Genelabs presents data on Hepatitis G.

GOLD COAST, Australia--(BUSINESS WIRE)--Aug. 30, 1995--Genelabs Technologies, Inc. (GNLB:NASDAQ) today presented information on Hepatitis G Virus (HGV), a recently discovered hepatitis virus, at the 3rd International Meeting on Hepatitis C Virus.

HGV was recently discovered by Genelabs scientists in collaboration with researchers from the U.S. Centers for Disease Control and Prevention (CDC) and the U.S. National Institutes of Health (NIH) as part of a program to identify human pathogens responsible for causing non A - E hepatitis.

Several papers on HGV were presented as part of a symposium sponsored by one of Genelabs corporate collaborators, Boehringer Mannheim, which included discussions of the molecular cloning and analysis of HGV, the clinical significance of HGV, and transmission of HGV via blood transfusion.

HGV is a novel RNA virus belonging to the Flaviviradae family and is distantly related to Hepatitis C, another hepatitis virus. The genomic sequence of HGV was presented. Data on the clinical significance and incidence of the virus was developed using a nucleic acid based assay for HGV, and work towards a commercial assay is proceeding.

Hepatitis G is distributed globally and cases have been identified not only in Australia but also in Asia, Europe and North America. HGV is associated with acute and chronic hepatitis and active infection has been observed to persist for up to 9 years. HGV is transmissible via blood transfusion and also can be acquired by exposure to blood and blood products. HGV is present in the US volunteer blood donor population.

Genelabs has entered into two worldwide license agreements covering commercialization of diagnostic and screening assays for HGV: one with Boehringer Mannheim and one with Chiron Corporation and Ortho Diagnostic Systems, a Johnson & Johnson company.

Genelabs Technologies, Inc. is an international biopharmaceutical and diagnostics company focused on viral and immunologic disorders. The Company operates facilities located in Redwood City, California; Singapore; Taiwan, ROC; Geneva, Switzerland; and Leuven, Belgium.

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The following are related abstracts presented at the 3rd International Meeting on Hepatitis C Virus:

"Molecular cloning and analysis of HGV"

Jungsuh Kim, Genelabs Technologies,Inc., Redwood City, CA, USA

Although sensitive and specific tests for detection of the known hepatitis viruses are available, the etiology of a significant fraction of post-transfusion and community-acquired hepatitis cases has remained unclear, suggesting the existence of additional infectious agents associated with hepatitis.

Using an immunoscreening approach we identified a new RNA virus from the plasma, PNF2161, of a patient with chronic hepatitis. The new virus is provisionally designated Hepatitis G Virus (HGV). Sequence analysis suggests that the HGV genome is about 2900 amino acids which includes highly conserved motifs: a helicase motif, 2 protease motifs, and an RNA dependent RNA polymerase motif.

The HGV organization is similar to that of the viruses in the Flaviviridae family with putative structural regions at the 5'-end and non-structural regions at the 3'-end. Sequence homology analysis with other members of the Flaviviridae family reveals that the closest related viruses to HGV are other flavi-like viruses associated with hepatitis in humans and animals, GBV-A, HCV, and GBV-B.

The nonstructural genes of these viruses are related to HGV. In contrast, the sequence of the predicted HGV structural genes shows virtually no conservation to that of HCV and GBV-B, and only limited conservation to that of GBV-A. To further assess the sequence variation among different isolates of HGV, we used RT-PCR to obtain sequences from the sera of patients of widely distributed geographic regions.

Multiple sequence alignments demonstrated the 5' untranslated region is highly conserved while the regions encoding the putative structural proteins vary significantly. The identification of highly conserved regions of the HGV genome has important implications for the development of both nucleic acid-based assays and immunoassays.

"Post-transfusion Hepatitis G Virus Infection"

Harvey J. Alter Dept. Transfusion Medicine, NIH, Bethesda MD., USA

Serologic analysis of transfusion-associated non-A, non-B hepatitis (NANBH) cases with evolving tests for the hepatitis C virus (HCV) demonstrated that a proportion of cases were unrelated to HCV and suggested the existence of an additional agent(s) (non-ABC). In a retrospective analysis of prospectively followed transfusion recipients in the NIH series, 12 of 98 NANB cases could be further classified as non-ABC.

These cases could not be distinguished from hepatitis C cases based on incubation period, but they tended to be clinically milder; none were icteric compared to 30% of HCV cases and the mean peak ALT was half that of HCV infections (302 U/L vs. 708 U/L); chronic hepatitis also appeared to be less frequent. With the cloning of HGV, these 12 cases were tested and 2 (17%) showed the appearance of HGV RNA after transfusion and prior to the first ALT elevation; pre- transfusion samples were PCR negative.

An additional referred case followed the same pattern. The clinical course of these 3 cases was variable, one showing rapid recovery, another delayed recovery and the third, chronic hepatitis. HGV RNA persisted in all cases for at least one year and in one case for at least 4 years. In 2 of 2 cases where donor sera were available, an HGV positive donor was identified.

Further analysis of the NIH cohort showed that HGV was also present in 14% of recipients who had minor ALT elevations that did not reach study criteria for the diagnosis of hepatitis and in 8% of those with HCV-related hepatitis. HGV RNA was also found in 2 of 48 (4%) blood recipients who had no post-operative ALT elevations, but in none of 49 similarly followed non-transfused controls. HGV RNA was found in 13 of 769 (1.7%) donors with normal ALT and in 11 of 709 (1.5%) donors with elevated ALT.

These data suggest that: 1) HGV infection is transfusion transmitted as evidenced by the temporal relation of HGV RNA to transfusion, by the absence of HGV in non-transfused controls and by donor-recipient linkages; 2) HGV related disease is generally mild, being as frequent in those with low level ALT elevation as in those who met study criteria for hepatitis diagnosis; 3) HGV and HCV infection can be simultaneously transmitted and result in persistent coinfection; 4) HGV infection can be persistent and accompanied by chronic hepatitis; 5) the prevalence of HGV in blood donors is higher than that of HCV and unrelated to the ALT status of the donor.

"Clinical significance of HGV"

Howard C. Thomas Dept. of Medicine, St. Mary's Hospital, London, United Kingdom

A novel RNA virus tentatively designated hepatitis G virus (HGV) has been cloned and partially sequenced. The sequence of the new virus appears to have motifs which are characteristic of the Flaviviridae family. The existence of only 26% homology at the amino-acid level with the hepatitis C virus, which also belongs to the same family, suggests that this virus is distinct from HCV.

The transmission of the virus through blood transfusion and by other parenteral routes of exposure, such as through intravenous drug use, have been clearly established. From these data, it was apparent that many HGV positive patients were co-infected with HBV or HCV, presumably because of shared risk factors of infection.

It follows therefore that screening of blood donations for these viruses also removes HGV infected blood donor units (surrogate marker phenomenon) thereby reducing the incidence of HGV related PTH. The observed low incidence of residual PTH in recent years, down to 0.6% from 30% in the 1960s, may be a result of this phenomenon.

We have studied the association of HGV infection to risk factors in chronic liver disease patient groups who were not regularly exposed to blood or blood products and were not IVDUs at the time, 66% (24/36) of these patients had identifiable risk factors such as blood transfusion during surgery, previous IVDU or high risk behaviour.

In addition, it is presently unknown whether all infected patients exposed to HGV develop an ALT rise and whether a normal carrier state exists. We have therefore analysed all positive patients with HGV infection alone or dual infections with HBV or HCV, in relation to ALT level.

The majority of patients without other infections (59%) had raised transaminase levels. In general therefore, although HGV infection was indeed associated with hepatitis, almost half of the patients appeared to have normal transaminases.

Some of these may have been normal carriers as shown by the first transplant patient, who had normal enzyme levels for at least 2 years before transplantation. Transmissibility of the virus in this patient who underwent liver transplantation for end stage autoimmune liver disease was demonstrated by increased levels of viraemia and recurrent inexplicable hepatitis in the homograft presumably representing recurrent HGV infection.

Indeed, this recurrence of HGV was accompanied by higher replication rates for the virus as shown by increased viral titres.

The effect of interferon treatment on HGV replication was also studied retrospectively in patients with dual infections, and who received treatment regimens for either their HBV or HCV chronic liver disease. Although the virus appears to be sensitive to interferon whilst the patient is on treatment, all cases relapsed on cessation of therapy.

This may be related to the amount of interferon or the duration for treatment, and future studies should address these variables. Whether the presence of HGV influences the outcome of interferon treatment of other hepatotropic viruses in dual infections, remains to be established.

In conclusion HGV infection is associated with hepatitis in the majority of patients investigated. Patients with normal transaminases also exist but whether these are healthy carriers or patients at a quiescent state of their disease, only sequential studies will define.

The association of the virus with chronic liver disease and its presence in patients with dual infections due to HBV or HCV is irrefutable. Its potential role however in fulminant hepatitis and hepatocellular carcinoma remains to be investigated.

CONTACT: Genelabs Technologies, Inc.

Jungsuh Kim, Ph.D., 61-412-635-122