Hepatitis G Virus Infection: A Work in Progress

Annals of Internal Medicine, 1 November 1996. 125:772-773.

Before the Hepatitis C virus (HCV) was identified in 1989, there was speculation about the existence of more than one blood-borne viral agent causing non-A, non-B hepatitis (1). This speculation has continued and is supported by evidence of several unexplained hepatitis-associated syndromes, including cryptogenic hepatitis and cirrhosis, fulminant hepatic failure of unknown cause, and aplastic anemia. None of these syndromes is clearly linked to any of the known hepatitis viruses. Thus, great interest was generated when separate groups of investigators announced the discovery of new hepatitis viruses in 1995 (2-4). Both discoveries were made by industry-based investigators who collaborated with researchers at academic and government institutions.

Researchers at Abbott Laboratories isolated three viral agents from the serum of a tamarin that was inoculated with serum from a surgeon who had contracted hepatitis and had been studied more than 20 years ago (2, 3, 5). Because this surgeon’s initials were GB, the researchers named the viral isolates after him as follows: GBV-A, GBV-B, and GBV-C. They found that GBV-A and GBV-B were probably tamarin agents incidentally infecting the animals used for inoculating the original GB serum and that GBV-C was the most likely viral hepatitis candidate in humans. At about the same time, researchers at Genelabs Technologies, Inc., announced that they, too, had discovered a new hepatitis virus, isolated from the serum of a patient with community-acquired non-A, non-B hepatitis (4). This patient was initially thought not to be infected with HCV; more sensitive second-generation assays then showed that the patient had antibodies to HCV in serum. The patient was probably dually infected. Genelabs tentatively called its isolate Hepatitis G virus (HGV).

The full genomic sequences of these two viral isolates have now been determined. Both are positive-stranded RNA viruses. Remarkably, their nucleotide sequences are almost identical, indicating that they represent the same organism. Their overall genomic organization is similar to that of HCV and other members of the Flavivirus family. Hepatitis G virus and GBV-C have 29% amino acid homology with HCV, indicating that they are distinct agents and not just serotypes of HCV. Similarly, they have 48% amino acid homology with GBV-A and 28% homology with GBV-B. This finding suggests that HCV and HGV are the first of a series of related viruses that until recently have escaped detection.

Diagnosis of HGV infection currently depends on the use of polymerase chain reaction (PCR) to detect viral RNA in serum or other infected fluids or tissues. Attempts to develop an antibody detection system suitable for diagnosis have thus far been unsuccessful. Although PCR is very sensitive, its exact sensitivity and specificity are not yet known. If anything, the use of PCR may underestimate the prevalence of HGV infection, particularly in persons who have recovered from that infection or are not currently viremic. the prevalence of HGV infection in various populations. Studies from the Centers for Disease Control and Prevention have found that among patients in the United States with newly diagnosed non-A, non-B hepatitis, approximately 18% were positive for HGV RNA (Alter HJ. Personal communication). Most of these patients (approximately 80%) were also infected with HCV. This close association with HCV is confirmed by the finding that approximately 10% to 15% of patients with chronic Hepatitis C have HGV RNA in serum. However, several studies have found that fewer than 20% of patients with cryptogenic cirrhosis or other forms of chronic hepatitis of unknown cause appear to be infected with HGV. It seems that HGV is not the agent primarily responsible for fulminant non-A, non-B hepatitis because no more than 40% of patients tested have HGV RNA in serum. In addition, some studies found no cases of HGV positivity in patients with fulminant hepatitis. No information is yet available on HGV infection in other extrahepatic syndromes associated with HCV infection, such as cryoglobulinemia, glomerulonephritis, or non-Hodgkin B-cell lymphoma. The prevalence of HGV infection in the general population is not known, but preliminary estimates indicate that as many as 1.6% of volunteer blood donors are seropositive for HGV RNA (Alter HJ. Personal communication).

Hepatitis G virus is clearly a transmissible agent that may be spread in the same manner as other conventional blood-borne viral agents. Studies of recipients of blood transfusion have documented the appearance of HGV RNA after transfusion of blood or blood products in patients previously negative for HGV RNA (6). In these cases, the source of HGV infection could be traced to donor blood that was positive for HGV RNA. Furthermore, experimental studies have shown that HGV can be transmitted by infected serum to various nonhuman primates, including tamarins, chimpanzees, and macaque monkeys. Hepatitis G virus infection also appears to be prevalent in intravenous drug users. A recent study (7) found that approximately 3% of patients receiving renal dialysis had HGV RNA, but other researchers (6) have found the prevalence in this population to be higher. In many cases, this high prevalence can be linked to blood transfusions, but the possibility of nosocomial infection in the context of dialysis cannot be excluded.

A major unresolved issue is to what extent, if at all, HGV causes hepatitis or any other disease. Because HGV and HCV infections are so closely associated, it has been difficult to tease out the effect of HGV alone. Relatively few cases of “pure” HGV infection have been studied. Hepatitis G virus infection may be associated with acute hepatitis; indeed, the surgeon GB apparently had jaundice. Chronic hepatitis characterized by elevated serum aminotransferase levels may also occur, but chronic infection with no evidence of hepatitis is also common. Among patients with HGV infection who develop hepatitis, liver injury appears to be no more severe and is often milder than that seen with HCV infection alone.

The study by Tanaka and colleagues in this issue (8) supports this idea. The authors studied 189 patients who had what appeared to be typical chronic Hepatitis C and found that in 21 (11%), HGV RNA was detectable in serum. This subgroup of patients did not have more severe liver disease, as assessed by measurement of serum aminotransferase levels or liver histology. Most of the patients were treated with interferon-a and had a decrease or disappearance of serum levels of HGV RNA during therapy. Two patients appeared to have sustained clearance of HGV RNA. Thus, HGV infection appears to respond interferon-a therapy.

Although much information has been learned about HGV infection in the short time since the discovery of HGV, a great deal of research must still be done to answer these important unresolved questions: 1) Can simple and reliable diagnostic tests to detect HGV infection be developed? These are needed to permit more detailed study of the epidemiology of HGV infection, including a determination of modes of transmission of HGV. 2) Does HGV infection cause any clinically significant disease? It currently seems that HGV is rarely, if ever, associated with severe liver injury. 3) Should donated blood be screened for HGV and be excluded if positive for the organism? This process may involve an unnecessary loss of large amounts of donated blood if HGV infection has no clinically significant consequences. I look forward to completion of the research in progress and hope that the research will determine whether HGV is just another virus in search of a disease or is worth a new chapter in medical textbooks.

Adrian M. Di Bisceglie,MD

St. Louis University School of Medicine

St. Louis, MO 63104

Requests for Reprints: Adrian M. Di Bisceglie, MD, Department of Internal Medicine, St. Louis University School of Medicine, 1402 South Grand Boulevard, St. Louis, MO 63104.

Ann Intern Med. 1996;125:772-773. Annals of Internal Medicine is published twice monthly and copyrighted © 1996 by the American College of Physicians.

References

1. Alter HJ. Transfusion-associated non-A, non-B hepatitis: the first decade. In: Zuckerman AJ, ed. Viral Hepatitis and Liver Disease. New York: Liss; 1988:537-42

2. Simons JN, Pilot-Matias TJ, Leary TP, Sawson GJ, Desai SM, Schlauder GG, et al. Identification of two flavivirus-like genomes in the GB hepatitis agent. Proc Natl Acad Sci U S A. 1995;92:3401-5.

3. Schlauder GG, Dawson GJ, Simons JN, Pilot-Matias TJ, Gutierrez RA, Heynen CA, et al. Molecular and serologic analysis in the transmission of the GB hepatitis agents. J Med Virol. 1995;46:81-90.

4. Linnen J, Wages J Jr, Zhang-Keck ZY, Fry KE, Krawczynski KZ, Alter H, et al. Molecular cloning and disease association of Hepatitis G virus: a transfusion-transmissible agent. Science. 1996;271:505-9.

5. Deinhardt F, Holmes AW, Capps RB, Popper H. Studies on the transmission of human viral hepatitis to marmoset monkeys. I. Transmission of disease, serial passages, and description of liver lesion. J Exp Med. 1967;125:673-87.

6. Alter HJ. The cloning and clinical implications of HGV and HGBV-C [Editorial]. N Engl J Med. 1996;334:1536-7.

7. Masuko K, Mitsui T, Iwano K, Yamazaki C, Okuda K, Meguro T, et al. Infection with Hepatitis GB virus C in patients on maintenance hemodialysis. N Engl J Med. 1996;334:1485-90.

8. Tanaka E, Alter HJ, Nakatsuji Y, Shih JW, Kim JP, Matsumoto A, et al. Effect of Hepatitis G virus infection on chronic Hepatitis C. Ann Intern Med. 1996;125:740-3.