A significant proportion of patients with chronic hepatitis C virus (HCV) infection develop cirrhosis and complications of end-stage liver disease over two to three decades and require liver transplantation. However, reinfection is common and leads to further adverse events under immunosuppression. Pretransplant antiviral or pre-emptive therapy is limited to mildly decompensated patients due to poor tolerance. The main stay of management represents directed antiviral therapy after evidence of recurrence of HCV in the transplanted patient.

1. Treatment of hepatitis C in liver transplant patient

2. Apollo Medicine 2012 March
Review Article
Volume 9, Number 1; pp. 50–54
© 2012, Indraprastha Medical Corporation Ltd
Treatment of hepatitis C in liver transplant patient
Sanjay Sikka*
*Senior Consultant, Department of Gastroenterology and Hepatology, Indraprastha Apollo Hospitals, Sarita Vihar,
New Delhi – 110076, India.
ABSTRACT
A significant proportion of patients with chronic hepatitis C virus (HCV) infection develop cirrhosis and complications
of end-stage liver disease over two to three decades and require liver transplantation. However, reinfection is com-
mon and leads to further adverse events under immunosuppression. Pretransplant antiviral or pre-emptive therapy
is limited to mildly decompensated patients due to poor tolerance.The main stay of management represents directed
antiviral therapy after evidence of recurrence of HCV in the transplanted patient.
Keywords: Chronic hepatitis C (HCV), interferon, liver transplant
Correspondence: Dr. Sanjay Sikka, E-mail: sikkageind55@gmail.com
doi: 10.1016/S0976-0016(12)60121-5
INTRODUCTION
According to the World Health Organization, 130–170
million people are chronically infected with hepatitis C virus
(HCV) worldwide.1
The expected median time for develop-
ment of cirrhosis in patients with HCV is 20–25 years. The
HCV is the major cause of chronic liver disease, cirrhosis,
and liver cancer in most developed countries,2
including
Japan.3
It is the most common indication for liver transplan-
tation (LT) in developed nations.4,5
Liver transplantation is
an effective treatment to reduce morbidity and mortality in
this population. Regretfully, recurrence of HCV infection is
almost universal after LT and is a critical complication with
major effects on graft and patients survival. Indeed, the real
challenge of controlling HCV begins after LT under lifelong
immunosuppression.
CLINICAL COURSE AFTER LIVER
TRANSPLANTATION
Spontaneous clearance of HCV after transplantation is
rare,6–10
and reinfection of the allograft is common.11,12
Large studies have demonstrated that recipients with HCV
have about 10% <5-year graft and patient survival rates
than non-HCV controls.13,14
Hepatitis C virus reinfection
occurs during transplantation in the reperfusion phase of the
graft, and acute hepatitis can be detected 1–3 months after
transplantation.15
The clinical course following reinfection
varies. In general, 8–30% of the recipients will present with
severe progression within 5 years.16–18
The median time to
cirrhosis in the non-transplant patient was 30 years19
and
in the transplanted patients with HCV disease is expected
to be 10 years. The risk of decompensation is 50% within
1 year after diagnosis in the absence of therapeutic interven-
tion.16,19
A small percentage of recipients can develop an
early cholestatic hepatitis within the first year after transplan-
tation with a risk (2–8%) of progressive liver dysfunction
and rapid development of cirrhosis.11,20
Retransplantation
in these patients is associated with poor outcomes and is
controversial.21
One of the most important issues in the man-
agement of HCV after LT is a correct follow-up of these
patients. It is now clear the fibrosis progression is signifi-
cantly faster in immunosuppressed than in normal individu-
als and that a close monitoring of liver damage is essential.
Assessment of the severity of HCV recurrence after LT is
performed by frequent liver biopsies is sampling variability,
which might become a relevant issue in individuals with rapid
disease progression. The presence of the portal hypertension
(hepatic venous pressure gradient, HVPG >6mmHg) is even
more accurate than liver biopsy at identifying with severe

3. Treatment of hepatitis C in liver transplant patient Review Article 51
© 2012, Indraprastha Medical Corporation Ltd
HCV recurrence who are at risk of clinical decompensation.22
This is relevant to adopt therapeutic decisions due to the
limited efficacy and high incidence of adverse events of
current antiviral therapy in HCV-infected LT patients.
Therefore, liver biopsy and/or HVPG measurement on
a protocol basis are highly recommended to monitor liver
damage in HCV-infected LT recipients.
Recently measurement of liver stiffness has shown a
good correlation with the fibrosis stage in LT recipients.
Carrion et al23
showed that using transient elastography most
HCV-infected LT patients with significant liver fibrosis
and/or portal hypertension were correctly identified. Apart
from liver stiffness, it is possible that in the near future the
use of serum fibrosis marker as may become an additional
tool to identify patients at risk of disease progression and in
whom antiviral therapy is indicated.24
RISK FACTORS FOR SEVERE RECURRENT
HEPATITIS C VIRUS
There are many variables which predict the recurrence of
severe HCV after LT. The most common variable factor to
have a negative impact of HCV infection on graft survival
is donor age and strong immunosuppressive regimens.25
Avoid the utilization of anti-lymphocyte antibodies or corti-
costeroid boluses as they may enhance viral replication and
induce a more severe liver disease. Other factors with a sig-
nificant negative impact on HCV infection on graft survival
is a preoperative model for end-stage liver disease (MELD)
score,26
fibrosis stage of 2 or greater at 12 month biopsy,
history of hepatocellular carcinoma (HCC) and early acute
rejection. Diabetes mellitus (DM), cytomegalovirus (CMV)
infection, early lobular hepatitis and chronic cholestasis due
to biliary complication.27,28
VIRAL KINETICS
Powers et al29
confirmed that viral loads begin to rise 15
hours after the anhepatic phase. In total, 19% heptocytes
are infected in an average of 37 days after transplantation.
Schiano et al30
demonstrated accelerated HCV kinetics in
living donor liver transplantation (LDLT) recipients (n=11)
compared to deceased donor liver transplantation (DDLT)
recipients (n=15). Another study27
focusing on the histologic
aspects of HCV recurrence with protocol biopsy reported
more severe progression of liver disease in LDLT compared
to DDLT.
TREATMENT OF HEPATITIS C VIRUS
RECURRENCE AFTER LIVER
TRANSPLANTATION
Once HCV recurs after transplantation, treatment can be ini-
tiated at different stages: immediately following transplan-
tation, during the acute phase of infection (acute hepatitis)
and once chronic hepatitis has been histologically proven.
Treatment of HCV infection in the early phase after LT
would prevent liver damage, but the potential risk of rejec-
tion, the poor tolerance of antiviral therapy immediately
after LT and early viral kinectics following LT are some of
the limitations of this strategy. Data from randomized con-
trolled studies analyzing the efficacy of interferon/pegylated
interferon (PEG-INF) monotherapy initiated as early as 2–3
weeks after LT did not show any efficacy in terms of viral
clearance.31,32
The safety and efficacy of antiviral therapy during the
acute phase of infection has been evaluated in one study.
Twenty-four patients with histologically proven HCV were
treated with PEG-INF alfa-2b and ribavirin for 48 weeks.33
Median time from transplantation to antiviral therapy was
4 months. Sustained virological response (SVR) was achieved
in 35% of the cases. The results of this are promising, but
they need to be validated in larger cohorts. Currently, treat-
ment in the acute phase of the disease would be reserved for
individuals with evidence of an early severe recurrence:
cholestatic hepatitis, high aspartate aminotransferase (AST)
or alanine aminotransferase (ALT) levels (>200), or severe
necroinflammation in the liver biopsy.
The most common strategy to treat HCV infection in
patients undergoing LT is to initate therapy several months
(or even years) after LT, once the presence of histological
(particularly liver fibrosis) has been documented. The pres-
ence of significant fibrosis (extending beyond the portal
tract) or portal hypertension (HVP>6) 1 year after transplan-
tation identifies individuals at risk of severe recurrence.22
Most studies indicate that the efficacy of antiviral therapy
in LT recipients is low; adverse events make it often neces-
sary to modify and/or discontinue therapy.31
Overall, using
PEG-INF the efficacy of combination therapy is around
30–35%.34–41
A systematic review of studies evaluating anti-
viral therapy with PEG-INF and ribavirin in >600 LT recipi-
ents showed a mean rate of SVR of 35%; the lack of an early
virologic response (3 months) was the strongest predictor of
non-response.42
As expected, dose reduction and discontin-
uation of treatment were common (73% and 28%, respec-
tively). Rejection induced by interferon is a rare event, but
changes in the liver enzyme profile (particularly in virologi-
cal responders) should prompt rapid liver biopsy to exclude
this possibility. It is important to notice that ductopenic

4. 52 Apollo Medicine 2012 March; Vol. 9, No. 1 Sikka
© 2012, Indraprastha Medical Corporation Ltd
rejection induced by interferon therapy may be severe and
cause graft loss.
One of the most important issues regarding antiviral
therapy is its potential long-term benefit in individuals who
achieve viral eradication. In the study by Carrion et al,36
it became clear that in individuals who achieved an SVR,
liver fibrosis improved or stabilized and, more importantly,
portal pressure normalized. These data, which were obtained
in a small prospective series, are strongly supported by
recent study by Berenguer et al.42
In this study, progression
to cirrhosis and clinical decompensation was assessed retro-
spectively in 89 HCV-infected patients who underwent anti-
viral therapy and 75 untreated disease-matched controls.
Patients survival was higher in treated compared to controls.
Regarding treated patients the 5-year risk of graft decom-
pensation is greater in non-responders compared to patients
who achieved SVRs (33% vs 16%; P=0.04), whereas the
5-year survival was higher in SVR as compared with non-
responders (93% vs 69%; P=0.032). Thus, antiviral therapy
appears to be associated with improved long-term outcome
in recurrent HCV.
NEW DRUGS AND LIVER
TRANSPLANTATION
With the introduction of HCV protease inhibitors (PIs),
telaprevir and boceprevir, which are DAA (direct-acting anti-
virals), the future of genotype-I HCV post transplant patient
is bright.
The PIs added to standard of care (SOC) therapy have
increased the rate of SVR-infected genotype-I naive chronic
HCV patients up to 70%. The expectations regarding the
efficacy of therapeutical regimens adding PI to the current
SOC in LT recipients are not as high as in immunocompetent
individuals.
In the post transplant setting, the type of problems
in patients undergoing triple therapy (PEG-INF, ribavarin,
and PI) will be quite different. The most relevant issue
will be the drug-drug interaction and high rate of adverse
events. Since most PIs are substrates and inhibitors of
P-glycoprotein and the cytochrome system (particularly
CYP3A4) drug-drug interaction with immunosuppressant
are expected. P-glycoprotein (both in gut and the liver)
decreases absorption and increases excretion of cyclosporin
A (CsA) and tacrolimus (TAC) and the two drugs are meta-
bolized by CYP3A4. After PI initiation or interruption
blood levels of CsA or TAC might dramatically increase or
decrease due to the narrow therapeutic ranges of these drugs.
Some adverse events due to rapid increase in CsA or TAC
levels when starting PI may be life-threatening (acute renal
failure, seizures, hypertension, and diabetes). Similarly, a
sudden decrease in CsA or TAC levels when interrupting the
administration of PI may lead to graft injection. An addi-
tional problem in LT recipient undergoing triple therapy will
be anemia.
It is well known that first cause of treatment adjustments
and discontinuations in LT recipients undergoing PEG-INF
and ribavirin therapy is anemia. Among the causes of high
rate of anemia are renal failure (which increases ribavirin
toxicity) and bone marrow suppression by several drugs.
Taking into account drug-drug interaction and additional
toxicity of PI, dose adjustments and/or discontinuation will
be frequent. In order to avoid PI dose adjustment, which
would facilitate the appearance of HCV-resistant state. It will
be relevant to use erythropoietin and/or reduce rebavirin
dose when required.
Despite all the abovementioned limitation, it is obvious
that the addition of PI to current SOC will increase the rate
of viral clearance in HCV-infected LT patients.
RERERENCES
1. Tamura S, SugawaraY. Treatment strategy for hepatitis C after
liver transplantation. J Hepatobiliary Pancreat Surg 2008;15:
111–23.
2. Lauer GM, Walker BD. Hepatitis C virus infection. New Engl
J Med 2001;345:41–52.
3. Kyosawa K, Umemura T, Ichijo T, et al. Hepatocellular
carcinoma: recent trends in Japan. Gastroenterology 2004;
127(5 Suppl 1):S17–26.
4. Hoofnagle JH, Seeff LB. Peginterferon and ribavirin for chronic
hepatitis C. New Engl J Med 2006;355:2444–51.
5. Manns MP, Wedemeyer H, Cornberg M. Treating viral hepa-
titis C: efficacy, side effects, and complications. Gut 2006;
55:1350–9.
6. Dale CH, Burns P, McCutcheon M, Hernandez-Alejandro R,
Marotta PJ. Spontaneous clearance of hepatitis C after liver
and renal transplantation. Can J Gastroenterol 2009;23:
265–7.
7. Suneetha PV, Mederacke I, Heim A, et al. Spontaneous clear-
ance of chronic hepatitis C after liver transplantation: are
hepatitis C virus-specific T cell responses the clue? Liver
Transplant 2008;14:1225–7.
8. Bhagat V, Foont JA, Schiff ER, Regev A. Spontaneous clear-
ance of hepatitis C virus after liver transplantation in two
patients coinfected with hepatitis C virus and human immu-
nodeficiency virus. Liver Transplant 2008;14:92–5.

5. Treatment of hepatitis C in liver transplant patient Review Article 53
© 2012, Indraprastha Medical Corporation Ltd
9. Samonakis DN, Cholongias E, Triantos CK, et al. Sustained
spontaneous disappearance of serum HCV-RNA under immu-
nosuppression after liver transplantation for HCV cirrhosis.
J Hepatol 2005;43:1091–3.
10. Doughty AL, Zekry A, Spencer JD, Turhan S, Painter D,
McCaughan GW. Spontaneous clearance of hepatitis C virus
infection post liver transplantation is associated with rapidly
changing quasispecies: a single case report. Liver Transplant
2000;6:648–53.
11. Wiesner RH, Sorrell M, Villamil E, et al. Report of the first
international Liver Transplantation Society Expert Panel Con-
sensus Conference on Liver Transplantation and Hepatitis C.
Liver Transplant 2003;9:S1–9.
12. Berenguer M, Lopez Labrador EX, Wright TL. Hepatitis C
and liver transplantation. J Hepatol 2001;35:666–78.
13. Mutimer DJ, Gunson B, Chen J, et al. Impact of donor
age and year of transplantation on graft and patient survival
following liver transplantation for hepatitis C virus.
Transplantation 2006;81:7–14.
14. Forman LM, Lewis JD, Berlin JA, Feldman HI, Lucey MR.
The association between hepatitis C infection and survival
after orthotropic liver transplantation. Gastroenterology 2002;
122:889–96.
15. Garcia-Retrotillo M, Forns X, Feliu A, et al. Hepatitis C virus
kinetics during and immediately after liver transplantation.
Hepatology 2002;35:680–7.
16. Berenguer M, Ferrell L, Watson J, et al. HCV-related fibrosis
progression following liver transplantation: increase in recent
years. J Hepatol 2000;32:673–84.
17. Samuel D, Forns X, Berenguer M, et al. Report of the mono-
thematic EASL Conference on Liver Transplantation for
Viral Hepatitis (Paris, France, January 12–14, 2006). J Hepatol
2006;45:127–43.
18. Gane EJ, Portmann BG, Naoumov NV, et al. Long-term
outcome of hepatitis C infection after liver transplantation.
New Engl J Med 1996;334:815–20.
19. Berenguer M, Prieto M, Rayon JM, et al. Natural history of
clinically compensated hepatitis C virus-related graft cirrho-
sis after liver transplantation, Part 1. Hepatology 2000;32:
852–8.
20. Peveling-Oberhag J, Zeuzem S, Hofmann WP. Antiviral ther-
apy of chronic hepatitis C in patients with advanced liver dis-
ease and after liver transplantation. Med Microbiol Immunol
2010;199:1–10.
21. McCaughan GW, Zerky A. Mechanisms of HCV reinfection
and allograft damage after liver transplantation. J Hepatol
2004;40:368–74.
22. Blasco A, Forns X, Carrion JA, et al. Hepatic venous pressure
gradient identifies patients at risk of severe hepatitis C recur-
rence after liver transplantation. Hepatology 2006;43:492–9.
23. Carrion JA, Navasa M, Bosch J, Bruguera M, Gilabert R,
Forns X. Transient elastography for diagnosis of advanced
fibrosis and portal hypertension in patients with hepatitis C
recurrence after liver transplantation. Liver Transplant 2006;
12:1791–8.
24. Carrion JA, Torres F, Crespo G, et al. Liver stiffness identifies
two different patterns of fibrosis progression in patients with
hepatitis C virus recurrence after liver transplantation.
Hepatology 2010;51:23–34.
25. Berenguer M, Prieto M, San Juan F, et al. Contribution of
donor age to the recent decrease in patient survival among
HCV-infected liver transplant recipients. Hepatology 2002;
36:202–10.
26. Firpi RJ, Clark V, Soldevila-Pico C, et al. The natural history of
hepatitis C cirrhosis after liver transplantation. LiverTransplant
2009;15:1063–71.
27. Garcia-Retortillo M, Forns X, Liover JM, et al. Hepatitis C
recurrence is more severe after living donor compared to
cadaveric liver transplantation. Hepatology 2004;40:699–707.
28. Gaglio PJ, Malireddy S, Levitt BS, et al. Increased risk
of cholestatic hepatitis C in recipients of grafts from living
versus cadaveric liver donors. Liver Transplant 2003;9:
1028–35.
29. Powers KA, Ribeiro RM, Patel K, et al. Kinetics of hepatitis
C virus reinfection after liver transplantation. LiverTransplant
2006;12:207–16.
30. Schiano TD, Gutierrez JA, Walewski JL, et al. Accelerated
hepatitis C virus kinetics but similar survival rates in recipients
of liver grafts from living versus deceased donors. Hepatology
2005;42:1420–8.
31. Garcia-Retortillo M, Forns X. Prevention and treatment
of hepatitis C virus recurrence after liver transplantation.
J Hepatol 2004;41:2–10.
32. Chalasani N, Manzurbeitia C, Ferenci P, et al. Peg-interferon
alfa-2a for hepatitis C after liver transplantation: two ran-
domized, controlled trials. Hepatology 2005;41:289–98.
33. Castells L, Vargas V, Allende H, et al. Combined treatment
with pegylated interferon (alpha-2b) and ribavirin in the acute
phase of hepatitis C virus recurrence after liver transplantation.
J Hepatol 2005;43:53–9.
34. Angrelico M, Petrolati A, Lionetti R, et al. A randomized
study on peg-interferon alfa 2a with or without ribavirin in
liver transplant recipients with recurrent hepatitis C. J Hepatol
2007;46:1009–17.
35. Berenguer M, Palau A, Fernandez A, et al. Efficacy, predic-
tors of response and potential risks associated with antiviral
therapy in liver transplant recipients with recurrent hepatitis
C. Liver Transplant 2006;12:1067–76.
36. Carrion JA, Navasa M, Carcia-Retortillo M, et al. Efficacy
of antiviral therapy on hepatitis C recurrence after liver

6. 54 Apollo Medicine 2012 March; Vol. 9, No. 1 Sikka
© 2012, Indraprastha Medical Corporation Ltd
transplantation: a randomized controlled study. Gastroenterology
2007;132:1746–56.
37. Fernandez I, Meneu JC, Colina F, et al. Clinical and histo-
logical efficacy of pegylated interferon and ribavirin therapy of
recurrent hepatitis C after liver transplantation. Liver Transplant
2006;112:1805–12.
38. Mukherjee S, Rogge J, Weaver L, Schafer DF. Pilot study of
pegylated interferon alfa-2b and ribavirin for recurrent hepa-
titis C after liver transplantation. Transplant Proc 2003;35:
3042–4.
39. Neff GW, Montalbano M, O’Brien CB, et al. Treatment of
established recurrent hepatitis C in liver transplant recipients
with pegylated interferon-alba-2b and ribavirin therapy.
Transplantation 2004;78:1303–7.
40. Oton E, Barcena R, Moreno-Planas JM, et al. Hepatitis C
recurrence after liver transplantation: viral and histologic
response to full-dose PEG-interferon and ribavirin. Am J
Transplant 2006;6:2348–55.
41. Picciotto FP, Tritto G, Lanza AG, et al. Sustained virological
response to antiviral therapy reduces mortality in HCV rein-
fection after transplantation. J Hepatol 2007;46:459–65.
42. Berenguer M. Systematic review of the treatment of estab-
lished recurrent hepatitis C with pegylated interferon in com-
bination with ribavirin. J Hepatol 2008;49:274–87.

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