Management of recurrent HCV infection following liver transplantation

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
80 | Hepatitis C Treatment
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
Management of recurrent HCV infection following liver transplantation | 81
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
82 | Hepatitis C Treatment
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
Management of recurrent HCV infection following liver transplantation | 83
signal transducers and activators of transcription (STAT-1)
(Matsumoto 2009).