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

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100000

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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

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0 1 3 5 7 14 21 28 42 56 84

Days

Med

ian

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IU/m

L)

NR VB REL SVR

BD

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0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

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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)

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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

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0 7 14 21 28

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HC

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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

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70Standard

Investigational

Week 24 Week 480

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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

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Investigational

Day0 7 14 21 28 35 42

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