and D

Ileana Constantinescu1, Ana Moise1,Adela Maria Toader, Daniela Nedelcu, Ioanel Sinescu 1Centre

for Immunogenetics , Fundeni Clinical Institute, Bucharest, Romania 2 Fundeni-Institute of Uronephrology and Renal Transplantation, Bucharest, Romania

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.

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.

Prevalence of HBsAg and anti-HCV in donors 2005-2006 Kidney

Bone marrow Liver 19 donors

45 donors

11 donors

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)

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, antiHBe 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).

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):

Results HBV viraemias in transplanted patients (N=25)

HBV genotypes distribution

Correlation between pretransplant HBV-DNA plasma levels and HBV genotype: Patient 1

HBV viraemia (IU/ml) undetectable

HBV genotype A

2

61.000

D

3

158.000

D

4

10.200

A

5

6.400

A+D

6

undetectable

D

7

120.000

A+D

8

undetectable

A+D

9

32.100

A

10

76.000

D

11

undetectable

A+D

12

47.200

A+D

13

5.600

A

14

13.300

A+D

15

174.000

D

16

21.400

D

17

8.900

D

18

undetectable

A

19

18.200

D

20

22.100

D

21

31.700

D

22

103.000

D

23

41.300

D

24

7.800

D

25

53.000

D

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 (