Hepatic events after bone marrow transplantation in patients ... - Nature

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of hepatic events of hepatitis B surface antigen positive a clinical picture of hepatitis and even hepatic failure and death.6 Bone marrow transplantation (BMT) ...
Bone Marrow Transplantation, (1997) 19, 795–799  1997 Stockton Press All rights reserved 0268–3369/97 $12.00

Hepatic events after bone marrow transplantation in patients with hepatitis B infection: a case controlled study GKK Lau, R Liang, EKW Chiu, CK Lee and SK Lam Department of Medicine, Queen Mary Hospital, Hong Kong

Summary: Hepatitis B reactivation following chemotherapy withdrawal may result in hepatitis, hepatic failure and death. We studied the clinical outcome and the causes of hepatic events of hepatitis B surface antigen positive recipients undergoing bone marrow transplantation. Twenty-four hepatitis B surface antigen patients were matched with 24 hepatitis B surface antigen negative patients for age, sex, CMV positive serology, underlying hematological disease and type of bone marrow transplantation. Post-BMT, there were 18 patients in the hepatitis B surface antigen positive group and four patients in the hepatitis B surface antigen negative group who suffered from hepatitis (P , 0.05). Thirteen of the 18 hepatitis were related to HBV reactivation in the hepatitis B surface antigen positive group and none of the four hepatitis in the hepatitis B surface antigen negative group (P = 0.01). The hepatitis B surface antigen positive group also had an increased incidence of acute graft-versus-host disease of liver (6 vs 1, P = 0.03). However, there was no significant increase in the incidence of veno-occlusive disease (10 vs 7, P = 0.40) and persistent hepatitis (3 vs 0, P = 0.07) in the hepatitis B surface antigen positive group. Using the log-rank test, there was no significant difference in survival between the hepatitis B surface antigen positive and negative recipients. Keywords: HBV; bone marrow transplantation; hepatitis; VOD; GVHD; HBV reactivation

Chronic hepatitis B infection is endemic in Hong Kong with a carrier rate of 10%.1 Previously, we reported a higher incidence of clinical hepatitis in lymphoma patients undergoing chemotherapy who were hepatitis B surface antigen (HBsAg) positive than in those who were negative.2,3 Around 72% of the hepatitis in HBsAg positive carriers could be attributed to reactivation of hepatitis B virus (HBV) replication.3 Reactivation of HBV is a well recognized complication in patients with chronic HBV infection who receive cytotoxic or immunosuppressive therapy.4,5 It Correspondence: Prof R Liang, Department of Medicine, Queen Mary Hospital, 102 Pokfulum Road, Hong Kong Presented in part at the American Association for the Study of Liver Diseases of Digestive Disease Week, May 1995, in San Diego, CA, USA Received 6 July 1996; accepted 30 November 1996

is generally believed that immunosuppresion enhances viral replication with consequent increase in hepatocyte infection. Withdrawal of cytotoxic or immunosuppressive drugs leads to restoration of immune function, resulting in rapid destruction of infected hepatocytes. This may give rise to a clinical picture of hepatitis and even hepatic failure and death.6 Bone marrow transplantation (BMT) has become a standard treatment for various hematological malignancies.7 During the procedure, intensive chemotherapy with and without total body irradiation was required to ablate the recipients’ marrow. Furthermore, immunosuppressive agents have to be administered for at least 6 months after BMT for prevention or treatment of graft-versus-host disease (GVHD). Therefore, one would anticipate that chemotherapy withdrawal HBV reactivation would be a problem after bone marrow transplantation. In fact, fatal fulminant hepatitis due to HBV reactivation has been reported in HBsAg positive carriers undergoing BMT.8 The aim of this study was to define the incidence of hepatic events (hepatitis and hepatic failure) in the HBsAg positive patients undergoing BMT and the causes of the hepatic events. Patients and methods Patients studied Two hundred and twenty-four patients received a BMT at Queen Mary Hospital between May 1990 and March 1995. All of them were screened before BMT for hepatitis serology (HBsAg/Ab, HBeAg/Ab, anti-HCV (EIA II), antiHDV). Twenty-five patients were HBsAg positive and among them one was also HCV Ab positive (EIA II). Twenty-four patients who were HBsAg positive alone (HBeAg positive/anti-HBe positive/HBV DNA positive: 11/13/9) were matched with 24 HBsAg negative (anti-HBs positive/negative: 11/13) and HCV Ab negative patients for age (30.5 6 8.6 years vs 28.7 6 8.4 years), sex (M/F:18/6 vs 19/5), CMV positive serology (24/24 vs 24/24), underlying hematological disease (AML or ALL/CML/aplastic anemia/others: 10/5/1/8 vs 5/8/4/7) and type of bone marrow transplantation (allogeneic/autologous: 17/7 vs 18/6). The median follow-up period was 32 months (1–68 months) (Table 1). Definitions Hepatitis was defined as an elevation of serum alanine aminotransferase (ALT) .2 × upper limit of normal (ULN)

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Table 1 studied

Demographic data of HBsAg positive and negative patients

HBsAg + ve (n = 24) Male/Female Mean age (years) Median follow-up (months) Primary disease ALL or AML/CML/AA/others Type of BMT Allogeneic/autologous Conditioning regimen CY-TBI/Bu-CY-TBI/VP16-CYTBI/Mel-TBI/Bu-CY/CBV/CYATG GVHD prophylaxis None/Short MTX-CsA/MTX Serology Hepatitis C antibody positive Cytomegalovirus antibody positive

HBsAg − ve (n = 24)

18/6

19/5

30.5 6 8.6

28.7 6 8.2

27.2

33.4

10/5/1/8

5/8/4/7

17/7

18/6

6/5/2/1/ 4/5/1

6/6/1/0/ 5/5/1

7/17/0

7/16/1

0 24

0 24

Statistical analysis

x2 test or Fisher’s exact analysis were used to compare the hepatic events (transient hepatitis, persistent hepatitis and hepatic failure) and death between patients who were HBsAg positive and HBV negative. Survival differences among the two groups were also compared using the logrank test. The Statistical Package of Social Sciences (SPSS) was used. Results Hepatic events

Bu = busulphan; CY = cyclophosphamide; TBI = total body irradiation; B = BCNU; VP16 = etoposide; ATG = anti-thymocyte globulin; M = melphalan; MTX = methotrexate; CsA = cyclosporin A.

on two consecutive determinations at least 5 days apart. Icteric hepatitis was defined as hepatitis associated with clinical jaundice and serum bilirubin level that exceeded 30 mmol/l (normal, ,19 mmol/l). Hepatitis was defined to be transient if the duration was less than 6 months and to be persistent if the duration was more than 6 months. Hepatitis would be related to reactivation of HBV if there was an accompanying elevation of serum HBV DNA .2 × of the pre-exacerbation baseline, or the serum HBV DNA turned from negative to positive with exacerbation of the hepatitis. Hepatic failure was defined as the presence of hepatic encephalopathy and deranged blood coagulation (prothrombin time .10 s above normal). Veno-occlusive disease (VOD) was defined using the Baltimore criteria9 and acute graft-versus-host-disease (GVHD) of the liver was defined and graded in accordance with the Glucksberg criteria.10 Hepatitis serology assays Hepatitis B serological markers: HBsAg/Ab, HBeAg/Ab, anti-HCV (EIA II), anti-HDV and anti-HIV were all tested by commercially available enzyme immunoassay (Abbott Laboratories, Chicago, IL, USA). Anti-HBc (total) was tested by radioimmunoassay (Corab; Abbott Laboratories). Serum HBV DNA Dot hybridization for the detection of hepatitis B virus DNA was performed by a modification of the method of Matsuyama et al.11 Serial samples from the same patient were tested in the same run to minimize interassay variations.

Pre-BMT, five HBsAg positive patients had elevations of serum alanine aminotransferase (ALT) and only one of the HBsAg negative patients had an elevation of ALT (5/24 vs 1/24, P = 0.08). None of the patients had clinical evidence of cirrhosis (ascites, esophageal varices, or hypersplenism). Post-BMT, there were 18 (75%) patients in the HBsAg positive group and four (16.7%) patients in the HBsAg negative group who suffered from hepatitis (P , 0.05) (Table 2). None of the patients had more than one episode of hepatitis. Among the 18 episodes of hepatitis in the HBsAg positive group, 15 were transient and three persistent. Of the 15 patients in the HBsAg positive group who suffered from transient hepatitis, there were 11 anicteric and two icteric episodes and two hepatic failures. In the HBsAg negative group, only four patients suffered from transient hepatitis (all four were anicteric) and none suffered from persistent hepatitis. There were significantly more cases of transient hepatitis in the HBsAg positive group (P = 0.001). The mean onset of transient hepatitis was 120 days in the HBsAg positive group (range: 27–425 days) and 112 days in the HBsAg negative group (range: Table 2

Hepatic complications after bone marrow transplantation

Hepatic events

HBsAg + ve (n = 24)

HBsAg − ve (n = 24)

P value

Transient hepatitis Anicteric Icteric Hepatic failure Overall

11 2 2 15

(7) (1) (2) (10)

4 (0) 0 0 4 (0)

0.001

Persistent hepatitis Anicteric Icteric Hepatic failure Overall Total hepatic events

1 (1) 0 2 (2) 3 (3) 18 (13)

0 0 0 0 4 (0)

0.07 0.0001

Acute hepatic GVHD Grade 1 2 3 4 Overall VOD

2 4 0 0 6 10

1 0 0 0 1 7

0.03 0.40

Number in parentheses denote the number of patients who developed hepatitis related to reactivation of HBV replication.

Hepatic events after BMT GKK Lau et al

11–236 days) after BMT (P = NS). HBV reactivation was considered to be the cause of hepatitis in 13 of the 18 hepatitis in the HBsAg positive group and none of the four cases in the HBsAg negative group (P = 0.01). Among the 15 cases of transient hepatitis in the HBsAg positive group, 10 (67.7%) were attributed to HBV reactivation, two (13.3%) related to relapse of the underlying hematological malignancy and one (6.7%) to systemic sepsis. The cause in the remaining two was indeterminate. In the HBsAg negative group, no cases of hepatitis were related to HBV (HBsAg, HBeAg, HBV DNA negative). Two were caused by systemic sepsis and the other two were indeterminate (Table 3). Three patients had persistent hepatitis in the HBsAg positive group and none in the HBsAg negative group (P = 0.07). These three episodes were all related to HBV reactivation. Onset of the persistent hepatitis was 130 days (range: 108–153 days). Two of these patients later died of hepatic failure. Altogether, there were four episodes of hepatic failure in the HBsAg positive group and none in the HBsAg negative recipients (P = 0.04). All four episodes of hepatic failure, including three deaths, were related to HBV reactivation. There were six cases of acute hepatic GVHD in the HBsAg positive group and only one in the HBsAg negative group (P = 0.03). Among the six cases of acute hepatic GVHD in the HBsAg positive group, two were grade one and four were grade two. In the HBsAg negative group, there was only one grade one. However, the differences in the severity of acute GVHD between the HBsAg positive and negative groups did not reach statistical significance. There was no significant increase in incidence of VOD in the HBsAg positive group as compared to the HBsAg negative group (10 vs 7, P = 0.40) (Table 2). Pre-BMT elevation of ALT was found in one (5.9%) of the 17 patients who suffered from VOD and six of the 31 (19.4%) patients who did not have VOD (P = 0.30). Of the 42 patients with normal ALT before BMT, 19 were HBsAg positive and 23 were HBsAg negative. There were nine (47.4%) VOD in the HBsAg positive group and seven (30.4%) in the HBsAg negative group (P = 0.26). Factors associated with hepatitis in the HBsAg positive patients Among the HBsAg positive patients, development of hepatitis was not associated with age, sex, underlying hematological diseases, type of bone marrow transplan-

Table 3

tation, conditioning regimen, presence or absence of HBeAg, HBeAb and serum HBV DNA prior to BMT (Table 4). Survival There were eight deaths in the HBsAg positive group and six deaths in the HBsAg negative group (P = NS). The causes of death (HBsAg positive/HBsAg negative) were disease relapse (4/3), fungal infection (1/3) and hepatic failure (3/0). Using the log-rank test, there were no significant differences in survival between HBsAg positive and HBsAg negative groups (P = 0.54) (Figure 1). Discussion Previously, we reported an increased incidence of hepatic events in HBsAg positive patients (21–67%) undergoing chemotherapy for lymphoma.2,3 In this retrospective study, we report an increased incidence of hepatitis in HBsAg positive patients receiving bone marrow transplantation (75%). Of the 18 episodes of hepatitis in these HBsAg positive patients, 13 (72.2%) were related to HBV reactivation.

Table 4 Comparison of the 24 HBsAg positive patients who did and did not develop hepatitis after BMT

No. of patients Sex (Male/Female) Age (years) Underlying hematological diagnosis ALL or AML/CML/AA/others

Hepatitis

No hepatitis

18 15/3 32.8 ± 7.6

6 3/3 23.5 ± 8.0

10/3/1/4

0/2/0/4

15/3

2/4

7/3/1/1/ 3/3/1

5/8/2/0/ 6/7/1

3 7/11 6

2 4/2 3

BMT type Allogeneic/autologous Conditioning regimen CY-TBI/Bu-CY-TBI/VP16CY-TBI/Mel-TBI/BuCY/CBV/CY-ATG Pre-BMT Elevation of ALT HBeAg/HBeAb HBV DNA+

Incidence and causes of hepatitis after BMT HBsAg + ve

No. of patients No. of hepatitis Reactivation of HBV replication Relapse Systemic sepsis Indeterminate

24 18 13 2 1 2

HBsAg − ve Anti-HBs + ve

Anti-HBs − ve

11 1 0 0 1 0

13 3 0 0 1 2

797

Hepatic events after BMT GKK Lau et al

798

The mean onset of these episodes was around 4 months after BMT and this coincides with the time of immune recovery12 and tailing down of immunosuppression. In the HBsAg positive group, there were four episodes of hepatic failure related to HBV reactivation, with three deaths. This is significantly higher than in the HBsAg negative group. Reactivation of hepatitis B virus (HBV) replication is generally postulated to be related to enhanced viral replication followed by restoration of immune function (on withdrawal of immunosuppression), resulting in rapid destruction of infected hepatocytes.13 Therefore, the development of hepatitis in these HBsAg positive patients may be prevented, at least theoretically by suppressing viral replication during and shortly after the tailing down of immunosuppression. Recently, second generation nucleoside analogues, such as lamivudine and famciclovir, have been shown in animal models and human studies to be effective in inhibiting HBV replication.14–16 The effectiveness of these agents in preventing HBV reactivation in HBsAg positive patients receiving chemotherapy or bone marrow transplantation remains to be assessed. Our previous study has shown that male sex or the presence of HBeAg was associated with the development of hepatitis in HBsAg positive patients following chemotherapy for lymphoma.2 In this study, we were unable to identify any factors as associated with the development of hepatitis in the HBsAg patients undergoing bone marrow transplantation. It is uncertain whether this is due to the relatively small number of patients in the present study. Also, some other factors, such as pre-BMT liver histology (the presence of cirrhosis), could play an important role in determining the hepatic outcome of these patients. As this is a retrospective study and liver biopsy was not routinely performed, this possibility could not be addressed. A future prospective study is thus awaited. Pretransplant liver disturbance, mostly hepatitis, has been shown to be the most significant risk factor for VOD.17 In most series, such patients had a 2.5 to four times increased risk of VOD. However, it was uncertain whether chronic HBV infection per se could increase the incidence of VOD. In our study, only six of the 48 patients had elevated ALTs before BMT. Of the 42 patients with normal ALTs before BMT (19 HBsAg positive and 23 HBsAg negative), we observed no significant association between the occurrence of VOD and positive HBsAg status. This might suggest that hepatitis, rather than HBV status, is more important in determining the occurrence of VOD. However, these are only preliminary observations which require a further larger study for confirmation. The previously observed increased incidence of VOD in patients with chronic hepatitis might relate more to the existing abnormal liver function rather than the carrier state of the hepatitis B virus. As most of the patients were profoundly thrombocytopenic early on, liver histology was not available in most cases and even with histology, distinguishing between other causes of hepatitis might be difficult.18 In our present study, the diagnosis of acute hepatic GVHD was thus defined as the presence of histological evidence of other target organ involvement with GVHD in conjunction with the development of abnormal serum liver biochemistry. Taking this shortcoming into consideration, an association between

acute hepatic GVHD and the HBsAg positive status of the recipients was found in this study. Previously, it has been shown that acute GVHD of the liver could be related to HCV and CMV infection.19,20 The exact mechanism is unknown. It is possible that viral infection could augment the expression of the minor MHC antigens in the recipients, which serve as targets for donor lymphocytes.21 Also, enhanced cytokines production has been found in patients with acute GVHD. 22 It could be that chronic HBV infection increases the production of cytokines and augments the development of acute GVHD. To conclude, BMT recipients who were HBsAg positive, as compared to those who were HBsAg negative, had an increased incidence of post-BMT hepatitis, hepatic failure and acute hepatic GVHD. However, the overall post-BMT survival was not affected by the HBsAg positive status of the recipients. Acknowledgements We thank Miss WS Yuen for her assistance in collecting the data and Mr Stanley Young for his help in data analysis.

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18 Snover DC, Weisdorf SA, Ramsay NK et al. Hepatic graftversus-host disease: a study of predictive value of liver biopsy in diagnosis. Hepatology 1984; 4: 123–130. 19 Appleton AL, Sviland L, Peiris JS et al. Role of target organ infection with cytomegalovirus in the pathogenesis of graftversus-host disease. Bone Marrow Transplant 1995; 15: 557–561. 20 Frickhofen N, Wiesneth M, Jainta C et al. Hepatitis C virus infection is a risk factor for liver failure from veno-occlusive disease after bone marrow transplantation. Blood 1994; 83: 1998–2004. 21 Appleton AL, Sviland L. Pathogenesis of GVHD: role of herpes viruses. Bone Marrow Transplant 1993; 11: 349–355. 22 Ferrara JL Cytokine inhibitors and graft-versus-host disease. Ann NY Acad Sci 1995; 770: 227–236.

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