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Treatment of hepatitis B-reinfection or de novo-infection after liver transplantation with famciclovir—how effective is it?
Treatment of Hepatitis B-Reinfection or De Novo-Infection After Liver Transplantation With Famciclovir—How Effective Is It? N. Rayes, R. Neuhaus, U. Naumann, U. Hopf, G.W. Haller, W.O. Bechstein, and P. Neuhaus
H
EPATITIS B infection is a controversial indication for liver transplantation.1,2 The 5-year survival rate in patients transplanted for this disease without any prophylaxis or therapy is 50% vs 75% to 80% for other indications, due mainly to the high rate of reinfections.3 Risk factors for recurrent HBV infection are preoperative HBV-DNA positivity and a pre-existing HBV cirrhosis.3 A second problem is de novo HBV infection after liver transplantation. In recent years, the purine analog, famciclovir, has been introduced in the treatment of hepatitis B.4 Thus, a prospective, open, compassionate-use trial was performed to assess the efficacy and safety of this drug in patients with recurrent or de novo hepatitis B infection.
Recurrent HBV
Of the 24 patients, 5 (21%) are long time responders (6 to 36 months) and still treated with famciclovir. Twelve patients (50%) responded transiently (4 to 36 months) to famciclovir, but relapsed and were switched successfully to lamivudine. Six patients died due to HBV cirrhosis because famciclovir was initiated too late. In one nonresponder treatment was also changed to lamivudine. De Novo HBV
One of six patients is still being treated successfully with famciclovir (6 months), the remaining five patients responded well for 5 to 14 months, relapsed, and were then switched to lamivudine.
PATIENTS AND METHODS From 174 patients transplanted for HBV infection between October 1988 and October 1997, 34% developed HBV reinfection despite prophylaxis with HBV hyperimmunoglobulin (Hepatect, aimed titer .100 U/L). In six additional patients a de novo infection with HBV was diagnosed. HBV infection was confirmed by HBs-Ag positivity and the detection of .10 pg/mL HBV-DNA in the serum (Hybridisation Assay, Abbott, Germany). Immunosuppression consisted of cyclosporine or FK 506 alone or in combination with low-dose prednisolone. Famciclovir 3 3 500 mg was given orally. In case of impaired renal function dosage was reduced. Liver enzymes and HBV-DNA were controlled every second week in the outpatient clinic.
RESULTS
Twenty-four patients with reinfection and six patients with de novo infection were enrolled in the trial from November 1993 to December 1997. HBV reinfection occurred 1 to 15 months (mean 6 months) and de novo infection 3 to 36 months (mean 12 months) after transplantation. Famciclovir therapy was started 1 week to 78 months after infection (mean 13 months). Twenty-two patients (95%) had initially good response with a decrease of HBV-DNA of 32% to 100% (mean 83%) 1 week to 9 months (mean 3 months) after treatment was started. Six patients became HBVDNA negative. Liver enzymes decreased for 32% to 97% (mean 66%). Famciclovir therapy was given from 1 week to 3 years (mean 15 months). The positive effect of the drug was maintained from 2 weeks to 3 years during treatment (mean 10 months). No drug-related side effects were noted. © 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
DISCUSSION
With HBV immunoglobulin prophylaxis the recurrence rate in patients transplanted for HBV infection could be lowered from 67% to 30%,5 and at our center 35%. Retransplantation does not offer a good alternative due to longterm survival rates of only about 5%.6 Promising results achieved with famciclovir were published by Kru ¨ger et al.7 From 12 liver transplant recipients with recurrent HBV infection treated with famciclovir, 9 responded well to treatment. In these patients, HBV-DNA levels declined for .95% after 12 months of treatment, and five patients became HBV-DNA negative. In contrast, 95% of our patients had an initial decline of HBV-DNA and liver enzymes; however, in the long term, 79% of patients with recurrent HBV infection and 83% of patients with de novo infection relapsed. Therefore, a mutation in the viral polymerase, leading to resistance to the drug, as already described for lamivudine,8 should be presumed. Our results demonstrate that famciclovir is a therapeutic option for patients with HBV infection after OLT. Lamivudine alone or in combination with famciclovir is effective in most cases of relapse. From the Departments of Surgery (N.R., R.N., G.W.H., W.O.B., P.N.), and Medicine (U.N., U.H.), Charite´, Campus Virchow, Berlin, Germany. Address reprint requests to Dr N. Rayes, Department of Surgery, Charite´, Campus Virchow, Augustenburger Platz 1, 13353 Berlin Germany. 0041-1345/98/$–see front matter PII S0041-1345(98)01718-7 481
Transplantation Proceedings, 31, 481–482 (1998)
482
REFERENCES 1. Van Thiel DH, Wright HI, Fagiuoli C: Hepatology 20:20, 1994 2. Todo S, Demetris AJ, Van Thiel DH, et al: Hepatology 13:619, 1991 3. Terrault NA, Wright TL: Gut 40:568, 1997 4. Bo ¨ker KHW, Ringe B, Kru ¨ger M, et al: Transplantation 57:1706, 1994
RAYES, NEUHAUS, NAUMANN ET AL 5. Samuel D, Mu ¨ller R, Alexander G, et al: N Engl J Med 329:1842, 1993 6. Crippin J, Foster B, Carlen S, et al: Transplantation 57:823, 1994 7. Kru ¨ger M, Tillmann H, Trautwein C, et al: Liver Transplant Surg 4:253, 1996 8. Ling R, Mutimer D, Ahmed M, et al: Hepatology 24:711, 1996
H
EPATITIS B infection is a controversial indication for liver transplantation.1,2 The 5-year survival rate in patients transplanted for this disease without any prophylaxis or therapy is 50% vs 75% to 80% for other indications, due mainly to the high rate of reinfections.3 Risk factors for recurrent HBV infection are preoperative HBV-DNA positivity and a pre-existing HBV cirrhosis.3 A second problem is de novo HBV infection after liver transplantation. In recent years, the purine analog, famciclovir, has been introduced in the treatment of hepatitis B.4 Thus, a prospective, open, compassionate-use trial was performed to assess the efficacy and safety of this drug in patients with recurrent or de novo hepatitis B infection.
Recurrent HBV
Of the 24 patients, 5 (21%) are long time responders (6 to 36 months) and still treated with famciclovir. Twelve patients (50%) responded transiently (4 to 36 months) to famciclovir, but relapsed and were switched successfully to lamivudine. Six patients died due to HBV cirrhosis because famciclovir was initiated too late. In one nonresponder treatment was also changed to lamivudine. De Novo HBV
One of six patients is still being treated successfully with famciclovir (6 months), the remaining five patients responded well for 5 to 14 months, relapsed, and were then switched to lamivudine.
PATIENTS AND METHODS From 174 patients transplanted for HBV infection between October 1988 and October 1997, 34% developed HBV reinfection despite prophylaxis with HBV hyperimmunoglobulin (Hepatect, aimed titer .100 U/L). In six additional patients a de novo infection with HBV was diagnosed. HBV infection was confirmed by HBs-Ag positivity and the detection of .10 pg/mL HBV-DNA in the serum (Hybridisation Assay, Abbott, Germany). Immunosuppression consisted of cyclosporine or FK 506 alone or in combination with low-dose prednisolone. Famciclovir 3 3 500 mg was given orally. In case of impaired renal function dosage was reduced. Liver enzymes and HBV-DNA were controlled every second week in the outpatient clinic.
RESULTS
Twenty-four patients with reinfection and six patients with de novo infection were enrolled in the trial from November 1993 to December 1997. HBV reinfection occurred 1 to 15 months (mean 6 months) and de novo infection 3 to 36 months (mean 12 months) after transplantation. Famciclovir therapy was started 1 week to 78 months after infection (mean 13 months). Twenty-two patients (95%) had initially good response with a decrease of HBV-DNA of 32% to 100% (mean 83%) 1 week to 9 months (mean 3 months) after treatment was started. Six patients became HBVDNA negative. Liver enzymes decreased for 32% to 97% (mean 66%). Famciclovir therapy was given from 1 week to 3 years (mean 15 months). The positive effect of the drug was maintained from 2 weeks to 3 years during treatment (mean 10 months). No drug-related side effects were noted. © 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
DISCUSSION
With HBV immunoglobulin prophylaxis the recurrence rate in patients transplanted for HBV infection could be lowered from 67% to 30%,5 and at our center 35%. Retransplantation does not offer a good alternative due to longterm survival rates of only about 5%.6 Promising results achieved with famciclovir were published by Kru ¨ger et al.7 From 12 liver transplant recipients with recurrent HBV infection treated with famciclovir, 9 responded well to treatment. In these patients, HBV-DNA levels declined for .95% after 12 months of treatment, and five patients became HBV-DNA negative. In contrast, 95% of our patients had an initial decline of HBV-DNA and liver enzymes; however, in the long term, 79% of patients with recurrent HBV infection and 83% of patients with de novo infection relapsed. Therefore, a mutation in the viral polymerase, leading to resistance to the drug, as already described for lamivudine,8 should be presumed. Our results demonstrate that famciclovir is a therapeutic option for patients with HBV infection after OLT. Lamivudine alone or in combination with famciclovir is effective in most cases of relapse. From the Departments of Surgery (N.R., R.N., G.W.H., W.O.B., P.N.), and Medicine (U.N., U.H.), Charite´, Campus Virchow, Berlin, Germany. Address reprint requests to Dr N. Rayes, Department of Surgery, Charite´, Campus Virchow, Augustenburger Platz 1, 13353 Berlin Germany. 0041-1345/98/$–see front matter PII S0041-1345(98)01718-7 481
Transplantation Proceedings, 31, 481–482 (1998)
482
REFERENCES 1. Van Thiel DH, Wright HI, Fagiuoli C: Hepatology 20:20, 1994 2. Todo S, Demetris AJ, Van Thiel DH, et al: Hepatology 13:619, 1991 3. Terrault NA, Wright TL: Gut 40:568, 1997 4. Bo ¨ker KHW, Ringe B, Kru ¨ger M, et al: Transplantation 57:1706, 1994
RAYES, NEUHAUS, NAUMANN ET AL 5. Samuel D, Mu ¨ller R, Alexander G, et al: N Engl J Med 329:1842, 1993 6. Crippin J, Foster B, Carlen S, et al: Transplantation 57:823, 1994 7. Kru ¨ger M, Tillmann H, Trautwein C, et al: Liver Transplant Surg 4:253, 1996 8. Ling R, Mutimer D, Ahmed M, et al: Hepatology 24:711, 1996