Acute flares in chronic hepatitis B: The natural and unnatural history of an immunologically mediated liver disease

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Acute Flares in Chronic Hepatitis B: The Natural and Unnatural History of an Immunologically Mediated Liver Disease ROBERT P. PERRILLO Section of Gastroenterology and Hepatology, Ochsner Clinic and Alton Ochsner Medical Foundation, New Orleans, Louisiana

Acute flares in chronic hepatitis B are common and may be caused by a number of identifiable and potentially treatable factors. The common link for many of these exacerbation episodes is a change in the immunologic response to hepatitis B virus (HBV), and this may have no identifiable cause or be triggered by an increase in viral replication or genotypic change. It is important to keep in mind the clinical situations in which patients are at increased risk of reactivated infection and secondary exacerbations. Reactivation is frequently induced by medical treatments such as cancer chemotherapy, antirejection drugs used in organ transplantation, and corticosteroids. The immunologic flares that often result from sudden withdrawal of these medications can be life-threatening unless recognized and treated promptly with antivirals, and there is increasing experience that preemptive antiviral treatment can diminish their occurrence and improve the outcome. The experience with lamivudine and other nucleoside analogues has increased our understanding of the molecular events behind hepatitis flares that occur when chronic hepatitis B is treated with drugs that potently inhibit HBV DNA polymerase. However, not all flares are explainable by events related to HBV infection alone. Depending on the population studied, as many as 20%–30% of flares may be caused by infection with other hepatotropic viruses, and this situation may inhibit HBV replication. Proper understanding of the etiology and effective treatment of acute flares in chronic hepatitis B requires an appreciation of high-risk clinical situations, assessment of HBV replication status, and testing for other viruses when appropriate.

cute flares in chronic hepatitis B occur in association with a number of circumstances and clinical situations (Table 1). Most of these flares are not explainable by superimposed infection with other hepatotropic viruses, but instead are caused by a change in the balance between immunologic responses to hepatitis B virus (HBV) and the extent of viral proliferation. Key to the understanding of these flares is the concept that the persistent necroinflammatory changes in liver tissue that characterize chronic hepatitis B are caused by a suboptimal or

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inadequate rather than totally deficient cellular immune response to nucleocapsid antigens.1 These antigens are expressed on the surface of hepatocytes where they can stimulate cell-mediated immune responses.1 Cytolytic T cells recognize nucleocapsid antigens such as core peptides that are bound to class I human leukocyte antigens (HLA) on the membrane surface of hepatocytes.2,3 The pathogenetic importance of this cellular location of core peptides to the inflammatory response is supported by immunohistochemical studies that have shown membranous core staining of hepatocytes with active disease and predominant nuclear staining with inactive disease.4 The greater the extent of deficiency in the cellular immune response to the encoded viral antigens, the more likely the host will be immunotolerant to the virus and lack significant histologic disease. The converse is also true, that is, the more robust the immunologic response to these antigens, the greater the likelihood of substantial inflammatory changes, damage to hepatocytes, and progressive fibrosis. Acute flares in chronic hepatitis B that are not explainable by infection with other hepatotropic viruses generally represent an intensification of the immunologic response to HBV, and this may occur as a secondary response to increased levels of replicating wildtype or mutant virus or as a result of therapeutic intervention with immunologic modifiers such as interferon, corticosteroids, or cancer chemotherapy. Initiating events for the acute exacerbations in chronic hepatitis B may not be readily identifiable, and these flares are considered to be spontaneous in nature. However, in many instances precipitating factors for reactivated hepatitis B can be readily identified and, in fact, should be anticipated because this may impact on the prompt need for antiviral therapy. This review will not discuss the effect that hepatotoxic drugs and acute or chronic ethanol consumption may have on the biochemAbbreviations used in this paper: BCP, basal core promoter; CTL, cytotoxic T lymphocytes. © 2001 by the American Gastroenterological Association 0016-5085/01/$35.00 doi:10.1053/gast.2001.22461

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Table 1. Etiologic Classification of Acute Flares in Chronic Hepatitis B Spontaneous reactivation of chronic hepatitis B Reactivated hepatitis due to immunosuppressive medications Cancer chemotherapy Antirejection drugs Corticosteroids Resulting from antiviral therapy Interferon Nucleoside analogues Corticosteroid withdrawal Induced by HBV genotypic variation Precore mutant Core promoter mutant HBV DNA polymerase mutant Due to superimposed infections with other hepatotropic viruses Hepatitis A virus Hepatitis C virus Hepatitis delta virus Caused by interaction with HIV infection Reactivated hepatitis Effect of immune reconstitution therapy

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ical and clinical features of patients with chronic hepatitis B, but instead focuses on the clinical settings in which acute flares occur, the potential mechanisms involved, and how they can be appropriately evaluated and managed.

Spontaneous Flares in the Natural History of Chronic Hepatitis B The natural history of chronic hepatitis B is punctuated by spontaneous flares of the disease in which substantial elevation of serum aminotransferase levels occur. The acute exacerbative episodes are precipitated by reactivated infection, and it has been reported that low basal viremia increases markedly before an increase in serum aminotransferase level is appreciated.5 In the past, these acute flares might have been mistaken for episodes of acute viral hepatitis.6 Histologic evidence for acute lobular hepatitis superimposed on the changes of chronic viral hepatitis is frequently observed during these flares (Figure 1 ).7 Immunoglobulin M (IgM) antibody to hepatitis B core antigen (HBcAg), a marker

Figure 1. Photomicrograph of patient with chronic hepatitis B who underwent liver biopsy during an acute flare (hematoxylin-eosin; original magnification 100⫻). Section reveals marked inflammatory changes in the liver lobule that are most intense around the central veins (arrows) reminiscent of acute viral hepatitis.

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which is often diagnostic of acute viral hepatitis, also may appear at this time.5 The reasons for reactivated infection are unknown but are likely explained by subtle changes in the immunologic control of viral replication, such as occurs with herpes virus. Reactivation seems to occur more commonly in male homosexuals, patients who are infected with human immunodeficiency virus (HIV), concurrent with bacterial infections or surgery, and when there is emotional or physical stress.7,8 Pregnancy may also be a risk factor.9 Liver injury during these spontaneous exacerbations appears to be mediated by expanded numbers of T cells that are reactive to hepatitis B e antigen (HBeAg) and HBcAg that are crossreactive at the T-cell level.10,11 Measurement of lymphocyte proliferation in response to these viral antigens has shown that increased T-cell responses occur in the early phase of acute flares and subside after recovery from acute exacerbation and HBeAg seroconversion.10 T-cell responses do not diminish if the patient does not enter a clinical remission and low-level responses to S gene products are noted throughout all phases of the flare, indicating that HBcAg/HBeAg-specific T cells play an important role in acute exacerbations. Immunopathologic studies during acute exacerbations have shown that the cellular infil-

Figure 2. Schematic illustration of immunopathogenesis of hepatocyte injury during chronic hepatitis B and the factors that can contribute to acute flares. Cytotoxic T-cell recognition of the viral peptide presented by class I human leukocyte antigens (HLA-I) and binding of tumor necrosis factor (TNF) or Fas ligands (FasL) produced by inflammatory cells all contribute to hepatocyte injury. Up-regulation of T cell responses may represent a reaction to increased levels of wild-type or mutant HBV, a response to withdrawal of immunologically modifying drugs, or the independent effects brought about by infection with other hepatotropic viruses. The originating events that lead to spontaneous flares are not well understood. TNF-R, TNFreceptor; TCR, T cell receptor; ICAM-1, intracellular adhesion molecule-1; lymphocyte function associated antigen, LFA-1.

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trates at the site of necroinflammatory reaction are mainly CD8⫹ cytotoxic T lymphocytes (CTL), which are generally considered to be directed to HBcAg peptides that reside on the surface of hepatocytes.12 It has been suggested that CTL action is mediated through perforin, tumor necrosis factor, and Fas lytic pathways (Figure 2).13 The flares are potentially important clinically because they can have severe or even fatal consequences.14,15 In one study from Greece, spontaneous reactivation was believed to account for 27% of cases of apparent acute hepatitis in hepatitis B surface antigen (HBsAg) carriers, and this was associated with a mortality rate of 18%.16 An estimated 10%–30% of hepatitis B carriers experience such episodes each year.17 It is not uncommon to encounter episodes of abrupt elevation of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) to 2 to 5 times previous levels. Less intense elevations are even more frequent if patients are monitored closely.7 The frequency with which flares in serum aminotransferases occur varies among reported series, and in individuals who acquire their infection early in life, flares become more common during adulthood because of a breakdown of immunotolerance to HBV.18 Some patients experience a number of symptoms such as fatigue, nausea, and anorexia during an acute flare, but many

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patients, particularly those who have mild or early disease, remain asymptomatic.19 Occasionally signs of frank liver failure will become obvious, particularly when this is superimposed on advanced chronic hepatitis B.20 Most clinically recognizable flares occur in patients who are in the nonreplicative phase of infection (i.e., initially anti-HBe positive and serum HBV DNA negative). During these episodes, serum aminotransferase levels increase in response to the sudden reemergence of viral replication.5,7,15 HBV DNA and HBeAg are often detectable when the patient is first seen, but if the flares have been ongoing for several weeks or months, the accompanying enhancement of the immune response may lead to a failure to detect serum HBV DNA by relatively insensitive molecular hybridization assays. Frequently these flares of hepatitis precede clearance of the virus and HBeAg to anti-HBe seroconversion.7,14 Similar observations have been found in HBeAg–positive children.21 Flares also can occur in patients who are in the replicative stage of infection (i.e., already positive for serum HBV DNA and HBeAg). In these instances, HBV replication intensifies, serum HBV DNA levels increase, and biochemical deterioration occurs without subsequent loss of HBeAg.22 These episodes can be viewed as an abortive attempt at seroconversion. Flares of this nature also occur in patients who are infected with precore mutant HBV, in which case serum HBV DNA levels increase but HBeAg remains negative.5 Some patients undergo multiple episodes in which flares precede HBeAg seroconversion only to have a second flare months later in which reactivated infection occurs.7 Multiple episodes of reactivation and remission have been shown to accelerate the progression of chronic hepatitis B.7,14 Notable differences exist in the frequency of acute flares of hepatitis in Asian and Western patients. Studies in Asian patients with chronic hepatitis B have shown more serological fluctuation than that occurring in patients in the United States. In a study of 224 HBeAg– positive Asian patients, flares of disease activity occurred in 40%, but unlike the experience in Western counterparts, this seldom led to seroconversion or a sustained virologic response.23 Instead, reactivated infection subsequently developed in more than 30% of patients who lost HBeAg. In this study, the likelihood of reactivation was greatest during the period after loss of HBeAg and before detection of anti-HBe, in which instance 58% of patients experienced serologic or biochemical relapse of disease, or both. The likelihood of reactivation in patients who initially developed anti-HBe was less, but still remarkably frequent (16%). These differences in the natural

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history of infection in Asian and Western patients become important when deciding on the need for antiviral treatment. Because most flares in Western patients that result in HBeAg seroconversion last for 2– 4 months and can be followed by prolonged virologic remission, it may be desirable to serially monitor serum HBV DNA or HBeAg levels before making a decision about the need for antiviral treatment.7,24 The same may not be true for Asian patients because of the frequent hectic swings in hepatitis.

Immunosuppressive Therapy and Viral Reactivation Reactivation of HBV replication is a well-recognized complication in patients with chronic HBV infection who receive cytotoxic or immunosuppressive therapy.25 Suppression of the normal immunological responses to HBV leads to enhanced viral replication and presumably results in widespread infection of hepatocytes.26,27 On discontinuation of immunosuppressive medications such as cancer chemotherapy, anti-rejection drugs, or corticosteroids, immune competence is restored and infected hepatocytes are rapidly destroyed.28 Theoretically, the more potent the immunosuppression, the greater the level of viral replication, and the greater the clinical consequences of sudden withdrawal. The first references to the deleterious effects of immunosuppressive therapy in chronic HBV infection were published approximately 25 years ago. One study surveyed patients with myeloproliferative and lymphoproliferative diseases who were administered antineoplastic chemotherapy and were serially evaluated for anti-HBs and HBsAg titers.29 Anti–HBs titers tended to decline during treatment, and in several patients this was accompanied by reappearance of HBsAg. The titer of HBsAg increased in patients who were positive before treatment. These serologic events were often accompanied by major increments in serum aminotransferase levels.30 In a second study, 3 HBsAg-positive patients developed massive liver failure following withdrawal of cancer chemotherapy for leukemia or choriocarcinoma.30 Since these initial reports, several case series have described exacerbations of hepatitis and reactivation of hepatitis B in patients who were given chemotherapy for other malignancies, including testicular cancer, small-cell lung cancer, and neuroendocrine tumors.26 –28,31–33 Several reports have indicated that the biochemical aberrations have been most intense after withdrawal of chemotherapy.26,28,30,31 Most reports have included patients with evidence of serious or massive liver injury. Postmortem study of liver tissue has documented sparse staining of

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viral antigens suggesting that patients were in an active state of immune clearance.28,31 The majority of patients reported in the literature have been HBsAg positive before treatment, but some studies have emphasized the reappearance of this marker in patients who were initially positive for anti-HBs or anti-HBc, either alone or in combination.27,29,34 The frequency with which hepatitis in HBsAg carriers undergoing cancer chemotherapy is caused by reactivation of hepatitis B has been reported to vary from 14% to 72%.27,32 In one study, hepatic complications occurred significantly more often in HBsAg–positive patients, and the authors found that 6 of 105 patients (6%) developed fulminant hepatitis, the same proportion developed icteric hepatitis, and anicteric hepatitis occurred in 10 patients (10%).34 Reactivated hepatitis B seems to occur less commonly in HBsAg-negative patients with detectable anti-HBc or anti–HBs. In a series of 100 Chinese patients who underwent treatment for lymphoma, hepatitis caused by reactivation of HBV replication occurred in 1 of 7 (14%) anti–HBs-positive cases, 1 of 2 (50%) with anti–HBc alone, versus 13 of 18 (72%) who were HBsAg–positive before treatment.27 Although the frequency of reactivated hepatitis varies substantially between published reports, it is clear that chemotherapy administered to cancer patients who are chronic hepatitis B carriers, leads to an increased risk of liver-related morbidity and mortality.35 The same clinical events described previously also occur in patients who are administered immunosuppressive medications for organ transplantation. Shortly after the relationship between cancer chemotherapy and reactivated hepatitis B had been described, cases were noted in which reactivated infection and reappearance of HBsAg occurred in anti–HBc positive patients who underwent renal transplantation.36 Since that time, there have been numerous reports of reactivated hepatitis B in HBsAg–positive or anti–HBs/anti–HBc positive patients who have undergone bone marrow, liver, renal, heart, or lung transplantation.37– 41 In both cancer chemotherapy and organ transplantation recipients, reactivated hepatitis in HBsAg-negative patients with anti–HBc or anti– HBs is explainable by the possible latency of HBV in liver and mononuclear cells and the large extrahepatic reservoir of HBV.42– 44 The prevalence of reactivated hepatitis may be more common in patients undergoing bone marrow transplantation due to extensive immunologic conditioning before transplantation and vigorous treatment regimens for graft versus host reactions.45 In one case-control study, 13 of 18 HBsAg patients who underwent bone marrow transplantation had hepatitis

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flares caused by reactivated infection versus 0 of 24 matched HBsAg–negative controls.45 The clinical spectrum in organ recipients with reactivated hepatitis B has varied from asymptomatic anicteric hepatitis to fulminant hepatitis and fibrosing cholestatic hepatitis, a rapidly progressive form of injury associated with inordinately high levels of HBsAg and HBcAg in liver tissue.46,47 There are numerous studies of the relationship of corticosteroid therapy to chronic HBV replication. HBV contains a glucocorticoid responsive element that stimulates viral replication and transcriptional activity.48 One of the earliest observations to clinically define the relationship between corticosteroids and HBV replication was that long-term treatment resulted in increased expression of HBcAg in the serum.49 It was subsequently discovered that HBV DNA polymerase activity increased in association with a decrease of serum AST during a short course of corticosteroid therapy,50 and the opposite effect, a significant increase of AST in association with a decrease in HBV DNA polymerase, was observed after withdrawal of corticosteroid therapy.51 The clinical sequelae resulting from withdrawal of corticosteroid-based immunosuppression generally have been less dramatic than those occurring with cancer chemotherapy, but the mechanisms involved, viral activation followed by immunologic rebound in response to increased viral antigen expression, are probably very much the same. Acute flares of hepatitis B secondary to cancer chemotherapy and other immunosuppressive drugs are often detected relatively late (Figure 3). The use of antiviral treatment after major biochemical abnormalities have been detected may have relatively little effect on reducing liver injury at this time because the immunologic events causing the flare have already been activated and viral elimination is ongoing. Thus, the key to managing this problem would seem to be in anticipating its occurrence followed by early recognition and prompt antiviral treatment. Interferon is unlikely to be effective in this situation because it has a slow onset of action and limited antiviral potency.52 Moreover, interferon has the theoretical disadvantage of being further immunostimulatory. Nucleoside analogues are more ideal in that they lack direct immunologic effects and have a more rapid effect on viral replication. Table 2 depicts the clinical experience using lamivudine to treat reactivated hepatitis B in the setting of chemotherapy and organ transplantation.53– 60 In several of these reports, antiviral therapy was applied late in the course of the flare and spontaneous recovery may have been occurring. However, a few studies,56,58,60 suggest that treatment can be helpful in pre-

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Figure 3. HBV reactivation secondary to cyclophosphamide (cytoxan) and prednisone therapy. The patient was a healthy HBsAg carrier who was administered immunosuppressive therapy for glomerulonephropathy. Prednisone had been tapered over the preceding 3 months from an initial dose of 40 to 20 mg daily. Note the sharp decline in serum HBV DNA early in the lamivudine therapy because of the brisk immunologic flare. The patient required liver transplantation despite disappearance of viral replication markers (asterisk 106 Eq/mL).

venting new episodes when cancer chemotherapy is continued (Table 2). A similar protective benefit has been observed in HBsAg–positive patients who are treated with famciclovir after bone marrow transplantation.61 Controlled, clinical trials are not available to assess the value of preemptive treatment, but this approach is likely to offer greater benefit than treatment of established episodes of reactivated hepatitis.

Antiviral Therapy-Induced Flares of Hepatitis Antiviral treatment of chronic hepatitis B can be associated with flares of hepatitis in 3 ways. Flares occur during interferon therapy, in response to nucleoside analogue treatment, and following corticosteroid withdrawal. Interferon Interferon-induced flares are explainable by the immunostimulatory properties of this drug. Interferon increases T cell cytolytic activity and natural killer cell function, and flares typically occur during the second to third month of treatment (Figure 4).52,62 Several studies have emphasized the importance of these flares in securing a virologic response. In one study, an increase in serum aminotransferase levels of more than 10 times the upper limit of normal occurred in 6 of 23 patients treated with lymphoblastoid interferon, and HBsAg and HBeAg seroconversion occurred in 5 and 6 patients, respectively.63 The relative efficacy of a 16-week course of low-dose (1 million units [MU] daily) and high-dose (5 MU daily)

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interferon alfa-2b was compared in a multicenter trial conducted in the United States.64 A flare, defined as a 2-fold or greater elevation in ALT activity relative to baseline, occurred in 33% of patients given the highdose regimen versus 32% administered the low-dose regimen. Flares were associated with a higher likelihood of a virologic response, and a sustained loss of HBV DNA occurred in 54% of treated patients who demonstrated a flare as compared with 28% of those without a flare. Flares tend to be particularly common in patients who have decompensated liver disease, having occurred in 50% of patients in one series.65 Doses of interferon as low as 1 MU administered on alternate days can evoke serious flares and further hepatic decompensation in these patients, and the interferon drug should be avoided in patients with Child’s–Pugh B or C status.66 Rare fatalities have even been reported in patients with stable Child’s A cirrhosis.67 Nucleoside Analogues Acute flares during nucleoside analogue therapy were uncommonly reported prior to the description of severe liver disease because of treatment with fialuridine.68 Although changes in serum ALT levels were occasionally noted with adenine arabinoside, the neuromuscular toxicity of this agent overshadowed transient elevations in serum aminotransferase levels during treatment.69 In general, the newer nucleoside analogues such as lamivudine and famciclovir have proven to be remarkably safe drugs. However, the treatment of chronic hepatitis B with lamivudine has been associated with increases in serum aminotransferase levels to 3 to 10 times baseline values in 10% of patients.70 Flares in ALT have also been reported with famciclovir.71 Unlike the late ALT elevations that occur with interferon, flares during lamivudine treatment tend to occur within the first 4 to 6 weeks, often after there has been a major decline in serum HBV DNA. They are not associated with symptoms and tend to not be sustained despite continued treatment. Review of the phase III lamivudine trials have suggested that these flares do not occur any more commonly with this drug than they do with placebo.72 The reason for these flares during the early part of treatment is not known, but this may be caused by a restoration of T-cell responsiveness that accompanies a reduction in viral proliferation.73,74 Perhaps of greater importance are the uncommon flares in hepatitis that occur on withdrawal of lamivudine. These have been attributed to resurgence of wildtype virus and have been associated with serious clinical exacerbations in Asians with advanced liver disease.75,76 In one reported case, discontinuation of lamivudine in an

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Table 2. Lamivudine to Treat or Prevent: Reactivated Hepatitis in the Immunocompromised Host Author (year)

No. of patients

53

Jung (1998)

6

Chronic hepatitis B, all HBV DNA (⫹), 3 HBeAg (⫹)

Renal transplant

Clark54 (1998)

1

FHF in HBV DNA (⫺) HBV carrier

Chemotherapy for non–Hodgkin’s lymphoma

Ter Borg55 (1998)

1

FHF in anti–HBe (⫹)/HBV DNA (⫹) patient

Al-Taie56 (1999)

1

Maguire57 (1999)

Type of patient

Clinical Setting

Timing of initiation of lamivudine

Lamivudine regimen

8 months before to 31 months after transplantation Two months after flare was appreciated

25 to 150 mg daily for 4 to 14 months 150 mg daily for 18 weeks

Chemotherapy for choriocarcinoma

After withdrawal of chemotherapy and initiation of prednisone

150 mg daily for 3 months

FHF in anti–HBe (⫹)/HBV DNA (⫹) patient

Chemotherapy for non–Hodgkin’s lymphoma/stem cell transplant

After recovery from reactivated hepatitis

1

Submassive necrosis in anti– HBe (⫹) HBV carrier

Chemotherapy for breast cancer

Ahmed58 (1999)

1

Reactivated hepatitis B in anti–HBc/anti– HBs (⫹) patient

Chemotherapy for non–Hodgkin’s lymphoma

9th day of flare and 21 days after discontinuation of chemotherapy After acute flare of hepatitis and 6 courses of chemotherapy

150 mg bid until 16 weeks after stem cell transplant 150 mg daily for 4 months

Yeo59 (1999)

8

5 patients known to be HBV carriers, 3 not previously suspected

Chemotherapy for lymphoma and solid organ cancers

Silvestri60 (2000)

4

Reactivated hepatitis in HBeAg and HBV DNA (⫺) HBV carriers

Chemotherapy for non–Hodgkin’s lymphoma; stem cell transplant in 1

After reactivated hepatitis appreciated; following 1–4 cycles of chemotherapy After spontaneous recovery and 17 to 110 days after increase in transaminase levels noted

150 mg daily, continued throughout chemotherapy

Outcome No hepatitis flares; clearance of HBV DNA in all No further reactivation; chemotherapy withheld No further reactivation; HBV DNA (⫺) by PCR. Chemotherapy withheld No flares subsequent to transplant

Survival with negative HBV DNA

100–150 mg daily for 32 to 195⫹ days

Survival without reactivation despite continued chemotherapy Death in one patient due to reactivated hepatitis

100 mg daily until 4–6 months after last chemotherapy

Continuation of chemotherapy without subsequent flare of hepatitis

FHF, fulminant hepatic failure; bid, twice per day.

HIV-infected patient who had recovered from acute hepatitis B 18 years earlier was followed in close sequence by reappearance of HBs antigen, detectable HBV DNA, and elevated serum aminotransferase levels to more than 10 times baseline.77 Phase III trial data revealed that posttreatment ALT elevations ⱖ3 times baseline occurred in 41 (19%) of 215 lamivudine-treated patients as compared with 5 (8%) of 66 placebo-treated controls.72 After treatment there was a slight preponderance of ALT levels that were 2 or more times baseline and in excess of 500 IU/L in treated patients (14% vs. 9%) but no difference in the number of patients having 2-fold or greater ALT elevations in conjunction with a 2-fold elevation in se-

rum bilirubin (1% and 2%, respectively). It is currently unknown whether these posttreatment flares should be managed with reinstitution of lamivudine therapy, but in the author’s experience this has successfully induced a prompt decline in elevated serum HBV DNA and aminotransferase levels. Prednisone Withdrawal In 1979, it was reported that a pronounced elevation of serum AST levels and inverse decline in HBsAg titers and HBV DNA polymerase occurred in chronic hepatitis B patients following withdrawal of corticosteroids.51 These findings were reaffirmed by other investigators and lead to

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Figure 4. A typical ALT flare that occurs during treatment with interferon (rIFN alfa-2b). Peak ALT was noted after 8 weeks of treatment. This patient had a sustained loss of HBV DNA and HBeAg seroconversion.

a series of studies in which a short course of corticosteroids was used with adenine arabinoside, interferon, and more recently lamivudine, to improve the response to treatment.64,78 – 81 The apparent immune rebound following withdrawal from a 4 to 8 week course of corticosteroids may be caused by increased activation of lymphocytes that promote Th-1 immune responses at a time when there is increased viral antigen expression.81,82 Peak ALT values typically occur 4 to 6 weeks after withdrawal, and the intensity of the flare may be modifiable by increasing the initial dose and shortening the duration of corticosteroid treatment (Figure 5).83,84 In the United States multicenter interferon alfa-2b trial, 43 patients were treated with a 6-week course of prednisone followed in sequence by a 2-week nontreatment interval and 16 weeks of interferon alfa-2b.64 ALT flares occurred in 53% of these patients and this was associated with a virologic response in 50% (R. Perrillo, unpublished observations, 2000).64 The mean level for the increase in ALT was 3.4 (range, 2– 6.5) when compared with pretreatment values. Flares occurred at a mean interval of 4.9 weeks after initiation of interferon in the combined therapy group versus 7.7 weeks in a group administered the identical dose of interferon alone preceded by a placebo. These flares are generally well tolerated in patients with mild to moderate hepatitis, but serious hepatic decompensation has been reported in patients with advanced disease.50,85,86 One study reported that the relative risk of hepatic decompensation in Asian cirrhotic patients was 16 times that of noncirrhotic patients after withdrawal from a 4 to 6 week course of corticosteroids.84

Flares Caused by HBV Genotypic Variation Acute flares in chronic hepatitis B may also occur in response to HBV genotypic variation. Chronic infec-

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tion with precore mutant HBV is often associated with multiple flares of liver cell necrosis interspersed with periods of asymptomatic HBV carriage.87 Experiments in HBeAg-expressing transgenic mice have indicated that a function of the HBeAg may be to induce immunologic tolerance.88 It is possible that the absence of HBeAg in patients harboring precore mutant HBV may permit a more vigorous immunologic response to core peptides expressed on the surface of hepatocytes. Episodic flares in patients with chronic hepatitis B have been attributed to increases in the concentration of precore mutants and changes in the proportion of precore to wild-type HBV.89,90 It has been suggested that disease exacerbations are uncommon during the earliest phase of chronic HBV at a time when wild-type HBV predominates and that flares become common with the gradual emergence of the precore variant.89 These flares have been thought to subside with time as the genetic heterogeneity disappears and patients become exclusively infected with precore HBV. The basal core promoter (BCP) region of the HBV genome controls transcription of core ribonucleic acid that is essential for viral replication.91 Mutations at this site are associated with decreased HBeAg synthesis, active liver histology, and increased viral replication.91,92 Multiple exacerbations of hepatitis due to reactivated HBV infection have been described in patients with BCP mutation, either alone, or in association with precore mutation.93 Sometimes these exacerbations have been fatal, presenting as fulminant liver failure.94 HBeAgnegative patients who harbor both the precore and corepromoter mutants may be particularly predisposed to

Figure 5. Time course of biochemical and virological events in a patient who initially did not respond to prednisone (Pred) followed by interferon (rIFN) alfa-2b. Note that a minor increment in ALT followed the withdrawal of prednisone during the first course. A second course of therapy, using a higher initial dose of prednisone and a shorter treatment cycle, resulted in a marked increase of ALT and loss of HBV DNA and HBeAg.

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severe reactivation episodes after chemotherapy for malignancies.95 Mutations in domains B and C of the HBV DNA polymerase gene occur during lamivudine therapy and become more frequent as therapy is prolonged.96 Some of these mutations confer high level resistance to lamivudine and should be suspected whenever serum HBV DNA reappears in a patient who was previously negative on treatment.91,96 A mild-to-moderate increase in ALT often precedes or accompanies the reappearance of HBV DNA but this is generally transient, and values for both often remain below pretreatment levels.91,97 The polymerase mutants have been found not to be as replication competent as wild-type HBV, which may partially explain the lower ALT and HBV DNA levels.98 There are occasional notable exceptions to these general findings, however. In one study, 13 of 32 Asian patients (41%) who were maintained on lamivudine after resistance was confirmed had 1 or more exacerbations of hepatitis (median, 24 weeks after first detection of polymerase mutants).99 During these episodes, ALT levels ranged from 247 to 2010 IU/L with the majority of peak values in excess of 10 times the upper limit of normal, and HBeAg seroconversion subsequently occurred in 75% of cases. Further study by the same group of investigators demonstrated the emergence of new polymerase mutants that replaced the original mutants in some cases, and this event was also often associated with flares in ALT.100 The author has had personal experience with a patient in whom a second course of lamivudine was associated with the rapid emergence of an HBV DNA polymerase mutant that was accompanied by a major increase in ALT and progressive increase in serum HBV DNA level (Figure 6). The findings in this case suggest that HBV DNA polymerase mutants can be rapidly selected during repeat courses of treatment. The reason for these varied responses to lamivudine-resistant HBV DNA polymerase mutants is not clear, but it is interesting to speculate that secondary mutations elsewhere in the polymerase gene might either stabilize viral replication or, because of the overlapping nature of the polymerase gene with the core gene, result in increased viral proliferation.

Hepatitis Flares Caused by Infection With Other Viruses Patients with chronic HBV infection may exhibit major flares in serum aminotransferases and even frank liver failure when superinfected with other hepatotropic viruses such as hepatitis A virus (HAV), hepatitis C virus (HCV), and hepatitis delta virus (HDV). Excess mortality has been reported by several investigators when hep-

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Figure 6. Pronounced flare in ALT that accompanied emergence of HBV DNA polymerase mutant during lamivudine treatment. This patient had previously received a 6-month course of lamivudine. Wildtype HBV predominated at the time of initiation of a second course of lamivudine (arrow). After a few weeks of treatment, restriction fragment length polymorphism detected a mixed viral species in which substitutions at nucleotides 528 and 552 of the HBV DNA polymerase gene were found in addition to wild-type virus. This occurred in conjunction with a major flare in ALT. HBV DNA levels subsequently increased and ALT declined, at which point only the lamivudineresistant HBV mutant was detectable.

atitis A is superimposed on chronic hepatitis B, although this has not been a consistent finding.101–104 The discrepancy between these studies may be based on differences in the severity of the underlying hepatitis B.105 Fulminant liver failure frequently occurs when delta virus superinfection is superimposed on chronic hepatitis B.106 Should infection with delta virus become chronically established, as is often the case, this frequently leads to an increase in disease activity and accelerated progression to cirrhosis, during which time multiple fluctuations in serum aminotransferase levels are common.106,107 Acute hepatitis C has also been shown to predispose to fulminant liver failure in patients with chronic hepatitis B.108 Similar to delta infection, infection with HCV frequently becomes chronic, and the subsequent course may be characterized by frequent fluctuations in ALT and AST values.109 The degree to which acute flares in chronic HBsAg patients can be explained by superinfection with other viruses in contrast to immunologic activation to HBV is contingent on a number of factors, including the background prevalence of these other viral infections, the frequency of spontaneous HBV reactivation in a given population, as well as the underlying HBeAg status of the individual. In one study, acute flares in serum aminotransferase levels (at least 10 times the normal value) were detected in 76 asymptomatic Asian HBsAg patients, and the etiology for these episodes was deter-

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mined by testing for HBeAg, anti-HBe, serum HBV DNA, IgM antibody to hepatitis A virus, and anti-delta. The authors found that nearly 90% of patients who were initially HBeAg–positive either were initially HBV DNA–negative or subsequently became negative, suggesting immune clearance of HBV as the cause for the flare.110 In contrast, 55% of anti–HBe-positive patients had delta superinfection, 21% were suspected of having non-A, non-B virus superinfection, and only 24% were considered to have reactivation of HBV. Patients with chronic hepatitis B who become infected with other hepatotropic viruses may become HBeAg– negative and serum HBV DNA negative by molecular hybridization testing due to a process of viral interference.111 This has been described with superimposition of HAV, HCV, and HDV infections112–114 and combined infections with HCV and HDV.115 In some instances, these secondary infections result in HBeAg and HBsAg seroconversion.112,116 Thus, serologic assessment for other hepatitis viruses and markers for HBV replication is sometimes required to correctly interpret or recognize the cause of acute exacerbations in patients with chronic hepatitis B. Interferon induced eradication of HCV in patients with underlying chronic HBV infection has occasionally been associated with major flares of serum aminotransferase levels caused by reactivation of HBV infection.117 The interrelationship between human HIV infection and HBV infection is complex. Abnormal levels of liver enzymes are common among persons infected with HIV and may be caused by multiple factors, including medication toxicity and coinfection with HBV or HCV. Early reports emphasized that patients coinfected with HIV and HBV had high serum HBV DNA levels, but acute hepatitis flares, implying an active cell mediated immune response to HBV, was seldom reported.118,119 The development of more effective antiretroviral regimens has led to immune reconstitution in many HIVinfected patients, however, and the clinical spectrum of chronic hepatitis B observed in these patients has more recently been described to be similar to that which occurs in non–HIV-infected hosts.120 –122 In one report, a flare of hepatitis was observed in association with clearance of serum HBV DNA thought to be attributable to the immune reconstituting effect of ritonavir.121 In another report, 2 cases were described in which reactivated hepatitis B was postulated to be caused by reductions in HIV viremia and loss of cytokine control of HBV replication.122 Lamivudine has also been implicated as a cause of hepatitis flares in patients with dual HBV and HIV infection. In one study, 5 HIV-infected patients showed

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exacerbations of their underlying hepatitis B during or after lamivudine treatment.123 In 3 cases the flares occurred after 13 to 18 months of therapy and were shown to be caused by the emergence of HBV DNA polymerase mutants. In the other 2 individuals, the flares occurred when lamivudine was discontinued and a more efficacious antiretroviral regimen was substituted. These findings are reminiscent of the posttreatment flares that have been reported in immune-competent hosts. The finding of increased hepatotoxicity of antiretroviral therapy, particularly ritonavir, in patients with chronic hepatitis B also needs consideration whenever a flare in serum aminotransferase levels is observed.124 In summary, acute flares are common in chronic hepatitis B and may occur caused by an increase in HBV replication, changes in the HBV genome, changes in immune status, and superimposed infections with other hepatotropic viruses. Flares can be clinically serious when superimposed on established chronic viral hepatitis. To minimize the clinical impact of these acute flares, one requires an appreciation of high-risk clinical situations and prompt antiviral treatment when appropriate.

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Received August 28, 2000. Accepted November 29, 2000. Address requests for reprints to: Robert P. Perrillo, M.D., Ochsner Clinic, 1514 Jefferson Highway, New Orleans, Lousiana 70121. e-mail: [email protected]; fax: (504) 842-7466.