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Evidence of serious graft damage induced by de novo hepatitis B virus infection after liver transplantation
Evidence of Serious Graft Damage Induced by De Novo Hepatitis B Virus Infection After Liver Transplantation Roberto Segovia,* Alberto Sa´nchez-Fueyo,* Antoni Rimola,* Luis Grande,† Miquel Bruguera,* Josep Costa,‡ Carolina Soguero,* and Juan Uriz* De novo hepatitis B virus (HBV) infection after orthotopic liver transplantation (OLT) is commonly believed to be a relatively benign condition, in contrast to post-OLT infection recurrence, considered a very aggressive complication. We reviewed the charts of 569 non–HBV-related OLTs performed at our institution and identified 19 patients (3%) with de novo HBV infection (appearance of hepatitis B surface antigen [HBsAg] after OLT). After a median follow-up of 25 months beyond the detection of HBsAg, 12 patients (63%) had developed serious HBVrelated graft damage (cirrhosis in 6 patients, bridging chronic hepatitis in 4 patients, and fulminant hepatitis in 2 patients); 7 patients (37%) had lost their grafts; and 4 patients (21%) had died. All graft losses and deaths were related to de novo HBV infection. Similar rates of severe graft damage (62%), graft loss (38%), and death (33%) related to HBV infection were found in a concomitant series of 21 patients with recurrent HBV infection after OLT. Responses to antiviral therapy (interferon or lamivudine) were also similar in the 2 groups of patients. In 12 patients with de novo HBV infection, evidence of past HBV infection (positive serum antibody to hepatitis B core antigen and/or serum or liver tissue HBV DNA) were detected in the donor (7 patients) or recipient (5 patients). No differences were observed in the clinical course after stratification according to the attributed origin of de novo HBV infection. We conclude that de novo HBV infection after OLT is associated with high rates of morbidity and mortality, similar to those described for post-OLT HBV infection recurrence. (Liver Transpl 2001;7:106-112.)
I
n the last years, an increasing number of apparently primary hepatitis B virus (HBV) infections after orthotopic liver transplantation (OLT) has been observed. These so-called de novo HBV infections have been reported to occur in 1% to 3% of liver transplant recipients without a known history of HBV infection.1-4 However, although some patients may have From the *Liver Unit and the Departments of †Surgery and ‡Microbiology, Hospital Clinic, Institut D’Investigacions Biome`diques August Pi i Sunyer (IDIBAPS), University of Barcelona, Spain. Support in part by a grant from Fundacio´n Pedro Pons (A.S-F.) and a grant from Fundacio´ Clı´nic (C.S.). Address reprint requests to Antoni Rimola, MD, Liver Unit, Hospital Clinic, Villarroel 170, Barcelona 08036, Spain. Telephone: 34-93-2275499; FAX: 34-93-451-5522; E-mail: [email protected] Copyright © 2001 by the American Association for the Study of Liver Diseases 1527-6465/01/0702-0019$35.00/0 doi:10.1053/jlts.2001.21457
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true primary infections acquired through parenteral exposure to blood products or risky lifestyle practices, most cases appear to be caused by reactivation of latent virus, either from recipient extrahepatic sources2,5 or, more frequently reported, from the liver graft itself.6,7 The use of allografts from donors with serum immunoglobulin G (IgG) antibodies to hepatitis B core antigen (anti-HBc), usually considered a marker of past exposure to HBV, has been associated with de novo HBV infection in 50% to 93% of the recipients.6-10 At variance with the poor prognosis of HBV infection recurrence in patients who undergo transplantation for HBV-related liver diseases, most studies have reported a comparatively benign course of de novo post-OLT HBV infection, with very slow progression to severe graft damage and rarely leading to graft loss.1,3,7,11 However, these findings have not been universal; recently, Crespo et al12 reported a series of 6 patients with de novo HBV infection after OLT, 2 of whom lost their grafts because of HBV-induced fulminant hepatitis. A clear understanding of the course of these infections is crucial because it may have great impact on the use of anti-HBc–positive liver donors, which constitute 5% of the donors in the United States6,10 and approximately 12% of the donors in Spain.13 The aim of the present study is to evaluate the natural history of de novo HBV infection after OLT in a single institution.
Patients and Methods Patients From June 1988 to August 1999 at the Hospital Clinic of Barcelona, Spain, 703 OLTs were performed in 636 adult patients. Fifty-eight grafts were lost during the first postoperative month, and 645 grafts survived longer. Seventy-six of these 645 OLTs were performed in patients with HBV-related liver diseases (cirrhosis or fulminant hepatitis), defined by the positivity of serum hepatitis B surface antigen (HBsAg) before the procedure, whereas in the remaining 569 patients, OLT was performed for non–HBV-related diseases (preOLT HBsAg negative). The development of de novo HBV infection was therefore studied in this group of 569 liver transplant recipients. Induction immunosuppression consisted of cyclosporine A, prednisone, and azathioprine in most patients, whereas
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De Novo Hepatitis B in Liver Transplantation
Table 1. Characteristics of Patients With De Novo HBV Infection After OLT Sex (men/women) Age* (yr) OLT indication† (no. of patients) Alcoholic cirrhosis HCV-induced cirrhosis Other Immunosuppression at time of HBV infection (no. of patients) CsA monotherapy CsA ⫹ prednisone FK monotherapy FK ⫹ prednisone HBsAg detection after OLT* (mo) Follow-up after HBV infection* (mo)
12/7 45 (20-60) 7 5 7
2 12 4 1 9 (4-81) 25 (0-108)
Abbreviations: CsA, cyclosporine A; FK, tacrolimus. *Values expressed as median (range). †Four patients with cirrhosis also had hepatocellular carcinoma.
some patients were initially treated with tacrolimus and prednisone. All patients were followed up at the Hospital Clinic outpatient clinic, and serum HBsAg levels were determined at month 3 after OLT and subsequently every 6 months and when clinically indicated. Tests for HBV DNA, hepatitis Be antigen (HBeAg), antibody to HBeAg (anti-HBe) and antibody to hepatitis D virus (anti-HDV) were also performed periodically in patients with HBsAg seroconversion. Percutaneous liver biopsies were performed when clinically indicated during the first months and routinely at 12 months after OLT and every 1 to 2 years thereafter in those patients who developed liver disease. Patients with HBV infection after OLT also underwent a liver biopsy when HBsAg was first detected postoperatively. Nineteen of the 569 transplant recipients (3%) who were HBsAg negative before OLT presented post-OLT with de novo HBV infection, defined by the detection of HBsAg after OLT. HBV infection recurrence, defined as the reappearance of HBsAg after OLT, occurred in 21 of the 76 HBsAg-positive liver transplant recipients (28%). Clinical data from the 19 patients with de novo HBV infection and the 21 patients with HBV infection recurrence were retrospectively collected and compared.
Virological Studies Serum HBsAg, antibody to HBsAg (anti-HBs), HBeAg, antiHBe, IgG anti-HBc, and anti-HDV were determined by enzyme-linked immunoassay using commercial kits. HBV DNA was detected by a spot hybridization technique until 1991, and thereafter by single-round polymerase chain reaction (PCR), as previously described.14 In 16 patients with de novo HBV infection in whom frozen (⫺70°C) pre-OLT sera from transplant recipients
were available, heminested PCR was performed to detect trace amounts of HBV DNA, as previously described.15 Sensitivity of this technique has been estimated to be 1 copy/mL. The presence of HBV DNA was also tested in paraffin-embedded liver biopsy specimens from the graft in 16 cases (biopsy obtained at reperfusion) and the explanted recipient liver in 18 cases. Extraction and HBV DNA amplification were performed as previously described.16,17 All donors were HBsAg negative. Donor serum anti-HBc has been routinely determined at our institution since 1996. Since then, serum anti-HBc has been found positive in 9% of organ donors.
Liver Histological Examination Liver biopsy specimens were reevaluated by a single pathologist (M.B.) blinded to the clinical diagnosis. Each liver specimen was assigned to 1 of the following diagnoses: acute hepatitis, submassive or massive hepatic necrosis, chronic hepatitis (mild, moderate, and severe, including those cases with bridging fibrosis), cirrhosis, and fibrosing cholestatic hepatitis.18,19
Statistical Analysis Results are expressed as median and range. Comparison of quantitative data was performed by nonparametric Mann Whitney test. Qualitative data were compared by using chisquared test. Survival curves were generated by the Kaplan-
Table 2. Characteristics of Patients With HBV Infection Recurrence After OLT Sex (men/women) Age* (yr) OLT indication† (no. of patients) HBV-induced fulminant hepatitis HBV-related cirrhosis HDV coinfection at time of OLT (no. of patients) HCV coinfection at time of OLT (no. of patients) Long-term HBIG prophylaxis (no. of patients) Immunosuppression at time of recurrence (no. of patients) CsA monotherapy CsA ⫹ prednisone FK ⫹ prednisone Time of HBsAg detection after OLT* (mo) Follow-up after HBV recurrence* (mo)
18/3 42 (19-63) 7 14 3 2 7
2 18 1 4 (1-11) 40 (3-117)
Abbreviations: CsA, cyclosporine A; FK, tacrolimus; HBIG, hepatitis B immune globulin. *Values expressed as median (range). †Three patients with cirrhosis also had hepatocellular carcinoma.
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Meier method to estimate survival of both allografts and recipients in the 2 groups of patients studied (de novo postOLT HBV infection and HBV infection recurrence). Logrank test was used to compare the curves. P less than .05 is considered statistically significant.
Results Patient Characteristics Clinical characteristics of the patients with de novo HBV infection and those with HBV infection recurrence are listed in Tables 1 and 2, respectively. In the 19 patients with de novo HBV infection, HBsAg was detected a median of 9 months (range, 4 to 81 months) after OLT, and patients were followed up for a median of 25 months (range, 0 to 108 months) after HBV infection. The median peak serum transaminase levels were 67 U/L (range, 19 to 2,346 U/L) for aspartate aminotransferase and 136 U/L (range, 33 to 2,819 U/L) for alanine aminotransferase. In only 5 cases did serum transaminase values remain less than 2 times the upper level of normal (40 U/L). Virological data and clinical course of the 19 cases are listed in Table 3. At the end of follow-up, 12 pa-
tients (63%) had serious HBV-related graft damage (severe chronic hepatitis, cirrhosis, or massive or submassive necrosis). It is noteworthy that 2 patients presented with fulminant hepatitis and 1 other patient experienced a severe reactivation of chronic hepatitis, all of whom subsequently died. No cases of fibrosing cholestatic hepatitis were observed. As listed in Table 3, there were 7 graft losses (37%) and 4 deaths (21%). In 4 patients, graft loss was directly related to de novo HBV infection, and in the remaining 3 patients, the grafts were lost because of a combination of both severe HBVrelated graft damage and other causes (hepatitis C virus [HCV] infection recurrence and biliary strictures). All 4 deaths were directly related to HBV infection. Interferon was administered to 3 patients, with HBV DNA negativization in all patients and seroconversion to antiHBs–positive status in 2 patients. Lamivudine is currently being administered to 5 other patients, with HBV DNA negativization but persistence of HBsAg in all patients. Spontaneous seroconversion to anti-HBs– positive status was observed in only 1 patient. In the 21 patients with HBV infection recurrence, the median time between OLT and HBsAg reappearance was 4 months (range, 1 to 11 months), which was
Table 3. Course of Patients With De Novo HBV Infection After OLT
Patient No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
OLT Indication Alcoholic cirrhosis Alcoholic cirrhosis HCV cirrhosis HCV cirrhosis HCV cirrhosis Re-OLT‡ HCV cirrhosis Type 1 primary hyperoxaluria Primary sclerosing cholangitis Alcoholic cirrhosis Alcoholic cirrhosis Alcoholic cirrhosis Biliary strictures (re-OLT) Alcoholic cirrhosis HCV cirrhosis Alcoholic cirrhosis Autoimmune hepatitis Caroli’s disease Cryptogenic cirrhosis
HBeAg at Infection
HBV DNA at Infection
Time of Infection After OLT (mo)
Follow-Up After Infection (mo)
ND ⫺ ⫹ ⫺ ⫺ ⫺ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫺ ⫹ ⫹
ND ⫺ ⫹ ⫺ ⫺ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹
5 9 15 81 6 8 14 14 10 4 7 11 11 4 8 6 10 14 4
0 108 25 12 57 64 57 49 56 52 48 20 21 28 21 16 9 9 1
Treatment (mo of therapy)
IFN (24)
Associated Graft Disorders
HCV recurrence HCV recurrence HCV recurrence
IFN (12) IFN (16) LMV (11) LMV (9)
Biliary strictures
LMV (8) LMV (9) LMV (5)
HCV recurrence Biliary strictures
Histology (end of follow-up) Massive necrosis ND Submassive necrosis† MCH Cirrhosis Cirrhosis MCH SCH Cirrhosis Cirrhosis SCH SCH Cirrhosis ND Cirrhosis MCH ND ND Submassive necrosis
Current Status Dead Alive Dead Alive Re-OLT/alive Re-OLT/alive Alive Alive Alive Dead Alive Alive Re-OLT/alive Alive Alive Alive Alive Alive Dead
Abbreviations: ND, not done; IFN, interferon; LMV, lamivudine; MCH, moderate chronic hepatitis; SCH, severe chronic hepatitis. *All deaths and re-OLTs were caused by HBV-related graft damage. Graft disorders other than HBV infection contributed to death or re-OLT in patients 5 and 13 (HCV recurrence and biliary strictures, respectively). †Chronic hepatitis with a final reactivation leading to submassive necrosis. ‡Re-OLT for graft failure caused by cirrhosis of undetermined origin (negative serum HBsAg and HBV DNA, but positive anti-HBc IgG and liver tissue HBV DNA). In patients 6 and 17, infection was attributed to a precore mutant on the basis of persistent HBeAg negativity in the presence of positivity for HBV DNA and anti-HBeAg.
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dine, and all have become negative for HBV DNA, although HBsAg is still present. Figure 1 shows cumulative graft and patient survival in the groups with de novo and recurrent HBV infection. Although a tendency toward poorer outcome was observed in the group with HBV recurrence, the difference is not statistically significant.
significantly shorter than in the de novo HBV group (P ⫽ .045). Virological characteristics and courses of these patients are listed in Table 4. After a median follow-up of 40 months (range, 3 to 117 months), 13 of 21 patients (62%) had severe HBV-related graft damage, a rate similar to that observed in the group with de novo HBV infection. Fourteen patients (67%) lost their grafts, and 13 patients (62%) died. As listed in Table 4, in 8 patients (38%), HBV infection recurrence had a direct (4 patients) or contributory role (4 patients) in graft loss, whereas the remaining 6 graft losses were from causes other than HBV infection. Seven deaths (33%) were either directly related to HBV infection recurrence (3 deaths) or caused by a combination of HBV infection recurrence and other graft lesions (4 deaths). Rates of graft loss and patient mortality from HBV infection recurrence did not significantly differ from those in the group with de novo HBV infection (37% v 38%; 21% v 33%, respectively). Four patients with HBV infection recurrence underwent treatment with interferon, and HBV DNA was cleared during treatment in 3 patients, although only 1 patient seroconverted to anti-HBs–positive status. Three other patients are currently undergoing treatment with lamivu-
Origin of De Novo HBV Infection After OLT As listed in detail in Table 5, evidence of past HBV infection was found in either the donor or recipient in 12 cases of de novo HBV infection, although pre-OLT serum anti-HBc was the only positive marker found in 2 transplant recipients. In 2 patients (no. 12 and 19), HBV infection could not be attributed to any potential origin after complete studies were performed. No relationship between the possible origin of de novo HBV infection and the clinical course of patients was observed.
Discussion Since the initial description in 1992 of de novo HBV infection in patients who underwent OLT for non–
Table 4. Course of Patients With HBV Infection Recurrence After OLT
Patient No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
OLT Indication Cirrhosis Cirrhosis Fulminant hepatitis Cirrhosis Cirrhosis Fulminant hepatitis Fulminant hepatitis Fulminant hepatitis Cirrhosis Cirrhosis Cirrhosis Cirrhosis Cirrhosis Fulminant hepatitis Fulminant hepatitis Fulminant hepatitis Cirrhosis Cirrhosis Cirrhosis Cirrhosis Cirrhosis
HBeAg at Recurrence
HBV DNA at Recurrence
Time of Recurrence After OLT (mo)
Follow-Up After Recurrence (mo)
⫹ ⫹ ⫹ ⫹ ⫹ ⫺ ⫹ ⫹ ⫹ ⫺ ⫹ ⫹ ⫺ ⫹ ⫹ ⫺ ⫹ ⫹ ⫺ ⫺ ⫺
⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫺ ⫹ ⫹ ⫺ ⫹ ⫹ ⫹ ⫹ ⫹
6 1 1 4 1 10 1 2 3 11 5 4 4 10 10 1 5 1 9 7 6
3 12 96 31 117 44 106 56 61 96 13 99 92 78 9 26 11 11 40 16 9
Treatment (mo of therapy)
Associated Graft Disorders
IFN (15) Chronic rejection
IFN (4) IFN (12)
Chronic rejection HCV recurrence Caval vein stenosis
IFN (38) Biliary strictures Chronic rejection Chronic rejection
LMV (16) LMV (12) LMV (6)
Histology (end of follow-up)
Current Status
Submassive necrosis SCH Cirrhosis Cirrhosis Mild CH MCH Cirrhosis FCH Cirrhosis Cirrhosis Cirrhosis Cirrhosis MCH Cirrhosis Acute hepatitis MCH Minimal changes Cirrhosis Cirrhosis MCH MCH
Dead* Dead Re-OLT/dead* Dead* Alive Dead Alive Dead* Dead* Alive Dead* Alive Re-OLT/alive Dead* Dead Dead Dead Dead* Alive Alive Alive
Abbreviations: IFN, interferon; LMV, lamivudine; MCH, moderate chronic hepatitis; SCH, severe chronic hepatitis; FCH, fibrosing cholestatic hepatitis; CH, chronic hepatitis. *Deaths and re-OLTs caused by HBV-related graft damage (other graft disorders contributed to death or re-OLT in patients 8, 9, 11, and 14). Patients 6, 10, 19, 20, and 21 were considered to be infected by precore mutants on the basis of persistent HBeAg negativity in the presence of positive for HBV DNA and anti-HBeAg.
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Figure 1. Graft and patient cumulative survival after OLT in de novo HBV infection (continuous line) and HBV infection recurrence (broken line).
HBV-related liver diseases,20 it has been generally assumed that this entity is mostly associated with a benign clinical course. This initial impression was supported by several studies. Douglas et al1 reported progression to severe liver disease in only 1 of 5 patients. Fabia et al3 found significant serum transaminase level elevations in only 2 of 14 patients after 28 months of follow-up, and Chazouille`res et al5 reported a series of 20 patients in which 10 patients developed chronic hepatitis and only 1 patient required re-OLT for HBV-induced graft failure. Conversely, Wachs et al,9 alerted to the possibility of severe consequences of de novo HBV infection in
OLT, published a short series of 3 patients, in which 1 patient developed active chronic hepatitis and 2 patients developed cirrhosis after HBV infection. Similarly, Roche et al2 reported 20 patients with de novo HBV infection; 5 patients developed cirrhosis, resulting in graft loss in 2 patients, and 9 patients evolved to chronic active hepatitis. In addition, 1 Spanish institution recently reported its experience showing a particularly severe clinical course of de novo HBV infection that included the first reported cases of fulminant hepatitis.12 In our series, 19 patients developed de novo HBV
Table 5. Pre-OLT Markers of HBV Infection in Donors and Recipients in 19 Cases of De Novo HBV Infection After OLT Donor
Recipient
Patient No.
Serum Anti-HBc
Serum HBV DNA
Liver Tissue HBV DNA
Serum Anti-HBc
Serum HBV DNA
Liver Tissue HBV DNA
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
ND ND ND ND ND ND ND ND ND ND ND ⫺ ⫹ ⫹ ND ⫹ ⫹ ⫹ ⫺
ND ND ND ND ND ND ND ND ND ND ND ⫺ ⫺ ⫺ ND ⫺ ⫹ ⫺ ⫺
ND ND ⫺ ⫺ ⫹ ⫺ ND ⫺ ⫹ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫹ ⫺ ⫺
ND ⫺ ND ⫹ ⫺ ⫹ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫹ ⫺ ⫺ ⫺ ⫺
ND ND ND ⫺ ⫺ ⫺ ⫺ ⫹ ⫺ ⫹ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺
⫺ ⫺ ⫺ ND ⫺ ⫹ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺
Abbreviations: ND, not determined; Anti-HBc, antibody to HBcAg.
De Novo Hepatitis B in Liver Transplantation
infection post-OLT, representing an incidence of 3%. In this group of patients, severe graft damage (cirrhosis, chronic hepatitis with bridging fibrosis, or massive or submassive liver necrosis) was observed in 63% of the patients. This incidence was almost identical to the incidence of severe graft damage observed in patients with recurrent HBV infection (62%), who constitute a population traditionally associated with a very poor prognosis.19 Although some patients with de novo HBV infection also had concomitant disorders that could contribute to graft injury (i.e., HCV infection recurrence or biliary strictures), the role of these conditions in the graft damage seems modest because they were present in only 3 of the 12 patients with severe HBV-related graft lesions (Table 3). In the group with HBV infection recurrence, associated serious graft disorders were present in 5 of 13 patients with severe HBV-related graft damage (Table 4). Actuarial probabilities of graft and patient survival in the 2 groups were not statistically different, although a tendency toward a worse outcome was observed in patients with HBV infection recurrence (Fig. 1). Nevertheless, when only graft loss and death related to HBV infection (as either the only cause or a major contributory cause) are considered, patients with de novo HBV infection and patients with HBV infection recurrence did not significantly differ with regard to these events: graft loss rates were 37% versus 38% and patient mortality rates were 21% versus 33% in the de novo and recurrent HBV infection groups, respectively. Interestingly, 2 patients with de novo HBV infection developed fulminant hepatic failure, a phenomenon previously described by Crespo et al,12 and a third patient (with chronic hepatitis) had a severe reactivation that caused submassive hepatic necrosis. We did not observe fibrosing cholestatic hepatitis, although its occurrence as a consequence of de novo HBV infections has been previously described.7 Only 1 patient spontaneously seroconverted to anti-HBs–positive status, reflecting the extremely high propensity to chronicity of HBV infection in the OLT setting.21 Eight patients with de novo HBV infection were administered either interferon or lamivudine. Despite the high antiviral efficacy of these therapies (HBV DNA became negative in all 8 patients), their impact on the graft damage is difficult to ascertain in the present series because these products were administered in most cases when severe graft injury had already developed. The origin of de novo HBV infection after OLT has often been attributed to the presence of trace amounts of latent HBV in the graft, with the presence of serum IgG anti-HBc in the donor considered its best
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marker.3,6,9 However, as shown by previous studies2,5,12 and our own data, the donor origin of HBV infection cannot always be found. An alternative source of HBV infection is the presence of cryptic hepatic or extrahepatic HBV infection in the recipient (defined as the detection of HBV DNA by PCR, either in serum or liver tissue, in the absence of other HBV serological markers).5 In our study, 3 cases of de novo HBV infection might have been attributed to this source. As the relationship between cryptic HBV infection and postOLT HBV hepatitis becomes more widely recognized, these cases will probably have to be reclassified as recurrent infections. In 2 other transplant recipients, serum anti-HBc was positive before OLT as the only serological marker, although the role of this condition in the pathogenesis of de novo HBV infection seems less clear. However, 2 of our patients developed HBV infection 4 and 11 months after OLT in the absence of either donor serum anti-HBc or recipient cryptic HBV infection, highlighting the difficulties in identifying all possible infective sources. Taking into account that serum anti-HBc tests are not routinely performed in blood donors at our institution, we believe this could be a potential source of transmission. A clear understanding of the potential severity of de novo HBV infection is extremely relevant to address the question of whether anti-HBc–positive donors should be used. This is probably not a major issue in areas of low anti-HBc serum prevalence, such as the United States (⬃3.8% to 5.3% of donors),6,22 but it is becoming increasingly important in countries of intermediate or high prevalence, such as Spain and Japan (12% and 27%, respectively).7,13 To date, there are no published data on the use of pharmacological prophylaxis with either hepatitis B immunoglobulin or lamivudine to reduce the risk for HBV transmission in patients receiving serum anti-HBc–positive grafts. Both strategies, along with the diversion of anti-HBc–positive grafts to serum anti-HBs–positive recipients, appear to be sensible.4 In summary, we believe that de novo HBV infection after OLT is not a benign event, but is associated with a high rate of morbidity and mortality. Efforts must be made to properly identify all potential transmission paths, and when this can be accomplished, empirical prophylactic regimens are probably indicated.
References 1. Douglas D, Rakela J, Wright T, Krom R, Wiesner R. The clinical course of transplantation-associated de novo hepatitis B infection in the liver transplant recipient. Liver Transpl Surg 1997;3: 105-111.
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2. Roche B, Samuel D, Gigou M, Feray C, Virot V, Schmets L, et al. De novo and apparent de novo hepatitis B virus infection after liver transplantation. J Hepatol 1997;26:517-526. 3. Fabia R, Levy M, Crippin J, Tillery W, Netto G, Aguanno J, et al. De novo hepatitis B infection after liver transplantation: Source of disease, incidence, and impact. Liver Transpl Surg 1998;4:119-127. 4. Pruett T. Editorial response: De novo HBV infections after liver transplantation. Liver Transpl Surg 1998;4:182-184. 5. Chazouille`res O, Mamish D, Kim M, Carey K, Ferrell L, Roberts JP, et al. “Occult” hepatitis B virus as source of infection in liver transplant recipients. Lancet 1994;343:142-146. 6. Dickson R, Everhart J, Lake J, Wei Y, Seaberg E, Wiesner R, et al. Transmission of hepatitis B by transplantation of livers from donors positive for antibody to hepatitis B core antigen. Gastroenterology 1997;113:1668-1674. 7. Uemoto S, Sugiyama K, Marusawa H, Inomata Y, Asonuma K, Egawa H, et al. Transmission of hepatitis B virus from hepatitis B core antibody-positive donors in living-related liver transplant. Transplantation 1998;65:494-499. 8. Caldwell S. Editorial response: Hard times and imperfect organs. Liver Transpl Surg 1997;3:181-184. 9. Wachs M, Amend W, Ascher N, Bretan P, Emond J, Lake J, et al. The risk of transmission of hepatitis B from HBsAg(⫺), HBcAb(⫹), HBIgM(⫺) organ donors. Transplantation 1995; 59:230-234. 10. Dodson S, Rakela J, Bonham C, Geller D, Fung J, Starzl T. The use of hepatic allografts from anti-HBc positive donors in antiHBs positive recipients [abstract]. Hepatology 1999;30:246A. 11. Cavallari A, De Raffele E, Bellusci R, Miniero R, Vivarelli M, Galli S, et al. De novo hepatitis B and C viral infection after liver transplantation. World J Surg 1997;21:78-85. 12. Crespo J, Fabrega E, Casafont F, Rivero M, de las Heras G, de la Pen˜a J, et al. Severe clinical course of de novo hepatitis B infection after liver transplantation. Liver Transpl Surg 1999;5:175183. 13. Prieto M, Gomez M, Garcia A, Berenguer M, Rayon J, Cordoba
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J, et al. Low rate of post-transplantation de novo hepatitis B virus infection from anti-HBc positive donors: Association with antiHBc/anti-HBs status in the recipient [abstract]. Hepatology 1999;30:242A. Costa J, Lo´pez-Labrador F, Sa´nchez-Tapias J, Mas A, Vilella A, Olmedo E, et al. Microwave treatment of serum facilitates detection of hepatitis B virus DNA by the polymerase chain reaction. Results of a study in anti-HBe positive chronic hepatitis B. J Hepatol 1995;22:35-42. Lindh M, Andersson AS, Gusdal AK. Genotypes, nt1858 variants, and geographic origin of hepatitis B virus—Large scale analysis using a new genotyping method. J Infect Dis 1997;175: 1285-1293. Soguero C, Ribalta T, Campo E, Sa´nchez-Tapias J, Sa´iz J, Bruguera M. Detection of hepatitis C virus (HCV) RNA in more than 20-year-old archival liver tissue. Lab Invest 1999;79:365366. Koike K, Kobayashi M, Gondo M, Hayashi I, Osuga T, Takada S. Hepatitis B virus DNA is frequently found in liver biopsy samples from hepatitis C virus-infected chronic hepatitis patients. J Med Virol 1998;54:249-255. Batts K, Ludwig J. Chronic hepatitis: An update on terminology and reporting. Am J Surg Pathol 1995;19:1409-1417. Davies S, Portmann B, O’Grady J, Aldis P, Chaggar K, Alexander G, et al. Hepatic histological findings after transplantation for chronic hepatitis B virus infection, including a unique pattern of fibrosing cholestatic hepatitis. Hepatology 1991;13:150-157. Douglas D, Rakela J, Taswell H, Mamish D, Wright T, Krom R, et al. Transmission of hepatitis B virus infection from orthotopic donor livers [abstract]. Hepatology 1992;16:49A. Di Bisceglie A, Hoofnagle J. Chronic hepatitis B. In: Zakim D, Boyer T (eds). Hepatology: A textbook of liver disease (ed 3). Philadelphia: Saunders, 1996:1301-1310. Dodson S, Issa S, Araya V, Gayowski T, Pinna A, Eghtesad B, et al. Infectivity of hepatic allografts with antibodies to hepatitis B virus. Transplantation 1997;64:1582-1584.
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n the last years, an increasing number of apparently primary hepatitis B virus (HBV) infections after orthotopic liver transplantation (OLT) has been observed. These so-called de novo HBV infections have been reported to occur in 1% to 3% of liver transplant recipients without a known history of HBV infection.1-4 However, although some patients may have From the *Liver Unit and the Departments of †Surgery and ‡Microbiology, Hospital Clinic, Institut D’Investigacions Biome`diques August Pi i Sunyer (IDIBAPS), University of Barcelona, Spain. Support in part by a grant from Fundacio´n Pedro Pons (A.S-F.) and a grant from Fundacio´ Clı´nic (C.S.). Address reprint requests to Antoni Rimola, MD, Liver Unit, Hospital Clinic, Villarroel 170, Barcelona 08036, Spain. Telephone: 34-93-2275499; FAX: 34-93-451-5522; E-mail: [email protected] Copyright © 2001 by the American Association for the Study of Liver Diseases 1527-6465/01/0702-0019$35.00/0 doi:10.1053/jlts.2001.21457
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true primary infections acquired through parenteral exposure to blood products or risky lifestyle practices, most cases appear to be caused by reactivation of latent virus, either from recipient extrahepatic sources2,5 or, more frequently reported, from the liver graft itself.6,7 The use of allografts from donors with serum immunoglobulin G (IgG) antibodies to hepatitis B core antigen (anti-HBc), usually considered a marker of past exposure to HBV, has been associated with de novo HBV infection in 50% to 93% of the recipients.6-10 At variance with the poor prognosis of HBV infection recurrence in patients who undergo transplantation for HBV-related liver diseases, most studies have reported a comparatively benign course of de novo post-OLT HBV infection, with very slow progression to severe graft damage and rarely leading to graft loss.1,3,7,11 However, these findings have not been universal; recently, Crespo et al12 reported a series of 6 patients with de novo HBV infection after OLT, 2 of whom lost their grafts because of HBV-induced fulminant hepatitis. A clear understanding of the course of these infections is crucial because it may have great impact on the use of anti-HBc–positive liver donors, which constitute 5% of the donors in the United States6,10 and approximately 12% of the donors in Spain.13 The aim of the present study is to evaluate the natural history of de novo HBV infection after OLT in a single institution.
Patients and Methods Patients From June 1988 to August 1999 at the Hospital Clinic of Barcelona, Spain, 703 OLTs were performed in 636 adult patients. Fifty-eight grafts were lost during the first postoperative month, and 645 grafts survived longer. Seventy-six of these 645 OLTs were performed in patients with HBV-related liver diseases (cirrhosis or fulminant hepatitis), defined by the positivity of serum hepatitis B surface antigen (HBsAg) before the procedure, whereas in the remaining 569 patients, OLT was performed for non–HBV-related diseases (preOLT HBsAg negative). The development of de novo HBV infection was therefore studied in this group of 569 liver transplant recipients. Induction immunosuppression consisted of cyclosporine A, prednisone, and azathioprine in most patients, whereas
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De Novo Hepatitis B in Liver Transplantation
Table 1. Characteristics of Patients With De Novo HBV Infection After OLT Sex (men/women) Age* (yr) OLT indication† (no. of patients) Alcoholic cirrhosis HCV-induced cirrhosis Other Immunosuppression at time of HBV infection (no. of patients) CsA monotherapy CsA ⫹ prednisone FK monotherapy FK ⫹ prednisone HBsAg detection after OLT* (mo) Follow-up after HBV infection* (mo)
12/7 45 (20-60) 7 5 7
2 12 4 1 9 (4-81) 25 (0-108)
Abbreviations: CsA, cyclosporine A; FK, tacrolimus. *Values expressed as median (range). †Four patients with cirrhosis also had hepatocellular carcinoma.
some patients were initially treated with tacrolimus and prednisone. All patients were followed up at the Hospital Clinic outpatient clinic, and serum HBsAg levels were determined at month 3 after OLT and subsequently every 6 months and when clinically indicated. Tests for HBV DNA, hepatitis Be antigen (HBeAg), antibody to HBeAg (anti-HBe) and antibody to hepatitis D virus (anti-HDV) were also performed periodically in patients with HBsAg seroconversion. Percutaneous liver biopsies were performed when clinically indicated during the first months and routinely at 12 months after OLT and every 1 to 2 years thereafter in those patients who developed liver disease. Patients with HBV infection after OLT also underwent a liver biopsy when HBsAg was first detected postoperatively. Nineteen of the 569 transplant recipients (3%) who were HBsAg negative before OLT presented post-OLT with de novo HBV infection, defined by the detection of HBsAg after OLT. HBV infection recurrence, defined as the reappearance of HBsAg after OLT, occurred in 21 of the 76 HBsAg-positive liver transplant recipients (28%). Clinical data from the 19 patients with de novo HBV infection and the 21 patients with HBV infection recurrence were retrospectively collected and compared.
Virological Studies Serum HBsAg, antibody to HBsAg (anti-HBs), HBeAg, antiHBe, IgG anti-HBc, and anti-HDV were determined by enzyme-linked immunoassay using commercial kits. HBV DNA was detected by a spot hybridization technique until 1991, and thereafter by single-round polymerase chain reaction (PCR), as previously described.14 In 16 patients with de novo HBV infection in whom frozen (⫺70°C) pre-OLT sera from transplant recipients
were available, heminested PCR was performed to detect trace amounts of HBV DNA, as previously described.15 Sensitivity of this technique has been estimated to be 1 copy/mL. The presence of HBV DNA was also tested in paraffin-embedded liver biopsy specimens from the graft in 16 cases (biopsy obtained at reperfusion) and the explanted recipient liver in 18 cases. Extraction and HBV DNA amplification were performed as previously described.16,17 All donors were HBsAg negative. Donor serum anti-HBc has been routinely determined at our institution since 1996. Since then, serum anti-HBc has been found positive in 9% of organ donors.
Liver Histological Examination Liver biopsy specimens were reevaluated by a single pathologist (M.B.) blinded to the clinical diagnosis. Each liver specimen was assigned to 1 of the following diagnoses: acute hepatitis, submassive or massive hepatic necrosis, chronic hepatitis (mild, moderate, and severe, including those cases with bridging fibrosis), cirrhosis, and fibrosing cholestatic hepatitis.18,19
Statistical Analysis Results are expressed as median and range. Comparison of quantitative data was performed by nonparametric Mann Whitney test. Qualitative data were compared by using chisquared test. Survival curves were generated by the Kaplan-
Table 2. Characteristics of Patients With HBV Infection Recurrence After OLT Sex (men/women) Age* (yr) OLT indication† (no. of patients) HBV-induced fulminant hepatitis HBV-related cirrhosis HDV coinfection at time of OLT (no. of patients) HCV coinfection at time of OLT (no. of patients) Long-term HBIG prophylaxis (no. of patients) Immunosuppression at time of recurrence (no. of patients) CsA monotherapy CsA ⫹ prednisone FK ⫹ prednisone Time of HBsAg detection after OLT* (mo) Follow-up after HBV recurrence* (mo)
18/3 42 (19-63) 7 14 3 2 7
2 18 1 4 (1-11) 40 (3-117)
Abbreviations: CsA, cyclosporine A; FK, tacrolimus; HBIG, hepatitis B immune globulin. *Values expressed as median (range). †Three patients with cirrhosis also had hepatocellular carcinoma.
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Meier method to estimate survival of both allografts and recipients in the 2 groups of patients studied (de novo postOLT HBV infection and HBV infection recurrence). Logrank test was used to compare the curves. P less than .05 is considered statistically significant.
Results Patient Characteristics Clinical characteristics of the patients with de novo HBV infection and those with HBV infection recurrence are listed in Tables 1 and 2, respectively. In the 19 patients with de novo HBV infection, HBsAg was detected a median of 9 months (range, 4 to 81 months) after OLT, and patients were followed up for a median of 25 months (range, 0 to 108 months) after HBV infection. The median peak serum transaminase levels were 67 U/L (range, 19 to 2,346 U/L) for aspartate aminotransferase and 136 U/L (range, 33 to 2,819 U/L) for alanine aminotransferase. In only 5 cases did serum transaminase values remain less than 2 times the upper level of normal (40 U/L). Virological data and clinical course of the 19 cases are listed in Table 3. At the end of follow-up, 12 pa-
tients (63%) had serious HBV-related graft damage (severe chronic hepatitis, cirrhosis, or massive or submassive necrosis). It is noteworthy that 2 patients presented with fulminant hepatitis and 1 other patient experienced a severe reactivation of chronic hepatitis, all of whom subsequently died. No cases of fibrosing cholestatic hepatitis were observed. As listed in Table 3, there were 7 graft losses (37%) and 4 deaths (21%). In 4 patients, graft loss was directly related to de novo HBV infection, and in the remaining 3 patients, the grafts were lost because of a combination of both severe HBVrelated graft damage and other causes (hepatitis C virus [HCV] infection recurrence and biliary strictures). All 4 deaths were directly related to HBV infection. Interferon was administered to 3 patients, with HBV DNA negativization in all patients and seroconversion to antiHBs–positive status in 2 patients. Lamivudine is currently being administered to 5 other patients, with HBV DNA negativization but persistence of HBsAg in all patients. Spontaneous seroconversion to anti-HBs– positive status was observed in only 1 patient. In the 21 patients with HBV infection recurrence, the median time between OLT and HBsAg reappearance was 4 months (range, 1 to 11 months), which was
Table 3. Course of Patients With De Novo HBV Infection After OLT
Patient No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
OLT Indication Alcoholic cirrhosis Alcoholic cirrhosis HCV cirrhosis HCV cirrhosis HCV cirrhosis Re-OLT‡ HCV cirrhosis Type 1 primary hyperoxaluria Primary sclerosing cholangitis Alcoholic cirrhosis Alcoholic cirrhosis Alcoholic cirrhosis Biliary strictures (re-OLT) Alcoholic cirrhosis HCV cirrhosis Alcoholic cirrhosis Autoimmune hepatitis Caroli’s disease Cryptogenic cirrhosis
HBeAg at Infection
HBV DNA at Infection
Time of Infection After OLT (mo)
Follow-Up After Infection (mo)
ND ⫺ ⫹ ⫺ ⫺ ⫺ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫺ ⫹ ⫹
ND ⫺ ⫹ ⫺ ⫺ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹
5 9 15 81 6 8 14 14 10 4 7 11 11 4 8 6 10 14 4
0 108 25 12 57 64 57 49 56 52 48 20 21 28 21 16 9 9 1
Treatment (mo of therapy)
IFN (24)
Associated Graft Disorders
HCV recurrence HCV recurrence HCV recurrence
IFN (12) IFN (16) LMV (11) LMV (9)
Biliary strictures
LMV (8) LMV (9) LMV (5)
HCV recurrence Biliary strictures
Histology (end of follow-up) Massive necrosis ND Submassive necrosis† MCH Cirrhosis Cirrhosis MCH SCH Cirrhosis Cirrhosis SCH SCH Cirrhosis ND Cirrhosis MCH ND ND Submassive necrosis
Current Status Dead Alive Dead Alive Re-OLT/alive Re-OLT/alive Alive Alive Alive Dead Alive Alive Re-OLT/alive Alive Alive Alive Alive Alive Dead
Abbreviations: ND, not done; IFN, interferon; LMV, lamivudine; MCH, moderate chronic hepatitis; SCH, severe chronic hepatitis. *All deaths and re-OLTs were caused by HBV-related graft damage. Graft disorders other than HBV infection contributed to death or re-OLT in patients 5 and 13 (HCV recurrence and biliary strictures, respectively). †Chronic hepatitis with a final reactivation leading to submassive necrosis. ‡Re-OLT for graft failure caused by cirrhosis of undetermined origin (negative serum HBsAg and HBV DNA, but positive anti-HBc IgG and liver tissue HBV DNA). In patients 6 and 17, infection was attributed to a precore mutant on the basis of persistent HBeAg negativity in the presence of positivity for HBV DNA and anti-HBeAg.
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dine, and all have become negative for HBV DNA, although HBsAg is still present. Figure 1 shows cumulative graft and patient survival in the groups with de novo and recurrent HBV infection. Although a tendency toward poorer outcome was observed in the group with HBV recurrence, the difference is not statistically significant.
significantly shorter than in the de novo HBV group (P ⫽ .045). Virological characteristics and courses of these patients are listed in Table 4. After a median follow-up of 40 months (range, 3 to 117 months), 13 of 21 patients (62%) had severe HBV-related graft damage, a rate similar to that observed in the group with de novo HBV infection. Fourteen patients (67%) lost their grafts, and 13 patients (62%) died. As listed in Table 4, in 8 patients (38%), HBV infection recurrence had a direct (4 patients) or contributory role (4 patients) in graft loss, whereas the remaining 6 graft losses were from causes other than HBV infection. Seven deaths (33%) were either directly related to HBV infection recurrence (3 deaths) or caused by a combination of HBV infection recurrence and other graft lesions (4 deaths). Rates of graft loss and patient mortality from HBV infection recurrence did not significantly differ from those in the group with de novo HBV infection (37% v 38%; 21% v 33%, respectively). Four patients with HBV infection recurrence underwent treatment with interferon, and HBV DNA was cleared during treatment in 3 patients, although only 1 patient seroconverted to anti-HBs–positive status. Three other patients are currently undergoing treatment with lamivu-
Origin of De Novo HBV Infection After OLT As listed in detail in Table 5, evidence of past HBV infection was found in either the donor or recipient in 12 cases of de novo HBV infection, although pre-OLT serum anti-HBc was the only positive marker found in 2 transplant recipients. In 2 patients (no. 12 and 19), HBV infection could not be attributed to any potential origin after complete studies were performed. No relationship between the possible origin of de novo HBV infection and the clinical course of patients was observed.
Discussion Since the initial description in 1992 of de novo HBV infection in patients who underwent OLT for non–
Table 4. Course of Patients With HBV Infection Recurrence After OLT
Patient No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
OLT Indication Cirrhosis Cirrhosis Fulminant hepatitis Cirrhosis Cirrhosis Fulminant hepatitis Fulminant hepatitis Fulminant hepatitis Cirrhosis Cirrhosis Cirrhosis Cirrhosis Cirrhosis Fulminant hepatitis Fulminant hepatitis Fulminant hepatitis Cirrhosis Cirrhosis Cirrhosis Cirrhosis Cirrhosis
HBeAg at Recurrence
HBV DNA at Recurrence
Time of Recurrence After OLT (mo)
Follow-Up After Recurrence (mo)
⫹ ⫹ ⫹ ⫹ ⫹ ⫺ ⫹ ⫹ ⫹ ⫺ ⫹ ⫹ ⫺ ⫹ ⫹ ⫺ ⫹ ⫹ ⫺ ⫺ ⫺
⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫺ ⫹ ⫹ ⫺ ⫹ ⫹ ⫹ ⫹ ⫹
6 1 1 4 1 10 1 2 3 11 5 4 4 10 10 1 5 1 9 7 6
3 12 96 31 117 44 106 56 61 96 13 99 92 78 9 26 11 11 40 16 9
Treatment (mo of therapy)
Associated Graft Disorders
IFN (15) Chronic rejection
IFN (4) IFN (12)
Chronic rejection HCV recurrence Caval vein stenosis
IFN (38) Biliary strictures Chronic rejection Chronic rejection
LMV (16) LMV (12) LMV (6)
Histology (end of follow-up)
Current Status
Submassive necrosis SCH Cirrhosis Cirrhosis Mild CH MCH Cirrhosis FCH Cirrhosis Cirrhosis Cirrhosis Cirrhosis MCH Cirrhosis Acute hepatitis MCH Minimal changes Cirrhosis Cirrhosis MCH MCH
Dead* Dead Re-OLT/dead* Dead* Alive Dead Alive Dead* Dead* Alive Dead* Alive Re-OLT/alive Dead* Dead Dead Dead Dead* Alive Alive Alive
Abbreviations: IFN, interferon; LMV, lamivudine; MCH, moderate chronic hepatitis; SCH, severe chronic hepatitis; FCH, fibrosing cholestatic hepatitis; CH, chronic hepatitis. *Deaths and re-OLTs caused by HBV-related graft damage (other graft disorders contributed to death or re-OLT in patients 8, 9, 11, and 14). Patients 6, 10, 19, 20, and 21 were considered to be infected by precore mutants on the basis of persistent HBeAg negativity in the presence of positive for HBV DNA and anti-HBeAg.
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Figure 1. Graft and patient cumulative survival after OLT in de novo HBV infection (continuous line) and HBV infection recurrence (broken line).
HBV-related liver diseases,20 it has been generally assumed that this entity is mostly associated with a benign clinical course. This initial impression was supported by several studies. Douglas et al1 reported progression to severe liver disease in only 1 of 5 patients. Fabia et al3 found significant serum transaminase level elevations in only 2 of 14 patients after 28 months of follow-up, and Chazouille`res et al5 reported a series of 20 patients in which 10 patients developed chronic hepatitis and only 1 patient required re-OLT for HBV-induced graft failure. Conversely, Wachs et al,9 alerted to the possibility of severe consequences of de novo HBV infection in
OLT, published a short series of 3 patients, in which 1 patient developed active chronic hepatitis and 2 patients developed cirrhosis after HBV infection. Similarly, Roche et al2 reported 20 patients with de novo HBV infection; 5 patients developed cirrhosis, resulting in graft loss in 2 patients, and 9 patients evolved to chronic active hepatitis. In addition, 1 Spanish institution recently reported its experience showing a particularly severe clinical course of de novo HBV infection that included the first reported cases of fulminant hepatitis.12 In our series, 19 patients developed de novo HBV
Table 5. Pre-OLT Markers of HBV Infection in Donors and Recipients in 19 Cases of De Novo HBV Infection After OLT Donor
Recipient
Patient No.
Serum Anti-HBc
Serum HBV DNA
Liver Tissue HBV DNA
Serum Anti-HBc
Serum HBV DNA
Liver Tissue HBV DNA
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
ND ND ND ND ND ND ND ND ND ND ND ⫺ ⫹ ⫹ ND ⫹ ⫹ ⫹ ⫺
ND ND ND ND ND ND ND ND ND ND ND ⫺ ⫺ ⫺ ND ⫺ ⫹ ⫺ ⫺
ND ND ⫺ ⫺ ⫹ ⫺ ND ⫺ ⫹ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫹ ⫺ ⫺
ND ⫺ ND ⫹ ⫺ ⫹ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫹ ⫺ ⫺ ⫺ ⫺
ND ND ND ⫺ ⫺ ⫺ ⫺ ⫹ ⫺ ⫹ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺
⫺ ⫺ ⫺ ND ⫺ ⫹ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺
Abbreviations: ND, not determined; Anti-HBc, antibody to HBcAg.
De Novo Hepatitis B in Liver Transplantation
infection post-OLT, representing an incidence of 3%. In this group of patients, severe graft damage (cirrhosis, chronic hepatitis with bridging fibrosis, or massive or submassive liver necrosis) was observed in 63% of the patients. This incidence was almost identical to the incidence of severe graft damage observed in patients with recurrent HBV infection (62%), who constitute a population traditionally associated with a very poor prognosis.19 Although some patients with de novo HBV infection also had concomitant disorders that could contribute to graft injury (i.e., HCV infection recurrence or biliary strictures), the role of these conditions in the graft damage seems modest because they were present in only 3 of the 12 patients with severe HBV-related graft lesions (Table 3). In the group with HBV infection recurrence, associated serious graft disorders were present in 5 of 13 patients with severe HBV-related graft damage (Table 4). Actuarial probabilities of graft and patient survival in the 2 groups were not statistically different, although a tendency toward a worse outcome was observed in patients with HBV infection recurrence (Fig. 1). Nevertheless, when only graft loss and death related to HBV infection (as either the only cause or a major contributory cause) are considered, patients with de novo HBV infection and patients with HBV infection recurrence did not significantly differ with regard to these events: graft loss rates were 37% versus 38% and patient mortality rates were 21% versus 33% in the de novo and recurrent HBV infection groups, respectively. Interestingly, 2 patients with de novo HBV infection developed fulminant hepatic failure, a phenomenon previously described by Crespo et al,12 and a third patient (with chronic hepatitis) had a severe reactivation that caused submassive hepatic necrosis. We did not observe fibrosing cholestatic hepatitis, although its occurrence as a consequence of de novo HBV infections has been previously described.7 Only 1 patient spontaneously seroconverted to anti-HBs–positive status, reflecting the extremely high propensity to chronicity of HBV infection in the OLT setting.21 Eight patients with de novo HBV infection were administered either interferon or lamivudine. Despite the high antiviral efficacy of these therapies (HBV DNA became negative in all 8 patients), their impact on the graft damage is difficult to ascertain in the present series because these products were administered in most cases when severe graft injury had already developed. The origin of de novo HBV infection after OLT has often been attributed to the presence of trace amounts of latent HBV in the graft, with the presence of serum IgG anti-HBc in the donor considered its best
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marker.3,6,9 However, as shown by previous studies2,5,12 and our own data, the donor origin of HBV infection cannot always be found. An alternative source of HBV infection is the presence of cryptic hepatic or extrahepatic HBV infection in the recipient (defined as the detection of HBV DNA by PCR, either in serum or liver tissue, in the absence of other HBV serological markers).5 In our study, 3 cases of de novo HBV infection might have been attributed to this source. As the relationship between cryptic HBV infection and postOLT HBV hepatitis becomes more widely recognized, these cases will probably have to be reclassified as recurrent infections. In 2 other transplant recipients, serum anti-HBc was positive before OLT as the only serological marker, although the role of this condition in the pathogenesis of de novo HBV infection seems less clear. However, 2 of our patients developed HBV infection 4 and 11 months after OLT in the absence of either donor serum anti-HBc or recipient cryptic HBV infection, highlighting the difficulties in identifying all possible infective sources. Taking into account that serum anti-HBc tests are not routinely performed in blood donors at our institution, we believe this could be a potential source of transmission. A clear understanding of the potential severity of de novo HBV infection is extremely relevant to address the question of whether anti-HBc–positive donors should be used. This is probably not a major issue in areas of low anti-HBc serum prevalence, such as the United States (⬃3.8% to 5.3% of donors),6,22 but it is becoming increasingly important in countries of intermediate or high prevalence, such as Spain and Japan (12% and 27%, respectively).7,13 To date, there are no published data on the use of pharmacological prophylaxis with either hepatitis B immunoglobulin or lamivudine to reduce the risk for HBV transmission in patients receiving serum anti-HBc–positive grafts. Both strategies, along with the diversion of anti-HBc–positive grafts to serum anti-HBs–positive recipients, appear to be sensible.4 In summary, we believe that de novo HBV infection after OLT is not a benign event, but is associated with a high rate of morbidity and mortality. Efforts must be made to properly identify all potential transmission paths, and when this can be accomplished, empirical prophylactic regimens are probably indicated.
References 1. Douglas D, Rakela J, Wright T, Krom R, Wiesner R. The clinical course of transplantation-associated de novo hepatitis B infection in the liver transplant recipient. Liver Transpl Surg 1997;3: 105-111.
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2. Roche B, Samuel D, Gigou M, Feray C, Virot V, Schmets L, et al. De novo and apparent de novo hepatitis B virus infection after liver transplantation. J Hepatol 1997;26:517-526. 3. Fabia R, Levy M, Crippin J, Tillery W, Netto G, Aguanno J, et al. De novo hepatitis B infection after liver transplantation: Source of disease, incidence, and impact. Liver Transpl Surg 1998;4:119-127. 4. Pruett T. Editorial response: De novo HBV infections after liver transplantation. Liver Transpl Surg 1998;4:182-184. 5. Chazouille`res O, Mamish D, Kim M, Carey K, Ferrell L, Roberts JP, et al. “Occult” hepatitis B virus as source of infection in liver transplant recipients. Lancet 1994;343:142-146. 6. Dickson R, Everhart J, Lake J, Wei Y, Seaberg E, Wiesner R, et al. Transmission of hepatitis B by transplantation of livers from donors positive for antibody to hepatitis B core antigen. Gastroenterology 1997;113:1668-1674. 7. Uemoto S, Sugiyama K, Marusawa H, Inomata Y, Asonuma K, Egawa H, et al. Transmission of hepatitis B virus from hepatitis B core antibody-positive donors in living-related liver transplant. Transplantation 1998;65:494-499. 8. Caldwell S. Editorial response: Hard times and imperfect organs. Liver Transpl Surg 1997;3:181-184. 9. Wachs M, Amend W, Ascher N, Bretan P, Emond J, Lake J, et al. The risk of transmission of hepatitis B from HBsAg(⫺), HBcAb(⫹), HBIgM(⫺) organ donors. Transplantation 1995; 59:230-234. 10. Dodson S, Rakela J, Bonham C, Geller D, Fung J, Starzl T. The use of hepatic allografts from anti-HBc positive donors in antiHBs positive recipients [abstract]. Hepatology 1999;30:246A. 11. Cavallari A, De Raffele E, Bellusci R, Miniero R, Vivarelli M, Galli S, et al. De novo hepatitis B and C viral infection after liver transplantation. World J Surg 1997;21:78-85. 12. Crespo J, Fabrega E, Casafont F, Rivero M, de las Heras G, de la Pen˜a J, et al. Severe clinical course of de novo hepatitis B infection after liver transplantation. Liver Transpl Surg 1999;5:175183. 13. Prieto M, Gomez M, Garcia A, Berenguer M, Rayon J, Cordoba
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J, et al. Low rate of post-transplantation de novo hepatitis B virus infection from anti-HBc positive donors: Association with antiHBc/anti-HBs status in the recipient [abstract]. Hepatology 1999;30:242A. Costa J, Lo´pez-Labrador F, Sa´nchez-Tapias J, Mas A, Vilella A, Olmedo E, et al. Microwave treatment of serum facilitates detection of hepatitis B virus DNA by the polymerase chain reaction. Results of a study in anti-HBe positive chronic hepatitis B. J Hepatol 1995;22:35-42. Lindh M, Andersson AS, Gusdal AK. Genotypes, nt1858 variants, and geographic origin of hepatitis B virus—Large scale analysis using a new genotyping method. J Infect Dis 1997;175: 1285-1293. Soguero C, Ribalta T, Campo E, Sa´nchez-Tapias J, Sa´iz J, Bruguera M. Detection of hepatitis C virus (HCV) RNA in more than 20-year-old archival liver tissue. Lab Invest 1999;79:365366. Koike K, Kobayashi M, Gondo M, Hayashi I, Osuga T, Takada S. Hepatitis B virus DNA is frequently found in liver biopsy samples from hepatitis C virus-infected chronic hepatitis patients. J Med Virol 1998;54:249-255. Batts K, Ludwig J. Chronic hepatitis: An update on terminology and reporting. Am J Surg Pathol 1995;19:1409-1417. Davies S, Portmann B, O’Grady J, Aldis P, Chaggar K, Alexander G, et al. Hepatic histological findings after transplantation for chronic hepatitis B virus infection, including a unique pattern of fibrosing cholestatic hepatitis. Hepatology 1991;13:150-157. Douglas D, Rakela J, Taswell H, Mamish D, Wright T, Krom R, et al. Transmission of hepatitis B virus infection from orthotopic donor livers [abstract]. Hepatology 1992;16:49A. Di Bisceglie A, Hoofnagle J. Chronic hepatitis B. In: Zakim D, Boyer T (eds). Hepatology: A textbook of liver disease (ed 3). Philadelphia: Saunders, 1996:1301-1310. Dodson S, Issa S, Araya V, Gayowski T, Pinna A, Eghtesad B, et al. Infectivity of hepatic allografts with antibodies to hepatitis B virus. Transplantation 1997;64:1582-1584.