"
"
Simona Ruta, Costin Cernescu and Richard Sebastian Wanless
The hepatitis C epidemic is still growing in importance. While
the incidence of hepatitis C virus (HCV) infections is falling in
some countries, the burden of the disease arising from the pool
of chronic infections continues to rise. It has been estimated
that, by 2030, HCV will cause substantially higher morbidity and
mortality than HIV. Chronic Hepatitis C (CHC) occurs in 70% to
80% of those who contract the virus, 20% of whom will progress
to cirrhosis within 2-3 decades; a quarter of these will develop
decompensated liver disease, hepatocellular carcinoma (HCC)
and will need liver transplantation. A recent study has shown
that HCV infected persons have three times higher death rates
than those of age-matched general population (Brok 2010).
Excess mortality is due to both liver related causes and comorbidities
and is related to age, treatment status, the degree of
fibrosis and mean alcohol consumption.
Antiviral therapy – Standard of Care (SoC)
According to all consensus guidelines (EASL 2011, NICE 2010,
AASLD 2009), the current standard of care (SoC) for CHC is the
combination of pegylated interferon alfa (PegIFN) and
ribavirin (RBV) for 24-48 weeks, depending on the viral
genotype.
14 | Hepatitis C Treatment
The primary goal of treatment for CHC is to obtain a sustained
virological response (SVR), defined as undetectable HCV RNA
level at 6 months after treatment completion. Long-term
follow-up studies have shown that 97-100% of sustained
responders retain undetectable HCV RNA in serum, and, in many
cases, also in liver and peripheral blood mononuclear cells,
strongly suggesting that SVR is associated with eradication of
HCV infection. SVR can be also attained, even if at lower rates,
in patients with extensive fibrosis or cirrhosis, decreasing the
risk of HCC development and improving the overall survival
rates (Dieterich 2009).
The decision to treat or not to treat is made on an
individualized basis. Treatment should be considered for all
infected patients, particularly for those at risk for progression of
liver disease. However, treatment regimens and treatment
inclusion criteria have changed over time, as new therapeutic
approaches are developed and more individualized regimens are
introduced. As we will see in chapter 4, in May 2011, The US Food
and Drug Administration (FDA) has approved two new drugs –
both viral protease inhibitors – to be used in combination with
PegIFN/RBV for the treatment of CHC genotype 1 infection:
– Boceprevir (Victrelis™, Merck)
– Telaprevir (Incivek™, Vertex Pharmaceuticals Inc.)
Interferons (IFNs) are cytokines with species-specific, but nonvirus-
specific antiviral, immunomodulatory and anticellular
activities. PegIFN derives from attachment of an inert
polyethyleneglycol (Peg) chain – a unique polymer that does not
have a definite tertiary structure – to conventional IFN-alfa. This
confers an improved pharmacokinetic profile for the drug, by
slowing subcutaneous absorption, reducing degradation and
clearance and prolonging its half-life. PegIFN maintains high
sustained plasma IFN levels that allow for weekly dosing
(compared with 3 times weekly administration of standard IFN),
while also reducing its adverse side effects (AEs) and
immunogenicity.
Antiviral Therapy: The Basics | 15
There are two FDA and EMA approved formulas of PegIFN that
can be administered subcutaneously once weekly, with different
dosing regimens and pharmacokinetics (Table 1.1):
– PegIFN alfa-2a (PEGASYS™, manufactured by Hofmann La-
Roche) in which standard IFN alfa-2a is covalently linked to
a 40-kDa branched Peg molecule, administered at a fixed
dose (180 μg/week), with a plasma half-life of 80 -160 hours.
– PegIFN alfa-2b (PegIntron™, manufactured by Schering–
Plough/Merck) in which standard IFN alfa-2b is covalently
linked to a 12-kDa linear Peg molecule, dosed according to
body weight (1.5 μg/kg/week), with a mean elimination
half-life of 40 hours.
Table 1.1 – Different characteristics of the available PegIFNs*
Characteristic PegIFN alfa-2a PegIFN alfa-2b
Trade name/
Manufacturer
Pegasys/
Hoffmann-La Roche
PegIntron/
Schering Corporationnow
Merck
Structure large, branched, 40 kD small, linear, 12 kD
Volume of distribution 8-12 L 0.99 L/kg body
Clearance 60-100 mL/hr 22mL/hr/kg
Absorption half-life (hrs) 50-60 4,6
Elimination half-life (hrs) 65 40
Time to reach maximum
concentration
80 15-44
Peak to trough ratio 1.5-2 >10
Cost of combination treatment
(PegIFN + RBV) for 24 wks £ †
5019 6743
Cost of treatment 48 wks £ † 10963-11889‡ 13468
* According to data from Foster 2010
† according to British national formulary, 50th edition, excluding VAT
‡ depending on body weight
These differences do not affect significantly the treatment
outcomes. Current evidence does not allow for a definitive
recommendation of one of the two forms of PegIFNs. A Cochrane
systematic review of head-to-head randomized trials (Awad
16 | Hepatitis C Treatment
2010) suggests that PegIFN alfa-2a may be associated with an
increased benefit in terms of SVR compared to PegIFN alfa-2b,
although the largest head-to-head trial (IDEAL study) failed to
find a significant difference in SVR rates between the two PegIFN
formulations (McHutchison 2009). Nevertheless, the two
products seem to be comparable in terms of adverse effects (AEs)
leading to treatment discontinuation.
As long as SVR is only a surrogate marker of clinical outcomes
(liver failure, HCC and mortality) and the data on the long-term
AEs are limited, both regimens seems to be equally effective in
the clinical practice.
It is important to mention that HCV has notable properties by
which it can inhibit the actions of IFNs. The HCV protease
NS3/4A blocks important proteins and enzymes within the cells
(such as IRF3, a key transcriptional regulator of the IFN
response, and retinoid-inducible gene 1- RIG1, a growth
regulator), leading to a reduction in the expression of IFNsignaling
genes (Bode 2008).
Ribavirin (RBV) has both antiviral and immunomodulatory
actions. Although RBV monotherapy has little influence against
HCV, in combination with interferon it improves dramatically
the response rates. Being a guanosine analog, RBV acts by direct
inhibition of nucleic acid elongation and of enzymes important
in viral replication, such as inosine monophosphate
dehydrogenase (IMPDH), as well as by induction of lethal
mutagenesis during the viral life-cycle. Although the specific
mechanism has not yet been completely elucidated, there is
increasing evidence of RBV acting as a true antiviral agent and
thus having a critical role in the suppression of viral replication.
RBV amplifies the effect of IFN, generating a significant decrease
in the relapse rate (Manns 2001, Fried 2002).
Adding RBV to PegIFNs was recommended by consensus in
Europe in 1999 and in the United States in 2002. Subsequently, it
has been shown that weight–dosed RBV is more effective in
acquiring a high rate of therapeutic success. In today’s regimens,
RBV is administered according to patient’s weight: 1000 mg/day
Antiviral Therapy: The Basics | 17
for patients <75 kg and 1200 mg/day for patients >75 kg. Recent
clinical trials with new antiviral compounds associated with
PegIFN/RBV have demonstrated that maintaining RBV in the
therapeutic regimen has an important additive effect.
Predictors of response before treatment
Experienced providers need to take treatment decisions on a
case-by-case basis. There are a series of virus, host and
treatment characteristics that influence the likelihood of
treatment success and are useful when assessing the benefits and
risks of therapy.
Virus factors
HCV genotype, pretreatment HCV RNA level (viral load-VL) and
the evolution of viral quasispecies (cluster of variant viruses that
arise from mutations over time in viral population) are strong
independent predictors of SVR to SoC therapy, as well as to
triple combination therapy with protease inhibitors.
– HCV Genotype is a major predictor of treatment response.
HCV genotypes can be ranked, in a decreasing order of
susceptibility to IFN-based treatment, as follows: genotypes
2, 3, 4 and 1. Furthermore, subtype 1b rather than 1a and
subtype 2b rather than 2a are likely to respond poorer to
IFN-based therapy. Permanent viral eradication (SVR) can
be achieved in up to 80% of individuals infected with
‘favorable’ or “easy-to-treat” HCV genotypes (G2/3), but
only in approximately 40% of those infected with
‘unfavorable’ or “difficult-to-treat” HCV genotypes
(G1/4).
– High baseline VL (with a cutoff value of 400000 IU/mL)
influences negatively the response rate in patients infected
with HCV G1 (41% versus 56%), but not significantly in those
with HCV G 2/ 3 (74% versus 81%).
– Higher viral quasispecies complexity at baseline has been
observed in nonresponders compared with sustained
18 | Hepatitis C Treatment
virological responders. Greater sequence heterogeneity
generates diverse quasispecies, thereby providing a
reservoir of mutations that enable virus-escape from
antiviral therapy (Fan 2009).
Host factors
Variation in the IL28B gene region (that encodes IFN-lambda
- type III IFN) has been reported by several genome-wide
association studies as a major predictor of HCV treatment
response (Ge 2009, Tanaka 2009, Suppiah 2009) and of viral
kinetics during HCV therapy (Rauch 2010).
The presence of the CC inherited polymorphism in the IL 28B
gene (on chromosome 19 at SNP rs12979860) has been associated
with higher rates of therapeutic success, especially for
genotypes 1 and 4, compared with the presence of CT or TT
polymorhisms. The same is true for HCV co-infection with HIV
(Medrano 2010). Alleles frequencies differ between racial
groups, the favorable CC polymorphism being most frequently
encountered in Asians and least frequently in African-
Americans, explaining, at least partially, the differences in the
treatment response between races (Ge 2009, Thomas 2009). The
same polymorphism in the IL28B gene is a determinant of
natural HCV clearance (Thomas 2009) and is associated with
lower pretreatment levels of ISG (Thompson 2010). In
transplanted individuals, both donor and recipient IL28B
genotypes influence the response to HCV therapy (Fukuhara
2010).
Host immune response. The baseline pretreatment level of IP-
10 (CXCL10 – a chemochine active on lymphocytes) in plasma
and the intrahepatic IP-10 mRNA are elevated in patients
chronically infected with HCV genotypes 1/4 who do not achieve
SVR (Lagging 2011).
Other host-related negative predictors of response include
older age, male sex, black race, high body mass index (BMI) and
presence of co-morbitities.
Antiviral Therapy: The Basics | 19
Age. Younger patients (<40 years) have higher SVR rates with
SoC. Nonresponders tend to be on average 5 years older than
sustained responders (Hadziyannis 2004). Therapy is generally
deferred in elderly patients with comorbid conditions since
these may be exacerbated by combination therapy with
PegIFN/RBV. Despite all these observations, age alone should not
preclude antiviral therapy, and treatment decisions should be
made on a case by case basis.
The efficacy and safety of the PegIFN/RBVcombination is also
evaluated for pediatric patients. Only a limited number of
children with HCV infection cleared viremia spontaneously over
a decade of follow-up, and those who did were more likely to be
infected with G3. Persistent viral replication led to end-stage
liver disease in a small subgroup characterized by perinatal
exposure, maternal drug use, and infection with HCV G1a.
Children with such features should be considered for early
treatment. After treating children, SVR was attained in 65% of
the cases, genotype being the main predictor of response (G1:
53%; G2/3: 93%; G4: 80%). The rate of SVR was similar in younger
and older children. Baseline VL was the main predictor of
response in the G1 cohort. AEs were generally mild or moderate
in severity (Wirth 2010).
Race. Racial differences in the response to PegIFN/RBV therapy
have been signaled, with Hispanics and African-Americans less
likely to respond compared to Whites or Taiwanese patients
(Ghany 2009).
Co-morbidities
Obesity and its histological correlate, steatosis, are common
determinants of liver disease progression in HCV infection. We
must keep in mind that “not all hepatic fat is alike” and that the
etiology of steatosis makes an important difference in the
progression of hepatic fibrosis, the development of HCC,
extrahepatic manifestations, and prognosis.
Patients with BMI>30 kg/m2 are more likely to be insulinresistant,
to have more advanced hepatic steatosis or fibrosis
20 | Hepatitis C Treatment
and to experience a reduced response to combination therapy
(Khattab 2010).
Insulin resistance (IR) is one of the strongest negative
predictors of response to HCV therapy. Improved insulin
sensitivity may be associated with better treatment response and
even with HCV clearance. It is important to control diabetes
before starting PegIFN/RBV therapy, because IFN induces a
decrease in glucose uptake by peripheral tissue and the liver.
New HCV protease inhibitors can restore insulin sensitivity in
patients chronically infected with G1 HCV. HCV G3 has a direct
steatogenic effect independent of IR.
Co-infections. Patients with human immunodeficiency virus-
HIV-HCV coinfection have been shown to respond less
favorably to antiviral therapy than patients infected with HCV
alone. Moreover, serious AEs were far more frequent (35%) than
have been reported among HIV-seronegative patients (10-15%).
However, co-infected patients have a rapid fibrosis progression
rate and experience complications of portal hypertension and
PegIFN/RBV should be initiated, if treatment response outweigh
the risks of complications from the AEs of therapy (see chapter 3
for details).
Dual infections of HCV and hepatitis B virus (HBV) occur in
up to 5% of the general population in HCV-endemic areas and
lead to more severe liver disease. Recently, a large, open-label,
comparative multicenter study confirmed the efficacy of
PegIFN/RBV for patients with chronic HCV-HBV dual infection
in Taiwan (Jamma 2010).
Treatment related factors
The key components of therapy that affect the success rate are:
the optimal duration of therapy (48 or 24 weeks depending on
the viral genotype), the need for different regimens for patients
with G1/4 versus G2/3 infections, the appropriate doses of both
PegIFN and RBV and the effective management of the treatmentassociated
side effects (Ferenci 2008).
Antiviral Therapy: The Basics | 21
Treatment interruption due to AEs are more frequent in
patients receiving PegIFN/RBV for the longer duration of 48
weeks.
All studies show the importance of adherence (McHutchison
2002) using the 80/80/80 rule (patients who took more than 80%
of their prescribed IFN, more than 80% of their prescribed RBV,
and are treated for more than 80% of the planned treatment
duration). Adherence seems to be influenced by several patients‘
baseline characteristics: HIV coinfection; previous HCV
treatment regimen; use of illicit drugs.
Adverse effects associated with therapy
In clinical trials, approximately 10–15% of patients discontinue
PegIFN/RBV therapy due to AEs; however, in clinical practice,
the rate of treatment withdrawal has been reported to be
substantially higher.
In addition, dose reduction of PegIFN and/or RBV owing to AEs
is necessary in 25–40% of patients (especially in elderly and in
those with low baseline hemoglobin level). Importantly, dose
reduction should be implemented at the earliest possible stage,
when slight signs of AEs are noted. Combination therapy should
then be prolonged to ensure the full scheduled doses of therapy.
Regional and global variability exists in the nature of AEs and
in the strategies employed to mitigate their impact (Sulkowsky
2011).
Influenza-like symptoms (such as fatigue, headache, fever,
and rigors) occur in virtually all patients after the first doses of
PegIFN, but usually subside after the first month of treatment.
Dermatologic effects (alopecia, dermatitis) and gastrointestinal
symptoms (nausea, diarrhea) are also very frequent. The most
prevailing severe AEs are
– hematologic
– neuropsychiatric
– autoimmune
Anemia occurrs in more than 30% of treated patients. Usually,
the lowest hemoglobin (Hb) values are recorded 6-8 weeks after
22 | Hepatitis C Treatment
treatment initiation and stay at the same level throughout the
remaining therapy period, up to 48 weeks. Severe anemia, with
hemoglobin levels <10 g/dL, occur in approximately 10 - 15% of
patients. IFN induces bone marrow suppression, while RBV cause
hemolytic anemia. Recently, genome-wide association studies
have identified an inherited genetic polymorphism at
chromosome 20, in the inosine triphosphatase gene (SNPs:
rs1127354 and rs7270101), as predictive for RBV induced anemia
(Fellay 2010). The presence of A/A and A/C vs. C/C genotypes
predicts protection from RBV induced hemolytic anemia during
the early stages of treatment.
The management of anemia follows several successive steps:
– RBV dose reduction by 200-400 mg/day, when Hb level
decreases between 8.5 - 10 g /dl;
– Discontinuation of RBV when Hb level declines to <8.5g/dl;
– Epoetin administration in patients with early onset of
anemia, in order to prevent treatment interruption. Use of
recombinant human erythropoietin-stimulating agents has
been associated with higher SVR rates and with reduced
dropout rates (Sulkowski 2009).
RBV induced anemia can precipitate occult coronary artery
disease, especially in older patients (due to age related reduction
in creatinine clearance). An accurate estimation of the
glomerular filtration rate and the administration of a lower dose
of RBV are recommendable in elderly patients.
Neutropenia (with absolute neutrophil count – ANC less than
1.5 x109/mL) and thrombocytopenia (less than 50 000
cells/mm3) are also common. Consequently, eligibility for
treatment may be restricted in patients with advanced liver
cirrhosis.
The following decision tree is recommended for the
management of neutropenia and thrombocytopenia:
– PegIFN dose reduction, when ANC< 750 cells/mm3 and
platelets count < 50,000 cells/mm3;
– treatment discontinuation, when ANC < 500 cells/mm3 and
platelets count< 25,000 cells/mm3. If neutrophils or platelets
Antiviral Therapy: The Basics | 23
counts go up, treatment can be restarted, but at a reduced
Peg IFN dose;
– use of stimulating factors (i.e. Filgastrim™ - granulocyte
macrophage colony stimulating factor or Eltrombopag™ -an
oral thrombopoietin receptor agonist) is not routinely
recommended in clinical practice, except for patients with
cirrhosis.
Neuropsychiatric symptoms such as depression, irritability,
insomnia, and, occasionally, aggressive behavior are some of the
most debilitating AEs of PegIFN therapy, occurring in
approximately 20% to 30% of patients after the first month of
treatment. Interventions may require an initial dose reduction,
followed by permanent discontinuation of IFN in the case of
persistently severe or worsening symptoms. In most cases, the
neuropsychiatric symptoms resolve after PegIFN
discontinuation. A multidisciplinary approach, including medical
treatment (administration of antidepressants – especially
serotonin uptake inhibitors and benzodiazepines, when
required) and psychiatric counseling is needed in order to
reduce the psychiatric side effects of antiviral therapy.
Autoimmune disorders involve most commonly the
development of autoimmune thyroiditis, but HCV infection has
been also related to mixed cryoglobulinemia, thyroid
dysfunction and papillary thyroid cancer. There is ample
evidence showing that 7–11% of HCV-infected patients have
thyroid dysfunction (frequently consistent with hypothyroidism,
with increases in thyroid-stimulating hormone -TSH and
decreases in free thyroxin -T4 -mean values) prior to the
initiation of treatment. This percentage goes up to 15-20%, once
combined PegIFN/RBV therapy is initiated. Thyroid function
should be monitored routinely before and during treatment,
with TSH and T4 levels measured every 12 weeks while on
therapy and again at 6 months after the end of treatment.
Specific therapy may be needed to maintain a euthyroid state.
A series of other side effects are reported at lower rates, such as
pulmonary (cough, dyspnea), cardiovascular (cardiomyopaty,
24 | Hepatitis C Treatment
hypertension, supraventricular arrhythmias and myocardial
infarction) and ocular (retinal abnormalities).
Usually, but not always, these side effects reverse within a
short period after the end of therapy. Extreme caution is
however recommended in patients with preexisting chronic
obstructive pulmonary disease, diabetes mellitus prone to
ketoacidosis, severe myelosuppression, and/or coagulation
disorders (including thrombophlebitis and pulmonary
embolism). RBV may cause birth defects and/or death of the
unborn infant. Pregnancy must be avoided in female patients
and in female partners of male patients.
Recognition and effective management of AEs are critical
components of the successful treatment of CHC. Additional
measures include life style modification (hypocaloric diet,
physical exercise) in order to decrease the BMI and to prevent
weight gain. There are reports suggesting the beneficial effects
of insulin sensitizers (Metformin™- to reduce hepatic
gluconeogenesis and Pioglitazone™ -to sensitize insulin
receptors and mobilize visceral fat to subcutaneous tissues). A
series of hepatoprotective drugs and antioxidants (vitamin E,
betaine, silymarin and β-carotine) inhibit the toxic effects of free
radicals and prevent the synthesis of proinflammatory cytokines
that promote steatosis (El-Zayadi 2009). Excessive alcohol use
could reduce the likelihood of therapy response and abstinence
should be recommended before and during treatment.
Response-guided therapy (RGT)
RGT is a dynamic algorithm that involves individualized
treatment based on the on-treatment virologic response.
Basically, the more rapidly HCV RNA becomes negative during
treatment, the higher the rate of SVR.
Several types of virological responses may occur, categorized
according to their timing during treatment (Di Bisceglie 2007,
McHutchinson 2009):
Antiviral Therapy: The Basics | 25
– rapid virological response (RVR): undetectable HCV RNA
at week 4 (measured by real-time PCR assay with lower limit
of detection <15 IU/mL)
– early virological response (EVR), assessed at week 12
– complete EVR (cEVR): undetectable HCV RNA at week 12
– partial EVR (pEVR): decrease of HCV RNA by >2 log10 (100
fold) from baseline values at week 12
– end-of-treatment virological response (EoTR):
undetectable HCV RNA at the end of therapy (week 24 for
genotypes 2/3 or week 48 for genotypes 1/4)
– sustained virologic response (SVR): undetectable HCV
RNA 6 months after completing therapy
The standard recommended duration of treatment (Table 1.2) is
48 weeks for HCV genotypes 1/4 (with SVR rates of about 50%
and 65%, respectively) and 24 week for genotypes 2/3 (with
SVR rates of more than 75%). There is so far insufficient
experience to provide recommendations for HCV genotypes 5/6.
High weight-based dose RBV (15 mg/kg body) is recommended
for patients with baseline factors suggesting low responsiveness
(IR, metabolic syndrome, severe fibrosis or cirrhosis, older age).
The most important marker of treatment success is SVR. An
EoTR does not accurately predict a SVR, but is necessary for it to
occur. A RVR is the best predictor of SVR, if patients fulfill the
complete duration of treatment. The absence of an EVR is highly
predictive of treatment failure.
Treatment should be stopped at
– week 12 if the HCV RNA decrease is less than 2 log10 IU/ml,
compared with the baseline value (the SVR rate in these
patients is less than 2%)
– week 24 in patients with detectable HCV RNA (>50 IU/ml),
due to a minimal chance of SVR (1–3%)
26 | Hepatitis C Treatment
Table 1.2 – First-line treatment recommendations for antiviral
therapy in Hepatitis C*
HCV
Genotypes
PegIFN alfa-2a
once per week
PegIFN alfa-2b
once per week
RBV
once per day
Planned
duration†
1 and 4 180 μg
Flat dose
1.5 μg/kg
weight-based
dose
15 mg/kg weightbased
dose
48 weeks
800 mg daily
flat dose, if BMI<25
2 and 3 180 μg
Flat dose
1.5 μg/kg
weight-based
dose 15 mg/kg weightbased
dose, if
BMI>25
24 weeks
*According to data from EASLD 2011
†Treatment duration should be tailored to the on-treatment virological response
at weeks 4 and 12, and eventually, week 24.
For RGT, the following recommendations can be made
(Tsubota 2011):
– Treatment duration can be reduced to 12 weeks for
genotypes 2/3 infected patients who obtain an RVR with
PegIFN and weight-based RBV dosing. This does not
compromise the likelihood of achieving an SVR, but reduce
the AEs and the associated costs.
– Treatment duration can be reduced to 24 weeks for
genotype 1 infected patients with low baseline
(pretreatment) VL who attain a RVR.
– Treatment may be extended to 72 weeks for genotype 1
infected patients who show a slow virological response (with
partial EVR and HCV RNA negative by week 24). However,
for those who do not attain an EVR, the chance of treatment
success is very low (Thomson 2008).
In the clinical trials of the new direct-acting antivirals, a new
marker has been implemented, namely extended RVR (Sherman
2010). Extended RVR (eRVR) is defined as undetectable HCV
RNA at week 4 of therapy, maintained through a later time point
(in some cases over a period of 12 weeks, in others over 24
weeks). eRVR is a good predictor of the ability to shorten triple
therapy with protease inhibitors. Patients with G1 HCV, who
Antiviral Therapy: The Basics | 27
obtain an eRVR under triple therapy containing a protease
inhibitor, are eligible for RGT and a shortened duration of
treatment (24 weeks). Failure to achieve an eRVR cannot be used
as a stopping rule; continuation of therapy leads to SVR in a
considerable number of patients.
Nonresponders and relapsers
Using on-treatment viral kinetics, the following categories of
treatment failure can be defined:
– virologic breakthrough: HCV RNA reappearance while still
on treatment
– virologic relapse: undetectable HCV RNA at the end of
therapy, but HCV RNA reappearance after completion of
therapy
– nonresponse: failure to achieve undetectable HCV RNA
throughout treatment
Further detailing of the nonresponse category have been made
based on the observation that SVR rates are significantly higher
if more than 1 log10 reduction was registered at week 12 (Zeuzem
2011):
– null responders – patients with <2 log10 decrease in HCV
RNA level by week 12, who never reach undetectable levels
throughout the course of treatment
– partial responders – patients with >2 log10 decrease by
week 12, despite remaining detectable during treatment
All HCV-infected individuals who fail to respond or who relapse
have a series of pre-treatment and on-treatment fixed factors
(genotypes 1/4, advanced fibrosis, older age, race and genetic
background- risk alleles at IL28B gene (CT or particularly TT)
or/and correctable factors (patient adherence, AEs associated
with therapy) that contribute to the therapy failure (Missiha
2008). Overcoming these obstacles substantially increase the
chances for success, as will be shown in detail in chapter 3.
Moreover, failure to eradicate HCV infection does not mean that
the patient is non-responsive to therapy, as most patients
28 | Hepatitis C Treatment
improve biochemically and histologically. Therapeutic options
for these individuals include (AISF 2009):
– Retreatment with current SoC; the use of higher doses
and/or extended duration of treatment, maintenance
therapy with PegIFN – described in detail in chapter 3.
– The use of newly developed direct-acting antivirals (DAA) –
described in detail in chapter 4.
The overall objectives of new therapeutic strategies are to
prevent complications of end-stage liver disease and death from
HCV infection. In this respect, patients with compensated
cirrhosis are candidate for (re)treatment in order to prevent
decompensation. For patients with decompensated disease the
aim of treatment is to improve survival, while waiting for liver
transplant. The benefits and challenges posed by these
approaches are detailed in chapter 5.
Outlook
The management of patients with CHC is complex and
challenging, due to the potential AEs of antiviral therapies and
common co-morbidities often found in this group of patients.
Studies have shown that a multidisciplinary team-based
management approach can improve treatment outcomes in a
cost-effective manner.
Early treatment involves providing SoC therapy to all patients
with mild disease, some of whom will never progress to the
moderate to severe stage. This approach is associated with
increased costs per quality-adjusted lifeyears (QALY) gains.
Moreover, drug costs and excess costs for monitoring patients
are all incurred in the first year of the strategy, rather than at a
future date determined by the rate of disease progression
(Hartwell 2011).
In contrast, the watchful waiting strategy involves providing
antiviral treatment only to those patients with disease
progression. This is mostly based on the fact that although
antiviral therapy prevents complications and decreases the
overall severity and duration of the illness, its long-term benefit
Antiviral Therapy: The Basics | 29
on the morbidity and mortality associated with chronic infection
is poorly quantified.
The best choice for treatment initiation is made on a case by
case basis. Individulised decisions are based on a thorough pretreatment
assessment of the virus, host and other associated
factors that contribute to treatment failure. Response-guided
therapy has demonstrated significant advantages compared to
the watchful waiting strategy.
The decision regarding retreatment of patients with advanced
liver diseases depends on clinical factors like expected
progression of diseases, degree of inflammation/fibrosis,
coinfection with HIV or/and HBV, co-morbidities (autoimmune
diseases, heart and renal failure). Furthermore, modified
regimens, with currently available medications, novel modified
IFNs and RBV or combinations with direct-acting antivirals
(DAAs), are developed. A more active and highly individualized
therapeutic strategy is a priority for nonresponders to current
SoC.
Links
– European Association for the Study of the Liver (EASLD)
http://www.easl.eu/clinical-practice-guideline
– The American Association for the Study of Liver Diseases
(AASLD)
http://www.aasld.org/practiceguidelines
– National Institute for Health and Clinical Excellence
http://www.nice.org.uk
The hepatitis C epidemic is still growing in importance. While
the incidence of hepatitis C virus (HCV) infections is falling in
some countries, the burden of the disease arising from the pool
of chronic infections continues to rise. It has been estimated
that, by 2030, HCV will cause substantially higher morbidity and
mortality than HIV. Chronic Hepatitis C (CHC) occurs in 70% to
80% of those who contract the virus, 20% of whom will progress
to cirrhosis within 2-3 decades; a quarter of these will develop
decompensated liver disease, hepatocellular carcinoma (HCC)
and will need liver transplantation. A recent study has shown
that HCV infected persons have three times higher death rates
than those of age-matched general population (Brok 2010).
Excess mortality is due to both liver related causes and comorbidities
and is related to age, treatment status, the degree of
fibrosis and mean alcohol consumption.
Antiviral therapy – Standard of Care (SoC)
According to all consensus guidelines (EASL 2011, NICE 2010,
AASLD 2009), the current standard of care (SoC) for CHC is the
combination of pegylated interferon alfa (PegIFN) and
ribavirin (RBV) for 24-48 weeks, depending on the viral
genotype.
14 | Hepatitis C Treatment
The primary goal of treatment for CHC is to obtain a sustained
virological response (SVR), defined as undetectable HCV RNA
level at 6 months after treatment completion. Long-term
follow-up studies have shown that 97-100% of sustained
responders retain undetectable HCV RNA in serum, and, in many
cases, also in liver and peripheral blood mononuclear cells,
strongly suggesting that SVR is associated with eradication of
HCV infection. SVR can be also attained, even if at lower rates,
in patients with extensive fibrosis or cirrhosis, decreasing the
risk of HCC development and improving the overall survival
rates (Dieterich 2009).
The decision to treat or not to treat is made on an
individualized basis. Treatment should be considered for all
infected patients, particularly for those at risk for progression of
liver disease. However, treatment regimens and treatment
inclusion criteria have changed over time, as new therapeutic
approaches are developed and more individualized regimens are
introduced. As we will see in chapter 4, in May 2011, The US Food
and Drug Administration (FDA) has approved two new drugs –
both viral protease inhibitors – to be used in combination with
PegIFN/RBV for the treatment of CHC genotype 1 infection:
– Boceprevir (Victrelis™, Merck)
– Telaprevir (Incivek™, Vertex Pharmaceuticals Inc.)
Interferons (IFNs) are cytokines with species-specific, but nonvirus-
specific antiviral, immunomodulatory and anticellular
activities. PegIFN derives from attachment of an inert
polyethyleneglycol (Peg) chain – a unique polymer that does not
have a definite tertiary structure – to conventional IFN-alfa. This
confers an improved pharmacokinetic profile for the drug, by
slowing subcutaneous absorption, reducing degradation and
clearance and prolonging its half-life. PegIFN maintains high
sustained plasma IFN levels that allow for weekly dosing
(compared with 3 times weekly administration of standard IFN),
while also reducing its adverse side effects (AEs) and
immunogenicity.
Antiviral Therapy: The Basics | 15
There are two FDA and EMA approved formulas of PegIFN that
can be administered subcutaneously once weekly, with different
dosing regimens and pharmacokinetics (Table 1.1):
– PegIFN alfa-2a (PEGASYS™, manufactured by Hofmann La-
Roche) in which standard IFN alfa-2a is covalently linked to
a 40-kDa branched Peg molecule, administered at a fixed
dose (180 μg/week), with a plasma half-life of 80 -160 hours.
– PegIFN alfa-2b (PegIntron™, manufactured by Schering–
Plough/Merck) in which standard IFN alfa-2b is covalently
linked to a 12-kDa linear Peg molecule, dosed according to
body weight (1.5 μg/kg/week), with a mean elimination
half-life of 40 hours.
Table 1.1 – Different characteristics of the available PegIFNs*
Characteristic PegIFN alfa-2a PegIFN alfa-2b
Trade name/
Manufacturer
Pegasys/
Hoffmann-La Roche
PegIntron/
Schering Corporationnow
Merck
Structure large, branched, 40 kD small, linear, 12 kD
Volume of distribution 8-12 L 0.99 L/kg body
Clearance 60-100 mL/hr 22mL/hr/kg
Absorption half-life (hrs) 50-60 4,6
Elimination half-life (hrs) 65 40
Time to reach maximum
concentration
80 15-44
Peak to trough ratio 1.5-2 >10
Cost of combination treatment
(PegIFN + RBV) for 24 wks £ †
5019 6743
Cost of treatment 48 wks £ † 10963-11889‡ 13468
* According to data from Foster 2010
† according to British national formulary, 50th edition, excluding VAT
‡ depending on body weight
These differences do not affect significantly the treatment
outcomes. Current evidence does not allow for a definitive
recommendation of one of the two forms of PegIFNs. A Cochrane
systematic review of head-to-head randomized trials (Awad
16 | Hepatitis C Treatment
2010) suggests that PegIFN alfa-2a may be associated with an
increased benefit in terms of SVR compared to PegIFN alfa-2b,
although the largest head-to-head trial (IDEAL study) failed to
find a significant difference in SVR rates between the two PegIFN
formulations (McHutchison 2009). Nevertheless, the two
products seem to be comparable in terms of adverse effects (AEs)
leading to treatment discontinuation.
As long as SVR is only a surrogate marker of clinical outcomes
(liver failure, HCC and mortality) and the data on the long-term
AEs are limited, both regimens seems to be equally effective in
the clinical practice.
It is important to mention that HCV has notable properties by
which it can inhibit the actions of IFNs. The HCV protease
NS3/4A blocks important proteins and enzymes within the cells
(such as IRF3, a key transcriptional regulator of the IFN
response, and retinoid-inducible gene 1- RIG1, a growth
regulator), leading to a reduction in the expression of IFNsignaling
genes (Bode 2008).
Ribavirin (RBV) has both antiviral and immunomodulatory
actions. Although RBV monotherapy has little influence against
HCV, in combination with interferon it improves dramatically
the response rates. Being a guanosine analog, RBV acts by direct
inhibition of nucleic acid elongation and of enzymes important
in viral replication, such as inosine monophosphate
dehydrogenase (IMPDH), as well as by induction of lethal
mutagenesis during the viral life-cycle. Although the specific
mechanism has not yet been completely elucidated, there is
increasing evidence of RBV acting as a true antiviral agent and
thus having a critical role in the suppression of viral replication.
RBV amplifies the effect of IFN, generating a significant decrease
in the relapse rate (Manns 2001, Fried 2002).
Adding RBV to PegIFNs was recommended by consensus in
Europe in 1999 and in the United States in 2002. Subsequently, it
has been shown that weight–dosed RBV is more effective in
acquiring a high rate of therapeutic success. In today’s regimens,
RBV is administered according to patient’s weight: 1000 mg/day
Antiviral Therapy: The Basics | 17
for patients <75 kg and 1200 mg/day for patients >75 kg. Recent
clinical trials with new antiviral compounds associated with
PegIFN/RBV have demonstrated that maintaining RBV in the
therapeutic regimen has an important additive effect.
Predictors of response before treatment
Experienced providers need to take treatment decisions on a
case-by-case basis. There are a series of virus, host and
treatment characteristics that influence the likelihood of
treatment success and are useful when assessing the benefits and
risks of therapy.
Virus factors
HCV genotype, pretreatment HCV RNA level (viral load-VL) and
the evolution of viral quasispecies (cluster of variant viruses that
arise from mutations over time in viral population) are strong
independent predictors of SVR to SoC therapy, as well as to
triple combination therapy with protease inhibitors.
– HCV Genotype is a major predictor of treatment response.
HCV genotypes can be ranked, in a decreasing order of
susceptibility to IFN-based treatment, as follows: genotypes
2, 3, 4 and 1. Furthermore, subtype 1b rather than 1a and
subtype 2b rather than 2a are likely to respond poorer to
IFN-based therapy. Permanent viral eradication (SVR) can
be achieved in up to 80% of individuals infected with
‘favorable’ or “easy-to-treat” HCV genotypes (G2/3), but
only in approximately 40% of those infected with
‘unfavorable’ or “difficult-to-treat” HCV genotypes
(G1/4).
– High baseline VL (with a cutoff value of 400000 IU/mL)
influences negatively the response rate in patients infected
with HCV G1 (41% versus 56%), but not significantly in those
with HCV G 2/ 3 (74% versus 81%).
– Higher viral quasispecies complexity at baseline has been
observed in nonresponders compared with sustained
18 | Hepatitis C Treatment
virological responders. Greater sequence heterogeneity
generates diverse quasispecies, thereby providing a
reservoir of mutations that enable virus-escape from
antiviral therapy (Fan 2009).
Host factors
Variation in the IL28B gene region (that encodes IFN-lambda
- type III IFN) has been reported by several genome-wide
association studies as a major predictor of HCV treatment
response (Ge 2009, Tanaka 2009, Suppiah 2009) and of viral
kinetics during HCV therapy (Rauch 2010).
The presence of the CC inherited polymorphism in the IL 28B
gene (on chromosome 19 at SNP rs12979860) has been associated
with higher rates of therapeutic success, especially for
genotypes 1 and 4, compared with the presence of CT or TT
polymorhisms. The same is true for HCV co-infection with HIV
(Medrano 2010). Alleles frequencies differ between racial
groups, the favorable CC polymorphism being most frequently
encountered in Asians and least frequently in African-
Americans, explaining, at least partially, the differences in the
treatment response between races (Ge 2009, Thomas 2009). The
same polymorphism in the IL28B gene is a determinant of
natural HCV clearance (Thomas 2009) and is associated with
lower pretreatment levels of ISG (Thompson 2010). In
transplanted individuals, both donor and recipient IL28B
genotypes influence the response to HCV therapy (Fukuhara
2010).
Host immune response. The baseline pretreatment level of IP-
10 (CXCL10 – a chemochine active on lymphocytes) in plasma
and the intrahepatic IP-10 mRNA are elevated in patients
chronically infected with HCV genotypes 1/4 who do not achieve
SVR (Lagging 2011).
Other host-related negative predictors of response include
older age, male sex, black race, high body mass index (BMI) and
presence of co-morbitities.
Antiviral Therapy: The Basics | 19
Age. Younger patients (<40 years) have higher SVR rates with
SoC. Nonresponders tend to be on average 5 years older than
sustained responders (Hadziyannis 2004). Therapy is generally
deferred in elderly patients with comorbid conditions since
these may be exacerbated by combination therapy with
PegIFN/RBV. Despite all these observations, age alone should not
preclude antiviral therapy, and treatment decisions should be
made on a case by case basis.
The efficacy and safety of the PegIFN/RBVcombination is also
evaluated for pediatric patients. Only a limited number of
children with HCV infection cleared viremia spontaneously over
a decade of follow-up, and those who did were more likely to be
infected with G3. Persistent viral replication led to end-stage
liver disease in a small subgroup characterized by perinatal
exposure, maternal drug use, and infection with HCV G1a.
Children with such features should be considered for early
treatment. After treating children, SVR was attained in 65% of
the cases, genotype being the main predictor of response (G1:
53%; G2/3: 93%; G4: 80%). The rate of SVR was similar in younger
and older children. Baseline VL was the main predictor of
response in the G1 cohort. AEs were generally mild or moderate
in severity (Wirth 2010).
Race. Racial differences in the response to PegIFN/RBV therapy
have been signaled, with Hispanics and African-Americans less
likely to respond compared to Whites or Taiwanese patients
(Ghany 2009).
Co-morbidities
Obesity and its histological correlate, steatosis, are common
determinants of liver disease progression in HCV infection. We
must keep in mind that “not all hepatic fat is alike” and that the
etiology of steatosis makes an important difference in the
progression of hepatic fibrosis, the development of HCC,
extrahepatic manifestations, and prognosis.
Patients with BMI>30 kg/m2 are more likely to be insulinresistant,
to have more advanced hepatic steatosis or fibrosis
20 | Hepatitis C Treatment
and to experience a reduced response to combination therapy
(Khattab 2010).
Insulin resistance (IR) is one of the strongest negative
predictors of response to HCV therapy. Improved insulin
sensitivity may be associated with better treatment response and
even with HCV clearance. It is important to control diabetes
before starting PegIFN/RBV therapy, because IFN induces a
decrease in glucose uptake by peripheral tissue and the liver.
New HCV protease inhibitors can restore insulin sensitivity in
patients chronically infected with G1 HCV. HCV G3 has a direct
steatogenic effect independent of IR.
Co-infections. Patients with human immunodeficiency virus-
HIV-HCV coinfection have been shown to respond less
favorably to antiviral therapy than patients infected with HCV
alone. Moreover, serious AEs were far more frequent (35%) than
have been reported among HIV-seronegative patients (10-15%).
However, co-infected patients have a rapid fibrosis progression
rate and experience complications of portal hypertension and
PegIFN/RBV should be initiated, if treatment response outweigh
the risks of complications from the AEs of therapy (see chapter 3
for details).
Dual infections of HCV and hepatitis B virus (HBV) occur in
up to 5% of the general population in HCV-endemic areas and
lead to more severe liver disease. Recently, a large, open-label,
comparative multicenter study confirmed the efficacy of
PegIFN/RBV for patients with chronic HCV-HBV dual infection
in Taiwan (Jamma 2010).
Treatment related factors
The key components of therapy that affect the success rate are:
the optimal duration of therapy (48 or 24 weeks depending on
the viral genotype), the need for different regimens for patients
with G1/4 versus G2/3 infections, the appropriate doses of both
PegIFN and RBV and the effective management of the treatmentassociated
side effects (Ferenci 2008).
Antiviral Therapy: The Basics | 21
Treatment interruption due to AEs are more frequent in
patients receiving PegIFN/RBV for the longer duration of 48
weeks.
All studies show the importance of adherence (McHutchison
2002) using the 80/80/80 rule (patients who took more than 80%
of their prescribed IFN, more than 80% of their prescribed RBV,
and are treated for more than 80% of the planned treatment
duration). Adherence seems to be influenced by several patients‘
baseline characteristics: HIV coinfection; previous HCV
treatment regimen; use of illicit drugs.
Adverse effects associated with therapy
In clinical trials, approximately 10–15% of patients discontinue
PegIFN/RBV therapy due to AEs; however, in clinical practice,
the rate of treatment withdrawal has been reported to be
substantially higher.
In addition, dose reduction of PegIFN and/or RBV owing to AEs
is necessary in 25–40% of patients (especially in elderly and in
those with low baseline hemoglobin level). Importantly, dose
reduction should be implemented at the earliest possible stage,
when slight signs of AEs are noted. Combination therapy should
then be prolonged to ensure the full scheduled doses of therapy.
Regional and global variability exists in the nature of AEs and
in the strategies employed to mitigate their impact (Sulkowsky
2011).
Influenza-like symptoms (such as fatigue, headache, fever,
and rigors) occur in virtually all patients after the first doses of
PegIFN, but usually subside after the first month of treatment.
Dermatologic effects (alopecia, dermatitis) and gastrointestinal
symptoms (nausea, diarrhea) are also very frequent. The most
prevailing severe AEs are
– hematologic
– neuropsychiatric
– autoimmune
Anemia occurrs in more than 30% of treated patients. Usually,
the lowest hemoglobin (Hb) values are recorded 6-8 weeks after
22 | Hepatitis C Treatment
treatment initiation and stay at the same level throughout the
remaining therapy period, up to 48 weeks. Severe anemia, with
hemoglobin levels <10 g/dL, occur in approximately 10 - 15% of
patients. IFN induces bone marrow suppression, while RBV cause
hemolytic anemia. Recently, genome-wide association studies
have identified an inherited genetic polymorphism at
chromosome 20, in the inosine triphosphatase gene (SNPs:
rs1127354 and rs7270101), as predictive for RBV induced anemia
(Fellay 2010). The presence of A/A and A/C vs. C/C genotypes
predicts protection from RBV induced hemolytic anemia during
the early stages of treatment.
The management of anemia follows several successive steps:
– RBV dose reduction by 200-400 mg/day, when Hb level
decreases between 8.5 - 10 g /dl;
– Discontinuation of RBV when Hb level declines to <8.5g/dl;
– Epoetin administration in patients with early onset of
anemia, in order to prevent treatment interruption. Use of
recombinant human erythropoietin-stimulating agents has
been associated with higher SVR rates and with reduced
dropout rates (Sulkowski 2009).
RBV induced anemia can precipitate occult coronary artery
disease, especially in older patients (due to age related reduction
in creatinine clearance). An accurate estimation of the
glomerular filtration rate and the administration of a lower dose
of RBV are recommendable in elderly patients.
Neutropenia (with absolute neutrophil count – ANC less than
1.5 x109/mL) and thrombocytopenia (less than 50 000
cells/mm3) are also common. Consequently, eligibility for
treatment may be restricted in patients with advanced liver
cirrhosis.
The following decision tree is recommended for the
management of neutropenia and thrombocytopenia:
– PegIFN dose reduction, when ANC< 750 cells/mm3 and
platelets count < 50,000 cells/mm3;
– treatment discontinuation, when ANC < 500 cells/mm3 and
platelets count< 25,000 cells/mm3. If neutrophils or platelets
Antiviral Therapy: The Basics | 23
counts go up, treatment can be restarted, but at a reduced
Peg IFN dose;
– use of stimulating factors (i.e. Filgastrim™ - granulocyte
macrophage colony stimulating factor or Eltrombopag™ -an
oral thrombopoietin receptor agonist) is not routinely
recommended in clinical practice, except for patients with
cirrhosis.
Neuropsychiatric symptoms such as depression, irritability,
insomnia, and, occasionally, aggressive behavior are some of the
most debilitating AEs of PegIFN therapy, occurring in
approximately 20% to 30% of patients after the first month of
treatment. Interventions may require an initial dose reduction,
followed by permanent discontinuation of IFN in the case of
persistently severe or worsening symptoms. In most cases, the
neuropsychiatric symptoms resolve after PegIFN
discontinuation. A multidisciplinary approach, including medical
treatment (administration of antidepressants – especially
serotonin uptake inhibitors and benzodiazepines, when
required) and psychiatric counseling is needed in order to
reduce the psychiatric side effects of antiviral therapy.
Autoimmune disorders involve most commonly the
development of autoimmune thyroiditis, but HCV infection has
been also related to mixed cryoglobulinemia, thyroid
dysfunction and papillary thyroid cancer. There is ample
evidence showing that 7–11% of HCV-infected patients have
thyroid dysfunction (frequently consistent with hypothyroidism,
with increases in thyroid-stimulating hormone -TSH and
decreases in free thyroxin -T4 -mean values) prior to the
initiation of treatment. This percentage goes up to 15-20%, once
combined PegIFN/RBV therapy is initiated. Thyroid function
should be monitored routinely before and during treatment,
with TSH and T4 levels measured every 12 weeks while on
therapy and again at 6 months after the end of treatment.
Specific therapy may be needed to maintain a euthyroid state.
A series of other side effects are reported at lower rates, such as
pulmonary (cough, dyspnea), cardiovascular (cardiomyopaty,
24 | Hepatitis C Treatment
hypertension, supraventricular arrhythmias and myocardial
infarction) and ocular (retinal abnormalities).
Usually, but not always, these side effects reverse within a
short period after the end of therapy. Extreme caution is
however recommended in patients with preexisting chronic
obstructive pulmonary disease, diabetes mellitus prone to
ketoacidosis, severe myelosuppression, and/or coagulation
disorders (including thrombophlebitis and pulmonary
embolism). RBV may cause birth defects and/or death of the
unborn infant. Pregnancy must be avoided in female patients
and in female partners of male patients.
Recognition and effective management of AEs are critical
components of the successful treatment of CHC. Additional
measures include life style modification (hypocaloric diet,
physical exercise) in order to decrease the BMI and to prevent
weight gain. There are reports suggesting the beneficial effects
of insulin sensitizers (Metformin™- to reduce hepatic
gluconeogenesis and Pioglitazone™ -to sensitize insulin
receptors and mobilize visceral fat to subcutaneous tissues). A
series of hepatoprotective drugs and antioxidants (vitamin E,
betaine, silymarin and β-carotine) inhibit the toxic effects of free
radicals and prevent the synthesis of proinflammatory cytokines
that promote steatosis (El-Zayadi 2009). Excessive alcohol use
could reduce the likelihood of therapy response and abstinence
should be recommended before and during treatment.
Response-guided therapy (RGT)
RGT is a dynamic algorithm that involves individualized
treatment based on the on-treatment virologic response.
Basically, the more rapidly HCV RNA becomes negative during
treatment, the higher the rate of SVR.
Several types of virological responses may occur, categorized
according to their timing during treatment (Di Bisceglie 2007,
McHutchinson 2009):
Antiviral Therapy: The Basics | 25
– rapid virological response (RVR): undetectable HCV RNA
at week 4 (measured by real-time PCR assay with lower limit
of detection <15 IU/mL)
– early virological response (EVR), assessed at week 12
– complete EVR (cEVR): undetectable HCV RNA at week 12
– partial EVR (pEVR): decrease of HCV RNA by >2 log10 (100
fold) from baseline values at week 12
– end-of-treatment virological response (EoTR):
undetectable HCV RNA at the end of therapy (week 24 for
genotypes 2/3 or week 48 for genotypes 1/4)
– sustained virologic response (SVR): undetectable HCV
RNA 6 months after completing therapy
The standard recommended duration of treatment (Table 1.2) is
48 weeks for HCV genotypes 1/4 (with SVR rates of about 50%
and 65%, respectively) and 24 week for genotypes 2/3 (with
SVR rates of more than 75%). There is so far insufficient
experience to provide recommendations for HCV genotypes 5/6.
High weight-based dose RBV (15 mg/kg body) is recommended
for patients with baseline factors suggesting low responsiveness
(IR, metabolic syndrome, severe fibrosis or cirrhosis, older age).
The most important marker of treatment success is SVR. An
EoTR does not accurately predict a SVR, but is necessary for it to
occur. A RVR is the best predictor of SVR, if patients fulfill the
complete duration of treatment. The absence of an EVR is highly
predictive of treatment failure.
Treatment should be stopped at
– week 12 if the HCV RNA decrease is less than 2 log10 IU/ml,
compared with the baseline value (the SVR rate in these
patients is less than 2%)
– week 24 in patients with detectable HCV RNA (>50 IU/ml),
due to a minimal chance of SVR (1–3%)
26 | Hepatitis C Treatment
Table 1.2 – First-line treatment recommendations for antiviral
therapy in Hepatitis C*
HCV
Genotypes
PegIFN alfa-2a
once per week
PegIFN alfa-2b
once per week
RBV
once per day
Planned
duration†
1 and 4 180 μg
Flat dose
1.5 μg/kg
weight-based
dose
15 mg/kg weightbased
dose
48 weeks
800 mg daily
flat dose, if BMI<25
2 and 3 180 μg
Flat dose
1.5 μg/kg
weight-based
dose 15 mg/kg weightbased
dose, if
BMI>25
24 weeks
*According to data from EASLD 2011
†Treatment duration should be tailored to the on-treatment virological response
at weeks 4 and 12, and eventually, week 24.
For RGT, the following recommendations can be made
(Tsubota 2011):
– Treatment duration can be reduced to 12 weeks for
genotypes 2/3 infected patients who obtain an RVR with
PegIFN and weight-based RBV dosing. This does not
compromise the likelihood of achieving an SVR, but reduce
the AEs and the associated costs.
– Treatment duration can be reduced to 24 weeks for
genotype 1 infected patients with low baseline
(pretreatment) VL who attain a RVR.
– Treatment may be extended to 72 weeks for genotype 1
infected patients who show a slow virological response (with
partial EVR and HCV RNA negative by week 24). However,
for those who do not attain an EVR, the chance of treatment
success is very low (Thomson 2008).
In the clinical trials of the new direct-acting antivirals, a new
marker has been implemented, namely extended RVR (Sherman
2010). Extended RVR (eRVR) is defined as undetectable HCV
RNA at week 4 of therapy, maintained through a later time point
(in some cases over a period of 12 weeks, in others over 24
weeks). eRVR is a good predictor of the ability to shorten triple
therapy with protease inhibitors. Patients with G1 HCV, who
Antiviral Therapy: The Basics | 27
obtain an eRVR under triple therapy containing a protease
inhibitor, are eligible for RGT and a shortened duration of
treatment (24 weeks). Failure to achieve an eRVR cannot be used
as a stopping rule; continuation of therapy leads to SVR in a
considerable number of patients.
Nonresponders and relapsers
Using on-treatment viral kinetics, the following categories of
treatment failure can be defined:
– virologic breakthrough: HCV RNA reappearance while still
on treatment
– virologic relapse: undetectable HCV RNA at the end of
therapy, but HCV RNA reappearance after completion of
therapy
– nonresponse: failure to achieve undetectable HCV RNA
throughout treatment
Further detailing of the nonresponse category have been made
based on the observation that SVR rates are significantly higher
if more than 1 log10 reduction was registered at week 12 (Zeuzem
2011):
– null responders – patients with <2 log10 decrease in HCV
RNA level by week 12, who never reach undetectable levels
throughout the course of treatment
– partial responders – patients with >2 log10 decrease by
week 12, despite remaining detectable during treatment
All HCV-infected individuals who fail to respond or who relapse
have a series of pre-treatment and on-treatment fixed factors
(genotypes 1/4, advanced fibrosis, older age, race and genetic
background- risk alleles at IL28B gene (CT or particularly TT)
or/and correctable factors (patient adherence, AEs associated
with therapy) that contribute to the therapy failure (Missiha
2008). Overcoming these obstacles substantially increase the
chances for success, as will be shown in detail in chapter 3.
Moreover, failure to eradicate HCV infection does not mean that
the patient is non-responsive to therapy, as most patients
28 | Hepatitis C Treatment
improve biochemically and histologically. Therapeutic options
for these individuals include (AISF 2009):
– Retreatment with current SoC; the use of higher doses
and/or extended duration of treatment, maintenance
therapy with PegIFN – described in detail in chapter 3.
– The use of newly developed direct-acting antivirals (DAA) –
described in detail in chapter 4.
The overall objectives of new therapeutic strategies are to
prevent complications of end-stage liver disease and death from
HCV infection. In this respect, patients with compensated
cirrhosis are candidate for (re)treatment in order to prevent
decompensation. For patients with decompensated disease the
aim of treatment is to improve survival, while waiting for liver
transplant. The benefits and challenges posed by these
approaches are detailed in chapter 5.
Outlook
The management of patients with CHC is complex and
challenging, due to the potential AEs of antiviral therapies and
common co-morbidities often found in this group of patients.
Studies have shown that a multidisciplinary team-based
management approach can improve treatment outcomes in a
cost-effective manner.
Early treatment involves providing SoC therapy to all patients
with mild disease, some of whom will never progress to the
moderate to severe stage. This approach is associated with
increased costs per quality-adjusted lifeyears (QALY) gains.
Moreover, drug costs and excess costs for monitoring patients
are all incurred in the first year of the strategy, rather than at a
future date determined by the rate of disease progression
(Hartwell 2011).
In contrast, the watchful waiting strategy involves providing
antiviral treatment only to those patients with disease
progression. This is mostly based on the fact that although
antiviral therapy prevents complications and decreases the
overall severity and duration of the illness, its long-term benefit
Antiviral Therapy: The Basics | 29
on the morbidity and mortality associated with chronic infection
is poorly quantified.
The best choice for treatment initiation is made on a case by
case basis. Individulised decisions are based on a thorough pretreatment
assessment of the virus, host and other associated
factors that contribute to treatment failure. Response-guided
therapy has demonstrated significant advantages compared to
the watchful waiting strategy.
The decision regarding retreatment of patients with advanced
liver diseases depends on clinical factors like expected
progression of diseases, degree of inflammation/fibrosis,
coinfection with HIV or/and HBV, co-morbidities (autoimmune
diseases, heart and renal failure). Furthermore, modified
regimens, with currently available medications, novel modified
IFNs and RBV or combinations with direct-acting antivirals
(DAAs), are developed. A more active and highly individualized
therapeutic strategy is a priority for nonresponders to current
SoC.
Links
– European Association for the Study of the Liver (EASLD)
http://www.easl.eu/clinical-practice-guideline
– The American Association for the Study of Liver Diseases
(AASLD)
http://www.aasld.org/practiceguidelines
– National Institute for Health and Clinical Excellence
http://www.nice.org.uk
