Page 24 - EASL Recommendations on Treatment of Hepatitis C 2015 - Full version
P. 24
(notably, history of alcohol drinking and/or type 2 diabetes) JOURNAL OF HEPATOLOGY
should be carefully and periodically subjected to a thorough clini-
cal assessment, as needed. Retreatment of non-sustained virological responders
Cirrhotic patients who achieve an SVR should remain under Retreatment of patients who failed after a double combination of
surveillance for HCC every 6 months by ultrasound, and for oeso-
phageal varices by endoscopy if varices were present at pretreat- PegIFN-a and ribavirin
ment endoscopy (though first variceal bleed is seldom observed
after SVR). The presence of cofactors for liver disease, such as his- Several studies indicate that patients who failed to achieve an
tory of alcohol drinking and/or type 2 diabetes, may determine
that additional assessments are necessary. The exact duration SVR after treatment with PegIFN-a and ribavirin alone do not
of HCC surveillance in patients with advanced fibrosis or cirrhosis
who achieve an SVR is unknown in the current state of knowl- respond differently to IFN-free regimens from treatment-naïve
edge, but is probably indefinite. Indeed, long-term post-SVR fol- patients. Thus, these patients should be retreated with an IFN-
low-up studies showed that, although it is significantly reduced free regimen according to the above recommendations (Tables
compared to untreated patients or patients who did not achieve 5 and 6).
an SVR, the risk of developing HCC remains in patients with cir-
rhosis who eliminate HCV [2,3]. The level of risk will be deter- Retreatment of genotype 1 patients who failed after a triple
mined in prospective studies.
combination of PegIFN-a, ribavirin, and either telaprevir or
There remains some concern that reinfection due to recurrent
or persistent risk behaviour may negate the potential benefit of boceprevir (Table 7)
treatment. Reported rates of reinfection following successful
HCV treatment among patients at high risk, such as people who IFN-free treatment regimens have been tested in patients
inject drugs or men who have sex with men, are low, with esti- infected with HCV genotype 1 who did not achieve an SVR after
mates of 1–5% risk per year [75–79]. However the ease of IFN-free
therapy may increase the likelihood of reinfection. In order to treatment with the triple combination of PegIFN-a, ribavirin,
maximize the benefit of therapy, the risks of reinfection should
be emphasized to patients at risk, and behavioural modifications and either telaprevir or boceprevir. Experience of retreatment
should be positively reinforced. of such patients with the combination of sofosbuvir and
simeprevir, with or without ribavirin, for 12 weeks is limited
Recommendations to on-going observational real-life cohorts. In the TARGET 2.0
cohort study, previous failure of triple combination therapy
• Non-cirrhotic patients with SVR should be retested for was a significant negative predictor of SVR4 [13]. The role of
ALT and HCV RNA at 48 weeks post-treatment, then the presence, at retreatment start, of protease inhibitor resis-
discharged if ALT is normal and HCV RNA is negative tance-associated variants is unknown. In the TRIO Network
(B1) real-life study [28], the SVR12 rate with sofosbuvir and
simeprevir was 82% (27/33) in patients who failed on triple
• Cirrhotic patients, and probably also patients with combination therapy, not different from patients who failed
advanced fibrosis (F3), with SVR should undergo
surveillance for HCC every 6 months by means of on PegIFN-a and ribavirin alone (80% [60/80]). Retreatment
ultrasound (B1) with the combination of PegIFN-a, ribavirin and sofosbuvir of
• Guidelines for management of portal hypertension and such patients yielded SVR rates of 73% (29/40) and 67% (24/
varices should be implemented, though index variceal 36), respectively [28].
bleed is seldom seen in low-risk patients after the
achievement of SVR (unless additional causes for on- In non-cirrhotic patients who failed on triple combination
going liver damage are present and persist) (A2) therapy, 24 weeks of the combination of sofosbuvir and daclatas-
vir yielded SVR rates of 95% (19/21) and 100% (21/21) without
• Patients with on-going drug use should not be excluded and with ribavirin, respectively [14]. In the ION-2 trial, the SVR
from HCV treatment on the basis of perceived risk of rates in patients without cirrhosis retreated with sofosbuvir
reinfection (B1) and ledipasvir for 12 weeks, without or with ribavirin, were
96% (50/52) and 100% (50/51), respectively; they were 97% (35/
• The risk of reinfection should be explained to individuals 36) and 100% (38/38) after 24 weeks of therapy without and with
with on-going risk behaviour, to positively modify risk ribavirin, respectively [35]. It is noteworthy that in the ION-2
behaviour (B1) trial, the SVR rates in cirrhotic patients retreated with sofosbuvir
and ledipasvir for 12 weeks, without or with ribavirin, were 86%
• Following SVR, monitoring for HCV reinfection through (12/14) and 85% (11/13), respectively; SVR rates increased to
annual HCV RNA assessment should be undertaken in 100% (14/14) and 100% (13/13) after 24 weeks of therapy without
people who inject drugs or men who have sex with men and with ribavirin, respectively [35]. In the SIRIUS study, the SVR
with on-going risk behaviour (B2) rates with sofosbuvir plus ledipasvir, for either 12 weeks with
ribavirin or 24 weeks without ribavirin, were 96% (74/77) and
97% (75/77), respectively [39].
Retreatment of patients who failed after a regimen containing one or
more second-wave DAAs (Table 7)
Sofosbuvir has a high barrier to resistance. Clinically meaningful
resistant HCV variants have been exceptionally reported with
sofosbuvir, and they rapidly disappeared after treatment cessa-
tion. Thus, retreatment strategies should include sofosbuvir. In
contrast, patients exposed to a protease inhibitor (simeprevir,
23
should be carefully and periodically subjected to a thorough clini-
cal assessment, as needed. Retreatment of non-sustained virological responders
Cirrhotic patients who achieve an SVR should remain under Retreatment of patients who failed after a double combination of
surveillance for HCC every 6 months by ultrasound, and for oeso-
phageal varices by endoscopy if varices were present at pretreat- PegIFN-a and ribavirin
ment endoscopy (though first variceal bleed is seldom observed
after SVR). The presence of cofactors for liver disease, such as his- Several studies indicate that patients who failed to achieve an
tory of alcohol drinking and/or type 2 diabetes, may determine
that additional assessments are necessary. The exact duration SVR after treatment with PegIFN-a and ribavirin alone do not
of HCC surveillance in patients with advanced fibrosis or cirrhosis
who achieve an SVR is unknown in the current state of knowl- respond differently to IFN-free regimens from treatment-naïve
edge, but is probably indefinite. Indeed, long-term post-SVR fol- patients. Thus, these patients should be retreated with an IFN-
low-up studies showed that, although it is significantly reduced free regimen according to the above recommendations (Tables
compared to untreated patients or patients who did not achieve 5 and 6).
an SVR, the risk of developing HCC remains in patients with cir-
rhosis who eliminate HCV [2,3]. The level of risk will be deter- Retreatment of genotype 1 patients who failed after a triple
mined in prospective studies.
combination of PegIFN-a, ribavirin, and either telaprevir or
There remains some concern that reinfection due to recurrent
or persistent risk behaviour may negate the potential benefit of boceprevir (Table 7)
treatment. Reported rates of reinfection following successful
HCV treatment among patients at high risk, such as people who IFN-free treatment regimens have been tested in patients
inject drugs or men who have sex with men, are low, with esti- infected with HCV genotype 1 who did not achieve an SVR after
mates of 1–5% risk per year [75–79]. However the ease of IFN-free
therapy may increase the likelihood of reinfection. In order to treatment with the triple combination of PegIFN-a, ribavirin,
maximize the benefit of therapy, the risks of reinfection should
be emphasized to patients at risk, and behavioural modifications and either telaprevir or boceprevir. Experience of retreatment
should be positively reinforced. of such patients with the combination of sofosbuvir and
simeprevir, with or without ribavirin, for 12 weeks is limited
Recommendations to on-going observational real-life cohorts. In the TARGET 2.0
cohort study, previous failure of triple combination therapy
• Non-cirrhotic patients with SVR should be retested for was a significant negative predictor of SVR4 [13]. The role of
ALT and HCV RNA at 48 weeks post-treatment, then the presence, at retreatment start, of protease inhibitor resis-
discharged if ALT is normal and HCV RNA is negative tance-associated variants is unknown. In the TRIO Network
(B1) real-life study [28], the SVR12 rate with sofosbuvir and
simeprevir was 82% (27/33) in patients who failed on triple
• Cirrhotic patients, and probably also patients with combination therapy, not different from patients who failed
advanced fibrosis (F3), with SVR should undergo
surveillance for HCC every 6 months by means of on PegIFN-a and ribavirin alone (80% [60/80]). Retreatment
ultrasound (B1) with the combination of PegIFN-a, ribavirin and sofosbuvir of
• Guidelines for management of portal hypertension and such patients yielded SVR rates of 73% (29/40) and 67% (24/
varices should be implemented, though index variceal 36), respectively [28].
bleed is seldom seen in low-risk patients after the
achievement of SVR (unless additional causes for on- In non-cirrhotic patients who failed on triple combination
going liver damage are present and persist) (A2) therapy, 24 weeks of the combination of sofosbuvir and daclatas-
vir yielded SVR rates of 95% (19/21) and 100% (21/21) without
• Patients with on-going drug use should not be excluded and with ribavirin, respectively [14]. In the ION-2 trial, the SVR
from HCV treatment on the basis of perceived risk of rates in patients without cirrhosis retreated with sofosbuvir
reinfection (B1) and ledipasvir for 12 weeks, without or with ribavirin, were
96% (50/52) and 100% (50/51), respectively; they were 97% (35/
• The risk of reinfection should be explained to individuals 36) and 100% (38/38) after 24 weeks of therapy without and with
with on-going risk behaviour, to positively modify risk ribavirin, respectively [35]. It is noteworthy that in the ION-2
behaviour (B1) trial, the SVR rates in cirrhotic patients retreated with sofosbuvir
and ledipasvir for 12 weeks, without or with ribavirin, were 86%
• Following SVR, monitoring for HCV reinfection through (12/14) and 85% (11/13), respectively; SVR rates increased to
annual HCV RNA assessment should be undertaken in 100% (14/14) and 100% (13/13) after 24 weeks of therapy without
people who inject drugs or men who have sex with men and with ribavirin, respectively [35]. In the SIRIUS study, the SVR
with on-going risk behaviour (B2) rates with sofosbuvir plus ledipasvir, for either 12 weeks with
ribavirin or 24 weeks without ribavirin, were 96% (74/77) and
97% (75/77), respectively [39].
Retreatment of patients who failed after a regimen containing one or
more second-wave DAAs (Table 7)
Sofosbuvir has a high barrier to resistance. Clinically meaningful
resistant HCV variants have been exceptionally reported with
sofosbuvir, and they rapidly disappeared after treatment cessa-
tion. Thus, retreatment strategies should include sofosbuvir. In
contrast, patients exposed to a protease inhibitor (simeprevir,
23
