:
Соф+дак и соф+велпа и резистентность.
PS-155
High sustained virologic response rates in hepatitis C virus
genotype 3 patients with and without cirrhosis treated with
daclatasvir/sofosbuvir or velpatasvir/sofosbuvir ± ribavirin
according to baseline resistance analysis
Background and Aims: Hepatitis C virus (HCV) genotype (GT) 3 is
currently the most difficult-to-treat genotype. Suboptimal sustained
virologic response (SVR) rates have been observed in patients who
received sofosbuvir (SOF) + ribavirin (RBV). Treatment with daclatasvir
(DCV) or velpatasvir (VEL) in combination with SOF ± RBV has
been shown to be superior to SOF/RBV alone. However, resistanceassociated
substitutions (RASs) in the NS5A gene were associated
with lower SVR rates with either treatment regimen. Here we
investigated the efficacy of individually tailored treatment based on
resistance analysis.
Methods: Patients with HCV GT3 infection were treated with DCV/
SOF ± RBV for 12–24 weeks or VEL/SOF ± RBV for 12 weeks according
to baseline (BL) RASs (A30K, Y93H), prior treatment failure and
presence of cirrhosis. Population sequencing of the NS5A coding
region was performed for all patients. In DCV-treated patients, in
whom NS5A RASs were detected, RBV was added and treatment was
extended to 24 weeks if they also had cirrhosis. RBV was also added
and treatment extended in patients with prior treatment failure and
cirrhosis regardless of BL RASs. In VEL-treated patients, RBV was
added if BL RASs or cirrhosis were present.
Results: In total,130 patients with HCV GT3 of whom 63%were male,
42% had cirrhosis, and 45% had failed previous therapy were treated
with DCV/SOF ± RBV (n = 97) or VEL/SOF ± RBV (n = 33). The A30K RAS
was detected in 15% and 4% of DCV- and VEL-treated patients. Y93H
was detected in 10% and 15%, respectively. Treatmentwas extended in
41% of DCVpatients. RBVwas added in 46% and 40% of patients treated
with DCV and VEL, respectively. In DCV patients, SVRwas achieved in
95% (n = 70/74; excluding patients lost to follow-up, who died or
discontinued treatment early due to non-treatment related reasons).
The SVR rate was 88% in patients with cirrhosis and prior treatment
failure (n = 22/25). There were only 4 virologic relapsers, all of who
had no RASs at baseline but Y93H was the dominant variant after
treatment failure. Three of 4 failure patients had been treated with
DCV/SOF + RBV for 24 weeks because of prior treatment failure and
cirrhosis. In contrast, all patients with baseline RASs achieved SVR. Full
SVR data for all DCV- and VEL-treated patients will be presented.
Conclusions: In this real-world cohort of HCV GT3-infected patients,
tailored treatment with consideration of baseline resistance analysis,
presence of cirrhosis and/or prior treatment failure achieved high
rates of virologic response.
Резистентность 3 генотип.
THU-202
Characterisation of resistance associated substitutions in direct
acting antivirals treatment naive patients with genotype 3
hepatitis C virus
Background and Aims: The development of direct acting antivirals
(DAAs) has led to a revolution in hepatitis C virus (HCV) therapy.
Efficacy in genotype (gt) 3 has been shown to be lower than in other
genotypes. The reasons for failure are unclear but viral variants,
carrying resistance associated substitutions (RASs), which occur at
baseline or in response to therapymay play a role. Currently gt3 RASs
are poorly characterised and the prevalence is not well understood.
Here, we report the prevalence of RASs in a cohort of DAA treatment
naïve patients infected with gt3 HCV. We then evaluate the effect of
these RASs on the efficacy of Daclatasvir and Sofosbuvir in the S52
gt3a replicon.
Methods: Baseline samples were obtained from 530 patients
enrolled in a clinical trial (BOSON Study). Sequencing library’s were
created using a probe based enrichment technique (ve-seq) and
sequenced using Ilumina Mi-seq to generate full viral genome
sequences. Sequence data were analysed and viral quasispecies
variants with a frequency as low as <1% were called. A literature
review was performed to identify RASs to currently approved DAA’s.
Where data on gt3 RASs where unavailable gt1 data was used as a
reference. Identified RASs to Daclatasvir and Sofosbuvir were then
tested using the S52 Delta Neomycin gt3a replicon using the Huh7.5-
SEC14L2 cell line.
Results: From the literature review, 36 known Sofosbuvir and
Daclatasvir associated RASs were identified at 8 genomic positions
in the NS5a and NS5b. Full sets of virus haplotype data for these
positions was obtained from 464 patients. RASs to Daclatasvir were
detected in 16.2% (n = 75) of patients with Y93H and A30K being the
most prevalent. RASs to Sofosbuvir were observed in 1% (n = 5) of
patients and no association with SVR was observed. We identified
RASs to both Daclatasvir and Sofosbuvir in <1% (n = 1) of patients. The
NS5a RASs Y93H, A30K, P58H and the NS5b RASs S282T V321Awere
shown to infer resistance to Daclatasvir or Sofosbuvir respectively in
the gt3a replicon (Figure 1).
Conclusions: This study reports the prevalence of RASs in the largest
cohort of gt3 DAA treatment-naïve infected patients. Using next
generation full genome sequencingwe identified RASs in up to 17% of
the patients. Characterising the gt3-associated RASs we found that
only 4 of the previously identified RASs for Sofosbuvir and Daclatasvir
were resistant in the gt3 replicon.We also report a modest effect from
P58H substitution to Daclatasvir, while no effect was observed from
L159F to Sofosbuvir.
КИ соф+дак на подростках в Египте:
THU-412
A pilot study for safety and efficacy of 12 weeks sofosbuvir plus
daclatasvir with or without ribavirin in egyptian adolescents with
chronic hepatitis C virus Infection
M. El-Sayed1,M. Hassany2,N. Asem3. 1Department of Pediatrics, Faculty
of Medicine, Ain Shams University; 2Tropical Medicine Department,
National Hepatology & Tropical Medicine Research Institute; 3Public
Health Department, Faculty of Medicine, Cairo University, Cairo, Egypt
E-mail:
mohamadhassany@yahoo.com
Background and Aims: Egypt hosts one of highest prevalence and
incidence rates of HCV worldwide with nearly half of its population
below the age of 25 years. Its national model treatment program for
HCV was scaled up with the introduction of DAAs targeting
elimination in 7–10 years’ time period. Global and national
elimination targets cannot be achieved without inclusion of children
and adolescents in this model. This prompted the urgent need for
evaluation of safety and efficacy of the currently available short
duration, pangenotypic regimen, sofosbuvir plus daclatasvir ± ribavirin,
in HCV-infected adolescents below 18 years.
Methods: This prospective pilot study included 13 adolescents
between 15 and 17 years (median: 16 years) with chronic HCV
infection. All subjects were negative for HBV, HIV and had no comorbidities;
while cirrhotics beyond CHILD “A” scorewere excluded.
The studywas approved by an independent ethical committee and all
subjects and their legal guardianswere consented before inclusion in
the study. Patients are classified according to the presence of cirrhosis
(defined as ≥12.5 Kpa by fibroscan) into: Group (1): non-cirrhotics
(n = 9): received sofosbuvir+daclatasvir for 12 weeks. Group (2):
cirrhotics (n = 4): received sofosbuvir + daclatasvir + ribavirin for 12
weeks.
Results: The medianweight of included subjectswas 45.0 kg and BMI
20.0 kg/m2. At baseline the mean ALT, AST, serum bilirubin and
albumin were 69.5 (±55.2) IU/L, 63.3 (±51.5) IU/L, 0.66 (±0.26) mg/dl
and 3.9 (±0.37) g/dl respectively with normal hemogram and
bleeding profile. The median baseline HCV-RNA level was 7.2 × 105
(range: 2.1 × 104–17 × 106) IU/ml. All 13 patients completed 12 weeks
of treatment with no encountered serious adverse events. Mild
adverse events were noted in the form of mild headache, dizziness,
itching and hemoglobin reduction of no more than 1 gm/dl (in the
ribavirin arm). All patients in both treatment arms showed sustained
viral response at 12 weeks post treatment (100%).
Conclusions: Sofosbuvir plus dacalatasvir is a safe, highly efficacious
pangenotypic regimen in adolescents with chronic HCV and added
ribavirin in cirrhotics does not increase the risk of adverse events.
This pilot study prompts larger scale clinical trials in adolescents and
children particularly in elimination models adopting treatment as
prevention.
Соф+дак 8 недель для наивных без цирроза
THU-249
Efficacy and safety of sofosbuvir and daclatasvir for 8 weeks in
treatment-naïve non-cirrhotic patients with chronic hepatitis C
virus Genotype 3 Infection
Background and Aims: HCV GT 3 is the second most common GT
worldwide. For non-cirrhotic patients with HCV GT 3 infection, the
EASL and AASLD/IDSA guidelines recommend treatment with the
IFN- and RBV-free regimen of DCV + SOF for 12 weeks, according to
the results of the ALLY-3 phase 3 study, in which this patient
group achieved a 96% SVR12 rate. The objective of this pilot study
was to investigate the efficacy and safety of 8 weeks of DCV + SOF
in treatment-naïve patients with HCV GT 3 infection without
cirrhosis.
Methods: This ongoing pilot study is a multicenter, open label, single
arm trial that enrolled treatment-naïve GT-3 patients without
cirrhosis. Key exclusion criteria included the presence of cirrhosis,
as determined by either a FibroScan score ≥12.5 kPa or a FibroTest
score of ≥0.75, and baseline HCV RNA level >6,000,000 IU/mL. The
regimen was DCV 60 mg and SOF 400 mg once daily for 8 weeks.
Efficacy was calculated as the percent of patients achieving SVR12
(HCV RNA <LLOD). Additional endpoints included the proportion of
patients experiencing virologic breakthrough or relapse. Adverse
events and clinical laboratory abnormalities were monitored to
assess safety and tolerability. Analysis of baseline RASs is ongoing and
will be presented; if a patient does not achieve SVR12, additional
resistance testing will be performed.
Results: 50 patients, median age: 50 (range: 36–56), median
FibroScan score: 7.65 kPa (range: 5.8–8.7; highest score: 11.5 kPa),
median HCV RNA level: 5.83 (5.12–6.22) Log10 IU/mL, were included.
At the time of the present analysis, the SVR4 and SVR12 rates were
94.3% (33/35) and 92.3% (24/26), respectively. Two patients relapsed
at post-treatment week 4.
Conclusions: The efficacyand safety of an 8-week DCV + SOF regimen
for chronic HCV GT3 in treatment-naïve patients without cirrhosis is
being investigated. Baseline characteristics, safety, SVR12 results and
resistance analysis for the 50 patients will be presented at the
meeting.
Соф+дак+риб до и после трансплантации.
THU-252
Real world efficacy of 12 weeks sofosbuvir, daclastivir with
ribavirin among cirrhotic pre and post-transplant genotype 3
hepatitis C infected patients
Background and Aims: Current EASL guidelines recommend
combined Sofosbuvir and Daclatasvir with Ribavirin (SOF + DCV +
RBV) for 24 weeks in compensated/decompensated cirrhosis for
genotype 3 patients.We investigated response to 12weeks treatment
in a large cohort of pre and post-transplant predominantly
compensated cirrhotic genotype 3 patients.
Methods: All patients who received a single dose and treated in 8
treatment centres within our hospital network included. SVR12 rates
for all patients who started treatment are reported on an intention to
treat (ITT) basis and we include a modified intention to treat (mITT)
analysis excluding non virological failures.
Results: 156 patients ((M:F) 109:47) mean age 51.5were commenced
on treatment. The overall SVR12 rate was 88.5% (138/156) (ITT) and
95.8% (138/144) (mITT). 2 patients stopped treatment without side
effects. Five patients did not attend for confirmation of SVR12, three
patients died on treatment (2 due to cardiac arrest, 1 due to sepsis)
and a further patient died following completion of treatment prior to
SVR12 (hepatocellular carcinoma). mITT SVR12 for patients with
compensated and decompensated cirrhosis (Child Pugh B/C) were
96.7% (116/120) and 82% (23/28) respectively. 96.4% (80/83) of
patients with previous exposure to interferon and ribavirin achieved
SVR12. All patients with HIV co infection achieved SVR (n =
. 89% of
liver transplant patients achieved SVR. 18%(5/28) of the decompensated
cohort (Child Pugh B/C) had died within 2 years of commencing
treatment.
Conclusions: SOF + DCV + RBV for 12 weeks achieved real world
SVR12 rates comparable with 24 weeks treatment in cirrhotic
genotype 3 patients or 12 weeks sofosbuvir/velpastasvir. This is the
largest reported cohort of post-transplant genotype 3 patients with
advanced fibrosis. Our data suggests 12 weeks treatment for all
cirrhotic patients may be considered regardless of previous interferon
and ribavirin exposure.
12 недель соф+дак+риб с циррозом.
THU-258
12 weeks of sofosbuvir, daclatasvir and ribavirin for GT3 patients
with cirrhosis
Background and Aims: The Ally 3+ trial suggested equivalent
results between 12 and 16 weeks of treatment with Sofosbuvir/
Daclatasvir/Ribavirin (SOF/DAC/RBV), amongst genotype 3 (GT3)
patients with cirrhosis (mITT SVR 88% vs 89%). However numbers
were small. We set out to examine the SVR rates amongst a cohort
of patients with cirrhosis treated for 12 weeks in routine clinical
practice.
Methods: Patients attending Greater Glasgow and Clyde treatment
centres, commencing 12 weeks SOF/DAC/RBV prior to 01/09/2016
with a diagnosis of cirrhosis were identified from the Scottish
Hepatitis C Database. Baseline data on Age, Child’s Score, Liver
stiffness (LSM), platelet count, viral load, premature discontinuation,
week 4 PCR and SVR12 were recorded.
Results: 58 patients were identified. Baseline characteristics are
summarised in the Table below. The cohort had advanced disease
with nearly half being Child’s B/C. 30% were treatment experienced
including 4 patients previously treated with SOF regimens. 2
patients discontinued treatment prematurely, one due to admission
to a psychiatric facility (achieved SVR12) and one due to death
from an overdose of recreational drugs (excluded from SVR12
analysis).
Of patients thus far attending for post treatment bloods, 45/58
(88.2%) have achieved SVR12. Rates were similar between treatment
naive (31/36 (86.1%)) and treatment experienced (14/15 (93.3%), p =
0.65) patients. Child’s A patients had numerically higher SVR rates
than Child’s B/C (24/26 (92.3%) vs 21/25 (84%), p = 0.42).
15/50 (30%) of patients had quantifiable RNA at week 4. Available
SVR rates for this group were 9/12 (75%) compared to 29/32 (90.6%)
amongst those with RNA below the lower limit of quantification
(LLOQ, 15 iu/ml), p = 0.32.
Conclusions: Patients with GT3 cirrhosis treated for 12 weeks with
SOF/DAC/RBV in routine clinical care had comparable SVR12 rates to
clinical trials, despite including patients with decompensated
cirrhosis. SVR rates amongst Child’s A (92.3%) and Child’s B/C (84%)
patient with cirrhosis are comparable with other 12 week Interferon
free regimens.
Соф+дак+риб 24 недели
SAT-257
Improved virological outcomes and excellent safety profile in
genotype 3 HCV-infected cirrhotic patients after an extended 24-
weeks course of daclatasvir, sofosbuvir + ribavirin: insights froma
real-life multicenter study
Background and Aims: Patients with HCV genotype 3 (G3) infection,
expecially if cirrhotics, show unsatisfactory virological outcomes
after conventional 12 weeks treatment with direct antiviral agents
(DAA). The ALLY-3 Plus study showed that treatment extension to 16
weeks was not associated with improved sustained virological
response (SVR12), which remained <90% in cirrhotic patients. The
National Italian Drug Agency rules allow prescription of 24 weeks of
DAA therapy in most difficult-to-treat patients, including cirrhotics
with G3 infection.
To evaluate the virological efficacy and safety of an extended 24-week
treatment with a combination of Daclatasvir (DCV), Sofosbuvir (SOF)
± Ribavirin (RBV) in G3 cirrhotic patients.
Methods: Seventy-four consecutive patients (15F, 59M) received the
above DAA combination for 24 weeks. The use of RBV was based on
patients’ clinical features and/or expected tolerability. RBV was
administered in 54 (72.9%) pts, at a median dose of 922 ± 200 mg/
day. Forty-seven patients were treatment-naïve and 27 had failed
after interferon-alfa and RBV therapy (12 relapsers and 15 nonresponders).
BMI was <26 in 37, 26–30 in 30 and >30 in 7 pts. At
baseline, disease severity, assessed by Child-Pugh, showed stage A in
65, stage B in 7 and stage C in 2, with a mean MELD score of 9.2 ± 2.9.
Baseline ALT values were 113 ± 96 IU and HCVRNA levels were
<800.000 IU in 47 and >800.000 IU in 27 pts.
Results: Sixty-eight patients reached a 12-week follow-up after endof
treatment, attaining a SVR12 rate of 97% (n = 66). Interestingly,
SVR12 was 100% among RBV treated patients vs. 90% (18/20) among
those treated without RBV. Of the remaining 6 treated patients all but
one achieved SVR4. No patients discontinued DAAs. The only relevant
side effect was anemia, reported in the RBV group only, and easily
managed by dose reductions. No changes in renal and liver function
were recorded baseline vs. follow up. The two patients who failed
(one previous non-responder and one treatment-naïve) showed the
development of resistance associated variants (Y93H in NS5A in both
cases and S282T in one only).
Conclusions: An extended 24-week treatment schedule with the
triple combination of DCV, SOF and RBV allows to achieve a 100%
SVR12 rate in the difficult-to-treat group of HCV G3-infected
cirrhotics, with very limited side effects. The role of RBV seems to
be crucial in this particular setting and should be always administered
if clinical conditions allow it, although larger confirmatory
studies are needed.
И т.д. и т.п, много разных отчетов из клинической практики:
SAT-263
Optimization of direct antiviral agent treatment schedule in
hepatitis C virus genotype 3 infection: an Italian, multicentetric
experience in real-life setting
Background and Aims: The era of direct antiviral agents (DAAs) for
hepatitis C virus (HCV) infection have led to very high rate of
sustained virologic response (SVR). However, HCV genotype 3 (GT3)
remains a challenge with lower SVR rate than other genotypes,
especially in patients with cirrhosis. The aim of this study was to
evaluate, in patients with HCV-GT3, the efficacy of different
treatment schedules in a real-life setting. The analysis of predictors
of response were also examined.
Methods: Twenty-four Italian centers participated to this prospective
study, in order to evaluate the efficacy of the two available treatments
of HCV- GT3 infection in a real-life scenario. Patients with HIV or HBV
co-infection were excluded. The treatment regimen was chosen by
the prescribing clinicians according to guidelines issued by the Italian
Association for the Study of Liver.
Results: We analyzed the data of 238 patients with HCV GT3
infection. Patients were cirrhotic in the 83.6% of cases (199/238) and
16% of them were Child B or C. One-hundred-fifty-six patients were
treatment-naïve (64%); 150/238 (63%) received sofosbuvir (SOF) and
daclatasvir (DCV) ± ribavirin (RBV) (group 1) while 81/238 patients
(34%) received SOF plus RBV (group 2). The SVR12 rates in group 1
was 92.7%, while in group 2 was 77.8% (p < 0.005). In group 1, the
SVR12 rate was 94.7% and 92.4% according to absence or presence of
cirrhosis (p: ns). In group 2, the SVR12 rate was 78.9% and 77.4%
according to absence or presence of cirrhosis (p: ns).
The multivariate analysis showed that female gender (OR 8.3, 95% CI:
1.0–63.9) and schedule of therapy with SOF + DVC ± RBV (OR 4.1, 95%
CI: 1.8–9.4) were the only independent predictors of likelihood
of SVR.
Conclusions: Our study demonstrates that the treatment schedule
with SOF + DVC ± RBV is highly efficacy in patients with GT3 HCV,
even in cirrhotics with a SVR rate of 92.7%. Treatment schedule and
female gender are the only independent factors associated with SVR.
SAT-264
Sustained virological response in HCV patients treated with
daclatasvir + sofosbuvir, with or without ribavirin: a multicenter,
field-practice experience
Background and Aims: The combination of daclatasvir (DAC) and
sofosbuvir (SOF) in clinical trials achieved sustained virological
response at post-treatment week 12 (SVR12) in >90% of chronicallyinfected
HCV patients (pts).We evaluated in real-life clinical practice
the efficacy of DAC + SOF treatment, with or without ribavirin (RBV),
in Genotype 1, 2, 3 and 4 pts with advanced liver disease.
Methods: We included 372 consecutive pts fulfilling eligibility
criteria of the Italian Drug Agency treated in 10 referral centers of
Tuscany, Italy. Fibrosis stage was evaluated by Transient Elastometry
(METAVIR F3 >10 kPa, F4 >13 kPa). Clinical cirrhosis was defined by at
least one of the followings: decompensation, oesophageal varices,
platelets <100,000/mmc. Pts received daily SOF + DAC for 12 (104) or
24 (268) weeks, 150 (40.3%) with RBV. The primary efficacy endpoint
was SVR12.
Results: Mean agewas 58 ± 8 years, 65.3%were males, mean BMIwas
24.7 ± 4.0 kg/m2, 59.5% were naïve. F4 fibrosis was found in 266
(71.5%), clinical cirrhosis in 187 (50.4%). HCV genotypes were 101 G1
(27.2%), 42 G2 (11.3%), 210 G3 (56.5%) and 18 G4 (4.9%). One pt (0.3%)
was co-infected with HBV and 44 (11.9%) with HIV. At baseline, 146/
369 (39.6%) showed HCV RNA ≥2 × 106 IU/mL. ALT mean levels were
101 ± 73 U/L. Six (1.6%) patients dropped out (1 OLT, 1 HCC, 1 death
and 3 lost to follow-up). In pts who completed the study, SVR12 rate
was 98.9% (363/366): 100% in G1, 97.6% in G2, 97.1% in G3 and 100% in
G4. Virological failures occurred in 1 G2 pt previously treated with
SOF + RBV and in 2 G3 naïve pts; all had F4 fibrosis (2 clinical
cirrhosis) and were treated without RBV. In one (HIV co-infected) G3
pt the viral breakthrough occurred atweek 24 of treatment, a classical
relapse was observed in the others. On therapy, HCV RNA was
undetectable in 27.3% of the pts at week 2 and in 52.5% at week 4. At
least one adverse events (AE) was reported in 170 (45.7%) pts; the
most frequent one (26.6%) was elevated bilirubin (mean maximum
value: 2.19 + 1.48 mg/mL) with grade 3–4 elevations in 16 (4.3%) and
1 (0.27%), respectively. Anemiawas the second AE, reported in 22.0%
of RBV treated pts and in 15.3% of the others, reaching grade 2 in 18
(4.8%), 9 RBV treated.
Conclusions: DAC + SOF combination showed an overall 98.9%
efficacy in an heterogeneous cohort of HCV patients with advanced
fibrosis. This study confirms the high efficacy and the pangenotypic
action of this combination that also proved well tolerated in clinicalpractice.
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