Hepatitis B virus reinfection after orthotopic liver transplantation

Journalof Hepato!ogy, 1992; 14: 104-111 @ 1992EisevierSciencePublishersB.V. All rightsreserved.01688278/92/$03.50

104 HEPAT 00899

Hepatitis B virus reinfection after orthotopic liver transplantation Serological and clinical implications Heather M. Smith, Susan E. Davies, Helena hf. Daniels, Peter T. Donaldson, K.C. Tan, Bernard Portmann, Graeme J.M. Alexander and Roger Williams

John G. ()‘Grady,

Institute of Liver&dies,

King’s Coliege School of Medicine and Dentistry, Loxdora, United Kingdom

(Received 12July 1991)

The implications of hepatitis B virus (HBV) reinfection after liver transplantation were studied in 29 patients followed for 1.7-15 years. Of 20 patients with HBV infection alone, nine were HBeAg and HBV DNA seronegative and 11 had evidence of HBV replication as measured by HBeAg or HBV DNA seropositivity. Nine patients had co-existing HBV and delta virus (HDV) infection. Five patients became HBsAg seronegative after transplantation (four immediately and one after an hepatitic episode). Of the 20 patients with HBV infection alone, 17 had evidence of viral replication after transplantation with markedly increased HBV DNA levels. Five patients with HDV infection had HBV DNA in serum, but in significantly lower amounts than in those with HBV infection alone. Twenty-five episodes of graft dysfunction attribute to recurrent HBV infection occurred in 19 patients (65.5%). Thirteen episodes (in 12 patients) were self-resolving acute hepatitic illnesses. Six patients had a rapidly progressive illness leading to graft loss within 6 weeks, with the distinctive histological features termed fibrosing cholestatic hepatitis (FCH). Liver function tests in these patients showed markedly abnormal serum bilirubin and prothrombin times, but only modest increases in serum transaminase levels. An additional six patients lost their graft as a consequence of HBV recurrence through various pathogenetic mechanisms including possible (but unproven) FCH, chronic active hepatitis or late-onset hepatic failure. Co-existing HDV infection appeared to confer some medium-term protection from graft loss.

Chronic hepatitis B virus (HBV) infection is potentially one of the commonest indications worldwide for liver transplantation, either because of end-stage liver disease or the development of hepatocellular carcinoma. In such cases reinfection of the graft with HBV is an additional hazard affecting outcome after transplantation. Data from the Pittsburg group showed l- and Z-year actuarial survival rates (in 36 patients) of 57% and 4Cl%, respectively, as compared to 78% and 71% for 240 patients with postnecrotic or cryptogenic cirrhosis (1). This group at one time suggested that the risk of reinfection in patients who are hepatitis B ‘e’ antigen positive (HBeAg) was prohibitive, and was an absolute contraindication to transplantation (2), a policy that seems to have been adopted by a number of other centres (3,4). Subsequently, howev-

er, this view was modified (5) and successful transplants have been reported in HBeAg positive patients both with and without long-term immunoglobulin prophylaxis (6,7). The outcome after liver transplantation in patients with co-existing HBV and delta virus (HDV) infection also appears to be variable (3,4,8-lo), although the interpretation of these data is complicated by the use of long-term immunoglobulin prophylaxis in the majority of these cases. In this paper we detail our experience of 29 patients with HBV infection whose selection for transplantation was not influenced by pre-transplant viral serology and who were not systematically subjected to protracted immunoprophylaxis regimens after transplantation. These data give an insight into the natural history of HBV infection after hver transplantation.

Correspondence:Dr. Roger Williams,Director, Institute of LiverStudies,King’s

College

Hospital,Denmark Hill, London 8E8 8=, U.K.

HEPATITIS I3 AND LIVER TRANSPLANTATION

Between December 1975 and April 1989, 39 patients with hepatitis B surface antigen (HBsAg) detectable in serum underwent orthotopic liver transplantation in the Cambridge/King’s College Hospital joint programme. Ten of these died within 21 days of transplantation (haemorrhage five, sepsis three, multisystem failure two) and were therefore not suitable for study with respect to recurrence of HBV infection. Of the remaining 29 patients, 18 (15 male; range 23-61 yrs) had end+tage chronic liver disease, including one patient with the Budd-Chiari syndrome (case 17). Eleven patients (nine male; age range 24 -63 yrs) had hepatocellular carcinoma (HCC), which was of the fibrolamellar variant in one instance (case 3), and in nine cases there was underlying cirrhosis. The former group of patients had higher prothrombin times, serum bilirubin and aspartate aminotransferase levels, and lower serum albumin levels than the tumour patients (Table 1). The transplant procedure and post-operative management were as previously described in detail elsewhere (llJ2). The three patients transplanted between 1975-8 (cases 1, 18 and 19) were immunosuppressed with prednisolone and azathioprine, four (cases 8, 17, 23 and 25) were maintained on cyclosporine and prednisolone and the remainder were on ‘triple immunosuppression’ with all three drugs, using previously published protocols (13). No specific modifications were made to the immunosuppression regimens because of rhe presence of HEW infecbi0rl. The serological profiles immediately prior to transplantation were used to divide the patients into three subgroups: (a) nine patients with HBV infection alone but without evidence of HBV replication, i.e., HBeAg and HBV DNA seronegative; (b) 11 patients with HBV infec-

TABLE 1 Laboratory parameters in 39 patients transplanted with HBsAg in serum (median and range) Tumour (n = 16) Haemoglobin (g/dl) White ceil count ( x lOgIl) Platelet count (X log/l) Prothombin time (s) Serum creatinine (jfmolil) Serum bilirubin @moUl)

12.5 (9.3-17.1) 4.4(1.9-10.1) 102 (38-271) 17 (13-30) 78 (58-138) 18 (5-65)

Aspartate aminotransferase (IUn) Alkalinephospbatase(WI) Serumalbumin(g/l)

83 (30-610) 284(112-434) 35 (22-44)

*jJ< 0.01; lp < 0.05.

No3-tumour (n = 23) 11.6 (7.7-14.0) 4.4(1.8-13.8) 84 (20-350) 22 (16-33)+ 76 (49-510) 65 (17-429)*

124(43-336)* 109(13-536) 28 (23-43)**

105 tion alone with evidence of viral replication; and (c) nine V and co-existing delta virus (NDV) infection (Table 2). IgM antibody to the I-IBV core antigen was found in only one patient (case 8). Antibodies to HDV were of the IgM category in eight of the nine patients (except case 28). Delta antigen was undetectable in serum in all six patients with IgM anti-delta antibodies who were tested. Four paricuts (cases 15, 20, 22 and 28) had received courses of interceron (varied doses of l-10 MU) for total periods of between 3-10 months within 3 years of being referred for rransplantation. No significant clinical or serological response to interferon was reported in any of these four patients. Five patients (cases 1, 12, 14,18 and 19) received varying doses of anti-HBsAg (HBIg) during the anhepatic phase of the transplant operation, and in one patient (case 14) this treatment was continued for 4 months post-transplant.

TABLE 2 Hepatitis B virus (HBV) and delta (HDV) serology before liver transplantation Case

HRsAg

HBsAb

HBeAg HBeAb HBV DNA

(a) HBV alone without viral replication 1

+

2 3 4 5 6 7 8 9

+ + + + + + + +

N.D. -

-

+ -

-

(b) HBV alone with viral replication 10 + 11 + 12 + 13 + 14 + + 15 + -+ 16 + 17 + + 18 + + N.D. + 19 + 20 + (c) HBV and Delta 21 + 22 + 23 + 24 + 25 + 26 + 27 + 28 + 29 + N.D., not done.

-

-

N.D.

-

+ + + + + N.D. +

11 10 10 76 N.D. 21 98 131 N.D. N.D. 11

12 15 9 -

AntiHDV

J.G. O’GBADY et al.

106 was used to measure HBsAg, HBeAg, anti-NBS and anti-HBe (Ausria II, Abbott HBe @DNA), Ausab, Abbott, North Chicago, IL). Anti-HBc IgM and total anti-delta were tested by enzyme immunoassay (Corzyme-M, Abbott anti-delta EIA, Abbott). Delta Ag and anti-delta IgM were also tested by enzyme immunoassay (Deltassay Ag, Deltassay IgM, Noctech, Dublin, Ireland). Serum HBV DNA was assayed by a modified spot hybridisation, with single-stranded DNA being prepared by alkali treatment of Dane particles concentrated from serum by ultracentrifugation and applied to nylon hybridisation membrane under vacuum. Hybridisation with 32P-labelled HBV DNA was by standard methods and HBV DNA quantification (expressed as pg/40@ serum) was by scintillation counting and comparison with standards (14). Kaplan-Meier survival curves are used to compare outcome in the 29 HBV patients and that of 141 HBsAg seronegative patients with chronic liver disease (71 primary biliary cirrhosis, 25 autoimmune chronic active hepatitis, 14 alcoholic, 31 post-hepatitic or cryptogenic) and 39 patients with hepatocellular carcinoma and negative HBV serology transplanted during the same period and who survived at least 60 days post-transplantation. The maintenance immunosuppressive regimens used in the HBsAg seronegative patients were prednisolone and azathioprine in 27, cyclosporine f low-dose prednisolone in 63 and triple therapy in 90. The Mann-Whitney U test wds used to compare non-parametrically distributed laboratory data. Chi-square test was used to test for differences in observed frequencies in patient subgroups. Radioimmunoassay

TABLE 3 Hepatitis B virus (HBV) and delta serology after liver transplantation Case

HBsAg HBsAb

HBeAg

HBeAb

HBV DNA

AntiHDV

(a) HBV alone without viral replication before transplantation 1 N.D. N.D. >800 + 2 + >a00 + 3 + + N.D. 4 + + >800 5 + + 130 6 + + >800 7 + + 8 + >a00 9 + (b) HBV alone with viral replication b&ore transplantation + 2 10 + + ~800 11 + >800 + 12 + + >800 13 + + >800 14 + + >800 15 + >a00 + 16 + >a00 + 17 + + N.D. 18 + + N.D. N.D. 19 + + >800 20 + -

-

(c) HBV and Delta 21 + 22 + 23a + b24 25 + 26 + 27 + 28 + 29 -

+ + + + + + + + + +

+ + + + -

-

+ +

242 126 235

797 8 -

N.D., not done.

Results Serologicalfindings The individual results are given in Table 3. HBsAg became undetectable in 11 patients between 1 day and 10 weeks (median 4 weeks) post-transplantation, and four of these remain seronegative for HBsAg at 20 months to 14 years despite not receiving long-term HBIg therapy. HBsAg was again detectable in serum at 8-18 weeks (median 15 weeks) in the remaining seven patients who were initially seronegative for HBsAg. However, one of the latter group (case 23) subsequently reverted to being HBsAg seronegative after a conventional hepatitic illness. The only one of these five HBsAg seronegative patients to develop anti-HBs was the single patient who had IgM antibody to core antigen pre-transplant. Three of the four patients given HBIg became seroposirive for HBsAg at 3, 3 and 17 weeks after transplantation, but one remains seronegative 15 years later. Three patients (cases

10, 17 and 19) developed IgM antibodies to core antigen after transplantation Active HBV replication was confirmed in six of eight patients in group (a), 11 of 11 patients in group (b) and five of nine patients - although only transiently in one instance - in group (c). The number of patients seropositive for HBeAg increased from five prior to transplantation to 15 afterwards. There was also a massive increase in HBV DNA levels in patients with HBV infection alone, and a significant but more modest increase in those with co-existing HBV and HDV infections. Four patients with antibodies to delta virus pretransplantation were found to have transient expression of delta antigen in serum, 12-32 weeks after surgery, which lasting for up to 7 weeks (cases 21,23,25 and 28). Graft diseaserelatedto recurrent HBV infection Nineteen of the 29 patients (65.5%) developed episodes of graft dysfunction leading to jaundice for which,

HEPATITIS B AND LIVER TRANSPLANTATION

after appropriate investigation with ultrasonic imaging, liver biopsy and cholangiography or angiography, no cause other than recurrence of HBV infection could be identified. In 12 of the patients, self-resolving episodes occurred at median durations of 12 weeks after transplantation. In each instance the predominant histological feature was an acute lobular hepatitis. Results of the liver function tests (median, range) were consistent with the pathology; serum bibrubin 170,38-426 ymol/l, aspartate aminotransferase 456, 115-2099 U/l, alkaline phosphatase 206, 116-500 W/l and prothrombin time 15, 12-20 s. One of these patients (case 22) had a second hepatitic illness 6 weeks after resolution of the first in close temporal association with the reappearance of IgM antibody to delta in serum. In 12 patients the HBV-related episodes resulted in graft loss, occurring at a median of 9 months (range 3-14 months) after transplant surgery. Six of these 12 patients (cases 5,7,9,14,15 and 20) appeared to have an unique lesion, which has been termed fibrosing cholestatic hepatitis (FCH) on the basis of certain histological criteria which have been described in detail elsewhere (15). However, the essential features are extensive serpiginous periportal fibrosis, canalicular and cellular cholestasis, prominent cytoplasmic HBsAg and HBeAg expression, and only a mild mixed inflammatory cell infiltrate (15). Three of these cases had been asymptomatic and had good liver function before the onset of FCH which led to death within 4 weeks of the onset of the jaundice. In the other three patients, FCH developed in a clinical episode that commenced as a histologically proven lobular hepatitis with markedly elevated aspartate aminotransferase levels, but progressed in a uniphasic pattern in two cases and a biphasic pattern (i.e., significant improvement in, but trot normalization of, the serum bilirubin and aspartate aminotransferase levels before onset of FHC) in one instance to loss of the graft. Clinically, the cases with FCH showed rapid and progressive deterioration in graft function leading to jaundice, a clinical coagulopathy, encephalopathy and death from liver failure within 4-6 weeks of onset. In comparison to the patients with self-resolving lobuIar hepatitis, the serum biiirubin levels were higher (median S40,umol/l, range 306-758pmol/l; p < 0.05) and the aspartate aminotransferase levels were lower (281, 94-600 U/l; p c 0.05). Alkaline phosphatase levels were similar (204, 125-282 U/l). The only discriminatory liver function test with no overlap between the two groups was the prothrombin time (median 50 sin FCH patients, range 28-80 s, as compared to a range of 12-20 s in lobular hepatitis) .

Another patient (case 21) had some histological features of FCH, but possible progression to the established

107 syndrome was considered to have been modified by early retransplantation. A further three patients (cases 4, 11 and 12) had clinical illnesses and derangements of liver function very similar to those seen with FCH leading to graft loss, but liver tissue was unavailable to establish the diagnosis. One patient (case 10) showed a typical clinical and histological picture of late-onset hepatic failure. Histological examination of the explanted graft in this case showed no features of FCH, but there was extensive hepatocyte necrosis, multiacinar collapse and a brisk inflammatory cell infiltrate. The last of the 12 patients considered to have died of recurrent disease (case 13) had severely abnormal liver function tests (serum bilirubin 232 pmol/l, prothrombin time 31%) with severe chronic active hepatitis on liver biopsy when he succumbed to cryptococcal meningitis. The rate of graft loss through recurrence of HBV infection was 44.1% in those with HBV but without evidence of viral replication before transplantation, 63.6% in those with active HBV replication and 11.1% in those with coexisting HBV and HDV infections (Chi-square 5.68, p = 0.058). Overall survival was higher in those with HDV infection (88.9%) than in those with isolated HBV infection (30%, p < 0.01). Effect of HLA marching

HLA A and B donor/recipient matching was known for 17 of the 29 patients, including nine who lost the graft as a consequence of HBV infection; six of ten with no matches lost the graft, as compared to three of six with one to three matches (N.S.). The HLA DR matching was known in 15 patients; 11 had no match and six of these lost the graft, as compared to hvo of four with one match (N.S.). Closer analysis of those losing their graft to HBV recurrence indicates that the four patients with FCH for whom data are available had variable degrees of matching for HLA A and B, but all had no match for HLA DR. In contrast the two cases to lose the graft through severe chronic active hepatitis and fulminant hepatitis had each one matched HLA DR antigen.

Long-term outcome and survival

Fourteen (48%) of the 29 patients are currently alive between 1.7-15 years (median 3.5 years) after transplantation. The most recent liver function tests in these patients are given in Table 4. This group includes two patients who survived retransplant operations, one for chronic rejection and the other for recurrence of HBV infection. The latter patient was given HBIg long-term after the retrensplant, in line with a change in policy implemented after this analysis was performed, and remains

J.G. G’GRADY et al.

Fig. 1. Liver histology in case 15. (a and b) Panacinar, pericellular fibrosis with mild inflammatory reaction and widespread occurrence of ductal

plates. (a) Heamatoxylin and eosin; (b) Reticulin x80. (c and d) Intermingled ductal plates and HBs containing hepatocytes, respectively demonstrated by AEl cytokeratin staining (c) and indirect immunoperoxidase using monoclonal anti-HBs antiserum (d) x360.

HEPATITIS B AND LfVER TRANSPLANTATION

109

TABLE 4 Long-term

Case

outcome after transplantation with HBV infection AIive

Survived

Cause of gra:t loss

Latest liver tests bilirubin

AST

alkphos.

PT

N.A. 11 14 420 491 19 306 16 540

N.A. 21 55 N.D. 281 37 116 25 947

N.A. 216 99 N.D. 142 566 221 280 89

N.A. 16 16 80 80 15 71 14 28

595a

298

12b 105c N.A. 232 768 591a 171d 16 21 335 N.A. 607

i7 75 N.A. 50 94 341 145 55 40 148 400 961

1050 173 134 N.A. 282 121 125 132 189 126 437 N.A. 155

30 15 22 N.A. ‘31%’ 34 37 18 16

652 23 18 21 32 20 15 17 564” 24b

280 66 30 27 113 55 58 138 533 25

(a) HBV alone without viral replication before transplantation

yes yes UO

no IlO yes

no yes II0

15 years 3.7 jrears 2.2 years 8 months 8 months 3.6 years 10 months 4.6 years 3 months

tumor recurrence HBV recurrence HBV recurrence HBV recurrence HBV recurrence

(b) HBV alone with viral replication before transplantation 10 11 12 13 14 15 16 17 18 19 20

yes no

1.7 years

HBV recurrence

no

11 months 1.2 ye7rs 1.Oyears 7 months 1.1years

HBV HBV HBV HBV HBV

no Yes no no no

1.4 years 5.7 years 9 months 3 months 6 months

biiiary sepsis

110

no no

(c) HBV and HDV before transplantation 21 no 5 months 22 yes 2.5 years 23 Yes 4.7 years 24 yes 3.5 years 25 yes 2.7 years 26 yes 2.9 years 27 Yes 2.7 years 28 1.7 years yes 29 yes 1.2 years

recurrence recurrence recurrence recurrence recurrence

chronic rejection tumour recurrence HBV recurrence

HBV recurrence

chronic rejection

204 61 65 74 118

N.A. 69 74 1105 182

15 N.A. 83

20 15 14 16 16 15 15 15 13 15

a Firstliver graft; b Second liver graft; ‘3 weeks before death; d6 weeks before death. N.A., not available; N.D., not done.

HBsAg seronegatjve st 1P mc+q. Four other patients were retransplanted for reaz;,e.!t 1-IBV infection; three died within 7 -Baysfrom m&system failure and the remaining patient: died from a fJrther recurrence of HBV infection 4 months aher the seLLGiL:transplant, despite having been given HBIg. The Z-year actuarial survival rate in the 29 patients with HBV infection (51.7%) was significantly lower than in the 141 patients with chronic liver disease of other aetiologies (primary biliary cirrhosis 74.6%, autoimmune chronic active hepatitis 88.0%, alcoholic cirrhosis 71.4% and post-necrotic or cryptogenic cirrhosis 74.2%; p < O.Ol), but was higher than in the 39 patients with hepatocellular carcinoma (38.5%; p < 0.05) transplanted during the same period.

Discussion

Consideration of HBV reinfection after liver transplantation involves both the changes in the pattern of HBV replication and its impact on graft function. In our series, 86% of patients reinfected the grafted liver with HBV and 82% became chronic HBsAg carriers after their first graft. The source of reinfection is presumably an extrahepatic reservoir of HBV, with possible contenders being peripheral blood mononuclear cells, pancreas, spleen or bone marrow (16,17). Evidence in favour of the potential involvement of peripheral blood mononuclear cells was recently described in a study of HBV patients who remained HBsAg seronegative while receiving HBIg after

110

liver transplantation. Using polymerase chain reaction (pCR) techniques, HBV DNA was detected in peripheral blood mononuclear cells in seven of 11 patients who, in addition to being HBsAg seronegative, had no evidence of HBV DNA in the liver graft as also determined by PCR assay (18). The failure of most patients who clear HEsAg after transplantation to produce HBsAb has been previously observed (19), and it is unclear whether such cases should be given the HBV vaccine. Following graft reinfection there was a marked increase in viral replication when compared to the pretransp!ant state; 100% of all patients replicating pretiansplant continued to do so afterwards, showing large increases in levels of circulating HBV DNA - rising from lo-132 pg/40~1 serum to >&JO0pgi40~1 serum in most cases. The apparent exception to this trend was the one case to develop fulminant hepatitis, and the low level of HBV DNA detected shortly before retransplantation is similar to findings in fulminant hepatitis B occurring in immunocompetent patients (20). Very high levels of HBV DNA were also seen in those patients with HBV infection alone who commenced viral replication after transplantation. Although the HBV DNA levels in patients with co-existing HBV and HDV infection also increased significantly after transplantation, they remained lower than those seen in isolated HBV infection, reflecting what has previously been described in other clinical situations (21). In this series, only two patients converted to a non-replicative state (case 5 in association with a typical acute hepatitis and clearance of HBsAg from serum, and case 10 after retransplantation for fulminant hepatitis), and in the remainder there was no evidence from HBV DNA levels of a decrease in replication with time after transplantation. This pattern is consistent with that documented when immunosuppressive therapy was commenced after renal transplantation - 91.5% and 55.5% of HBsAg seropositive patients initiated or increased viral replication, respectively, in one prospective series (22). Of considerable interest is the variable impact of HBV reinfection on liver graft function. Some patients have excellent graft function despite having active HEW replication for periods of up to 5.5 years after transplantation. In contrast, however, 41.3% of the cohort lost their primary graft as a consequence of HBV infection within 14 months. Most of the cases who died as a consequence of HBV recurrence had a rapidly progressive illness, and in six cases a unique histological pattern, recently described as fibrosing cholestatic hepatitis (15) was documented. The histological findings in these patients are unlike those found in immunocompetent patients with HBV fulminant hepatitis, especially in terms of the degree of hepatocyte necrosis and lobular collapse, a finding that is reflected in

J.G. O’GFUDY et al.

the relatively modest increases in serum aminotransferase levels observed in FCH. The pattern of liver function test abnormalities seen in FCH - rapidly increasing bilirubin and prothrombin time, static or near normal alkaline phosphatase, relatively low transaminase levels - is very unusual at more than 2 months after transplantation. It most resembles that seen with the functional cholestatic syndrome seen in the first few weeks (23), except for the severe coagulopathy and poor outcome. The pattern is unlike that found with other pathologies causing graft dysfunction at this time; acute cellular rejection, ischemia and viral hepatitis normally result in marked elevations of aminotransferases when sufficiently severe to cause a coaguloparhy, while chronic rejection or biliary obstruction/cholangitis are characterized by high alkaline phosphatase levels. In keeping with the Pittburg data (l), the rate of graft loss is significantly higher in HBV patients than in other varieties of cirrhosis, except those complicated by hepatocellular carcinoma. Interestingly, the co-existence of HDV infection appears to confer some medium-term benefit, although more detailed statistical analysis in a larger cohort is needed to verify this finding. HDV may produce this effect by partially inhibiting HBV replication. Although the impact of HjJV infection on survival in renai transplant patients remains controversial (24), the most pessimistic report calculates the risk of death from liver disease at 5% per patient-year a& no atypical histological features similar to those seen in FCH were described in that study (25). This suggests that in liver transp!snt patients the increase in HBV replication after initiation of immunosuppression is not the only factor contributing to poor graft survival. Some alteration in liver tissue characteristics may be a factor in accelerating the consequent liver disease, or even in determining the pathogenetic mechanisms by which the graft is lost. It has been suggested that HLA class I matching is responsible for the hepatic lesions in recurrent viral hepatitis after liver transplantation (26). Our data are skewed towards/recipient mismatches and fail to confirm this finding or detect any overall effect of HLA matching on graft survival. However, none of our cases of FCH had an HLA DR match, and while the numbers :..re very small it is interesting that a similar observation was recently made by the Pittsburg group in two ‘peculiar’ patients who appear to have the characteristics of FCH (19). Superior survival figures have been reported by some centres with the use of immuno-prophylaxis with HBIg and HBV vaccine. Combined active and passive immunization (up to 6 weeks post-transplant) in patients with HBV replication at the time of transplantation was thought to delay the reappearance of HBsAg in serum

HEPATITIS

B AND LIVER

TRANSPLANTATION

and decrease the clinical impact on graft function (7). The duration of passive immunisation has been extended to at least 12 months and the outcome of these studies in patients with HBV replication is awaited. However, in one French group of 16 highly selected patients who were delta positive and HBV DNA negative, this approach protected against the reappearance of HBsAg in serum in 13, although ten of these had detectable HBsAg in histologically ‘normal’ liver tissue (4). While these results appear to be good, 50% of six similar patients in this present series were also seronegative for I-IBsAg more than 6 months after transplantation. A less aggressive approach to passive immunisation (1600-2100 I.U. Ig during the anhepatic phase) protected against the reappearance

References 1

2

3

4

5

6

7

8 9

10

11

12

13

14

IwatsukiS, Stan1 TE, Todo S. et al. Experience in loo0 liver transplants under cyclosporine-steroid therapy: a survival report. Trans Proc 1988; 20: 498-504. Van Thiel DH, Schade RR, Gavder f§, Shaw BW. Iwatsuki S, Starzl TE. Medical aspects of liver transplantation. Hepatology 1984; 4: 79s-83s. Agnes S, Avolio AW, Magalini SC, et al. Results of liver transplantation for hepatitis delta virus disease without immunoprophyiaxis. Trans Proc 1989; 21: 2426-8. Reynes M, Z&ego L, Samuei D, et al. Graft hepatitis delta virus reinfection after orthotopic Iiver transplantation in HDV cirrhosis. Trans Proc 1989,21: 2424-5. Dindzans VJ, Schade RR, Van Thiel DH. Medical problems before and after transplantation. Gastroenterol Ciin N Am 1988; 17: 19-31. Demetris AJ, Jaffe R, Sheahan DG, et al. Recurrent hepatitis B in liver allografts recipients: differentiation between viral ;lepatitis B and rejection. Am J Path01 lY86; 125: 161-72. Lauchart W, Muher R, Pichimayr R. Immunoprophylaxis of hepatitis B virus reinfection in recipients of human liver ahografts. Traos Proc 1987; 19: 2387-9. Rizzetto M, Macagno S, Chiaberge E, et al. Liver transplantation in hepatitis delta virus disease. Lancet 1987; ii: 469-71. Marinucci G, Valeri L, Alfani D, Rossi Mt Di Giacomo C, Cortesini R. Delta infection and liver disease recurrence in hepatic allografts. Trans Proc 1986; 18: 1402-4. ColIedan M, Grendele M, Gridelli B, et al. Long-term results after liver transplantation in B and delta hepatitis. Trans Proc 1989; 21: 2421-3. Caine RY. Pre-treatment assessment laparotomy in tumour cases, recipient operation in adults and in children and retransplantation. In: Calne RY, ed. Liver Transplantation. London: Grune and Stratton, 1987: 221-46. Forbes GM, Caine RY, Williams R. Orthotopic liver transplartation: improved surgical techniques and early postoperative complications. J Gastroenterol Hepatoll989; 4: 449-56. O’Grady JG, Forbes A, RoUes K, Cahte RY, Williams R. Au analysis of cyclosporine efficacy and toxicity after liver transplantation. Transplantation>988; 45: 575-9. Fagan EA. Guarner P, Perza SDK, et al. Quantitation of hepatitis B virus DNA (HBV-DNA) in serum using the spot hybridi-

121 of I-IBsAg in serum for at least 10 months in seven of 11 patients, nine of whom had I-IDV (27). These observations illustrate the need for carefully designed controlled clinical trials of immunoprophylaxis in determining optimal regimens and place in management.

We thank our surgical, anaesthetic and nursing colleagues in both King’s College Hospital and Cambridge programmes for their help in the management of the patients described in this study.

ZatiOn technique and scintillation counting. J Viral Meth 1985; 12: 251-62. 15 Davies S, Portmann B, O’Grady 16, et al. Hepatic histological findings after transplantation for chronic hepatitis B virus infection, including a unique pattern of fibrosing cholestatic hepatitis. Hepatology 1991; 13: 150-7. 16 Pontisso P, Poon MC, Tiollais P, Brechot C. Detection of hepatitis B virus DNA in mononuclear blood ceils. Br Med J 1984; 288: 1563-6. 17 Davison F, Alexander GJM, Trowbridge R, Agan EA, Williams R. Detection of hepztitis B virus DNA in spermatozoa, urine, saliva and leucocytes, of chronic HBsAg carriers: a lack of relationship with serum markers of replication. 5 Hepatoll987; 4: 37-44. i8 Feray C, Zignego AL, Samuel D, et al. Persistent hepatitis B virus infection of mononuclear blood cells without conct>mitant liver infection. Transplantation 1990; 49 1155-8. 19 Demetris AJ, Todo S, Van Thiel, et al. Evolution of hepatitis B virus in iiver disease after hepatic replacement. Am J Pathol 1990; 137: 667-76. 20 Brechot C, Bernuau J, Thiers V, et al. Multiplication of hepatitis B virus in fuhninant hepatitis B. Br Med J 1984; 288: !70- 1. 21 Krogsgaard K, Kryger P, Aldershvile J, et al. Delta-infection and suppression of hepatitis B virus replication in chronic HBsAg carriers. Hepatology 1987; 7: 42-S. 22 Degos F, Lugassy C, Degott C, et al. Hepatitis B virus and hepatitis B-related viral infection in renal transplant recipients: a prospective study of 90 patients. Gastroenterol1988; 94: 151-6. 23 Williams JW, Vera S, Peters TG, et al. Cholestatic jaundice after hepatic transplantation: a nonimmunologically mediated event. Am J Surg 1986; 151: 65-70. 24 Dienstag JL. Renal transplantation and hepatitis B. (Editorial) Gastroenterology 1988; 94: 235-8. 25 Parfrey PS, Farge D, Clarke-Forbes RD, Dandavino R, Kenick S, Guttmann RD. Chronic hepatitis in end-stage renal disease: comparison of I-IBsAg-negative and HBsAg-positive patients. Kidney International 1985; 28: 959-67. 26 CalmusY, Hannoun L, Dousset B, et al. HLA class I matching is responsible for the hepatic lesions in recurrent viral hepatitis after liver transplantation. J Hepato11989: 9 (Abstr.): S16. 27 Cobedan M, Grendele M, Gridelli B, et al. Long-term results after liver transplantation in B and delta hepatitis. Trans Proc 1989; 21: 2421-3.