Hepatitis C treatment
Approach Considerations
Patients with
acute hepatitis C virus (HCV) infection appear to have an excellent chance of
responding to 6 months of standard therapy with interferon (IFN). Because
spontaneous resolution is common, no definitive timing of therapy initiation
can be recommended; however, waiting 2-4 months after the onset of illness
seems reasonable.
acute hepatitis C virus (HCV) infection appear to have an excellent chance of
responding to 6 months of standard therapy with interferon (IFN). Because
spontaneous resolution is common, no definitive timing of therapy initiation
can be recommended; however, waiting 2-4 months after the onset of illness
seems reasonable.
Treatment of
chronic HCV infection has 2 goals. The first is to achieve sustained
eradication of HCV (ie, sustained virologic response [SVR]), which is defined
as the persistent absence of HCV RNA in serum 6 months or more after completing
antiviral treatment. The second goal is to prevent progression to cirrhosis,
hepatocellular carcinoma (HCC), and decompensated liver disease requiring liver
transplantation.
chronic HCV infection has 2 goals. The first is to achieve sustained
eradication of HCV (ie, sustained virologic response [SVR]), which is defined
as the persistent absence of HCV RNA in serum 6 months or more after completing
antiviral treatment. The second goal is to prevent progression to cirrhosis,
hepatocellular carcinoma (HCC), and decompensated liver disease requiring liver
transplantation.
Antiviral
therapy for chronic hepatitis C should be determined on a case-by-case basis.
However, treatment is widely recommended for patients with elevated serum
alanine aminotransferase (ALT) levels who meet the following criteria[4] :
therapy for chronic hepatitis C should be determined on a case-by-case basis.
However, treatment is widely recommended for patients with elevated serum
alanine aminotransferase (ALT) levels who meet the following criteria[4] :
- Age
greater than 18 years - Positive
HCV antibody and serum HCV RNA test results - Compensated
liver disease (eg, no hepatic encephalopathy or ascites) - Acceptable
hematologic and biochemical indices (hemoglobin at least 13 g/dL for men
and 12 g/dL for women; neutrophil count >1500/mm3, serum
creatinine < 1.5 mg/dL) - Willingness
to be treated and to adhere to treatment requirements - No
contraindications for treatment
A further
criterion is liver biopsy findings consistent with a diagnosis of chronic
hepatitis. However, a pretreatment liver biopsy is not mandatory. It may be
helpful in certain situations, such as in patients with normal transaminase
levels, particularly those with a history of alcohol dependence, in whom little
correlation may exist between liver enzyme levels and histologic findings.
criterion is liver biopsy findings consistent with a diagnosis of chronic
hepatitis. However, a pretreatment liver biopsy is not mandatory. It may be
helpful in certain situations, such as in patients with normal transaminase
levels, particularly those with a history of alcohol dependence, in whom little
correlation may exist between liver enzyme levels and histologic findings.
Patients with
normal liver enzyme levels and minimal histologic damage noted on liver biopsy
may elect to defer treatment until more effective and less toxic medications
become available, whereas patients with more advanced liver injury may prefer
to initiate treatment sooner. Patients should be informed that the treatment of
HCV infection in the setting of normal liver enzyme levels remains
controversial.
normal liver enzyme levels and minimal histologic damage noted on liver biopsy
may elect to defer treatment until more effective and less toxic medications
become available, whereas patients with more advanced liver injury may prefer
to initiate treatment sooner. Patients should be informed that the treatment of
HCV infection in the setting of normal liver enzyme levels remains
controversial.
The treatment
of hepatitis C has evolved over the years (see the following image). Initial
studies used IFN monotherapy, but current treatments are combination therapy
consisting of ribavirin and IFN or of IFN to which polyethylene glycol (PEG)
molecules have been added (ie, PEG-IFN).
of hepatitis C has evolved over the years (see the following image). Initial
studies used IFN monotherapy, but current treatments are combination therapy
consisting of ribavirin and IFN or of IFN to which polyethylene glycol (PEG)
molecules have been added (ie, PEG-IFN).
Protease
inhibitors are emerging as a third feature of combination therapy. The first
protease inhibitor indicated for use in HCV infection, boceprevir (Victrelis),
was approved by the FDA in May 2011.
inhibitors are emerging as a third feature of combination therapy. The first
protease inhibitor indicated for use in HCV infection, boceprevir (Victrelis),
was approved by the FDA in May 2011.
Patients with
HCV-related decompensated cirrhosis should be referred for consideration of
liver transplantation.
HCV-related decompensated cirrhosis should be referred for consideration of
liver transplantation.
Interferons and Pegylated
Interferons
The 2 most frequently used
recombinant IFN preparations in clinical trials are IFN alfa-2b (Intron-A) and
IFN alfa-2a (Roferon), which differ from each other by only a single amino acid
residue. IFN alfacon-1 (Infergens), or consensus IFN, is a genetically
engineered compound synthesized by combining the most common amino acid
sequences from all 12 naturally occurring IFNs.
IFN alfacon-1 has greater
cytokine-induction, antiviral, antiproliferative, natural killer cell, and
gene-induction activities than both IFN alfa-2a and IFN alfa-2b on an
equal-mass basis. However, initial studies of the recommended consensus IFN
dose of 9 mcg in IFN-naive patients with chronic hepatitis C, such as that by
Tong et al,[41] have resulted in viral response rates
similar to those of standard IFN-alfa monotherapy.
The addition of propylene glycol
(PEG) molecules to IFN has led to the development of long-lasting IFNs that
have better sustained absorption, a slower rate of clearance, and a longer
half-life than unmodified IFN, which permits more convenient once-weekly
dosing. The FDA has approved PEG-IFNs for the treatment of chronic hepatitis C.
Two PEG-IFN preparations are
available. PEG-IFN alfa-2b (PEG-Intron) consists of IFN alfa-2b attached to a
single 12-kd PEG chain; it is excreted by the kidneys. PEG-IFN alfa-2a
(Pegasys) consists of IFN alfa-2a attached to a 40-kd branched PEG molecule; it
is metabolized predominantly by the liver.
IFN monotherapy in acute
hepatitis C
Although the short courses of
standard IFN monotherapy introduced in the 1980s by Hoofnagle et al,[42] Davis et al,[7] and Di Bisceglie et al[43] led to sustained improvement in liver
disease and loss of virus in less than 10% of patients, these therapies were
the first to cure chronic viral hepatitis. While combination therapy with IFN
or PEG-IFN and ribavirin have become the standard of care for chronic disease,
IFN monotherapy may play a role in the treatment of acute HCV infection.
Jaeckel et al reported that
treatment with IFN alfa-2b prevented chronic infection in 98% of a group of 44
German patients with acute hepatitis C.[44] In this study, patients received 5 million
U/day of IFN alfa-2b subcutaneously for 4 weeks and then 3 times per week for
another 20 weeks; the IFN alfa-2b was well tolerated in all patients but one.[44] Because spontaneous resolution is common,
no definitive timing of therapy can be recommended; however, waiting 2-4 months
after the onset of illness seems reasonable.
PEG-IFN monotherapy
Several reports have documented
improved SVR with PEG-IFN monotherapy. In a randomized study of patients with
chronic hepatitis C, Zeuzem et al found that PEG-IFN alfa-2a at 180 mcg
subcutaneously administered once per week was associated with a higher rate of
virologic response than IFN alfa-2a at 6 million U subcutaneously administered
3 times per week for 12 weeks followed by 3 million U 3 times per week for 36
weeks.[45] Findings were 69% versus 28% at week 48 of
therapy and 39% versus 19% at week 72 of therapy.[45]
In a controlled trial of persons with
cirrhosis, Heathcote and colleagues reported an SVR rate of 30% after 48 weeks
of therapy with PEG-IFN alfa-2a, compared with 8% for patients treated with
standard IFN alfa. Adverse effects were not significantly higher with the
pegylated product.[46]
Interferons and Ribavirin
A major advance
in the treatment of chronic hepatitis C was the addition of the oral nucleoside
analogue ribavirin to the IFN regimen. As reported in the landmark 1998 studies
by McHutchison et al[47]and Poynard et
al,[48] IFN alfa-2b and
ribavirin combination therapy for 6-12 months resulted in sustained eradication
rates of 30-40%. However, patients with HCV genotype 1 who were treated for 12
months had a much less favorable response than patients infected with genotypes
2 and 3 who received a 6-month course of therapy.
in the treatment of chronic hepatitis C was the addition of the oral nucleoside
analogue ribavirin to the IFN regimen. As reported in the landmark 1998 studies
by McHutchison et al[47]and Poynard et
al,[48] IFN alfa-2b and
ribavirin combination therapy for 6-12 months resulted in sustained eradication
rates of 30-40%. However, patients with HCV genotype 1 who were treated for 12
months had a much less favorable response than patients infected with genotypes
2 and 3 who received a 6-month course of therapy.
PEG-IFN therapy with ribavirin
As with IFN
alfa, the addition of ribavirin to PEG-IFN heralded a new era in the treatment
of chronic HCV. The benefits of combination therapy were documented in 3
landmark trials: Manns et al from 2001,[49] Fried et al
from 2002,[50] and Hadziyannis
et al from 2004.[51]
alfa, the addition of ribavirin to PEG-IFN heralded a new era in the treatment
of chronic HCV. The benefits of combination therapy were documented in 3
landmark trials: Manns et al from 2001,[49] Fried et al
from 2002,[50] and Hadziyannis
et al from 2004.[51]
Manns et al
reported a significantly higher SVR rate in patients given higher-dose PEG-IFN
alfa-2b plus ribavirin than in patients given lower-dose PEG-IFN alfa-2b plus
ribavirin or given IFN alfa-2b plus ribavirin.[49] Adverse-effect
profiles in the 3 treatment groups were similar. Secondary analyses identified
body weight and HCV RNA viral load less than 1 million copies per milliliter as
important predictors of SVR. (See the image below.)
reported a significantly higher SVR rate in patients given higher-dose PEG-IFN
alfa-2b plus ribavirin than in patients given lower-dose PEG-IFN alfa-2b plus
ribavirin or given IFN alfa-2b plus ribavirin.[49] Adverse-effect
profiles in the 3 treatment groups were similar. Secondary analyses identified
body weight and HCV RNA viral load less than 1 million copies per milliliter as
important predictors of SVR. (See the image below.)
Fried at al
found that patients who received PEG-IFN alfa-2a plus ribavirin had a
significantly higher SVR rate than patients who received IFN alfa-2b plus
ribavirin (56% vs 44%) or PEG-IFN alfa-2a alone (56% vs 29%).[50] The SVR rates
for patients with HCV genotype 1 were 46%, 36%, and 21%, respectively, for the
3 regimens.
found that patients who received PEG-IFN alfa-2a plus ribavirin had a
significantly higher SVR rate than patients who received IFN alfa-2b plus
ribavirin (56% vs 44%) or PEG-IFN alfa-2a alone (56% vs 29%).[50] The SVR rates
for patients with HCV genotype 1 were 46%, 36%, and 21%, respectively, for the
3 regimens.
Hadziyannis et
al reported that in patients infected with HCV genotype 1, 48 weeks of
treatment was statistically superior to 24 weeks, and standard-dose ribavirin
was statistically superior to low-dose ribavirin.[51] In this study,
1311 persons were randomized to PEG-IFN alfa-2a at 180 mcg/wk for 24 or 48
weeks plus a low dose (800 mg/day) or standard weight-based dose (1000 or 1200
mg/day) of ribavirin.[51]In patients
with HCV genotypes 2 or 3, there were no statistically significant differences
in SVR rates in the 4 treatment groups.
al reported that in patients infected with HCV genotype 1, 48 weeks of
treatment was statistically superior to 24 weeks, and standard-dose ribavirin
was statistically superior to low-dose ribavirin.[51] In this study,
1311 persons were randomized to PEG-IFN alfa-2a at 180 mcg/wk for 24 or 48
weeks plus a low dose (800 mg/day) or standard weight-based dose (1000 or 1200
mg/day) of ribavirin.[51]In patients
with HCV genotypes 2 or 3, there were no statistically significant differences
in SVR rates in the 4 treatment groups.
In a study of
ribavirin in combination with either PEG-IFN alfa-2b or PEG-IFN alfa-2a for the
treatment of chronic HCV infection, Ascione et al reported a higher SVR rate
with PEG-IFN alfa-2a than with PEG-IFN alfa-2b (68% versus 54.4%).[52] SVR rates were
not statistically different in patients with a baseline HCV RNA of 500,000
IU/mL or less or in those with cirrhosis.[52]
ribavirin in combination with either PEG-IFN alfa-2b or PEG-IFN alfa-2a for the
treatment of chronic HCV infection, Ascione et al reported a higher SVR rate
with PEG-IFN alfa-2a than with PEG-IFN alfa-2b (68% versus 54.4%).[52] SVR rates were
not statistically different in patients with a baseline HCV RNA of 500,000
IU/mL or less or in those with cirrhosis.[52]
In a similar
trial, Rumi et al reported that treatment with ribavirin plus PEG-IFN alfa-2a
resulted in a significantly higher SVR rate than ribavirin plus PEG-IFN
alfa-2b. The 2 regimens showed a similar safety profile.[53]
trial, Rumi et al reported that treatment with ribavirin plus PEG-IFN alfa-2a
resulted in a significantly higher SVR rate than ribavirin plus PEG-IFN
alfa-2b. The 2 regimens showed a similar safety profile.[53]
In a study of
patients coinfected with HCV and HIV with compensated cirrhosis, Mira et al
found that SVR to PEG-IFN plus ribavirin significantly reduced the incidence of
liver-related decompensations and overall mortality.[54] The probability
of hepatic decompensation was 0% at 1 year and 4% at 3 years for SVR patients,
compared with 15% and 32%, respectively, for non-SVR patients. The probability
of overall mortality was 0% at 1 year and 4% at 3 years for SVR patients,
compared with 12% and 20%, respectively, for non-SVR patients.
patients coinfected with HCV and HIV with compensated cirrhosis, Mira et al
found that SVR to PEG-IFN plus ribavirin significantly reduced the incidence of
liver-related decompensations and overall mortality.[54] The probability
of hepatic decompensation was 0% at 1 year and 4% at 3 years for SVR patients,
compared with 15% and 32%, respectively, for non-SVR patients. The probability
of overall mortality was 0% at 1 year and 4% at 3 years for SVR patients,
compared with 12% and 20%, respectively, for non-SVR patients.
In conclusion,
treatment with PEG-IFN alfa-2a and ribavirin may be individualized by genotype.
Patients with HCV genotype 1 require treatment for 48 weeks and a standard dose
of ribavirin; those with HCV genotype 2 or 3 seem to be adequately treated with
a low dose of ribavirin for 24 weeks.[55]
treatment with PEG-IFN alfa-2a and ribavirin may be individualized by genotype.
Patients with HCV genotype 1 require treatment for 48 weeks and a standard dose
of ribavirin; those with HCV genotype 2 or 3 seem to be adequately treated with
a low dose of ribavirin for 24 weeks.[55]
Response to
therapy of HCV genotype 1 (i.e. achievement of SVR) can now be predicted by
identifying the single neoceotide polymorphisms (SNPs) located in the region of
interleukin (IL)-28B gene through genome-wide association studies.
Patients with CC genotype of the IL-28B have much more favorable response as
compared to CT or TT genotypr (70% vs 25-30%). Testing for IL-28B genotype is
thus a useful tool in the managemet of patients.[56]
therapy of HCV genotype 1 (i.e. achievement of SVR) can now be predicted by
identifying the single neoceotide polymorphisms (SNPs) located in the region of
interleukin (IL)-28B gene through genome-wide association studies.
Patients with CC genotype of the IL-28B have much more favorable response as
compared to CT or TT genotypr (70% vs 25-30%). Testing for IL-28B genotype is
thus a useful tool in the managemet of patients.[56]
Adverse effects
Adverse effects
are common with IFN and ribavirin combination therapy. Approximately 75% of
patients experience one or more of adverse effects.
are common with IFN and ribavirin combination therapy. Approximately 75% of
patients experience one or more of adverse effects.
Adverse effects
of IFN include the following:
of IFN include the following:
- Hematologic
complications (ie, neutropenia, thrombocytopenia) - Neuropsychiatric
complications (ie, memory and concentration disturbances, visual
disturbances, headaches, depression, irritability) - Flulike
symptoms - Metabolic
complications (ie, hypothyroidism, hyperthyroidism, low-grade fever) - Gastrointestinal
complications (ie, nausea, vomiting, weight loss) - Dermatologic
complications (ie, alopecia) - Pulmonary
complications (ie, interstitial fibrosis)
Adverse effects
of ribavirin include the following:
of ribavirin include the following:
- Hematologic
complications (ie, hemolytic
anemia) - Reproductive
complications (ie, birth defects) - Metabolic
complications (ie, gout)
Because of the
risk of reproductive complications from ribavirin, recommend that patients and
their spouses not become pregnant while either is on therapy and for 6 months
after the completion of treatment.
risk of reproductive complications from ribavirin, recommend that patients and
their spouses not become pregnant while either is on therapy and for 6 months
after the completion of treatment.
Growth factors,
such as granulocyte-stimulating factor (GSF) and erythropoietin, are frequently
used to counteract the adverse hematologic effects of IFN and ribavirin,
respectively. Despite the encouraging early results reported by Afdhal et al[57] and Van Thiel
et al,[58] cost-effectiveness
data supporting the routine use of these agents as a means of avoiding IFN and
ribavirin dose reductions are insufficient.
such as granulocyte-stimulating factor (GSF) and erythropoietin, are frequently
used to counteract the adverse hematologic effects of IFN and ribavirin,
respectively. Despite the encouraging early results reported by Afdhal et al[57] and Van Thiel
et al,[58] cost-effectiveness
data supporting the routine use of these agents as a means of avoiding IFN and
ribavirin dose reductions are insufficient.
In November
2012, the US Food and Drug Administration (FDA) approved eltrombopag
(Promacta), an oral thrombopoietin agonist, for treatment of thrombocytopenia
in patients with chronic hepatitis C to allow the initiation and maintenance of
interferon-based therapy. The approval was based on results from the phase 3 Endoscopic Ab lation Using L ight E nergy (ENABLE) 1 and
2 trials, which showed eltrombopag significantly reduced the time to the first
interferon dose reduction compared with placebo.[59, 60] Because of
this, a significant improvement in virologic response was observed in the
eltrombopag group compared with placebo. These randomized, double-blind,
placebo-controlled, multicenter studies collectively enrolled 1521 patients
with platelet counts less than 75,000/mcL. ENABLE 1 utilized peginterferon
alfa-2a plusribavirin for antiviral treatment and ENABLE 2 utilized
peginterferon alfa-2b plus ribavirin.
2012, the US Food and Drug Administration (FDA) approved eltrombopag
(Promacta), an oral thrombopoietin agonist, for treatment of thrombocytopenia
in patients with chronic hepatitis C to allow the initiation and maintenance of
interferon-based therapy. The approval was based on results from the phase 3 Endoscopic Ab lation Using L ight E nergy (ENABLE) 1 and
2 trials, which showed eltrombopag significantly reduced the time to the first
interferon dose reduction compared with placebo.[59, 60] Because of
this, a significant improvement in virologic response was observed in the
eltrombopag group compared with placebo. These randomized, double-blind,
placebo-controlled, multicenter studies collectively enrolled 1521 patients
with platelet counts less than 75,000/mcL. ENABLE 1 utilized peginterferon
alfa-2a plusribavirin for antiviral treatment and ENABLE 2 utilized
peginterferon alfa-2b plus ribavirin.
In patients who
are at risk of depression or who develop depression during treatment, any
antidepressant is better than none. Because available evidence suggests that
all antidepressants will have an effect, Schaefer et al reported that treatment
must be individualized on the basis of adverse effect profile, drug-to-drug
interactions, and general considerations (eg, speed of onset, efficacy).[61]
are at risk of depression or who develop depression during treatment, any
antidepressant is better than none. Because available evidence suggests that
all antidepressants will have an effect, Schaefer et al reported that treatment
must be individualized on the basis of adverse effect profile, drug-to-drug
interactions, and general considerations (eg, speed of onset, efficacy).[61]
Fatigue is
common in patients with chronic hepatitis C but is poorly associated with
biochemical parameters. Sustained response is accompanied by substantial
improvement of fatigue.[62]
common in patients with chronic hepatitis C but is poorly associated with
biochemical parameters. Sustained response is accompanied by substantial
improvement of fatigue.[62]
Protease Inhibitors
Despite the improved results
achieved with the addition of ribavirin to PEG-IFN, the current available
therapies for chronic HCV infection are effective in fewer than 50% of patients
with HCV genotype 1. A new class of direct-acting antiviral agents (DAAs) has
revolutionized the treatment of HCV genotype 1 infection. These drugs target
specific enzymes involved in viral replication. The addition of these new
protease inhibitors to pegylated interferon and ribavirin is becoming the new
standard of care for the treatment of chronic HCV infection.
Boceprevir (Victrelis) and
telaprevir (Incivek) are HCV NS3/4A protease inhibitors and were approved by
the US Food and Drug Administration in May, 2011. Each is indicated for
treatment of chronic HCV genotype 1 infection in combination with PEG-IFN alfa
and ribavirin in adults with compensated liver disease, including cirrhosis,
who are previously untreated or who have failed previous interferon and ribavirin
therapy.
Boceprevir was evaluated in 2
phase 3 clinical trials with nearly 1,500 participants. In both trials, two
thirds of patients receiving boceprevir in combination with peginterferon alfa
and ribavirin experienced a significantly increased sustained virologic
response (ie, undetectable HCV RNA level) compared with those taking
peginterferon alfa and ribavirin alone.[63, 64]
In a recent double-blind,
placebo-controlled trial of 201 patients with HCV genotype-1 who had relapsed
or not responded to previous therapy, the addition of boceprevir after 4 weeks
of lead-in therapy with PEG2a/R significantly increased the rate of SVR from
21% in the PEG2a/R group to 64% in the BOC/PEG2a/R group (P <
.0001).[65] . In this study a ≥1-log10
decline in HCV RNA at treatment week 4 was the strongest independent predictor
of SVR to added boceprevir therapy (39% vs 71%).
The safety and effectiveness of
telaprevir was evaluated in 3 phase III clinical trials with about 2,250 adult
patients who were previously untreated or who had received prior therapy. In
previously untreated patients, 79% of those receiving telaprevir experienced a
sustained virologic response (SVR) compared with PEG-IFN alfa and ribavirin
treatment alone. SVR for patients treated with telaprevir across all studies
and across all patient groups was 20-45% higher than the current standard of
care.[66]
The Protease Inhibition for Viral
Evaluation 1 (PROVE1) study demonstrated that the addition of
telaprevir to the current treatment regimen improved virologic response to HCV.[67] In early studies, there was a rapid
reduction of chronic HCV RNA levels. However, the telaprevir groups had a
higher rate of discontinued treatment (21%) compared with the placebo group
(11%) because of adverse effects, particularly rash.
In another recent study,
telaprevir monotherapy for 2 weeks reduced levels of HCV RNA in patients with
chronic HCV genotype 2 infections, but had limited activity in patients with
HCV genotype 3.[68]
Newer approaches to hepatitis C
therapy involve treatment with 2 direct-acting antiviral agents. In a
preliminary study a combination of NS5A replication complex inhibitor
daclatasvir (60 mg once daily) and the NS3 protease inhibitor asunaprevir (600
mg twice daily) resulted in a sustained virologic response in patients with HCV
genotype 1 infection who had not responded to prior therapy with peginterferon
and ribavirin.[69]
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