Managing chronic hepatitis C in the difficult-to-treat patient.

Abstract

Patients with chronic hepatitis C virus (HCV) infection and disease-related complications - among them cirrhosis and liver failure - pose a particular management challenge. Some of these patients may fail to respond to current therapy (non-responders), and some are affected so severely that treatment puts them at an unacceptable risk for complications. Treatment with pegylated interferon (peg-IFN) plus ribavirin improves hepatic enzyme levels and eradicates the virus in approximately 50% of patients; however, a significant number of patients do not respond to therapy or relapse following treatment discontinuation. Several viral, hepatic and patient-related factors influence response to IFN therapy; many of these factors cannot be modified to improve long-term outcomes. Identifying risk factors and measuring viral load early in the treatment can help to predict response to IFN therapy and determine the need to modify or discontinue treatment. Retreatment options for patients who have failed therapy are limited. Retreatment with peg-IFN has been successful in some patients who exhibit an inadequate response to conventional IFN treatment, particularly those who have relapsed. Consensus IFN, another option in treatment-resistant patients, has demonstrated efficacy in the retreatment of non-responders and relapsers. Although the optimal duration of retreatment and the benefits and safety of maintenance therapy have not been determined, an extended duration is likely needed. This article reviews the risk factors for HCV treatment resistance and discusses the assessment and management of difficult-to-treat patients.

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REVIEW ARTICLE
ManagingchronichepatitisCinthedi⁄cult-to-treatpatient
Nyingi Kemmer and Guy W. Neff
Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati, OH, USA
OnlineOpen: This article is available free online at www.blackwell-synergy.com
Keywords
consensus interferon – hepatitis C – non-
responders – pegylated interferon – relapsers
– retreatment – ribavirin – sustained
virological response
Correspondence
Guy W. Neff, MD, Associate Professor of
Medicine, Department of Internal Medicine,
Division of Digestive Diseases, University of
Cincinnati College of Medicine, 231 Albert
Sabin Way, Cincinnati, OH 45267-0595, USA
Tel: 11 513 558 7200
Fax: 11 513 558 1744
e-mail: Guy.Neff@uc.edu
Received 19 February 2007
accepted 15 September 2007
DOI:10.1111/j.1478-3231.2007.01613.x
Abstract
Patients with chronic hepatitis C virus (HCV) infection and disease-related
complications – among them cirrhosis and liver failure – pose a particular
management challenge. Some of these patients may fail to respond to current
therapy (non-responders), and some are affected so severely that treatment puts
them at an unacceptable risk for complications. Treatment with pegylated
interferon (peg-IFN) plus ribavirin improves hepatic enzyme levels and eradicates
the virus in ? 50% of patients; however, a significant number of patients do not
respond to therapy or relapse following treatment discontinuation. Several viral,
hepatic and patient-related factors influence response to IFN therapy; many of
these factors cannot be modified to improve long-term outcomes. Identifying risk
factors and measuring viral load early in the treatment can help to predict response
to IFN therapy and determine the need to modify or discontinue treatment.
Retreatment options for patients who have failed therapy are limited. Retreatment
with peg-IFN has been successful in some patients who exhibit an inadequate
response to conventional IFN treatment, particularly those who have relapsed.
Consensus IFN, another option in treatment-resistant patients, has demonstrated
efficacy in the retreatment of non-responders and relapsers. Although the optimal
duration of retreatment and the benefits and safety of maintenance therapy have
not been determined, an extended duration is likely needed. This article reviews
the risk factors for HCV treatment resistance and discusses the assessment and
management of difficult-to-treat patients.
As the most common blood-borne pathogen in the
United States, hepatitis C virus (HCV) is an escalating
healthcare concern (1). Approximately 60–85% of
patients acutely infectedwithHCV progressto chronic
disease, defined as the presence of HCV RNA in the
blood for more than 6 months (2). The National
Center for Health Statistics recently estimated that
1.3% of the US population – or 3.2 million people –
have chronic HCV infection (3). The prevalence of
infection is highest among patients aged 40–49 years
(3); as these individuals age and the disease progresses
(Fig. 1) (4), HCV-related complications will become
more evident and severe (3, 4).
Among individuals with chronic HCV infection,
15–20% progress to end-stage liver disease (5).
Cirrhosis and hepatocellular carcinoma, in parti-
cular, are life-threatening complications, with an
estimated 42% of cirrhosis and 48% of liver cancer
cases in the United States, Canada and Cuba attri-
buted to chronic HCV infection (6). HCV-induced
liver disease results in 8000–10000 US deaths each
year (7).
Achieving viral eradication is the goal of antiviral
therapy and is defined by sustained virological re-
sponse (SVR; Table 1) (5, 8). The rates of SVR have
increased with improvements in antiviral therapy. SVR
rates with interferon (IFN) monotherapy are approxi-
mately 6–12%, increasing to 38–42% with conven-
tional IFN and ribavirin (RBV), and increasing as
high as 55% in major clinical trials of pegylated IFN
(peg-IFN) and RBV (9–12). Regardless, the number of
Re-use of this article is permitted in accordance with the Creative
Common Deed, Attibution 2.5, which does not permit commercial
exploitation.
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patients infected with HCV who are at risk for conti-
nued hepatic injury is substantial.
Although some factors that influence SVR rates, such
as inadequate dosage, inappropriate management of
side effects and earlydose reductions, may be corrected,
others, such as HCV genotype, baseline viral load, race
and age, cannot be specifically modified to improve
outcomes (13). Ongoing alcohol and substance abuse
has also been shown to contribute to the failure of IFN-
based treatment (14–16), as well as the development of
hepatocellular carcinoma (17). Identifying the risk
factorsforpoorresponsecanaidcliniciansinpredicting
response and making treatment and retreatment deci-
sions. The patient who does not respond to or who fails
prior therapy and is referred for new treatment options
poses a particular challenge; for example, a patient who
discontinues therapy because of treatment-related ad-
verse effects would have to be carefully evaluated before
starting subsequent IFN-based retreatment, especially
to determine appropriate management of complica-
tions. This article describes viral and host-related risk
factors for poor treatment response to initial IFN
therapy, evaluates current pharmacological options for
the difficult-to-treat HCV-infected population and dis-
cusses methods to predict potential treatment failure.
Viral factors influencing treatment response
in hepatitis C virus infection
Hepatitis C virus population dynamics
Hepatitis C virus exists as a quasispecies, comprising
closely related variants that are genetically distinct
(18–20). The continuous production of these variants
allows HCV to escape host defences and resist clear-
ance by antiviral therapies (18). Thus, patients who
have minimal HCV complexity (i.e. small quasispecies
sequence) are more likely to achieve SVR than patients
with large HCV complexity and significant changes
in the quasispecies composition (18, 21). To further
understand HCV resistance to antiviral therapies,
HCV replicon cell lines were developed with an IFN-
resistant phenotype (22). Namba et al. (22) suggested
that genetic alterations within the cell lines underlie
IFN resistance; however, further research is needed to
explain fully the mechanisms of antiviral resistance in
HCV infection.
Hepatitis C virus genotype
The HCV genotype, in particular, is a primary pre-
dictor of response to IFN therapy. Currently, six major
HCV genotypes with multiple subtypes are character-
ized, and HCV subtypes 1a and 1b are isolated most
often in the United States (23). Unfortunately, chronic
infection with HCV genotype 1 is associated with
greater resistance and lower SVR rates than other
genotypes (21, 24–27). In a study of peg-IFN-a-2a
and RBV, Fried et al. (9) noted that an HCV genotype
other than 1 was an independent and significant
predictor of SVR (odds ratio, 3.25; 95% confidence
interval, 2.09–5.12; Po0.001). Nguyen et al. (26) also
found lower SVR rates with IFN-based therapies in US
veterans infected with HCV genotype 1 vs. genotypes
2/3 (13 vs. 61% respectively).
Viral load
Patients with pretreatment high viral loads have worse
long-term outcomes than patients with low loads (24,
28). Evaluating 24-h HCV kinetics, Boulestin et al.
(24) noted a better response to antiviral therapy when
Table 1. Treatment outcomes in hepatitis C management (5, 8)
Treatment outcomeDefinition
o2-log decline in baseline HCV RNA levels after 12 weeks of therapy
Z2-log decline in serum HCV RNA occurs, but the virus is detectable after 24 weeks of treatment
HCV RNA remains undetectable in the serum 6 months after therapy is discontinued
Reappearance of HCV RNA following treatment withdrawal
Non-response
Partial response
Sustained virological response
Relapse
HCV, hepatitis C virus.
Exposure
Acute infection
Chronic hepatitis C
(≈55–86% of acutely
infected patients)
Spontaneous resolution
(≈25–45% of acutely
infected patients)
Slow
fibrosis progression
Intermediate
fibrosis progression
Rapid
fibrosis progression
Cirrhosis (≈20% of all
patients with chronic
hepatitis C)
Decompensated
liver disease
Hepatocellular carcinoma
(2–5% of patients with
cirrhosis annually)
Death
Alcohol, HIV, and
hepatitis B may
accelerate fibrosis
Fig. 1. Natural history of hepatitis C virus (HCV) infection.
[Reprinted from Postgraduate Medical Journal, Lo Ro VIII et al.
‘Management of Chronic hepatitis C’ 2005; 81: 378; with
permission from BMJ Publishing Group Ltd (4).]
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baseline viral loads were o5.55log10copies/mL. Dur-
ing the first 24h of IFN-a-2b therapy, reductions in
viraemia were greater in patients with low viral loads
vs. those with baseline loads Z5.55log10copies/mL
(1.26?0.14 vs. 0.70?0.22 respectively; P=0.016).
These investigators also associated large viral loads
withslowerday1 viral decay, as reductions Z0.5log10/
24h were documented in 82% of patients with base-
line viral levels o5.55log10copies/mL (range of viral
decay: 0.38–1.72log10copies/mL) vs. 45% of patients
with significant baseline viraemia (range of viral
decay: 0.09–2.49logcopies/mL) (24). Similarly, Jess-
ner et al. (28) found that responders to peg-IFN-a-2a
plus RBV exhibited lower baseline viraemia vs. non-
responders (P=0.039).
Host factors influencing treatment response
in hepatitis C virus infection
Fibrosis and cirrhosis
Cirrhosis and cirrhotic liver disease are estimated to
develop in 12.5% of patients with a 20-year history
of hepatitis C (29). Although patients with advanced
fibrosis or early-compensated cirrhosis generally have
lower response rates, they can be successfully treated
and may achieve SVR (30). In a trial of 1311 patients
with advanced liver disease, 63% of all patients and
52% of patients with genotype 1 treated with peg-IFN
plus RBV achieved SVRs (31). However, the success
of antiviral therapy diminishes in the face of decom-
pensated cirrhotic disease owing to the severity of
adverse effects in these severely ill patients (29, 32). In
addition, in a subanalysis of the HALT-C (Hepatitis C
Antiviral Long-term Treatment Against Cirrhosis)
study conducted by Everson et al., the presence of
advanced fibrosis and cirrhosis was a major indepen-
dent predictor of non-response to antiviral therapy.
This study compared four groups of patients with
increasingly severe liver disease, as determined by
Ishak scores and platelet counts. SVR rates decreased
from 23 to 9% as Ishak scores increased and
platelet counts decreased (Po0.0001 for trend),
confirming the effect of advanced liver disease in
antiviral therapy (33).
Race
Hepatitis C virus kinetics and drug pharmacokinetics
are influenced by select demographical and patient-
specific characteristics such as race (34). For example,
HCV-infected African American patients are less re-
sponsive to antiviral therapy than the non-Hispanic
white population (35, 36). In 401 patients infected
with HCV genotype 1, peg-IFN-a-2a- and RBV-pro-
duced SVR rates of 28% for African American patients
and 52% for white patients (Po0.0001) (37). Break-
through viraemia (13 vs. 6%; P=0.05) was also more
common among African Americans. Importantly,
rates of serious adverse events, dose reductions and
discontinuations were similar between the groups,
suggesting another mechanism for the observed effi-
cacy difference.
The mechanism behind a lack of response in African
Americans has not been fully elucidated (38). One
possible explanation is a high prevalence of HCV
genotype 1 among African American patients (88–96%)
(36, 39), but this cannot fully explain the insufficient
response. Layden-Almer et al. (38) noted that compared
with white patients, African Americans infected with
genotype 1 exhibited significantly lower decreases in
first-phase viral RNA (88.6 vs. 98.2% respectively;
P=0.005), slower elimination of infected cells (0.13/day
vs. 0.20/day respectively; P=0.006) and smaller declines
in mean viral RNA over 1 month (1.15log10copies/mL
vs. 3.61logcopies/mL respectively; P=0.001). This sug-
gests that African Americans may have an impaired
ability to block viral production.
Fontana et al. (40) developed a model to estimate
the probability of severe fibrosis in African American
and white patients based on commonly available
clinical and laboratory parameters. The Ishak fibrosis
scores of 205 for white and 194 for African American
patients were modelled using simple and multiple
logistical regressions. These scores were found to be
equally predictive in both groups of patients and may
be useful in identifying difficult-to-treat patients in the
African American cohort.
Age
In the elderly population (age 465 years), immuno-
logical suppression, chronic disease and concurrent
medications adversely affect response and heighten the
probability of adverse reactions to antiviral therapy.
However, research focusing on the efficacy and safety
of antiviral therapy in the older population is limited
to a few small, single-centre studies (41–43). In a
retrospective cohort study of 84 elderly patients age
Z65 years without genotype 1b or high viral load, 30
patients (35.7%) receiving IFN monotherapy achieved
SVRs (41). Eleven patients (13%) withdrew because of
adverse events, and univariate analysis showed a high-
er likelihood of withdrawal owing to adverse events
among those age 470 years than those age ? 70
(Po0.009). The likelihood of SVR was significantly
lower among those with high baseline viraemia (HCV
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RNA 4100KIU/mL; Po0.0001), advanced liver
fibrosis (P=0.04) and HCV genotype 1 (41). Thus,
advanced age alone reduces antiviral effectiveness, but
the addition of viral and hepatic risk factors further
worsens response.
Obesity
About 20–37% of HCV-infected patients are obese, a
potential barrier to treatment success (44, 45). The
body mass index inversely correlates with SVR (46),
and serum leptin, which is elevated in obese patients,
is a predictor of antiviral treatment resistance in HCV
infection with low viraemia (47). One of several
explanations developed to explain the interaction
between obesity and antiviral therapy response (46)
focuses on hepatic steatosis, because obesity is an
independent risk factor for fatty liver disease (45, 48,
49). Other explanations include an obesity-triggered
inflammatory reaction that decreases response and
impairs IFN absorption owing to high levels of sub-
cutaneous fat (44, 46). Regardless of the cause of lower
response ratesin obese HCV-infected patients(44, 50),
weight loss is an important component of treatment,
as it may lower elevated liver enzymes and improve
liver fibrosis (51). Weight-based dosing of antiviral
medications also becomes an important consideration
in patients with higher body mass indices (52).
Hepatitis C virus/human immunodeficiency virus
co-infection
An estimated 1 million individuals are human immu-
nodeficiency virus (HIV) positive in the United States
alone, and as many as 300000 are said to be co-
infected with HCV (53). Co-infection is associated
with substantial morbidity and mortality, including
end-stage liver disease, which is the leading cause of
death in the hospitalized HIV population (54).
Human immunodeficiency virus co-infection com-
plicates HCV antiviral therapy. Common adverse
effects of IFN and RBV therapy, such as depression
and anaemia, are often amplified in patients also
receiving antiretroviral therapy (55), and the risk of
drug–drug interactions is substantial. HCV clearance
may be slower in patients co-infected with HIV (56),
and relapse is common among co-infected responders
(57, 58). In a study by Soriano et al. (58) in 89 HIV/
HCV-infected patients, 48 (53.9%) exhibited a nega-
tive plasma HCV RNA at the end of treatment with
peg-IFN-a-2b and RBV, but only 29 (32.6%) achieved
SVRs 6 months after treatment discontinuation. In
another study (55), 133 patients infected with HCV
and HIV were randomly assigned to receive either
peg-IFN-a-2a or standard IFN-a-2a with RBV.
Although the group receiving the peg-IFN regimen
showed higher SVR rates (27 vs. 12%, P=0.03), the
rate was still lower than the rates reported in patients
infected with HCValone (9, 10, 57).
Management of the co-infected patient must be
individualized and should focus on viral suppression
with a peg-IFN regimen (59, 60). As stated above,
HCV progression is likely enhanced in co-infected
patients and, therefore, may justify more aggressive
and earlier therapy. Treatment options include HCV-
specific regimens, maintenance therapy, alternative
IFN formulations and observation (60). Maintenance
therapy with low-dose peg-IFN may slow progression
of fibrosis, and observation may be an appropriate
option for patients with more mild hepatic histology
(60). An important issue in this population is whether
HCV treatment could enable more extensive use of
retroviral agents. This question will likely be answered
as more co-infected patients are treated successfully
with anti-HCVagents.
Liver transplantation
Graft re-infection in liver transplantation resulting
from chronic HCV infection is common, as the
virus is seeded from the bloodstream to the new graft
(61). Orthotopic liver transplantation affects response
to HCV therapies, with SVR rates of 20–30%
(61–68), which are lower than those achieved in
non-transplantation patients. A meta-analysis of 48
studies examined the safety and efficacy of both
standard IFN and peg-IFN in liver transplant recipi-
ents (69). The overall SVR rates were 24% with IFN
and RBV and 27% with peg-IFN and RBV; disconti-
nuation rates were 24 and 26%, and pooled rates of
graft rejection were 2 and 5% respectively. The slight
efficacy advantage for peg-IFN was attenuated by the
slight disadvantage in the rates of discontinuation and
graft rejections.
Adverse effects also compromise outcomes. Adverse
effects can prompt premature treatment discontinua-
tion in up to 50% of patients (61, 70). Severe neutro-
paenia and the corresponding increased risk of
infection and haemolytic anaemia are primary treat-
ment-limiting toxicities associated with IFN plus RBV
(61, 71). In 34 HCV-infected transplant recipients
treated with peg-IFN-a-2a 180mg/week for 48 weeks,
Chalasani et al. (72) documented an SVR rate of only
12% and awithdrawal rate attributed to adverse effects
of 30%.
Several investigations regarding optimal regimens
for transplant recipients were encouraging (73, 74).
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One pilot study in 24 post-transplantation patients
who did not respond to previous IFN-RBV therapy
found that adding amantadine to IFN and RBV led to
an SVR rate of 33% (73). In another post-transplanta-
tion study, 27 non-responders to recurrent HCV
treatment with IFN and RBV were retreated with peg-
IFN-a-2b and RBV and compared with 21 untreated
patients (74). Only two patients (7%) discontinued
therapy because of adverse effects, and eight patients
(30%) in the intent-to-treat population achieved an
SVR. Interestingly, cyclosporine use (as immunosup-
pressive therapy) was significantly associated withviral
clearance (P ? 0.03). Fibrosis scores determined on
graft biopsy improved in 76% of treated patients and
only 5% of untreated patients. Improvement did not
correlate with SVR; fibrosis scores improved in 65% of
treated patients who did not achieve SVR (74).
Kidney transplantation
Human immunodeficiency virus infection complicates
the treatment of kidney transplantation candidates and
graft recipients. Up to 32.1% of patients on mainte-
nance dialysis are anti-HCV positive (75–78), as are
6.8% of adult cadaveric renal graft recipients (79). HCV
infection is an independent risk factor that increases the
risk of death among dialysis patients up to 2.39-fold
(80–82) and increases mortality rates among transplant
recipients(80,81).ChronichepatitisCisalsoassociated
with mixed essential cryoglobulinaemia (83), increasing
post-transplantation morbidity byenhancing the riskof
de novo or recurrent HCV-associated glomerulopathies
(84–88). Recurrence of HCV-associated kidney disease
can adversely affectgraftsurvivaland has been linkedto
higher serum creatinine levels (85, 89).
Data support treating patients who have chronic
hepatitis C and are awaiting kidney transplantation
(90, 91), improving both renal histology and biochem-
ical markers of renal function (90). IFN monotherapy
is the treatment of choice in HCV-positive dialysis
patients awaiting transplantation (92, 93); data are
limited on peg-IFN in dialysis patients (94–97). In
addition, RBV is generally avoided in dialysis pati-
ents, because it may induce haemolytic anaemia (98).
Two meta-analyses found that IFN monotherapy
produced SVR rates of 33–39% (92, 99). RBV may also
be indicated in patients with HCV-related glomerulo-
pathy because it may reduce rates of proteinuria.
Importantly, virological relapse rates are very low in
dialysis patients who achieve an SVR before transplan-
tation (91). Pre-transplantation treatment may also
prevent postoperative complications such as fibrosing
cholestatic hepatitis (91).
Amantadine monotherapy was not efficacious in
treating HCV infection in renal transplantation pa-
tients, showing no effect on HCV viraemia or liver
histology (100). The addition of amantadine to RBV
was also not superior to RBV in renal transplantation
patients with chronic hepatitis C, perhaps because of
the poor tolerability of both medications in patients
with impaired renal function (101).
Routine antiviral therapy for patients after kidney
transplantation is not recommended because of risk of
graft rejection (102–106). Exceptions may include
patients with HCV-associated glomerulonephritides
to prevent graft loss. Patients with advanced fibrosis
may also receive treatment to prevent death from liver-
related complications.
Other factors
Patient non-compliance and incorrect medication
administration may be modifiable risk factors for
treatment failure. Illicit drug or alcohol abuse are
associated with non-compliance, and adverse events
prompt treatment discontinuation in up to 14% of
patients receiving peg-IFN regimens (2). The com-
mon, occasional and rare adverse events seen with IFN
and RBVare listed in Table 2 (107). Similarly, psychia-
tric disorders (e.g. depression) present before treat-
ment initiation or resulting from treatment may
compromise compliance and cause early treatment
discontinuation (8, 26).
Treatment of difficult-to-treat human
immunodeficiency virus patients
Preventing complications is a prominent considera-
tion in the management of HCV infection, and
aggressive attempts are required to treat patients at
risk for complications. The natural history of the
disease should also be a major factor in deciding on a
course of therapy, as patients with mild or no fibrosis
may not require such aggressive therapy.
Patients exhibiting any of the multiple risk factors,
influencingresponsetoantiviraltherapy,poseachallenge
in the management of chronic hepatitis C. Although a
regimen of peg-IFN and RBV is the standard of care,
consensus IFN (CIFN) and RBV also may also be
efficacious in treatment-naı ¨ve patients at risk for poor
response. In an open-label, prospective study by
Sjogren et al. (108), 128 treatment-naı ¨ve patients with
chronic HCV infection were randomized to receive
CIFN 15mg or IFN-a-2b 3MU three times weekly plus
RBV 1000mg/day for 48 weeks. The results showed a
substantial difference in SVR rates: At 72 weeks, 57%
of the CIFN treatment group was HCV RNA negative
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