV RNA seropositive and seronegative patients were compared. Results—The prevalence of HGV infection was 3% in blood donors, 7% in chronic hepatitis C, 8% in chronic hepatitis B, 2% in alcoholic liver disease, 4% in hepatocellular carcinoma, and 8% in cryptogenic chronic liver disease. HGV infected patients tended to be younger than non-infected patients but no differences concerning sex, possible source of infection, clinical manifestations, biochemical and virological parameters, or severity of liver lesions were found. Conclusions—The prevalence of HGV infection in chronic liver disease seems to be relatively low in our area. Infection with HGV does not seem to play a significant pathogenic role in patients with chronic liver disease related to chronic HBV or HCV infection or to increased alcohol consumption, or in those with cryptogenic chronic liver disease.

Internal initiation of translation efficiency in different hepatitis C genotypes isolated from interferon treated patients

SummaryInitiation of translation of hepatitis C viral RNA occurs internally and it is mediated by a segment of about 330 nucleotides termed Internal Ribosome Entry Site (IRES) located in the 5′ end region. While being the most conserved part of the genome, this region also accumulates nucleotide substitutions which are often covariant. In this study we have examined the activity and sequence variation of IRES elements belonging to genotypes 1b, 2a/2c and 3a in patients that responded or not to interferon therapy. The substitutions found in the IRES region analyzed were predicted to maintain the secondary structure of the RNA. Comparison of their efficiency to promote internal initiation of translation in bicistronic constructs supported the conclusion that for both 1b and 3a genotypes, response to interferon therapy and IRES activity are unrelated, although sequence homology was not always found among isolates from patients with different type of response. IRES activity of the studied genotypes varied about 4-fold under the conditions used in our in vivo assays depending on the cell line used for transfection. Such differences were not evidenced in vitro suggesting that the differences observed depend on trans-acting factors present in the transfected cell.

Antimitochondrial antibodies in patients with chronic hepatitis C virus infection: description of 18 cases and review of the literature

Summary.  To describe the clinical and immunologic patterns of disease expression of patients with chronic hepatitis C virus (HCV) infection and positive antimitochondrial antibodies (AMA). We investigated the presence of AMA in 237 consecutive HCV patients with extrahepatic manifestations from an International Registry. AMA were detected by indirect immunofluorescence in triple rat tissue (liver, stomach and kidney), aceton‐fixed criosections and FITC‐conjugated rabbit anti‐human immunoglobulins. We found positive AMA in 18 (8%) out of 237 HCV patients. All patients were female with a mean age at protocol inclusion of 65.8 years (ranging from 37 to 87 years). Twelve (67%) patients fulfilled classification criteria for systemic autoimmune diseases (SAD), including Sjögrens syndrome (n = 7), systemic sclerosis (n = 3) and systemic lupus erythematosus (n = 2). Fourteen (78%) of the HCV‐AMA patients presented at least one of the highly suggestive characteristics of primary biliary cirrhosis (PBC): 9 (50%) had a specific M2 pattern, 6 (33%) had more than twice normal levels of alkaline phosphatase, 5 (28%) had raised IgM levels and 4 (22%) a histological pattern compatible with PBC. Five (28%) patients developed neoplasia after detection of AMA. Seven (39%) patients died, due to neoplasia (n = 4), cirrhotic complications (n = 2) and hepatopulmonary syndrome (n = 1). We describe a subset of HCV patients with positive AMA who presented a broad spectrum of clinical features, including liver, autoimmune and neoplasic manifestations. Two‐thirds of these patients presented an associated SAD, mainly Sjögrens syndrome or systemic sclerosis, together with a high frequency of multiple autoantibodies and an increased prevalence of cirrhosis and neoplasia.