Twice Weekly Peg-IFN-alpha-2a with Ribavirin Improves Early Viral Kinetics over Standard Therapy Among HIV/HCV Co-Infected African American Patients Alison Murphy Princeton University
Twice Weekly Peg-IFN-alpha-2a with Ribavirin Improves Early Viral Kinetics over
Standard Therapy Among HIV/HCV Co-Infected African American Patients
Alison MurphyPrinceton University
Introduction
Co-infection with Hepatitis C virus (HCV) is seen in approximately one-third of all HIV-infected persons in the US due to shared routes of transmission.
HCV/HIV co-infected patients have a more rapid rate of progression of liver fibrosis when compared to that of HCV mono-infected individuals.
Finally, co-infection with HIV decreases the rates of sustained virological response (SVR) to combination therapy.
Clinical Definition
100
1000
10000
100000
1000000
10000000
Day 0
Wee
k 1
Wee
k 4
Wee
k 12
Wee
k 24
Wee
k 36
Wee
k 48
Wee
k 64
Wee
k 72
HC
V V
L (
IU/m
L)
Non-responder
Viral Breakthrough
Relapser
Sustained Responder
Peg-Interferon- + Ribavirin
Lower limit of detection
Relationship Between Early Viral Kinetics and Therapeutic Response
2
3
4
5
6
7
0 1 3 5 7 14 21 28 42 56 84
Days
Med
ian
HC
V-R
NA
(log
IU/m
L)
NR VB REL SVR
BD
1
2
3
4
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Days
Med
ian
seru
n IF
N-a
(log
pg/
mL)
NR VB REL SVRBD
Neumann et al. 3rd IAS abstract (2005)
Non-responder
Viral Breakthrough
Relapser
Sustained Responder
Study rationale
Studies have shown that early HCV viral kinetics can predict SVR in HIV/HCV co-infected individuals.
These studies have suggested that twice weekly dosing of pegylated interferon may:
Prevent end of week rebound
Improve early viral response
Potentially increase SVR among HIV/HCV co-infected individuals.
Study Design
Primary Endpoint
Change in log HCV viral levels on day 7.
Secondary Endpoints
Log change in HCV response on days 14, 21 and 28 of treatment.
Change in pharmacokinetics of peginterferon. Safety and tolerability of twice weekly peginterferon.
Change in end of treatment response
Change in sustained viral response
Change in liver fibrosis score per liver biopsy results.
Change in liver enzymes at all time points.
Study Subjects
Eligibility Criteria included:
18 years of age or older,
CD4+ T cell counts > 100 cells/mm3,
absolute neutrophil counts >1000 cells/mm3,
HCV viral load >2000 IU/mL,
histologic evidence of chronic hepatitis C and
stable HIV disease with or without ART.
Laboratory Studies
HCV and HIV RNA concentration in plasma were measured by VERSANT RNA 3.0 Assay during all study visits.
The assay has a lower limit of detection for HCV of 615 IU/mL.
HCV RNA concentration was measured in plasma on day 0, 3, 5, 6, 7, 10, 14, 21, 28, 42, 56 and then every 4 weeks for 72 weeks.
Liver chemistry and safety laboratory tests were performed prior to the treatment and during each study visit.
Liver biopsy was obtained prior to initiation of therapy and at week 72 visit.
Statistical Analysis
The non-parametric Mann-Whitney U test was used to test the significance of differences in distribution of continuous variables.
Non-parametric Spearman test was used to test the significance of correlation between variables. Significance was assumed at p<0.05.
Baseline characteristics of patients
Median Min MaxHIV Viral Load (LOG) Standard 1.69 1.69 3.64
Investigational 2.56 1.69 3.53
HCV Viral Load (LOG) Standard 6.00 5.03 6.58
Investigational 5.41 4.38 6.33
Base CD4 + T cell count (%) Standard 464 (22) 127 (16) 1167 (36)
Investigational 483 (31) 181 (19) 907 (46)
Genotype 1a Male African American 10 patients received standard therapy 9 patients received investigational therapy
Patients on investigational arm had better early virologic response
P=0.04
0 7 14 21 28 35 422
3
4
5
6Standard
Investigational
LLD
Day
Patients on investigational arm had better early virologic response
Week 1 Day 10 Week 2 Week 4 Week 12 Week 242
3
4
5
6Standard
Investigational
LLD
P=0.04
Patients on investigational arm had better clinically relevant early virologic end points
EVR2, EVR4 and EVR12 (2 logs or more drop in HCV VL)RVR4, EVR24 and ETR (less than 615 IU/mL of HCV VL)
0
10
20
30
40
50
60
70
EVR2
EVR4
RVR4
EVR12
EVR24 ET
RSV
R
Virologic Responses
Pati
ents
wit
h indic
ate
d R
esponse (
%)
Standard
Investigational
Biweekly Peg-IFN Dosing Improves HCV Viral Kinetics in African Americans
-2.5
-2
-1.5
-1
-0.5
0
0.5
0 7 14 21 28
Days
HC
V R
NA
Dec
lin
e
P<0.04
QW median
BW median
Patients receiving investigational therapy achieved normalization of ALT and AST earlier than patients receiving standard therapy.
P=0.03P=0.04
Week 24 Week 480
10
20
30
40
50
60
70Standard
Investigational
Week 24 Week 480
50
100Standard
Investigational
ALT AST
Adverse Event Profiles were similar among both groups
No significantly higher number of adverse events in investigational over standard therapy.
P>0.05
1 2 3 40
25
50
75
100
125Standard
Investigational
Grade
Most patients experienced hematologic toxicities
No significantly higher number of more common adverse events in investigational over standard therapy
P>0.05
P>0.05
Anemia Neutropenia0
50
100Standard
Investigational
Conclusions (1)
Twice weekly Peg IFN-alpha 2a therapy yields higher rate of early virological response when compared to standard treatment.
Twice weekly Peg IFN-alpha 2a treatment is safe and is tolerated to the same extent as standard IFN treatment.
Twice weekly Peg IFN-alpha 2a treatment is associated with rapid normalization of hepatic enzymes.
Twice weekly Peg IFN-alpha 2a treatment may be a viable therapeutic option for African American patients who are also infected with HIV.
All patients who had sustained virologic response had improvement in hepatic histology at week 72 irrespective of therapeutic regimen
Future studies are warranted to validate the clinical utility of using twice weekly Peg IFN treatment to improve SVR in HCV and HIV co-infected patients.
Conclusions (2)
Acknowledgments
• NIAID, LIR/BRB/CCMD
– Shyam Kottilil MD.– Michael A. Polis MD.
– William Sachau– Marie Angeline O’Shea– Lynne Wu MD.– Catherine A. Rehm– Michael Proschan Ph.D.– Henry Masur MD.– OP8 Clinic Staff– H. Clifford Lane MD.– Anthony S. Fauci MD.
• NIMH, NIH
– Donald Rosenstein MD.– Haniya Raza MD.– Joseph J. Rasimas MD.
• Bar-Ilan University, Israel
– Avidan U. Neumann Ph.D.– Lynne Rozenberg MSc
• NCI, NIH
– David E. Kleiner MD.
• Erasmus University, The Netherlands– Bart Haagmans Ph.D.
HIV/HCV Co-infected Patients
Both Groups Experienced a decline in CD4 counts but not percentage
Comparable CD4 levels throughout Standard and Investigational therapy
0 7 14 21 28 35 42300
400
500Standard
Investigational
Day0 7 14 21 28 35 42
0
10
20
30
40Standard
Investigational
Day