Management of recurrent HCV infection following liver transplantation

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Natural history of recurrent HCV infection after
liver transplantation
Chronic hepatitis C (CHC) is a worldwide health problem and,
despite a decline in the incidence of new HCV infections, the
prevalence of cirrhosis and the incidence of its complications
will not peak until the year 2040 (Davis 2003). CHC has become
the leading indication for both cadaveric and living donor liver
transplantation (LT), accounting for approximately 50% of cases
in the United States, Europe and Japan.
Demand does not slow down because of the constant increase
of the number of patients with HCV end-stage liver disease
(ESLD) and HCH.
Unfortunately, HCV infection invariably recurs after LT and the
natural course of the disease is accelerated compared to the nontransplant
setting. The influence of HCV infection on allograft
histology is highly variable, but at least 50% of recipients
develop histological evidence of recurrent disease within 1 year

post-transplant. The progression of fibrosis occurs at a rate 1.4
times faster when compared to progression of fibrosis in the
non-transplant population (Mohsen 2003).
The estimated rate of allograft cirrhosis reaches 30% at 5 years
of follow-up, leading to increasing incidence of
retransplantation in HCV recipients. After the diagnosis of
cirrhosis, the decompensation risk appears to be accelerated
(17% and 42% at 6 and 12 months, respectively). Patient survival
is also significantly decreased: 66% and 30% at 1 and 5 years,
respectively (Berenguer 2000). HCV infection-associated
allograft injury is incriminated as the most common cause of
both death (28-39%) and graft failure (~40%) among transplant
recipients (Charlton 2004). Retransplantation represents the last
option for these patients in the context of increasing demands
for LT.
Many factors such as donor and host characteristics, virologic
features and immunosuppression have been shown to influence
the progression of post-transplant liver disease.
Viral factors. As early as the first week postoperatively, the
HCV RNA level increases 10- to 20-fold and plateaus at 1 month,
with higher levels noted in those with more severe recurrent
hepatitis (Berenguer 2001). However, the role of HCV RNA levels
in determining severity of HCV recurrence remains
controversial. The single exception is the well-proven
relationship between very high VL and occurrence of cholestatic
hepatitis (~2-5% of patients). Other viral factors that may
influence the severity of the recurrence are difficult-to-treat
viral genotype (1 and 4) and the quasi-species.
Recipient factors. Increasing age of the recipient (>50 years)
and female sex, as well as non-Caucasian (Afro-American, Asian)
have a more aggressive recurrence (Belli 2007). Thus, a
combination of a liver from an old donor with an old recipient
should be avoided. Presence of a necroinflammatory score ≥2 in
the explants was shown to be a predictor of progressive fibrosis.
Also, the HLA donor-recipient matching was associated with a

more severe HCV recurrence, although overall graft survival was
not influenced (Langrehr 2006).
Donor factors. Evidence suggests the following donor factors
to be associated with negative outcome in HCV-infected LT
recipients: donor age, donor fat content (>30%) and ischemic
time. Older donor age (≥50 years) was an independent predictor
for HCV related cirrhosis after 5 years and reduced graft survival
in several studies (Iacob 2007, Samonakis 2005). Prolonged warm
ischemia time (begins as the liver is secured in place and extends
until reperfusion with recipient blood starts) represents a higher
risk for a severe histological recurrence; this risk increases by
13% for each hour increase of cold ischemia time (time elapsed
between removal and cooling of the donor liver and extends
until the donor liver is rewarmed during implantation). Recent
studies have demonstrated that living-related LT is not a risk
factor for severe HCV recurrence. The HCV histological
recurrence rate was 58% after 4 months, 90% at 1 year and 100%
after 2 years in patients transplanted with a living donor
compared to 71% at 4 months, 94% at 1 year and 95%,
respectively, after 2 years in deceased donor LT (Guo 2006).
Clinical factors. A number of potentially modifiable posttransplant
factors have also been associated with increased
severity of HCV recurrence and poorer patient and graft survival
such as immunosuppression, acute rejection episodes treated
with bolus corticosteroids or T-lymphocyte depleting agents,
cytomegalovirus or herpes simplex 6 virus infection, metabolic
syndrome or insulin resistance.
Much emphasis has been placed on the different
immunosuppressive regimens and their changes during the
last 20 years. CHC is more aggressive in LT recipients than in
immuno-competent patients. However, a sudden change in the
degree of immunosuppression, rather than the absolute amount
of immunosuppression, is deleterious for HCV-infected
recipients.
Regarding the calcineurin inhibitors (CNI), most of the studies
suggest that there is no significant difference between

tacrolimus and cyclosporine with respect to their impact on
histologically diagnosed HCV recurrence and graft or patient
survival (Iacob 2007, Berenguer 2007). Cyclosporine has a strong
in vitro suppressive effect on HCV replication (Watashi 2003).
Several clinical although relatively small studies suggested a
higher sustained virologic response (SVR) in HCV LT patients
receiving cyclosporine and interferon therapy.
The cornerstone of immunosuppressive agents, the
corticosteroids, slowly tapered off over a long time, may prevent
progression to severe forms of recurrent disease (Iacob 2007,
Brillanti 2002). In contrast, the boluses of methylprednisolone
(MP) used for acute rejection episodes were deleterious to the
HCV-related graft survival. Outcome of HCV-positive patients
who received multiple pulses of MP is significantly worse than
that in patients with a single pulse therapy (Bahra 2005). High
levels of viremia can determine an HCV-cytopathic mechanism
involved in the allograft injury. Currently, steroid-free
immunosuppression regimens are preferred in HCV recipients.
Actual data for mycophenolate mofetil (MMF), a morpholino
ester prodrug of mycophenolic acid (MPA), favor its use in
recurrent hepatitis C. MPA is a selective, noncompetitive,
reversible inhibitor of inosine monophosphate dehydrogenase
(IMPD), a key enzyme in the biosynthetic pathway of the guanine
nucleotides. It is also a potent inhibitor of both B and T cell
proliferation. MMF in combination with CNI taper showed a
positive effect on fibrosis progression, graft inflammation and
ALT levels (Lake 2009, Iacob 2007). Less data are available for
azathioprine, but its inclusion in the maintenance regimen was
associated with survival advantage.
The potential antifibrotic and antiviral benefit of mTOR
(mammalian target of rapamycin) inhibitors after LT in HCV
positive patients awaits further investigation in prospective
randomized controlled trials. Sirolimus, a macrolide isolated
from Streptomyces hygroscopius reduces TGF-β and procollagen,
inhibits hepatic stellate cell proliferation and may have an
inhibitory action on HCV replication through phosphorylation of

Prophylactic antiviral therapy in cirrhosis
The main goals of treating cirrhotic patients with antiviral
therapy are to prevent the complications of the disease, to halt
disease progression or allow for the regression of cirrhosis, and
to attain sustained viral clearance in order to prevent
reinfection in the graft in patients undergoing LT.
SVR in patients with Child-Pugh (CP) class A cirrhosis has
improved from 5% with interferon monotherapy to 50% with
pegylated interferon alfa (PegIFN) + ribavirin (RBV) in genotype
1 (Everson 2005).
The safety of combination therapy in cirrhotics is a major
concern. Bone marrow suppression by administration of either
standard or PegIFN alfa leads to significant decrease in all three
lineages of the hematopoietic system (Iacobellis 2008). However,
erythropoietic agents are effective in treating anemia,
preventing RBV dose reduction, improving patients‘ quality of
life, but the effect on SVR is not fully elucidated. Granulocyte
colony-stimulating factor is effective in raising ANC; however,
neutropenic HCV-infected patients on combination treatment
may not experience increased bacterial infections. Eltrombopag,
a new oral thrombopoietin mimetic, may allow combination
treatment in patients with cirrhosis and thrombocytopenia.
Antiviral therapy is commonly deferred in cirrhotics with signs
of liver decompensation, due to even more compelling concerns
over treatment-induced side effects (up to 60%).
There are several studies reporting experience with interferonbased
therapy in pre-transplant patients aiming to prevent
reinfection of the new graft (Alsatie 2007). The largest study
(Everson 2005) included 124 patients with an average CP score of
7.4 and a mean MELD (Model for End Stage Liver Disease – the
currently used allocation system, introduced in 2002 in USA in
order to prioritize patients on the waiting list) score of 11, who
received a low-accelerating-dose regimen. An SVR of 24% was

achieved and 12 of 15 patients who were HCV RNA-negative
before LT remained HCV RNA-negative ≥6 months
postoperatively. The following predictors of response in these
studies were identified: non-1 genotype, CTP class A (genotype 1
only), ability to tolerate full dose and duration of treatment,
lower pretreatment VL, a VL decrease ≥2 log10 at week 4 of
treatment (Alsatie 2007). Premature discontinuation of the
therapy due to side effects was reported in 13-30% and dose
reductions were more frequent.
On the basis of available data, prophylactic antiviral therapy in
this setting to prevent recurrent HCV infection post-LT has a
limited role and may be associated with serious AEs.
Pretransplant therapy, using a low-accelerating dose regimen, is
an important treatment strategy but is applicable to selected
patients only. Prophylactic antiviral therapy should not be
considered in those with high MELD score (≥20) or CTP class B or
C. It is to be noted that up to two-thirds of patients who become
HCV RNA–negative on treatment will be HCV-free posttransplantation.
Pre-emptive antiviral therapy after LT
Preemptive antiviral therapy started within 2-6 weeks after
transplantation has the advantage of a relatively low VL and the
absence or minimal evidence of histologic recurrence, but is
limited by tolerability, particularly in patients with high MELD
scores pre-transplantation.
Rates of SVR vary from 5% to 39% (Terrault 2008). Better results
were reported in adult-to-adult right lobe live donor LT for HCC
and low MELD scores as well as in planned living donor LT cases
with splenectomy (Sugawara 2010). Dose reductions were
required, more frequently for RBV than interferon, and
treatment discontinuations were highly variable across the
studies, ranging from 0% to 57%.
Two small trials have evaluated the efficacy of PegIFN in this
setting, one of which noted that only 41% of screened transplant
recipients were eligible to begin therapy (Chalasani 2005

Histological benefits in virologic nonresponders have been
demonstrated in a study where only 22% in a group receiving
preemptive therapy progressed vs. 49% of patients not receiving
preemptive therapy (Kuo 2008). However, this prophylactic
approach cannot be used in a considerable proportion of
patients due to initially intense immunosuppression,
pancytopenia, postoperative infections and insufficient recovery
after the surgery.
Therapy of recurrent hepatitis C after LT
Posttransplant antiviral therapy in recipients with evidence of
biochemical and histological recurrent disease, usually 6 months
after LT, is the mainstay of management. Although a high
number of transplant centers use antiviral therapy, the
treatment is not standardized and is still associated with low
rates of SVR, less than those reported in the non-transplant
setting. The main reasons include high VL post-LT, a higher
frequency of genotype 1 patients, poor tolerability of treatment
after LT, and need for frequent dose reductions.
The combination of PegIFN/RBV is the treatment of choice also
in transplant recipients. The SVR associated with PegIFN/RBV
therapy in predominantly genotype 1 infected populations has
been reported to range from 12% to as high as 50% (Gonzalez
2010). A recent extensive review of 19 prospective and
retrospective clinical studies describing antiviral therapy with
PegIFN/RBV in this population reported a mean SVR of 30.2%
(Berenguer 2008). End of treatment virologic response (EoTR)
was 42.2% (range 17-68%), indicating that relapse was a major
factor in the low SVR rates. Biochemical responses were
registered in 54.8% and histological endpoints were judged to be
too heterogeneous in definition and assessment to provide a
summary estimate. However, it was noted that histological
improvements were generally confined to treated patients who
achieve SVR. Fibrosis has been shown to progress significantly
more in nonresponders to antiviral therapy. Even in the absence
of virological response, the rate of progression of fibrosis was

significantly slowed in patients treated for more than 6 months
(Walter 2009). Using long-term maintenance antiviral therapy
has recently been shown to increase the probability of
biochemical and histological responses, regardless of the timing
of the HCV recurrence (de Martin 2010).
Achievement of SVR in the setting of recurrent HCV following
LT has a major impact on long-term outcomes, including
improved graft and patient survival. Identifying patients with a
greater likelihood of achieving SVR is an important
consideration in the selection of potential treatment candidates
and is a key factor in developing strategies for optimizing
response to therapy.
Predictors of response to therapy identified in different studies
(Terrault 2008, Selzner 2009, Gonzalez 2010, Fukuhara 2010)
were
– Non-1 HCV genotype
– Absence of prior antiviral therapy
– Donor age
– Pretreatment necroinflammatory activity and fibrosis stage
– Concomitant cyclosporine use
– Course completion (the rule of 80/80/80, see chapter 1)
– Low pretreatment HCV RNA (<1 million IU/ml)
– IL28B polymorphism in recipient and donor tissues
– RVR or EVR – that hold the highest predictive values of SVR.
Undetectable VL at 24 weeks of therapy was also noted to
confer a high predictive value (92%) for SVR and prolonged
treatment protocol was suggested in these LT recipients.
Side effects and safety of PegIFN/RBV therapy
The clinical spectrum of AEs is similar to the non-transplant
setting (see chapter 1). Dose reductions are frequent and drug
discontinuation rates are higher than in nontransplant patients.
A major limitation of antiviral therapy is tolerability,
particularly with respect to the hematologic AEs of PegIFN/RBV.
In a recent Cochrane review, up to 87.5% of patients required a
dose reduction and up to 42.9% of patients stopped treatment

mediated complications unique to the posttransplant
setting. Acute and chronic rejections are infrequent
complications of antiviral therapy often associated with
concomitant low or negative serum HCV RNA. The reported
incidence of ACR during interferon based therapy ranges from 0
to 35%. It is to be noted that the incidence of ACR in HCV positive
LT recipients treated with combination antiviral therapy for
HCV recurrence does not seem to be higher than that observed
in non treated HCV positive LT recipients (Seltzner 2010).
An autoimmune-like hepatitis (de novo autoimmune hepatitis)
has been reported in LT recipients treated with PegIFN/RBV for
recurrent hepatitis C. In general, these patients have no history
of autoimmune disease, and HCV RNA is undetectable at the time
of the secondary rise in liver enzymes. In HCV infected patients,
it remains controversial whether these cases represent a true
autoimmune (alloimmune) process, as opposed to an atypical
manifestation of recurrent disease or of acute or chronic
allograft rejection. Histologic findings are an essential part in
the differential diagnosis between these entities. Any flare in
liver enzymes in patients treated with antiviral therapy,
particularly in those with undetectable HCV RNA, should raise

the suspicion of these complications and warrant the
performance of a liver biopsy.
Retransplantation for recurrent HCV cirrhosis
Retransplantation is the only therapeutic option to achieve
long-term survival in patients with decompensated HCV
cirrhosis after LT. Retransplantation for this indication ranges
from 3.6% to 44%. Patient and graft survival rates after
retransplantation are inferior to those after primary LT. HCVinfected
recipients had a significantly lower survival rate
compared to non-HCV-infected patients who underwent
retransplantation at least 90 days after primary LT.
Progression to cirrhosis is faster after retransplantation than
after primary LT, particularly in patients with severe hepatitis C
recurrence (cholestatic hepatitis and graft failure within the first
year) (Carrion 2010). Predictors of poor outcome are: bilirubin
≥10 mg/dL, serum creatinine ≥2 mg/dL, donor age >40, recipient
age >55 and early HCV recurrence (cirrhosis <1 year after LT)
(Wiesner 2003). Thus, the optimal timing to perform elective
retransplantation in HCV patients is a matter of debate.
However, bilirubin and creatinine serum levels are essential for
deciding about retransplantation candidates. Patients with a CTP
score ≥10 or a MELD score >25 have a very high risk of death
after retransplantation.
Outlook
HCV is and will continue to be the most common indication for
LT worldwide and recurrent disease associated with HCV is a
major cause of allograft loss and mortality.
A better understanding of the recipient, donor and viral risk
factors for progressive disease and vigilant post-transplant
monitoring through histologic assessment may guide
management aimed toward reducing the potential for graft
failure as well as helping identify candidates for antiviral
therapy.

Antiviral therapy in patients with HCV cirrhosis awaiting LT
should be considered only in selected individuals due to poor
tolerability and limited virologic response. Pre-emptive therapy
is not well tolerated in the post-LT population. Antiviral therapy
with PegIFN/RBV should be considered in transplant recipients
with recurrent HCV infection. Achievement of SVR is associated
with increased allograft and patient survival; however, efficacy
may be limited by poor tolerability, risk of cellular rejection and
risk of alloimmune hepatitis, requirement for dose reductions,
and treatment discontinuation.
Retransplantation is the only therapeutic option to achieve
long-term survival in patients with decompensated cirrhosis
after LT.
Links
– American Liver Foundation: www.liverfoundation.org
– The United Network for organ sharing (UNOS):
www.unos.org
– American College of Gastroenterology, Hepatitis C
Treatment Resource Kit (PDF, 56 pages): goo.gl/qCz3v
– European Liver Transplant Registry: www.eltr.org
– Organ Procurement and Transplantation Network (OPTN):
http://optn.transplant.hrsa.gov