Coinfections with hepatitis g and/or c virus in hepatitis B-related chronic liver disease

Concurrent infections with HGV and/or HCV (HGV/HCV) were investigated in 196 patients with HBV-related chronic liver disease (115 chronic hepatitis, 31 liver cirrhosis, 50 hepatocellular carcinoma), and in 100 HBsAg carriers. Coinfections were detected in 18 (9.2%) patients with HGV (10) or HCV (5) or both agents (3), but in none of the HBsAg carriers. Patients with coinfection were more frequently exposed to blood transfusions (55.6% vs 5.6%) and also were more commonly anti-HBe positive. Serum levels of HBV-DNA were lower in patients with HCV coinfection than in those coinfected with HGV. Interferon was administered to 39 patients with chronic active hepatitis including 7 patients with HGV/HCV coinfection. Sustained clearance of HBV-DNA was observed in 10 (25.6%) patients who were solely infected with HBV. These patients were significantly younger and had much lower histological scores than non-responders. Patients with HCV coinfection had significantly higher pre-treatment histological scores than those without HCV. After interferon treatment, a significant reduction in histological scores was observed in all patients except those coinfected with HGV/HCV. None of the 7 patients with coinfection had sustained clearance of HBV-DNA or HCV-RNA, and only one had cleared HGV-RNA. These results suggest that parenteral exposure is a risk factor for HGV/HCV coinfection in chronic HBV infection. HGV infection shows no significant impact on chronic HBV infection. HCV coinfection appears to inhibit HBV replication, but causes more severe chronic hepatitis and increases resistance to interferon therapy.     

A new hepatitis C virus-like flavivirus in patients with cryptogenic liver disease associated with elevated GGT and alkaline phosphatase serum levels

Summary. The intriguing co-infection of two flaviviruses (GBV-A and GBV-B) in tamarins and the recent discovery of another flavivirus (GBV-C/HGV) in humans raises the question of the relations between hepatitis C virus (HCV) and GBV-C/HGV. To address this issue the sera of 285 patients with liver disease (102 patients with cryptogenic and 183 with known forms of chronic liver disease) and 19 patients without liver disease were tested for HGV-RNA. GBV-C/HGV-RNA was detected by RT-PCR using primers encompassing 5'NC and NS5 regions and hybridization with specific biotinilated and radiolabelled probes. GBV-C/HGV RNA was found in 11 of 20 (55%) acute hepatitis C patients, in 13 of 117 (11.1%) patients with chronic hepatitis C, in 11 of 27 patients with a liver transplant (40.7%), one of 19 (5.3%) patients with chronic HBV infection, 15 out of 102 (14.7%) patients with cryptogenic liver disease and two out of 19 patients with inflammatory bowel disease. In cryptogenic patients, elevated serum gammaglutamyl transpeptidase (GGT, higher than twice the normal values) and alkaline phosphatase (ALP, above normal values) levels were significantly associated with GBV-C/HGV-RNA infection ( P <0.001). In conclusion GBV-C/HGV appears to be transmitted in humans by blood exposure and to be associated with liver disease in HCV co-infected patients and in a minority of patients with cryptogenic disease. The virus is only occasionally pathogenic for the liver and when liver damage is present; the association with the combined elevation of GGT and APH serum levels might represent a specific feature of the liver tropism of the agent.     

Hepatitis G virus infection in Japanese haemophiliacs

The recently identified hepatitis G virus (HGV) (also known as GB virus-C) has been considered as a blood-transmissible agent. As many haemophiliacs have risk factors for infectious agents, to clarify the frequency of HGV infection is important. HGV-RNA was investigated in 77 Japanese haemophiliacs who had been treated with nonvirus-inactivated concentrates derived from pooled plasma. Detection of HGV-RNA was performed with a nested RT-PCR that recognizes the 5'-NCR of the HGV genome. HGV-RNA was detected in 19 (24.7%), including four (21.0%) infected with HGV alone, 12 (63.2%) co-infected with HCV and three (15.8%) who were HBV carriers. The patients infected with HGV alone showed a normal ALT level of 18.7 ± 4.1 IU L⁻¹. Most (36/37, 97.3%) of the patients with abnormal ALT levels had HCV-RNA. Patients infected with HCV alone or co-infected with HCV and HGV showed higher ALT levels of 108.8 ± 90.2 IU L⁻¹ ( n = 39) and 67.6 ± 62.6 IU L⁻¹ ( n = 11), respectively. However, there was no significant difference ( P = 0.16) in ALT levels between HCV infection alone and HCV/HGV co-infection. On the other hand, four of the patients who could be followed over 10 years showed HGV-RNA persistently. In two who underwent liver biopsy, the histological evidence showed no definitive fibrotic and necro-inflammatory changes. These results indicate that HGV infection has frequently occurred in haemophiliacs. It is possible that HGV infection does not cause aggressive hepatitis with elevated ALT levels, and that co-infection with HGV may not aggravate hepatitis caused by HCV.     

Influence of GB virus-C/hepatitis G virus infection on the long-term course of chronic hepatitis B

Abstract: Aims/Background: The clinical significance of GB virus-C/hepatitis G virus (GBV-C/HGV) infection in chronic hepatitis B is not well known and its role in the outcome of liver disease was investigated. Methods: HGV-RNA and antibody to HGV (anti-E2) were studied in 125 patients with chronic hepatitis B (41 with multiple hepatitis virus exposure), 82 asymptomatic HBsAg carriers and 103 healthy adults. Results: In chronic hepatitis B, HGV-RNA was more frequent in patients with HDV infection and/or anti-HCV positivity than in those without (29% vs 6%, p<0.0001), mainly in drug addicts (38%). At diagnosis the overall prevalence of any marker (HGV-RNA plus anti-E2) was similar in chronic hepatitis due to HBV alone (17%), in HBsAg carriers (16%) and in healthy adults (17%) and increased to 58% in those exposed to HDV and/or HCV. During 1–11 years of follow-up, HGV infection persisted in 70% of patients with chronic hepatitis B. About 40% of HGV persistently coinfected patients underwent sustained biochemical remission, whereas continuing disease activity was observed in 80% of patients who cleared HGV-RNA. Conclusions: In chronic HBV infection the rate of exposure to HGV is similar to that in healthy adults, except for high risk patients. Long lasting HGV coinfection or anti-E2 seroconversion did not modify the course of chronic hepatitis B.     

Hepatitis G virus infection in haemodialysis patients and its relationship with hepatitis C virus RNA positivity

A novel RNA virus designated hepatitis G virus (HGV) was identified recently in patients with acute and chronic liver disease. Since HGV may be transmitted parenterally, chronic haemodialysis (HD) patients are at increased risk for acquiring this infection. 110 chronic HD patients were studied (56 HCV-RNA and anti-HCV-positive, and 54 HCV-RNA and anti-HCV-negative). HGV-RNA and HCV-RNA were studied by RT-PCR. HCV genotype determination was applied to all 56 HCV-RNA-positive patients. 28 of 110 (25%) patients were found be HGV-RNA-positive. HCV-RNA-positive patients had higher rate of HGV-RNA positivity compared with HCV-RNA-negative patients. The HCV genotypes of HGV-RNA-positive patients were mostly 4 (48%) and 1b (33%). HGV was not linked with HBsAg positivity. While there was a significant correlation between HCV-RNA positivity and the number of blood transfusions and duration of HD, we did not observe this relationship in HGV-RNA-positive patients. These results indicate that the prevalence of HGV is high in HD patients and that HGV-RNA positivity is higher in HCV-RNA-positive patients.     

Clinical Course of Chronic Hepatitis C Virus Infection Is Not Influenced by Concurrent Hepatitis G Virus Infection

To determine the effects of hepatitis G virus(HGV) infection on chronic hepatitis C virus infection(HCV) and to evaluate HGV response to interferon, weinvestigated HGV RNA by polymerase chain reaction in 247 Japanese patients with chronic HCVinfection (166 men and 81 women; 124 had chronichepatitis and 26 cirrhosis, and 97 hepatocellularcarcinoma). HGV RNA was detectable in 22 (8.9%)patients, among whom 21 were men: this male predominance wasstatistically significant (P < 0.01). There were nodifferences in age, aminotransferase level, stage ofliver disease, HCV RNA level by competitive polymerase chain reaction, genotype, or interferonresponse to HCV RNA between patients with HCV infectionalone or with HCV/HGV coinfection. Sustained eliminationof HGV RNA was found in 28.6% of the 14 treated patients with HCV/HGV coinfection. In the 14 treatedpatients, sustained elimination of both viruses was seenin two, HCV alone was eliminated in two, and HGV alonewas eliminated in two. Aminotransferase level improvement by interferon treatment wasassociated with clearance of HCV, but not of HGV. Thus,HGV infection had no apparent effects on HCV infection,and the sensitivity of HGV to interferon is comparable to but independent of HCV.     

GB virus C/hepatitis G virus in serum and liver of patients with chronic C and non B non C hepatitis: molecular and immunological aspects

GB virus C/hepatitis G Virus (HGV) is a single-stranded RNA virus that is transmitted parenteraly. This study investigates GB virus C in 62 patients with chronic hepatitis C (CHC) and non B non C hepatitis (CNBNC). The viral E2 protein was examined in the sera of the patients (using western blott assay) while viral replication in the liver was examined by detecting the negative strand of HGV-RNA and its E2 protein in liver tissue using in situ hybridization and immunohistochemical staining respectively. E2 protein was detected in 28% of patients with chronic hepatitis C and in 13.3% of patients with non B non C chronic hepatitis, while not detected in healthy blood donors (0%). HGV- E2 protein and the negative strand of HGV -RNA were detected in hepatocytes of only 3 out of the 13 examined liver biopsies from HGV infected patients (23%). The mean level of ALT in chronic HCV hepatitis patients who were +ve for HGV was significantly lower than those who were -ve for HGV. There was a significant difference between the mean value of HCV -RNA level by real time PCR in sera of hepatitis C positive patients with + ve HGV-E2 when compared with HCV patients with - ve HGV-E2 (p < 0.001). It is concluded that HGV co-infection may occur in some cases with CHC and CNBNC. Sites of replication, other than liver, are suggested as the virus was detected in liver tissue of only 23 % of cases inspite of its presence in their sera.     

PREVALENCE AND CLINICAL SIGNIFICANCE OF HEPATITIS G VIRUS INFECTION IN ADULT BETA-THALASSAEMIA MAJOR PATIENTS

The risk of polytransfused patients for hepatitis C virus (HCV) infection is likely to extend to another recently identified member of the Flaviviridae, hepatitis G virus (HGV). We investigated the prevalence of HGV in 40 adult Italian patients with transfusion-dependent thalassaemia and evaluated the clinical significance of HGV infection. HGV-RNA was detected in 9/40 patients (22.5%). HGV infection was significantly associated with HCV viraemia ( P  =0.0012), with all patients positive for HGV being also viraemic for HCV. Overall, the clinical picture of patients with HCV/HGV co-infection was not different from that of patients with isolated HCV. However, patients co-infected with both viruses had lower values of alanine-transferase ( P  =0035) and a lower titre of HCV viraemia ( P  =0042) in the absence of other evident factors which could influence the clinical expression of HCV infection. In conclusion, HGV is highly prevalent among Italian polytransfused patients. No evidence of a clinically significant pathogenic role for HGV in liver disease could be found in these patients. In a subset of cases a possible interference of HGV with HCV infection was observed.     

HGV/GBV-C in liver tissue and in sera from patients with chronic hepatitis C

Summary  Forty-eight persons (M=45, F=3; age range=20–53, mean=32.2) affected with chronic hepatitis C were tested for HGV/GBV-C RNA and HCV-RNA by nested PCR and DEIA in serum and in liver specimens to evaluate the prevalence and the impact of HGV/GBV-C coinfection in patients with chronic HCV-related hepatitis. Sera were also assayed for antibodies to HGV/GBV-C E2 protein. Serum HGV/GBV-RNA could be detected in nine (19%) patients, and anti-E2 antibodies in 22 (46%) patients. The presence of HGV/GBV-C RNA or anti-E2 antibodies was mutually exclusive. The cumulative prevalence of HGV/GBV-C infection was 65% (31/48); the majority of these patients (26/31, 84%) were intravenous drug users (IVDUs). In eight of nine patients viraemic for HGV/GBV-C, RNA positivity could be revealed even in liver specimens; these eight patients were also positive for HCV-RNA both in serum and the liver and did not exibit any specific association with HCV genotype. HGV/GBV-C RNA negative strand RT-PCR testing was negative in all of the eight liver specimens, providing little support to the hypothesis that liver represents the primary site of HGV/GBV-C replication. Moreover, patients with HGV/GBV-C and HCV coinfection were comparable to those with HCV infection alone in terms of biochemistry and liver histology.     

Liver histology in co-infection of hepatitis C virus (HCV) and hepatitis G virus (HGV)

As little is known about liver histology in the co-infection of hepatitis C virus (HCV) and hepatitis G virus (HGV), HGV RNA was investigated in 46 blood donors with hepatitis C, 22 of them with liver biopsy: co-infection HCV / HGV (n = 6) and HCV isolated infection (n = 16). Besides staging and grading of inflammation at portal, peri-portal and lobular areas (Brazilian Consensus), the fibrosis progression index was also calculated. All patients had no symptoms or signs of liver disease and prevalence of HGV / HCV co-infection was 15.2%. Most patients had mild liver disease and fibrosis progression index, calculated only in patients with known duration of infection, was 0.110 for co-infection and 0.130 for isolated HCV infection, characterizing these patients as "slow fibrosers". No statistical differences could be found between the groups, although a lesser degree of inflammation was always present in co-infection. In conclusion co-infection HCV / HGV does not induce a more aggressive liver disease, supporting the hypothesis that HGV is not pathogenic.     

HGV-RNA阳性与阴性慢性乙型肝炎患者的对比研究

目的 研究慢性乙型肝炎（ＣＨＢ）患者庚型肝炎病毒（ＨＧＶ）感染的意义。方法 ＲＴ＿ＰＣＲ法对１４６例ＣＨＢ患者血清进行了ＨＧＶ－ＲＮＡ检测,并将ＨＧＶ－ＲＮＡ阳性与阴性患者进行临床与病理学对比。结果 ＨＧＶ－ＲＮＡ阳性２３例（１５．７５％）。ＨＧＶ－ＲＮＡ阳性与阴性２肝功能等生化指标水平,肝脏病理损害程度、ＨＢＶ－ＤＮＡ阳性率均无显著性差异。５例ＨＧＶ－ＲＮＡ阳性、１６例ＨＧＶ－ＲＮＡ阴性ＣＨＢ患     

Hepatitis G virus RNA and its relation to hepatitis C infection in adult haemophilic patients

The prevalence of hepatitis C virus (HCV) infection and hepatitis G virus (HGV) RNA were studied in 50 adult haemophilic patients who had received commercial clotting factors prior to 1980. HGV RNA was detectable in 6/50 patients (12%); 49/50 (98%) had antibody to HCV and 40/49 (82%) of these were viraemic with detectable HCV RNA; 5/6 patients with detectable HGV RNA had co-existing HCV infection and viraemia. The HGV PCR products from all six patients were directly sequenced and all were shown to be similar to that of HGV but more diverse from that of GB virus C. One patient who had persistent abnormal liver function tests had detectable HGV RNA but no evidence of hepatitis B or C. The presence of HGV RNA in the absence of hepatitis B and C infection indicates that this virus is capable of independent transmission. Independent response to interferon was demonstrated in one patient with co-infection who lost HGV but not HCV after interferon therapy.     

Epidemiology and clinical aspects on hepatitis C

Hepatitis C virus (HCV) infects an estimated 170 million persons worldwide, and 2 million persons in Japan. HCV is a major cause of chronic liver diseases, especially hepatocarcinogenesis, and the number of patients with HCV-related hepatocellular carcinoma (HCC) is increasing worldwide as well as in Japan. Most patients with acute hepatitis C develop chronic hepatitis. Spontaneous disappearance of HCV in patients with type C chronic liver disease is uncommon, and it tends to progress to further advanced and more severe liver disease, ultimately to HCC over a period of 30 years in most cases. Chronic liver disease due to HCV infection is commonly associated with extrahepatic manifestation, for example cryoglobulinemia. Antiviral treatment for HCV infection with interferon alone during 24 weeks was associated with a low rate (less than 10%) of sustained virologic response (SVR), especially in patients infected with HCV genotype 1b and high HCV RNA concentration. However, combination therapy of interferon and ribavirin raises the SVR rate. More recently, pegylated interferon used for treatment of chronic hepatitis C resulted in a high SVR rate. These modalities of antiviral treatment will reduce HCC occurrence. So far, there is no HCV vaccine in spite of many efforts.     

BRIEF COMMUNICATION: Efficacy of ribavirin plus interferon α on viraemia of GB virus-C/hepatitis G virus: Comparison with interferon α alone

We investigated the efficacy of ribavirin plus interferon (IFN) α on GB virus-C (GBV-C)/hepatitis G virus (HGV) viraemia and compared it with that of interferon α 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 IFNα and three received oral ribavirin plus IFNα. 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 IFNα alone and ribavirin plus IFNα 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 IFNα and ribavirin plus IFNα may not induce a higher sustained response.     

Impact of hepatitis G virus co-infection on the course of hepatitis C virus infection before and after liver transplantation

Background/Aims: Hepatitis G virus (HGV), a new RNA virus that is parenterally transmitted, has frequently been found in patients with chronic hepatitis C (HCV) infection but its role in chronic liver disease is unknown. The purpose of this study was to determine the prevalence of HGV infection in transplantation patients infected with hepatitis C and to assess the impact of HGV co-infection on the course of HCV infection after liver transplantation.Methods: Eighty-nine liver transplantation recipients with persistent hepatitis C viremia detected by polymerase chain reaction (PCR) were evaluated. Serum samples were tested before and after liver transplantation for HGV RNA by two different PCR methods: LC^TM assay (Abbott Laboratories) and an RT-PCR procedure which we developed using the silica gel technique for extraction of the HGV RNA. E2 antibodies were detected before orthotopic liver transplantation by an EIA-test. HCV RNA was quantified by branched DNA assay, and HCV genotype was determined. A mean of nine liver biopsy specimens were examined for each patient and the severity of the lesions was compared in HCV-positive patients with or without HGV co-infection.Results: The concordance between the two HGV RNA detection methods was excellent and the reproducibility of our RT-PCR procedure was confirmed. The prevalence of pretransplantation and posttransplantation HGV infection was 11% and 19%, respectively. Pretransplantation HGV infection was positively correlated with posttransplantation HGV infection (p<0.001). Before transplantation the E2 antibodies seroprevalence was 34%. Seven patients became HGV RNA positive after transplantation, but all of them were negative for E2 antibodies. Among the patients who remained RNA negative after liver transplantation, 40% were positive for E2 antibodies (p = 0.04). Pretransplantation clinical features (except AST mean value) were not different in patients with HCV and HGV co-infection and those with HCV only. After a mean follow-up of 34 months (range: 6 to 70), (75%) patients developed histological features of recurrent hepatitis but the frequency of the occurrence of graft hepatitis was not different between HGV/HCV co-infected patients and those with HCV alone (p=0.89). The mean interval from orthotopic liver transplantation to recurrence was 12.2 months (range: 3–63), which was not different for HVG/HVC-co-infected patients and HCV-infected patients. The histological severity of posttransplantation liver disease, and the graft and patient survival were not different for patients with and without HGV co-infection.Conclusions: Our results suggest the general persistence of HGV infection after liver transplantation, but HGV co-infection did not appear to influence the posttransplantation course of HCV infection. Before transplantation the prevalence of E2 antibodies was 34%, and our data clearly indicate that E2 antibodies were protective against HGV infection.     

The clinical significance of simultaneous infection with hepatitis G virus in patients with chronic hepatitis C

OBJECTIVES: Hepatitis G virus (HGV) is a recently discovered member of the flavivirus family that has been associated with acute and chronic hepatitis. HGV infection has been reported to coexist in 10-20% of patients with chronic hepatitis C. The significance of simultaneous infection with HGV and hepatitis C virus (HCV) remains to be clarified, as do the effects on HGV of therapeutic interventions such as interferon treatment or liver transplantation. The aims of our study were: 1) to examine the frequency of HGV infection in the settings of liver transplantation and interferon therapy for hepatitis C; and 2) to compare HGV RNA levels before and after liver transplantation or interferon treatment. METHODS: Pre-treatment sera were available in 65 patients with chronic hepatitis C treated with interferon; pretransplant sera were available in 49 patients transplanted for end stage liver disease associated with chronic hepatitis C. Information collected included age, sex, risk factors for hepatitis, concurrent liver disease, patient and allograft survival, biochemical response to interferon, histological activity index, and degree of fibrosis/cirrhosis. HCV genotyping was performed by sequencing the NS-5 region. HGV quantitation was performed using a research-based branched DNA (bDNA) assay with a set of probes directed at the 5' untranslated region. RESULTS: HGV was detected in 10 of 49 patients (20%) before transplant and in 13 of 65 patients (20%) treated with interferon. There was a female predominance among HGV-positive compared with HGV-negative transplant patients (80% vs 20%; p < 0.01), but such a difference was not observed in the interferon-treated group. Hepatic iron concentration was lower in hepatic explants from patients who were HGV-positive than in those who were HGV-negative (318 +/- 145 microg/g dry weight vs 1497 +/- 2202 microg/g dry weight; p = 0.02). HCV exposure after 1980 was more common in the HGV-positive patients than in those who were HGV-negative for the entire study population (10 of 20 [50%] vs 16 of 66 [24%]; p = 0.03), as well as for the nontransplant subgroup (8 of 12 [67%] vs 12 of 39 [31%]; p = 0.03). HGV RNA levels declined at 1 yr after transplant in seven of eight patients. Among nine patients tested during or after interferon treatment, HGV RNA levels declined from pretreatment levels in all and disappeared in three. CONCLUSIONS: Among patients with chronic hepatitis C treated with either interferon or liver transplantation, the frequency of coinfection with HGV is about 20%. HGV may be a more recent virus in the US than HCV. Coinfection with HGV does not appear to affect the likelihood of response to interferon in patients with hepatitis C. Finally, HGV RNA levels appear to decline after both liver transplantation and interferon therapy, suggesting possible suppression by increased HCV replication in the former case, and a possible drug treatment effect in the latter.