Outcomes of Liver Transplantation in Simultaneously Hepatitis B Surface Antigen and Hepatitis C Virus RNA Positive Recipients: The Deleterious Effect of Donor Hepatitis B Core Antibody Positivity

Outcomes of Liver Transplantation in Simultaneously Hepatitis B Surface Antigen and Hepatitis C Virus RNA Positive Recipients: The Deleterious Effect of Donor Hepatitis B Core Antibody Positivity F. Tandoi, R. Romagnoli, S. Martini, E. Mazza, E. Nada, D. Cocchis, F. Lupo, and M. Salizzoni ABSTRACT Background. Recent data from Italian studies have shown excellent results of liver transplantation (LT) in hepatitis B virus (HBV)–infected patients with grafts from hepatitis B core antibody (HBcAb)—positive donors, whereas such grafts in hepatitis C virus (HCV)–infected recipients have displayed poorer outcomes. We investigated the results of LT with HBcAb-positive grafts in patients with ongoing HBV and HCV coinfections. Methods. From August 1999 to December 2009, we performed 27 adult primary LTs from deceased heart-beating donors into recipients showing hepatitis B surface antigen (HBsAg)- and HCV-RNA-positivity simultaneously: 12 patients received a graft from an HBsAg-negative HBcAb-positive donor (core⫹D group) and 15 from an HBcAb-negative donor (core⫺D group). Immunosuppression included a calcineurin inhibitor, antimetabolite and steroids which were suspended at 6 months. Anti-HBV prophylaxis was always perfomed with anti-HBs immunoglobulins and nucleos(t)idic analogues. Results. The groups were similar regarding variables of donor, recipient, donor-recipient match, LT procedure, and acute rejection treatment. Median follow-up for surviving grafts was 67 months (range, 16 –141). Among all patients, HCV-RNA remained positive after LT. The prevalence of histologically proven recurrent HCV hepatitis was similar in the 2 groups: 83% core⫹D vs 73% core⫺D. No recurrent HBV hepatitis occurred during the follow-up. Graft survival at 5 years was significantly lower in the core⫹D group (core⫹D 48% vs core⫺D 87%; P ⫽ .018), in which a significantly higher prevalence of graft loss was caused by HCV recurrence (core⫹D 5/12, 42% vs core⫺D 1/15, 7%; P ⫽ .03). All of the 5 core⫹D patients who lost their grafts due to HCV recurrence did not receive anti-HCV therapy (4 owing to an aggressive disease and 1 because of patient refusal). Conclusions. Outcomes of LT in patients with ongoing HBV and HCV coinfection are adversely affected by donor HBcAb positivity, an effect that is mainly mediated by the dismal course of HCV recurrence after LT. ecently, in Italy, multicenter studies have provided data on the outcomes of liver transplantation (LT) with grafts from hepatitis B core antibody (HBcAb)–positive donors.1,2 Although excellent results have been documented in hepatitis B virus (HBV)–infected patients, a negative impact on prognosis has been suggested by the presence of hepatitis C virus (HCV) in the recipient. Our single-center experience in the past decade confirmed those findings, indicating the existence of an adverse effect on graft survival exerted by donor HBcAb positivity in HCV-

R

RNA–positive recipients.3 The possibility of an increased risk of severe graft damage due to recurrent HCV hepatitis after LT in an HBcAb-positive graft transplanted into a coinfected recipient was hypothesized based on a possible synergistic viral injury by HBV and HCV in the same From the Liver Transplant Center, General Surgery Unit (F.T., R.R., E.M., E.N., D.C., F.L., M.S.), and Liver Transplant Center (S.M.), Gastrohepatology Unit, S Giovanni Battista Hospital, University of Turin, Turin, Italy.

0041-1345/12/$–see front matter http://dx.doi.org/10.1016/j.transproceed.2012.07.061

© 2012 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710

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Transplantation Proceedings, 44, 1960 –1962 (2012)

HBcAb-POSITIVE LIVER GRAFTS IN HBV/HCV COINFECTED RECIPIENT

hepatocyte, as already described in immunocompetent hosts.4,5 In the present paper, we focused on the outcomes of LT among patients who are simultaneously hepatitis B surface antigen (HBsAg) and HCV-RNA positive depending on the HBcAb status of the donor. METHODS From August 1999 to December 2009, we performed 27 adult primary LTs from deceased heart-beating donors into simultaneously HBsAg- and HCV-RNA–positive recipients: 12 patients (44%) received a graft from an HbsAg-negative HBcAb-positive donor (core⫹D group) and 15 (56%) from an HBcAb-negative donor (core⫺D group). We analyzed donor features of age, sex, body mass index (BMI), body surface area (BSA), cause of brain

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death, donor risk index (DRI), macrovesicular steatosis, and prevalence of F1 fibrosis or suboptimal graft (defined as a graft from donor ⱖ65 years and/or with macrovesicular steatosis ⱖ15%).6 In addition, we examined recipient features of age, sex, biochemical Model for End-Stage Liver Disease (MELD) score at LT, hepatocellular carcinoma (HCC) and HCV genotype 1 prevalence, and HCV-RNA and HBV-DNA serum levels at LT. We assessed donor-recipient match based on sex mismatch (female donor to male recipient) and D-MELD (donor age ⫻ biochemical MELD at LT) as well as transplantation procedure variables of total, cold (CIT), and warm (WIT) ischemia times. The immunosuppression included calcineurin inhibitors, antimetabolites (azathioprine replaced by mycophenolate from 2002), and steroids which were tapered to suspension by 6 months. Acute cellular rejection episodes, histologically defined as moderate or severe

Table 1. Characteristics of the 27 Adult Primary Transplantations Performed in Simultaneously HBsAg- and HCV-RNA–Positive Recipients as a Function of Donor HBcAb Positivity Core⫹D Group (n ⫽ 12)

Donor Age (y) Age ⱖ70 y Sex, M:F BMI BSA (m2) Cause of brain death Cerebrovascular Trauma Others Donor risk index Macrovesicular steatosis (%) Macrovesicular steatosis ⱖ25% F1 fibrosis Suboptimal graft Recipient Age (y) Sex, M:F Biochemical MELD at LT HCC HCV genotype 1 HCV-RNA at LT (copies/mL) HBV-DNA at LT (copies/mL) Donor-recipient match Sex mismatch (Female D to male R) D-MELD Transplant procedure Total ischemia (min) Cold ischemia (min) Warm ischemia (min) Treatment of acute rejection Steroid boluses Anti-CD3 monoclonal antibody HCV recurrence Histological recurrent HCV hepatitis Time after LT (d) Ishak grading at presentation Ishak staging at presentation Antiviral therapy Duration of therapy (d) SVR

Core⫺D Group (n ⫽ 15)

P Value

61.5 (30.0–74.0) 2 (17%) 10:2 25 (19–35) 1.82 (1.63–2.27)

60.1 (21.0–81.0) 4 (27%) 11:4 25 (17–28) 1.83 (1.47–2.02)

.7 .7 .7 .4 .4

8 (67%) 3 (25%) 1 (8%) 1.77 (1–2.33) 5 (2–40) 1 (8%) 0 6 (50%)

9 (60%) 5 (33%) 1 (7%) 1.64 (1–2.16) 5 (0–30) 2 (13%) 0 9 (60%)

.9

56.4 (40.4–66.2) 12:0 15 (8–27) 6 (50%) 6 (50%) 418,470 (4,542–4,485,641) 199 (0–16,000)

53.5 (37.0–62.2) 14:1 14 (7–27) 7 (47%) 10 (67%) 206,753 (15,980–2,450,540) 149 (0–11,900)

.8 .9 .9 .7 .5 .9 .9 .8 .4 .6 .6

2 (17%) 888 (448–1485)

4 (26%) 913 (407–1539)

.7 .7

474 (255–662) 442 (224–642) 25 (20–43)

541 (261–656) 512 (232–635) 24 (13–40)

.5 .5 .5

1 (8%) 0

2 (13%) 0

10 (83%) 142 (30–1197) 5 (2–9) 2 (0–6) 5/10 (50%) 257 (28–367) 1/5 (20%)

11 (73%) 153 (89–3292) 4 (2–6) 2 (0–4) 10/11 (91%) 347 (34–571) 2/10 (20%)

Quantitative variables are expressed as median (range). Categorical variables are expressed as n (%).

.9

.9 .8 .9 .3 .038 .3 .9

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TANDOI, ROMAGNOLI, MARTINI ET AL

grade, were treated with high-dose intravenous methylprednisolone boluses. Corticoid-resistant rejection required the use of anti-CD3 monoclonal antibody. In all cases, anti-HBV prophylaxis included anti-HBs immunoglobulins (starting from the anhepatic phase and subsequently adjusted to protective serum levels) and nucleos(t)idic analogues. During follow-up, liver biopsies were performed according to clinical and/or biochemical suspicions of graft abnormality. In particular, recurrent HCV hepatitis was graded and staged according to Ishak score. HCV-RNA serum levels were regularly monitored after LT. Administration of post-LT anti-HCV therapy (ribavirin plus Peg-interferon or alfa-interferon) was evaluated for prevalence, duration, and efficacy. The principal cause of graft loss was recorded in each case. Qualitative variables were analysed with ␹2 test, quantitative variables with Mann-Whitney test. Liver graft survivals were evaluated with Kaplan-Meier analysis for comparisons with the log-rank test. The level of significance was set at P ⬍ .05.

RESULTS

Table 1 summarizes the characteristics of donor, recipient, donor-recipient match, transplantation procedure, and treatment of acute rejection in the 2 groups. No significant differences were observed for those features. Under combined anti-HBV prophylaxis, no case of recurrent HBV hepatitis occurred over a follow-up ranging from 16 to 141 months (median 67) for surviving grafts. HCV-RNA remained positive after LT in all patients. First available HCV-RNA positive serum levels in the core⫹D group had a median value of 1.128.867 (9.680 – 69.000.000) copies/mL at a median time of 23 (9 – 62) days after LT, in the core⫺D group 1.000.000 (1.040 – 4.079.355) copies/mL at a median time of 18 (8 – 41 days; P ⫽ not significant [ns]). Regarding histologically proven recurrent HCV hepatitis, there was no difference in prevalence between the 2 groups (83% core⫹D vs 73% core⫺D; P ⫽ ns) nor in severity at presentation (Table 1). Regarding anti-HCV therapy, the portion of patients with recurrent HCV hepatitis who received treatment was significantly smaller in the core⫹D than in the core⫺D group (5/10, 50% vs 10/11, 91%; P ⫽ .038), whereas anti-HCV therapy duration and efficacy in terms of sustained virologic response (SVR) was similar (Table 1). Graft survival at 5 years was significantly lower in the core⫹D cohort (core⫹D 48% vs core⫺D 87%; P ⫽ .018), in which we observed a significantly higher prevalence of graft loss caused by HCV recurrence (core⫹D 5/12, 42% vs core⫺D 1/15, 7%; P ⫽ .03; Fig 1). Notably, all 5 core⫹D patients who lost their grafts owing to HCV recurrences did not receive anti-HCV therapy: 1 because of patient refusal and the other 4 due to aggressive courses of the disease rapidly leading to hepatic decompensation. DISCUSSION

Our study showed that the outcomes of LT in patients with ongoing HBV and HCV coinfections are adversely affected

Fig 1. Cumulative graft survival in the 2 study groups. Causes of graft loss are detailed in the labels. DNF ⫽ delayed nonfunction; Biliary ⫽ biliary complication; HCV-Rec ⫽ HCV recurrence.

by donor HBcAb positivity. The dismal course of HCV recurrence after LT in those grafts appears to be the main reason for the deleterious effects. We speculate that a liver that already hosts occult HBV infection, as happens in the majority of cases of HBcAb-positive donors,7 is particularly liable to suffer rapidly progressive damage when infected by HCV in the setting of immunosuppression for LT.

REFERENCES 1. Angelico M, Marianelli T, Cillo U, et al: The current allocation policy of liver grafts from HBcAb positive donors needs to be improved: evidence from Liver-Match cohort study. J Hepatol 54(Suppl 1):35, S16, 2011 2. Avolio AW, Agnes S, Salizzoni M, et al: Use of HBcAb positive liver grafts. Medium term results according to donorrecipient risk factors. Liver Transpl 17 (Suppl 1):P-239, S202, 2011 3. Tandoi F, Romagnoli R, Catalano G, et al: Transplantation of the liver from a HBcAb positive donor into HCV-RNA positive recipient adversely affects graft survival and worsens the course of HCV recurrence. J Hepatol 54 (Suppl 1):571, S232, 2011 4. Zarski JP, Bohn B, Bastie A, et al: Characteristics of patients with dual infection by hepatitis B and C viruses. J Hepatol 28:27, 1998 5. Rodríguez-Iñigo E, Bartolomé J, Otiz-Movilla N, et al: Hepatitis C virus (HCV) and hepatitis B virus (HBV) can coinfect the same hepatocyte in the liver of patients with chronic HCV and occult HBV infection. J Virol 79:15578, 2005 6. Salizzoni M, Franchello A, Zamboni F, et al: Marginal grafts: finding the correct treatment for fatty livers. Transpl Int 16:486, 2003 7. Raimondo G, Navarra G, Mondello S, et al: Occult hepatitis B virus in liver tissue of individuals without hepatic disease. J Hepatol 48:743, 2008