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
(<50.000 IU/ml).
HCV viraemias in transplanted patients (N=19)
In some cases CsA decreased HCV viraemias but longer follow up of
these patients is needed.

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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
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.
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 HBV kidney 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.