Page 17 - EASL Recommendations on Treatment of Hepatitis C 2015 - Full version
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Clinical Practice Guidelines genotypes and results in a small group of genotype 3-infected
without and with cirrhosis, respectively). The POSITRON trial patients, the triple combination of PegIFN-a, ribavirin and sofos-
included patients considered ineligible or intolerant to IFN, who
were treated for 12 weeks with sofosbuvir and ribavirin [46]. buvir appears to be valuable. The IFN-free combination of sofos-
SVR was achieved in 93% (101/109) of cases. When comparing buvir and daclatasvir, with or without ribavirin, is another
12 and 16 weeks of therapy in the FUSION trial [46], SVR was attractive option for patients infected with HCV genotype 3.
achieved in 82% (32/39) and 89% (31/35) of cases, respectively,
60% (6/10) and 78% (7/9) in patients with cirrhosis, respectively. Ledipasvir is considerably less potent against genotype 3 than
This indicates that patients with cirrhosis may benefit from daclatasvir in vitro; in clinical trials with ledipasvir, the respective
longer than 12 weeks of therapy. In the VALENCE trial [47], the roles of ledipasvir and ribavirin in combination with sofosbuvir
SVR rates after 12 weeks of treatment were 97% (29/30) in treat- cannot be determined in the absence of control arms with sofos-
ment-naïve non-cirrhotic individuals, 100% (2/2) in treatment- buvir and ribavirin alone. Thus, although this combination has
naïve cirrhotic patients, 91% (30/33) in treatment-experienced been used, pending further studies in larger populations includ-
non-cirrhotic patients, and 88% (7/8) in treatment-experienced ing appropriate control arms, the combination of sofosbuvir plus
cirrhotic patients. In another study, 1 of 2 patients who relapsed ledipasvir is not recommended in patients infected with HCV
after treatment with sofosbuvir and ribavirin retreated 24 weeks genotype 3.
with sofosbuvir and ribavirin achieved an SVR [48]. The com-
bination of sofosbuvir and ribavirin was well tolerated in all these In settings where none of these options is available, the com-
studies. No virological breakthroughs were observed in treat-
ment-adherent patients, and relapses were not associated with bination of PegIFN-a and ribavirin remains acceptable, according
the selection of resistant HCV variants.
to previous EASL Clinical Practice Guidelines [5].
Genotype 2, Option 2
Genotype 3, Option 1
• Cirrhotic and/or treatment-experienced patients can
be treated with weekly PegIFN-α, daily weight-based • Patients infected with HCV genotype 3 can be treated
ribavirin (1000 or 1200 mg in patients <75 kg or ≥75 kg, with a combination of weekly PegIFN-α, daily weight-
respectively), and daily sofosbuvir (400 mg) 12 weeks based ribavirin (1000 or 1200 mg in patients <75 kg or
(B1) ≥75 kg, respectively), and daily sofosbuvir (400 mg) 12
weeks (B1)
Comments: In the LONESTAR-2 Phase IIb study [49], a single cen-
tre study in which 23 treatment-experienced patients infected • This combination is a valuable option in patients who
with HCV genotype 2, including 14 with cirrhosis, received failed to achieve an SVR after sofosbuvir plus ribavirin
treatment (B1)
12 weeks of PegIFN-a, ribavirin and sofosbuvir, the SVR rate was
Comments: This combination has been evaluated in 10 treatment-
96%. In another study, 4/4 patients who relapsed after treatment naïve non-cirrhotic patients infected with genotype 3. Nine of
with sofosbuvir and ribavirin retreated 12 weeks with the triple them achieved an SVR, whereas the remaining one was lost to fol-
low-up [50]. In addition, data with this combination in patients
combination of PegIFN-a, ribavirin and sofosbuvir achieved an infected with HCV genotype 3 are available from the LONESTAR-
2 Phase IIb trial in treatment-experienced individuals [49], who
SVR [48]. achieved an SVR in 83% (20/24) of cases, including 10/12 patients
with cirrhosis. However, the pangenotypic activity of sofosbuvir
.Genotype 2, Option 3 together with high SVR rates with other genotypes (89% (259/
291) overall for genotypes 1 and 4 to 6) indicate that this com-
• Cirrhotic and/or treatment-experienced patients can be bination can be safely used in patients infected with HCV genotype
treated with an IFN-free combination of daily sofosbuvir 3. In another study, patients infected with genotype 3 who
(400 mg) and daily daclatasvir (60 mg) for 12 weeks relapsed after treatment with sofosbuvir and ribavirin retreated
(B1)
with the triple combination of PegIFN-a, ribavirin and sofosbuvir
Comments: Daclatasvir is active against genotype 2 in vitro. In a
Phase II trial, 92% (24/26) of patients infected with genotype 2 for 12 weeks achieved an SVR in 91% (20/22) of cases [48].
achieved an SVR12 after 24 weeks of sofosbuvir and daclatasvir.
Based on data with other, more difficult-to-cure HCV genotypes, Genotype 3, Option 2
12 weeks is probably sufficient for this regimen that should be
reserved for patients who failed with other options. • Patients infected with HCV genotype 3 can be treated
with daily weight-based ribavirin (1000 or 1200 mg
Treatment of HCV genotype 3 infection in patients <75 kg or ≥75 kg, respectively), and daily
sofosbuvir (400 mg) for 24 weeks (A1)
Three treatment options are available for patients infected with
HCV genotype 3. The combination of sofosbuvir and ribavirin is • This therapy is suboptimal in treatment-experienced
suboptimal, in particular in patients with cirrhosis who have pre- cirrhotic patients and in patients who failed to achieve
viously failed IFN and ribavirin. Based on data with other an SVR after sofosbuvir plus ribavirin treatment, who
should be offered an alternative treatment option (B1)
16
without and with cirrhosis, respectively). The POSITRON trial patients, the triple combination of PegIFN-a, ribavirin and sofos-
included patients considered ineligible or intolerant to IFN, who
were treated for 12 weeks with sofosbuvir and ribavirin [46]. buvir appears to be valuable. The IFN-free combination of sofos-
SVR was achieved in 93% (101/109) of cases. When comparing buvir and daclatasvir, with or without ribavirin, is another
12 and 16 weeks of therapy in the FUSION trial [46], SVR was attractive option for patients infected with HCV genotype 3.
achieved in 82% (32/39) and 89% (31/35) of cases, respectively,
60% (6/10) and 78% (7/9) in patients with cirrhosis, respectively. Ledipasvir is considerably less potent against genotype 3 than
This indicates that patients with cirrhosis may benefit from daclatasvir in vitro; in clinical trials with ledipasvir, the respective
longer than 12 weeks of therapy. In the VALENCE trial [47], the roles of ledipasvir and ribavirin in combination with sofosbuvir
SVR rates after 12 weeks of treatment were 97% (29/30) in treat- cannot be determined in the absence of control arms with sofos-
ment-naïve non-cirrhotic individuals, 100% (2/2) in treatment- buvir and ribavirin alone. Thus, although this combination has
naïve cirrhotic patients, 91% (30/33) in treatment-experienced been used, pending further studies in larger populations includ-
non-cirrhotic patients, and 88% (7/8) in treatment-experienced ing appropriate control arms, the combination of sofosbuvir plus
cirrhotic patients. In another study, 1 of 2 patients who relapsed ledipasvir is not recommended in patients infected with HCV
after treatment with sofosbuvir and ribavirin retreated 24 weeks genotype 3.
with sofosbuvir and ribavirin achieved an SVR [48]. The com-
bination of sofosbuvir and ribavirin was well tolerated in all these In settings where none of these options is available, the com-
studies. No virological breakthroughs were observed in treat-
ment-adherent patients, and relapses were not associated with bination of PegIFN-a and ribavirin remains acceptable, according
the selection of resistant HCV variants.
to previous EASL Clinical Practice Guidelines [5].
Genotype 2, Option 2
Genotype 3, Option 1
• Cirrhotic and/or treatment-experienced patients can
be treated with weekly PegIFN-α, daily weight-based • Patients infected with HCV genotype 3 can be treated
ribavirin (1000 or 1200 mg in patients <75 kg or ≥75 kg, with a combination of weekly PegIFN-α, daily weight-
respectively), and daily sofosbuvir (400 mg) 12 weeks based ribavirin (1000 or 1200 mg in patients <75 kg or
(B1) ≥75 kg, respectively), and daily sofosbuvir (400 mg) 12
weeks (B1)
Comments: In the LONESTAR-2 Phase IIb study [49], a single cen-
tre study in which 23 treatment-experienced patients infected • This combination is a valuable option in patients who
with HCV genotype 2, including 14 with cirrhosis, received failed to achieve an SVR after sofosbuvir plus ribavirin
treatment (B1)
12 weeks of PegIFN-a, ribavirin and sofosbuvir, the SVR rate was
Comments: This combination has been evaluated in 10 treatment-
96%. In another study, 4/4 patients who relapsed after treatment naïve non-cirrhotic patients infected with genotype 3. Nine of
with sofosbuvir and ribavirin retreated 12 weeks with the triple them achieved an SVR, whereas the remaining one was lost to fol-
low-up [50]. In addition, data with this combination in patients
combination of PegIFN-a, ribavirin and sofosbuvir achieved an infected with HCV genotype 3 are available from the LONESTAR-
2 Phase IIb trial in treatment-experienced individuals [49], who
SVR [48]. achieved an SVR in 83% (20/24) of cases, including 10/12 patients
with cirrhosis. However, the pangenotypic activity of sofosbuvir
.Genotype 2, Option 3 together with high SVR rates with other genotypes (89% (259/
291) overall for genotypes 1 and 4 to 6) indicate that this com-
• Cirrhotic and/or treatment-experienced patients can be bination can be safely used in patients infected with HCV genotype
treated with an IFN-free combination of daily sofosbuvir 3. In another study, patients infected with genotype 3 who
(400 mg) and daily daclatasvir (60 mg) for 12 weeks relapsed after treatment with sofosbuvir and ribavirin retreated
(B1)
with the triple combination of PegIFN-a, ribavirin and sofosbuvir
Comments: Daclatasvir is active against genotype 2 in vitro. In a
Phase II trial, 92% (24/26) of patients infected with genotype 2 for 12 weeks achieved an SVR in 91% (20/22) of cases [48].
achieved an SVR12 after 24 weeks of sofosbuvir and daclatasvir.
Based on data with other, more difficult-to-cure HCV genotypes, Genotype 3, Option 2
12 weeks is probably sufficient for this regimen that should be
reserved for patients who failed with other options. • Patients infected with HCV genotype 3 can be treated
with daily weight-based ribavirin (1000 or 1200 mg
Treatment of HCV genotype 3 infection in patients <75 kg or ≥75 kg, respectively), and daily
sofosbuvir (400 mg) for 24 weeks (A1)
Three treatment options are available for patients infected with
HCV genotype 3. The combination of sofosbuvir and ribavirin is • This therapy is suboptimal in treatment-experienced
suboptimal, in particular in patients with cirrhosis who have pre- cirrhotic patients and in patients who failed to achieve
viously failed IFN and ribavirin. Based on data with other an SVR after sofosbuvir plus ribavirin treatment, who
should be offered an alternative treatment option (B1)
16
