# Presentation: 492935

## Clinical Performance of HBIg in Preventing Recurrent HBV After Liver Transplantation

**David K. Imagawa, MD, PhD**
**Professor of Clinical Surgery**
**Department of Hepatobiliary and Pancreas Surgery**
**University of California, Irvine Medical Center**
**July 2006**

## Introduction

- Orthotopic liver transplantation (OLT) remains the primary curative modality for end-stage liver disease from chronic hepatitis B (HBV) infection
- Initial attempts at OLT without immunoprophylaxis in this patient population resulted in over 80% re-infection of the allograft followed by accelerated graft failure

## Extra-hepatic reservoirs of HBV, such as peripheral blood mononuclear cells and various organs, likely contributed to the high rate of re-infection 

These disappointing results caused many centers to abandon transplantation as a treatment option for chronic HBV infection in the late 1980s 

- These disappointing results caused many centers to abandon transplantation as a treatment option for chronic HBV infection in the late 1980s

**Introduction**

## HBIg Immunotherapy

- A review of domestic and international reports on combination therapy with HBIg and a nucleoside analog after OLT reveals consistent results
- Low recurrence rates up to 5 years post-transplant
- Data covers all HBV patients, including patients with high viral loads

## Large Studies and Long-term Follow-up for HBIg Combination Therapy

| Author | Location | # of 
Patients | Follow-up | Recurrences |
| --- | --- | --- | --- | --- |
| Roche 2003 | France | 24 | 60 months | 2 (8.3%) |
| Aribizu 2003 | Spain | 14 | 58.8 (15-107) months | 1 (7%)* |
| Honaker 2002 | Univ. of Tenn, USA  | 9 | 4.2 +/- 1.0 yr | 0 (0%) |
| Dumortier 2003 | France | 17 | 30 (12-48) months | 0 (0%) |
| Marzano 2001 | Italy | 26 | 29 +/- 9 months | 1 (4%) |
| Engler 2002 | Germany | 5 | 26.6 (20-36) months | 1 (20%)* |
| Rosenau 2001 | Germany | 21 | 643 (73-1473) days | 4 (19%) |
| Angus 2000 | Australia-New Zealand | 37
 | 18.4 +/- 12.1 (5-45) months | 0 (0%)
 |

- *recurrence occurred after deviation from HBIg protocol

## Alternatives

_**Lamivudine Monotherapy**_
- Not a viable solution for all patients
- Routine development of escape mutants/drug resistance
- Historically 24-67% recurrence rate across all patients undergoing OLT for HBV

**There are no good alternatives to HBIg for **
**preventing recurrent HBV after OLT**

## The UC Irvine Experience

- Patients with HBV-related end-stage liver failure, followed at our institution
- Transplanted between 1993 and 2001 to ensure long-term follow up
- After OLT, all patients received combination therapy with HBIg and lamivudine

## The UC Irvine Experience

_**HBIg Protocol**_
- During the anhepatic phase, 10,000 IU of HBIg was given intravenously (IV) followed by 10,000 IU of HBIg IV daily for 6 days
- Administration of HBIg was then changed to the intramuscular (IM) route and the frequency of doses was adjusted to maintain HBsAb titers above 150 IU/L
- Patients were evaluated on a monthly basis for the presence of HBV DNA and HBsAg until the HBsAb titers stabilized at therapeutic levels
- Thereafter, serology and HBsAb titers were checked every 2 months.

## The UC Irvine Experience

**The UC Irvine Experience**

**Kaplan-Meier Survival**
-      95.0% at 1-month
-      85.0% at 1-year
-      79.7% at 3-years
-      73.1% at 5-years
-      66.4% at 10-years
-    mean 87.8 month follow-up

## The UC Irvine Experience

| # of Patients | # DNA + prior to OLT | Continued HBIg | Recurrent HBV | Follow-up months
 |
| --- | --- | --- | --- | --- |
| 10 | 2 | Yes | 0 (0%) | 80.2 
(range 34-115)  |
| 6 | 0 | No | 3 (50%) | 100.6
(range 36.3-148.7)  |

**Overall Results**

## The UC Irvine Experience

- 3 patients experienced recurrent HBV after cessation of HBIg and institution of lamivudine monotherapy
- Retrospectively, laboratory data demonstrates a marked increase in viral replication as HBsAb titers were depleted

## Conclusions

- Published data strongly supports the use of combination therapy with HBIg and a nucleoside analog to prevent recurrent HBV after OLT
- There are no viable alternatives at this time

## References

- Anselmo DM, Ghobrial RM, Busuttil RW., et al. New era of liver transplantation for hepatitis B: a 17-year single-center experience. Ann Surg. 2002 May;235(5):611-9; discussion 619-20.
- Todo S, Demetris AJ, Van Thiel D, et al. Orthotopic liver transplantation for patients with hepatitis B virus-related liver disease. Hepatology 1991;13:619-626.
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- Omata M. Significance of extrahepatic replication of hepatitis B virus. Hepatology 1990;12:364-366.
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- Mutimer D, Dusheiko G, Barrett C, Grellier et al. Lamivudine without HBIg for prevention of graft reinfection by hepatitis B: long-term follow-up. Transplantation 2000;70:809-15.

## References

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- Mutimer D, Pillay D, Dragon E, et al. High pre-treatment serum hepatitis B virus titre predicts failure of lamivudine prophylaxis and graft re-infection after liver transplantation. J Hepatology 1999;30:715-721.
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- Angus PW, McCaughan GW, Gane EJ, et al. Combination low-dose hepatitis B immune globulin and lamivudine therapy provides effective prophylaxis against posttransplantation hepatitis B. Liver Transpl. 2000 Jul;6(4):429-33.
- Neff GW, O’Brien CB, Nery J, et al. Outcomes in liver transplant recipients with hepatitis B virus: resistance and recurrence patterns from a large transplant center over the last decade. Liver Transpl 2004;10:1372-1378.
- Albeniz Arbizu E, Barcena Marugan R, Oton Nieto E, et al. Use of combined treatment of hepatitis B immune globulin and lamivudine as prevention of hepatitis B virus recurrence in liver allograft. Transplant Proc. 2003 Aug;35(5):1844-5.
- Engler S, Sauer P, Klar E, et al. Prophylaxis of hepatitis B recurrence after liver transplantation with lamivudin and hepatitis B immunoglobulin. Transplant Proc. 2002 Sep;34(6):2285-7.
- Dumortier J, Chevallier P, Scoazec JY, et al. Combined lamivudine and hepatitis B immunoglobulin for the prevention of hepatitis B recurrence after liver transplantation: long-term results. Am J Transplant. 2003 Aug;3(8):999-1002.
- Rosenau J, Bahr MJ, Tillmann HL, et al. Lamivudine and low-dose hepatitis B immune globulin for prophylaxis of hepatitis B reinfection after liver transplantation possible role of mutations in the YMDD motif prior to transplantation as a risk factor for reinfection. J Hepatol. 2001 Jun;34(6):895-902.