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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.
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