Protease Inhibitor Use for Chronic Hepatitis C infection in Prior Null Responders

TITLE: Protease Inhibitor Use for Chronic Hepatitis C infection in Prior Null Responders
and Recurrent Hepatitis C Infection Post Liver Transplant: A Review of the
Clinical Evidence
DATE: 29 May 2013
CONTEXT AND POLICY ISSUES
Chronic hepatitis C (CHC) remains a significant medical and economic burden in Canada,
affecting nearly 1% of the population.1 In 2007, it was estimated that 242,000 Canadians had
chronic HCV infection and about 7,000 new infections occurred.2 Of those with chronic
infection,15% to 25% will develop progressive liver disease, end stage liver disease,
hepatocellular carcinoma or will require liver transplant.3,4 Hepatitis C is the principal cause of
death from liver disease and the leading indication for liver transplantation.1,5,6 Recurrence of
HCV occurs in more than 95% of patients after liver transplantation.7 Modelling data suggest
that the incidence of more advanced HCV-related sequelae (e.g, decompensated liver disease,
hepatocellular carcinoma [HCC] and liver transplantations) are expected to rise for at least
another decade.1 Fibrosis progression may be accelerated in patients with recurrent HCV
infection post-liver transplantation, with 6% to 23% of patients developing cirrhosis after a
median of 3.4 years.4 However, the indications for treatment, the optimal timing, dose and
duration of treatment for patients with recurrent HCV infection post-transplantation are not
clear.4 Therapy may be initiated preemptively, before the development of recurrent hepatitis, or
may be started once recurrent clinical disease is evident.4 Analyses of studies examining the
efficacy of treatment for recurrent HCV infection are hampered by the enrollment of small
numbers of patients at single centers and the use of different immunosuppressive regimens,
which may play a role in the accelerated liver disease following liver transplantation.8 One of the
most important objectives of the treatment of HCV infection is to achieve the sustained viral
response (SVR) , which is defined as having undetectable plasma HCV RNA level 24 weeks
after the last planned dose of study medication. It has been reported that standard
peginterfenon/ribavirin (PR) therapy results in a SVR of up to 30% in patients with histological
HCV recurrence after liver transplantation.8
Boceprevir (BOC) and telaprevir (TP) are two NS3 protease inhibitors (PI) indicated for the
treatment of CHC genotype 1 infection. They have shown statistically significant improvement of
the SVR rate in patients with CHC who are treatment naïve9,10 or failed to respond to prior
standard PR therapy.11,12 However, the comparative effectiveness and safety of triple therapy of
BOC or TP plus PR compared with standard PR therapy alone in patients who are prior null
responder (defined as less than 2 log10 HCV RNA reduction after 12 weeks of PR therapy)13 or
patients who have recurrent HCV after liver transplantation were not well established.1,4 The
addition of PI to the established PR regimen may provide another opportunity for patients who
have had a null response to prior PR therapy.12 It is therefore important to ascertain the efficacy
of PI-PR triple therapy in this population. The use of BOC or TP in the post-transplant setting in
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patients with genotype 1 HCV disease has been limited.7,14 It has been indicated that drug–drug
(PI and immunosuppressive agents) interactions remain a significant clinical issue. The aim of
this review is to evaluate the effective and safety evidence of BOC or TP-containing triple
therapy regimens in the treatment of the above special populations.
RESEARCH QUESTIONS
1.

What is the clinical evidence on sustained virological response rates with the protease
inhibitors in patients who are classified as null responders on prior PR therapy?

2.

What is the clinical evidence on sustained virological response rates with the protease
inhibitors for patients who have undergone a liver transplant?

KEY FINDINGS
Patients with chronic hepatitis C (CHC) who are null responders to previous
peginterfenon/ribavirin (PR) therapy may benefit from telaprevir-PR triple therapy. There is no
RCT data on this population for boceprevir (BOC)-PR triple therapy. At present, there is no
evidence to determine the clinical benefit (in terms of sustained viral response) and harm of
adding BOC or TP to PR therapy in patients with recurrent hepatitis C virus who have
undergone a liver transplant.
METHODS
Literature Search Strategy
A limited literature search was conducted on key resources including Medline, Embase,
PubMed, The Cochrane Library (2013, Issue 4), University of York Centre for Reviews and
Dissemination (CRD) databases, Canadian and major international health technology agencies,
as well as a focused Internet search. Methodological filters were applied to limit retrieval to
health technology assessments, systematic reviews, meta-analyses, randomized controlled
trials, non-randomized studies and conference abstracts. Where possible, retrieval was limited
to the human population. The search was also limited to English language documents published
between January 1, 2008 and April 30, 2013.
Selection Criteria and Methods
One reviewer screened the titles and abstracts of the retrieved publications and evaluated the
full-text publications for the final article selection, according to the selection criteria presented in
Table 1.
Table 1: Selection Criteria
Population
Q1: Patients with chronic hepatitis C infection who are classified as
null responders on prior PR therapy
Q2: Patients with chronic hepatitis C infection who have undergone a
liver transplantation
Intervention
PR plus protease inhibitor (boceprevir or telaprevir)
Comparator

PR alone or no comparator in a single arm study

Protease Inhibitors for Hepatitis C in Prior Null Responders and Liver Transplant Patients

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Outcomes

Clinical benefit: SVR, AE, morbidity, mortality

Study Designs

Health technology assessments, systematic reviews and metaanalyses, randomized controlled trials, non-randomized studies,
Emerging evidence (e.g. conference abstracts)

Exclusion Criteria
Studies not meeting the inclusion criteria, duplicate data reporting, and conference abstracts
older than 2 years were excluded.
Critical Appraisal of Individual Studies
Randomized controlled trials (RCT) and non-RCTs were assessed with Scottish Intercollegiate
Guidelines Network, Methodology checklist 2 (SIGN 50 Checklist 2).15 Critical appraisal of
emerging evidence (i.e, abstract) was not performed due to the limited study information
available for this type of evidence.
SUMMARY OF EVIDENCE
Quantity of Research Available
The literature search yielded 513 citations. Upon screening titles and abstracts, 484 citations
were excluded and 29 potentially relevant articles were retrieved for further review. Of the 29
potentially relevant reports, three studies12,16,17 including one conference abstract17 are included
in this review. Twenty six articles were excluded due to unmet the inclusion criteria, duplicate
data report or abstracts presented at greater than two years ago. The study selection process is
outlined in a Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA)
flowchart (Appendix 1). No systematic reviews were identified for inclusion in this report.
One RCT (REALIZE)12 and one uncontrolled, single treatment arm study16 were identified that
studied the effectiveness (SVR) of triple therapy of TP combined with PR in the prior null
responders to PR dual therapy. There is no evidence of BOC in prior null responders. No
studies were found that reported the SVR and harms of triple therapy of BOC or TP with PR in
patients with recurrent HCV who have undergone a liver transplant.
Emerging evidence
There was one open label, single treatment arm study (PROVIDE, Poordad et al.)17 that was
identified relating to BOC treatment of prior null responders to PR; In this study, Poordad et al.17
reported that SVR result in patients who were prior null responder to PR therapy in previous
BOC trials (SPRINT-29 and RESPOND-211).
Summary of Study Characteristics
Details of the characteristics of the included studies are provided in Appendix 2.

Protease Inhibitors for Hepatitis C in Prior Null Responders and Liver Transplant Patients

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1.

What is the clinical evidence on sustained virological response rates with the protease
inhibitors in patients who are classified as null responders on prior PR therapy?

The RCT (REALIZE)12 was a multicentre study sponsored by the manufacturer of TP, which
studied the comparative effectiveness and harms of TP plus PR in patients with CHC who failed
previous PR therapy including 184 prior null responders. Null response was defined as less than
2 log10 HCV RNA reduction at 12 weeks of PR therapy. The primary outcome was SVR,
defined as maintenance of undetectable viral load 24 weeks after completion of therapy.
Patients in the two TP groups received TP for 12 weeks. However, one of the two groups began
the first four weeks of the study on placebo-PR before switching to TP-PR for the next 12 weeks
('delayed start'), while the other group began treatment with TP-PR. TP was administered orally
at a dose of 750 mg every 8 hours; peginterferon alpha-2a was administered subcutaneously at
a dose of 180 μg per week; and ribavirin was administered orally at a dose of 1000 to 1200 mg
per day, based on weight.
In the open-label uncontrolled study, Muir et al.16 evaluated the efficacy and safety of TP-based
triple therapy (TP/PR) in patients who were null responders to PR treatment (defined as less
than a 1 log10 decrease in HCV RNA at week 4 or less than a 2 log10 decrease in HCV RNA at
week 12). Patients were enrolled from the control arms of the three previous phase II PROVE
studies (PROVE1,18 PROVE-219 and PROVE-320). The treatment was 12 weeks of TP/PR
followed by an additional 12 weeks or 36 of PR alone. TP was administered orally at a dose of
750 mg every 8 hours. Peginterferon alpha-2a was administered at a dose of 180 µg weekly,
subcutaneously. Ribavirin was administered twice daily at a dose of 1,000 mg/day for patients
weighing less than 75 kg and a dose of 1,200 mg/day for patients weighing 75 kg or more.
Outcomes were SVR and adverse events. However, no adverse events were reported for the
null responder’s subgroup.
Emerging evidence
In an open-label uncontrolled single arm study (PROVIDE), Poordad et al.17 evaluated the SVR
of triple therapy of BOC plus PR in the patients who were null responders to prior PR therapy
(defined as <2 log10 decline in HCV RNA at treatment week 12). Included patients were from
PR control arms in previous registered two BOC trials, i.e. SPRINT-29 and RESPOND-2.11 BOC
(800 mg, three times per day with food) given with peginterferon1.5 µg/kg/week subcutaneously
and weight-based ribavirin (600 to 1,400 mg/day) twice daily for up to 44 weeks.
2. What is the clinical evidence on sustained virological response rates with the protease
inhibitors for patients who have undergone a liver transplant?
No evidence ware identified that reported the SVR and harms of BOC or TP in patients with
recurrent HCV who have undergone a liver transplant.
Summary of Critical Appraisal
A summary of the strengths and limitations of individual included studies is provided in Appendix
3.
1. What is the clinical evidence on sustained virological response rates with the protease
inhibitors in patients who are classified as null responders on prior PR therapy?

Protease Inhibitors for Hepatitis C in Prior Null Responders and Liver Transplant Patients

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The REALIZE12 trial was randomized and double-blinded. The randomization was stratified
based on the previous response (i.e. null response, partial response and relapse).
Randomization appeared to be centralized, and measures were taken to maintain adequate
allocation concealment. Overall, the loss to follow-up rate was small and intention to treat (ITT)
analysis was employed.
The study by Muir16 was an open label, single treatment arm study; therefore it was neither
blinded nor randomized. The methodological quality of this study was considered low because
of the heterogeneity of the population and intervention. In terms of the population, two
definitions of null response were applied (i.e. less than a 1 log10 decrease in HCV RNA at week
4 or less than a 2 log10 decrease in HCV RNA at week 12). Previous PR treatment history also
varied, such as some of the patients (from study PROVE 3)20 failed more than one course of
prior PR therapies). In terms of intervention, the duration of additional PR treatment following
TP/PR 12 weeks was either 24 weeks or 48 weeks because of a protocol amendment during
the trial.
Summary of Findings
The main findings of the included studies are described in Appendix 4.
1. What is the clinical evidence on sustained virological response rates with the protease
inhibitors in patients who are classified as null responders on prior PR therapy?
In the REALIZE study, 184 patients who were prior null responders were included. SVR rates
were lower in patients who were prior null responders compared to the overall study population.
For example, in the group that received 12 weeks TP/48 weeks PR, SVR rates were 29% in the
subgroup identified as null responders versus 64% in overall population. SVR rates among prior
null responders were, however, still statistically higher with TP-PR than with placebo-PR (29%
versus 5%). Similar results (33%) were seen in the TP group that had a ‘delayed start’ of TP.
Adverse events and other outcomes were not reported for prior null responder’s subgroup.
In the open label, uncontrolled single treatment arm study, 51 prior null responders were
included. Muir et al.16 found that the SVR rates were 17% and 56% in TP 12 / PR24 weeks and
TP 12 weeks/PR 48 weeks respectively. The pooled overall SVR rate in the null responder
subgroup was 37% (19/51). No adverse events reported for subgroup of null responders.
However, it was reported that the adverse events were similar to those in previous registered
TP trials. The author concluded that their findings demonstrated the benefit of retreatment with a
TP-based triple therapy (T12/PR48) for patients who was prior null responder to standard PR
therapy.
Emerging evidence
In the study by Poordad, et al. (PROVIDE),17 48 patients met the criteria for a null response (<2
log10 decrease in HCV RNA by week 12). It was reported that 38% (16/42) achieved SVR (27%
of black patients, 42% of non-black patients and 41% genotype 1a) with BOC/PR. No adverse
events and other outcomes were reported.
2. What is the clinical evidence on sustained virological response rates with the protease
inhibitors for patients who have undergone a liver transplant?

Protease Inhibitors for Hepatitis C in Prior Null Responders and Liver Transplant Patients

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No studies were identified that reported SVR of triple therapy of BOC or TP in combination with
PR therapy in the treatment of recurrent HCV after liver transplantation.
Emerging evidence
An ongoing phase III RCT(REPLACE study)21 that evaluated the efficacy and safety of triple
therapy of TP with PR in patients with genotype 1 hepatitis C infection after liver transplantation
was identified. The primary outcome is SVR12 defined as having plasma HCV RNA level less
than 25 IU/mL 12 weeks after the last planned dose of study medication. However, no results
had been reported at the time of the present review.
Two full text articles22,23 and 12 conference abstracts24-35 were identified that reported the early
treatment experience of triple therapy of TP22,24-27,30-35 or BOC23,28,29 in combination with PR
therapy in the treatment of recurrent HCV after liver transplantation. The study designs were
either small uncontrolled single arm studies or case series reports. The outcomes were focused
on early virological response. No SVR were reported. The main characteristics and key findings
were summarized in Appendix 5.
Limitations
The comparative evidence of triple therapy with TP (TP/PR) versus PR alone in prior null
responders is limited to a relatively small sample size trial. No trials of BOC were identified that
reported the comparative efficacy and safety of triple therapy with BOC (BOC/PR) compared
with PR alone in previous null responders to PR. Only emerging (i.e., non-peer reviewed,
abstract only) evidence from a single arm study was available for this agent.
A limitation of the identified studies is that they were not designed to detect differences in hard
clinical outcomes such as morbidity and mortality, relying instead on SVR rates as the key
measure of efficacy.
CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING
Although SVR rates are significantly lower in prior null responders to PR than those seen in the
general CHC population, there is a statistically significant treatment effect of triple therapy of
TP-PR over PR alone in this population. There is no comparative SVR data for BOC in the null
responder population. However, a single arm treatment study with a small sample size (n = 48,
presented in abstract form only) reported that 38% of prior null responders to PR achieved SVR
with the treatment of BOC plus PR. No comparative efficacy and safety evidence on the use of
triple therapy (TP or BOC plus PR) were identified in recurrent HCV infection post
transplantation recipients, although preliminary early virological response were presented in
abstracts and based on small single arm uncontrolled studies or case series. Further welldesigned randomized controlled trials are warranted to determine the comparative clinical
efficacy and safety profile of BOC or TP in treatment of CHC patients who are prior null
responders to PR therapy or recurrent HCV infection who have undergone a liver transplant.

PREPARED BY:
Canadian Agency for Drugs and Technologies in Health
Tel: 1-866-898-8439
www.cadth.ca

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McCashland TM, Martinez MA, De Sicilia MGS, Mukherjee S, Rochling FA, Schafer DF,
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Pereira AP, Shin HJ, Safdar A, Tobias H, Gelb B, Morgan G, et al. Post liver transplant
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35.

Rogers CC, Stevens DR, Kim M, Ghaziani T, Malik R, Curry MP. Teleprevir can be sued
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Boston; June 2-6, 2012).

Protease Inhibitors for Hepatitis C in Prior Null Responders and Liver Transplant Patients

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Appendix 1: Selection of Included Studies
513 citations identified from
electronic literature search and
screened
484 citations excluded

29 potentially relevant articles
retrieved for scrutiny (full text, if
available)

0 potentially relevant
report retrieved from
other sources (grey
literature, hand
search)

29 potentially relevant reports

26 reports excluded:
-Study design not of interest (3)
-Population not of interest (5)
-Intervention not of interest (1)
-Outcome not of interest (12)
-Abstract older than 2 years (2)
-Duplicate data (3)

3 reports included in review

Protease Inhibitors for Hepatitis C in Prior Null Responders and Liver Transplant Patients

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Appendix 2: Characteristics of Included Randomized and Non-Randomized Controlled
Trials*
First Author,
Publication
Year,
Country
12

Zeuzem 2011
(REALIZE
study)
Multi-countries
(USA, Canada,
etc.)

Study Design,
Length of
Follow-up

Patient Characteristics,
Sample Size (n)

Intervention/
Comparator(s)

Key Outcomes

Double blind
RCT
Multicentre

● CHC genotype 1 with HCV
RNA level ≥1000 IU/mL,
treatment failure (including
null responder**) with at
least one prior course of PR
therapy
● Null responder subgroup
N=184

●TP + PR for 12 weeks
then
PL + PR for 4 weeks
then
PR for 32 weeks (n=72)
●PL + PR for 4 weeks
then
TP + PR for 12 weeks
then
PR for 32 weeks (n=75)

SVR

Comparator(s)

●PL + PR for 16 weeks
then PR for 32 weeks
(n=37)
CHC genotype 1 with HCV
●TP + PR for 12 weeks SVR
RNA level ≥1000 IU/mL,
then
PR for 12 or 36 weeks
Prior no response (null) to
(T12PR24 or T12PR48)
PR-treatment*** in PRcontrol arms in three phase II ●No comparator
18-20
(TP
PROVE studies
trials) n=51
Poordad,
Open-label, non- CHC genotype 1 with HCV
●BOC + PR for up to
SVR
17
2012
RCT, rollover,
RNA level ≥1000 IU/mL,
44 weeks
●No comparator
(PROVIDE
no control arm
Prior null response to PRstudy) (USA,
(single arm)
treatment** (in PR-control
Canada, etc.)
arms) in two phase III RCTs
9
(SPRINT-2 and RESPOND11
2 (BOC trials) n=48
BOC=boceprevir; CHC=chronic hepatitis C; HCV=hepatitis C virus; PL=placebo; PR=peginterferon plus ribavirin;
RCT=randomized controlled trial; SVR=sustained virologic response; TP=telaprevir;
16

Muir, 2011
28 sites in 7
countries (USA,
Canada, etc.)

Open-label, nonRCT, rollover,
no control arm
(single arm)

*Only prior null response-subgroup data was extracted in this review
** Null response (no response) defined as less than a 2 log10 decrease in HCV RNA at week 12 in the REALIZE Study.
***Null response defined as less than a 1 log10 decrease in HCV RNA at week 4 or less than a 2 log10 decrease in HCV RNA at
week 12 in parent studies(PROVE1, PROVE2 and PROVE3);

Protease Inhibitors for Hepatitis C in Prior Null Responders and Liver Transplant Patients

12

Appendix 3: Summary of Study Strengths and Limitations
First Author,
Publication Year
12

Zeuzem 2011
(REALIZE study)

Strengths

Limitations

•
•

•

•
•
•
•
Muir, 2011

16

•
•

17

Poordad, 2012
(PROVIDE study)

•

Research question was clearly defined
Randomization was stratified based on
the previous response to PR.
Double blinding process was clearly
described
Only difference between groups is
treatment under investigation
Outcome was standard, valid and
reliable
Intention to treat analysis was well
reported
Null response population was clearly
defined
No drop outs

•

Key patient characteristics of the nullresponse subgroup at baseline are not
reported.
Follow up too short to assess clinical
outcomes such as mortality/morbidity

•
•

No control arm
Two definitions of null response were
applied ( less than a 1 log10 decrease in
HCV RNA at week 4 or less than a 2
log10 decrease in HCV RNA at week 12)
• Follow up too short to assess clinical
outcomes such as mortality/morbidity
This was a single arm, non-controlled study. Data reported in abstract. Not appraisable.

Protease Inhibitors for Hepatitis C in Prior Null Responders and Liver Transplant Patients

13

Appendix 4: Summary of Main Study Findings and Author Conclusions
First author,
publication
year

Main findings

Randomized controlled trial on telaprevir
12
Zeuzem 2011
SVR:
(REALIZE
Overall (T12PR48 plus T12(DS)/PR48): 31%
(46/147)
study)
T12PR48 : 29% (21/72)

Author conclusions

On page 2417: “Telaprevir combined with
peginterferon plus ribavirin significantly improved
rates of SVR in patients with previously treated
HCV infection, regardless of whether there was a
lead-in phase.”

T12(DS) PR48: 33% (25/75)
PR48: 2/37 (5%)
AE : NR for null responder subgroup
Non-RCT on telaprevir
16
Muir, 2011
SVR:
Overall : T12PR24-48: 37% (9/51)
T12PR24: 17% (4/24)

On page 1538: “This study demonstrated the
benefit of retreatment with a telaprevir-based
regimen for patients with well-characterized
nonresponse (null and partial) or relapse to a prior
course of PR treatment.”

T12PR48: 56% (5/27)

AE: NR for null responder subgroup
However, it was reported that the safety
profile was similar to that observed in the
earlier phase II studies
Non-RCT on boceprevir
17
Poordad, 2012
SVR:
(PROVIDE
study)
BOC/PR : 16/42 (38%)
AE : NR

On page 166: “When retreated with BOC/PR 38%
of prior PR null responders achieved SVR, which
compares to SVR rate (33%) observed in poorly
IFN responsive patients treated in the SPRINT-2
17
and RESPOND-2 studies.”

AE=adverse event; BOC=boceprevir; HCV=hepatitis C virus; DS=delayed start; IFN=interferon; NR=not report; PEG=pegylated;
PR=peginterferon plus ribavirin; RCT=randomized controlled trial; SVR=sustained virological response; TP=telaprevir;

Protease Inhibitors for Hepatitis C in Prior Null Responders and Liver Transplant Patients

14

Appendix 5: Summary of Findings and Author Conclusions in Uncontrolled Studies on Recurrent HCV Post-Liver
Transplant
First author,
publication year
Telaprevir
Nair, 2012

Study Characteristics

Main findings

Author conclusions

24

P: 12 pts with recurrent
hepatitis C post LT
I:TP12PR48 wks; (ISA:
TAC)
C: none
O: HCV virologic response

All patients who received
12 wks of therapy with TP
were RNA undetectable at
week 12;
-No adverse event related
to TAC was noted

25

P: seven adult pts with
recurrent HCV post LT with
null response to PR for 12
wks (< 2 log10 reduction)
I: Four week lead-in PR
followed by adding TP. (IS:
CYA)
C: none
O:virologic response

No virological response
data extractable

P: 17 pts with recurrent
hepatitis C post LT
I:TP12PR24 or 48 wks (IS:
TAC)
C: none
O: HCV virologic response

Of the 17 patients, 6 had
rapid virological response
and extended (e)RVR;
additionally 6 patients
became aviremic at
32,33,40,55,62 84 and 90
days and had complete
early virologic response.

P: 12 pts with recurrent
hepatitis C post LT
I:TP plus PR (duration:
NR) (IS: RAP or TAC or
CYA)
C: none
O: HCV virologic response

7/12 (58%) patients had
undetectable viral loads at
wk 4 of triple therapy, 5/12
patients had <43 IU/mL. All
9/9 patients treated for 12
weeks had no detectable
virus (cEVR). 5/5 patients
treated for 24 weeks are

“Telaprevir based regimens can be used in posttransplantation patients with reduced dosing of
tacrolimus. Once a week dosing of tacrolimus is
sufficient to keep the level in therapeutic range and
avoid toxicity. Early virological response indicates
effectiveness in these difficult to treat patients. As
anticipated, pancytopenia is a major concern in
these patients and requires intense monitoring.”
“Conversion to CYA followed by four week PR leadin with addition of telaprevir can lead to significant
clearance rates at week 24 in null responders with
advanced fibrosis though high rates of anemia/RBV
dose reduction, growth factor, and transfusion
requirements were noted. Dose reduction of RBV to
200 mg was associated with treatment failure. CYA
Interactions were easily managed by CYA dose
adjustment. EOT results will be available for 3/4
individuals who are HCV RNA undetected at week
24 by 11/2012.”
“We report the first experience of treating HCV
recurrence in post liver transplant recipients with
telaprevir based triple therapy in setting of TAC
based immunosuppression. We observed robust
virologic responses in a majority of patients and
TAC/Telaprevir interactions and side effects were
manageable. Our preliminary data show that this
treatment shows promising virologic responses in
patients and merits prospective evaluation.”
“Triple therapy with telaprevir after a Peg-RBV leadin was safe and achieved 100% cEVR in LT
recipients on rapamune, tacrolimus, or cyclosporine.
However, drug interactions necessitate close
monitoring and use only in highly compliant patients
with good renal function.”

Kwo, 2012

Mantry, 2012

26

O'Leary,2012

27

Protease Inhibitors for Hepatitis C in Prior Null Responders and Liver Transplant Patients

15

First author,
publication year
Pungpapong, 2012

30

31

Burton,2012

Shin,2012

32

33

McCashland,2012

Study Characteristics

P: seven pts with recurrent
hepatitis C post LT
I:TP plus PR (duration:
NR) (IS: CYA)
C: none
O: HCV virologic response

Main findings
virus negative.
At last visits, 4 patients
(57%) had undetectable
HCV RNA (first at wk1, 5,
9, 12).

P: 12 pts with recurrent
hepatitis C post LT
I:TP12/PR48 wks; (IS:
CYA or MMF)
C: none
O: HCV virologic response

Mean HCV RNA (IU/ml)
prior to starting TP was
2.4x106 (55-15x106 IU/ml).
Mean 1 week HCV RNA
was 1895 IU/ml (0-19,400
IU/ml). By week 4, 11/12
had HCV RNA <43 IU/ml.

P: five pts with rHCV post
LT
I:TP plus PR(duration NR);
(IS: TAC or EVE)
C: none
O: HCV virologic response

Two patients achieved 2log (3,330 from 1,000,000
IU/ml) and 3-log (734 from
1,010,000 IU/ml) viral
reductions in the 1st week
follow-up. Two other
patients successfully
obtained “SVR” after 5
weeks of therapy (from
2,790,000 and from
167,000 IU/ml,
respectively). One patient
has persisted “SVR” after
12 week course of therapy.
(SVR was not defined in
the abstract)
2 out of 9 patients
achieved RVR; 3/3 patients
who have completed 12
weeks of TT have nondetectable HCV RNA; 1
patient is HCV RNA

P: 10 pts with rHCV post
LT
I:TP plus PR(duration 1-24
wks); (IS: CYA)
C: none
O: HCV virologic response

Protease Inhibitors for Hepatitis C in Prior Null Responders and Liver Transplant Patients

Author conclusions

“In our initial experience utilizing telaprevir+PR to
treat HCV genotype 1 after LT, 1/6 patients (17%)
achieved undetectable HCV RNA by wk4 (RVR) and
3/3 patients (100%) achieved undetectable HCV
RNA by wk12 (cEVR). Adjustment of CYA dose and
interval was required. Cytopenias were common.
Ongoing follow-up would provide additional insights
into the safety and efficacy of Telaprevir+PR to treat
HCV genotype 1 in LT recipients.”
“CsA-based immunosuppression and C2 monitoring
effectively maintains immunosuppression and
prevents rejection during TT for recurrent HCV.
Rates of early virologic response with TT exceed
those previously published using PR alone. Anemia
is a significant problem, but rash events are rare.
Telaprevir-based TT is manageable and may
enhance virologic responses in liver recipients.”
“Triple combination therapy has shown potent effect
on HCV reduction on patients who tolerated
therapy. This new therapy might have a role in
improving both graft and patient survival. As drug
tolerance is pivotal to completing this therapy
course, it is necessary to determine the timing of
onset of therapy and the management of the
adverse effects. Further study with more patients is
ongoing.”

“RVR was achieved in 22% of patients on TT after
LT . TT does not have a negative impact in
achieving CSA target levels. Hematological AE are
common while on TT after L.”

16

First author,
publication year
22

Werner,2012

Study Characteristics

Main findings

P: nine pts with rHCV post
LT
I:TP plus PR(duration 12
wks); (IS: CYA, TAC)
C: none
O: HCV virologic response

negative at week 24.
7 completed the 12 weeks
of triple therapy. At week 4,
4 of the patients were
found to be HCV RNAnegative, and importantly,
8 were found to be
negative at week 12.

Pereira, 2012

34

P: Six pts with rHCV post
LT
I:TP plus PR(duration 12
wks); (IS: TAC)
C: none
O: HCV virologic response

Rogers, 2012

35

P: two pts with rHCV post
LT
I:TP plus PR(duration 12
wks); (IS: TAC)
C: none
O: HCV virologic response

BOC
Aqel,2012

28

Schilsky,2012

29

One patientt had to stop
the therapy due to skin
rash and headche after
one week;
Two patients achieved 3
log 10 HCV reduction after
1-2 week therapy;
Two patients achieved
“SVR” after 5 weeks
therapy. (SVR not defined)
Patient one achieved
undetectable HCV and
remained after 10 weeks of
therapy.
Virologic response for
patient two: not reported

P: 23 pts with recurrent
hepatitis C post LT
I:BOC plus PR (duration:
24wks) (IS: CYA)
C: none
O: HCV virologic response

Ten patients (43%)
achieved complete early
virologic response; four of
them continue to be
negative at week 24.

P: three pts with recurrent
hepatitis C post LT
I: BOC plus PR (duration:
NR) (IS: CYA)
C: none

Patient one achieved
undetectable HCV viral
load by day 19 of BOC.
Patient two experienced
greater than a 2 log

Protease Inhibitors for Hepatitis C in Prior Null Responders and Liver Transplant Patients

Author conclusions

“In conclusion, this pilot study provides evidence
showing that TVR-based triple therapy is effective
within the first 4 to 12 weeks in LT patients suffering
from HCV genotype 1 recurrence, and it also
provides evidence showing that drug-drug
interactions between TVR and immunosuppressants
can be handled appropriately through the close
monitoring of trough levels and adequate dosage
adjustments.”
“Triple combination therapy has shown a potent
effect on HCV reduction in patients who tolerated
therapy. This new therapy may have a role in
improving both graft and patient survival. As drug
tolerance is pivotal to completing this therapy
course, it is necessary to determine the optimal time
of therapy and the management of adverse effects,
Further study is ongoing”

“TP can safely be administered post-transplant with
careful monitoring and tacrolimus dose adjustment.
The tacrolimus target was increased by 30% to
minimize the risk of rejection and IFN induced
immune mediated graft injury while on TP. Longer
follow-up is needed to determine if TP use posttransplant is beneficial.”
“Boceprevir based triple therapy can be used post
LT but requires close clinical monitoring. Antiviral
efficacy of this regimen is better than standard
therapy in difficult to treat population. Patients
should be closely monitored for adverse events.
Ongoing follow up will provide additional data
regarding safety and efficacy of this regimen.”
“Our experience demonstrates that triple therapy
with BOC offers promising early results in the
treatment of severe recurrent genotype 1 HCV in
LTRs.”

17

First author,
publication year

Coilly, 2012

23

Study Characteristics

Main findings

Author conclusions

O: HCV virologic response

decrease in HCV viral load
by day 19 of BOC; patient
three had a delayed
biochemical response but
showed improved
histology.
A virological response was
observed in all patients
(mean HCV viral load
[HVL] decrease at week
12, 6.64 +/- 0.35 log(10)
IU/ml).

On page 5728: “A virological response was
observed in all patients (mean HCV viral load [HVL]
decrease at week 12, 6.64 +/- 0.35 log(10) IU/ml).
These preliminary results in liver transplant patients
with HCV recurrence demonstrate the feasibility and
safety of coadministration of boceprevir and IT”

P: Five pts with recurrent
hepatitis C post LT
I: BOC plus PR (duration:
NR) (IS: CYA, TAC, EVE)
C: none
O: HCV virologic response

AE=adverse event; BOC=boceprevir; C=comparator; C2=2 hr post-dose CSA level; CSA= cyclosporine; cEVR=complete early virological response;
CYA=cyclosporine; EOT=end of treatment; EVE=everolimus; HCV=hepatitis C virus; I=intervention; IFN=interferon; ISA=immunosuppression agent; IT=
mmunosuppressive therapy; LT=liver transplantation; LTRs=liver transplant recipients; MMF=mycophenolate mofetil; NR=not report; O=outcome;
P=population; PEG=pegylated; PR=peginterferon plus ribavirin; RAP=rapamune; rHCV=recurrent HCV; RVR=rapid viral response; RBV=ribavirin;
RCT=randomized controlled trial; SIR=sirolimus; TAC=Tacrolimus; TP=telaprevir; wks=weeks. TT= triple therapy.

Protease Inhibitors for Hepatitis C in Prior Null Responders and Liver Transplant Patients

18