Correspondence
Hepatitis B Virus Infection
N Engl J Med 1998; 338:1311-1313April 30, 1998
- Article
To the Editor:
In his review of hepatitis B virus (HBV) infection, Lee (Dec. 12 issue)1 stated that “HBV DNA can no longer be detected by any means” in patients who become negative for hepatitis B surface antigen (HBsAg) and in whom antibodies to HBsAg develop after an episode of acute hepatitis B (stage 4, or the immune stage, of HBV infection). We believe that this assertion is not in accord with recent data.2,3
It has been shown that HBV DNA can be detected by the polymerase chain reaction in serum and peripheral-blood mononuclear cells long after the clinical, biochemical, and serologic cure of acute hepatitis B.2,3 There is evidence that in these cases HBV DNA is encapsulated within intact virions and is transcriptionally active.2,3 In our study eight of eight hemodialysis staff members had detectable serum HBV DNA 13 to 21 years after an episode of acute hepatitis B. There was no biochemical evidence of liver disease, tests for HBsAg were negative, and antibodies against HBsAg had developed in six of them.2 By contrast, HBV DNA was not detected in 16 staff members without a history of hepatitis.2 HBV DNA was detected in the serum or peripheral-blood mononuclear cells in 82 percent of patients undergoing hemodialysis who had antibodies to HBsAg and hepatitis B core antigen.2 There is no explanation for the persistence of HBV DNA in the serum in the absence of liver disease. It has been suggested that antiviral T-cell responses keep the remaining virus under control.4 The importance of this finding in terms of the possibility of the reactivation of infection by immunosuppression or transmission to organ-transplant recipients is still being studied.5
5 ReferencesAlberto Ortiz, M.D.
Patricia de Sequera, M.D.
Vicente Carreño, M.D.
Carlos Caramelo, M.D.
Fundacion Jimenez Diaz, 28040 Madrid, Spain1
Lee WM . Hepatitis B virus infection. N Engl J Med 1997;337:1733-1745
Full Text | Web of Science | Medline2
Cabrerizo M ,Bartolome J ,de Sequera P ,Caramelo C ,Carreno V . Hepatitis B virus DNA in serum and blood cells of hepatitis B surface antigen-negative hemodialysis patients and staff. J Am Soc Nephrol 1997;8:1443-1447
Web of Science | Medline3
Michalak TI ,Pasquinelli C ,Guilhot S ,Chisari FV . Hepatitis B virus persistence after recovery from acute viral hepatitis. J Clin Invest 1994;93:230-239[Erratum, J Clin Invest 1994;94:905.]
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Penna A ,Artini M ,Cavalli A , et al. Long-lasting memory T cell responses following self-limited acute hepatitis B. J Clin Invest 1996;98:1185-1194
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Chazouilleres O ,Mamish D ,Kim M , et al. “Occult“ hepatitis B virus as source of infection in liver transplant recipients. Lancet 1994;343:142-146
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To the Editor:
In his excellent review, Dr. Lee indicates that people with evidence of previously healed HBV infection — the absence of HBsAg and the presence of antibodies to hepatitis B core antigen and HBsAg in serum — may still harbor HBV DNA in the liver, indicating a latent infection. These people are not considered at risk for a reactivation of infection, and indeed, this complication has not been observed in otherwise healthy persons. However, Dr. Lee does not mention that reactivation may occur in the setting of virally induced or drug-induced immunosuppression.
Indeed, reactivation occurred in several patients who were infected with the human immunodeficiency virus (HIV)1 or who were receiving chemotherapy for malignant blood conditions2 or immunosuppressive drugs for transplantation,2,3 even though protective antibodies to HBsAg were present in serum before immunosuppression. Reactivation of HBV infection was manifested by the reappearance of HBsAg in blood, together with the disappearance of antibodies to HBsAg. It is likely that immunosuppression increases the risk of reactivation because it impairs the effector functions of T cells and B cells involved in the control of HBV infection. Furthermore, glucocorticoids, which were administered to some patients, may directly stimulate HBV replication.4 Whatever the mechanisms, hepatitis developed in several patients,1-3 and some died of acute hepatic failure.1,2 Physicians caring for patients with apparently healed HBV infection should be aware of the risk of reactivation in the setting of immunosuppression.
4 ReferencesDaniel Abramowicz, M.D.
Cedric Blanpain, M.D.
Christiane Knoop, M.D.
Hôpital Erasme, 1070 Brussels, Belgium1
Vento S ,di Perri G ,Luzzati R , et al. Clinical reactivation of hepatitis B in anti-HBs-positive patients with AIDS. Lancet 1989;1:332-333
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Martin BA ,Rowe JM ,Kouides PA ,DiPersio JF . Hepatitis B reactivation following allogeneic bone marrow transplantation: case report and review of the literature. Bone Marrow Transplant 1995;15:145-148
Web of Science | Medline3
Marcellin P ,Giostra E ,Martinot-Peignoux M , et al. Redevelopment of hepatitis B surface antigen after renal transplantation. Gastroenterology 1991;100:1432-1434
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Tur-Kaspa R ,Laub O . Corticosteroids stimulate hepatitis B virus DNA, mRNA and protein production in a stable expression system. J Hepatol 1990;11:34-46
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To the Editor:
Dr. Lee states that HIV infection does not “alter the evolution of HBV infection, despite the recognized effects of HIV on the immune system.” To the contrary, we and others clearly have demonstrated that HIV infection increases the risk of a patient's becoming a chronic HBsAg carrier when HIV infection precedes HBV infection.1-3 Recently, Gilson et al.4 reported that HIV-infected patients who were chronic carriers of HBsAg had higher HBV DNA levels and a lower rate of loss of hepatitis B early antigen than did carriers who were not infected with HIV. However, viral replication, as measured by HBV DNA levels, declines over time, and therefore, studies comparing HIV-infected chronic carriers of HBsAg with uninfected carriers must take into account the duration of HBV infection. We, for example, found that high levels of HBV replication among chronic carriers of HBsAg with HIV infection were, in fact, most likely a reflection of the duration of the carrier state rather than a result of the HIV infection itself.5 Therefore, we believe that HIV infection does affect the outcome of HBV infection by increasing the probability of a chronic carrier state. However, the effect of HIV infection on HBV replication remains controversial.
5 ReferencesBeryl A. Koblin, Ph.D.
Patricia E. Taylor, Ph.D.
Cladd E. Stevens, M.D.
New York Blood Center, New York, NY 100211
Taylor PE, Stevens CE, Rodriguez de Cordoba S, Rubinstein P. Hepatitis B virus and human immunodeficiency virus: possible interactions. In: Zuckerman AJ, ed. Viral hepatitis and liver disease. New York: Alan R. Liss, 1988:198-200.
2
Monno L, Angarano G, Lo Caputo S, et al. Unfavorable outcome of acute hepatitis B in anti-HIV-positive drug addicts. In: Zuckerman AJ, ed. Viral hepatitis and liver disease. New York: Alan R. Liss, 1988:205-6.
3
Hadler SC ,Judson FN ,O'Malley PM , et al. Outcome of hepatitis B virus infection in homosexual men and its relation to prior human immunodeficiency virus infection. J Infect Dis 1991;163:454-459
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Gilson RJ ,Hawkins AE ,Beecham MR , et al. Interactions between HIV and hepatitis B virus in homosexual men: effects on the natural history of infection. AIDS 1997;11:597-606
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Koblin BA ,Taylor PE ,Rubinstein P ,Stevens CE . Effect of duration of hepatitis B virus infection on the association between human immunodeficiency virus type-1 and hepatitis B viral replication. Hepatology 1992;15:590-592
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To the Editor:
In his comprehensive review of HBV infection, Lee also discussed its satellite virus, the hepatitis D virus (HDV), and stated that “in virtually all circumstances, HDV cannot replicate in the absence of HBV, because whole virions cannot be formed.” Dr. Lee has overlooked some recent developments in research on HDV.
In both special clinical settings and experimental systems, HDV has been shown to replicate in the absence of HBV. Studying patients with terminal HDV-associated cirrhosis who were undergoing orthotopic liver transplantation, David et al.1 found an atypical hepatitis in half of them 1 to 24 weeks after transplantation. In five of nine liver grafts, the investigators found active HDV replication, but they did not find HBV, as shown by the absence of both hepatitis B core antigen in hepatocytes and detectable HBV DNA. Five to 16 months later, hepatitis returned, with prominent expression of both hepatitis B core antigen and hepatitis D antigen in the liver grafts. The early phase was caused by an isolated HDV infection (also by replication), and the later phase by recurrent HBV, which “rescued” preexisting HDV and spread the infection further. HDV infection and replication was produced by inoculating HDV alone into woodchucks that did not have helper hepadnavirus.2 As in patients who have undergone transplantation, the hepatitis D lasted for a few weeks, subsided progressively, and then disappeared within a period of six months.
In fact, HDV only needs the HBsAg to form the envelope of virions3 and to maintain transmissibility. HDV virions or genome, once within permissive cells, can replicate without the helper HBV.
3 ReferencesPei-Jer Chen, M.D., Ph.D.
Ding-Shinn Chen, M.D.
National Taiwan University Hospital, Taipei, Taiwan 100161
David E ,Rahier J ,Pucci A , et al. Recurrence of hepatitis D (delta) in liver transplants: histopathological aspects. Gastroenterology 1993;104:1122-1128
Web of Science | Medline2
Netter HJ ,Gerin JL ,Tennant BC ,Taylor JM . Apparent helper-independent infection of woodchucks by hepatitis delta virus and subsequent rescue with woodchuck hepatitis virus. J Virol 1994;68:5344-5350
Web of Science | Medline3
Wang CJ ,Chen PJ ,Wu JC ,Patel D ,Chen DS . Small-form hepatitis B surface antigen is sufficient to help in the assembly of hepatitis delta virus-like particles. J Virol 1991;65:6630-6636
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Author/Editor Response
Dr. Lee replies:
To the Editor: There are a great many subtleties to hepatitis B, and it appears that I have not met the challenge of including all of them in my review. However, each of the four groups of letter writers comments on a fine point of hepatitis B infection and points out how oversimplified our current understanding of the virus may be.
As Ortiz et al. point out, there are instances in which HBV DNA is not totally cleared from the serum when the most sensitive assays are used, even in a patient who is HBsAg-negative. For practical purposes, this is irrelevant as long as the immune system holds the virus permanently in check. Abramowicz et al. and Koblin et al. both raise the question of whether HIV alters the course of HBV infection. It certainly seems intuitively likely. My position, based on clinical data, was that a more aggressive HBV disease was not generally apparent; I agree that the likelihood of incurring the chronic carrier state is greater in those who are already infected with HIV.
I was intrigued by the data concerning hepatitis D and the comments of Chen and Chen. The comments of all the letter writers demonstrate how complex HBV infection is, how fast the field continues to move, and how difficult it is to write an absolutely complete review, covering all nuances and exceptions.
William M. Lee, M.D.
University of Texas Southwestern Medical School, Dallas, TX 75235-9151- Citing Articles (1)
Citing Articles
1
Michel P. Cooreman, Mark H. van Roosmalen, Ren
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