ALT - ICAR 2016

P222
Integrated study of HCV and ALT kinetics in cirrhotic patients treated with directacting antiviral agents differentiate the effect of interferon and DAA inhibitors
Valeria Cento1, Thi Huyen Tram Nguyen2, Domenico Di Carlo1, Elisa Biliotti3, Laura Gianserra4, Ilaria Lenci5, Daniele Di Paolo5, Vincenza Calvaruso6, Elisabetta Teti7, Maddalena
Cerrone8, Dante Romagnoli9, Michela Melis10, Elena Danieli11, Barbara Menzaghi12, Ennio Polilli13, Massimo Siciliano14, Laura Ambra Nicolini15, Antonio Di Biagio15, Carlo
Magni16, Matteo Bolis16, Francesco Paolo Antonucci1, Velia Chiara Di Maio1, Roberta Alfieri17, Loredana Sarmati7, Paolo Casalino18, Sergio Bernardini18, Valeria Micheli19,
Giuliano Rizzardini16, Giustino Parruti13, Tiziana Quirino12, Massimo Puoti11, Sergio Babudieri10, Antonella D’Arminio Monforte8, Massimo Andreoni7, Antonio Craxì6, Mario
Angelico5, Caterina Pasquazzi4, Gloria Taliani3, Jeremie Guedj2, Francesca Ceccherini-Silberstein1, Carlo Federico Perno1
1 Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Rome, Italy; 2 Infection. Antimicrobials. Modelling. Evolution (IAME) UMR 1137, Inserm and Université Paris Diderot, Paris, France; 3 Tropical Diseases, Policlinic “Umberto I”, Rome, Italy; 4 Infectious Diseases, Sant’Andrea
Hospital -“La Sapienza” University, Rome, Italy; 5 Hepatology Unit, Policlinic of Rome Tor Vergata, Rome, Italy; 6 Gastroenterology, “P. Giaccone” University Hospital, Palermo, Italy; 7 Infectious Diseases, Policlinic of Rome Tor Vergata, Rome, Italy; 8 Clinic of Infectious Disease, Department of Health Sciences, San
Paolo University Hospital, University of Milan, Milan, Italy; 9 Department of Biomedical, Metabolic and Neural Sciences, NOCSAE Baggiovara; 10 Infectious Diseases Unit, Department of Clinical and Experimental Medicine, University of Sassari, Italy; 11 S.C.. Malattie Infettive/Infectious Diseases Dept., AO
Ospedale Niguarda Cà Granda, Milan, Italy; 12 Infectious Diseases, Ospedale di circolo di Busto Arsizio, Busto Arsizio, Varese, Italy; 13 Infectious Disease Unit, Pescara General Hospital, Pescara, Italy; 14 Gastroenterology, Catholic University of Rome, Rome, Italy; 15 University of Genoa (DISSAL) Infectious
Diseases Unit/AOU IRCCS San Martino-IST Genoa, Italy; 16 Division of Infectious Disease, Hospital Sacco of Milan, Milan, Italy; 17 Istituto Nazionale di Genetica Molecolare (INGM) "Romeo ed Enrica Invernizzi", Milan, Italy; 18 Laboratory Medicine, Policlinic Tor Vergata, Rome, Italy; 19 Unit of Microbiology,
Hospital Sacco of Milan, Milan, Italy.
Results
Introduction
With pegInterferon-Ribavirin (PR) treatment, alanine
aminotransferase (ALT) normalization is slow and
follows HCV-RNA clearance, driven by the cytotoxic
effect of PR. The new mode of action of direct-acting
antivirals (DAAs), has instead potential of a rapid
“cure” of infected cells.
Results
HCV-RNA Decay and ALT Kinetics during allDAAs IFN-free treatment in cirrhotic patients
After treatment initiation, a decay in ALT values was
observed in all 81 patients analyzed, concomitant to a
biphasic HCV-RNA decline in serum.
Mathematical modelling of HCV-RNA and ALT
kinetic parameters
The kinetics of HCV-RNA decline was well described by a
standard biphasic model. A significant effect of NS5A on the
clearance of free virus (c) was observed during first-phase
HCV-RNA kinetics.
The comparative kinetics of ALT and HCV-RNA
dynamics in cirrhotic patients during all-DAAs
treatment (not yet explored) can shed light upon the
complex interactions occurring in a cirrhotic liver
between the virus and hepatocytes, as well as
provide information about the mechanisms
underlying the restoration of liver homeostasis
induced by all-DAAs treatment.
HCV-RNA Standard biphasic model
β
ρ
VL0
(logIU/ml)
c
δ
Objectives
The objective of this study is to provide a
comprehensive clinical and mathematical
characterization of the early dynamics (and their
correlations) of HCV-RNA and ALT in cirrhotic GT-1
patients treated with all-DAA based antiviral regimens;
data were then compared with those obtained with the
combination of IFN/ribavirin + 1st generation DAAbased therapy.
57 (70.4)
58 (52-65)
22 (73.3)
55 (51-63)
0.760
0.300
24 (17-32)
21 (19-26)
0.367
16 (19.8)
7 (23.3)
0.793
Non responder
42 (51.9)
15 (50.0)
1.000
Relapser
16 (19.8)
8 (26.7)
0.445
2 (2.5)
0 (0.0)
1.000
5 (6.2)
8 (9.9)
0 (0.0)
0 (0.0)
0.321
0.074
5.6 (5.2-6.1)
6.0 (5.7-6.7)
0.006
96 (69-138)
94 (66-133)
95 (65-144)
72 (51-100)
0.963
0.015
Breakthrough
Other
PI experienced, N(%)
Baseline HCV-RNA (logIU/ml),
Median (IQR)
Baseline ALT (IU/ml), Median (IQR)
Baseline AST (IU/ml), Median (IQR)
a
0.545
P-values were calculated by Fisher exact test for categorical variables
and by Mann-Whitney test for continuous variables. HCV, hepatitis C
virus; DAAs, Direct-Acting Antiviral Agents; IFN, interferon; RBV,
ribavirin; BMI, body mass index; IQR, interquartile range; PI, protease
inhibitor; ALT, alanine transaminase; AST, aspartate aminotransferase.
IFN administration had
instead a strong influence
a l s o o n l o n g - t e r m A LT
kinetics
1.0
1.0
17 (56.7)
0.8
0.8
51 (63.0)
0.6
0.6
30
13 (43.3)
ALT kinetics was significantly influenced by use
of NS5A-inhibitors (accelerating ALT decline),
and by IFN co-administration (reducing ALT
decline)
NS5A inhibitors were able to
enhance both early HCVRNA and ALT declines, but
their effect was limited to the
first phase of viral kinetics,
and after week-2 of
treatment ALT kinetics was
no longer DAA-class
dependent.
0.4
All-DAAs regimens
98%
TVR+PR
84%
53%
0.4
81
30 (37.0)
ε
Additive residual errors
ALT exponential model
ALT0
All-DAA regimens
ALTss
TVR+PR
NS5A-containing treatment
λ
NS5A-free treatment
TVR+PR treatment
Correlation ηALTss, ηALT0
Proportional residual errors
0.2
0.0
70%
by log-rank test
0
7
80
30
67
30
12
14
Days of antiviral treatment
36
30
Patients with altered ALT values
28
3
9
0.0984 (7)
0.265 (19)
0.406 (8)
0.166 (10)
0.298 (4)
0.424 (8)
0.481 (8)
0.296 (25)
0.567 (14)
0.209 (5)
Infected hepatocytes are cleared with a rate δ. The free virions V are released from the
infected cells at a rate p, infect the target cells at a rate β and are cleared from the circulation
with a rate c. In this model, antivirals block the production of new virus with an effectiveness ε.
ALTss represent ALT values at steady-stade, represented by week-4 value in this study; λ is the
rate of ALT decline from the baseline to a new lower set point value after treatment initiation.
Differences in ALT kinetics were confirmed after
adjusting for HCV-RNA decay
By Cox analysis, the use of IFN and of NS5A-free
regimens were associated with higher risk of not
achieving normal ALT values, even after normalization for
HCV-RNA levels.
Hazard ratio of achieving normal ALT
Crude
Adjusteda
Adjusteda
HR
HR
HR
pp-value
p-value
(95% C.I.)
(95% C.I.)
(95% C.I.)
value
-
HCV subtype
(1ab vs. 1b)
1.4 (0.9-2.1)
0.098
1.1 (0.7-1.8)
0.577
1.1 (0.7-1.6)
0.789
ALT values at
baseline
1.0
(1.0-0.00)
0.001
0.1
(0.1-1.00)
<0.001
1.0
(1.0-1.0)
<0.001
7.1
(3.8-13.1)
<0.001
NS5A-inhibitors
administration
(0b vs. 1)
HCV-RNA decay BL-2
weeks
(per 1 log10 increase)
Baseline HCV-RNA
(per 1 log10 increase)
c mode
δ mode
ε mode
3.4 (2.3-5.1) <0.001
-
1.3 (1.0-1.7)
0.076
1.2 (0.8-1.6)
0.348
0.8 (0.6-1.2)
0.220
0.7 (0.5-0.9)
0.004
0.8 (0.6-1.2)
0.239
0.6 (0.4-0.9)
0.009
0.089
1.1 (1.0-1.2)
0.049
0.8 (0.7-0.9)
0.003
0.168
0.317
-
1.1
(1.00-1.2)
0.2 (0.0-1.9)
0.9 (0.7-1.1)
-
Adjusted for pegIFN administration, NS5A-inhibitors, HCV-RNA decay BL-2w, baseline
HCV-RNA, c mode. b Reference group (dummy). Only factors with p<0.100 in univariate
analysis were included in multivariate analysis. HR in boldface represents factors having a pvalue <0.050.
a
Conclusion
!  We
provided a detailed, integrated analysis of HCV-RNA
and ALT kinetics profiles in cirrhotic GT-1 patients treated
with different all-DAAs regimens, highlighting the effect of
NS5A-inhibitor and IFN administration.
!  We
showed that all-DAAs regimens are associated with
strikingly fast ALT normalization, much faster of that
observed with TVR+PR, and this difference still holds after
adjusting for viral decline.
!  Since
p<0.0001
-
103 (4)
43.4 (9)
26.3 (6)
0.267 (8)
0.173 (8)
0.173 (8)
pegIFN administration
0.3 (0.2-0.5) <0.001 0.3 (0.2-0.5) <0.001
(0b vs. 1)
Normal ALT values
were considered as
<55 IU/ml in men,
and <45 IU/ml in
women.LLOD, lower
limit of detection
(<12-15 IU/ml, not
detected).
0.2
Treatment
experience, N(%)
Telaprevir,
P-valuea
pegIFN, RBV
10-7 (Fixed)
10 (Fixed)
5.97 (2)
5.62 (1)
10.1 (12)
7.38 (8)
4.96 (8)
6.8 (12)
0.209 (6)
0.283 (5)
0.998 (2)
GT 1a
GT 1b
DCV+ASV treatment
3D+RBV and DCV+SOF
SOF+SMV
TVR+PR
NS5A-containing treatment
NS5A-free treatment
Variables
0.0
Baseline characteristics of the
study population
Patients, N
1a
HCV
genotype,
1b
N(%)
Males, N(%)
Age (years), Median (IQR)
Stiffness at baseline (Kpa), Median
(IQR)
Naive patients, N(%)
The first-phase HCV-RNA kinetics (during the first 24h-30h
since treatment start) was very rapid. During secondphase kinetics, HCV-RNA continued to decline, though
more slowly.
Probability of achieving
normal ALT
•  111 HCV-infected patients (39% GT1a, 61% GT1b)
with cirrhosis (11% Child-B; median[IQR] stiffness=
22[176-31]kPa) were treated: 81 with all-DAA
regimens, and 30 with telaprevir (TVR)+PR.
•  Patients were included in the study, according to
the following characteristics: a) high baseline ALT,
defined as >55 IU/ml in men, and >45 IU/ml in
women; b) baseline and week-4 HCV-RNA and ALT
available; c) at least one HCV-RNA determination
within the first week of treatment, and one HCVRNA and ALT determination at week-1 and/or at
week-2.
•  HCV-RNA and ALT kinetics during treatment
(4-8-24-48-72h, 1-2-3-4 weeks) were studied using
a standard biphasic model and an exponential
model, respectively.
All-DAAs
treatment
regimens
Median values with 95% confidence interval of HCV-RNA (red) and ALT (green)
during all-DAAs treatment are reported. Red dotted line represents the lower limit of
detection of HCV-RNA (12-15 IU/ml). Green dotted line represents normality range of
ALT values in females (45 IU/ml).
ALT kinetics was faster than HCV-RNA kinetics
in all-DAA treated patients
ALT values within standard normality ranges were reached
before the complete clearance of HCV-RNA in serum.
Methods
Fixed effect Standard deviation
(RSE%)
(RSE%)
Parameters
serum ALT levels are valid surrogate parameters of
hepatocyte turnover [Zeuzem S, Hepatology 1998;
Kronenberger B, Journal of Hepatology 2000], this result
suggests that viral clearance in IFN-free regimen may not
only be driven by the progressive elimination of infected
cells, but also by a possible “cure” of the infected
hepatocytes.