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Hepatitis G

By Howard J. Worman, M. D.

In 1995 and 1996, several novel human RNA viruses were identified and partially characterized that apparently can cause acute and chronic hepatitis. These new viruses are related to, but distinct from, the flavivirus hepatitis C. Three viruses, identified by investigators at Abbott Labs, have been termed GB-A, GB-B and GB-C. GB-A and GB-B are likely tamarin viruses; GB-C can infect humans. The genomic sequences of these viruses have been determined. Another group at Genelabs Technologies has identified, and determined the complete genomic sequence of, a virus they termed hepatitis G virus (HGV). Based on genomic sequence comparisons, HGV is probably the same as GB-C. Below is an annotated list of some references published in 1995-1997 concerning the initial identification and characterization of these novel viruses. The precise role of HGV/GB-C in human disease is currently under investigation; however, most experts now feel that this virus is not responsible for clinically significant cases acute or chronic hepatitis.

Simons, J. N., Pilot-Matias, T. J., Leary, T. P., Dawson, G. J., Desai, S. M., Schlauder, G. G., Muerhoff, A. S., Erker, J. C., Buijk, S. L., Chalmers, M. L., Van Sant, C. L., and Mushahwar, I. K. 1995. Identification of two flavivirus-like genomes in the GB hepatitis agent. Proceedings of the National Academy of Sciences U. S. A. 92:3401-3405.

GB was a 34 year-old surgeon who contracted hepatitis. His serum was able to infect monkeys and the "GB agent" has been passaged in monkeys over the years. It is known to be distinct from other human hepatitis viruses (A, B, C, D, E). Using a technique called representational difference analysis, the authors of this paper isolated genetic sequences in the infectious serum of a tamarin infected with the "GB agent." Analysis shows that the "GB agent" contains two flavivirus sequences related to, but distinct from, the hepatitis C virus. These findings suggest that novel flaviviruses may cause hepatitis in man and other primates.

Simons, J. N., Leary, T. P., Dawson, G. J., Pilot-Matias, T. J., Muerhoff, A. S., Schlauder, G. G., Desai, S. M., and Mushahwar, I. K. 1995. Isolation of novel virus-like sequences associated with human hepatitis. Nature Medicine. 1:564-569.

This group of investigators at Abbott Laboratories previously identified two viruses, GB-A and GB-B, in the blood of a surgeon GB who developed acute hepatitis (see above). Other human serum samples that contained antibodies against GB-A and GB-B viral polypeptides were subjected to reverse transcription-polymerase chain reaction studies with degenerate oligonucleotide primers capable of amplifying a segment of the GB-A, GB-B and hepatitis C (HCV) genomes. Novel sequences, related to but different from GB-A, GB-B and HCV, were amplified from the sera of 12 individuals, including 4 with hepatitis. These findings suggest that a novel flavivirus, tentatively termed GB-C, may be responsible for some cases of non-A, non-B, non-C, non-D, non-E hepatitis.

Yoshiba, M., Okamoto, H., and Mishiro, S. 1995. Detection of the GBV-C hepatitis virus genome in serum from patients with fulminant hepatitis of unknown aetiology. Lancet. 346:1131-1132.

The recently isolated GB-C virus (GBV-C), which is likely the same as the hepatitis G virus (HGV), is similar to the hepatitis C virus but clearly a distinct species. This virus, along with two other recently identified viruses called GBV-A and GBV-B, have been implicated in acute and chronic hepatitis. In this study, six Japanese patients with fulminant non-A, non-B, non-C, non-D, non-E hepatitis were investigated for the presence of GBV-C genomic RNA sequences in their serum. GBV-C sequences were amplified from three of these six patients, implicating this virus as the cause of fulminant hepatitis. GBV-C/HGV may therefore be a cause of fulminant hepatitis in Japan and possibly in other parts of the world.

Aikawa, T., Sugai, Y., and Okamoto, H. 1996. Hepatitis G infection in drug abusers with chronic hepatitis C (letter). New England Journal of Medicine. 334:195-196.

The authors use reverse transcription-polymerase chain reaction to amplify the genome of the GB-C (HGV) virus from serum of intravenous drug abusers. Forty-nine male intravenous drug users with hepatitis C-associated liver disease were examined for the presence of GBV-C RNA sequences. GBV-C infection was detected in 12 (24%). Only 7% of male patients with hepatitis C-associated liver disease that did not use intravenous drugs had detectable GBV-C infection. Patients with hepatitis C are likely at increased risk for GBV-C infection and intravenous drug use may be a common vehicle for parenteral spread.

Linnen, J., Wages, J., Jr., Zhang-Keck, Z.-Y., Fry, K. E., Krawczynski, K. Z., Alter, H., Koonin, E., Gallagher, M., Alter, M., Hadziyannis, S., Karayiannis, P., Fung, K., Nakatsuji, Y., Shih, W.-K., Young, L., Piatak, M., Jr., Hoover, C., Fernandez, J., Chen, S., Zou, J.-C., Morris, T., Hyams, K. C., Ismay, S., Lifson, J. D., Hess, G., Foung, S. K. H., Thomas, H., Bradley, D., Margolis, H., and Kim, J. P. 1996. Molecular cloning and disease association of hepatitis G virus: a transfusion-transmissible agent. Science. 271:505-508.

These authors, primarily at Genelabs Technologies, present the complete genomic sequences of two isolates of a RNA virus that they call hepatitis G virus (HGV). HGV is associated with acute and chronic hepatitis. It is similar to the previously identified GB-C virus and distantly related to the hepatitis C, GB-B and GB-A viruses. A cDNA expression library was constructed from the plasma of a patient with chronic hepatitis C. Immunoscreening of the expression library with the patient's serum identified several hepatitis C virus sequences and several other sequences that were unique. From these unique sequences, an anchored polymerase chain reaction method was used to amplify overlapping clones for the entire viral genome. The virus was termed the hepatitis G virus (HGV). Using these sequences, overlapping cDNAs for HGV were also isolated from the plasma of another patient. The polyprotein sequence identities between HGV and GB-A, GB-B and a hepatitis C virus (HCV) isolate were 43.8%, 28.4% and 26.8%, respectively. HGV was 85.5% identical in nucleotide sequence and 100% identical in amino acid sequence to the corresponding portion of GB-C that has been characterized. Using reverse transcription-polymerase chain reaction, HGV sequences were identified in 13% of 38 patients with non-A-E hepatitis in the U. S. It was also identified in about 18% of patients with hepatitis C. HGV was detected in serum samples from patients in the U. S., Australia, South America and Europe. HGV was also implicated in two prospectively studied patients with post-transfusion hepatitis who were negative for HGV prior to transfusion. These findings demonstrate that HGV, a virus the same as or very similar to GB-C, is associated with acute and chronic hepatitis worldwide.

Masuko, K., Mitsui, T., Iwano, K., Yamazaki, C., Okuda, K., Meguro, T., Murayama, N., Inoue, T., Tsuda, F., Okamoto, H., Mitakawa, Y., and Mayumi, M. 1996. Infection with hepatitis GB virus C in patients on maintenance hemodialysis. New England Journal of Medicine. 334:1485-1490.

The hepatitis G virus (HGV)/hepatitis GB virus-C (HGBV-C) is a recently characterized Flavivirus that may cause acute and chronic hepatitis. In this study, 519 patients in Japan on maintenance hemodialysis were examined for the presence of serum HGV/HGBV-C RNA by reverse transcription-polymerase chain reaction. Viral RNA was detected in 16 patients (3.1%) as compared with 4 of 448 (0.9%) healthy blood donors (P<0.03). None of the 16 patients with detectable serum HGV/HGBV-C RNA had elevated serum aminotransferase activities or other evidence of clinical liver disease. Seven of the 16 patients with HGV/HGBV-C infection had concurrent hepatitis C infection and one was infected with hepatitis B. Of the 519 hemodialysis patients studied, 107 (20.6%) had detectable serum hepatitis C virus RNA but only 6 of these had abnormally elevated serum aminotransferase activities. Fifteen of the study patients (2.9%) were hepatitis B surface antigen positive. Eight patients with HGV/HGBV-C infection were studied for 7 to 16 years and in all except for one the infection was persistent. In five of these patients, HGV/HGBV-C RNA was detected after blood transfusion. Sequencing of a small portion of the viral genome showed that the nucleotide sequences of various isolates can vary up to approximately 20 percent. These results show that patients on maintenance hemodialysis are at increased risk for HGV/HGBV-C infection. HGV/HGBV-C produces persistent infections and, in maintenance hemodialysis patients, infection appears to result in minimal or no clinical liver disease.

de Lamballerie, X., Charrel, R. N., and Bussol, B. 1996. Hepatitis GB virus C in patients on hemodialysis. New England Journal of Medicine. 334:1549.

These investigators tested the serum of 61 patients on hemodialysis in France for the presence of HGV/HGBV-C RNA using reverse transcription-polymerase chain reaction. Of the 61 patients tested, 57.5 percent had detectable serum viral RNA. Only 4 of the 61 patients had elveated serum alanine aminotransferase activity and all were HGV/HGBV-C positive. None of these four had detectable serum hepatitis C virus RNA. These results show that HGV/HGBV-C infection is highly prevalent in patient on hemodialysis.

Alter, H. J. 1996. The cloning and clinical implications of HGV and HGBV-C. New England Journal of Medicine. 334:1536-1537.

In this editorial, the author reviews the identification and cloning of the hepatitis G/hepatitis GBV-C virus. He states that the previously identified GBV-A and GBV-B may be tamarin viruses and that GBV-C/HGV is a human virus. He further proposes, based on published data and unpublished data of his own group, that HGBV-C/HGV may not be a common cause of human hepatitis.

Tanaka, E., Alter, H. J., Nakatsuji, Y., Shih, W.-K., Kim, J. P., Matsumoto, A., Kobayashi, M., and Kiyosawa, K. 1996. Effect of hepatitis G virus infection on chronic hepatitis C. Annals of Internal Medicine. 125:740-743.

Hepatitis G virus (HGV) is a flavivirus related to the hepatitis C virus (HCV). In this paper, the authors retrospectively studied 189 randomly selected patients from a university hospital in Japan with chronic hepatitis C. Of these 189 patients, 21 (11%) were co-infected with HGV as determined by serum reverse transcription-polymerase chain reaction. On average, patients with serum HGV RNA were slightly younger but similar in other demographic and clinical features to those without HGV. Patients with and without HGV co-infection were infected with similar distributions of HCV genotypes. Ten of 101 patients treated with interferon-alpha for chronic hepatitis C had HGV co-infection, and the rate of sustained response to therapy in this small sample was similar to that for patients without HGV. Serum HGV RNA levels decreased during therapy with interferon-alpha in 9 patients in whom in was measured, however, in most of these patients, HGV RNA was again detectable after therapy was stopped. In summary, this retrospective analysis suggests that patients with chronic HCV and HGV co- infection do not differ from patients with only HCV infection. It also appears that HGV is sensitive to therapy with interferon-alpha.

DiBisceglie, A. M. 1996. Hepatitis G virus infection: a work in progress. Annals of Internal Medicine. 125:772-773.

This editorial is a brief and clear review on the identification of HGV/GB-C and related viruses, their epidemiology and their possible role in human disease. The editorial also contains some comments on the paper by Tanaka et al., 1996 (Annals of Internal Medicine. 125:740-743).

Alter, M. J., Gallagher, M., Morris, T. T., Moyer, L. A., Meeks, E. L., Krawczynski, K., Kim, J. P., and Margolis, H. S., for the Sentinel Counties Viral Hepatitis Study Team. 1997. Acute Non-A-E hepatitis in the United States and the role of hepatitis G virus infection. New England Journal of Medicine. 336:741-746.

and

Alter, H. J. , Nakatsuji Y., Melpolder, J., Wages, J., Wesley, R., Shih, W.-K., and Kim, J. P. 1997. The incidence of transfusion-associated hepatitis G virus infection and its relation to liver disease. New England Journal of Medicine. 336:747-754.

These two studies show that persistent infection with HGV is common in the United States. They also suggest that HGV may cause mild acute hepatitis but that it does not cause clinically significant chronic disease. Both of these studies used reverse-transcription polymerase chain reaction to detect HGV RNA in serum. In the study by M. J. Alter et al., a portion of patients reported to the Sentinel Counties surveillance system from 1982 to 1995 with acute viral hepatitis were studied. HGV RNA was detected in 4 of 45 patients with acute non-A-E hepatitis (9%), 23 of 116 with hepatitis C (20%), 25 of 100 with hepatitis A (25%) and 32 of 100 with hepatitis B (32%). The prevalence of HGV in patients with hepatitis B was significantly higher than those with hepatitis C or hepatitis non-A-E. The clinical characteristics of the acute illness were similar in patients with HGV alone and those infected with the other viruses with or without HGV. Of the 4 patients with HGV alone, 3 remained persistently positive for HGV RNA for 1 to 9 years, however, none had clinically apparent chronic hepatitis (although liver biopsies were not performed). Of the patients with both HCV and HGV infection, 87% were persistently positive for HGV RNA. The rates of chronic hepatitis C were essentially the same in patients with hepatitis C alone (60%) and those with HGV co-infection (61%). In the study by H. J. Alter et al., serum samples were collected between 1972 and 1995 from 357 transfusion recipients, 157 controls who did not receive transfusions, 500 random volunteer blood donors and 230 donors of blood received by HGV-infected individuals. Of 79 patients with transfusion-associated hepatitis, 63 (80%) were related to HCV and 3 had preexisting HCV infection and the cause of acute hepatitis could not be determined. Six of the 63 with HCV-related hepatitis had co-infection with HGV (10%). Of the remaining 13 patients, 3 had HGV alone and 10 possible infections with unidentified agents. The 3 patients with HGV alone had mild acute hepatitis and did not develop clinically apparent chronic hepatitis (although liver biopsies were not done). There were 35 HGV infections among all of the 357 transfusion recipients and only 3 had HGV as the only virus. One of the 157 controls and 7 of the 500 random blood donors also had detectable HGV (1.4%). In all instances in which a recipient had acute HGV after transfusion and samples from donors could be tested, at least one HGV-positive donor was identified. These two studies show that HGV is fairly common in the United States and that it can be transmitted by blood and blood products. HGV may cause mild acute hepatitis, but despite persistent infection, it does not appear to cause clinically significant chronic hepatitis.

Lopez-Alcorocho, J. M., Millan, A., Garcia-Trevijano, E. R., Bartolome, J., Ruiz-Moreno, M., Otero, M., and Carreno, V. 1997. Detection of hepatitis GB virus type C RNA in serum and liver from children with chronic viral hepatitis B and C. Hepatology. 25:1258-1260.

and

Kanda, T., Yokosuka, O., Ehata, T., Maru, Y., Imazeki, F., Saisho, H., Shiratori, Y., and Omata, M. 1997. Detection of GBV-C RNA in patients with non-A-E fulminant hepatitis by reverse-transcription polymerase chain reaction. Hepatology. 25:1261-1265.

and

Pessoa, M. G., Terrault, N. A., Ferrell, L. D., Kim, J. P., Kolberg, J., Detmer, J., Collins, M. L., Yun, A. J., Viele, M., Lake, J. R., Roberts, J. P., Ascher, N. L., and Wright, T. L. 1997. Hepatitis G virus in patients with cryptogenic liver disease undergoing liver transplantation. Hepatology. 25:1266-1270.

and

Fried, M. W., Khudyakov, Y. E., Smallwood, G. A., Cong, M.-E., Nichols, B., Diaz, E., Siefert, P., Gutekunst, K., Gordon, R. D., Boyer, T. D., and Fields, H. A. 1997. Hepatitis G virus co-infection in liver transplantation recipients with chronic hepatitis C and nonviral chronic liver disease. Hepatology. 25:1271-1275.

The role of the hepatitis G virus (HGV) (also known as GB-C) in human hepatitis remains unclear. These four papers published in the May 1997 issue of Hepatolgoy provide further evidence that HGV may not be a significant cause of acute or chronic liver disease. Lopez-Alcoroch et al. show that 15% of children with chronic hepatitis C or hepatitis B are infected with HGV, however, HGV co-infection does not appear to cause more severe liver disease. Kanda et al. and Pessoa et al. both show that HGV is frequently transmitted by blood transfusions to patients who either have fulminant hepatic failure or undergo orthotopic liver transplantation. However, Kanda et al. show that HGV is usually absent on initial presentation in persons with fulminant hepatic failure and Pessoa et al. showed no differences in the frequencies of post-transplantation hepatitis or graft survival in individuals with or without HGV infection. Fried et al. also show no differences in graft or patient survival in individuals who undergo liver transplantation for hepatitis C. These four papers, along with other publications (see above), suggest that HGV, although common in the blood supply, may not be major cause of hepatitis in humans.

Martinot, M., Marcellin, P., Boyer, N., Detmer, J., Pouteau, M., Castelnau, C., Degott, C., Auperin, A., Collins, M., Kolberg, J., Wilber, J., Benhamou, J.-P., and Erlinger, S. 1997. Influence of hepatitis G virus infection on the severity of liver disease and response to interferon-alpha in patients with chronic hepatitis C. Annals of Internal Medicine. 126:874-881.

In this study, Martinot et al. report on 228 patients in France with chronic hepatitis C who were retrospectively examined for HGV co-infectio. HGV co-infection was detected in 21% of all patients and 32% of those who were intravenous drug users. Serum HCV RNA levels, liver histology and response to treatment with interferon-alpha did not differ between patients with and without HGV co-infection. Loss of serum HGV RNA did not correlate with a biochemical response whereas loss of serum HCV RNA did. These results show that HGV co-infection frequently occurs in individuals infected with HCV and that HGV does not influence the severity of liver disease or response to treatment with interferon-alpha in patients with chronic hepatitis C.

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Copyright, 1995, 1998, Howard J. Worman, M. D. All rights reserved. Printing or other reproduction is prohibited without the written authorization of Howard J. Worman.
Hepatitis G/Howard J. Worman, M. D./hjw14@columbia.edu