Pres. - Virology Education

O_18
Early ribavirin concentration is a
critical response factor in the subpopulation of patients infected by
HCV-1 and unfavourable IL28B
genotype
Amedeo De Nicolò, Jessica Cusato, Lucio Boglione, Francesca Patti,
Alessia Ciancio, Antonina Smedile, Danilo Agnesod, Giuseppe Cariti, Mario
Rizzetto, Giovanni Di Perri, Antonio D'Avolio
Unit of Infectious Diseases, Department of Medical
Sciences, University of Turin, Amedeo di Savoia Hospital,
Turin, Italy
14th
Amsterdam (the Netherlands), April 22-24 2013
International Workshop on Clinical Pharmacology of HIV Therapy
Background
Epidemiology of HCV infection
The World Health Organization estimates around 2-3%
prevalence of infection worldwide, with approximately
170 million HCV-positive individuals
• In Africa and Eastern
Mediterranean are present
the highest rates of
seroprevalence (> 10%)
• In Western Europe,
Canada and Australia the
lowest rates (<1%)
• In Italy we have an
average prevalence rate of
2%, with an incidence of
0.5 / 100,000
Background
Treatment of chronic hepatitis C
At the time 6 viral genotypes were identified, and more than 50 subtypes.
The therapy currently used is based on pegylated-interferon (PEG-IFN) and
ribavirin (RBV), administered according to HCV genotypes:
• Genotypes 1 and 4
PEG-IFN α (α2a or α2b) + ribavirin at
higher doses (1000-1200 mg / day) for 48
weeks.
Numerous new anti-HCV drugs acting as
true antivirals (DAAs) are being
developed. Two protease inhibitors
(telaprevir and boceprevir) have been
approved for clinical use as third
component of PEG-INF/ ribavirin
regimens.
• Genotypes 2 and 3
PEG-IFN α (α2a or α2b) + ribavirin in
lower doses (800 mg / day) for 24 weeks.
Definitons of treatment response
The treatment failures are as follows:
• NR: non responders
• VBT: virologic break through
• RL: virologic relapse
ETVR
• RVR: 4 weeks
• EVR: 12 weeks
- c EVR (complete)
- p EVR (partial)
• ETVR: end of treatment
• SVR: 6 months follow-up
PREDICTORS OF EFFICACY
RVR and EVR achievement has been associated
with SVR in HCV-1 and other HCV-genotypes.
RIBAVIRIN
DOSAGE
WEIGHT
VIROLOGICAL
RESPONSE
GENDER
PREDICTORS OF EFFICACY
Ribavirin exposure was associated
virological response in several studies.
to
RIBAVIRIN
DOSAGE
WEIGHT
VIROLOGICAL
RIBAVIRIN
PHARMACOKINETIC
RESPONSE
GENDER
VIROLOGICAL
RESPONSE
Interleukin IL28B and the outcome of HCV
infection
Specific polymorphisms in the region upstream of the gene encoding for IL28B,
such as rs12979860 T>C (IL 28-B 860 CC) and rs8099917 G>T (IL 28-B 917 TT), were
found to be associated to both an higher rate of spontaneous viral clearance
and an higher rate of therapeutic response to PegIFN and RBV.
IL28B-860
IL28B-917
IL28B-917
RIBAVIRIN
DOSAGE
WEIGHT
IL28 (and OTHERS)
GENETIC
VARIANTS
RIBAVIRIN
PHARMACOKINETIC
GENDER
VIROLOGICAL
RESPONSE
TRIPLE THERAPY FOR HCV-1
Boceprevir and Telaprevir improve the achievement
of SVR (but with many side effects).
•Triple therapy is very
expensive! ( …and it does not
always work ...)
•Despite Guidelines, dual
therapy could be an option!
Objectives
Our aims were:
• To investigate the relationship between RBV
early (1 month) plasma concentrations and
the achievement of early virological response
(EVR).
• To define a early RBV concentration cut-off
value, specific for HCV genotype-1 infected
patients with unfavourable IL28B profile,
above which there is a better probability to
achieve EVR.
Methods
- 67 HCV-1 patients in dual therapy were recruited in Turin,
Italy (in ongoing observational study).
- Inclusion criteria were:
• Older than 18 years
• No concomitant interacting drugs
• No hepatic or renal function impairment
• Self-reported adherence more than 95%
- Blood sampling at the end of dosing interval (Ctrough) was
performed at week 2, week 4 and week 12 on therapy.
- RBV Plasma samples were analyzed by HPLC-UV method
[D’Avolio A. et al. 2006]
- Interleukin 28B polymorphisms (860 and 917 SNPs) were
evaluated by RT-PCR.
Results
Baseline characteristics
Number of patients
(Tot. 67)
Median
IQR Range
Males (%)
46 (68.6)
-
Age, years
47
37 – 55
BMI, kg/m2
25.2
22.9 – 27.0
HCV Log BL (IU/mL)
6.5
2.9 – 7.9
ALT BL (IU/mL)
115
13 – 669
Hb BL (g/dL)
12.9
11.3 – 14.4
RBV dose (mg)
1000
1000 – 1000
Results (Genetics)
Baseline characteristics (SNPs are in Hardy-Weinburg equilibrium)
Polymorphism
Frequency N.
Percentage (%)
TT
38
56.7
TG
27
40.3
GG
2
3.0
TT
8
11.9
TC
38
56.7
CC
21
31.3
Rs8099917 T>G
Rs1297860 T>C
Results
PK exposure
Number of patients
(n = 67)
Median
(ng/mL)
IQR Range
2 weeks RBV Plasma concentrations
1327
897– 1821
1 month RBV Plasma concentrations
1719
1214– 2330
3 months RBV Plasma concentrations
1914
1336– 2449
After three months of therapy
Number of patients
(n = 67)
Frequency (n.)
Percentage
(%)
EVR
43
64.2
Results [all 67 patients]
(Spearman Correlation)
RVR
Rho
RVR
Rho
3M
RBV
IL28B_917
TT
IL28B_860
CC
1M
RBV
3M
RBV
IL28B_917
TT
IL28B_860
CC
0.356
-0.040
-0.093
-0.138
0.259
0.437
0.003
0.749
0.459
0.360
0.036
<0.001
0.172
0.175
-0.133
0.415
0.236
0.163
0.157
0.378
<0.001
0.054
0.835
0.786
0.128
-0.043
<0.001
<0.001
0.303
0.728
0.841
0.049
-0.113
<0.001
0.693
0.362
-0.215
-0.320
0.152
0.030
0.356
EVR
1M
RBV
2W
RBV
P-Value
2W
RBV
EVR
P-Value
0.003
Rho
-0.040
0.172
P-Value
0.746
0.163
Rho
-0.093
0.175
0.835
P-Value
0.459
0.157
<0.001
Rho
-0.138
-0.133
0.786
0.841
P-Value
0.360
0.378
<0.001
<0.001
Rho
0.259
0.415
0.128
0.049
-0.215
0.493
-
P-Value
0.036
<0.001
0.303
0.693
0.152
Rho
0.437
0.236
-0.043
-0.113
-0.320
<0.001
0.493
-
P-Value
<0.001
0.054
0.728
0.362
0.030
<0.001
Results
[29 patients with unfavorable 917 SNP]
(Spearman Correlation)
RVR
Rho
RVR
Rho
3M
RBV
1M
RBV
3M
RBV
0.324
0.423
0.260
0.434
0.086
0.022
0.173
0.056
0.343
0.460
0.322
0.068
0.012
0.067
0.729
0.777
<0.001
<0.001
0.324
EVR
1M
RBV
2W
RBV
P-Value
2W
RBV
EVR
P-Value
0.086
Rho
0.423
0.343
P-Value
0.022
0.068
Rho
0.260
0.460
0.729
0.756
-
P-Value
0.173
0.012
<0.001
<0.001
Rho
0.434
0.322
0.777
0.756
P-Value
0.056
0.067
<0.001
<0.001
-
Results
RBV plasma concentrations after 1 month in unfavourable IL28B
genotype patients were significantly (p=0.015) higher in patients
presenting EVR.
.
N=17
P=0.015
.
N=12
Results
ROC curve analysis of RBV plasma concentrations (1 month) and
EVR in unfavourable IL28B genotype patients.
1800 ng/mL
Sensibility 69%
Specificity 82%
AUROC= 0.770
p=0.015
Results
Predictors of EVR in univariate and multivariate logistic regression
analysis in unfavourable IL28B genotype patients.
Factors
Univariate
Multivariate
P value
P value
Gender (male)
0.584
Weight (kg)
0.950
Age (years)
0.589
Hb BL
0.241
HCV RNA BL
0.387
RBV dose (mg/kg)
0.864
RBV Plasma concentrations > 1800 ng/mL
0.011
IL28B_860 CC
0.356
0.011
The only independent predictors of EVR was RBV plasma
concentrations (1 month) above 1800 ng/mL.
Summary
For the first time, an early “genotype-specific”
cut-off of RBV plasma concentration was
determined for the prediction of virological response
at 3 months of therapy.
This preliminary findings were observed only on 67
[29 IL28B-917 unfavourable] patients.
 SNPs are the most important factors in the
definition of response to therapy, but early RBV
exposure is critical in patients which are
genetically predisposed to fail treatment.
Conclusion
RBV TDM has an important role in a geneticspecific subset of patients, with lower probability of
achieving SVR.
 This information could be useful for patient
selection in need of therapy with protease
inhibitors.
Triple therapy gives higher probability of response (data
from clinical studies), but in “real life” the probability of
failure in HCV-1 patients remains high.
...HCV guidelines are not “clear” about the role of IL28B!!!
Could higher dosage of ribavirin be a option for dual
therapy re-treatment or treatment in HCV-1?
Acknowledgements
University of Turin
Prof. Giovanni Di Perri
Prof. Stefano Bonora
Dr. Andrea Calcagno
Dr. Amedeo De Nicolò
Dr. Marco Simiele
Dr. Jessica Cusato
Dr. Lorena Baietto
Mauro Sciandra
Dr. Alessandra Airaudo
Danilo Agnesod
Stefano Turini
Sarah Allegra
Amedeo di Savoia
Hospital
Dr. Giuseppe Cariti
Dr. Lucio Boglione
Dr. Maria Cristina Tettoni
Dr. Laura Trentini
Dr. Davide Penno
Molinette Hospital
Prof. Mario Rizzetto
Prof. Antonina Smedile
Dr. Alessia Ciancio
University of Liverpool
Prof. David Back
Dr. Marco Siccardi