Page 15 - EASL Recommendations on Treatment of Hepatitis C 2015 - Full version
P. 15
Clinical Practice Guidelines Genotype 1, IFN-free Option 2
Comments: This recommendation is based on the results of the • Patients infected with HCV genotype 1 can be treated
three Phase III trials ION-1, ION-2 and ION-3 [34–36]. In ION-1, with an IFN-free regimen comprising the fixed-dose
treatment-naïve patients, including 16% with compensated cir- combination of ombitasvir (75 mg), paritaprevir (12.5
rhosis, achieved SVR12 in 99% (211/214) and 97% (211/217) mg) and ritonavir (50 mg) in one single tablet (two
of cases after 12 weeks of the fixed-dose combination of sofos- tablets once daily with food), and dasabuvir (250 mg)
buvir and ledipasvir without or with ribavirin, respectively. The (one tablet twice daily) (A1)
SVR12 rates were 98% (212/217) and 99% (215/217) after
24 weeks of the same combination without or with ribavirin, • Patients infected with subtype 1b without cirrhosis
respectively [34]. In ION-3 in treatment-naïve patients without should receive this combination for 12 weeks without
cirrhosis (F3 in only 13% of patients who underwent liver ribavirin (A1)
biopsy), the SVR12 rates were 94% (202/215) without ribavirin
for 8 weeks, 93% (201/216) with ribavirin for 8 weeks and 95% • Patients infected with subtype 1b with cirrhosis should
(205/216) without ribavirin for 12 weeks. The absolute number receive this combination for 12 weeks with daily weight-
of post-treatment relapses was, however, higher in the 8-weeks based ribavirin (1000 or 1200 mg in patients <75 kg or
arms: 11/215, 9/216 and 3/216, respectively. Post hoc analysis ≥75 kg, respectively) (A1)
indicated that only patients with an HCV RNA level <6 million
(6.8 Log) IU/ml at baseline could be treated for 8 weeks [36]. • Patients infected with subtype 1a without cirrhosis
However, HCV RNA level determination can be inaccurate should receive this combination for 12 weeks with daily
within this range of values with currently available HCV RNA weight-based ribavirin (1000 or 1200 mg in patients <75
assays and real-life confirmation is needed to determine that kg or ≥75 kg, respectively) (A1)
8 weeks of treatment with this combination is sufficient.
Interestingly, the relapse rates were 1% (1/84) and 1% (1/96) • Patients infected with subtype 1a with cirrhosis should
in female patients treated for 8 weeks with sofosbuvir and ledi- receive this combination for 24 weeks with daily weight-
pasvir without and with ribavirin, respectively, and 8% (10/129) based ribavirin (1000 or 1200 mg in patients <75 kg or
and 7% (8/114) in males, respectively, in the ION-3 study [36]. ≥75 kg, respectively) (A1)
In another Phase II study, the combination of sofosbuvir and
ledipasvir was given for 12 weeks without ribavirin to patients Comments: This recommendation is based on the results of seven
with HCV genotype 1 infection coinfected with HIV, including Phase III trials. In SAPPHIRE-I in treatment-naïve patients without
13 not treated for their HIV infection and 37 receiving antire- cirrhosis treated with this combination together with ribavirin for
troviral therapy. All but one patient (98%) achieved an SVR12 12 weeks, the SVR12 rates were 95% (307/322) in subtype 1a and
[37]. 98% (148/151) in subtype 1b patients [40]. In PEARL-IV, the
SVR12 rates were 90% (185/205) and 97% (97/100) without and
In ION-2, in treatment-experienced patients (prior PegIFN-a with ribavirin, respectively, in treatment-naïve non-cirrhotic
and ribavirin or PegIFN-a, ribavirin and either telaprevir or patients infected with subtype 1a. In PEARL-III, the SVR12 rates
were 99% (207/209) and 99% (209/210) without and with ribavirin,
boceprevir), including 20% with cirrhosis, the SVR12 rates were respectively, in treatment-naïve non-cirrhotic patients infected
94% (102/109) and 96% (107/111) without or with ribavirin, with subtype 1b [41]. In the TURQUOISE-I study in treatment-
respectively. After 24 weeks of therapy, SVR rates were 99% naïve, non-cirrhotic patients coinfected with HIV-1 and stable on
(108/109) and 99% (110/111), respectively [37]. antiretroviral treatment containing atazanavir or raltegravir, the
SVR12 rates were 93% (29/31) and 91% (29/32) after 12 or 24 weeks
An integrated analysis of 513 genotype 1 patients with com- of treatment, respectively; SVR12 was achieved in 91% (51/56) of
pensated cirrhosis treated with the fixed-dose combination of subtype 1a and 100% (7/7) of subtype 1b patients [42].
sofosbuvir and ledipasvir, with or without ribavirin, in different
Phase II and III studies showed overall SVR12 rates of 95% (305/ In non-cirrhotic treatment-experienced patients (PegIFN-a
322) after 12 weeks and 98% (188/191) after 24 weeks of therapy
[38]. Neither treatment duration nor ribavirin had an impact on and ribavirin failures) treated with this combination with
SVR12 in treatment-naïve patients (SVR12 rates between 96% ribavirin for 12 weeks in SAPPHIRE-II, the SVR12 rates were
and 100%). In contrast, in treatment-experienced patients, the 96% (166/173) in subtype 1a and 97% (119/123) in subtype 1b
SVR12 rates were 90% after 12 weeks without ribavirin, 96% after patients. Overall, the SVR12 rates were 95% (82/86) in prior relap-
12 weeks with ribavirin, 98% after 24 weeks without ribavirin, sers, 100% (65/65) in prior partial responders and 95% (139/146)
and 100% after 24 weeks with ribavirin. A platelet in prior null responders [43]. SVR12 was achieved in 100% (91/
91) of cases without ribavirin and 97% (85/88) with ribavirin in
count <75 Â 103/ll was associated with a lower rate of SVR patients infected with subtype 1b receiving this combination in
the PEARL-II trial [44].
among treatment-experienced patients (based on 28 patients)
[38]. In treatment-naïve and treatment-experienced patients with
compensated cirrhosis, the rates of SVR were 92% (191/208) after
In the SIRIUS study, 12 weeks of the fixed-dose combination 12 weeks and 96% (165/172) after 24 weeks of the combination
of sofosbuvir and ledipasvir with ribavirin or 24 weeks of the
same combination without ribavirin in patients with compen-
sated cirrhosis who failed to achieve an SVR after treatment with
PegIFN-a, ribavirin and either telaprevir or boceprevir yielded
SVR12 rates of 96% (74/77) and 97% (75/77), respectively [39].
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Comments: This recommendation is based on the results of the • Patients infected with HCV genotype 1 can be treated
three Phase III trials ION-1, ION-2 and ION-3 [34–36]. In ION-1, with an IFN-free regimen comprising the fixed-dose
treatment-naïve patients, including 16% with compensated cir- combination of ombitasvir (75 mg), paritaprevir (12.5
rhosis, achieved SVR12 in 99% (211/214) and 97% (211/217) mg) and ritonavir (50 mg) in one single tablet (two
of cases after 12 weeks of the fixed-dose combination of sofos- tablets once daily with food), and dasabuvir (250 mg)
buvir and ledipasvir without or with ribavirin, respectively. The (one tablet twice daily) (A1)
SVR12 rates were 98% (212/217) and 99% (215/217) after
24 weeks of the same combination without or with ribavirin, • Patients infected with subtype 1b without cirrhosis
respectively [34]. In ION-3 in treatment-naïve patients without should receive this combination for 12 weeks without
cirrhosis (F3 in only 13% of patients who underwent liver ribavirin (A1)
biopsy), the SVR12 rates were 94% (202/215) without ribavirin
for 8 weeks, 93% (201/216) with ribavirin for 8 weeks and 95% • Patients infected with subtype 1b with cirrhosis should
(205/216) without ribavirin for 12 weeks. The absolute number receive this combination for 12 weeks with daily weight-
of post-treatment relapses was, however, higher in the 8-weeks based ribavirin (1000 or 1200 mg in patients <75 kg or
arms: 11/215, 9/216 and 3/216, respectively. Post hoc analysis ≥75 kg, respectively) (A1)
indicated that only patients with an HCV RNA level <6 million
(6.8 Log) IU/ml at baseline could be treated for 8 weeks [36]. • Patients infected with subtype 1a without cirrhosis
However, HCV RNA level determination can be inaccurate should receive this combination for 12 weeks with daily
within this range of values with currently available HCV RNA weight-based ribavirin (1000 or 1200 mg in patients <75
assays and real-life confirmation is needed to determine that kg or ≥75 kg, respectively) (A1)
8 weeks of treatment with this combination is sufficient.
Interestingly, the relapse rates were 1% (1/84) and 1% (1/96) • Patients infected with subtype 1a with cirrhosis should
in female patients treated for 8 weeks with sofosbuvir and ledi- receive this combination for 24 weeks with daily weight-
pasvir without and with ribavirin, respectively, and 8% (10/129) based ribavirin (1000 or 1200 mg in patients <75 kg or
and 7% (8/114) in males, respectively, in the ION-3 study [36]. ≥75 kg, respectively) (A1)
In another Phase II study, the combination of sofosbuvir and
ledipasvir was given for 12 weeks without ribavirin to patients Comments: This recommendation is based on the results of seven
with HCV genotype 1 infection coinfected with HIV, including Phase III trials. In SAPPHIRE-I in treatment-naïve patients without
13 not treated for their HIV infection and 37 receiving antire- cirrhosis treated with this combination together with ribavirin for
troviral therapy. All but one patient (98%) achieved an SVR12 12 weeks, the SVR12 rates were 95% (307/322) in subtype 1a and
[37]. 98% (148/151) in subtype 1b patients [40]. In PEARL-IV, the
SVR12 rates were 90% (185/205) and 97% (97/100) without and
In ION-2, in treatment-experienced patients (prior PegIFN-a with ribavirin, respectively, in treatment-naïve non-cirrhotic
and ribavirin or PegIFN-a, ribavirin and either telaprevir or patients infected with subtype 1a. In PEARL-III, the SVR12 rates
were 99% (207/209) and 99% (209/210) without and with ribavirin,
boceprevir), including 20% with cirrhosis, the SVR12 rates were respectively, in treatment-naïve non-cirrhotic patients infected
94% (102/109) and 96% (107/111) without or with ribavirin, with subtype 1b [41]. In the TURQUOISE-I study in treatment-
respectively. After 24 weeks of therapy, SVR rates were 99% naïve, non-cirrhotic patients coinfected with HIV-1 and stable on
(108/109) and 99% (110/111), respectively [37]. antiretroviral treatment containing atazanavir or raltegravir, the
SVR12 rates were 93% (29/31) and 91% (29/32) after 12 or 24 weeks
An integrated analysis of 513 genotype 1 patients with com- of treatment, respectively; SVR12 was achieved in 91% (51/56) of
pensated cirrhosis treated with the fixed-dose combination of subtype 1a and 100% (7/7) of subtype 1b patients [42].
sofosbuvir and ledipasvir, with or without ribavirin, in different
Phase II and III studies showed overall SVR12 rates of 95% (305/ In non-cirrhotic treatment-experienced patients (PegIFN-a
322) after 12 weeks and 98% (188/191) after 24 weeks of therapy
[38]. Neither treatment duration nor ribavirin had an impact on and ribavirin failures) treated with this combination with
SVR12 in treatment-naïve patients (SVR12 rates between 96% ribavirin for 12 weeks in SAPPHIRE-II, the SVR12 rates were
and 100%). In contrast, in treatment-experienced patients, the 96% (166/173) in subtype 1a and 97% (119/123) in subtype 1b
SVR12 rates were 90% after 12 weeks without ribavirin, 96% after patients. Overall, the SVR12 rates were 95% (82/86) in prior relap-
12 weeks with ribavirin, 98% after 24 weeks without ribavirin, sers, 100% (65/65) in prior partial responders and 95% (139/146)
and 100% after 24 weeks with ribavirin. A platelet in prior null responders [43]. SVR12 was achieved in 100% (91/
91) of cases without ribavirin and 97% (85/88) with ribavirin in
count <75 Â 103/ll was associated with a lower rate of SVR patients infected with subtype 1b receiving this combination in
the PEARL-II trial [44].
among treatment-experienced patients (based on 28 patients)
[38]. In treatment-naïve and treatment-experienced patients with
compensated cirrhosis, the rates of SVR were 92% (191/208) after
In the SIRIUS study, 12 weeks of the fixed-dose combination 12 weeks and 96% (165/172) after 24 weeks of the combination
of sofosbuvir and ledipasvir with ribavirin or 24 weeks of the
same combination without ribavirin in patients with compen-
sated cirrhosis who failed to achieve an SVR after treatment with
PegIFN-a, ribavirin and either telaprevir or boceprevir yielded
SVR12 rates of 96% (74/77) and 97% (75/77), respectively [39].
14
