Page 18 - EASL Recommendations on Treatment of Hepatitis C 2015 - Full version
P. 18
Comments: Results from four Phase III trials have been pub- JOURNAL OF HEPATOLOGY
lished. In the FISSION trial in treatment-naïve patients treated
12 weeks [25], the SVR rate was 56% (102/183). The response rate Treatment of HCV genotype 4 infection
was better in patients without cirrhosis (61% and 34% in patients
without and with cirrhosis, respectively). The POSITRON trial Six treatment options are available in 2015 for patients infected
included patients ineligible or intolerant to IFN-based therapy with HCV genotype 4, including two IFN-containing regimens
who were treated for 12 weeks with sofosbuvir and ribavirin and four IFN-free regimens. In settings where none of these options
[46]; SVR was achieved in 61% (60/98) of cases. When comparing
12 and 16 weeks of therapy in the FUSION trial [46], SVR was is available, the combination of PegIFN-a and ribavirin remains
achieved in 30% (19/64) and 62% (39/63) of cases, respectively,
19% (5/26) and 61% (14/23) in patients with cirrhosis, respec- acceptable; see prior EASL Clinical Practice Guidelines [5].
tively. In the VALENCE trial [51], the SVR rates after 24 weeks
of treatment were 94% (86/92) in treatment-naïve non-cirrhotic IFN-containing options
individuals, 92% (12/13) in treatment-naïve cirrhotics, 87% (87/
100) in treatment-experienced non-cirrhotic patients, and 60% Genotype 4, IFN-containing Option 1
(27/45) in treatment-experienced cirrhotic patients. These results
indicate that 24 weeks is the appropriate duration for this regi- • Patients infected with HCV genotype 4 can be treated
men in patients infected with HCV genotype 3, and that this regi- with a combination of weekly PegIFN-α, daily weight-
men is suboptimal in treatment-experienced patients with based ribavirin (1000 or 1200 mg in patients <75 kg or
cirrhosis. In another study, patients infected with genotype 3 ≥75 kg, respectively), and daily sofosbuvir (400 mg) 12
who relapsed after treatment with sofosbuvir and ribavirin and weeks (B1)
were retreated 24 weeks with sofosbuvir and ribavirin achieved
an SVR in only 63% (24/38) of cases, indicating that this regimen Comments: This combination has been evaluated in the
is suboptimal in such patients [48]. NEUTRINO Phase III trial in treatment-naïve patients [25]. The
SVR rate in genotype 4 patients was 96% (27/28). The patient
The combination of sofosbuvir and ribavirin was well toler- who failed on this regimen did not select HCV variants resistant
ated and very few patients stopped therapy. No virological break- to sofosbuvir. No data with this regimen is available in treat-
throughs were observed in treatment-adherent patients, and ment-experienced patients or in HIV-coinfected patients.
relapses were not associated with the selection of resistant HCV Whether longer treatment duration would be needed in the most
variants. difficult-to-treat population is unknown.
Genotype 4, IFN-containing Option 2
Genotype 3, Option 3
• Patients infected with HCV genotype 4 can be treated
• Patients infected with HCV genotype 3 without cirrhosis with a combination of weekly PegIFN-α, daily weight-
can be treated with an IFN-free combination of daily based ribavirin (1000 or 1200 mg in patients <75 kg or
sofosbuvir (400 mg) and daily daclatasvir (60 mg) for 12 ≥75 kg, respectively), and daily simeprevir (150 mg)
weeks (A1) (B1)
• Treatment-naïve and treatment-experienced patients • Simeprevir should be administered 12 weeks in
infected with HCV genotype 3 with cirrhosis should combination with PegIFN-α and ribavirin. PegIFN-α
receive this combination with daily weight-based and ribavirin should then be administered alone for
ribavirin (1000 or 1200 mg in patients <75 kg or ≥75 an additional 12 weeks (total treatment duration 24
kg, respectively) for 24 weeks, pending further data weeks) in treatment-naïve and prior relapser patients,
comparing 12 weeks with ribavirin and 24 weeks with including cirrhotic patients, an additional 36 weeks (total
and without ribavirin in this population (B1) treatment duration 48 weeks) in prior partial and null
responders, including cirrhotic patients (B1)
Comments: In a Phase IIb trial with this combination for
24 weeks [14], the SVR rate was 89% (16/18) in treatment-naïve • HCV RNA levels should be monitored on treatment.
non-cirrhotic patients infected with HCV genotype 3. In the Treatment should be stopped if HCV RNA level is ≥25
ALLY-3 Phase III trial, patients were treated for 12 weeks with IU/ml at treatment week 4, week 12 or week 24 (A2)
the combination of sofosbuvir and daclatasvir, without ribavirin.
The SVR12 rates were 97% (73/75) and 58% (11/19) in treatment- Comments: Simeprevir is active against genotype 4 in vitro. Phase
naïve non-cirrhotic and cirrhotic patients, respectively; they III data in 107 patients infected with genotype 4 indicate that the
were 94% (32/34) and 69% (9/13) in treatment-experienced
non-cirrhotic and cirrhotic patients, respectively [52]. This regi- combination of PegIFN-a, ribavirin and simeprevir is effective in
men was well tolerated, with rare adverse events, none of which
led to treatment discontinuation. The impact of pre-existing sub- treatment-naïve patients and prior relapsers to IFN-based treat-
stitutions in the NS5A protein sequence known to confer resis- ment, but suboptimal in prior partial responders and null respon-
tance to daclatasvir at baseline on the response is unknown ders [53]. Indeed, SVR12 was achieved in 83% (29/35) of treatment-
with this genotype. naïve patients, 86% (19/22) of prior relapsers, 60% (6/10) of prior
partial responders, and 40% (16/40) of prior null responders. No
patient had a Q80K substitution detectable in the NS3 protease
sequence at baseline.
17
lished. In the FISSION trial in treatment-naïve patients treated
12 weeks [25], the SVR rate was 56% (102/183). The response rate Treatment of HCV genotype 4 infection
was better in patients without cirrhosis (61% and 34% in patients
without and with cirrhosis, respectively). The POSITRON trial Six treatment options are available in 2015 for patients infected
included patients ineligible or intolerant to IFN-based therapy with HCV genotype 4, including two IFN-containing regimens
who were treated for 12 weeks with sofosbuvir and ribavirin and four IFN-free regimens. In settings where none of these options
[46]; SVR was achieved in 61% (60/98) of cases. When comparing
12 and 16 weeks of therapy in the FUSION trial [46], SVR was is available, the combination of PegIFN-a and ribavirin remains
achieved in 30% (19/64) and 62% (39/63) of cases, respectively,
19% (5/26) and 61% (14/23) in patients with cirrhosis, respec- acceptable; see prior EASL Clinical Practice Guidelines [5].
tively. In the VALENCE trial [51], the SVR rates after 24 weeks
of treatment were 94% (86/92) in treatment-naïve non-cirrhotic IFN-containing options
individuals, 92% (12/13) in treatment-naïve cirrhotics, 87% (87/
100) in treatment-experienced non-cirrhotic patients, and 60% Genotype 4, IFN-containing Option 1
(27/45) in treatment-experienced cirrhotic patients. These results
indicate that 24 weeks is the appropriate duration for this regi- • Patients infected with HCV genotype 4 can be treated
men in patients infected with HCV genotype 3, and that this regi- with a combination of weekly PegIFN-α, daily weight-
men is suboptimal in treatment-experienced patients with based ribavirin (1000 or 1200 mg in patients <75 kg or
cirrhosis. In another study, patients infected with genotype 3 ≥75 kg, respectively), and daily sofosbuvir (400 mg) 12
who relapsed after treatment with sofosbuvir and ribavirin and weeks (B1)
were retreated 24 weeks with sofosbuvir and ribavirin achieved
an SVR in only 63% (24/38) of cases, indicating that this regimen Comments: This combination has been evaluated in the
is suboptimal in such patients [48]. NEUTRINO Phase III trial in treatment-naïve patients [25]. The
SVR rate in genotype 4 patients was 96% (27/28). The patient
The combination of sofosbuvir and ribavirin was well toler- who failed on this regimen did not select HCV variants resistant
ated and very few patients stopped therapy. No virological break- to sofosbuvir. No data with this regimen is available in treat-
throughs were observed in treatment-adherent patients, and ment-experienced patients or in HIV-coinfected patients.
relapses were not associated with the selection of resistant HCV Whether longer treatment duration would be needed in the most
variants. difficult-to-treat population is unknown.
Genotype 4, IFN-containing Option 2
Genotype 3, Option 3
• Patients infected with HCV genotype 4 can be treated
• Patients infected with HCV genotype 3 without cirrhosis with a combination of weekly PegIFN-α, daily weight-
can be treated with an IFN-free combination of daily based ribavirin (1000 or 1200 mg in patients <75 kg or
sofosbuvir (400 mg) and daily daclatasvir (60 mg) for 12 ≥75 kg, respectively), and daily simeprevir (150 mg)
weeks (A1) (B1)
• Treatment-naïve and treatment-experienced patients • Simeprevir should be administered 12 weeks in
infected with HCV genotype 3 with cirrhosis should combination with PegIFN-α and ribavirin. PegIFN-α
receive this combination with daily weight-based and ribavirin should then be administered alone for
ribavirin (1000 or 1200 mg in patients <75 kg or ≥75 an additional 12 weeks (total treatment duration 24
kg, respectively) for 24 weeks, pending further data weeks) in treatment-naïve and prior relapser patients,
comparing 12 weeks with ribavirin and 24 weeks with including cirrhotic patients, an additional 36 weeks (total
and without ribavirin in this population (B1) treatment duration 48 weeks) in prior partial and null
responders, including cirrhotic patients (B1)
Comments: In a Phase IIb trial with this combination for
24 weeks [14], the SVR rate was 89% (16/18) in treatment-naïve • HCV RNA levels should be monitored on treatment.
non-cirrhotic patients infected with HCV genotype 3. In the Treatment should be stopped if HCV RNA level is ≥25
ALLY-3 Phase III trial, patients were treated for 12 weeks with IU/ml at treatment week 4, week 12 or week 24 (A2)
the combination of sofosbuvir and daclatasvir, without ribavirin.
The SVR12 rates were 97% (73/75) and 58% (11/19) in treatment- Comments: Simeprevir is active against genotype 4 in vitro. Phase
naïve non-cirrhotic and cirrhotic patients, respectively; they III data in 107 patients infected with genotype 4 indicate that the
were 94% (32/34) and 69% (9/13) in treatment-experienced
non-cirrhotic and cirrhotic patients, respectively [52]. This regi- combination of PegIFN-a, ribavirin and simeprevir is effective in
men was well tolerated, with rare adverse events, none of which
led to treatment discontinuation. The impact of pre-existing sub- treatment-naïve patients and prior relapsers to IFN-based treat-
stitutions in the NS5A protein sequence known to confer resis- ment, but suboptimal in prior partial responders and null respon-
tance to daclatasvir at baseline on the response is unknown ders [53]. Indeed, SVR12 was achieved in 83% (29/35) of treatment-
with this genotype. naïve patients, 86% (19/22) of prior relapsers, 60% (6/10) of prior
partial responders, and 40% (16/40) of prior null responders. No
patient had a Q80K substitution detectable in the NS3 protease
sequence at baseline.
17
