JOURNAL
OF HEPATOLOGY
[14] Bolondi L, Burroughs A, Dufour JF, Galle PR, Mazzaferro V, Piscaglia F,
et al. Heterogeneity of patients with intermediate (BCLC B) Hepatocel-
lular Carcinoma: proposal for a subclassification to facilitate treatment
decisions. Semin Liver Dis 2012;32:348–359.
Friedrich Foerster
Marcus-Alexander Wörns
⇑
Peter Robert Galle
Department of Internal Medicine,
University Medical Centre of the Johannes Gutenberg-University Mainz,
Langenbeckstrasse 1, 55131 Mainz, Germany
Direct-acting antiviral therapy in patients with hepatocellular cancer:
The timing of treatment is everything
To the Editor:
We read with interest the recent publication by Beste and col-
leagues, which focused on the negative impact of hepatocellular
cancer (HCC) on SVR in a large cohort of patients treated with
direct-acting antiviral agents (DAA) in the Veteran Affairs (VA)
program.1 The authors report that patients who had undergone
liver transplantation for HCC (HCC/LT) had a rate of SVR similar
to patients without HCC (no-HCC), with a lower rate of SVR seen
in those patients with HCC who did not undergo LT (HCC).
The debate about DAA treatment and HCC continues, and
many unanswered questions remain: (i) does DAA treatment
increase the risk of HCC? (ii) does DAA therapy influence the
type/pattern of recurrence of HCC? (iii) does HCC influence
DAA SVR rates? and (iv) what are the implications for the liver
transplant (LT) pathway for patients with HCC? Contradictory
data has been presented on the impact of DAA therapy on the
risk of HCC in patients with cirrhosis. Furthermore, a possible
lack of effectiveness of DAA regimens has been reported in
patients with active HCC.2 Beste’s recent publication attempts
to assess questions (iii) and (iv) together, but sheds little clarity
on this important topic.
In this study, patients with HCC were more likely to have
advanced liver disease (85% vs. 28%), and decompensated
cirrhosis (31% vs. 7%) compared to patients with no-HCC.1 More-
over, advanced liver disease has been shown to negatively
impact on the rate of SVR in patients treated with DAAs.3 Lower
SVR rates were seen in patients with genotype 1 HCV treated
with a sofosbuvir based regimen, than patients treated with
protease inhibitor based regimens. The patients who received
sofosbuvir are likely to have had more advanced liver disease,
which may have also impacted the rate of SVR, rather than
HCC or post-LT status per se. In addition, genotype 3 was iden-
tified as the single independent predictor of treatment failure in
patients with HCC,1 but the majority of these patients were
treated with suboptimal regimens, such as SOF/RBV and SOF/
LDV.4 Furthermore, the patients who did not undergo LT may
have had significant co-morbidities precluding LT, so it is likely
that there are many confounding factors influencing the results
presented.
Prenner et al. recently reported a higher rate of SVR in
patients who had inactive tumor or had undergone liver resec-
tion or LT, than in those with an active HCC.2 In this study, Beste
Journal of Hepatology 2018 vol. 68 j 199–220
⇑
Corresponding author. Address: Department of Internal Medicine,
University Medical Centre of the Johannes Gutenberg-University,
Langenbeckstrasse 1, 55131 Mainz, Germany.
Tel.: +49 6131 17 7275; fax: +49 6131 17 5595.
E-mail address: galle@uni-mainz.de
et al., report a remarkably lower rate of SVR in patients treated
with sorafenib (59%), than patients who underwent surgical
resection (78.9%) (Supplementary data Table S3). This suggests
that patients undergoing curative treatment for HCC have a
more favorable response to DAA therapy, consistent with Pren-
ner’s data, but it is important to note that such patients are
more likely to have compensated liver disease. It is likely that
the true impact of HCC on the likelihood of SVR is also influ-
enced by advancing liver disease.
Beste et al. suggest that in patients with HCV undergoing LT
for HCC, postponing DAA treatment to the post-LT period could
increase the success rate of therapy. As Transplant Hepatolo-
gists we believe that this is speculative, and potentially
misguided, especially given the data presented. Recent interna-
tional guidelines recommend that pre-LT DAA therapy should
be considered.5,6 There may be a MELD cut-off at which pre-
LT DAA therapy may not be helpful, but this feeds into organ
allocation systems and wait-list time to LT, and the potential
for clinical ‘salvage’. The waiting time for LT in some areas, such
as the UK, mandates aggressive management of HCC for patients
on the waiting list, and so any retrieval of liver function with
DAA therapy can be beneficial. Whilst we would agree that
the timing of LT is relatively fixed, whereas the timing of DAA
therapy may be flexible, it is pertinent to note that patients with
HCC as a primary indication for LT are more likely to tolerate an
extended organ, and thus need to be optimized prior to LT.
Contrary to the conclusion of a recent Cochrane review,7 SVR
positively influences the clinical course (liver function, survival)
of HCV patients with or without HCC.8
The ongoing debate around DAA therapy and HCC has gener-
ated much discussion. The elegant rebuttal to the initial Reig
publication9 by Craxi’s group10 encapsulates the issues around
the heterogeneity of HCC, its classification, and utilization of
management interventions, as well as reaffirming the urgent
need for better stratification systems with a molecular basis.
LT for HCC remains a curative option and HCC-LT outcomes
should not be compromised by a delay in initiation of DAA
therapy.
Financial support
No financial support was received in relation to this manuscript.
217
Letters to the Editor
Conflict of interest
Chiara Mazzarelli reports no conflict of interest.
Mary D Cannon has received advisory fees and conference
travel/accommodation costs from AbbVie, Merck Sharp and
Dohme, and Gilead.
Luca Belli received advisory fees from Abbvie and a personal
grant from Gilead.
Kosh Agarwal has received consultancy/advisory fees from
AbbVie, Astellas, BMS, Gilead, Intercept, Janssen, Novartis and
Merck, and grants from BMS, Gilead and Roche.
Authors’ contributions
All authors contributed to the preparation of this manuscript.
References
[1] Beste LA, Green PK, Berry K, et al. Effectiveness of hepatitis C antiviral
treatment in a USA cohort of veteran patients with hepatocellular
carcinoma. J Hepatol 2017;67:32–39.
[2] Prenner S, VanWagner LB, Flamm SL, et al. Hepatocellular carcinoma
decreases the chance of successful hepatitis C virus therapy with direct-
acting antivirals. J Hepatol 2017;66:1173–1181.
[3] Dailey F, Ayoub W. Hepatitis C virus therapy for decompensated and
posttransplant patients. J Clin Gastroenterol 2017;51:215–222.
[4] EASL recommendations on treatment of hepatitis C 2016. J Hepatol
2017;66:153–194.
[5] Terrault NA, McCaughan GW, Curry MP, et al. International liver
transplantation society consensus statement on hepatitis C management
in liver transplant candidates. Transplantation 2017;101:945–955.
More extended indication of DAA therapy in patients with HCC,
affordability, and further statistical considerations
To the Editor:
We read with interest the study by Beste et al.1 identifying the
remarkable achievement of a hepatitis C (HCV) viral cure with
direct-acting antivirals (DAAs) in patients diagnosed with hepa-
tocellular carcinoma (HCC), who did or did not receive liver
transplantation (LT).
The findings of Beste et al.1 are consistent with recent studies
by Yang et al.2 showing that HCC was the leading cause of LT
among waitlisted patients. The post-DAAs era (year 2011–
2014) was associated with a decreased risk of graft loss or
death, with the largest effect seen in HCV-infected recipients.
Using a population-based cohort study of the Scientific Registry
of Transplant Recipients (SRTS) by Flemming et al.3, there were
striking declines (approximately 30%) in LT listing for HCV-
related decompensated liver disease during the era of DAA ther-
apy, when compared to patients with other etiologies (hepatitis
B and non-alcoholic steatohepatitis) in conjunction with a sig-
nificant overall rise in waitlist among patients with HCV.
In the study by Beste et al.1, 426 patients with HCC were ana-
lyzed using the Veteran Affairs (VA) health care system dataset.
Considering that approximately 30,000 new cases of HCC occur
in the US4 annually and VA patients have more generous access
to DAA therapy than Medicaid patients,5 the findings from Beste
et al.1 should be cautiously tested before application to real
practice. According to Wang et al.5, approximately one-third of
patients with HCC were Medicaid or uninsured, had a more
218 Journal of Hepatology 2018 vol. 68 j 199–220
[6] Belli LS, Duvoux C, Berenguer M, et al. ELITA consensus statements on the
use of DAAs in liver transplant candidates and recipients. J Hepatol
2017;67:585–602.
[7] Jakobsen JC, Nielsen EE, Feinberg J, et al. Direct-acting antivirals for
chronic hepatitis C. Cochrane Database Syst Rev 2017. http://dx.doi.org/
10.1002/14651858.CD012143.pub2.
[8] Bruno S, Di Marco V, Iavarone M, et al. Improved survival of patients with
hepatocellular carcinoma and compensated hepatitis C virus-related
cirrhosis who attained sustained virological response. Liver Int 2017.
http://dx.doi.org/10.1111/liv.13452.
[9] Reig M, Mariño Z, Perelló C, et al. Unexpected high rate of early tumor
recurrence in patients with HCV-related HCC undergoing interferon-free
therapy. J Hepatol 2016;65:719–726.
[10] Cammà C, Cabibbo G, Craxì A. Direct antiviral agents and risk for HCC
early recurrence: Much ado about nothing. J Hepatol 2016;65:861–862.
⇑
Chiara Mazzarelli1,2,
Mary D. Cannon1
Luca S. Belli2
Kosh Agarwal1
1
Institute of Liver Studies, King’s College Hospital, London SE5 9RS,
United Kingdom
2
Hepatology Unit and Gastroenterology, ASST Ospedale Metropolitano
Niguarda, P.za dell’ospedale Maggiore 3, 20100 Milan, Italy
⇑
Corresponding author. Address: Institute of Liver Studies,
King’s College Hospital, London SE5 9RS, United Kingdom.
Tel.: +44 7542416332; fax: +44 2032993167.
E-mail address: chiara.mazzarelli@ospedaleniguarda.it
advanced tumor stage, and were less likely to receive treat-
ment.5 Additionally, most state Medicaid reimbursement pro-
grams for DAA therapy were not fully implemented until the
end of 2016.6 Yet significant barriers to DAA therapy access
remain, as qualifying for treatment is largely based on liver
fibrosis, substance dependency history, and other medical
comorbidities.6 According to Beckman et al.7, who analyzed
more than 10% of US prisoners from 41 states, less than 1% of
those inmates with HCV were being treated with DAAs. This
inequality in HCV treatment due to insurance or other barriers
is not limited to the US and is a common dilemma in other
developed countries including those under a universal health
system, such as the UK and Korea. Kieslich et al.8 explored the
coverage process of DAAs in the US, UK, and Korea and identi-
fied the limitations of budget impact analysis, the common
approach of payer’s perspectives, in HCV treatment. Uncertainty
remains about the Trump administration’s actions on DAA cov-
erage for HCV treatment. The major challenge facing the Amer-
ican Health Care Act (2017 H.R. 1628) is the loss of insurance
coverage for an estimated 23 million people. Uninsured HCV
patients are expected to be more vulnerable to worse health
outcomes unless timely actions are implemented. In these cir-
cumstances, international health care administration experts
suggested that patients and the public should proactively pro-
mote coverage for DAAs as an urgent agenda item for both
media and policymakers.8