Efficacy of ribavirin plus interferon alpha on viraemia of GB virus-C/hepatitis G virus: comparison with interferon alpha alone

We investigated the efficacy of ribavirin plus interferon (IFN) alpha on GB virus-C (GBV-C)/hepatitis G virus (HGV) viraemia and compared it with that of interferon alpha alone in patients coinfected with hepatitis C virus (HCV) and GBV-C/HGV. Serum HCV and GBV-C/HGV-RNA were studied in eight patients with HCV and GBV-C/HGV coinfection, five received IFN alpha and three received oral ribavirin plus IFN alpha. Mean serum GBV-C/HGV titre at the end of therapy was significantly lower than the titre just before therapy and patients with lower pretreatment titre had a better sustained response rate. Sustained virological response of GBV-C/HGV to IFN alpha alone and ribavirin plus IFN alpha at the end of follow up was observed in one each, respectively. Thus, GBV-C/HGV in patients with HCV and GBV-C/HGV coinfection does respond to IFN alpha and ribavirin plus IFN alpha may not induce a higher sustained response.     

GB virus-C/hepatitis G virus infection in an area endemic for viral hepatitis, chronic liver disease, and liver cancer

BACKGROUND & AIMS: GB virus-C/hepatitis G virus (GBV-C/HGV) is a newly identified flavivirus, and little is known about its clinical significance. GBV-C/HGV was investigated in different populations, and its coinfection was investigated in patients with liver disease in Taiwan where hepatitis B and C are endemic. METHODS: Viral RNA was studied in 70 high-risk individuals, 20 patients with chronic non-B, non-C hepatitis, 13 with non-A-E fulminant hepatitis, 100 with asymptomatic hepatitis B surface antigen carriage, 120 with hepatitis B surface antigen-positive chronic liver disease and hepatocellular carcinoma, 100 patients with chronic hepatitis C, and 100 healthy adults. RESULTS: GBV-C/HGV infection was more frequent in high-risk groups (15%-30%) and hepatitis C virus carriers (10%) than in healthy adults (1%) and hepatitis B virus carriers (3.2%). Eighty-three percent of those infected had undergone blood transfusions previously. The prevalence in hepatitis B virus carriers increased with the severity of liver disease, being 1% in asymptomatic carriers and 10% in hepatocellular carcinoma. In chronic hepatitis C, clinical and virological data were comparable between those with and without coinfection. CONCLUSIONS: In Taiwan, GBV-C/HGV infection is common in high-risk groups, and its coinfection seems to not aggravate the course of chronic hepatitis B or C.     

Responsiveness to interferon alpha treatment in patients with chronic hepatitis C coinfected with hepatitis G virus

BACKGROUND/AIMS: Patients with chronic hepatitis C are often coinfected with the new identified Flaviviridae-like agent, termed hepatitis G virus (HGV). The aim of the study was to investigate the responsiveness of hepatitis G virus to interferon alpha and to evaluate whether a hepatitis G virus coinfection negatively influences the outcome of treatment in chronic hepatitis C. METHODS: One hundred and fifteen patients with histologically proven chronic hepatitis C were treated with interferon alpha and investigated for the presence of hepatitis G virus coinfection by nested polymerase chain reaction with primers from the helicase region of hepatitis G virus. All patients received at least 3 MU (range 3-6) interferon alpha thrice weekly for at least 6 months (mean 8, range 6-12). Polymerase chain reaction products of seven pre- and post-treatment hepatitis G virus positive patients were directly sequenced for identification of sequence variability during the follow-up. RESULTS: Eighteen (16%) patients were coinfected with hepatitis G virus. Although nine (50%) of these patients became HGV RNA negative during interferon alpha therapy, only three patients (17%) remained HGV RNA negative at the end of follow-up (mean 24 months). The rate of sustained response of chronic hepatitis C was not significantly different between patients with hepatitis C virus infection and HCV/HGV coinfection (19% vs 28%). Severity of liver disease as determined by alanine aminotransferase levels, histology and hepatitis C virus viremia was not significantly different in patients with hepatitis C virus or HCV/HGV coinfection. Sequence analysis of the helicase region revealed that our isolates all belonged to the hepatitis G virus and not to the GBV-C like genotype. No amino acid exchanges during the observation period of up to 48 months were observed, indicating that this region is highly conserved. CONCLUSIONS: The responsiveness of hepatitis G virus to interferon alpha in chronic HCV/HGV coinfected patients is similar to that observed in chronic hepatitis C. Hepatitis G virus coinfection seems not to interfere with the efficacy of interferon alpha treatment in patients with chronic hepatitis C.     

Natural history and molecular biology of hepatitis G virus/GB virus C

BACKGROUND: The hepatitis G virus (HGV) or GB virus C (GBV-C) is a new member of the Flaviviridae family. The virus is transmitted by transfusion of blood, infusion of some blood products, and by parenteral exposure to blood during intravenous drug use (IVDU) and haemodialysis. Transmission from mother to infant and by sexual contact has also been documented. Although the virus has been found in patients with acute and chronic hepatitis, evidence of disease association has not been forthcoming. The majority of patients carry the virus in the absence of liver enzyme abnormalities. OBJECTIVES: To review what is currently known about HGV/GBV-C in order to evaluate its similarity with other members of the Flaviviridae and the association of the virus with disease. RESULTS: The genomic organisation of the virus is typical for Flaviviridae, with long 5' and 3' untranslated regions (UTR). However, a clearly identifiable nucleocapsid encoding region is lacking. Polyprotein synthesis is mediated through an internal ribosome entry site (IRES) contained within the 5' UTR. Phylogenetic tree analysis of sequences derived from this region has demonstrated the existence of at least three genotypes. Apart from serum, HGV-RNA has been detected in lymphocytes also, but the quasispecies present in the two compartments appear to be different. The envelope glycoprotein E2 lacks a hypervariable region and is potentially the target of a neutralising antibody response. CONCLUSION: Molecular analysis of HGV reveals close similarity of the virus with HCV. However, an association of the virus with liver disease remains unresolved and no association of the virus with hepatocellular carcinoma has been reported.     

Clinical implications of GBV-C/HGV infection in patients with "HCV-related" chronic hepatitis

BACKGROUND/AIMS: To evaluate the clinical, biochemical and histological implications of a concomitant HGV infection in "HCV-related" chronic liver disease. METHODS: Eighty-three HCV-RNA positive patients with chronic liver disease were tested for GBV-C/HGV coinfection by heminested PCR. RESULTS: Twenty-two (26.5%) patients were found to be positive for GBV-C/HGV RNA. GBV-C/HGV+ patients differed significantly from GBV-C/HGV- ones for younger age, higher frequency of history of drug addiction, which in turn might favor coinfection with interferon-sensitive HCV genotypes (3a), and increased probability of long-term response to interferon. GBV-C/HGV infection appears to have no responsibility for specific aspects of HCV infection such as biochemical or histological cholestatic features, lymphoid follicles, symptomatic cryoglobulinemia or presence of serum autoantibodies, including LKM1. It does not worsen the HCV-related disease (ALT levels and histological activity) and does not significantly interfere with HCV infection, as explored by the number of hepatocytes positive for HCV antigens. The amount of steatosis (mean score) was shown to be higher in GBV-C/HGV+ patients. A virological follow up was performed in 17 interferon-treated GBV-C/HGV+ patients On the whole, GBV-C/HGV seems to be as sensitive to IFN treatment as HCV, but recurrence after withdrawal is more frequent. In spite of this, ALT levels often remain normal after treatment withdrawal. CONCLUSIONS: The present data suggest that GBV-C/HGV infection, apart from more marked liver steatosis, does not modify the overall picture of chronic hepatitis due to HCV infection.     

High prevalence of hepatitis G virus (HGV) infection in renal transplantation

INTRODUCTION: The newly discovered (1995) hepatitis G virus (HGV) is an RNA virus from the Flaviviridae family with 85% genomic homology to GB virus C (GBV-C). We studied the prevalence of HGV infection among a cohort of 398 renal transplant recipients (RTR), all of whom had previously received blood transfusions, been grafted between August 1984 and December 1991, and been treated by cyclosporin A (CsA) as the main immunosuppressant. SUBJECTS AND METHODS: According to hepatitis C virus (HCV) antibody status, and after exclusion of 28 HBs antigen-positive recipients, this cohort had previously been divided into an HCV +ve subgroup (106 RTR; 62 M vs 44 F; 29 French vs 77 non-French) and an HCV -ve subgroup (264 RTR; 181 M vs 83 F, 196 French vs 68 non-French). We randomly selected 27 RTR in the HCV+/HBV- subgroup (14 M vs 13 F, 10 French vs 17 Italians) and 27 RTR in the HCV-/HBV- subgroup (19 M vs 8 F, 18 French vs 9 Italians) for HGV screening. The detection of HGV RNA sequences in serum (viraemia) was done by double nested RT-PCR using specific primers chosen in the 5' non-coding genomic region. The serum detection of specific antibodies (anti E2) was done by ELISA test. All sera (at time of liver biopsy or at last follow-up) were tested in duplicate. RESULTS: The prevalence of HGV viraemia was 26% (14/54) in the whole group and in both HCV +ve and -ve subgroups (7/27). The prevalence of HGV infection (viraemia + and/or anti E2 antibodies +) was 44% (24/54) in the whole group and in both HCV +ve and -ve subgroups (12/27). In addition, the prevalence was similar in males vs females and in French vs foreigners recipients (mostly Italians). In the HCV +ve subgroup, the seven HGV viraemia-positive patients who previously had liver biopsies disclosed chronic active hepatitis in four (mean Knodell score 5.75) and normal livers in three, with only one case of elevated ALT (CAH 5). In the HCV- subgroup, none of the seven HGV+ viraemic patients had elevated ALT and liver biopsy was not performed. CONCLUSION: HGV infection prevalence is high (44%) in RTR, but clearly independent of HCV status and/or the geographical origin of the recipients. This data indicates a different epidemiology as compared to our HCVs previous experience.     

Hepatitis GB virus C genome in the serum of aplastic anaemia patients receiving frequent blood transfusions

GB virus C (GBV-C) RNA was detected in five of 18 patients with aplastic anaemia who had received blood transfusions, whereas it was not detected in eight patients who had not received any transfusions. Antibody against hepatitis C virus (anti-HCV) was detected in nine patients in the transfusion group, compared with one of eight who had not received any transfusions. Therefore, the route of transmission of both GBV-C and HCV in these patients appeared to have been multiple blood transfusion. Since all of the GBV-C RNA-positive patients harboured anti-HCV, GBV-C seems to frequently superinfect with HCV. Neither GBV-C nor HCV is likely to have been a causative agent of the anaemia in the cases examined.     

Mother-to-infant transmission of GB virus C/hepatitis G virus: the role of high-titered maternal viremia and mode of delivery

To study mother-to-infant transmission of GB virus C/hepatitis G virus (GBV-C/HGV), blood samples of infants born to carrier mothers were collected beginning 3 months after birth and were tested for GBV-C/HGV RNA until 1 year of age. Of 2046 mothers, 2.1% were positive for GBV-C/HGV RNA, and 25 of their infants were followed for a median of 12 months. Thirteen infants (52%) were viremic, and infection became persistent in all. Maternal GBV-C/HGV RNA levels of this group were >10(7) copies/mL. Nucleotide sequence comparison in 5 viremic mother-infant pairs revealed a homology of 93%-98.2%, and none delivered by elective cesarean section. In comparison, of the 12 uninfected infants' mothers, 10 had lower GBV-C/HGV RNA levels (mean, 5 x 10(4) copies/mL), and the remaining 2 high-titered mothers had elective cesarean section. Thus, high-titered maternal viremia and mode of delivery are closely associated with the mother-to-infant transmission of GBV-C/HGV to infants, and the infection usually becomes persistent.     

Infection with hepatitis G virus among recipients of plasma products

BACKGROUND: Hepatitis G virus (HGV or GBV-C) is a newly discovered human flavivirus distantly related to hepatitis C virus (HCV). Little information is available on its natural history or routes of transmission, although it can be transmitted parenterally. We investigated the prevalence of persistent infection of HGV and HCV in patients exposed to non-virus-inactivated pooled blood products associated with transmission of HCV. METHODS: RNA was extracted from the plasma of 112 patients with haemophilia and 57 with hypogammaglobulinaemia, as well as from 64 different batches of archived coagulation-factor concentrates and immunoglobulins. RNA was reverse transcribed and amplified with primers from the 5' non-coding region of HCV and HGV by a nested polymerase chain reaction (PCR). Viral RNA was quantified by titration of complementary DNA before amplification. FINDINGS: Among non-renumerated UK blood donors HGV infection (detected by PCR) was more common than HCV infection (four [3.2%] of 125 compared with 137 [0.076%] of 180658 in southeast Scotland). Testing of batches of factor VIII and factor IX concentrates prepared without viral inactivation procedures showed high frequencies of contamination with HGV (16 of 17 factor VIII batches positive; six of six factor IX batches positive), with no difference between renumerated and non-renumerated donors. However, among 95 haemophiliacs who had received non-virus-inactivated concentrates, 13 (14%) were positive for HGV compared with 79 (83%) who were positive for HCV. Two of 37 recipients of long-term immunoglobulin replacement therapy were positive for HGV. Virus inactivation of blood products substantially reduced or eliminated contamination by HGV RNA sequences. INTERPRETATION: Despite the extremely high level of HGV contamination of non-virus-inactivated blood products, their use was not associated with high rates of persistent infection in recipients. The infectivity of HGV in blood products may be lower than that of HCV, or the virus may be less able to establish persistent infection in humans. Whatever the case, the high prevalence of active HGV infection in the general population remains difficult to explain.     

Serum hepatitis G virus RNA in patients with chronic viral hepatitis

OBJECTIVES: The hepatitis G virus (HGV) is a newly described flavivirus that affects a high proportion of patients with chronic viral hepatitis: our objective was to determine what role HGV might play in the course of disease. METHODS: We evaluated stored serum samples from 108 patients with chronic hepatitis B and 99 patients with chronic hepatitis C who participated in trials of alpha-interferon or ribavirin for the presence of hepatitis B virus (HBV) DNA and hepatitis C virus (HCV) RNA by branched DNA and for the presence of HGV RNA by polymerase chain reaction (PCR), using primers from the NS5 region of the genome. RESULTS: Initially, 20 (19%) patients with hepatitis B and 11 (11%) with hepatitis C had HGV RNA in their serum. Patients with and without HGV infection were similar with regard to clinical features, laboratory tests, and hepatic histology. HGV RNA levels fell during interferon therapy and became undetectable in those receiving the highest doses; however, HGV RNA levels returned to pretreatment values when therapy was stopped. With ribavirin therapy, HGV RNA levels did not change. Two- to 12-yr follow-up serum samples were available from 17 initially HGV RNA-positive patients, of whom only 10 (59%) were still positive. CONCLUSIONS: HGV infection is common among patients with chronic hepatitis B and C but has little effect on the short-term course of disease or response to therapy. HGV RNA levels are suppressed but not eradicated by alpha-interferon and are unaffected by ribavirin treatment. Spontaneous loss of HGV RNA occurs over time in a proportion of patients.     

Prevalence, incidence, and clinical characteristics of hepatitis G virus/GB virus C infection in Scottish blood donors

The prevalence, incidence, clinical features, and natural history of hepatitis G virus (HGV) or GB virus C (GBV-C) were investigated in a non-remunerated blood donor population to determine its clinical significance and its impact on blood safety. Of 1020 regular blood donors, 23 (2.25%) were positive for plasma HGV/GBV-C RNA. Alanine aminotransferase levels were lower than in uninfected donors (median, 20 IU/mL; 32 IU/mL in controls; P=.015). Clinical examination produced no other evidence for hepatitis or for shared nonhepatic diseases. Fifteen of 17 donors excreted HGV/GBV-C in saliva (mean level, 8x103 copies of RNA/mL). Testing of previous donations indicated an incidence of 170-200 new infections with HGV/GBV-C per 100,000 donor-years. The absence of further clinicopathologic data and the limitations of current polymerase chain reaction-based methods for screening suggests that it is neither necessary nor practical to commence screening.     

Hepatitis G virus in the general population and in patients on hemodialysis

To determine the routes of transmission of hepatitis G virus (HGV) and the relationship between HGV and hepatitis C virus (HCV) infections, we tested for HGV RNA by polymerase chain reaction and antibody to HCV (anti-HCV) in 494 hemodialysis patients, 638 inhabitants of two HCV endemic areas, and in 400 blood donors in Japan. HGV RNA was detected in 6.9% of hemodialysis patients, in 1.4% of inhabitants, and in 0.8% of donors, and anti-HCV was detected in 39.3%, 12.4%, and 1.8%, respectively. Of HGV RNA-positive hemodialysis patients, and HGV RNA-positive inhabitants, 64.7% and 11.1%, respectively, had been given blood transfusions. The prevalences of HGV RNA and anti-HCV significantly increased with the duration of hemodialysis. Of all HGV RNA positives, 74.4% were coinfected with HCV and subjects with HGV RNA alone had normal liver function. In conclusion, HGV is transmitted by blood transfusion and within the hemodialysis unit itself. HGV does not seem to injure hepatocytes.     

Hepatitis G virus co-infection in liver transplantation recipients with chronic hepatitis C and nonviral chronic liver disease

Hepatitis G virus (HGV) is a newly described RNA virus that is parenterally transmitted and has been found frequently in patients with chronic hepatitis C infection. To determine the impact of hepatitis G virus co-infection on morbidity and mortality following liver transplantation, we measured HGV RNA by polymerase chain reaction in pre and posttransplantation sera from a cohort of patients transplanted for chronic hepatitis C and a control group of patients transplanted for nonviral causes who were negative for hepatitis C virus (HCV) RNA in serum. The overall prevalence rate of HGV RNA in transplanted patients with chronic hepatitis C was 20.7%. HGV infection was present before transplantation in 13% while it appeared to have been acquired at the time of transplantation in 7.4%. Mean serum alanine aminotransferase activity, hepatic histological activity, and patient and graft survival were similar between HGV-positive and HGV-negative patients. The prevalence rate of HGV RNA in transplanted controls was 64% (P < .01) with a significantly higher rate of acquisition of HGV infection following transplantation (53%, P < .001) when compared with patients with chronic hepatitis C. Mean serum alanine aminotransferase activity was significantly lower in the control patients with HGV infection alone following transplantation than in patients co-infected with hepatitis C (37 +/- 9 vs. 70 +/- 33 U/L, P < .01). Thus, HGV is frequently found in transplantation patients co-infected with hepatitis C although it appears to have minimal clinical impact. In patients transplanted for nonviral causes of end-stage liver disease, a high rate of hepatitis G acquisition at the time of transplantation may occur but does not appear to predispose to chronic hepatitis.