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12. Standard therapy of chronic hepatitis C virus infection
https://t.me/medicina_free
Sofosbuvir and Ledipasvir (SOF/LDV)
The combination of SOF and LDV is available as a single-tablet ixeddose combination (Harvoni®, Gilead Sciences). The single pill contains the
NS5B polymerase inhibitor SOF (400 mg) and the NS5A inhibitor LDV
(90 mg). SOF/LDV is recommended for patients infected with genotype
1, 4-6. Some data (phase 2 and real-world) are available for GT3 patients
(Cornberg 2017), but as better treatment options for GT3 are available, SOF/
LDV is not recommended for GT3 (EASL 2018). SOF/LDV is not primarily
recommended for patients with chronic kidney disease (CKD with GFR<30
mL/min) but can be used in these patients when no other relevant treatment
options are available, e.g. in patients with decompensated cirrhosis where
protease inhibitors are not recommended. The FDA has updated the label
and now state that that no dosage adjustment is recommended in patients
with any degree of renal impairment including patients on dialysis based
on pharmacokinetic data obtained from studies involving HCV-infected
patients with renal impairment including dialysis patients.
Genoytpe 1
SOF/LDV was studied in the ION-1 (Afdhal 2014b) and ION-3 (Kowdley
2014) trials in treatment-naive patients (Table 6). ION-1 studied 12 vs. 24
weeks SOF/LDV in 865 patients, including cirrhotic patients, and ION-3
investigated 8 vs. 12 weeks in 647 non-cirrhotic patients. In non-cirrhotic
patients, SOF/LDV demonstrated an SVR12 of >99.5% irrespective of the use
of RBV or a 12 or 24-week treatment duration (Afdhal 2014b). Shortening
treatment duration to 8 weeks was evaluated in the ION-3 trial, which showed
an SV of 93% and 94% with and without RBV, respectively (Kowdley et al.,
2014). Relapse occurred more frequently in patients with baseline viral load
>6 million IU/mL (relapse 10% versus 2% without RBV) and male patients
(relapse 8% versus 1%). In real-world data, excellent SV rates are conirmed
with 8 weeks SOF/LDV in patients who fall into this category but the cut-of
of 6 million IU/mL may not be so important (Buggisch2017). However, SV
was slightly diminished to 90% in patients taking proton pump inhibitors
(PPI) (Terrault 2016). The timing of PPI dosing needs consideration. Based on
the approvals of FDA and EMA, treatment can be shortened to 8 weeks in
treatment-naive non-cirrhotic patients with a baseline viral load <6 million
IU/mL (Table 4). AASLD/IDSA does only recommend 8 weeks SOF/LDV in
naïve GT1 patients without cirrhosis who are non-black, HIV-uninfected,
and whose HCV RNA level is <6 million IU/mL (https://www.hcvguidelines.
org/treatment-naive/gt1a/no-cirrhosis).
Cirrhotic patients had an SV of 100% if SOF/LDV was combined with
RBV for 12 or 24 weeks. Without the concomitant use of RBV, an SV of
97% was achieved with 12 or 24 weeks of treatment (Afdhal 2014b). Based
on these results, the FDA recommends 12 weeks of treatment in treatmentnaïve patients with cirrhosis, while the EMA recommends 24 weeks of
treatment, which may be shortened to 12 weeks in patients with a slow
disease progression and the option for retreatment. The concomitant use of
RBV is not recommended in naïve patients with compensated cirrhosis. A
retrospective analysis of >500 patients with cirrhosis conirmed that naïve
patients with compensated cirrhosis can be treated for 12 weeks with SOF/
LDV without RBV (Reddy 2015a). SOF/LDV plus RBV over 12 or 24 weeks has
been investigated in patients with decompensated liver cirrhosis (ChildPugh B and C) before or ater liver transplantation. SVR12 was around 75%
in Child-C patients and more than 80% in Child-B patients. Some patients
died during the study period mainly because of complications related to
hepatic decompensation (Charlton 2015, Manns 2016) (see section cirrhosis
below). Due to limited data at the time of approval in patients with advanced
or decompensated cirrhosis EMA recommended 24 weeks SOF/LDV + RBV
for decompensated cirrhosis pre-/post liver transplant.
The use of IFN-free SOF/LDV in PEG-IFN+RBV treatment-experienced
patients was investigated in the ION-2 trial in cirrhotic and non-cirrhotic
patients (Afdhal 2014a). Previous treatment was either with PEG-IFN+RBV
or PEG-IFN+RBV + TLV or BOC. Overall, no marked diference could be
shown between the treatment duration of 12 or 24 weeks and the addition
of RBV to the SOF/LDV combination in non-cirrhotic patients. 12 weeks of
SOF/LDV achieved an SV of 95%, whereas 24 weeks achieved 99%. The
addition of RBV to 12 weeks of SOF/LDV demonstrated an SV of 100% and
99% for 24 weeks of treatment. In cirrhotic patients the SV rates decreased
to 86% for 12 weeks of SOF/LDV and 82% for SOF/LDV+RBV. Treatment for
24 weeks achieved an SV of 100% regardless of the use of RBV (Table 7).
However, each study arm consisted of only 22 treatment-experienced
cirrhotic patients. Based on these indings the FDA recommended a duration
of 12 weeks for treatment-experienced non-cirrhotic patients and 24 weeks
for treatment-experienced cirrhotic patients with SOF/LDV. Of note, a
retrospective analysis of >500 patients with cirrhosis treated within all
Gilead SOF/LDV Phase 2 and Phase 3 trials revealed that SV ater 12 weeks
SOF/LDV was 5-9% lower in the treatment-experienced patients compared
to naïve patients (Reddy 2015a). The addition of RBV to a 12 weeks regimen
of SOF/LDV demonstrates SV rates of 96% and is comparable with the
24 weeks regimen in treatment-experienced patients with compensated
cirrhosis. Although the addition of RBV is not part of the EMA or FDA label,
it may be considered in treatment-experienced patients with compensated
cirrhosis as an option to shorten treatment, while maintaining a reasonable
SV rate. The EASL IFN and RBV free recommendations recommend 12
weeks SOF/LDV only in treatment-experienced GT1b patients (EASL 2018).
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12. Standard therapy of chronic hepatitis C virus infection
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The eicacy of SOF/LDV in patients with prior exposure to a PI has been
investigated in the ION-2 and the SIRIUS trial (Afdhal 2014a, Bourlière
2015). Overall, response rates were similar to the response rates in patients
who were treated with PEG-IFN+RBV. In total, 231 patients in the ION-2 trial
had previous exposure to a PI. LDV/SOF for 12 weeks led to an SV of 94%,
and for 24 weeks 97%. The addition of RBV resulted in SV rates of 97% and
100%, respectively (Afdhal 2014a). In the SIRIUS trial 155 GT1 patients with
previous PEG-IFN+RBV+PI non-response and compensated cirrhosis have
been treated either with SOF/LDV + RBV for 12 weeks or SOF/LDV + placebo
for 24 weeks. 12 weeks SOF/LDV + RBV or SOF/LDV for 24 weeks provided
similarly high SVR12 rates of 96-97% (Bourlière 2015).
Genotypes 2 and 3
SOF/LDV is not recommended for GT2 (EASL 2018). There are limited
data for SOF/LDV in naïve patients with GT3. 51 patients were treated either
with SOF/LDV or with SOF/LDV+RBV for 12 weeks in the ELECTON-2
study. 64% of patients treated with SOF/LDV achieved SV while 100% of
patients achieved SV with SOF/LDV plus RBV. SOF/LDV+RBV for 12 weeks
has been studied in 50 treatment-experienced patients with GT3. SV was
89% for patients without cirrhosis and 73% for patients with cirrhosis (Gane
2015). EMA (not FDA) approved SOF/LDV + RBV for 24 weeks for GT3 patients
with cirrhosis. Thus, some real-world data are available. For example,
in Germany SOF/LDV + RBV for 24 weeks achieved 89-93% in cirrhotic
patients (Cornberg 2017). Despite these data we will not recommend SOF/
LDV + RBV for 24 weeks for GT3 because alternative treatment options are
available (see below).
Genotype 4
SOF/LDV is approved for GT4 although data were limited at that time.
SOF/LDV given for 12 weeks resulted in 95% SV in 21 GT4 patients (Kapoor
2014). A phase 3 study from Egypt has investigated SOF/LDV in 255 patients.
Treatment-naive patients showed 95% and 90% SV with 8 weeks of SOF/
LDV and SOF/LDV + RBV, respectively, and 98% for 12 weeks SOF/LDV ±
RBV. Among PEG-IFN-experienced patients, SV rates were 94% for 12
weeks SOF/LDV and 100% for SOF/LDV + RBV (Shiha 2018) (Table 8).
Real-world studies have shown >90% SV in GT4 infected patients
(Ahmed 2018).
weeks has been studied in 41 GT5 and 25 naïve GT6 patients. SV for GT5
and GT6 are 95-96% (Abergel 2016, Gane 2015) (Table 8).
Table 6. Pivotal phase 3 studies with SOF/LDV treatment regimens in treatment-naïve
patients with HCV genotype 1. Studies are not head-to-head and it is difficult to compare
SVR between different studies because the populations had significant differences in genetic
and socioeconomic backgrounds.
Study Dosing SVR
ION-1
(Afdhal 2014b)
N=865
ION-3
(Kowdley 2014)
N=647
No cirrhosis
SOF: sofosbuvir, LDV: ledipasvir, RBV: ribavirin
Table 7. Pivotal phase 2-3 studies with DAA treatment regimens in PEG-IFN+RBV based
treatment-experienced patients infected with HCV genotype 1. Studies are not head-
to-head and SVR between studies are difficult to compare because they had significant
differences in genetic and socioeconomic backgrounds.
Study Dosing SVR
IO N-2
(Afdhal et al., 2014a)
n=440 (treatmentexperienced, incl. n=231 pts
with failure to previous PI
-based therapy)
SIRIUS
(Bourlière et al., 2015)
n=155 pts with failure to
previous PI -based therapy
and compensated cirrhosis
63% HCV GT1a
a) 400/90 mg SOF/LDV 12 weeks No cirrhosis: 100%
Cirrhosis: 97%
b) 400/90 mg SOF/LDV + 1000–
1200 mg RBV 12 weeks
c) 400/90 mg SOF/LDV 24 weeks No cirrhosis: 99.5%
d) 400/90 mg SOF/LDV + 1000–
1200 mg RBV 24 weeks
a) 400/90 mg SOF/LDV 8 weeks 94%
b) 400/90 mg SOF/LDV + 1000–
1200 mg RBV 8 weeks
c) 400/90 mg SOF/LDV 12 weeks 95%
a) 400/90 mg SOF/LDV 12 weeks No cirrhosis: 95%
b) 400/90 mg SOF/LDV + 10001200 mg RBV 12 weeks
c) 400/90 mg SOF/LDV 24 weeks No cirrhosis: 99%
d) 400/90 mg SOF/LDV + 10001200 mg RBV 24 weeks
a) 400/90 mg SOF/LDV + 10001200 mg RBV 12 weeks
b) 400/90 mg SOF/LDV 24 weeks 97%
No cirrhosis: 100%
Cirrhosis: 100%
Cirrhosis: 96.9%
No cirrhosis: 100%
Cirrhosis: 100%
93%
Cirrhosis: 86%
No cirrhosis: 100%
Cirrhosis: 82%
Cirrhosis: 100%
No cirrhosis: 99%
Cirrhosis: 100%
96%
Genotype 5-6
Data with IFN free regimens are still rare for GT5 and 6. SOF/LDV for 12
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SOF: sofosbuvir, LDV: ledipasvir, RBV: ribavirin
12. Standard therapy of chronic hepatitis C virus infection
https://t.me/medicina_free
Table 8. Pivotal phase 2-3 studies with DAA treatment regimens in HCV GT4-6 infection.
Studies are not head-to-head and SVR between studies are difficult to compare because they
had significant differences in genetic and socioeconomic backgrounds.
Study Dosing SVR
(Kapoor 2014)
n=21 GT4
(Shiha et al., 2018)
n=255 GT4
(Abergel et al., 2016)
n=41 G T5
(Gane et al., 2015)
n=25 GT6, 92% naïve
SOF: sofosbuvir, LDV: ledipasvir, RBV: ribavirin, Exp.: treatment experienced patients
400/90 mg SOF/LDV 12 weeks 95%
400/90 mg SOF/LDV 8 weeks 95% (naïve)
400/90 mg SOF/LDV + RBV 8 weeks 90% (naïve)
400/90 mg SOF/LDV 12 weeks 94% (IFN-Exp.)
400/90 mg SOF/LDV + RBV 12 weeks 100% (IFN-Exp.)
400/90 mg SOF/LDV + RBV 12 weeks
(SOF exp.)
400/90 mg SOF/LDV 12 weeks 95%
400/90 mg SOF/LDV 12 weeks 96%
100% (SOF-Exp.)
Cirrhosis 89%
Grazoprevir and Elbasvir (GZR/EBR)
The combination of GZ and EB is available as a single-tablet ixeddose combination (Zepatier®, MSD). GZ is a second-generation PI (Summa
2012). EB is a selective inhibitor of the HCV NS5a replication complex
(Coburn 2013). The combination of GZR/EB (Zepatier ®) is a ixed dose
single tablet regimen. The FDA and EMA approved GZR/EB (Zepatier®)
in 2016 for genotype 1 and 4. GZR/EBV can be used in patients with CKD
including hemodialysis. GZR/EB is not recommended for patients with
decompensated cirrhosis based on pharmacokinetic data (EASL 2018).
Genotype 1
Treatment naïve GT1 patients have been treated in phase 2 (C-WOTHY)
and phase 3 (C-EDGE) trials (Table 9) (Sulkowski 2015, Zeuzem 2015,
Cornberg and Manns 2015). Based on this data, naïve patients with GT1
with or without cirrhosis should receive 12 weeks GZR/EB (Table 4 & 5).
Patients with GT1a (naïve as well as PEG-IFN+RBV experienced) who have
baseline NS5A RASs have demonstrated lower SV rates (Table 3). However,
this was only relevant for patients with baseline HCV RNA <800,000 IU/
mL. It is recommended that GT1a patients with baseline NS5A RASs or a
baseline viral load >800,000 IU/mL should be treated for 16 weeks plus RBV.
One study analysed if 8 weeks GZR/EB with or without RBV is suicient
in naïve GT1b patients without cirrhosis. The SV rate was 93-94% (Vierling
2015). Interim data from a phase 3 study (STREAGER) indicate even higher
SV rates of 98% in GT1b patients with F0-2 ibrosis (Abergel 2018). Thus,
the EASL recommendations suggested using 8 weeks GZR/EB in treatment
naïve GT1b patients with F0-2 ibrosis (EASL 2018). However, 8 weeks GZR/
EB is so far only approved in Switzerland and Canada.
GZR/EB has also been evaluated in PEG-IFN+RBV treatmentexperienced GT1 patients in the C-EDGE study (Kwo 2017). 35% of the study
cohort had cirrhosis. Patients were randomised to receive 12 weeks GZR /EBR,
12 weeks GZR/EB plus RBV, 16 weeks GZR/EB or 16 weeks GZR/EB plus
RBV (SV by intention-to-treat analysis is shown in Table 10). All patients
who had a previous relapse and all patients with GT1b achieved SV with
12 weeks GZR/EB in the per protocol analysis. GT1a patients with previous
non-response to PEG-IFN+RBV had lower SV rates with 12 weeks GZR/
EB (91%) and may beneit from 16 weeks GZR/EB plus RBV (100% SVR).
However, the reason for relapse was most likely due to baseline NS5A RASs.
The open-label C-SALVAGE study investigated 12 weeks GZR/EB plus
RBV in 79 patients with GT1 and failure to PEG-IFN+RBV plus either BOC,
TLV or SMV (Forns 2015). Overall 96% of patients achieved SVR12. There
was no signiicant diference between GT1a and GT1b with 93% versus 96%,
respectively. Patients with baseline NS3 RASs had 91% SVR.
A retrospective pooled analysis of all GT1b patients from 11 trials
conformed the high eicacy of 12 weeks GZR/EBR. Only 15 out of 1077 (1.4%)
treated patients experienced a virological failure (Zeuzem 2018).
Several real-world cohorts conirm the excellent safety and eicacy
proile of 12 weeks GZR/EB with 95-99% SV rates in GT1 (Flamm 2018,
Kramer 2018). Interestingly, in real world patients with GT1a have been
treated with 12 weeks GZR/EB without RAS testing. The SV in those
patients was 98% in the TRIO network analysis (Flamm 2018).
Genotype 3
GZR/EB was investigated in combination with SOF in treatment
naïve and experienced patients with GT3 and compensated liver cirrhosis.
Treatment naïve patients were treated for 8 or 12 weeks and achieved 91%
and 96% SVR, respectively, Treatment experienced patients were treated 12
weeks, 16 weeks and 12 weeks plus RBV and achieved 100%, 94% and 94%
SVR, respectively (Foster 2018). SV was 100% in the per protocol analysis.
Thus, 12 weeks GRZ/EB + SOF could be an option for GT3. Actually this
is recommended by AASLD as one of two irst line treatment options in
interferon treatment experienced GT3 patients with cirrhosis (https://www.
hcvguidelines.org/treatment-experienced/gt3/p-r/compensated-cirrhosis).
However, this combination is not approved and other options are available.
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Genotype 4
GZR/EB is also efective against genotype 4. The integrated analysis of
the phase 2-3 trials showed SVR12 rates of 96% (97/101) for treatment-naïve
patients treated with 12 weeks and 100% (8/8) in treatment-experienced
participants treated with 16weeks GZR/EB plus ribavirin (Asselah 2018b)
(Table 11). Baseline NS5A RAS did not impact SV in this analysis. Based
on the data treatment naïve GT4 patients without cirrhosis may be treated
with 12 weeks GZR/EBR. However, EASL recommends 12 weeks GZR/EB
in GT4 (no cirrhosis and cirrhosis) if baseline HCV RNA is <800.000 IU/mL.
Other genotypes
The phase 2 C-SCAPE study evaluated GZR/EBR, with or without
ribavirin (RBV), in participants with HCV genotype 2, 4, 5 or 6 infections.
GT2 patients received 12 weeks GZ + RBV ±EBR. SV was suboptimal
with 73-80%. Those with genotype 4, 5 or 6 infections were randomised to
receive EBR/GZ±RBV for 12weeks. SV in GT4 was 90-100%. GT5 SV
was 25% without and 100% with RBV. GT 6 SV was 75% irrespective of
RBV (Brown 2018). Thus, GZR/EB is not recommended for GT 2, 5 and 6
(EASL 2018).
Table 9. Pivotal phase 2-3 studies with GZR/EBR/ treatment regimens in treatment-naïve
patients with HCV genotype 1. Studies are not head-to-head and it is difficult to compare
SVR between different studies because the populations had significant differences in genetic
and socioeconomic backgrounds.
Study Dosing SVR
C-EDGE TN
(Zeuzem et al., 2015)
n=288 / 94 (treatment-naïve
GT1, 22% cirrhosis)
C-WORTHY, part C
(Vierling et al., 2015)
n=61 (treatment-naïve
GT1b, no cirrhosis)
STRE AGER
(Abergel et al., 2018)
n=90 (treatment-naïve
GT1b, no cirrhosis,
fibroscan <9.5kPa)
RBV: ribavirin, GZR: grazoprevir, EBR: elbasvir
a) 50/100 mg GZR/EBR 12 weeks
(n=288 GT1)
b) Deferred / placebo
(n=94 GT1)
a) 50/100 mg GZR/EBR 8 weeks 94%
b) 50/100 mg GZR/EBR + 10001200 mg RBV 8 weeks
a) 50/100 mg GZR/EBR 8 weeks 97%
GT1a: 92%
No NS5A RAS: 98%
GT1b: 99%
93%
Table 10. Pivotal phase 2-3 studies with GZR/EBR in PEG-IFN+RBV based treatmentexperienced patients infected with HCV genotype 1. Studies are not head-to-head and SVR
between studies are difficult to compare because they had significant differences in genetic
and socioeconomic backgrounds.
Study Dosing SVR
C-EDGE TE
(Kwo et al., 2017)
n=374 (PEG-IFN+RBV
treatment-experienced,
35% cirrhosis GT1)
C-SA LVAG E
(Forns et al., 2015)
n=79 pts. with failure to
previous PI based therapy,
43% cirrhosis
RBV: ribavirin, GZR: grazoprevir, EBR: elbasvir, mI T T: modified ITT excluding virological failures
Table 11. Pivotal phase 2-3 studies with GZR/EBR/ treatment regimens in patients with
HCV genotype 4. Studies are not head-to-head and SVR between studies are difficult to
compare because they had significant differences in genetic and socioeconomic backgrounds.
Study Dosing SVR
C-EDGE TN
(Zeuzem et al., 2015)
n=18 GT4
Pooled analysis
(Asselah et al., 2018)
n=155, N=111 naïve
(13.5% cirrhosis), n=44
exp (41% cirrhosis).
RBV: ribavirin, GZR: grazoprevir ,EBR: elbasvir, Exp.: treatment (PEG-IFN + RBV) experienced
patients
a) 50/100 mg GZR/EBR 12
weeks
b) 50/100 mg GZR/EBR +
1000-1200 mg RBV 12 weeks
c) 50/100 mg GZR/EBR 16
weeks
d) 50/100 mg GZR/EBR +
1000-1200 mg RBV 16 weeks
50/100 mg GZR/EBR + 10001200 mg RBV 12 weeks
50/100 mg GZR/EBR 12 weeks GT4: 10 0%
50/100 mg GZR/EBR 12 weeks (naïve, n=101) 96%
50/100 mg GZR/EBR + RBV 12 weeks (naïve, n=10) 100%
50/100 mg GZR/EBR 12 weeks (exp., n=16) 89%
50/100 mg GZR/EBR + RBV 12 weeks (exp., n=15) 93%
50/100 mg GZR/EBR ± RBV 16 weeks (exp., n=13) 6 0 -100%
GT1a: 90.2%
GT1b: 100%
GT1a: 93.3%
GT1b: 96.6%
GT1a: 93.8%
GT1b: 95.8%
GT1a: 94.8% (mIT T 100%)
GT1b: 100%
96.2%, cirrhosis 94.1%
GT1a: 93.3%
GT1b: 95.5%
NS3 RASs: 91.2%
NS5A RASs: 75%
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Glecaprevir and Pibrentasvir (GLE/PIB)
The combination of GLE and PIB is available as a ixed-dose combination
(Maviret®, Mavyret®, Abbvie). GLE is a NS3/4A protease inhibitor. PIB is a
selective second-generation inhibitor of the HCV NS5a replication complex.
The combination of GLE/PIB (Maviret ®, Mavyret®) was approved in
2017. All genotypes can be treated with GLE/PIB. GLE/PIB can be used in
patients with CKD and hemodialysis but is not recommended in patients
with decompensated cirrhosis.
Genotype 1
The integrated analysis of all phase 2 and 3 studies showed that 8 or 12
weeks GLE/PIB resulted in ≥99% SV in GT1 patients without cirrhosis.
There was only one treatment failure in the 8-week group (Puoti 2018). Thus,
there were no diferences in naïve or treatment-experienced patients. The
EXPEDITION-1 trial investigated 12 weeks GLE/PIB in 87 GT1 patients with
compensated cirrhosis. Only one GT1a patients had a relapse (Forns 2017)
(Table 12). International guidelines recommend 8 weeks GLE/PIB for noncirrhotic GT1 and until recently 12 weeks for patients with compensated
cirrhosis (EASL 2018). Based on the EXPEDITION-8 trial published in 2019
(Brown 2019), 8 weeks GLE/PIB can be recommended in treatment naïve
GT1 patients with cirrhosis. 231 GT1 patients with compensated cirrhosis
(95 GT1a / 136 GT1b) showed 100% (PP) SVR12 ater 8 weeks GLE/PIB.
Thus, 8 weeks GLE/PIB can be recommended in naïve GT1 patienst with
compensated cirrhosis.
Genotype 3
The ENDURANCE-3 study analysed >500 naïve GT3 patients without
cirrhosis. 12 weeks GLE/PIB were compared with 12 weeks SOF + DCV. In
addition, the study contained an additional arm testing 8 weeks GLE/PIB.
SV was ≥95% in all treatment arms (Table 14). There were numerically more
treatment failures in the eight week group (Zeuzem 2018). Most of the patients
treated in the phase 3 ENDURANCE-3 trial had mild F0-F2 ibrosis and only
17% had F3 ibrosis. The integrated analysis of all phase 2 and 3 GT3 studies
showed that 8 or 12 weeks GLE/PIB resulted in 95% SV in treatment-naïve
GT3 patients without cirrhosis, respectively (Puoti 2018). The SUVEYO-II
- Part 3 trial investigated 12 or 16 weeks GLE/PIB in treatment-experienced
(PEG-IFN + RBV ± SOF) without cirrhosis. In addition, treatment-naïve
patients with cirrhosis were treated for 12 weeks and treatment-experienced
patients with cirrhosis for 16 weeks. SV was 91-98% (Wyles 2017) (Table 14).
Based on the results, the EMA label recommends 8 weeks GLE/PIB for naïve
non-cirrhotic GT3 patients and 12 weeks for treatment naïve patients with
cirrhosis. For treatment experienced patients with or without cirrhosis, 16
weeks are recommended. EASL recommends for treatment-experienced
patients without cirrhosis only 12 weeks GLE/PIB (EASL 2018), while AASLD/
IDSA recommends 16 weeks (https://www.hcvguidelines.org/treatmentexperienced/gt3/p-r/without-cirrhosis). The EXPEDITION-8 trial (Brown
2019) demonstrated in 63 GT3 treatment naïve patients with compensated
cirrhosis a 98.4% SVR12 ater 8 weeks GLE/PIB. Thus, 8 weeks GLE/PIB
can be recommended in naïve GT3 patienst with compensated cirrhosis.
However, EMA approval is pending (1/2020).
Genotype 2
The integrated analysis of all phase 2 and 3 studies showed that 8 or 12
weeks GLE/PIB resulted in ≥98% SV in GT2 patients without cirrhosis.
There were two treatment failure in the 8-week group (Puoti et al., 2018).
Thus, there were no diferences in naïve or treatment-experienced patients.
The EXPEDITION-1 trial investigated 12 weeks GLE/PIB in 31 GT2 patients
with compensated cirrhosis. SV was 100% (Forns 2017) (Table 13). A
Japanese study (CETAIN-2) conirmed 100% SV in 18 patients (Toyoda
2017). International guidelines recommend 8 weeks GLE/PIB for noncirrhotic GT2 and until recently 12 weeks for patients with compensated
cirrhosis (EASL 2018). The EXPEDITION-8 trial (Brown 2019) included 26
naïve GT2 patients with compensated cirrhosis. 100% achieved SVR12 ater
8 weeks GLE/PIB. Thus, 8 weeks GLE/PIB can be recommended in naïve GT2
patienst with compensated cirrhosis.
288 289
Genotype 4-6
The integrated analysis of all phase 2 and 3 studies showed that 8 or 12
weeks GLE/PIB resulted in 92-100% SV in GT4- 6 patients without cirrhosis.
However, no virological failure was documented (Puoti 2018) (Table 15). So far
there are only limited data for GT4-6 in patients with cirrhosis. However, no
relapse has been documented with 12 weeks GLE/PIB (Gane 2017b). Thus, the
treatment recommendations for GT4-6 are the same as for GT1, which is 8
weeks for patients without cirrhosis and 12 weeks for patients with cirrhosis
(Table 4 & 5). The EXPEDITION-8 trial (Brown 2019) demonstrated in 13 GT4,
1 GT5 and 9 GT6 treatment naïve patients with compensated cirrhosis a 100%
SVR12 ater 8 weeks GLE/PIB. Thus, 8 weeks GLE/PIB can be recommended
in naïve GT4-6 patients with compensated cirrhosis.
12. Standard therapy of chronic hepatitis C virus infection
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Table 12. Pivotal phase 2-3 studies with GLE/PIB in patients infected with HCV genotype 1.
Studies are not head-to-head and SVR between studies are difficult to compare because they
had significant differences in genetic and socioeconomic backgrounds.
Study Dosing SVR
Integrated analysis of phase 2
and 3 studies
(Puoti et al., 2018)
N=875 GT1, no cirrhosis
(naïve and exp.)
EXPEDITION-1
(Forns et al., 2017)
N=87 GT1, cirrhosis
EXPEDITION-8
(Brown et al., 2019)
N=231 GT1 (95 GT1a / 136
GT1b), naïve, cirrhosis
GLE: glecaprevir, PIB: pibrentasvir, Exp.: treatment (PEG-IFN) experienced patients,
IT T: intention-to-treat analysis, mITT: modified ITT excluding virological failures
Table 13. Pivotal phase 2-3 studies with GLE/PIB in patients infected with HCV genotype 2.
Studies are not head-to-head and SVR between studies are difficult to compare because they
had significant differences in genetic and socioeconomic backgrounds.
Study Dosing SVR
Integrated analysis of phase 2
and 3 studies
(Puoti et al., 2018)
N=436 GT2, no cirrhosis
(naïve and exp.)
EXPEDITION-1
(Forns et al., 2017)
N=31 GT2, cirrhosis
CE RTAIN -2
(Toyoda et al., 2017)
N=18 GT2, cirrhosis
EXPEDITION-8
(Brown et al., 2019)
N=26 GT2, naïve, cirrhosis
GLE: glecaprevir, PIB: pibrentasvir, Exp.: treatment (PEG-IFN + RBV) experienced patients,
mI T T: modified intention-to-treat excluding non-virological failures
a) 300/120 mg GLE/PIB 8
weeks
b) 300/120 mg GLE/PIB 12
weeks
300/120 mg GLE/PIB 12
weeks
300/120 mg GLE/PIB 8
weeks
a) 300/120 mg GLE/PIB 8
weeks
b) 300/120 mg GLE/PIB 12
weeks
300/120 mg GLE/PIB 12
weeks
300/120 mg GLE/PIB 12
weeks
300/120 mg GLE/PIB 8
weeks
99% ITT, 99.8% mITT
99.8% ITT, 100% mITT
GT1a: 98%
GT1b: 100%
GT1: 97.8% ITT, 100%
PP
98% ITT, 99% mITT
99% ITT, 100% mITT
100%
100%
100%ITT, 10 0% PP
Table 14. Pivotal phase 2-3 studies with GLE/PIB in patients infected with HCV genotype 3.
Studies are not head-to-head and SVR between studies are difficult to compare because they
had significant differences in genetic and socioeconomic backgrounds.
Study Dosing SVR
ENDURANCE-3
(Zeuzem et al., 2018)
N=505 GT3, naïve, no
cirrhosis
SURVEYOR-2, part 3
(Wyles et al., 2017)
N=131 GT3, Exp. without
cirrhosis, naïve and exp. with
cirrhosis
EXPEDITION-8
(Brown et al., 2019)
N=63 GT3, naïve, cirrhosis
GLE: glecaprevir, PIB: pibrentasvir, Exp.: treatment (PEG-IFN + RBV ± SOF ) experienced patient s
Table 15. Pivotal phase 2-3 studies with GLE/PIB in patients infected with HCV genot ype 4-6.
Studies are not head-to-head and SVR between studies are difficult to compare because they
had significant differences in genetic and socioeconomic backgrounds.
Study Dosing SVR
Integrated analysis of phase 2 and
3 studies
(Puoti et al., 2018)
N=174 GT4 | n=30 GT5 | n=43
GT6, no cirrhosis
(naïve and exp.)
Integrated analysis of phase 2 and
3 studies
(Gane et al., 2017b)
N=22 GT4 | n=2 GT5, | n=7 GT6,
cirrhosis
(naïve and exp.)
EXPEDITION-8
(Brown et al., 2019)
N=13 GT4, n=1 GT5 and n=9 GT6,
naïve, cirrhosis
a) 300/120 mg GLE/PIB 8
weeks
b) 300/120 mg GLE/PIB 12
weeks*
c) 300/120 mg SOF + DCV 12
weeks*
* 2:1 randomisation
a) Naïve cirrhosis: 300/120
mg GLE/PIB 12 weeks
300/120 mg GLE/PIB 8
weeks
a) 300/120 mg GLE/PIB
8 weeks
b) 300/120 mg GLE/PIB
12 weeks
300/120 mg GLE/PIB
12 weeks
300/120 mg GLE/PIB 8
weeks
95% (149/157)
95% (222/233)
97% (111/115)
98%
95.2% ITT, 98.4% PP,
1 relapse
GT4: 95% ITT, 100% PP
GT5: 100% IT T, 100 PP
GT6: 92% ITT, 100% PP
GT4: 99% ITT, 100% PP
GT5: 100% IT T, 100% PP
GT6: 100% ITT, 100% PP
GT4: 100% ITT, 100% PP
GT5: 100% IT T, 100 PP
GT6: 100% ITT, 100% PP
100%ITT, 10 0% PP
290 291
GLE: glecaprevir, PIB: pibrentasvir, Exp.: treatment (PEG-IFN + RBV) experienced patients,
PP: per-protocol population
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Sofosbuvir and velpatasvir (SOF/VEL)
The combination of SOF and VEL is available as a ixed-dose
combination (Epclusa®, Gilead Sciences). VEL is a selective inhibitor of the
HCV NS5a replication complex. SOF/VEL was approved in 2016 as the irst
regimen that is efective in all genotypes. Based on the phase 3 studies (Feld
2015, Curry 2015b), treatment duration of 12 weeks is the standard for all
GT1,2,4-6 patients and GT3 patients without cirrhosis (Table 4 & 5). For
genotype 3 patients with cirrhosis, baseline RASs may be relevant. SOF/
VEL is not primarily recommended for patients with CKD (GFR<30 mL/
min), but can be used in these patients when no other relevant treatment
options are available, e.g. in patients with decompensated cirrhosis where
protease inhibitors are not recommended. The FDA has updated the label
and now state that no dosage adjustment is recommended in patients
with any degree of renal impairment including patients on dialysis based
on pharmacokinetic data obtained from studies involving HCV-infected
patients with renal impairment including dialysis patients.
Genotype 1
The eicacy of 12 weeks SOF/VEL in previously treated patients with
GT1 with or without cirrhosis was investigated in the ASTRAL-1 trial. In
the ASTRAL-1 trial, 32% of the SOF/VEL treated patients were treatment
experienced. A small number of 56 SOF/VEL treated patients were PEGIFN+RBV+PI treatment-experienced. As the SV rate was 98-99% for all GT1
(Table 16), there was no obvious diference between treatment-experienced
and naïve patients (Feld 2015).
An integrated analysis of patients with advanced ibrosis and cirrhosis
showed 98% SV and 99% SVR, respectively (Asselah 2018a). Patients with
CHILD-B cirrhosis were treated in the ASTRAL-4 study. Here 12 weeks SOF/
VEL was compared with 12 weeks SOF/VEL + RBV and 24 weeks SOF/VEL.
SV rates were 88-100%. There was a numerically higher SV rate with 12
weeks SOF/VEL + RBV (Curry 2015b).
Thus, 12 weeks SOF/VEL is recommended for all GT1 patients, including
cirrhosis or PEG-IFN+RBV+PI treatment-experienced. RBV may be added
in patients with decompensated cirrhosis or treatment duration can be
extended to 24 weeks if patients are ineligible for RBV (EASL 2018) (https://
www.hcvguidelines.org/unique-populations/decompensated-cirrhosis).
Genotype 2
The ASTRAL-2 and 3 trials (Foster 2015) investigated 12 weeks SOF/VEL
versus SOF+RBV in 266 GT2 patients. SV was 99% with 12 weeks SOF/VEL
and 94% w ith 12 weeks SOF+RBV (Table 17). In addition, the ASTRAL-4 study
analysed the responses to 12 weeks SOF/VEL in decompensated cirrhosis
(Curry 2015b). However, the study enrolled only 12 decompensated patients
with GT2. All patients achieved SVR. 12 weeks SOF/VEL is recommended
for all GT2 patients, including compensated cirrhosis. RBV may be added
in patients with decompensated cirrhosis or treatment duration can be
extended to 24 weeks if patients are ineligible for RBV, as data are limited
for this speciic group of patients (EASL 2018) (https://www.hcvguidelines.
org/unique-populations/decompensated-cirrhosis).
Genotype 3
The ASTRAL-2 and 3 trials (Foster 2015) investigated 12 weeks SOF/VEL
versus SOF+RBV in 552 GT3 patients. For GT3, the additional beneit for SOF/
VEL was higher (SV 95% versus 80%) (Table 18). The integrated analysis of
patients with ibrosis and cirrhosis showed 99% SV in patients with ibrosis
but only 91% SV in patients with cirrhosis (Asselah 2018a). Treatmentexperienced patients with advanced ibrosis and cirrhosis showed 90% SV
versus 97% in naïve patients (Asselah 2018a). Patients with baseline RAS in
GT3 and advanced ibrosis and cirrhosis achieved SV in only 79% with 12
weeks SOF/VEL (Asselah 2018a). This was one reason that EASL does not
recommend 12 weeks SOF/VEL without RBV in GT3 cirrhosis, if RAS testing
is not available (EASL 2018). In the POLARIS-3 study, 109 GT3 patients
with cirrhosis received SOF/VEL. The only 2 virological treatment failures
were prior PEG-IFN + RBV non-responder (Jacobson et al., 2017). AASLD/
IDSA guidance recommends 12 weeks SOF/VEL in naïve GT3 patients with
cirrhosis and 12 weeks SOF/VEL/VOX or SOF/VEL + RBV in treatmentexperienced patients with cirrhosis, if RAS test is not available (https://
www.hcvguidelines.org/treatment-experienced/gt3/p-r/compensatedcirrhosis). A randomised trial in 204 GT3 patients with cirrhosis showed
91% SV with 12 weeks SOF/VEL and 96% with 12 weeks SOF/VEL + RBV.
In this study, treatment-experienced GT3 patients with cirrhosis had even
better responses with 12 weeks SOF/VEL compared with naïve patients. The
impaired SV was related to NS5A RAS (Table 18). Patients without NS5A
RAS (Y93H) had 96% SV with or without RBV (Buti 2018). The frequency of
baseline NS5A RAS (Y93H) may impact the response to 12 weeks SOF/VEL
in patients with GT3 cirrhosis. Thus, in areas with a high frequency of NS5A
RAS, GT3 patients with cirrhosis should either receive additional RBV or
RAS testing should be performed. Otherwise alternative treatment options
should be preferred.
In contrast, patients with mild ibrosis may require only 8 weeks SOF/
VEL. 8 weeks SOF/VEL in 90 patients receiving opiate substitution therapy
(OST) showed 93% SV but no patients had a virological failure (Boyle 2018)
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(Table 18). However, in 2018 8 weeks SOF/VEL are not recommended by
international guidelines.
The ASTRAL-4 study analysed the responses to 12 weeks SOF/VEL in
decompensated cirrhosis (Curry 2015b). SV with 12 weeks SOF/VEL in GT3
patients was low with 50%. The addition of RBV increased SV rate to 85%
(Table 18). Thus, RBV needs to be added in patients with decompensated
cirrhosis and GT§ infection. For patients with decompensated cirrhosis
who are RBV ineligible, SOF/VEL for 24 weeks is currently recommended,
although this did not result in higher SV rates compared to 12 weeks in
the ASTRAL-4 trial. However, the number of patients analysed was quite
small. (EASL 2018) (https://www.hcvguidelines.org/unique-populations/
decompensated-cirrhosis).
Genotype 4-6
ASTRAL-1 included 116 GT4 treatment-naive patients without cirrhosis
or with compensated cirrhosis, all of whom achieved SVR12 (100%) (Feld
2015). In the POLARIS-2 study, 57 patients with GT4 received 12 weeks SOF/
VEL and 98% achieved SV (Table 19) (Jacobson 2017).
ASTRAL-1 included 35 GT5 and 41 GT6 treatment-naive patients without
cirrhosis or with compensated cirrhosis. 97% of GT5 and 100% of GT6
patients achieved SV with 12 weeks SOF/VEL (Feld 2015).
Treatment recommendations are the same as for GT1 patients (EASL
2018).
Table 16. Pivotal phase 3 studies with SOF/VEL treatment regimens in treatment-naïve
patients with HCV genotype 1. Studies are not head-to-head and it is difficult to compare
SVR between different studies because the populations had significant differences in genetic
and socioeconomic backgrounds.
Study Dosing SVR
AS T R AL-1
(Feld et al., 2015)
n=393 (GT1, 19%
cirrhosis, 68-72%
naive)
AS T R AL- 4
(Curry et al., 2015)
n=207(G T1,
decompensated
cirrhosis, 36-53%
naive)
GT: genotype, RBV: ribavirin, SOF: sofosbuvir, VEL: velpatasvir,
Exp.: treatment-experienced patients
Table 17. Pivotal phase 3 studies with SOF/VEL treatment regimens in HCV GT2 infection
(naïve and treatment-experienced). Studies are not head-to-head and SVR between studies
are difficult to compare because they had significant differences in genetic and socioeconomic
backgrounds.
Study Dosing SVR
AS T R AL-2
(Foster et al., 2015)
GT2: 266
14-30% cirrhosis
a) 400/100mg SOF/VEL 12 weeks
(n=328)
b) placebo
(n=65)
a) 400/100mg SOF/VEL 12 weeks
(n=90)
b) 400/100mg SOF/VEL + 1000-1200 mg
RBV 12 weeks
(n=87)
c) 400/100mg SOF/VEL 24 weeks
(n=90)
a) 400/100 mg SOF/VEL 12 weeks 99%
b) 400 mg SOF + 1000-1200 mg RBV 12 weeks 94%
GT1a: 98%
GT1b: 99%
GT1a: 88%
GT1b: 89%
GT1a: 94%
GT1b: 100%
GT1a: 93%
GT1b: 88%
294 295
Pooled analysis
(Asselah et al., 2018)
n=155, N=111 naïve
(13.5% cirrhosis),
n=44 exp (41%
cirrhosis).
GT: genotype, RBV: ribavirin, SOF: sofosbuvir, VEL: velpatasvir,
Exp.: treatment-experienced patients
a) 400/100mg SOF/VEL 12 weeks
(n=90)
b) 400/100mg SOF/VEL + 1000-1200 mg RBV
12 weeks
(n=87)
c) 400/100mg SOF/VEL 24 weeks
(n=90)
100%
100%
75% (3/4)
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Table 18. Pivotal phase 3 with SOF/VEL treatment regimens in HCV GT3 infection (naïve
and treatment-experienced). Studies are not head-to-head and SVR between studies are
difficult to compare because they had significant dif ferences in genetic and socioeconomic
backgrounds.
Study Dosing SVR
AS T R AL- 3
(Foster et al., 2015)
n=552
14-30% cirrhosis
AS T R AL- 4
(Curry et al., 2015)
n=39
with decompensated
cirrhosis
POLARIS-3
(Jacobson et al., 2017)
n=109, cirrhosis, n=32 exp.
(Pianko et al., 2015)
n=105 GT3 treated with
400/100 mg SOF/VEL,
n=52 with cirrhosis
(Buti et al., 2018)
N=204 with cirrhosis, 27%
exp., 19-22% NS5A RAS
(Boyle et al., 2018)
n=90 GT3, F0-F3 (31%
F3), mainly OST patients
GT: genotype, RBV: ribavirin, SOF: sofosbuvir, VEL: velpatasvir, Exp.: treatment-experienced
patients, m IT T: modified intention-to-treat excluding non-virological failures
Table 19. Pivotal phase 3 with SOF/VEL treatment regimen in HCV GT4-6 infection. Studies
are not head-to-head and SVR between studies are difficult to compare because they had
significant differences in genetic and socioeconomic backgrounds.
Study Treatment SVR
AS T R AL-1
(Feld et al., 2015)
n=116 GT4 | 35 GT5 | 41 GT6
AS T R AL- 4
(Curry et al., 2015)
n=8 GT4 | 1 GT6 with
decompensated cirrhosis
GT: genotype, RBV: ribavirin, SOF: sofosbuvir, VEL: velpatasvir,
Exp.: treatment-experienced patients
a) 400/100 mg SOF/VEL 12 weeks 95%
exp. cirrhosis 89%
b) 400 mg SOF + 1000-1200 mg
RBV 24 weeks
a) 400/100mg SOF/VEL 12 weeks
(n=90)
b) 400/100mg SOF/VEL + 100 01200 mg RBV 12 weeks (n=87)
c) 400/100mg SOF/VEL 24 weeks
(n=90)
400/100 mg SOF/VEL 12 weeks
(control group)
a) 400/100 mg SOF/VEL 12 weeks 100% no cirrhosis
b) 400/100 mg SOF/VEL weeks +
1000-1200 mg RBV 12 weeks
a) 400/100 mg SOF/VEL 12 weeks 91% (5 relapser)
b) 400/100 mg SOF/VEL weeks +
1000-1200 mg RBV 12 weeks
400/100 mg SOF/VEL 8 weeks 93% ITT, 100 mITT
400/100 mg SOF/VEL 12 weeks GT4: 10 0%
a) 400/100 mg SOF/VEL 12 weeks G T4 : 4/4
b) 400/100 mg SOF/VEL weeks + 1000-
1200 mg RBV 12 weeks
c) 400/100 mg SOF/VEL 24 weeks GT4: 2/2,
80%
exp. cirrhosis 58%
50%
85%
50%
96%, mITT 98%
Naïve: 100% mITT
Exp.: 93.75% mITT
92% (24/26) cirrhosis
100% no cirrhosis
96% (25/26) cirrhosis
Naïve 89%, exp. 96%
NS5A-RAS 84%
96% (2 relapser)
Naïve 96%, exp. 96%
NS5A-RAS 96%
GT5: 97%
GT6: 10 0 %
GT4: 2/2
GT6: 1/1
Sofosbuvir and velpatasvir and voxilaprevir (SOF/VEL/VOX)
Voxilaprevir (VOX) is an HCV N3/4A protease inhibitor (Rodriguez-Torres
2016) that is combined with SOF/VEL in a single tablet (Vosevi®). SOF/VEL/
VOX was approved in 2017. It is the irst approved RBV free DAA therapy
for patients who failed an NS5A-containing DAA regimen (see Treatment of
patients with prior DAA treatment failure below). SOF/VEL/VOX has also
been approved for DAA naive patients by EMA (not FDA) but as other options
are available SOF/VEL/VOX should be restricted to patients with DAA failure.
SOF/VEL/VOX may be used with caution in patients with CKD (GFR<30 mL/
min) and hepatic impairment due to the combination of sofosbuvir and the
protease inhibitor voxilaprevir.
Treatment of DAA naïve patients
Two phase 3 studies investigated SOF/VEL/VOX in DAA naïve patients.
POLARIS-2 compared the eicacy of 8 weeks of SOF/VEL/VOX to 12 weeks of
SOF/VEL. The study included 941 patients infected with all HCV genotypes
with or without cirrhosis, except patients with genotype 3 and cirrhosis.
POLARIS-3 enrolled 219 GT3 patients with cirrhosis (Jacobson 2017). 8 weeks
SOF/VEL/VOX missed the pre-speciied non-inferiority criteria, mainly
because of a lower SV in GT1a patients (Table 20). The lower SV in GT1a
patients was associated with the Q80K variant. However, 8 weeks SOF/VEL/
VOX showed a similar SV compared with 12 weeks SOF/VEL in GT3 patients
with and without compensated cirrhosis. At least, 29% of GT3 patients treated
with SOF/VEL/VOX had platelets <100/nl. Thus, 8 weeks SOF/VEL/VOX can
be an option for all GT3 patients according to the EMA label. However, EASL
recommends 12 weeks SOF/VEL/VOX for GT3 patients with cirrhosis (EASL
2018). AALSD/IDSA considers also 12 weeks SOF/VEL/VOX but speciically
only for naïve GT3 patients with cirrhosis if baseline Y93H is present (https://
www.hcvguidelines.org/treatment-naive/gt3/compensated-cirrhosis) or
in PEG-IFN+RBV experienced GT3 patients with cirrhosis (https://www.
hcvguidelines.org/treatment-experienced/gt3/p-r/compensated-cirrhosis).
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Table 20. Pivotal phase 3 studies with SOF/VEL/VOX treatment regimens in DAA naive
patients with HCV genotype 1-6. Studies are not head-to-head and it is difficult to compare
SVR between different studies because the populations had significant differences in genetic
and socioeconomic backgrounds.
Study Dosing SVR
POLARIS-2
(Jacobson et al., 2017)
n=941 GT1-6, 23-24%
exp., 18-19% cirrhosis
(GT3 only no cirrhosis)
POLARIS-3
(Jacobson et al., 2017)
n=219 GT3
with cirrhosis
GT: genotype, SOF: sofosbuvir, VEL: velpastasvir, VOX: voxilaprevir
a) 400/100mg SOF/VEL 12 weeks
(n=440)
b) 400/100/100mg SOF/VEL/VOX 8 weeks
(n=501)
a) 400/100mg SOF/VEL 12 weeks
(n=109)
b) 400/100/100mg SOF/VEL/VOX 8 weeks
(n=110)
GT1a: 99%
GT1b: 97%
GT2: 100%
GT3: 97%
GT4: 98%
GT5: GT6: 10 0 %
GT1a: 95%
GT1b: 97%
GT2: 97%
GT3: 99%
GT4: 94 %
GT5: 94
GT6: 10 0 %
GT3: 96%
GT3: 96%
Treatment of patients with prior DAA treatment failure
As more patients are treated, the size of the population of patients
who fail to achieve SV with DAA-including regimens might expand in
the future. Retreatment of patients with previous treatment failure is one
important topic in the treatment of chronic hepatitis C. RAS testing may be
performed (Dietz 2018) to select the therapy based on susceptibility to the
corresponding drug class.
However, the only EMA approved RBV free treatment for patients with
DAA treatment failure in 2018 is SOF/VEL/VOX.
The POLARIS-4 study investigated patients with HCV genotype 1, 2, or
3 infection who had previously received a DAA regimen but not an NS5A
inhibitor. Patients received either SOF/VEL/VOX or SOF/VEL for 12 weeks. An
additional 19 GT4 patients were treated with SOF/VEL/VOX. Overall, SV was
98% with SOF/VEL/VOX and 90% with SOF/VEL (Bourlière 2017) (Table 21).
NS5A inhibitors are part of all currently used DAA combinations. NS5A
RAS, unlike NS3 and NS5B RAS, appear to maintain the viability of the virus
ater unsuccessful treatment with an NS5A inhibitor containing therapy.
Thus, NS5A remain at high frequency in the majority of patients for more than
ive years ater the end of treatment (Pawlotsky 2016). As a result, retreatment
of patients ater NS5A failure is of special importance. The POLARIS-1 trial
investigated 263 patients who failed previous NS5A based therapy. Overall,
the SV was 96% with 12 weeks SOF/VEL/VOX (Bourlière 2017) (Table 21). SV
was 99% in patients without cirrhosis and 93% in patients with cirrhosis. 147
of the 152 patients in the placebo group have been treated later with 12 weeks
SOF/VEL/VOX and 97% achieved SV (Bourlière 2018). The recommended
treatment duration for SOF/VEL/VOX for DAA experienced patients is 12
weeks. However, GT3 patients with c irrhosis (espe cially those with NS5A RAS)
may be considered for additional RBV to minimise the relapse risk (https://
www.hcvguidelines.org/treatment-experienced/gt3/daa). In the POL ARIS -4 study,
all 4 GT3 patients who experienced a relapse had cirrhosis (Bourlière 2017).
In patients with contraindications for SOF/VEL/VOX (i .e. decompensated
cirrhosis), SOF/VEL + RBV for 24 weeks could be an alternative and is not
of-label use according to the EMA label.
However, not all patients with previous DAA therapy must be treated
with SOF/VEL/VOX. Data for retreatment of patients with HCV GT1
infection and failure to previous therapy with PEG-IFN+RBV + TLV or BOC
are available for SOF/LDV, GZR/EB and SOF/VEL regimens (see above).
Thus, these combinations can be used for these patients.
Also patients that failed a SOF + SMV retreatment do not necessarily
require SOF/VEL/VOX.
Retreatment with GLE/PIB for 12 weeks could be an option. In the
MAGELLAN-1 Part 2 study, GLE/PIB was investigated in patients who failed
previous NS3/4A protease and/or NS5A inhibitor-containing therapy.
SVR12 was achieved by 89% (39 of 44) and 91% (43 of 47) of patients who
received 12 and 16 weeks GLE/PIB, respectively (Poordad 2018) (Table 22).
Patients with failure to NS3/4A inhibitor-based therapy showed 100% SV
even with 12 weeks therapy. However, there were only 3 patients enrolled
who failed SOF + SMV but all were treated for 16 weeks. In another study,
patients who failed NS5A inhibitor-based therapy were treated 12 (with
ribavirin in cirrhosis) or 16 weeks with GLEB/PIB. Based on the results,
patients with cirrhosis require 16 weeks therapy (Lok 2018).
Of note, GLE/PIB is only approved for DAA failures in the FDA label and
not in EMA.
Finally, t he combination of GLE/PIB + SOF + RBV would be the most powerful
therapy because it combines SOF with GLE and the second-generation NS5A
inhibitor PIB, which has a higher barrier to NS5A resistance. This combination
has been used in the MAGELLAN-3 study in patients who failed prior GLE/PIB
therapy. Only one of 23 patients showed a relapse ater 12 weeks or 16 weeks
therapy (Wyles 2018). EASL recommends 12 weeks GLE/PIB + SOF for patients
ater DAA failure with complex NS5A RAS proiles or in combination with RBV
for patients who failed multiple DAA therapies (EASL 2018).
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