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INITIAL TREATMENT OF HCV INFECTION

Initial treatment of HCV infection includes patients with chronic hepatitis C who have not been previously
treated with IFN, PEG-IFN, ribavirin, or any HCV direct-acting antiviral (DAA) agent, whether
experimental, investigational, or US Food and Drug Administration (FDA) approved.

Expansions and notes for abbreviations used in this section can be found in Methods Table 3.

A summary of recommendations for initial treatment is found in the BOX.

The level of evidence available to inform the best regimen for each patient and the strength of the
recommendation vary, and are rated accordingly. (see Methods Table 2) In addition, specific
recommendations are given when treatment differs for a particular group (eg, those infected with various
genotypes). Recommended regimens are those that are favored for most patients in that subgroup,
based on optimal efficacy, favorable tolerability and toxicity profiles, and duration. Alternative regimens
are those that are effective but have, relative to Recommended regimens, potential disadvantages,
limitations for use in certain patient populations, or less supporting data than Recommended regimens.
In certain situations, an Alternative regimen may be an optimal regimen for a specific patient situation.
Not Recommended regimens are clearly inferior compared to Recommended or Alternative regimens
due to factors such as lower efficacy, unfavorable tolerability and toxicity, longer duration, and/or higher
pill burden. Unless otherwise indicated, such regimens should not be administered to patients with HCV
infection. Specific considerations of persons with HIV/HCV coinfection, decompensated cirrhosis
(moderate or severe hepatic impairment; Child Turcotte Pugh [CTP] class B or C), HCV infection post-liver
transplant, and those with severe renal impairment or end-stage renal disease (ESRD) are addressed in
other sections of the Guidance.

Recommended and Alternative regimens are listed in order of level of evidence. When several regimens
are offered at the same recommendation level, they are listed in alphabetical order. Choice of regimen
should be determined based on patient-specific data, including drug interactions. As always, patients
receiving antiviral therapy require careful pretreatment assessment for comorbidities that may influence
treatment response. All patients should have careful monitoring during treatment, particularly for anemia
if ribavirin is included in the regimen. (See Monitoring Section)
I. Genotype 1

Six highly potent DAA oral combination regimens are Recommended for patients with HCV genotype 1
infection, although there are differences in the Recommended regimens based on the HCV subtype, the
presence or absence of baseline NS5A resistance-associated variants (RAVs), and the presence or
absence of cirrhosis. With certain regimens, patients infected with genotype 1a may have higher rates of
virologic failure than those infected with genotype 1b. HCV genotype 1 infection that cannot be subtyped
should be treated as genotype 1a infection.

Approximately 10-15% of HCV genotype 1-infected patients without prior exposure to NS5A inhibitors will
have detectable HCV NS5A RAVs at the population level prior to treatment. While the clinical impact of
NS5A RAVs remains to be fully elucidated, in patients with genotype 1a infection the presence of baseline
NS5A RAVs that cause a large reduction in the activity of NS5A inhibitors (>5 fold) adversely impact
response to NS5A-containing regimens. (Zeuzem, 2015b); (Jacobson, 2015b) These RAVs include variants
at positions M28, Q30, L31, and Y93 in genotype 1a and are found by population sequencing in roughly
5-10% of patients. Given that baseline NS5A RAVs are one of the strongest pre-treatment predictors of
treatment outcome with certain regimens, testing for these RAVs prior to deciding on a therapeutic
course is now recommended in select situations. (Zeuzem, 2015c)

The introduction of DAAs into HCV treatment regimens increased the risk of drug interactions with
concomitant medications, and now with combinations of DAAs, attention to drug interactions is all the
more important. (see Drug Interactions Table) The product prescribing information and other resources
(eg, http://www.hep-druginteractions.org) should be referenced regularly to ensure safety when
prescribing DAA regimens. Important interactions with commonly used medications (eg, antacids, lipid-
lowering drugs, anti-epileptics, antiretrovirals, etc) exist for all of the regimens discussed below.

A. Genotype 1a

Genotype 1a Treatment-Naïve Patients Without Cirrhosis - Recommended

Recommended regimens are listed in groups by level of evidence, then alphabetically.

■ Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) for 12 weeks is a
Recommended regimen for treatment-naïve patients with HCV genotype 1a infection who
do not have cirrhosis and in whom no baseline NS5A RAVs§ for elbasvir are detected.
Rating: Class I, Level A

■ Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks is a
Recommended regimen for treatment-naïve patients with HCV genotype 1a infection who
do not have cirrhosis.
Rating: Class I, Level A

■ Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25

mg) plus twice-daily dosed dasabuvir (250 mg) with weight-based ribavirin for 12 weeks is
a Recommended regimen for treatment-naïve patients with HCV genotype 1a infection who
do not have cirrhosis.
 Rating: Class I, Level A

■ Daily simeprevir (150 mg) plus sofosbuvir (400 mg) for 12 weeks is a Recommended
regimen for treatment-naïve patients with HCV genotype 1a infection who do not have
cirrhosis.
Rating: Class I, Level A

■ Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks is a
Recommended regimen for treatment-naïve patients with HCV genotype 1a infection who
do not have cirrhosis.
Rating: Class I, Level A

■ Daily daclatasvir (60 mg*) plus sofosbuvir (400 mg) for 12 weeks is a Recommended
regimen for treatment-naïve patients with HCV genotype 1a infection who do not have
cirrhosis.
Rating: Class I, Level B

§
Includes G1a polymorphisms at amino acid positions 28, 30, 31, or 93. Amino acid substitutions
that confer resistance.
*The dose of daclatasvir may need to increase or decrease when used concomitantly with
cytochrome P450 3A/4 inducers and inhibitors, respectively. Please refer to the prescribing
information and the section on HIV/HCV coinfection for patients on antiretroviral therapy.

Genotype 1a Treatment-Naïve Patients with Compensated Cirrhosis‡ -

Recommended
Recommended regimens are listed in groups by level of evidence, then alphabetically.

■ Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) for 12 weeks is a
Recommended regimen for treatment-naïve patients with HCV genotype 1a infection who
have compensated cirrhosis and in whom no baseline NS5A RAVs§ for elbasvir are detected.
Rating: Class I, Level A

■ Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks is a
Recommended regimen for treatment-naïve patients with HCV genotype 1a infection who
have compensated cirrhosis.
Rating: Class I, Level A

■ Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks is a
Recommended regimen for treatment-naïve patients with HCV genotype 1a infection who
have compensated cirrhosis.
Rating: Class I, Level A

‡
For decompensated cirrhosis, please refer to the appropriate section.
§
Includes G1a polymorphisms at amino acid positions 28, 30, 31, or 93. Amino acid substitutions
that confer resistance.
Genotype 1a Treatment-Naïve Patients Without Cirrhosis - Alternative

■ Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) with weight-based
ribavirin for 16 weeks is an Alternative regimen for patients with HCV genotype 1a
infection who do not have cirrhosis but have baseline NS5A RAVs§ for elbasvir.
Rating: Class IIa, Level B

§
Includes G1a polymorphisms at amino acid positions 28, 30, 31, or 93. Amino acid substitutions
that confer resistance.

‡
Genotype 1a Treatment-Naïve Patients with Compensated Cirrhosis - Alternative
Alternative regimens are listed in groups by level of evidence, then alphabetically.

■ Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25

mg) plus twice-daily dosed dasabuvir (250 mg) with weight-based ribavirin for 24 weeks is
an Alternative regimen for treatment-naïve patients with HCV genotype 1a infection who
have compensated cirrhosis.†
Rating: Class I, Level A

■ Daily simeprevir (150 mg) plus sofosbuvir (400 mg) with or without weight-based ribavirin
for 24 weeks is an Alternative regimen for treatment-naïve patients with HCV genotype 1a
infection who have compensated cirrhosis and in whom no Q80K polymorphism is detected.
Rating: Class II, Level B

■ Daily daclatasvir (60 mg*) plus sofosbuvir (400 mg) with or without weight-based ribavirin
for 24 weeks is an Alternative regimen for treatment-naïve patients with HCV genotype 1a
infection who have compensated cirrhosis.
Rating: Class IIa, Level B

■ Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) with weight-based
ribavirin for 16 weeks is an Alternative regimen for treatment-naïve patients with HCV
genotype 1a infection who have compensated cirrhosis and have baseline NS5A RAVs§ for
elbasvir.
Rating: Class IIa, Level B

For decompensated cirrhosis, please refer to the appropriate section.

†
Please see statement on FDA warning regarding the use of PrOD or PrO in patients with cirrhosis.
* The dose of daclatasvir may need to increase or decrease when used concomitantly with
cytochrome P450 3A/4 inducers and inhibitors, respectively. Please refer to the prescribing
information and the section on HIV/HCV coinfection for patients on antiretroviral therapy.
§
Includes G1a polymorphisms at amino acid positions 28, 30, 31, or 93. Amino acid substitutions
that confer resistance.
For HCV genotype 1a-infected, treatment-naïve patients without cirrhosis, there are six regimens
recommended based on comparable efficacy, as outlined above. For cirrhotic patients, some are
classified as Alternative regimens because compared to the Recommended, they have longer duration,
potentially reduced efficacy, and/or limited supporting data.

Elbasvir/grazoprevir

The fixed-dose combination of elbasvir (50 mg) and grazoprevir (100 mg) (hereafter elbasvir/grazoprevir)
can be recommended based on data from the phase III C-EDGE trial, which assessed the efficacy and
safety of elbasvir/grazoprevir for 12 weeks in treatment-naïve adults (genotypes 1, 4, and 6). (Zeuzem,
2015) Patients were enrolled from 60 centers in 9 countries on 4 continents. Three hundred and eighty-
two patients (91% of study cohort) receiving 12 weeks of elbasvir/grazoprevir were infected with
genotype 1 (50% genotype 1a, 41% genotype 1b). The sustained virologic response rate at 12 weeks
(SVR12 ) was 92% in treatment-naïve patients with HCV genotype 1a infection (144/157) and 99% in
genotype 1b (129/131) patients receiving 12 weeks of elbasvir/grazoprevir. Findings from this phase III
study supported earlier phase II findings from the C-WORTHY trial in which SVR12 rates of 92% (48/52)
and 95% (21/22) were demonstrated among genotype 1a and genotype 1b treatment-naïve non-cirrhotic
HCV-infected patients respectively, who received 12 weeks of elbasvir/grazoprevir without ribavirin.
(Sulkowski, 2015b) The C-WORTHY trial enrolled both HCV-monoinfected and HIV/HCV-coinfected
patients. Recommendations for cirrhotic patients are based on 92 (22%) patients in the phase III C-EDGE
trial who had Metavir F4 disease. (Zeuzem, 2015) SVR12 was 97% in the subgroup of cirrhotic patients. A
similar 97% (28/29) SVR12 rate had previously been demonstrated in genotype 1 cirrhotic treatment-
naïve patients treated with 12 weeks of elbasvir/grazoprevir without ribavirin in the open-label phase II C-
WORTHY trial. (Lawitz, 2015c) Presence or absence of compensated cirrhosis does not appear to alter the
efficacy of the elbasvir/grazoprevir regimen. (Lawitz, 2015c); (Zeuzem, 2015)

Presence of certain baseline NS5A RAVs significantly reduces rates of SVR12 with a 12-week course of
the elbasvir/grazoprevir regimen in genotype 1a-infected patients. (Zeuzem, 2015) NS5A RAVs were
identified at baseline in 12% (19/154) of genotype 1a-infected patients enrolled in the C-EDGE study of
which 58% (11/19) achieved SVR12 compared to an SVR12 rate of 99% (133/135) in patients without
these RAVs receiving 12 weeks of elbasvir/grazoprevir. (Zeuzem, 2015) Among treatment-naïve patients,
the presence of baseline NS5A RAVs with a larger than 5-fold shift to elbasvir was associated with the
most significant reductions in SVR12 with only 22% (2/9) of genotype 1a patients with these RAVs
achieving SVR12. Recommendations for prolonging duration of treatment to 16 weeks with inclusion of
ribavirin for treatment-naïve genotype 1a patients with baseline NS5A RAVs is based on extrapolation of
data from the C-EDGE TE trial. In this phase III open-label trial of elbasvir/grazoprevir that enrolled
treatment-experienced patients, among 58 genotype 1a patients who received 16 weeks of therapy with
elbasvir/grazoprevir plus ribavirin, there were no virologic failures. (Kwo, 2015)

Subsequent integrated analysis of the elbasvir/grazoprevir phase II and III trials have demonstrated
SVR12 rates of 100% (6 of 6 patients) in genotype 1 patients with pre-treatments NS5A RAVs treated
with elbasvir/grazoprevir for 16/18 weeks plus ribavirin. (Jacobson, 2015b); (Thompson, 2015) Based on
known inferior response in patients with presence of baseline NS5A RAVs, NS5A resistance testing is
recommended in genotype 1a patients who are being considered for therapy with elbasvir/grazoprevir. If
baseline RAVs are present, ie, polymorphisms at amino acid positions 28, 30, 31, or 93, treatment
extension to 16 weeks with the addition of weight-based ribavirin (1000 mg [<75 kg] to 1200 mg [≥ 75
kg]) is recommended to decrease relapse.

Lack of RAV testing results or lack of access to RAV testing should not be used as a means to limit access
to HCV therapy.

Ledipasvir/sofosbuvir

The fixed-dose combination of ledipasvir (90 mg) and sofosbuvir (400 mg) (hereafter,
ledipasvir/sofosbuvir) was approved by the FDA for the treatment of HCV genotype 1 infection in
treatment-naïve patients based on two registration trials: ION-1 (865 treatment-naïve patients; those
with cirrhosis were included) and ION-3 (647 treatment-naïve patients; those with cirrhosis were
excluded). ION-1 investigated length of treatment (12 weeks vs 24 weeks) and the need for ribavirin.
(Afdhal, 2014a) SVR12 was 97% to 99% across all arms, with no difference in SVR based on length of
treatment, use of ribavirin, or HCV genotype 1 subtype. Sixteen percent of subjects enrolled were
classified as having cirrhosis. There was no difference in SVR12 rate in those with cirrhosis (97%) versus
those without cirrhosis (98%). ION-3 excluded patients with cirrhosis and investigated shortening therapy
from 12 weeks to 8 weeks (with or without ribavirin). (Kowdley, 2014) SVR12 rate was 93% to 95% across
all arms, with no difference in SVR in the intention-to-treat analysis. However, relapse rates were higher
in the 8-week arms (20 of 431) regardless of ribavirin use compared with the 12-week arm (3 of 216).
Post-hoc analyses of the 2 ribavirin-free arms assessed baseline predictors of relapse and identified lower
relapse rates in patients receiving 8 weeks of ledipasvir/sofosbuvir who had baseline HCV RNA levels
below 6 million IU/mL (2%; 2 of 123), and was the same for patients with similar baseline HCV RNA levels
who received 12 weeks (2%; 2 of 131). This analysis was not controlled and thus limits the
generalizability of this approach to clinical practice. Preliminary real-world (non-randomized) cohort data
show conflicting results on the comparable effectiveness of 8 and 12 weeks in treatment-naïve patients
without cirrhosis. Based on available data, shortening treatment to less than 12 weeks is Not
Recommended for HIV-infected patients (see HIV/HCV coinfection section), African-American patients, or
those with known IL28B polymorphism CT or TT. (Wilder, 2016); (O'Brien, 2014) For others, it should be
done at the discretion of the practitioner.

Paritaprevir/ritonavir/ombitasvir + dasabuvir

The daily fixed-dose combination of paritaprevir (150 mg), ritonavir (100 mg), and ombitasvir (25 mg)
plus twice-daily dosed dasabuvir (250 mg) (PrOD) plus weight-based ribavirin was approved by the FDA
for the treatment of HCV genotype 1a infection in treatment-naïve patients based on three registration
trials: SAPPHIRE-I (322 treatment-naïve patients with genotype 1a HCV infection without cirrhosis),
PEARL-IV (305 treatment-naïve patients with genotype 1a without cirrhosis), and TURQUOISE-II (261
treatment-naïve and -experienced patients with HCV genotype 1a and cirrhosis). The SAPPHIRE-I trial
reported a high SVR12 rate (95.3%) with 12 weeks of PrOD and ribavirin. (Feld, 2014) Overall, virologic
failure was higher for patients with HCV genotype 1a (7 of 8 failures had genotype 1a) than patients with
HCV genotype 1b (1 virologic failure). PEARL-IV was specifically designed to determine the role of PrOD
with or without weight-based ribavirin for treatment-naïve, HCV genotype 1a-infected patients without
cirrhosis. (Ferenci, 2014) SVR12 was lower in the ribavirin-free arm than in the ribavirin-containing arm
(90% vs 97%, respectively) owing to higher rates of virologic failure (7.8% vs 2%, respectively),
confirming the need for weight-based ribavirin for patients with HCV genotype 1a. TURQUOISE-II enrolled
treatment-naïve and -experienced patients (261 patients with HCV genotype 1a) with CTP class A
cirrhosis to receive either 12 weeks or 24 weeks of treatment with PrOD plus ribavirin. Overall, SVR12
rates were 89% in the 12-week arm and 95% in the 24-week arm. (Poordad, 2014) This difference in
SVR12 rate between arms was primarily driven by patients with null response to PEG-IFN/ribavirin; there
was less difference in SVR rates in the patients with cirrhosis who were naïve to therapy (92% and 95%,
respectively). (paritaprevir/ritonavir/ombitasvir prescribing information); (Poordad, 2014)

In October 2015, the FDA released a warning regarding the use of the PrOD or PrO (without dasabuvir) in
patients with cirrhosis. (This statement is based on our review of the limited data available from the FDA
and will be updated if and when more data become available.) PrOD and PrO are contraindicated in
patients with Child Turcotte Pugh (CTP) class B or C hepatic impairment (decompensated liver disease).
The manufacturer’s pharmacovigilance program reported rapid onset of liver injury and in some cases
hepatic decompensation in patients with cirrhosis, including CTP class A compensated cirrhosis and
decompensated cirrhosis, who were receiving PrOD or PrO. The liver injury and decompensating events
occurred largely during the first 4 weeks of therapy and primarily involved a rapid increase in total and
direct bilirubin, often associated with a concomitant increase in liver enzyme levels. In most cases, early
recognition and prompt discontinuation of PrOD or PrO resulted in resolution of injury, although some
patients, including at least 2 patients with CTP class A compensated cirrhosis, died or required liver
transplantation. Although cirrhosis carries a 2% to 4% annual risk of hepatic decompensation, the rapid
onset of hepatic decompensation and in many cases its resolution with discontinuation of treatment with
PrOD or PrO is suggestive of drug-induced liver injury. Although PrOD and PrO are contraindicated in
patients with CTP class B or C cirrhosis and decompensated liver disease, predictors of these events in
patients with CTP class A cirrhosis are currently unclear.

For patients with CTP class A cirrhosis, the unlikely but real possibility of drug-induced liver injury should
be discussed with the patient. If the decision is made to initiate treatment with PrOD or PrO, close
monitoring of total and direct bilirubin and transaminase levels every 1 week or 2 weeks for the first 4
weeks is recommended to ensure early detection of drug-induced liver injury. Also, educating patients
about the importance of reporting systemic symptoms such as jaundice, weakness, and fatigue is
strongly recommended. The regimen should be discontinued immediately if drug-induced liver injury is
detected. If a patient is already taking PrOD or PrO and is tolerating the regimen, laboratory monitoring
as above without discontinuation is recommended unless there are signs or symptoms of liver injury. If
heightened monitoring cannot be provided in the first 4 weeks of therapy with PrOD or PrO in patients
with cirrhosis, the use of these regimens is not recommended.

Simeprevir + sofosbuvir

The OPTIMIST-1 and -2 trials investigated the safety and efficacy of simeprevir (150 mg) and sofosbuvir
(400 mg) in chronically infected patients with HCV genotype 1 without and with cirrhosis, respectively. In
the OPTIMIST-1 study, 310 treatment-naïve and -experienced patients without cirrhosis were randomly
assigned to 12 versus 8 weeks of the simeprevir plus sofosbuvir regimen. (Kwo, 2016) The overall SVR12
rate was 97% (150/155) versus 83% (128/155), respectively, with a statistically significantly greater
relapse rate in the 8-week arm. In the 12-week arm there was no difference in SVR12; treatment-naïve
and -experienced patients achieved SVR12 rates of 97% and 95%, respectively. There was also no
difference in SVR12 based on genotype 1 subtype or presence of the baseline Q80K resistance mutation.
A post-hoc analysis suggested that patients with a baseline HCV RNA level below 4 million IU/mL
achieved the same SVR12 rate (96%) regardless of the length of treatment. This defined baseline HCV
RNA level is different than the 6 million IU/mL defined in the ION-3 trial, suggesting these post-hoc
analysis cut-offs are arbitrary and unlikely to translate to clinical practice. At this time an 8-week regimen
of simeprevir and sofosbuvir cannot be recommended.
The OPTIMIST-2 study was a single arm, open-label trial investigating 12 weeks of simeprevir plus
sofosbuvir in 103 treatment-naïve and -experienced patients with cirrhosis. (Lawitz, 2015) The overall
SVR12 rate was 83% (86/103), with 88% (44/50) of treatment-naïve and 79% (42/53) of treatment-
experienced patients achieving SVR12. In addition, patients infected with HCV genotype 1a and 1b
without the Q80K mutation had similar SVR12 rates (84% [26/31] and 92% [35/38], respectively).
However, patients with HCV genotype 1a infection and the Q80K mutation had lower SVR12 rates (74%
[25/34]). Thus, extending treatment to 24 weeks, with or without ribavirin, is recommended for patients
with cirrhosis receiving simeprevir plus sofosbuvir to decrease the risk of relapse. At this time it is
unclear whether extending treatment, with or without the addition of ribavirin, will increase efficacy in
genotype 1a-infected patients with the Q80K mutation. Given the lower response rate in patients with
cirrhosis, it is reasonable to avoid this regimen in patients with this baseline mutation.

Sofosbuvir/velpatasvir

The fixed-dose combination of 12 weeks of sofosbuvir (400 mg) and velpatasvir (100 mg) (hereafter,
sofosbuvir/velpatasvir) was approved by the FDA for the treatment of HCV genotype 1 infection in
treatment-naïve patients based on ASTRAL-1, a placebo-controlled trial that gave 12 weeks of
sofosbuvir/velpatasvir to 624 participants with HCV genotypes 1, 2, 4, 5, and 6 who were treatment-naïve
(n=423) or previously treated (n=201) with interferon-based therapy with or without ribavirin or a
protease inhibitor. (Feld, 2015) Of the 328 genotype 1 patients included, 323 achieved SVR with no
difference in SVR observed by HCV genotype (98% 1a and 99% 1b). Of 121 participants (all genotypes)
classified as having cirrhosis, 120 achieved SVR (99%). The presence of baseline NS5A resistance-
associated variants (at 15% cut off), reported in 11% of genotype 1a and 18% of genotype 1b participant
samples tested, did not influence SVR rate for genotype 1. (Hezode, 2016) Of the 2 virologic failures in
ASTRAL-1 (<1% of treated participants), both were genotype 1 and had baseline RAVs present. There
was no significant difference in the rates of adverse events in the sofosbuvir/velpatasvir group and the
placebo group.

Daclatasvir + sofosbuvir

Daclatasvir in combination with sofosbuvir for the treatment of HCV genotype 1 infection can be
recommended based on data from the phase III ALLY-2 trial, which assessed the efficacy and safety of
daclatasvir and sofosbuvir for 12 weeks in patients coinfected with HIV and HCV (genotypes 1-4). (Wyles,
2015) One hundred twenty-three (83%) patients receiving 12 weeks of therapy in the trial were infected
with HCV genotype 1. Eighty-three (54%) of these patients were treatment-naïve. The sustained virologic
response (SVR) rate was 96% in treatment-naïve patients with HCV genotype 1a infection (n=71)
receiving 12 weeks of therapy. However, only 9 treatment-naïve patients had cirrhosis. Similarly, in the
phase IIb study of daclatasvir and sofosbuvir (A1444040) in 88 treatment-naïve patients with HCV
genotype 1a infection, 21 were treated for 24 weeks (11 with ribavirin) and 67 were treated for 12 weeks
(33 with ribavirin), and there were no virologic relapses. However, there were only 14 patients with
cirrhosis in the 12-week and 24-week study arms. (Sulkowski, 2014a) Because patients with cirrhosis
were not adequately represented in these studies, the optimal duration of treatment for patients with
cirrhosis remains unclear. Cohort studies of a compassionate-use program in Europe suggest that
patients with cirrhosis may benefit from extension of therapy with daclatasvir and sofosbuvir to 24
weeks, with or without ribavirin. (Welzel, 2015); (de Ledinghen, 2015) The phase III ALLY-1 trial
investigated daclatasvir and sofosbuvir with ribavirin (initial dose of 600 mg, then titrated) in 60 patients
with advanced cirrhosis. (Poordad, 2016) Only 76% of patients with HCV genotype 1a (n=34) and 100%
of patients with HCV genotype 1b (n=11) achieved an SVR at 12 weeks (SVR12). It is unclear how many
treatment failures were among treatment-naïve patients or those with CTP class A cirrhosis. More data
are needed; however, owing to the risk of the emergence of resistance to nonstructural protein 5A
(NS5A) inhibitor treatment at the time of failure, extending treatment to 24 weeks for all patients with
HCV genotype 1a infection and cirrhosis is recommended, and the addition of ribavirin may be
considered. In patients with favorable characteristics, a 12-week treatment course that includes weight-
based ribavirin (1000 mg [<75 kg] to 1200 mg [≥75 kg]) may be considered but is supported by limited
data.

The safety profiles of all the Recommended regimens above are excellent. Across numerous phase III
programs, less than 1% of patients without cirrhosis discontinued treatment early and adverse events
were mild. Most adverse events occurred in ribavirin-containing arms. Discontinuation rates were higher
for patients with cirrhosis (approximately 2% for some trials) but still very low.

B. Genotype 1b

Genotype 1b Treatment-Naïve Patients Without Cirrhosis - Recommended

Recommended regimens are listed in groups by level of evidence, then alphabetically.

■ Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) for 12 weeks is a
Recommended regimen for treatment-naïve patients with HCV genotype 1b infection who
do not have cirrhosis.
Rating: Class I, Level A

■ Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks is a
Recommended regimen for treatment-naïve patients with HCV genotype 1b infection who
do not have cirrhosis.
Rating: Class I, Level A

■ Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25

mg) plus twice-daily dosed dasabuvir (250 mg) for 12 weeks is a Recommended regimen for
treatment-naïve patients with HCV genotype 1b infection who do not have cirrhosis.
Rating: Class I, Level A

■ Daily simeprevir (150 mg) plus sofosbuvir (400 mg) for 12 weeks is a Recommended
regimen for treatment-naïve patients with HCV genotype 1b infection who do not have
cirrhosis.
Rating: Class I, Level A

■ Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks is a
Recommended regimen for treatment-naïve patients with HCV genotype 1b infection who
do not have cirrhosis.
Rating: Class I, Level A

■ Daily daclatasvir (60 mg*) plus sofosbuvir (400 mg) for 12 weeks is a Recommended
regimen for treatment-naïve patients with HCV genotype 1b infection who do not have
 cirrhosis.
Rating: Class I, Level B

*The dose of daclatasvir may need to increase or decrease when used concomitantly with
cytochrome P450 3A/4 inducers and inhibitors, respectively. Please refer to the prescribing
information and the section on HIV/HCV coinfection for patients on antiretroviral therapy.

Genotype 1b Treatment-Naïve Patients with Compensated Cirrhosis‡-

Recommended
Recommended regimens are listed in groups by level of evidence, then alphabetically.

■ Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) for 12 weeks is a
Recommended regimen for treatment-naïve patients with HCV genotype 1b infection who
have compensated cirrhosis.
Rating: Class I, Level A

■ Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks is a
Recommended regimen for treatment-naïve patients with HCV genotype 1b infection who
have compensated cirrhosis.
Rating: Class I, Level A

■ Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25

mg) plus twice-daily dosed dasabuvir (250 mg) for 12 weeks is a Recommended regimen for
treatment-naïve patients with HCV genotype 1b infection who have compensated cirrhosis.†
Rating: Class I, Level A

■ Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks is a
Recommended regimen for treatment-naïve patients with HCV genotype 1b infection who
have compensated cirrhosis.
Rating: Class I, Level A

For decompensated cirrhosis, please refer to the appropriate section.

†
Please see statement on FDA warning regarding the use of PrOD or PrO in patients with cirrhosis.

Genotype 1b Treatment-Naïve Patients with Compensated Cirrhosis‡- Alternative

Alternative regimens are listed in groups by level of evidence, then alphabetically.

■ Daily daclatasvir (60 mg*) plus sofosbuvir (400 mg) with or without weight-based ribavirin
for 24 weeks is an Alternative regimen for treatment-naïve patients with HCV genotype 1b
infection who have compensated cirrhosis.
Rating: Class IIa, Level B

■ Daily simeprevir (150 mg) plus sofosbuvir (400 mg) with or without weight-based ribavirin
 for 24 weeks is an Alternative regimen for treatment-naïve patients with HCV genotype 1b
infection who have compensated cirrhosis.
Rating: Class IIa, Level B

For decompensated cirrhosis, please refer to the appropriate section.

* The dose of daclatasvir may need to increase or decrease when used concomitantly with
cytochrome P450 3A/4 inducers and inhibitors, respectively. Please refer to the prescribing
information and the section on HIV/HCV coinfection for patients on antiretroviral therapy.

For HCV genotype 1b-infected, treatment-naïve patients without cirrhosis, there are six regimens of
comparable efficacy, as outlined above. For cirrhotic patients, some are classified as Alternative
regimens, because compared to the Recommended, they have longer duration, potentially reduced
efficacy, and/or limited supporting data.

There are no significant differences demonstrated to date in treatment responses to daclatasvir and
sofosbuvir, ledipasvir/sofosbuvir, or sofosbuvir/velpatasvir for HCV genotype 1 subtypes, thus the
supporting evidence remains the same as for HCV genotype 1b-infected patients (see Genotype 1). In the
ALLY-2 arm of daclatasvir and sofosbuvir for 12 weeks in treatment-naïve patients, only 12 were
genotype 1b and all achieved SVR12. (Wyles, 2015) Furthermore, in the ALLY-1 study all 11 genotype 1b-
infected patients with advanced cirrhosis achieved SVR12. Due to the limited numbers of genotype 1b
patients represented in the phase III trials of this regimen, there is not enough evidence to support a
different approach by subtype at this time.

For elbasvir/grazoprevir, 99% of genotype 1b (129/131) patients receiving 12 weeks achieved SVR in the
phase III C-EDGE trial. (Zeuzem, 2015c) In contrast to genotype 1a, the presence of baseline
polymorphisms associated with NS5A resistance did not appear to affect response to
elbasvir/grazoprevir. Thus, current data do not support extending the duration or adding ribavirin in
genotype 1b patients with NS5A resistance-associated variants. PrOD (plus ribavirin for those with
cirrhosis) was approved by the FDA for the treatment of HCV genotype 1b infection in treatment-naïve
patients based on three registration trials: SAPPHIRE-I (151 treatment-naïve patients with HCV genotype
1b and without cirrhosis), PEARL-III (419 treatment-naïve patients, all with genotype 1b and without
cirrhosis), and TURQUOISE-II (119 treatment-naïve and -experienced patients with genotype 1b with
cirrhosis). SAPPHIRE-I reported a high SVR12 rate (98%) with 12 weeks of PrOD and ribavirin in patients
with HCV genotype 1b. (Feld, 2014) Given the high SVR12 rates seen in SAPPHIRE-I, PEARL-III was
specifically designed to determine the role of weight-based ribavirin with PrOD in treatment-naïve
patients with HCV genotype 1b without cirrhosis. (Ferenci, 2014) SVR12 rate was 99% in both arms,
confirming that there is no added benefit from the use of weight-based ribavirin for patients without
cirrhosis who have HCV genotype 1b infection. TURQUOISE-II enrolled treatment-naïve and -experienced
patients with CTP class A cirrhosis to receive either 12 weeks or 24 weeks of treatment with PrOD and
ribavirin. Overall, SVR12 rates were 98.5% in the 12-week arm and 100% in the 24-week arm. (Poordad,
2014) To address the need for ribavirin with this regimen in patients with HCV genotype 1b and cirrhosis,
the TURQUOISE-III study evaluated the safety and efficacy of PrOD without ribavirin for 12 weeks in
patients with HCV genotype 1b infection and compensated cirrhosis. Sixty patients (62% men, 55%
treatment-experienced, 83% with the IL28B non-CC genotype, 22% with platelet counts <90 x 109/L, and
17% with albumin levels <3.5 g/dL) were enrolled. All patients completed treatment, and all patients
achieved an SVR12. On the basis of this study, treating patients with HCV genotype 1b with PrOD but
without ribavirin is recommended, regardless of prior treatment experience or presence of cirrhosis.
(Feld, 2016)

To date, there is no measurable difference demonstrated in treatment response to simeprevir plus

sofosbuvir for HCV genotype 1 subtypes (with the exception of patients with genotype 1a with cirrhosis
who also have the baseline Q80K mutation described above), thus the supporting evidence remains the
same as for HCV genotype 1a-infected patients. (see Genotype 1)

The safety profiles to date of all recommended regimens above are excellent. Across numerous phase III
programs, less than 1% of patients without cirrhosis discontinued treatment early and adverse events
were mild. Most adverse events occurred in ribavirin-containing arms. Discontinuation rates were higher
for patients with cirrhosis (approximately 2% for some trials) but still very low.

II. Genotype 2

Genotype 2 Treatment-Naïve Patients Without Cirrhosis - Recommended

■ Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks is a
Recommended regimen for treatment-naïve patients with HCV genotype 2 infection who do
not have cirrhosis.
Rating: Class I, Level A

Genotype 2 Treatment-Naïve Patients Without Cirrhosis - Alternative

■ Daily daclatasvir (60 mg*) plus sofosbuvir (400 mg) for 12 weeks is an Alternative regimen
for treatment-naïve patients with HCV genotype 2 infection who do not have cirrhosis.
Rating: Class IIa, Level B

* The dose of daclatasvir may need to increase or decrease when used concomitantly with
cytochrome P450 3A/4 inducers and inhibitors, respectively. Please refer to the prescribing
information and the section on HIV/HCV coinfection for patients on antiretoviral therapy.

Genotype 2 Treatment-Naïve Patients with Compensated Cirrhosis‡ -

Recommended

■ Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks is a
Recommended regimen for treatment-naïve patients with HCV genotype 2 infection who
have compensated cirrhosis.
Rating: Class I, Level A
 ‡

For decompensated cirrhosis, please refer to the appropriate section.

Fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks was approved by the
FDA for the treatment of HCV genotype 2 infection in patients with and without cirrhosis. ASTRAL-2
compared 12 weeks of sofosbuvir/velpatasvir to 12 weeks of sofosbuvir plus ribavirin in 266 treatment-
naïve and -experienced subjects with and without cirrhosis and showed superior efficacy (99% compared
to 94%). (Foster, 2015a) ASTRAL-1 also included 104 genotype 2 treatment-naïve and -experienced
subjects with and without cirrhosis, all of whom achieved SVR12. (Feld, 2015) Pooled analysis of all
genotype 2 subjects in ASTRAL-1 and -2, demonstrated 100% SVR12 in subjects with cirrhosis (29/29)
and 99% SVR12 in naïve subjects (194/195). Among patients with HCV genotype 2 receiving
sofosbuvir/velpatasvir, the presence of baseline NS5A or NS5B resistance-associated variants was not
associated with virologic failure.

Genotype 2 Treatment-Naïve Patients with Compensated Cirrhosis‡- Alternative

■ Daily daclatasvir (60 mg*) plus sofosbuvir (400 mg) for 16 weeks to 24 weeks is an
Alternative regimen for treatment-naïve patients with HCV genotype 2 infection who have
compensated cirrhosis.‡
Rating: Class IIa, Level B

For decompensated cirrhosis, please refer to the appropriate section.

* The dose of daclatasvir may need to increase or decrease when used concomitantly with
cytochrome P450 3A/4 inducers and inhibitors, respectively. Please refer to the prescribing
information and the section on HIV/HCV coinfection for patients on antiretoviral therapy.

Daclatasvir with sofosbuvir for 12 weeks was approved by the FDA for the treatment of HCV genotype 3
infection in patients without and with cirrhosis. Although daclatasvir with sofosbuvir was not approved for
the treatment of HCV genotype 2 infection, daclatasvir maintains adequate activity against HCV
genotype 2 despite a 50% effective concentration (EC50) that increases by several logs in the presence of
the prevalent M31 polymorphism. (Wang, 2014) In fact, daclatasvir with sofosbuvir was associated with
high rates of SVR in treatment-naïve patients with HCV genotype 2 infection with both 12 weeks and 24
weeks of therapy. (Wyles, 2015); (Sulkowski, 2014a) It is unclear if there is a subgroup of HCV genotype
2-infected patients who would benefit from extending treatment. For patients who require treatment but
cannot tolerate ribavirin, a regimen of daclatasvir with sofosbuvir for 12 weeks is reasonable.

III. Genotype 3

Genotype 3 Treatment-Naïve Patients Without Cirrhosis - Recommended

Recommended regimens are listed in groups by level of evidence, then alphabetically.
 ■ Daily daclatasvir (60 mg*) plus sofosbuvir (400 mg) for 12 weeks is a Recommended
regimen for treatment-naïve patients with HCV genotype 3 infection who do not have
cirrhosis.
Rating: Class I, Level A

■ Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks is a
Recommended regimen for treatment-naïve patients with HCV genotype 3 infection who do
not have cirrhosis.
Rating: Class I, Level A

* The dose of daclatasvir may need to increase or decrease when used concomitantly with
cytochrome P450 3A/4 inducers and inhibitors, respectively. Please refer to the prescribing
information and the section on HIV/HCV coinfection for patients on antiretoviral therapy.

Genotype 3 Treatment-Naïve Patients with Compensated Cirrhosis‡-

Recommended
Recommended regimens are listed in groups by level of evidence, then alphabetically.

■ Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks is a
Recommended regimen for treatment-naïve patients with HCV genotype 3 infection who
have compensated cirrhosis.¶
Rating: Class I, Level A

■ Daily daclatasvir (60 mg*) plus sofosbuvir (400 mg) for 24 weeks with or without weight-
based ribavirin is a Recommended regimen for treatment-naïve patients with HCV
¶
genotype 3 infection who have compensated cirrhosis.
Rating: Class IIa, Level B

For decompensated cirrhosis, please refer to the appropriate section.

¶
RAV testing for Y93H is recommended for cirrhotic patients and ribavirin should be included in
regimen if present.
* The dose of daclatasvir may need to increase or decrease when used concomitantly with
cytochrome P450 3A/4 inducers and inhibitors, respectively. Please refer to the prescribing
information and the section on HIV/HCV coinfection for patients on antiretoviral therapy.

Sofosbuvir/velpatasvir

Fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks was approved by the
FDA for the treatment of HCV genotype 3 infection in patients with and without cirrhosis. ASTRAL-3
compared 12 weeks of sofosbuvir/velpatasvir to 24 weeks of sofosbuvir plus ribavirin in 552 treatment-
naïve and -experienced subjects with and without cirrhosis and showed superior efficacy. In treatment-
naïve non-cirrhotic subjects, SVR12 rates were 98% (160/163) compared to 90% (141/156). In those with
cirrhosis SVR12 was 93% (40/43) compared to 73% (33/45). Of the 250 subjects that received
sofosbuvir/velpatasvir 43 (16%) had baseline NS5A RAVs; of which 88% achieved SVR12 compared to
97% without baseline polymorphisms. 84% (21/25) with Y93H achieved SVR12. Pending further data on
optimal therapy in the setting of baseline Y93 polymorphism, the addition of ribavirin for patients with
cirrhosis is recommended.

Daclatasvir + sofosbuvir

Daclatasvir with sofosbuvir for 12 weeks was approved by the FDA for treatment of HCV genotype 3
infection. The recommendation is based on ALLY-3, a phase III study of the once-daily NS5A inhibitor
daclatasvir plus sofosbuvir for 12 weeks; the study included 101 treatment-naïve patients and
demonstrated an SVR12 rate of 90%. In treatment-naïve patients without cirrhosis (Metavir F0-F3), 97%
achieved SVR12, and in treatment-naïve patients with cirrhosis (Metavir F4), 58% achieved SVR12.
(Nelson, 2015) This suggests that patients with genotype 3 infection and cirrhosis are likely to benefit
from an extension of therapy. This has been confirmed in cohort studies, including the European
compassionate-use program, which reported SVR12 rates of 70% versus 86% when daclatasvir and
sofosbuvir were used for 12 weeks and 24 weeks in HCV genotype 3-infected patients with cirrhosis,
respectively. The role of ribavirin could not be clarified, as only 4 patients received daclatasvir plus
sofosbuvir and ribavirin for 12 weeks, all or which achieved SVR12. SVR12 was comparable between the
24-week arms irrespective of the addition of ribavirin (85.9% [116/135] without compared to 81.3%
[39/48] with ribavirin). SVR12 rates were also higher in those with compensated Child-Pugh A cirrhosis
(85-90% compared to 70.6% in Child B/C). Again the addition of ribavirin did not increase SVR12 rates in
the 24-week arms. (Hezode, 2015b) 73% of patients were treatment-experienced, however earlier data
suggested that SVR12 rates were higher in treatment-naïve patients (91-100%) compared to experienced
(81-82%). SVR12 rates were similar in those that received ribavirin (88%, 29/33) and those that did not
(86%, 42/49). (Hezode, 2015b)

The exact duration of therapy for a treatment-naïve genotype 3 patient with compensated cirrhosis is not
known. The phase III study, ALLY3-+, investigated the combination of daclatasvir plus sofosbuvir and
ribavirin for 12 weeks or 16 weeks in treatment-naïve and -experienced genotype 3 patients with both
stage 3 and compensated cirrhosis. Overall SVR12 rates were 86% with cirrhosis, the majority of which
were treatment-experienced. Extending the duration to 16 weeks did not have a strong impact with 88%
(15/17) achieving SVR12 with 12 weeks and 89% (16/18) achieving SVR12 with 16 weeks. All 14 patients
with stage 3 disease achieved SVR12 irrespective of treatment duration. (Leroy, 2016)

Presence of baseline NS5A RAVs significantly reduces rates of SVR 12 with a 12-week course of
daclatasvir plus sofosbuvir in genotype 3-infected patients. In analysis of 175 subjects infected with HCV
genotype 3 and nucleotide sequence data in the ALLY-3 trial, the presence of a NS5A Y93H polymorphism
was associated with a reduced SVR12 rate; 54% (7/13) compared to 92% (149/162). Although the small
numbers make interpretation difficult, only 7% (13/175) had NS5A Y93H polymorphism, all of which were
sub genotype 3a. SVR rates were numerically lower in those with both cirrhosis and Y93H. In non-
cirrhotic subjects with Y93H, 67% (6/9) achieved SVR12 compared to 98% (125/128) of those non-
cirrhotic without Y93H. In those with both cirrhosis and Y93H, 25% (1/4) achieved SVR12 compared to
71% (24/34) in those with cirrhosis but without the polymorphism. (Daklinza PI) 3a replicon variants also
suggest reduced susceptibility to single mutations at A30K, L31F, L31I in cell culture. (Daklinza PI) In the
ALLY-3 trial, subjects with A30K and without cirrhosis achieved 100% SVR12 (9/9), however those with
cirrhosis had lower SVR12 rates (1/5). (Nelson, 2015) The impact of this single mutation is difficult to
discern as 2/5 had compound mutations with Y93H. Pending further data on optimal therapy in the
setting of baseline Y93 polymorphism, the addition of ribavirin for patients with cirrhosis is
recommended.
Elbasvir/grazoprevir + sofosbuvir

C-SWIFT investigated the efficacy of triple therapy with the daily fixed-dose combination of
elbasvir/grazoprevir and sofosbuvir (400 mg) for 8 weeks to 12 weeks in genotype 3 treatment-naïve
patients with and without compensated cirrhosis. 93% (14/15) of non-cirrhotic patients achieved SVR12
with 8 weeks and 100% (14/14) with 12 weeks of this combination. 91% (10/11) compensated cirrhotic
subjects achieved SVR12 with 12 weeks of therapy. (Poordad, 2016)

IV. Genotype 4

Genotype 4 Treatment-Naïve Patients Without Cirrhosis - Recommended

Recommended regimens are listed in groups by level of evidence, then alphabetically.

■ Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25

mg) and weight-based ribavirin for 12 weeks is a Recommended regimen for treatment-
naïve patients with HCV genotype 4 infection who do not have cirrhosis.
Rating: Class I, Level A

■ Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks is a
Recommended regimen for treatment-naïve patients with HCV genotype 4 infection who do
not have cirrhosis.
Rating: Class I, Level A

■ Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) for 12 weeks is a
Recommended regimen for treatment-naïve patients with HCV genotype 4 infection who do
not have cirrhosis.
Rating: Class IIa, Level B

■ Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks is a
Recommended regimen for treatment-naïve patients with HCV genotype 4 infection who do
not have cirrhosis.
Rating: Class IIa, Level B

Genotype 4 Treatment-Naïve Patients with Compensated Cirrhosis‡ -

Recommended
Recommended regimens are listed in groups by level of evidence, then alphabetically.

■ Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25

mg) and weight-based ribavirin for 12 weeks is a Recommended regimen for treatment-
naïve patients with HCV genotype 4 infection, who have compensated cirrhosis.†
Rating: Class I, Level A

■ Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks is a
 Recommended regimen for treatment-naïve patients with HCV genotype 4 infection, who
have compensated cirrhosis.
Rating: Class I, Level A

■ Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) for 12 weeks is a
Recommended regimen for treatment-naïve patients with HCV genotype 4 infection, who
have compensated cirrhosis.
Rating: Class IIa, Level B

■ Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks is a
Recommended regimen for treatment-naïve patients with HCV genotype 4 infection, who
have compensated cirrhosis.
Rating: Class IIa, Level B

For decompensated cirrhosis, please refer to the appropriate section.

†
Please see statement on FDA warning regarding the use of PrOD or PrO in patients with cirrhosis.

Paritaprevir/ritonavir/ombitasvir

PEARL-I was an open-label phase IIb study that included a cohort of 86 treatment-naïve patients with HCV
genotype 4 infection without cirrhosis who received 12 weeks of the daily fixed-dose combination of
paritaprevir/ritonavir/ombitasvir (PrO) with or without weight-based ribavirin. SVR12 rates were 100%
(42/42) in the group receiving ribavirin and 90.9% (40/44) in the group not receiving ribavirin. Adverse
effects were generally mild, with headache, asthenia, fatigue, and nausea most commonly reported.
There were no discontinuations owing to adverse events. (Hezode, 2015) The AGATE-I trial, in its first
phase, randomized 120 treatment-naïve and -experienced patients with genotype 4 HCV and
compensated cirrhosis to receive 12 weeks or 16 weeks of paritaprevir/ritonavir/ombitasvir (PrO) plus
weight-based ribavirin. The SVR12 rates in the 12-week and 16-week arms were 96% and 100%,
respectively. The regimens were well tolerated. (Asselah, 2015a) Similarly, the ongoing AGATE-II trial
offered 100 treatment-naïve and -experienced noncirrhotic patients with genotype 4, PrO plus weight-
based ribavirin for 12 weeks. The SVR12 was 94%. Additionally, AGATE-II randomized 60 treatment-naïve
and -experienced genotype 4-infected patients with compensated cirrhosis to receive either 12 or 24
weeks of PrO plus weight-based ribavirin. The SVR12 rate from the 12-week arm, reported recently, was
97%. These data continue to support the use of PrO plus ribavirin for 12 weeks in treatment-experienced
genotype 4 patients, including those with cirrhosis. (Esmat, 2015)

Sofosbuvir/velpatasvir

Fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks was approved by the
FDA for the treatment of HCV genotype 4 infection in patients with and without cirrhosis. (Gilead, 2016)
ASTRAL-1 included 64 genotype 4 treatment-naïve subjects with and without cirrhosis, all of whom
achieved SVR12 (100%). (Feld, 2015)

Elbasvir/grazoprevir

Sixty-six treatment-naïve genotype 4 patients have been treated with daily elbasvir (50 mg)/grazoprevir
(100 mg) for 12 weeks with (n=10) and without (n=56) weight-based ribavirin in the phase 2/3 clinical
program. 9.1% (n=6) were cirrhotic and 42.4% (n=28) had HIV/HCV coinfection. Overall 97% (64/66)
achieved SVR12. There was 1 treatment failure and 1 subject was lost to follow-up. The impact of
ribavirin was not able to be assessed, however the addition of ribavirin numerically increased the SVR12
rates in treatment-experienced subjects. Baseline RAVs and subgenotype did not appear to impact
SVR12 rates. (Asselah, 2015)

C-EDGE evaluated 18 treatment-naïve genotype 4 patients who were treated with 12 weeks of the fixed-
dose combination therapy, elbasvir (50 mg)/grazoprevir (100 mg). All 18 achieved SVR12. (Zeuzem,
2015f)

Ledipasvir/sofosbuvir

The SYNERGY trial was an open-label study evaluating 12 weeks of ledipasvir/sofosbuvir in 21 HCV
genotype 4-infected patients, of whom 60% were treatment-naïve and 43% had advanced fibrosis
(Metavir stage F3 or F4). (Kohli, 2015) One patient took the first dose and then withdrew consent. All of
the 20 patients who completed treatment achieved an SVR12; thus, the SVR12 rate was 95% in the
intention-to-treat analysis and 100% in the per-protocol analysis. Abergel and colleagues reported data
from an open-label single-arm study including 22 HCV genotype 4-infected, treatment-naïve patients
(only 1 with cirrhosis) with an SVR12 rate of 95% (21/22). (Abergel, 2016) These two pilot studies support
the use of this regimen in patients with HCV genotype 4 infection.

V. Genotype 5 or 6

Genotype 5/6 Treatment-Naïve Patients with and Without Cirrhosis -

Recommended

■ Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks is a
Recommended regimen for treatment-naïve patients with HCV genotype 5 or 6 infection
regardless of cirrhosis status.
Rating: Class I, Level A

■ Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 12 weeks is a
Recommended regimen for treatment-naïve patients with HCV genotype 5 or 6 infection,
regardless of cirrhosis status.
Rating: Class IIa, Level B

Sofosbuvir/velpatasvir

Fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) for 12 weeks was approved by the
FDA for the treatment of HCV genotype 5 and 6 infection in patients with and without cirrhosis. (Feld,
2015) ASTRAL-1 included 24 genotype 5 treatment-naïve subjects with and without cirrhosis, 23 of which
achieved SVR12 (96%), and 38 genotype 6 treatment-naïve subjects with and without cirrhosis, all of
whom achieved SVR12 (100%).
Ledipasvir/sofobuvir

Although there are limited data on patients with HCV genotype 5 infection, the in vitro activity for
sofobuvir and ledipasvir is quite good with EC50 of 15 nM and 0.081 nM, respectively. Abergel and
colleagues reported data from an open-label, single-arm study that included 41 HCV genotype 5-infected
patients with an overall SVR12 rate of 95% (39/41). (Abergel, 2016) The SVR12 rate was also 95%
specifically in treatment-naïve patients (20/21), of whom only 3 had cirrhosis but who all 3 achieved
SVR12.

Ledipasvir has in vitro activity against most HCV genotype 6 subtypes (except for 6e). (Wong, 2013);
(Kohler, 2014) A small, two-center, open-label study (NCT01826981) investigated the safety and in vivo
efficacy of ledipasvir/sofosbuvir for 12 weeks in treatment-naïve and -experienced patients with HCV
genotype 6 infection. Twenty-five patients (92% were treatment-naïve) who were primarily Asian (88%)
had infection from seven different subtypes (32%, 6a; 24%, 6e; 12%, 6l; 8%, 6m; 12%, 6p; 8%, 6q;
4%,6r). Two patients (8%) had cirrhosis. The SVR12 rate was 96% (24/25), and the 1 patient who
experienced relapse had discontinued therapy at week 8 because of drug use. No patient discontinued
treatment owing to adverse events.

Elbasvir/grazoprevir

C-SCAPE evaluated the efficacy and safety of 12 weeks of elbasvir (50 mg)/grazoprevir (100 mg) with or
without weight-based ribavirin for 12 weeks in treatment-naïve, non-cirrhotic genotype 2,4,5, and 6.
Eight genotype 5 and eight genotype 6 patients were included in this trial. In patients with HCV genotype
5 infection, administration of a 12-week regimen of elbasvir (50 mg)/grazoprevir (100 mg) plus ribavirin
appears to be more active (SVR 100%, 4/4) than the same regimen without ribavirin (SVR12 25%, 1/4).
Administration of a 12-week regimen of elbasvir (50 mg)/grazoprevir (100 mg) ± ribavirin is effective in
treating HCV infection among noncirrhotic, treatment-naïve patients with HCV genotype 6 infection with
an SVR12 of 75% irrespective of the addition of ribavirin. (Brown, 2015)

C-EDGE evaluated 10 treatment-naïve genotype 6 patients who were treated with 12 weeks of the fixed-
dose combination therapy, elbasvir (50 mg)/grazoprevir (100 mg). Eight of 10 (80%) achieved SVR12.
(Zeuzem, 2015f)

Mixed Genotypes

Rarely, genotyping assays may indicate the presence of a mixed infection (eg, genotypes 1a and 2).
Treatment data for mixed genotypes with direct-acting antivirals are sparse, and awaiting availability of a
pangenotypic regimen may be considered. Until then, when treatment is necessary, the choice of
antiviral combination and duration of treatment should maximize efficacy against each genotype
represented in the assay. When the correct combination or duration is unclear, expert consultation
should be sought.

> Click Here to Review Regimens Not Recommended in HCV Treatment <

Changes made July 6, 2016.

Source URL: http://www.hcvguidelines.org/full-report/initial-treatment-hcv-infection