In recent years, the use of direct-acting antivirals (DAAs) has been a major step
forward in the treatment of chronic hepatitis C. The combination of several of these
drugs in the absence of interferon (IFN; IFN-free regimens), has shown high sustained
virological response (SVR) rates and a significantly better tolerance when compared
with IFN-containing regimens.[1]
One area with an urgent need to assess the safety and efficacy of IFN-free regimens
is the peri-liver transplantation (LT) setting. HCV recurrence is universal after
LT in individuals with detectable HCV RNA at the time of LT[2] and the consequences of graft infection are well known. Graft and patient survival
are significantly lower in HCV-infected liver transplant recipients as compared with
individuals who undergo LT for other indications. In approximately one-third of HCV-infected
LT recipients, graft cirrhosis develops within the first 5 years following transplantation
(“rapid fibrosers”).[3]
Treatment of HCV infection in the peri-transplant setting is indicated in two different
situations. First, in patients awaiting LT to prevent HCV infection of the graft;
second, in patients with hepatitis C recurrence after LT in whom HCV-related graft
damage has already occurred. Current IFN-based regimens are very disappointing in
both situations. Thus, there is plenty of room for improvement.[4] In the last few months, the first data on the safety and efficacy of an IFN-free
regimen (sofosbuvir plus ribavirin [RBV]) in patients awaiting LT and in individuals
with hepatitis C recurrence after LT have been presented. In the near future, other
regimens will be evaluated in this setting. Here we will review the current status
and future therapies in this group of patients.
Treatment of Patients Awaiting Liver Transplantation
Patients with advanced cirrhosis, particularly those who are awaiting a LT, are one
of the most difficult-to-treat populations. The main aim of antiviral treatment while
on the waiting list is to prevent HCV infection of the graft. Most centers indicate
therapy for a short period to achieve undetectable HCV RNA at the time of LT; the
latter is associated with a high chance of preventing graft infection following transplantation.[5] A second aim of antiviral therapy in these patients is to improve liver function
(which might, in some cases, imply delisting). Although this has been clearly achieved
in patients with HBV-related cirrhosis treated with nucleo(s)tide analogues,[6]
[7] information on this particular topic in HCV-infected cirrhotics is insufficient.[8]
Current Antiviral Regimens
Current IFN-based treatments are far from optimal in patients with advanced cirrhosis.
A few studies have shown that pegylated interferon (PegIFN) plus RBV administered
while on the waiting list can prevent graft infection in patients who achieve viral
clearance (undetectable HCV RNA).[5]
[9]
[10]
[11] As expected, response rates are higher in individuals infected with HCV genotypes
2 and 3 as compared with genotype 1, as well as in those with the IL28B CC genotype.[12] In those patients who achieve viral clearance, a longer duration of treatment (>
16 wk of therapy) is associated with lower rates of HCV recurrence after LT.[10] Nevertheless, IFN-based therapy can only be administered in cirrhotics with a good
liver function (Child-Pugh ≤ 7 or Model for End-Stage Liver Disease [MELD] score ≤ 18),
in whom the indication of transplantation is hepatocellular carcinoma.[3] In patients with more advanced disease, serious adverse events (i.e., bacterial
infections such as spontaneous bacterial peritonitis or spontaneous bacteriemia,[9] grade 3 and 4 cytopenias, clinical decompensation) are frequent and can be life
threatening. Thus, only a small proportion of HCV-infected patients can undergo IFN-based
therapy and barely 25% of them will achieve a virological response that is maintained
after LT.
The recent approval of two first-wave, first-generation protease inhibitors (PIs),
boceprevir and telaprevir, has been a major step forward in the treatment of chronic
hepatitis C. SVR rates have increased by nearly 30% with triple therapy as compared
with PegIFN plus RBV in naïve genotype 1 patients, and by 25 to 50% in treatment-experienced
genotype 1 patients (depending on previous treatment responses).[13]
[14]
[15]
[16]
[17] Unfortunately, response rates are lower in cirrhotic patients, particularly in those
who are previous null responders (a common situation in patients awaiting LT).
Beyond efficacy results, PIs-based regimens in compensated cirrhotics may be associated
with serious adverse events (SAEs), such as severe infections (4–6%), clinical decompensation
(3–4%), and even death.[18]
[19] It is interesting to notice that the type of infections reported in cirrhotic patients
treated with triple therapy did not follow the expected pattern (spontaneous bacteriemia,
spontaneous bacterial peritonitis, or urinary infection caused by gram-negative bacteria).
In contrast, infections of the respiratory tract or sepsis caused by gram-positive
bacteria or other germs were frequently reported, some of them resulting in fatal
outcomes.[19]
[20] These serious side effects were not reported in the registration trials because
patients included in these studies were mostly very well-compensated cirrhotics without
significant portal hypertension (low platelet count— < 90,000 for telaprevir[14]
[15]
[17] and < 100,000 for boceprevir[13]
[16]—was an exclusion criterion). The main predictive factors of severe complications
in cirrhotics undergoing triple therapy (severe infections, clinical decompensation,
or death) were a low platelet count (< 100,000/mm3) and low serum albumin levels (< 35 g/L). Importantly, the risk for severe complications
was 44% in patients with both factors as compared with 3.4% in patients with normal
platelet count and serum albumin levels.[19] Overall, the data reported in these studies indicate that the proportion of patients
in the waiting list that may benefit from triple therapy is very small: < 10% of genotype
1-infected patients, slightly higher in centers with a high proportion of patients
with hepatocellular carcinoma in the waiting list (M-C Londoño, unpublished results).
To date, data on triple therapy in HCV-infected patients awaiting LT are limited.
Verna et al[21] showed results of triple therapy in a small cohort of HCV-infected G1 cirrhotics
(n = 20) in the waiting list for LT. Most of them were previous nonresponders and had
hepatocellular carcinoma at the time of treatment initiation. Patients underwent triple
therapy (90% with telaprevir) for a median time of 14 weeks; at week 12, up to 77%
of patients had undetectable HCV RNA. Seven out of the eight transplanted patients
by the time of the analysis reached LT with undetectable HCV RNA and six patients
remained RNA-negative 12 weeks after transplantation. From a safety point of view,
25% of patients discontinued therapy and two of them were hospitalized due to de novo
liver decompensation. A French multicenter phase II trial is assessing the safety
and efficacy of boceprevir-based triple therapy (NCT 01463956)[22] in G1 patients in the waiting list with a MELD score ≤ 18.
In summary, IFN-based regimens should be only indicated in compensated cirrhotics
who are awaiting LT due to hepatocellular carcinoma; treatment in patients with more
advanced disease should be restricted to those individuals with a MELD score below
18 (or Child-Pugh B < 8 points) who have a good chance to achieve a virological response
(i.e., genotype 2/3; genotype 1 IL28B CC).[3]
[12] Triple therapy should be restricted to genotype 1-infected patients with compensated
cirrhosis and good liver function, preferably those who are treatment-naïve, relapsers,
or partial responders to previous IFN–ribavirin therapy ([Fig. 1A]).
Fig. 1 Algorithm for the management of patients with hepatitis C virus (HCV) infection awaiting
liver transplantation in 2013[3] (A). Proposed algorithm for the management of patients with HCV infection awaiting liver
transplantation in 2014–2015 (B).
Interferon-Free Regimens in Patients Awaiting LT
Efficacy of Interferon-Free Regimens in Patients with Compensated Cirrhosis
Although data on the safety and efficacy of IFN-free regimens are very limited in
decompensated cirrhotics, it is important to review the results of such regimens in
compensated patients because some of them are close to regulatory approval or in late-phase
3 development.
In most phase 2 and registration trials, the proportion of patients with cirrhosis
included is relatively small and most of them are treatment-naïve. In the waiting
list, a significant proportion of patients are treatment-experienced (some with a
first-generation PI in triple therapy) and most of them have clinically significant
portal hypertension. Despite these differences, we found it was relevant to review
the efficacy data of IFN-free regimens including cirrhotics, as depicted in [Table 1].[23]
[24]
[25]
[26]
[27]
[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
[37]
Table 1
Phase 2 and 3 Clinical Trials with IFN-free regimens including compensated cirrhotic
patients
|
Therapeutic regimen in trial arm including cirrhotic population
(Trial name)
|
Response to previous IFN based therapy
|
Lower limit of platelets
(mm3)
|
Treatment duration in the specific arm
|
Cirrhotic patients
N (%)
|
Study phase
|
Genotype
spectrum
|
SVR in cirrhotic patients
|
|
SOF +RBV
(FISSION)[23]
|
Naïve
|
75.000
|
12 W
|
50 (20%)
|
3
|
2.3
|
SVR12 47%
|
|
SOF +RBV
(POSITRON)[24]
|
IFN intolerant
|
No lower limit
|
12 W
|
31 (15%)
|
3
|
2.3
|
SVR12 61%
(G2 94% and G3 21%)
|
|
SOF + RBV
(FUSION)[24]
|
Non-responder
|
50.000
|
12 W
16 W
|
36 (35%)
32 (33%)
|
3
|
2.3
|
SVR12
G2 60% and 78%
G3 19% and 61%
(12 and 16 W respectively)
|
|
SOF + RBV
(VALENCE)[25]
|
Naïve and treatment experienced
|
50.000
|
12 W G2
24 W G3
|
10 (14%) G2
59 (22%) G3
|
3
|
2. 3
(G3 78%)
|
SVR12[a]
G2 100% and 88%
G3 92% and 60%
(naïve and treatment experience respectively)
|
|
SOF + RBV
(NIH SPARE)[26]
Part 2
|
Naïve
|
50.000
|
24 W
|
13 (26%)
F3-4
|
2
|
1
(G1a 70%)
|
SVR24
50% and 29%
(weight-based and low-dose RBV respectively)
|
|
SOF + RBV or
GS-0938 or
GS-0938 + SOF (± RBV)
(QUANTUM)[27]
|
Naïve
|
50.000
|
12 W
24 W
|
21 (9%)
|
2
|
1-4
|
SVR12 50%
(SOF + RBV arm,24W)
|
|
SOF + LDV ±RBV
(ELECTRON)[28]
6th and 7th arms
|
Null-responder
|
N.S.
|
12 W
|
19 (100%)
|
2
|
1
|
SVR12
100% and 70%
(with and without RBV respectively)
|
|
SOF + LDV
(NIAID SYNERGY)[29]
arm A
|
Naïve
|
50.000
|
12 W
|
3 (15%)
|
2
|
1
(G1a 55%)
|
SVR12[a]
100%
|
|
SMV + SOF ± RBV
(COSMOS)[30]
Cohort 2
|
Naïve and null responder
|
N.S.
|
12 W
24 W
|
39 (47%)
|
2
|
1
(G1a 78%)
|
SVR4 (for 12 wk group)
100% and 100% naïve
100% and 93% nulls
(with and without RBV, respectively)
|
|
SOF + LDV ± RBV
(LONESTAR)[31]
(Cohort B)
|
Non-responder to protease inhibitor regimen
|
N.S.
|
12 W
|
22 (55%)
|
2
|
1
(G1a 85%)
|
SVR12
100% and 95%
(with and without RBV respectively)
|
|
DCV + ASV + BMS-791325[32]
|
Naïve
|
N.S.
|
12 W
|
15 (9%)
|
2
|
1
(G1a 86%)
|
SVR12
71% and 100% with 75 mg and 100 mg of BMS-791325, respectively
|
|
SOF + RBV[33]
|
Naïve and treatment experienced
|
N.S.
|
12 W
24 W
|
14 (23%)
|
2
|
4
|
SVR4
33% and 100% in naïve
50% and 100% in treatment-experienced
(12 and 24 W, respectively)
|
|
DCV + ASV[34]
|
IFN ineligible naïve/intolerant and non-responder
|
N.S.
|
24 W
|
22 (10%)
|
3
|
1b
|
SVR24[a]
90.9%
|
|
FDV + DBV ± RBV
(SOUND C2)[35]
|
Naïve
|
100.000
|
16.28,40 W
|
33 (9%)
|
2
|
1
|
SVR12
33%-63%
according to different regimens
|
|
FDV + DBV + RBV
(SOUND C3)[36]
|
Naïve
|
90.000
|
16 W
|
4 (20%)
|
2
|
1
|
SVR12
100%
|
|
ABT-450/r + ABT-267 + ABT-333 + RBV
(TURQUOISE II)[37]
|
Naïve and treatment experienced
|
60.000
|
12 W
24 W
|
380 (100%) estimated enrollment
|
3
|
1
|
SVR12
92% and 96%
(12 and 24 W respectively)
|
|
SOF + DCV ± RBV[104]
|
Naive and treatment experienced (including protease inhibitors)
|
N.S
|
12 W
24 W
|
32 (15%)
|
2
|
1-3
|
SVR12
100%
|
Abbreviations: ABT-450/r, NS3/4A protease inhibitor; ABT-267, NS5A inhibitor; ABT-333,
nonnucleoside NS5B inhibitor; ASV, Asunaprevir (NS3 protease inhibitor); BMS-791325
(nonnucleoside NS5B inhibitor); DBV, Deleobuvir (NS5B nonnucleoside analog inhibitor);
DCV, Daclatasvir (NS5A inhibitor); FDV, Faldaprevir (NS3/4A protease inhibitor); LDV,
Ledipasvir (NS5A inhibitor); N.S., no specified platelet lower limit; RBV, Ribavirin,
GS-0938 (NS5B nucleotide polymerase inhibitor); SMV, Simeprevir (NS3/4A protease inhibitor);
SOF, Sofosbuvir (NS5B nucleotide polymerase inhibitor); SVR, sustained virological
response .
a SRV results updated at AASLD Liver Meeting 2013.
In two recent published studies, ELECTRON[28] and LONESTAR,[31] HCV genotype 1 patients with compensated cirrhosis who did not respond to a prior
PegIFN/RBV regimen and a protease inhibitor-containing triple combination regimen,
respectively, were enrolled to receive 12 weeks of sofosbuvir plus ledipasvir with
or without RBV. Despite the small sample size, the results were excellent: SVR12 rates
were 100% in both studies when RBV was part of the regimen, and 70% and 95% for the
ELECTRON and LONESTAR trials, respectively, when RBV was not part of the regimen.
Similar results were obtained in the COSMOS study,[30] in which treatment-naïve and experienced patients underwent 12 to 24 weeks of therapy
with sofosbuvir and simeprevir (± RBV). Despite the small number of cirrhotics, SVR4
rates in the group of patients who underwent the 12-week regimens ranged between 93%
and 100%.
The results of a large randomized clinical trial performed in cirrhotic patients with
an all-oral DAA combination (TURQUOISE II) have been recently shown (press release).[37] This trial has been designed to evaluate the safety and efficacy of ABT-450 boosted
with ritonavir, ABT-267, and ABT-333 coadministered with RBV for 12 or 24 weeks in
HCV genotype 1-infected patients with compensated cirrhosis (both treatment-naïve
and experienced). SVR rates in the 12 week group were 92% and 96% in the 24 week group.
Specific Features of Interferon-Free Regimens in Patients Awaiting LT
There are some distinct features that should be taken into consideration in individuals
awaiting LT. First, the goal in these patients is to achieve undetectable HCV RNA
at the time of transplantation: Because by far the main source of viral production
will be removed (liver explant), a short treatment course may be enough to prevent
graft infection. In any case, a minimum length of undetectable HCV RNA before transplantation
will be necessary to prevent graft infection and this will depend on viral kinetics.
In the LONESTAR and ELECTRON trials, rapid virological response (RVR) rates ranged
from 94 to 100%: These studies are limited for their small size, but they support
the potential efficacy of a short-treatment course before LT to prevent graft infection.
Nevertheless, studies in patients with significant portal hypertension are crucial
because first- and second-phase HCV RNA decay may differ from patients with early
cirrhosis. Indeed, the first phase viral load decline in patients awaiting LT was
significantly slower than in noncirrhotic patients when treated with daily intravenous
silibinin (SIL) monotherapy for 7 days (no significant differences were found between
both groups for the second-phase viral decline).[38] These data, however, cannot be directly translated into DAA due to the complex and
multifactorial mode of action of silibinin.[39] The combination of sofosbuvir plus ledipasvir and RBV is currently being assessed
in patients with more advanced liver cirrhosis (Child-Pugh class B and C) in a clinical
trial (NCT 01938430).[40]
A second distinct feature in patients with advanced liver disease is the impact of
drug pharmacokinetics (PK) on liver function: Metabolic liver functions are significantly
involved in the total clearance of several drugs. In fact, PK studies in patients
with liver disease are an important clinical pharmacology component of drug development.
In 2003, the Food and Drug Administration (FDA) released the guidance for industry
on “Pharmacokinetics in Patients with Impaired Hepatic Function,” which provides recommendations
to sponsors on study design, data analysis, and impact on dosing and labeling.[41] PK data on several new antivirals are already available[42]
[43]
[44]
[45]
[46]
[47]
[48]
[49]
[50]
[51]
[52]
[53]
[54]
[55]
[56] and summarized in [Table 2]
Table 2
Pharmacokinetics of DAAs: Exposure change in hepatic and renal impairment groups versus
controls
|
Drug
|
Hepatic impairment
|
Renal impairment
|
|
Mild (CTP A)
|
Moderate (CTP B)
|
Severe (CTP C)
|
Action required
|
Severe GFR ≤ 30 mL/min
|
Action required
|
|
Simeprevir[a]
[42]
[43]
|
x < 2
|
×2.6
|
×5.2
|
Not recommended in CTP-C patients
|
↑ × 1.62
|
No
|
|
Faldaprevir[b]
[44]
|
x < 2
|
−
|
−
|
No
|
↑ × < 2
|
No
|
|
Deleobuvir[b]
[45]
|
x < 2
|
−
|
−
|
No
|
−
|
−
|
|
Asunaprevir[c]
[46]
[47]
|
x < 2
|
×9.8
|
×32.1
|
Not recommended in CTP-B or C patients
|
× 0.9
|
No
|
|
Daclatasvir[d]
[48]
[49]
[50]
|
x < 2
|
x < 2
|
x < 2
|
No
|
−
|
−
|
|
ABT-450/r[d]
[51]
[52]
|
x < 2
|
x < 2
|
×18
|
Not recommended in CTP-C patients
|
−
|
−
|
|
ABT-267[d]
[52]
|
x < 2
|
x < 2
|
x < 2
|
No
|
−
|
−
|
|
ABT-333[d]
[52]
|
x < 2
|
x < 2
|
x < 2
|
No
|
−
|
−
|
|
Sofosbuvir[c]
[53]
[54]
[55]
|
x < 2
|
x < 2
|
x < 2
|
No
|
↑ × 2
|
Not recommended
|
|
Ledipasvir[56]
|
x < 2
|
x < 2[c]
|
x < 2[d]
|
No
|
−
|
−
|
Abbreviations: CTP, Child-Turcotte-Pugh score; GFR, glomerular filtration rate; DAAs,
direct-acting antivirals.
Note: x < 2: twofold increase or decrease in the area under the concentration curve
(AUC) is considered nonsignificant and does not need dose adjustment.
a AUC24h is given.
b Cmin is given.
c AUCTAU is given.
d AUCinf is given.
As an example, exposure to sofosbuvir was two-fold higher in HCV-infected patients
without hepatic impairment as compared with patients with advanced liver disease.
Consequently, patients with moderate and severe hepatic impairment experienced a less-profound
viral decline than those with normal liver function when sofosbuvir was administered.[54] These data may have clinical consequences and explain why in patients with advanced
liver disease, longer treatment duration could reduce the rates of virological relapse.
A third distinct feature of patients awaiting LT is the potential risk of viral breakthrough
or relapse during or after treatment, which may theoretically induce flares that could
trigger liver decompensation. It is thus very relevant to choose the best treatment
combination (high potency and high genetic barrier) to minimize the possibility of
virological relapse or the selection of resistant-associated viral strains (RAVs).
Regarding the latter point, special emphasis should be taken to avoid the selection
of RAVs because they could infect the new graft and persist for prolonged time in
the setting of a strong immunosuppression. The fitness of resistant strains is usually
lower than that of the wild-type and sensitive virus tends to progressively replace
them (except RAVs selected by NS5A inhibitors that appear to persist for a very long
time). However, the presence of RAVs after transplantation may hamper antiviral therapy
in case of severe hepatitis C recurrence (i.e., fibrosing cholestatic hepatitis C).
The evolution of posttransplant HCV quasispecies in patients who failed pre-LT treatment
with DAA should be studied carefully in the future to clarify the impact of RAVs on
clinical outcomes and for the selection of the appropriate antivirals.
Finally, another aim of antiviral therapy in patients with decompensated cirrhosis
should be improvement of liver function. No data are available so far, but the clinical
trial assessing the safety and efficacy of sofosbuvir, ledipasvir and RBV in decompensated
cirrhotics (NCT 01938430)[40] will probably give us some hints in the near future. Preliminary data from the post-LT
compassionate use program using sofosbuvir and ribavirin (see below) strongly suggest
that viral clearance is associated with a rapid improvement in liver function.
Looking at the results of several combinations of new DAAs, it seems very likely that
the use of IFN-free regimens will be able to prevent hepatitis C recurrence in most
patients (if not in all) awaiting LT ([Fig. 1B]). The few data on IFN-free regimens in patients awaiting LT[57]
[58]
[59] are summarized in [Table 3]. Other clinical trials combining two or more DAA are ongoing in patients awaiting
LT.[40]
[60]
Table 3
Phase I and II Clinical Trials with IFN-free regimens including patients awaiting
liver transplantation (recruitment closed)
|
Therapeutic regimen in cirrhotic population (Trial name)
|
Response to previous IFN- based therapy
|
Child-Pugh (CTP) or MELD
|
Treatment duration
|
Patients enrolled in the study/Transplanted patients
|
Study phase
|
Genotype spectrum
|
Undetectable HCV RNA at LT
|
SVR12 post-LT
|
|
SOF + RBV[57]
|
Naïve and treatment experienced (75%)
|
CTP ≤ B-7
MELD < 22
|
Up to 48 W
|
61/40
|
2
|
1–6
|
37 (92%)
|
69%
|
|
SIL intravenous[58]
|
Naïve and treatment experienced
|
Any CTP score
|
21 d before LT and 7 d after LT
|
11/8
|
2
|
1,3,4
|
2 (25%)
|
0%
|
|
ITX5061[59]
|
Not reported
|
Not reported
|
Immediately pre-LT and post-LT (up to 1 wk)
|
10/10
|
1b
|
56% G1
|
0/10
|
0%
|
Abbreviations: CTP, Child-Turcotte-Pugh Score; d,day; HCV, hepatitis C virus; IFN,
interferon; ITX5061, antagonist of scavenger receptor; LT, liver transplantation;
LOQ, lower limit of quantification; LOD, lower limit of detection; MELD, Model for
End-Stage Liver Disease score; SIL, silibinin; SOF, sofosbuvir; wk, weeks.
Safety and Efficacy Data of Sofosbuvir and Ribavirin in Patients Awaiting LT
The first data on the safety and efficacy of an oral IFN-free regimen in patients
awaiting LT were presented at the annual American Association for the Study of Liver
Diseases (AASLD) meeting in November 2013.[57] In this phase-2 open-label study, 61 patients received up to 48 weeks of treatment
before LT while on the waiting list (median duration 17 wk). Preliminary results can
be considered excellent. Forty patients underwent LT and of these, 37 (92%) had HCV
RNA < 25 IU/mL before LT. Of them, 26 individuals reached 12 weeks of follow-up after
transplantation and 18 (69%, 90 confidence interval: 51–84%) achieved SVR12. Seven
patients (27%) had a virological relapse and one died before reaching the endpoint.
These efficacy results are encouraging and most likely, longer treatment duration
and/or the addition of a second DAA (currently under evaluation with ledipasvir),
will be able to prevent graft infection in most patients. Safety and tolerance of
this regimen was good. The most frequently reported adverse events were mild and only
one patient discontinued treatment due to anemia attributed to RBV.
Safety and Efficacy Data of Silibinin in Patients Awaiting LT
Another IFN-free regimen for patients awaiting LT was recently explored in a randomized,
double-blind, placebo controlled, phase 2 trial using silibinin monotherapy.[58] This natural flavonoid has been shown to exert potent antiviral properties both
in vivo[61]
[62]
[63] and in vitro.[64] The study included only a very small number of patients, but demonstrated a consistent
antiviral effect of intravenous silibinin and a good safety profile in these very
ill patients. Despite the fact that some patients reached undetectable HCV RNA during
therapy and at the time of LT, none of them had a durable response following LT. The
main problem of this approach was the short treatment duration, limited by the fact
that the drug needs to be administered intravenously.
Treatment of HCV Recurrence after Liver Transplantation
HCV-related cirrhosis with or without hepatocellular carcinoma is nowadays the leading
indication for LT in industrialized countries.[65] Virological recurrence after transplantation is constant in patients with detectable
viremia at the time of LT.[2] One of the main characteristics of hepatitis C recurrence after LT is the accelerated
course of the disease when compared with immunocompetent patients.[66]
[67]
[68]
[69]
[70] Approximately one third of the patients progress to graft cirrhosis within only
5 years after transplantation.[71]
[72] This accelerated fibrosis rate impacts both the allograft and recipient survivals,
which are significantly reduced when compared with non-HCV LT recipients.[66]
[71]
[73]
[74]
[75]
[76]
Current Interferon-Based Regimens to Treat Hepatitis C Recurrence after LT
The most common approach to treat hepatitis C after LT has been to start antiviral
therapy once the histological damage (in particular liver fibrosis) is confirmed in
the graft. The presence of significant fibrosis beyond the portal tract (METAVIR F ≥ 2)
or portal hypertension (hepatic venous pressure gradient [HVPG] ≥ 6 mm Hg) one year
after LT accurately identify patients at higher risk for clinical decompensation and
death,[77] who are at urgent need for treatment ([Fig. 2A]). In patients with a severe recurrence occurring during the first months after transplantation
(i.e., fibrosing cholestatic hepatitis), antiviral therapy is critical, but current
treatment choices are unable to eradicate HCV in most cases and patients die or need
retransplantation.
Fig. 2 Algorithm for the management of hepatitis C recurrence after liver transplantation
in 2013[3](A). Proposed algorithm for the management of hepatitis C recurrence after liver transplantation
in 2014–2015 (B).
Peginterferon plus Ribavirin
The overall SVR rates with PegIFN plus RBV are low, ranging between 30 and 40% across
different series.[78]
[79]
[80] These modest virological results are mainly explained by high rates of treatment
discontinuation (20–38%), dose reductions (66–73%), and poor tolerance or adverse
events. Liver-transplant recipients are prone to hematological toxicity (particularly
anemia). RBV dose reductions and the use of erythropoietin (EPO) are very frequent
(75–80%) in this setting.[81] The risk of rejection is small, of the order of ∼ 5% in treated patients.[82]
[83]
Despite these results, the positive impact of SVR on survival is evident. A study
performed a few years ago[84] assessed the impact of SVR on hepatic-venous-pressure gradient (HVPG) measured before
and after antiviral treatment. Portal pressure decreased or stabilized in patients
who achieved SVR compared with those who did not, in whom HVPG increased rapidly overtime.
Patients achieving SVR after LT have a better survival probability compared with nonresponders.[78]
Triple Therapy in the LT Setting
Regarding triple therapy with PIs in the post-LT setting, results of four different
series are available.[85]
[86]
[87]
[88]
[89]
[90] These studies have evaluated the safety and efficacy of such regimens in over 300
liver-transplant recipients with hepatitis C recurrence. Two-thirds of the patients
received telaprevir (with or without a lead-in phase) and the rest were treated with
boceprevir. Most of the patients had an advanced fibrosis stage (≥ F2) or fibrosing
cholestatic hepatitis. Approximately half of the patients had received a previous
course of antiviral therapy. Rapid virological response rates ranged between 53% and
67% and, more importantly, SVR12 rates ranged between 48% and 62%.[85]
[86]
[87]
[88]
[89]
[90] Despite these encouraging results in terms of efficacy, the major concern of triple
therapy in LT recipients is the high rate of serious-adverse events leading to treatment
discontinuation. Indeed, in the Canadian study,[85] 13 (17%) out of the 76 patients discontinued treatment, 10 due to adverse events.
Forty-three percent of the patients presented grade 3 anemia (< 8 g/L) with EPO requirement.
In the European study,[86]
[87] 42 (53%) out of the 79 the patients discontinued treatment, half of them due to
adverse events. Eighty-five percent of the patients presented anemia and 95% required
EPO alone or together with ribavirin dose reduction. Six patients died during antiviral
therapy. Similar safety results have also been reported by the investigators of the
REFRESH[88] and the CRUSH-C studies.[89]
[90]
Drug–drug interactions have become a challenge for transplant hepatologists using
protease inhibitors. It is well known that CYP 3A4 isoenzymes are the most abundant
in the liver and are involved in the metabolism of the majority of drugs, including
cyclosporine (CsA) and tacrolimus. First-wave, first-generation PIs (telaprevir, boceprevir)
are not only substrates, but are also inhibitors of this system (as well as P-glycoprotein
transporter), thus strongly interacting with many drugs. Boceprevir has been shown
to increase the area under the curve of CsA and tacrolimus by 2.7 and of 17, respectively[91]; the figures for telaprevir are 4.6 and 70, respectively.[92] Taking into account the narrow therapeutic range of CsA and tacrolimus, dose adjustments
are crucial and require very close monitoring when combined with PIs. These data,
along with the experience accumulated by several groups, have been developed into
general recommendations when indicating triple therapy in HCV-infected transplant
patients.[81]
New DAAs and Interferon-Free Regimens after LT
Specific Features of IFN-Free Regimens in HCV-Infected Liver-Transplant Recipients
Treatment with IFN-free regimens in patients with hepatitis C recurrence is challenging
for several reasons. First, treatment may be indicated in individuals with very aggressive
forms of hepatitis C (such as fibrosing cholestatic hepatitis), which occur very early
after transplantation. The latter poses several difficulties because in this early
period individuals are still under strong immunosuppression, at risk of opportunistic
infections, not uncommonly recovering or being treated from surgical complications,
and undergoing treatment with multiple drugs. Indeed, DDI is one of the most relevant
issues in LT recipients, particularly due to the potential interaction of DAA with
cyclosporine, tacrolimus, or other immunosuppressants. Fortunately, most anti-HCV
compounds in phase 3 development have been assayed for potential interactions with
CsA and tacrolimus, at least in healthy volunteers. A slight increase in sofosbuvir
concentration was observed in LT-patients receiving CsA ([Table 4]).[81]
[91]
[92]
[93]
[94]
[95]
[96]
Table 4
Drug–drug interactions between DAAs and calcineurin inhibitors
|
DAA
|
Cyclosporine
|
Tacrolimus
|
|
Healthy volunteers
|
LT recipients
|
Dose adjustment
|
Healthy volunteers
|
LT recipients
|
Dose adjustment
|
|
Boceprevir[a]
[91]
[93]
|
AUC ↑ 2.7-fold
|
Oral clearance ↓ 50%
|
↓ 2-fold
|
AUC ↑ 17-fold
|
Oral clearance ↓ 80%
|
↓ 5-fold
|
|
Telaprevir[a]
[81]
[92]
|
AUC ↑ 4.6-fold
|
|
↓ 4-fold
|
AUC ↑ 70- fold
|
|
↓ 35-fold
|
|
Sofosbuvir[a]
[94]
|
No significant change
|
|
Not necessary
|
No change
|
|
Not necessary
|
|
Simeprevir[b]
[95]
|
AUC ↑ 19%
|
|
Not necessary
|
AUC ↓ 17%
|
|
Not necessary
|
|
Daclatasvir[96]
|
No change
|
|
Not necessary
|
No change
|
|
Not necessary
|
Abbreviations: AUC, under the concentration curve; DAAs, direct-acting antivirals;
LT, liver transplant.
a AUCinf is given.
b AUCLast is given.
Renal failure is also common in liver-transplant recipients. Most patients have decreased
glomerular filtration rate (GFR) due (at least in part) to the long-term use of cyclosporine
or tacrolimus. Dose adjustments may be necessary in some cases ([Table 2]): Sofosbuvir, for instance, is not recommended if GFR is below 30 mL/min.[55]
A final issue that needs particular consideration in the liver transplant setting
is that these patients usually have high viral loads, making it easier to select for
drug-resistant strains or to develop virological relapse if the appropriate DAA combinations
are not used.
Sofosbuvir and Ribavirin to Treat Recurrent Hepatitis C
Sofosbuvir and RBV is the first IFN-free combination that has been assessed in hepatitis
C recurrence in a clinical trial[97] and in a compassionate-use program.[98]
A pilot single-arm study assessed the safety and efficacy of sofosbuvir 400 mg/d and
RBV (dose escalating regimen starting at 400 mg/d) for 24 weeks in 40 patients with
HCV recurrence (any genotype) at least 6 months after LT. The study included treatment-naïve
and treatment-experienced patients. Individuals with decompensated cirrhosis were
excluded. The primary efficacy endpoint was SVR12.
From the 40 patients, 22 were infected with genotype 1a, 11 with genotype 1b, 6 with
genotype 3, and 1 with genotype 4. Most included patients had been previously treated
with IFN and RBV (9 with PIs), mean baseline HCV RNA was 6.55 Log10 IU/mL and 40%
were cirrhotic. Despite these characteristics, by week 4 on treatment all individuals
had HCV RNA < 25 IU/mL. The SVR4 was 77% in the 35 individuals who had reached this
time point. These results can be considered excellent, though SVR12 data are awaited,
particularly due to the special RBV-dosing schedule (starting with 400 mg), which
may facilitate virological relapse in some cases. From a safety point of view, severe
adverse events (all unrelated to the study drug) occurred in 15% of individuals. Most
side effects were mild; no rejection episodes occurred during therapy.[97] Although there was no IFN-based control arm in the study, it is obvious that the
safety and tolerance profile of this combination is significantly better than that
of the current standard of care.
Preliminary results from the compassionate-use program using sofosbuvir were recently
presented at an AASLD meeting.[98] Sofosbuvir was provided in an institutional-review-board-approved compassionate-use
study; results from the first 45 patients who had received more than 4 weeks of treatment
were presented. The antiviral regimen included sofosbuvir 400 mg/d for up to 48 weeks,
with appropriate doses of RBV (PegIFN was added at the investigators' discretion).
The investigators provided periodic updates on clinical status, laboratory tests,
and serious adverse events. The patients included in this program differed substantially
from those included in the pilot study described above because most patients had decompensated
liver disease. Baseline mean bilirubin was 6 mg/dL, mean albumin 21 g/L, and 19 (45%)
had histologically documented fibrosing cholestatic hepatitis. From an efficacy standpoint,
the clinical condition of 32 (71%) patients improved (significant amelioration of
liver function and/or reduction/disappearance of clinical decompensation episodes).
At week 4 of therapy, ∼ 75% of patients had an HCV RNA below 25 IU/mL. Preliminary
results based on a small group of patients who reached long-enough follow-up indicate
an SVR12 of the order of 50%. Seven patients (16%) died after initiation of therapy,
with all cases attributed to progression of hepatitis C recurrence. Severe adverse
events were frequent, but none was considered related to the study drug. Overall,
the preliminary results of this program indicate that a regimen containing sofosbuvir
was able to inhibit hepatitis C replication in most patients and that this was associated
with an improvement in the clinical condition in a significant number of them. Although
longer follow-up and a higher number of patients are needed to assess the rate of
SVR and its impact on disease progression, these results can be considered very encouraging.
A particularly relevant result of this study was the excellent response in cases with
fibrosing cholestatic hepatitis, in which deeply perturbed laboratory values (bilirubin,
albumin, international normalized ratio) returned to normal a few weeks after treatment
initiation and viral clearance. The latter proves the benefit of this treatment in
this very severe form of HCV recurrence.
Other IFN-Free Regimens in HCV-Infected LT Recipients
There are only a few isolated reports of the use of other IFN-free regimens in the
LT setting. Fontana et al[99] showed for the first time the success of combined treatment with daclatasvir and
sofosbuvir for 24 weeks in a LT recipient suffering from a severe HCV recurrence 8
months after LT.
Silibinin has also been used in the posttransplant setting. Barcena et al[100] have recently performed a single-center, pilot study to evaluate the safety and
efficacy of intravenous silibinin monotherapy administered during the first 21 days
posttransplant in 9 LT recipients with HCV genotype 1 infection. As a control group,
7 nontreated recipients were included. Silibinin led to a significant decrease of
viral load (–4.1 ± 1.3 log), and 44% of the treated patients achieved undetectable
HCV RNA while on treatment. As expected, all patients relapsed after silibinin withdrawal.
No significant adverse events were observed during silibinin administration. Nevertheless,
there have been previous reports of successful treatment of established graft hepatitis
with intravenous silibinin plus standard therapy in patients after LT.[101]
Fortunately, three multicentric clinical trials using oral DAAs are recruiting patients
to assess the safety and efficacy of these regimens in hepatitis C recurrence: (1)
ABT450/r + ABT267 + ABT333 + RBV 24 weeks in patients with ≤ F2 fibrosis score (NCT01782495)[102]; (2) simeprevir + daclatasvir 24 weeks in patients with ≤ F3 (NCT01938625)[103]; and (3) sofosbuvir/ledipasvir + ribavirin 12 or 24 weeks in patients with all types
of HCV recurrence after LT (NCT01938430).[40] Most likely, the approval of these combinations will change the management of these
patients in the next 2 years ([Fig. 2B]).
Treating before or after Liver Transplantation?
As discussed above, treatment of patients in the transplant setting can be indicated
before or after transplantation, once hepatitis C has recurred. Treatment before transplantation
seems ideal because apart from preventing infection of the graft, viral clearance
may be associated with improvement in liver function, and in some cases, delisting.
Nevertheless, PK and particularly safety data are not available for all compounds
in individuals with advanced liver disease (patients with Child-Pugh B and C). Thus,
it is mandatory to wait for the results of studies addressing these issues. Another
potential problem in patients awaiting LT is the uncertainty of treatment duration,
which cannot be predicted due to the inherent complexity of the waiting list. Finally,
regimens used in this setting should have a high barrier to resistance to minimize
the risk of virological breakthrough or relapse.
In the near future, it is very likely that all patients awaiting LT will be candidates
to receive antiviral therapy while awaiting an organ, as occurs with hepatitis B.
Data from studies conducted in immunocompetent patients strongly suggest that some
drug combinations will be able to prevent infection of the graft in most cases ([Fig. 1B]).
Regarding treatment after LT, there are a few issues to consider. First, PK and safety
data are also needed in this patient population, particularly for individuals with
advanced liver disease. Second, drug-drug interaction studies are relevant because
CsA and tacrolimus undergo metabolism through the CYP3A4 system and have a narrow
therapeutic range. Interactions may occur not only with immunosuppressants, but also
with other commonly used drugs (e.g., statins, some antihypertensive drugs). The use
of regimens with a high barrier to resistance is also relevant, particularly if used
early after LT because at this stage HCV-RNA levels can be very high.
Finally, there are several patients who have already developed graft damage following
transplantation and in whom the only choice in the coming years will be IFN-free regimens.
These patients include nonresponders to IFN-based regimens (including those with a
first generation PI), individuals intolerant or unable to receive IFN (comorbidities
are frequent in this population), and patients with decompensated cirrhosis ([Fig. 2B]). In the latter group the use of IFN-free regimens could allow retransplantation
avoiding HCV graft infection.
