HEPATITIS B AND C IN KIDNEY TRANSPLATED PATIENTS

1. HEPATITIS B AND C IN KIDNEY TRANSPLATED PATIENTS Ileana Constantinescu1, Ana Moise1,Adela Maria Toader, Daniela Nedelcu,IoanelSinescu 1Centre for Immunogenetics , Fundeni Clinical Institute, Bucharest, Romania 2 Fundeni-Institute of Uronephrology and Renal Transplantation, Bucharest, Romania

2. Background: In Romania the prevalence of HBV and HCV infections among individuals is high. Therefore situations in which HBV and HCV patients with renal insuffiency need the transplant are more and more often. The management of kidney transplantation in HCV and HBV patients have to be individualized and closely monitored. Chronic HBV and HCV infections are highly prevalent among renal transplant patients, probably as a result of previous parenteral exposures. In hepatitis B surface antigen (HBsAg) positive renal transplant recipients, immunosuppression therapy determines the increase of HBV viral replication leading on a long term basis to severe hepatitis. When pre-transplantation check-up reveals serum HBsAg presence, the decision to perform kidney transplantation should be made selectively. To identify patients who are likely to be affected by progressive life-threatening hepatitis after kidney transplantation, liver biopsies are recommended in both chronic HBV, HCV patients. Preliminary data on HBV, HCV kidney transplanted patients suggest that these subjects exhibit less intense portal/periportal necroinflamatory activity as compared to immunocompetent individuals.

6. Effects of Viral Infection in Transplantation • Direct etiology of infectious disease syndromes—invasive disease • Immunomodulatory effects • Systemic immune suppression  other infections • “Indirect” or cellular effects  graft rejection • Oncogenesis, cell proliferation • Hepatitis B virus (HBV): hepatocellular carcinoma • Epstein-Barr virus: B-cell lymphoma (PTLD) • Hepatitis C virus (HCV): splenic lymphoma • HHV-8 (KSHV): Kaposi’s sarcoma • CMV: accelerated atherogenesis • Hepatitis B and C Viruses in Transplantation • Accelerated clinical outcome with immunosuppression of the host • Upregulation of viral replication following transplantation • Response to therapy is variable: HBV usually controllable, HCV often more difficult to manage because of Interferon viral non-specific immunomodulation combined with host immunosuppression posttransplantation • Correlation of viral loads with disease is useful in the transplanted individual.

7. Prevalence of HBsAg and anti-HCV in donors 2005-2006 Kidney Bone marrow Liver 19 donors 45 donors 11 donors

8. Currently, 8 genotypes of HBV have been identified.Genotypes A (adw) and D (ayw) are common in the United States and Europe. Genotypes B (adw) and C (adr) are most frequent in China and South-East Asia. (Stuyver et al.,J of General Virology,81:67-71,2000) Preliminary HBV serotyping results in Romania showed presence of serotype A and D. (Prof.Vincent Babes MD, PhD, 1985) Core promoter mutations in Romanian patients with chronic hepatitis B. Preliminary data. Stop codon mutation (28 Tryptophan -> stop codon 131 Arginine-> Lysine (aac -> aaa) 145 Glycine-> Arginine (gga -> aga) (I. Constantinescu, T.J.Harrison,R.Ling – Unpublished data,2000)

9. The A genotype of HBV has been associated with better disease outcome and long term survival.The B genotype of HBV has been associated with development of hepatocellular carcinoma.  The C genotype of HBV has been associated with more severe disease.(Kao JH, Chen PJ, Lai MY, Chen DS. Hepatitis B genotypes correlate with clinical outcomes in patients with chronic hepatitis B. Gastroenterology 2000;118:554-559).The precore stop codon mutation associated with fulminant hepatitis is much more prevalent in genotype D of HBV.(Kidd-Ljunggren K. Variability in hepatitis B virus DNA:Phylogenetic, epidemiological and clinical implications. Scandinavian J Infect Dis 1996;28:111-116).

10. Material and methods: • We sought to evaluate the impact of CsA on HBV, HCV viraemias levels using data retrospectively collected from naïve renal transplanted treated patients. • A total of 365 adult patients who received a renal transplant with a functioning graft after the first year were included. • Patients have been tested for HBsAg, anti-HBc, anti-HBs, HBeAg, anti-HBe and anti-HCV using MEIA methods (Axsym , ABBOTT). HBV DNA and HCV RNA samples were worked by Real-Time PCR methods (artus HBV RG PCR kit, Qiagen) and HBV genotyping was performed with INNO-LiPA DR Amplification and INNO-LiPA HBV Genotyping kit (Innogenetics).

11. Results: Pretransplant prevalence of chronic hepatitis infection for patients tested in our centre (N=735): Chronic HBV and HCV infection in kidney transplanted patients (N=365):

12. Results HBV viraemias in transplanted patients (N=25) HBV genotypes distribution

13. Correlation between pretransplant HBV-DNA plasma levels and HBV genotype:

14. Posttransplant, all patients were treated with Lamivudine as antiviral therapy except four patients ( 3, 7, 10, 12), with very high viral load, who were treated with Telbivudine. These patients also received Tacrolimus as immunosuppressant. Their outcome was favorable with decrease of HBV-DNA plasma levels. It should be noted that the HBV genotype was D, except patient 12 with genotype A+D. In patients with low HBV viraemias before transplantation, treatment with Lamivudine mentained the viraemias at low levels (<50.000 IU/ml).

15. HCV viraemias in transplanted patients (N=19) In some cases CsA decreased HCV viraemias but longer follow up of these patients is needed.

16. Conclusions for treatment • Virological Assessment • Immunological Assessment • Individualized treatment • Anti-viral treatment • Hepatoprotection • Stimulatory drugs for enhancement of the host immune response against the virus • Follow up of the patients

17. Remarks In renal allograft recipients, most cases of liver dysfunction are caused by HCV and HBV chronic hepatitis. On a long term outcome, HBV patients had a lower risk of graft disfunction related to liver disease than HCV patients. Co-infections did not worsen patient survival because the two viruses inhibit replication one to an other. HCV inhibits HBV replication. Antiviral treatment with nucleosides has improved the short-term outcome of kidney transplant recipients with HBV chronic hepatitis, but its long-term impact remains to be followed. Lamivudine has been reported to be able to stabilize liver enzyme and hepatitis B virus (HBV) replication in renal transplant recipients. Because large number of hepatitis antigenemia patients among renal transplant patients experience recurrent hepatic dysfunction with HBV recurrence and permanent histological deterioration, preemptive or primary use of lamivudine or telbivudine before transplantation may be beneficial. Genotype A and D HBV have different outcome. Patients with genotype A have an inactive carrier status in comparison with genotype D patients who are prone to higher viral replication post kidney transplantation. CsA inhibits HCV replication in cell culture replicon models. CsA has an in vivo anti-hepatitis C virus activity, probably acting by antagonizing the effect of cyclophilin B on HCV replication. CsA could prevent necroinflamatory changes through various pathways, including inhibition of the release of proinflamatory cytokines and alteration of lymphocytes distribution and function. Patients on Cyclosporine A (CsA) had a decline in their HCV, HBV viraemias during the second half of the first year post kidney transplantation.

18. CONCLUSIONS: ● Renal transplant recipients who are HBV positive prior to transplantation are more likely to experience reactivation or enhancement of viral replication but, antiviral treatment with nucleosides holds the viral replication burn out. ● To prevent viral replication in HBsAg-positive patients who are scheduled for renal transplantation, it is best to initiate lamivudine therapy before or immediately after transplantation. ● Treatment of HBVkidney transplanted recipients with nucleoside analogues alows long-term survival benefits. ●In HCV kidney transplanted patients, immunosuppression regimens with Cyclosporine A, viraemia levels were lower than in HCV patients treated with Tacrolimus.