INITIAL TREATMENT OF HCV INFECTION IN PATIENTS STARTING TREATMENT
HCV infection who are naive to HCV treatment or
who have achieved an undetectable level of virus during a prior
treatment course of PEG/RBV and relapsed (relapsers). Although PEG/RBV
relapsers are being retreated, their treatment recommendations are
presently the same as for persons being treated for the first time as
described below. This section assumes that
a decision to treat has been made
and provides guidance regarding optimal treatment. In many instances,
however, it may be advisable to delay treatment for some patients with
documented early fibrosis stage (F 0-2), because waiting for future
highly effective, pangenotypic, DAA combinations in IFN-free regimens
may be prudent. Potential advantages of waiting to begin treatment will
be provided in a future update to this guidance.
The level of evidence available to inform the best treatment
decisions for each patient varies, as does the strength of the
recommendation, and is graded accordingly (see
Methods Table 2).
In addition, when treatment differs for a particular group, such as
those infected with specific HCV genotypes, specific recommendations are
given. A regimen is classified as either "Recommended" when it is
favored for most patients or "Alternative" when optimal in a particular
subset of patients in that category. When a treatment is clearly
inferior or is deemed harmful, it is classified as "Not Recommended."
Unless otherwise indicated, such regimens should not be administered to
patients with HCV infection. Specific considerations of persons with
HIV/HCV coinfection, compensated and decompensated cirrhosis (moderate
or severe hepatic impairment;
CTP class B or C), post-liver transplant HCV, and those with severe renal impairment or ESRD are addressed in other sections of the document.
As always, patients receiving antiviral therapy require careful
pretreatment assessment for comborbidities that may influence treatment
response. All patients should have careful monitoring during treatment,
particularly for anemia if ribavirin is included in the regimen.
Recommended regimen for treatment-naive patients with HCV genotype 1 who are eligible to receive IFN.
Daily sofosbuvir (400 mg) and weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75
kg]) plus weekly PEG for 12 weeks is recommended for IFN-eligible
persons with HCV genotype 1 infection, regardless of subtype.
Rating: Class I, Level A
Sofosbuvir is a prodrug of a nucleotide analogue inhibitor of the HCV
NS5B RNA-dependent RNA polymerase. The phase 3 NEUTRINO trial evaluated
sofosbuvir (400 mg daily) in combination with PEG (2a) (180 μg by
subcutaneous injection weekly) and weight-based RBV (1000 mg to 1200 mg
daily) for 12 weeks in 291 treatment-naive patients with chronic HCV
genotype 1 infection. (
Lawitz, 2013b)
The SVR12 for patients with genotype 1 infection was 89%. SVR12 did not
differ substantially by baseline characteristic but was lower in
patients with cirrhosis (80%) than in those without cirrhosis (92%). (
Lawitz, 2013b)
Recommended regimen for treatment-naive patients with HCV genotype 1 who are not eligible to receive IFN.
Daily sofosbuvir (400 mg) plus simeprevir (150 mg), with or without weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg] for 12 weeks is recommended for IFN-ineligible patients with HCV genotype 1 infection, regardless of subtype.
Rating: Class I, Level B
COSMOS is an ongoing phase 2 clinical trial of sofosbuvir (400 mg
daily) plus simeprevir (150 mg daily), a specific inhibitor of the HCV
NS3/4A serine protease, with or without RBV for 12 or 24 weeks. (
Jacobson, 2013b)
The study enrolled 2 cohorts: cohort 1 included patients with a prior
null response to PEG/RBV with Metavir fibrosis stage of 0 or 2 (n=80);
Cohort 2 included patients who were either treatment-naive or had a
prior null response with Metavir fibrosis stage of 3 or 4 (n=87). In
cohort 1, the 12-week treatment groups, SVR12 was 96% and 93% in
patients treated with or without RBV, respectively. The 24-week
treatment groups had SVR12 of 79.3% and 93% in patients treated with or
without RBV, respectively. No viral breakthrough was observed in cohort 1
during treatment, and 3 patients experienced viral relapse after
stopping therapy. All 3 patients with viral relapse were infected with
HCV genotype 1a and had the Q80K polymorphism.
Preliminary SVR4 results are available for cohort 2. The 12-week
treatment duration group had 100% SVR in treatment-naive patients
treated with or without RBV, and 100% and 93.3% in prior null responder
patients treated with or without RBV, respectively. No viral
breakthrough was observed during treatment; 1 patient infected with HCV
genotype 1a/Q80K experienced viral relapse after stopping therapy. No
SVR data are yet available from cohort 2, which received 24 weeks of
treatment.
Among patients who had viral relapse, simeprevir (protease)
resistance-associated variants have been observed; sofosbuvir
(polymerase) resistance-associated variants have not been detected.
Safety data have been presented for all 167 patients treated. The
combination was well tolerated, with only 2.4% of patients prematurely
discontinuing therapy due to adverse events. Data on the use of
simeprevir in patients with hepatic impairment are not available at this
time.
For patients infected with genotype 1a HCV, baseline resistance
testing for the Q80K polymorphism may be considered. However, in
contrast to using simeprevir to treat a genotype 1a HCV patient with
PEG/RBV when the mutation markedly alters the probability of an SVR, the
finding of the Q80K polymorphism does not preclude treatment with
simeprevir and sofosbuvir, because the SVR rate was high in patients
with genotype 1a/Q80K infection (SVR12 rate for cohort 1 was 86% [24 of
28 patients]; SVR4 rate for cohort 2 was 90% [10 of 11 patients]). To
date, virologic failure has not been observed in patients in either
cohort infected with HCV genotype 1b and with HCV genotype 1a in the
absence of the Q80K polymorphism. Thus Q80K testing can be considered
but is not strongly recommended.
This regimen should be considered only in those patients who require
immediate treatment, because it is anticipated that safer and more
effective IFN-free regimens will be available by 2015.
Alternative regimens for treatment-naive patients with HCV genotype 1 who are eligible to receive IFN.
Daily simeprevir (150 mg) for 12 weeks and weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) plus weekly PEG for 24 weeks is an acceptable regimen for IFN-eligible persons with either
-
HCV genotype 1b or
-
HCV genotype 1a infection in whom the Q80K polymorphism is not detected prior to treatment.
Rating: Class IIa, Level A
Two randomized, placebo-controlled phase 3 trials evaluated the
efficacy and safety of simeprevir (150 mg once daily) for 12 weeks plus
PEG and weight-based RBV for a total of 24 weeks (RGT design found no
advantage to extending PEG/RBV to 48 weeks). (
Jacobson, 2013a); (
Poordad, 2013)
In both studies, SVR24 rates were significantly higher among the
simeprevir-containing arms (80% to 81%) than in the
non-simeprevir-containing arms (50%). If the HCV RNA at week 4 of
treatment is less than 25 IU/mL, therapy should be continued to week 24.
If the HCV RNA is greater than 25 IU/mL at treatment week 4 or any
treatment week thereafter, the regimen should be discontinued. In
patients with HCV genotype 1a infection, the presence of a naturally
occurring NS3-4A protease polymorphism (Q80K) prior to treatment was
associated with a substantial reduction in SVR among patients treated
with simeprevir. A statistically significant difference in SVR12 rates
exists between simeprevir-treated persons who are infected with HCV
genotype 1a but do not have the Q80K polymorphism and placebo-treated
patients who likewise have no such polymorphism. This difference was
noted in both the pooled treatment-naive studies and the relapser study
(SVR rates of 84% versus 43%, respectively [treatment-naive study] and
78% versus 24%, respectively [relapse study]). The overall SVR in the
subgroup of patients with baseline Q80K polymorphism was no better than
that in the placebo group. In the United States, persons with genotype
1a HCV infection have a high prevalence of Q80K polymorphism. Because
these persons may require alternative therapy, baseline testing for Q80K
is recommended for all patients before treatment with the simeprevir
plus PEG/RBV regimen is initiated.
For the simeprevir plus PEG/RBV treatment regimen, if the HCV RNA at
week 4 of treatment is less than 25 IU/mL, therapy should be continued
to week 24. If the HCV RNA is greater than 25 IU/mL at treatment week 4
or any treatment week thereafter, the regimen should be discontinued.
Alternative regimens for treatment-naive patients with HCV genotype 1 who are not eligible to receive IFN.
Daily sofosbuvir (400 mg) and weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) for 24 weeks is an acceptable regimen for IFN-ineligible
persons with HCV genotype 1 infection, regardless of subtype; however,
preliminary data suggest that this regimen may be less effective than
daily sofosbuvir (400 mg) plus simeprevir (150 mg), particularly among
patients with cirrhosis.
Rating: Class IIb, Level B
Sofosbuvir plus RBV was evaluated in 60 treatment-naive patients with
HCV genotype 1 with unfavorable treatment characteristics (eg, African
American race and advanced fibrosis). (
Osinusi, 2013)
In part 1 of the study, 10 participants with early to moderate liver
fibrosis were treated with sofosbuvir (400 mg daily) plus weight-based
RBV for 24 weeks. Nine participants (90%) achieved SVR24. In part 2, 50
participants with any stage of liver fibrosis were randomized 1:1 to
receive 400 mg sofosbuvir with RBV either weight-based or low-dose (600
mg daily) for 24 weeks; SVR24 was 68% (17/25) in the weight-based group
and 48% (12/25) in the low-dose group. The regimens used in part 2 of
this study were well tolerated, with no discontinuations due to adverse
events. Seven of the 13 participants (54%) with advanced liver fibrosis
treated in this study relapsed, including all 4 with cirrhosis.
Several additional studies have evaluated the effectiveness of
sofosbuvir in persons with HCV genotype 1. In the QUANTUM trial, 38
treatment-naive patients with HCV genotype 1 who did not have cirrhosis
were assigned either 12 (n=19) or 24 (n=19) weeks of sofosbuvir (400 mg
daily) and weight-based RBV. (
Lalezari, 2013)
Ten of 19 (53%) in the 12-week arm and 9 of 19 (47%) subjects in the
24-week arm achieved SVR12 (overall 50%). In the ELECTRON trial, 25
treatment-naive subjects with HCV genotype 1 who did not have cirrhosis
received sofosbuvir plus RBV for 12 weeks. Twenty-one (84%) achieved
SVR12. (
Gane, 2013b)
In the PHOTON-1 trial, 86 of 113 (76%) treatment-naive subjects with
genotype 1 HCV/HIV coinfection achieved SVR12 with sofosbuvir plus RBV
for 24 weeks. (
Sulkowski, 2013c)
Taken together, in a total of 211 subjects, the range of SVR for
regimens incorporating sofosbuvir plus daily weight-based RBV (1000 mg
to 1200 mg) for up to 24 weeks in treatment-naive persons with HCV
genotype 1 was 50% to 84%, with an overall SVR of 72%. Sofosbuvir
resistance-associated amino acid variants have not been detected among
those patients treated with this combination who did not achieve SVR.
This regimen should be considered only in those patients who require
immediate treatment. It is estimated that the FDA will approve safer and
more effective IFN-free regimens by 2015.
The following regimens are NOT recommended for treatment-naive patients with HCV genotype 1.
-
PEG/RBV with or without telaprevir or boceprevir for 24 to 48 weeks
Rating: Class IIb, Level A
-
Monotherapy with PEG, RBV, or a DAA
Rating: Class III, Level A
Although regimens of PEG/RBV plus telaprevir or boceprevir for 24 to
48 weeks using RGT are also FDA approved, they are markedly inferior to
the preferred and alternative regimens. These regimens are associated
with their higher rates of serious adverse events (eg, anemia and rash),
longer treatment duration, high pill burden, numerous drug-drug
interactions, frequency of dosing, intensity of monitoring for
continuation and stopping of therapy, and the requirement to be taken
with food or with high-fat meals.
PEG/RBV for 48 weeks for treatment-naive subjects with HCV genotype 1
has been superseded by treatments incorporating DAAs and should not be
used.
II. Genotype 2
Recommended regimen for treatment-naive patients with HCV genotype 2, regardless of eligibility for IFN therapy:
Daily sofosbuvir (400 mg) and weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) for 12 weeks is recommended for treatment-naive patients with HCV genotype 2 infection.
Rating: Class I, Level A
Sofosbuvir (400 mg daily) was combined with weight-based RBV (1000 mg
to 1200 mg) to treat HCV genotype 2 treatment-naive patients across 3
clinical trials: FISSION, POSITRON, and VALENCE. (
Lawitz, 2013b); (
Jacobson, 2013c); (
Zeuzem, 2013b)
The FISSION study randomized patients to daily PEG/RBV (800 mg) for 24
weeks or sofosbuvir plus daily weight-based RBV (1000 mg to 1200 mg). (
Lawitz, 2013b)
The SVR was higher (94%) in patients who received sofosbuvir plus RBV
compared with those who received PEG/RBV (78%) (52/67). Across all 3
trials, 201 of 214 (94%) patients with HCV genotype 2 achieved SVR with
sofosbuvir plus RBV. Among patients who did not achieve SVR, sofosbuvir
resistance-associated amino acid variants were not detected. (
US FDA, 2013a)
Alternative Regimens for treatment-naive patients with genotype 2:
None
The following regimens are NOT recommended for treatment-naive patients with HCV genotype 2.
-
PEG/RBV for 24 weeks
Rating: Class IIb, Level A
-
Monotherapy with PEG, RBV, or a DAA
Rating: Class III, Level A
-
Telaprevir-, boceprevir-, or simeprevir-based regimens
Rating: Class III, Level A
PEG (2a) (180 µg weekly) or PEG (2b) (1.5 µg/kg weekly) plus RBV (800
mg daily) for 24 weeks was directly compared with sofosbuvir (400 mg
daily) plus weight-based RBV (1000 mg to 1200 mg daily) in the FISSION
trial. (
Lawitz, 2013b)
The SVR12 achieved with PEG/RBV was lower than that achieved with
sofosbuvir/RBV overall (78% and 95%, respectively) and in the subgroups
of patients with or without cirrhosis. Safety and tolerability of
PEG/RBV was inferior to the profile observed with sofosbuvir and RBV,
with greater frequency of reported adverse events and laboratory
abnormalities as well as a higher rate of treatment due to adverse
events. Further, the duration of therapy with PEG/RBV is 12 weeks longer
than that of sofosbuvir plus RBV.
Due to their poor in vitro and in vivo activity, boceprevir and
simeprevir should not be used as therapy for patients with HCV genotype 2
infection. Although telaprevir combined with PEG/RBV has antiviral
activity against HCV genotype 2, (
Foster, 2011) the additional side effects and longer duration of therapy do not support use of this regimen.
III. Genotype 3
Recommended regimen for treatment-naive patients with HCV genotype 3, regardless of eligibility for IFN therapy:
Daily sofosbuvir (400 mg) and weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) for 24 weeks is recommended for treatment-naive patients with HCV genotype 3 infection.
Rating: Class I, Level B
The VALENCE study assessed the efficacy and safety of sofosbuvir (400
mg daily) plus RBV for 24 weeks in 250 treatment-naive (42%) and
treatment-experienced (58%) subjects with HCV genotype 3 infection. The
overall SVR12 was 84% and was higher among treatment-naive than
treatment-experienced patients (93% versus 77%, respectively). These
results suggest higher response rates can be achieved with a 24-week
duration of sofosbuvir plus RBV than those reported for the 12- or
16-week durations studied in the FISSION (
Lawitz, 2013b) (12 weeks, SVR12: 63%), POSITRON, (
Jacobson, 2013c)
(12 weeks, SVR 12: 61%) and FUSION (12 weeks, SVR12: 30%, 16 weeks,
SVR12: 62%) trials. The primary reason for the higher SVR with extended
therapy among treatment-naive patients was a reduction in the relapse
rate from 40% to 5%. In sub-analysis, response rates were similarly high
among those with (n=45) and without (n=100) cirrhosis (92% and 93%,
respectively).
Alternative regimens for treatment-naive patients with genotype 3 who are eligible to receive IFN.
Daily sofosbuvir (400 mg) and weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) plus weekly PEG for 12 weeks is an acceptable regimen for IFN-eligible persons with HCV genotype 3.
Rating: Class IIa, Level A
The combination of sofosbuvir plus PEG/RBV has been evaluated in
patients with genotype 3 infection. In 2 phase 2 clinical trials, PROTON
and ELECTRON, 38 of 39 (97%) treatment-naive patients with genotype 3
infection achieved SVR with sofosbuvir plus PEG (4 to 12 weeks of
therapy)/RBV. (
Gane, 2013b)
For many patients with genotype 3, the adverse effects and increased
monitoring requirements of PEG make this less acceptable than the
recommended regimen of sofosbuvir plus weight-based RBV.
The following regimens are NOT recommended for treatment-naive patients with HCV genotype 3.
-
PEG/RBV for 24 to 48 weeks
Rating: Class IIb, Level A
-
Monotherapy with PEG, RBV, or a DAA
Rating: Class III, Level A
-
Telaprevir-, boceprevir-, or simeprevir-based regimens should not be used for patients with genotype 3 HCV infection.
Rating: Class III, Level A
Although the combination of PEG/RBV is an FDA-approved regimen for
HCV genotype 3, its less acceptable adverse effect profile, requirement
for more intensive monitoring, and overall lower efficacy make it less
desirable than the recommended regimen.
Because of their limited in vitro and in vivo activity against
genotype 3, boceprevir, telaprevir, and simeprevir should not be used as
therapy for patients with HCV genotype 3 infection.
IV. Genotype 4
Few data are available to help guide decision-making in patients
infected with HCV genotype 4. Nonetheless, for those patients for whom
immediate treatment is required, the following recommendations have been
drawn from available data.
Recommended regimen for treatment-naive patients with HCV genotype 4 who are eligible to receive IFN.
Daily sofosbuvir (400 mg) and weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) plus weekly PEG for 12 weeks is recommended for IFN-eligible persons with HCV genotype 4 infection.
Rating: Class IIa, Level B
In the Phase 3 NEUTRINO trial, (
Lawitz, 2013b)
28 treatment-naive patients with HCV genotype 4 infection were treated
with sofosbuvir (400 mg daily) plus PEG (2a) (180 µg weekly) and
weight-based RBV (1000 mg 1200 mg once daily) for 12 weeks. Of the 28
patients with genotype 4, 27 (96%) achieved SVR12. The one patient who
did not achieve SVR had cirrhosis and relapsed after therapy. The
adverse event profile was similar to that seen with PEG/RBV therapy.
Recommended regimen for treatment-naive patients with genotype 4 who are not eligible to receive IFN.
Daily sofosbuvir (400 mg) plus weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) for 24 weeks is recommended for IFN-ineligible patients with HCV genotype 4 infection.
Rating: Class IIb, Level B
In a small study of Egyptian patients in the United States treated
with sofosbuvir plus weight-based RBV (1000 mg to 1200 mg), SVR12 was
achieved in 11/14 (79%) and 14/14 (100%) in treatment-naive patients
treated for 12 weeks and 24 weeks, respectively. In
treatment-experienced patients treated for 12 weeks and 24 weeks, SVR12
was achieved in 10/17 (59%) and 13/15 (87%), respectively. (
Ruane, 2014)
Alternative regimens for treatment-naive patients with HCV genotype 4 who are eligible to receive IFN.
Daily simeprevir (150 mg) for 12 weeks and weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) plus weekly PEG for 24 to 48 weeks is an alternative regimen for IFN-eligible persons with HCV genotype 4 infection.
Rating: Class IIb, Level B
A Phase 3 trial in patients with HCV genotype 4 is currently under
way. This trial compares PEG and weight-based RBV (1000 mg to 1200 mg)
for 48 weeks with a 12-week regimen of simeprevir 150 mg once daily plus
PEG and weight-based RBV (1000 mg to 1200 mg) followed by an additional
12 or 36 weeks of PEG/RBV alone. (
Moreno, 2013)
In another study, the RESTORE trial, an RGT approach is used in place
of the simeprevir arm. Patients who have HCV RNA below 25 IU/mL at week 4
and undetectable HCV RNA by week 12 continue PEG/RBV for an additional
12 weeks, and those who do not achieve this response continue PEG/RBV
for an additional 36 weeks (total 48 weeks of therapy). The study has
enrolled 107 patients, of whom 35 are treatment-naive, including 2 with
cirrhosis. To date, 10 of 11 patients (91%) who met criteria for
shortened therapy have achieved SVR4, and 3 of 3 have achieved SVR12. To
date, therapy has failed in 4 patients: 3 had detectable virus at the
end of treatment and 1 experienced virologic relapse. Anemia was
reported in 8.4% and hyperbilirubinemia in 1.9% of all study
participants (n=107) (including treatment-experienced patients). Four
serious adverse events were attributed to simeprevir. No episodes of
rash were reported. (
Moreno, 2013)
The following regimens are NOT recommended for treatment-naive patients with HCV genotype 4.
-
PEG/RBV for 48 weeks
Rating: Class IIb, Level A
-
Monotherapy with PEG, RBV, or a DAA
Rating: Class III, Level A
-
Telaprevir- or boceprevir-based regimens
Rating: Class III, Level A
PEG/RBV for 48 weeks was the previously recommended regimen for
patients with HCV genotype 4. The addition of sofosbuvir (400 mg daily)
to PEG/RBV increases response rates and markedly shortens therapy with
no apparent additional adverse effects. The addition of simeprevir to
PEG/RBV increases response rates with a minimal increase in adverse
events and can shorten therapy to 24 weeks.
Because of their limited in vitro and in vivo activity against
genotype 4, boceprevir or telaprevir should not be used as therapy for
patients with HCV genotype 4 infection.
V. Genotype 5 or 6
Few data are available to help guide decision-making in patients
infected with HCV genotype 5 or 6. Nonetheless, for those patients for
whom immediate treatment is required, the following recommendations have
been drawn from available data. No data are available to support the
use of a non-PEG containing regimen for patients with HCV genotype 5 or 6
infection.
Recommended regimen for treatment-naive patients with HCV genotype 5 or 6.
Daily sofosbuvir (400 mg) and weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) plus weekly PEG for 12 weeks is recommended for IFN-eligible persons with HCV genotype 5 or 6 infection.
Rating: Class IIa, Level B
In the Phase 3 NEUTRINO trial (
Lawitz, 2013b),
treatment-naive patients with genotypes 1 (n=291), 4 (n=28), 5 (n=1),
and 6 (n=6) were treated with sofosbuvir (400 mg daily) plus PEG (2a)
(180 µg per week) and weight-based RBV (1000 mg 1200 mg once daily) for
12 weeks. All 6 patients with HCV genotype 6 and the 1 patient with
genotype 5 achieved SVR12. The adverse event profile in these patients
and in the larger study population was similar to that seen with PEG/RBV
therapy.
Alternative regimens for treatment-naive patients with HCV genotype 5 or 6.
Daily weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) plus weekly PEG for 48 weeks is an acceptable regimen for persons infected with HCV genotype 5 or 6.
Rating: Class IIb, Level A
PEG/RBV for 48 weeks was the previously recommended regimen for
patients infected with HCV genotype 5 or 6. Sofosbuvir has activity
against genotypes 5 and 6, and when combined with PEG/RBV for 12 weeks
led to SVR in the 6 patients in whom it was studied. (
Lawitz, 2013b)
The addition of sofosbuvir (400 mg daily) to PEG/RBV shortens duration
of therapy with no apparent additional adverse effects and likely
substantially increases response rates.
