Correspondence
Hepatitis GB Virus C
N Engl J Med 1996; 335:1392-1394October 31, 1996
- Article
To the Editor:
Masuko et al. (June 6 issue)1 described hepatitis GB virus C (HGBV-C) infection in patients on hemodialysis, reporting a prevalence of 3.1 percent among 519 Japanese patients on hemodialysis as compared with 0.9 percent among 448 healthy blood donors.
Since HGBV-C2 and the recently described hepatitis G virus (HGV)3 could represent different genotypes of the same virus, we looked for HGBV-C/HGV in 100 patients (52 men and 48 women; mean age, 58.1±15 years) who had been on hemodialysis for a mean of 117±94 months (range, 6 to 336). Viral RNA was extracted from serum by spin chromatography (QIAamp HCV kit, Qiagen, Hilden, Germany); reverse transcription and amplification were performed by a single-tube reverse-transcription heminested polymerase chain reaction (PCR) as described previously4 with primers from the 5' untranslated region of HGBV-C/HGV. The primers were deduced from the published sequences of HGBV-C and HGV as well as from our own sequence data and were capable of amplifying all known HGBV-C and HGV sequences.
Nineteen patients (19 percent) tested positive, 14 of whom also tested positive with a commercial assay specific for HGV (HGV Primer and Capture Probe Set, Boehringer Mannheim, Mannheim, Germany). We conclude that HGBV-C/HGV is highly prevalent in our group of patients on hemodialysis, a group already characterized by a high prevalence of hepatitis C virus (HCV) infection,5 with HGV being the predominant strain.
Several factors could account for the higher prevalence of HGBV-C/HGV in our patients than in those described by Masuko et al., not the least of which is a genuinely lower risk of infection with this viral agent among Japanese patients on hemodialysis. However, as the authors point out, the primers they used were based on the HGBV-C sequence, and mismatches between that sequence and the HGV sequence could prevent the amplification of HGV or decrease the sensitivity of their assay. It is therefore possible that the prevalence they report underestimates the actual epidemiologic relevance of the infection among patients on hemodialysis.
The geographic distribution of HGBV-C and HGV is not yet known. However, HGBV-C was initially isolated from blood samples in West Africa and North America,2 and there is no evidence that it is the predominant strain in Japan. Among our patients on hemodialysis who are infected with HGBV-C/HGV, HGV is the predominant genotype in 73.6 percent of infections.
5 ReferencesMaurizio Sampietro, M.D.
University of MilanSalvatore Badalamenti, M.D.
Giovanna Lunghi, M.D.
IRCCS Ospedale Maggiore, I-20122 Milan, Italy1
Masuko K ,Mitsui T ,Iwano K , et al. Infection with hepatitis GB virus C in patients on maintenance hemodialysis. N Engl J Med 1996;334:1485-1490
Full Text | Web of Science | Medline2
Simons JN ,Leary TP ,Dawson GJ , et al. Isolation of novel virus-like sequences associated with human hepatitis. Nat Med 1995;1:564-569
CrossRef | Web of Science | Medline3
Linnen J ,Wages J Jr ,Zhang-Keck Z-Y , et al. Molecular cloning and disease association of hepatitis G virus: a transfusion-transmissible agent. Science 1996;271:505-508
CrossRef | Web of Science | Medline4
Sampietro M ,Salvadori S ,Corbetta N ,Badalamenti S ,Graziani G ,Fiorelli G . Single-tube reverse transcription and heminested polymerase chain reaction of hepatitis C virus RNA to detect viremia in serologically negative hemodialysis patients. Int J Clin Lab Res 1995;25:52-54
CrossRef | Medline5
Sampietro M ,Badalamenti S ,Salvadori S , et al. High prevalence of a rare hepatitis C virus in patients treated in the same hemodialysis unit: evidence for nosocomial transmission of HCV. Kidney Int 1995;47:911-917
CrossRef | Web of Science | Medline
To the Editor:
Since we reported the association of HGBV-C with fulminant hepatitis of unknown cause,1 there has been controversy about whether HGBV-C causes such a severe liver disease.2,3 In his editorial (June 6 issue),4 Alter claims that HGBV-C can be an innocent bystander transmitted through transfusions given after the onset of fulminant hepatitis. As the first to report the association between HGBV-C and fulminant hepatitis, we wish to clarify the relation between a history of transfusion and positivity for HGBV-C in our patients with fulminant hepatitis.
Our study now includes 63 patients with various types of viral fulminant hepatitis: hepatitis A virus (HAV) in 8, hepatitis B virus (HBV) with acute infection in 12, HBV as an acute exacerbation of the hepatitis B carrier state in 14, HCV in 13, and non-A–E virus in 16. HGBV-C RNA was detected by PCR for HGBV-C RNA1 in one patient (12.5 percent with HAV), two (16.7 percent) with fulminant hepatitis due to acute HBV infection, one (7.1 percent) hepatitis B carrier, five (38.5 percent) with HCV, and six (37.5 percent) with non-A–E. Although PCR was performed on serum collected from the patients on admission to our hospital and before any therapeutic transfusions, some patients may have received transfusions at other hospitals (60 patients were referred). The history of every patient was therefore scrutinized again in detail. The investigation revealed that the patient with HAV, one of the two patients with acute HBV infection, and the hepatitis B carrier who had positive tests for HGBV-C RNA all had a history of therapeutic transfusions in other hospitals. One with HCV and one with non-A–E fulminant hepatitis had a history of therapeutic transfusions. Thus, only some of the patients with what was formerly called non-A, non-B fulminant hepatitis associated with positive tests for HGBV-C RNA had received therapeutic transfusions before admission to our hospital.
These observations suggest that although transfusions received before the onset of fulminant hepatitis may have had some role in the disease, therapeutic transfusions received after the onset of fulminant hepatitis had only a minor role in the transmission of HGBV-C to our patients with what was formerly called non-A, non-B fulminant hepatitis.
4 ReferencesMakoto Yoshiba, M.D.
Kazuaki Inoue, M.D.
Kazuhiko Sekiyama, M.D.
Showa University Fujigaoka Hospital, Yokohama 227, Japan1
Yoshiba M ,Okamoto H ,Mishiro S . Detection of the GBV-C hepatitis virus genome in serum from patients with fulminant hepatitis of unknown aetiology. Lancet 1995;346:1131-1132
CrossRef | Web of Science | Medline2
Kuroki T ,Nishiguchi S ,Tanaka M ,Enomoto M ,Kobayashi K . Does GBV-C cause fulminant hepatitis in Japan? Lancet 1996;347:908-908
CrossRef | Web of Science | Medline3
Sallie R ,Shaw J ,Mutimer D . GBV-C virus and fulminant hepatic failure. Lancet 1996;347:1552-1552
CrossRef | Web of Science | Medline4
Alter HJ . The cloning and clinical implications of HGV and HGBV-C. N Engl J Med 1996;334:1536-1537
Full Text | Web of Science | Medline
To the Editor:
We treated a patient infected with HGV who became seronegative on PCR after treatment with interferon alfa-2a for chronic myeloid leukemia. The 35-year-old man was given a diagnosis of Philadelphia chromosome–positive chronic myeloid leukemia in July 1986. In July 1987 he underwent an allogeneic bone marrow transplantation from an HLA-identical sibling donor. In November 1992 a hematologic relapse occurred, and a second bone marrow transplantation from the same donor was performed in April 1994. Mild veno-occlusive disease of the liver developed after the second transplantation, and one year later (May 1995) a cytogenetic relapse was documented. In June 1995 the patient started treatment with interferon alfa-2a for cytogenetic relapse, with no response, and in November 1995 he received leukocyte infusions from his bone marrow donor while still being treated with interferon alfa-2a (3 million U per day five days a week). He had a complete cytogenetic and molecular response (amplification of transcripts of bcr-abl). Liver-biopsy–proven graft-versus-host disease developed after the donor leukocyte infusions and was successfully treated with corticosteroids. Stored serum samples from the patient were available beginning in March 1994. The patient was positive for HCV RNA (genotype 1b) before the second bone marrow transplantation; this infection was probably acquired during the first transplantation. We also evaluated whether HGBV-C RNA was present in the samples examined (Table 1Table 1
Results of Assays for HCV RNA and HGBV-C RNA after a Second Bone Marrow Transplantation for a Cytogenetic Relapse of Chronic Myeloid Leukemia and during Treatment with Interferon Alfa-2a.). As shown in Table 1, after treatment with interferon alfa-2a HGBV-C RNA disappeared from the circulation while HCV RNA persisted in serum, although a decrease in the number of copies was observed (0.051×106 copies per milliliter on day 370 after bone marrow transplantation, as compared with 0.017×106 copies per milliliter on day 642).This case illustrates the complexity of evaluating liver dysfunction after bone marrow transplantation, since different factors can be at work simultaneously — in our patient, HCV, HGBV-C, and graft-versus-host disease. Nevertheless, although no role for HGBV-C in liver disease could be established in this patient, we found that treatment with interferon alfa-2a can affect HGBV-C infection status and that the response of patients coinfected with HCV and HGBV-C to interferon alfa-2a may be different.
José F. Tomás, M.D.
Hospital Universitario La Princesa, 28006 Madrid, SpainJavier Bartolomé, Ph.D.
Vicente Carreño, M.D.
Fundación Jimenez Díaz, 28040 Madrid, SpainAuthor/Editor Response
The authors reply:
To the Editor: Dr. Sampietro and his colleagues found HGBV-C RNA or HGV RNA in 19 percent of their 100 patients on hemodialysis in Italy, which represents a much higher frequency than the 3.1 percent we found in our 519 Japanese patients.1 They expressed concern about the nonstructural region 3 (helicase) primers we used, suggesting that we might have missed some HGBV-C RNA isolates with a sequence similar to that of HGV RNA. We have tested serum from the same 519 patients for HGBV-C RNA by PCR with nested primers deduced from the 5' untranslated region,2 and detected HGBV-C RNA in 18 (3.5 percent), including 2 additional patients missed on PCR with helicase primers. Hence, our lower frequency of detection of HGBV-C RNA is not due to the use of helicase primers.
There appear to be at least three genotypes of HGBV-C/HGV that are separated by an evolutionary distance of 0.1 from each other. One is represented by HGBV-C (G1) and another by HGV (G2). The majority of HGBV-C/HGV isolates from Japan belong to a third genotype (G3). HGBV-C/HGV RNA can be detected with equal sensitivity by PCR with helicase primers1 or PCR with the 5' untranslated region.2 We therefore consider that PCR with helicase-region primers would not be as genotype-dependent as Sampietro et al. suggest.
In other reports, HGBV-C/HGV infection has been detected in 20 percent of patients on hemodialysis in the United States and Europe,3 58 percent of those in France,4 and 55 percent of those in Indonesia.5 Hence, patients on maintenance hemodialysis are at increased risk for HGBV-C/HGV infection, but the prevalence rates differ widely from country to country.
Transfusion and patient-to-patient spread may be responsible for the high prevalence of HGBV-C/HGV RNA in patients on hemodialysis, and they can be distinguished by sequencing a part of the HGBV-C/HGV genome.1 Infection transmitted by transfusion should result in unique sequences that differ substantially among patients, whereas identical sequences would be expected with nosocomial infection within a dialysis unit. Perhaps Dr. Sampietro and his colleagues would like to determine the prevalence of HGBV-C/HGV RNA in the general population in Italy and compare sequences among isolates from their patients to learn more about the reasons for the high prevalence they observed.
5 ReferencesKazuo Masuko, M.D.
Masuko Hospital, Aichi-Ken 453, JapanHiroaki Okamoto, M.D.
Makoto Mayumi, M.D.
Jichi Medical School, Tochigi-Ken 329-04, Japan1
Masuko K ,Mitsui T ,Iwano K , et al. Infection with hepatitis GB virus C in patients on maintenance hemodialysis. N Engl J Med 1996;334:1485-1490
Full Text | Web of Science | Medline2
Shimizu M, Osada K, Okamoto H. Transfusion-transmitted hepatitis GBV-C following open heart surgery. Transfusion (in press).
3
Alter HJ . The cloning and clinical implications of HGV and HGBV-C. N Engl J Med 1996;334:1536-1537
Full Text | Web of Science | Medline4
de Lamballerie X ,Charrel RN ,Dussol B . Hepatitis GB virus C in patients on hemodialysis. N Engl J Med 1996;334:1549-1549
Full Text | Web of Science | Medline5
Tsuda F ,Hadiwandowo S ,Sawada N , et al. Infection with GB virus C (GBV-C) in patients with chronic liver disease or on maintenance hemodialysis in Indonesia. J Med Virol 1996;49:248-252
CrossRef | Web of Science | Medline
- Citing Articles (11)
Citing Articles
1
Ravinder K. Wali, Jay R. Kaluvapalle, Alfred K. Cheung. 2008. Complications Associated with Hemodialysis. , 894-912.
CrossRef2
M. A. Sathar, P. N. Soni, D. York. (2000) GB Virus C/Hepatitis G Virus (GBV-C/HGV): still looking for a disease. International Journal of Experimental Pathology 81:5, 305-322
CrossRef3
Magdalena Robaczewska, Lucyna Cova, Anna J. Podhajska, Bogdan Falkiewicz. (1999) Hepatitis G virus: Molecular organization, methods of detection, prevalence, and disease association. International Journal of Infectious Diseases 3:4, 220-233
CrossRef4
E. Schulte-Frohlinde, S. Schmolke, W. Reindl, G. Schatzle, J. Scherf, K. F. Kopp, M. Classen, V. Schluter. (1998) Significance of antibodies to the recombinant E2 protein of hepatitis G virus in haemodialysis patients. Journal of Viral Hepatitis 5:5, 341-344
CrossRef5
Isa K. Mushahwar, Jane N. Zuckerman. (1998) Clinical implications of GB virus C. Journal of Medical Virology 56:1, 1-3
CrossRef6
José L. Rodríguez Agulló, Avelina Suárez, José M. Ladero, Gustavo López-Alonso, Juan J. Picazo, Manuel Díaz-Rubio. (1998) Hepatitis G virus infection in Spanish patients with hepatocellular carcinoma. Liver 18:4, 255-258
CrossRef7
Alison Casteling, Ernie Song, John Sim, Duane Blaauw, Anthon Heyns, Rose Schweizer, Larry Margolius, Eben Kuun, Steve Field, Barry Schoub, Eftyhia Vardas. (1998) GB virus C prevalence in blood donors and high risk groups for parenterally transmitted agents from Gauteng, South Africa†. Journal of Medical Virology 55:2, 103-108
CrossRef8
C. Micha Nübling, Heike Bialleck, Andreas J. Fürsch, Inge Scharrer, Wolfgang Schramm, Erhard Seifried, Urban Schmidt, Schlomo Staszewski, Johannes Löwer. (1997) Frequencies of GB virus C/hepatitis G virus genomes and of specific antibodies in German risk and non-risk populations. Journal of Medical Virology 53:3, 218-224
CrossRef9
KUNIO OKUDA, TATSUO KANDA, OSAMU YOKOSUKA, HARUYUKI HAYASHI, KAZUO YOKOZEKI, YOSHIO OHTAKE, YASUBUMI IRIE. (1997) GB virus-C infection among chronic haemodialysis patients: Clinical implications. Journal of Gastroenterology and Hepatology 12:11, 766-770
CrossRef10
Klaus Stark, Christian G. Meyer, Michael Tacke, Anke Schwarz, Claudia Braun, Daniela Huzly, Alfred M. Engel, J??rgen May, Ulrich Bienzle. (1997) HEPATITIS G VIRUS RNA AND HEPATITIS G VIRUS ANTIBODIES IN RENAL TRANSPLANT RECIPIENTS. Transplantation 64:4, 608-612
CrossRef11
XH. Zhang, H. Shinzawa, L. Shao, M. Ishibashi, K. Saito, S. Ohno, N. Yamada, H. Misawa, H. Togashi, T. Takahashi. (1997) Detection of hepatitis G virus RNA in patients with hepatitis B, hepatitis C, and non-A-E hepatitis by RT-PCR using multiple primer sets. Journal of Medical Virology 52:4, 385-390
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