Antiviral therapy for hepatitis C virus recurrence after liver transplantation in HIV-infected patients: outcome in the Bonn cohort
Wojcik, Kamilaa; Vogel, Martinb; Voigt, Estherb; Speidel, Nicolac; Kalff, Jörg Cc; Goldmann, Georgd; Oldenburg, Johannesd; Sauerbruch, Tilmanb; Rockstroh, Jürgen Kurtb; Spengler, Ulrichb
aDepartment of Infectious Diseases and Hepatology, Medical University of Lodz, 91-347 Lodz, Poland
bDepartments of Internal Medicine I, Germany
dInstitute of Experimental Hematology and Transfusion Medicine, University of Bonn, D-53105 Bonn, Germany.
Received 17 November, 2006
Accepted 28 November, 2006
Recurrent hepatitis C is a major cause of mortality in HIV/hepatitis C virus (HCV)-co-infected patients after orthotopic liver transplantation. We report sustained viral clearance in all four transplanted HIV/HCV-positive patients treated with pegylated interferon/ribavirin. Early therapy after HCV recurrence, tailoring treatment duration to the individual decline in HCV-RNA and the management of side effects are key factors for improved efficacy. At experienced centres interferon treatment is a valuable option for recurrent hepatitis C in HIV-positive patients.
Hepatitis C has become a frequent cause of orthotopic liver transplantation (OLT) in HIV-infected patients [1,2]. The recurrence of chronic hepatitis C is, however, universal and within 5 years can lead to cirrhosis in approximately 20% of HIV-infected patients [1–5]. Treatment for hepatitis C virus (HCV)/HIV-positive patients to eliminate recurrent hepatitis after OLT is urgently needed.
Overall, four HIV patients have been transplanted between 1997 and 2006 for end-stage chronic hepatitis C at our centre. All patients received cyclosporine A and prednisone for immunosuppression. Prednisone was withdrawn 5 months after OLT. In one patient cyclosporine A was switched to tacrolimus after 2 months because of renal toxicity. HAART was interrupted for a month at transplantation to facilitate immunosuppressive treatment. All patients had recurrent hepatitis C and were treated with 180 μg pegylated interferon alfa-2a subcutaneously once a week plus 11 mg/kg ribavirin a day by mouth. Three patients (patients 1, 2 and 3) also received 200 mg amantadine a day by mouth. The patients had a median follow-up of 45 months (range 21–54 months) after OLT and 32 months after the end of interferon treatment (range 10–40 months).
HCV genotypes were determined using the INNO-LiPA, HCV II kit (Innogenetics, Heiden, Germany). HCV-RNA and HIV-RNA were measured by transcription-mediated amplification and branched DNA assays (TMA Versant, HCV 3.0 and HIV 3.0 Versant; Bayer Diagnostics, Leverkusen, Germany) before OLT, before and at months 3, 6 and 12 of HCV treatment as well as 6 months after end of HCV therapy. Liver biopsies were performed before and after anti-HCV treatment.
Side effects were monitored weekly for the first 4 weeks and twice monthly, thereafter.
Hepatitis C re-infection occurred in all four men with haemophilia who had been transplanted for chronic hepatitis C, two of whom were non-responders before transplantation, whereas the other two were treatment naive. Two patients had genotype 1a, and one patient each had genotypes 2a/c and 3a. The patient characteristics are summarized in Table 1. After OLT HCV-RNA levels were seven to 101-fold higher than before OLT and fibrocholestatic hepatitis was diagnosed in patients 1 and 3. Pre-treatment liver biopsies revealed Metavir scores A1/F0 in patient 1 at week 2, A1/F0 in patient 2 at week 3, A1/F0 in patient 3 at week 6, and A0/F1 in patient 4 at week 4 after OLT. Anti-HCV treatment was started 9 weeks (range from 6 to 15 weeks) after OLT.
Patients with HCV genotype 1 were treated for 10 and 12 months, the patient with genotype 3 was treated for 6 months. At week 12 HCV-RNA had become undetectable in two of them and was reduced by at least 1.8 log in patient 1. Patient 3 only achieved a 0.9 log reduction at week 12, but became HCV-RNA negative at week 24. His therapy was extended to 12 months. At the end of the treatment and at follow-up all patients were HCV-RNA negative with normal aminotransferases and improved histology (Table 1).
Severe neutropenia (patients 1 and 2), thrombocytopenia (patients 3 and 4), and haemolytic anaemia (patients 2 and 3) occurred in two patients each. Ribavirin was reduced from 800 to 200 mg and erythropoietin alfa 30 μg twice a week was added in two patients. Pegylated interferon alfa 2a was reduced to 135 μg in patient 3, who developed retinal vein thrombosis. Patient 2 experienced acute graft rejection after 3 months of treatment. HCV therapy was interrupted for 2 months and continued after rejection was controlled. Antiviral therapy was discontinued early in patient 1 at 10 months as a result of a liver abscess. During hepatitis C treatment HIV RNA remained undetectable (< 50 copies/ml), but CD4 cell counts decreased from a median of 136 to 71 cells/μl. No AIDS-defining events were observed, however, and CD4 cell counts returned to pretreatment levels after the completion of HCV therapy.
Approximately 25% of HCV-monoinfected recipients of a liver allograft develop severe recurrent disease and die or require retransplantation within 5 years [1,6]. Even worse, four out of seven HCV/HIV-positive patients transplanted at the Kings College had died within 2 years as a result of the complications of recurrent hepatitis C despite HCV therapy in three of them . Here, we report the sustained elimination of HCV in all four HIV/HCV-infected patients transplanted at our centre. This observation illustrates that a high sustained virological response (SVR) is also possible in this difficult-to-treat patient group.
Several facts may have contributed to improve outcomes in our patients. First, we had treated our patients early after HCV recurrence and recovery from transplantation, which was more efficacious and better tolerated than preemptive therapy [8,9]. Although the best time for treatment has not yet been determined, early HCV therapy may improve graft and patient survival. In support of this concept, Samuel et al.  achieved a 31% SVR in HCV-monoinfected transplant recipients treated with conventional interferon alfa 2b plus ribavirin for 48 weeks. Moreover, Rodrigez-Luna et al.  and Oton et al.  reported 26% and 43.6% SVR in their patients treated with pegylated interferon alfa/ribavirin, respectively. Finally, Feliu et al.  observed greater efficacy of antiviral therapy after OLT, when comparing treatment outcomes before and after OLT. Finally, improved outcomes of HCV treatment after transplantation might reflect favourable changes in the circulating HCV quasispecies and gene expression profiles of the graft.
HCV-RNA clearance occurs more slowly in HIV/HCV-co-infected patients than in HCV-monoinfected patients . We therefore tailored treatment duration according to HCV-RNA disappearance and prolonged therapy in the patient who failed to achieve a clear early response. This concept is supported by two recent studies that independently demonstrated the extension of treatment beyond 48 weeks to improve SVR and relapse rates in genotype 1 patients with slow initial treatment responses [13,14].
The management of side effects was difficult in our patients. In line with observations by Cooper , however, CD4 cell counts declined transiently and none of our patients had experienced opportunistic complications.
Therefore, although the low number of patients in our study limits interpretation, early therapy after HCV reinfection and an individualized approach taking into account differences in viral treatment kinetics may be key factors for a high SVR after OLT.
1. Prachalias AA, Pozniak A, Taylor C, Srinivasan P, Muiesan P, Wendon J, et al
. Liver transplantation in adults coinfected with HIV. Transplantation 2001; 72:1684–1688.
2. Rockstroh JK, Spengler U. HIV and HCV coinfection. Lancet 2004; 4:437–444.
3. Moreno A, Barcena R, Garcia-Garzon S, Muriel A, Quereda C, Moreno L, et al
. HCV clearance and treatment outcome in genotype 1 HCV-monoinfected, HIV-coinfected and liver transplanted patients on peg-IFN-alpha-2b/ribavirin. J Hepatol 2005; 43:783–790.
4. Neff GW, Bonham A, Tzakis AG, Ragni M, Jayaweera D, Schiff ER, et al
. Orthotropic liver transplantation in patients with human immunodeficiency virus and end-stage liver disease. Liver Transplant 2003; 9:239–247.
5. Sharma P, Lok A. Viral hepatitis and liver transplantation. Semin Liv Dis 2006; 26:285–294.
6. Samuel D, Bizollon T, Feray C, Roche B, Ahmed SN, Lemonnier C, et al
. Interferon alfa 2b plus ribavirin in patients with chronic hepatitis after liver transplantation: a randomized study. Gastroenterology 2003; 124:624–650.
7. Norris S, Taylor C, Muiesan P, Portmann BC, Knisely AS, Bowles M, et al
. Outcome of liver transplantation in HIV-infected individuals: the impact of HCV and HBV infection. Liver Transplant 2004; 10:1271–1278.
8. Shergill AK, Khalili M, Straley S, Bollinger K, Roberts JP, Ascher NA, et al
. Applicability, tolerability and efficacy of preemptive antiviral therapy in hepatitis C-infected patients undergoing liver transplantation. Am J Transplant 2005; 5:118–124.
9. Oton E, Barcena R, Moreno-Planas JM, Cuervas-Mons V, Moreno-Zamora A, Barrios C, et al
. Hepatitis C recurrence after liver transplantation: viral and histologic response to full-dose PEG-interferon and ribavirin. Am J Transplant 2006; 6:2348–2355.
10. Rodrigez-Luna H, Vargas HE. Management of hepatitis C virus infection in the setting of liver transplantation. Liver Transplant 2005; 11:479–489.
11. Feliu A, Carrion JA, Massaguer A, Martinez-Bauer E, Garcia-Retortillo M, Gonzalez P, et al
. Sensitivity to antiviral therapy may change after liver transplantation in patients with chronic hepatitis C virus infection. J Viral Hepat 2006; 13:544–551.
12. Beckebaum S, Cicinnati VR, Zhang X, Malago M, Dirsch O, Erim Y, et al
. Combination therapy with peginterferon alpha-2B and ribavirin in liver transplant recipients with recurrent HCV infection: preliminary results of open prospective study. Transplant Proc 2004; 36:1489–1491.
13. Berg T, Wagner M, Nasser S, Sarrazin C, Heintges T, Gerlach T, et al
. Extended treatment duration for hepatitis C virus type 1: comparing 48 versus 72 weeks of peginterferon-alfa-2a plus ribavirin. Gastroenterology 2006; 130:1086–1097.
14. Sanchez-Tapias JM, Diago M, Escartin P, Enriquez J, Romero-Gomez M, Barcena R, et al
. Peginterferon-alfa2a plus ribavirin for 48 versus 72 weeks in patients with detectable hepatitis C virus RNA at week 4 of treatment. Gastroenterology 2006; 131:451–460.
15. Cooper CL. Therapeutic interventions for HIV infection and chronic viral hepatitis. Clin Infect Dis 2005; 41:69–72.
© 2007 Lippincott Williams & Wilkins, Inc.