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.     

Predictors of GBV-C infection among patients referred for renal transplantation

The etiology of liver disease remains unknown in about 4 to 23% of dialysis patients and 10 to 16% of renal transplant recipients. A search for other causative agents of liver disease led to the discovery of the GB group of viruses. We studied the association between the presence of GB virus C (GBV-C) infection, known risk factors for parenterally-transmitted infections and history or laboratory evidence of liver disease among end-stage renal disease (ESRD) patients referred for renal transplantation to the New England Organ Bank, MA. Stored sera from patients on the renal transplantation waiting list between November 1986 and June 1990 were tested for antibody to hepatitis C virus (HCV). Sera were available in 1544 of 3243 (48%) patients, and anti-HCV was detected by ELISA3 in 287 (19%). All 287 anti-HCV positive patients formed the anti-HCV positive cohort and 286 randomly selected anti-HCV negative patients formed the anti-HCV negative cohort (573 patients overall). Additional sera were available for GBV-C RNA testing in 465 of 573 (81%) patients, and GBV-C RNA was detected by RT-PCR in 146. The overall extrapolated prevalence of serum GBV-C RNA was 29%. The prevalence of serum GBV-C RNa among anti-HCV positive patients (35%) was not significantly different from that among anti-HCV negative patients (29%; P = 0.22). In a univariate analysis, compared to patients without GBV-C RNA, patients with serum GBV-C RNA were younger [odds ratio (OR) 0.98 per year of age, P = 0.01], had a lower proportion of males (OR 0.64, P = 0.03), lower proportion of patients with diabetes mellitus (OR 0.44, P = 0.01), higher proportion of patients with a previous transplantation (OR 1.53, P = 0.04), longer duration of dialysis at the time of enrollment (OR 1.004 per month on dialysis, P = 0.03), and a higher proportion of patients with history of transfusions (OR 4.58, P = 0.01). Serum GBV-C RNA was not associated with a significantly increased OR for history of liver disease or non-A, non-B hepatitis, or elevated serum alanine aminotransferase levels. In a step-wise multivariate regression analysis, a younger age (OR 0.98 per year of age, P = 0.03), and history of blood transfusions (OR 3.89, P = 0.03) were associated with an increased OR for serum GBV-C RNA, while diabetes mellitus was associated with a decreased OR for GBV-C RNA (OR 0.47, P = 0.01). Anti-HCV was not a predictor of serum GBV-C RNA (OR 1.07, P = 0.77). The results of this study support the fact that GBV-C is a parenterally transmitted virus and shed light on the modes of transmission of GBV-C among ESRD patients. However, the association with liver disease remains to be established.     

Gradual loss of IgG antibodies against GB virus C/hepatitis G virus in a patient with AIDS

GB virus C/hepatitis G virus (GBV-C/HGV) is a positive-sense, single-stranded RNA virus belonging to the family Flaviviridae and is distantly related to hepatitis C virus (HCV). GBV-C/HGV can be transmitted by the parenteral and the sexual route. Among individuals infected with human immunodeficiency virus type 1 (HIV-1) by the sexual route, we and others have demonstrated a high prevalence of GBV-C/HGV infection. Recently, Woolley and colleagues reported that AIDS patients co-infected with GBV-C/HGV had a significantly lower mean CD4 cell count than AIDS patients without GBV-C/HGV infection, suggesting that GBV-C/HGV antibody may be lost with progression to AIDS. To our knowledge no data are available on the loss of antibody against GBV-C/HGV in AIDS patients. We now report on an HIV-infected patient who exhibited gradual loss of IgG antibodies against GBV-C/HGV, as well as HCV, with progression of HIV disease.     

GB virus C infection in patients with primary antibody deficiency

Sera from 77 patients with common variable immunodeficiency (CVID) were tested for GB virus C (GBV-C) RNA, because they are prone to unexplained chronic hepatitis, and from 28 patients with X-linked agammaglobulinemia (XLA) who have a similar primary antibody deficiency but are not prone to hepatitis. Eight CVID and 8 XLA patients were positive; 6 positive CVID and 3 XLA patients had abnormal liver enzymes, explained in 3 by either hepatitis B or C virus infection. Most patients tested had antibodies to the E2 antigen of GBV-C, apparently passively acquired from their immunoglobulin therapy. The high prevalence of GBV-C viremia in CVID and XLA patients is probably explained by their long-term exposure to blood products. Our data indicate that GBV-C does not cause chronic hepatitis in immunocompromised XLA patients and is not the cause of chronic non-B or -C hepatitis in the majority of CVID patients.     

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.     

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.     

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.     

Modeling perceived relationships between melody, harmony, and key

A small open reading frame (ORF) was found in the hepatitis delta virus (HDV) antigenomic RNA encoding a short peptide that shares structural similarity with a region of the hepatitis B virus terminal protein. Analysis of all published HDV genome sequences indicates a high degree of conservation for the small ORF. This ORF is located at the 3'-terminal region of the gene encoding the hepatitis delta antigen (HDAg). We speculated that a peptide encoded by this ORF can be represented as the C-terminal domain of a new protein called HDAg'. This protein contains almost the entire sequence represented in the small form of HDAg and a peptide as an additional 'extension' sequence at the C-terminus. Two long synthetic peptides representing the two different types of peptides encoded by the small ORF were synthesized. These peptides were used for the development of an immunoassay for the detection of antibody to the HDAg' specific domain in sera of patients with HDV infection. Among 162 serum samples analyzed, 13 were found to be positive for an antibody reactive with these synthetic peptides. These antibodies were identified in patients with HDV infections and were not found in patients infected with hepatitis B virus, hepatitis C virus, or non-A,non-B,non-C virus. Thus, these data support the identification and existence of a new antigen encoded by the antigenomic RNA of the HDV.     

Virus inactivation and prevalence of GBV-C in haemophiliacs

A new putative hepatitis virus has recently been discovered and termed GB virus C (GBV-C). We investigated the prevalence of this virus among 50 haemophiliacs treated with non-virus-inactivated clotting factor concentrates prior to 1985 and 21 haemophiliacs treated exclusively with virus-inactivated clotting factor concentrates. In the first group the prevalence of GBV-C based on PCR and ELISA was 46%. In the second group the prevalence of GBV-C was similar to that of healthy blood donors (5%). We therefore conclude that GBV-C is reliably inactivated by modern virucidal methods such as vapour heating, pasteurization and treatment with solvent/detergent mixtures.