Hepatitis C Information Central

IDENTIFICATION OF A NEW TRANSMISSIBLE VIRAL AGENT ASSOCIATED WITH VIRAL HEPATITIS OF UNKNOWN ETIOLOGY (NANE HEPATITIS)

DiaSorin Inc. , July 20, 1999

Today a significant number of annual cases of viral acute and chronic hepatitis/cirrhosis – conservatively estimated at 300,000 worldwide – cannot be attributed to the known viruses A, B, C, D and E. As a consequence, major efforts have been undertaken toward the discovery of new hepatitis viruses that could be linked to non-A / non-E (NANE) hepatitis. To that end, we wish to confirm that the DiaSorin Biomolecular Research Center in Brescia, Italy under the direction of Dr. Daniele Primi has discovered a new family of viruses that appear to be responsible for most of those cases of viral hepatitis of unexplained origin.

The discovery of hepatitis C virus (HCV) in 1989 and of hepatitis E virus (HEV) in 1990 fostered the belief that virtually all cases of viral hepatitis would be attributable to the known hepatitis agents. Despite the development of very sensitive assays to detect viral proteins, antibodies to these proteins, or viral nucleic acids, 10-20% of both acute community-acquired hepatitis and transfusion associated hepatitis remained unexplained. After exclusion of known viruses and rigorous application of criteria to exclude drug exposure, alcohol abuse, autoimmune diseases and other conditions that cause liver damage, this evidence strongly suggests that other viral agents may be responsible for these cases of NANE.

In the past few years two newly discovered viral agents, named HGV and TTV, have been proposed to be responsible for transmission of NANE hepatitis. Several independent studies, however, have cast doubt on the pathogenicity of these agents. Data from transfusion recipients demonstrated, in fact, that the rates of HGV and TTV infections are fairly similar in persons who did and did not develop hepatitis.

We recently amplified, from the plasma of an HIV infected intravenous drug user (IVDU) patient, a novel nucleotide sequence that did not match with any of the sequences contained in the available data bank. The same sequence was found in a large percentage of IVDU and polytransfused patients but in a very low percentage of healthy blood donors.

The virus has been completely sequenced and PCR assays capable of selectively amplifying the virus have been developed. The incidence of these viral agents in different cohorts of highly selected patients has been studied by hybridizing the specific amplicons to selected probes using a commercially available DNA enzyme immunoassay (DEIA, DiaSorin). Preliminary studies suggested that the virus, named SEN-V NANE, could be involved in the transmission of cryptogenic hepatitis; thus additional studies have been selectively focused on assessing the prevalence of this virus in selected patient populations.

CLINICAL STUDIES

Parenteral transmission

Initially, we wanted to establish the prevalence of SEN-V virus in various cohorts of patients, including patients with no liver pathologies (105 healthy blood donors, 80 patients with gastrointestinal neoplasms and 47 patients with various autoimmune diseases) and patients at high risk to be parenterally infected (intravenous drug users and HIV patients).

table 1 shows the results of this study:

These data indicate that the virus has a low prevalence in the general population; in contrast, its prevalence is 20 fold higher in individuals at risk for parenteral infection. Of note, we observed a "dose effect," in that the prevalence of the virus increased with the amount of blood transfused (data not shown).

Chronic NANE hepatitis

Sera from 19 Japanese patients with documented chronic NANE hepatitis, originally studied by Dr. Kendo Kiyosawa, were obtained from the NIH serum bank. The sera from 25 patients with chronic liver disease not of viral origin and sera from 80 patients with documented HBV and HCV infection were used as controls.

table 2 shows the result of this study:

PBC: primary biliary cirrhosis

PSC: primary sclerosing cholangitis

These data demonstrate that the virus was detected in a high proportion of patients with chronic NANE hepatitis, in a moderate proportion of patients with hepatitis B and C, and thus far in no patients with non-viral liver disease.

That a significant proportion of HBV and HCV patients was positive for the SEN-V virus probably reflects co-infection of SEN-V with other hepatitis viruses through common routes of transmission. Whether the presence of the SEN-V virus in these patients modifies their clinical course or response to treatment remains to be evaluated.

SEN-V NANE causes post-transfusion hepatitis

Serum samples were obtained from donors in the NIH donor base and from recipients who were enrolled in prospective studies of transfusion associated hepatitis conducted by Dr. Harvey Alter at the NIH.

Three cohorts were examined for SEN-V prevalence. They included 49 patients who had heart surgery but did not require transfusions, nor develop hepatitis; 50 patients who were transfused and did not develop hepatitis; and 12 patients who developed transfusion associated NANE hepatitis. All samples had been stored at –70C before testing for SEN-V DNA.

table 3 shows the results of this study:

1. There is virtually no nosocomial transmission of the SEN-V virus, as evidenced by its low frequency in patients who were not transfused.
2. The SEN-V virus is the likely cause of NANE hepatitis associated with blood transfusion in that 83% of those who developed NANE hepatitis had molecular evidence for a new SEN-V infection following transfusion.

In conclusion, our data document that a novel virus, provisionally named SEN-V, most likely causes acute and chronic hepatitis, probably accounting for the majority of the cases of NANE hepatitis. This virus is parenterally transmitted, and therefore, its spread could be controlled by appropriate screening of blood and blood products. In addition, this virus appears capable of co-infecting patients who have other types of viral liver disease raising the possibility that it may aggravate their clinical course and/or their response to treatment.

© Copyright 1998, DiaSorin Inc.

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