Leevy, Carroll

Update on Pathobiology andUpdate on Pathobiology and

Treatment of Hepatitis C in HIVTreatment of Hepatitis C in HIVCoinfection Coinfection

Carroll B. Leevy, M.D.New Jersey Medical School

Liver Centerand

Sammy Davis Jr. National Liver InstituteNewark, New Jersey

HCV Progression and End Stage Liver Disease in African Americans

Blacks have a higher rate of cirrhosis,

HCC, and death due to HCV

Howell C et al. Gastroenterology. 2000

Although African Americans represent 12.8% of the U.S. population and are more likely to have chronic liver disease than whites, they are less likely to undergo liver transplantation

HCV disproportionately affects both the Latino and African-American communities in the U.S

• HCV is 2- to 3-fold more common among African-Americans and Latinos than non-Hispanic whites

– 1.8% of the adult, civilian, non-institutionalized U.S. population had anti-HCV

– Rates of anti-HCV were higher among African American (3.2%) and Hispanic (2.1%) populations as compared with non-Hispanic white populations (1.8%)

– African Americans, who represent 12%–13% of the population, account for 22% of the estimated 2.7 million people in the United States with chronic HCV

• The peak prevalence of anti-HCV was found in the 4th and 5th decades in African Americans, but peaked in the 4th decade in whites, declining thereafter

– On average, African American patients were older than whites (49 vs. 45 years) and had a longer duration of infection (27 vs. 23 years) at the time of liver biopsy

NHANES III; Howell C et al. Gastroenterology. 2000

Chronic Hepatitis C in African Chronic Hepatitis C in African AmericansAmericans

0

5

10

15

20

25

Percent

Percent of Population Percent of HCV Positive

Black

White

White

Black

6-11 12-19 20-29 30-39 40-49 50-59 70+60-69 6-11 12-19 20-29 30-39 40-49 50-59 70+60-69

Age

Per

cen

t W

ith

An

ti-H

CV

5

4

3

2

1

0

543210

6789

10

Source: NHANES III

Per

cen

t W

ith

An

ti-H

CV

Age

Prevalence of HCV byGender and Race

Males Females

Progression of Fibrosis in Patients with Progression of Fibrosis in Patients with Chronic Hepatitis CChronic Hepatitis C

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

African Americans Caucasians

N=53 N=116

Stages per Year

HCV and HIV: The two most prevalent blood-borne infections in the US

• Chronic hepatitis C affects approximately four million Americans and HIV almost one million.

• Nationally, 30 percent of HIV-infected individuals are co-infected with HCV.

• It is also estimated that 60-90 percent of individuals infected with HIV through intravenous drugs use have HCV.

• In total, it is estimated that 300,000 individuals in the United States have co-infection.

Modifiers of HCV InfectionModifiers of HCV InfectionNew Jersey Medical SchoolNew Jersey Medical School

VIREMIA CIRRHOSIS HCC

AIDS + 300% +30% +20%

ALCOHOLISM +50% +300% +200%

Death From End-Stage Liver Disease Among Death From End-Stage Liver Disease Among Patients with HIV InfectionPatients with HIV Infection

05

101520253035404550

1991 1996 1998

McGoven et. al

Percent Mortality

Addition of Ribavirin to Interferon for Addition of Ribavirin to Interferon for Treatment of Recurrent HCV in Combined Treatment of Recurrent HCV in Combined

Treatment for AIDS and Hepatitis CTreatment for AIDS and Hepatitis C

0

1000

2000

3000

4000

5000

6000

7000

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

Months

HIV Copies / ml HCV Million Copies / ml

HCV

HIV

Alpha Interferon

Alpha Interferonand

RibavirinAZTLamivudineNelfinavir

Treatment at UMDNJ-Liver Center with Treatment at UMDNJ-Liver Center with Pegasys and Copegus in Coinfected Pegasys and Copegus in Coinfected

Patients Using Growth FactorsPatients Using Growth Factors

0

20

40

60

80

EVR ETR SVR

N=211N=211 35% Cirrhotic35% Cirrhotic84% Genotype 1 and 484% Genotype 1 and 4

52% required Growth Factors52% required Growth Factors

APRICOT Study Design APRICOT Study Design

PEGASYS combination therapy blinded (COPEGUS vs placebo)

Stratified

– Genotype 1 vs non-1– CD4+ 100 to <200/L vs 200/L– ART vs no ART– Cirrhotic vs non-cirrhotic– Geographic region

Follow-upFollow-upPEGASYS (40 kDa) (180 µg, qw) plus RBV placebo

Follow-upFollow-upPEGASYS (40 kDa)(180 µg, qw)plus COPEGUS (800 mg daily)

Follow-upFollow-upIFN alfa-2a (Roferon®-A) (3 MIU, tiw) plus COPEGUS (800 mg daily)

Study WeeksStudy Weeks

00 48482424 7272

APRICOT Study DesignAPRICOT Study Design

n = 285n = 285

n = 286n = 286

n = 289n = 289

860 received at least one dose860 received at least one dose

12%12%

n = 285

20%20%

n = 286

40%40%

n = 289

Sustained Virologic Response*Sustained Virologic Response*

PP = 0.0084 = 0.0084

PP 0.00010.0001

PP 0.00010.0001

* Defined as <50 IU/mL HCV RNA at week 72; ITT* Defined as <50 IU/mL HCV RNA at week 72; ITT

% R

esp

on

se%

Res

po

nse

0%0%

10%10%

20%20%

30%30%

40%40%

50%50%

60%60%

IFN alfa-2a + RBVIFN alfa-2a + RBV PEGASYSPEGASYS(40 kDa) + (40 kDa) + PlaceboPlacebo

PEGASYSPEGASYS(40 kDa) + COPEGUS(40 kDa) + COPEGUS

8%

21%

38%

7%

14%

29%

0%

10%

20%

30%

40%

50%

60%

Virologic Response* – End of Virologic Response* – End of Treatment vs End of Follow-up Treatment vs End of Follow-up

(Genotype 1)(Genotype 1)

% R

esp

on

se%

Res

po

nse

* Defined as <50 IU/mL HCV RNA* Defined as <50 IU/mL HCV RNA

IFN alfa-2a + RBVIFN alfa-2a + RBV PEGASYSPEGASYS(40 kDa) + (40 kDa) + PlaceboPlacebo

PEGASYSPEGASYS(40 kDa) + COPEGUS(40 kDa) + COPEGUS

End of treatmentEnd of treatment End of follow-upEnd of follow-up

27%

57%

20%

36%

64% 62%

0%

10%

20%

30%

40%

50%

60%

70%

Virologic Response* – End of Virologic Response* – End of Treatment vs End of Follow-up Treatment vs End of Follow-up

(Genotype 2 and 3)(Genotype 2 and 3)

% R

esp

on

se%

Res

po

nse

* Defined as <50 IU/mL HCV RNA* Defined as <50 IU/mL HCV RNA

IFN alfa-2a + RBVIFN alfa-2a + RBV PEGASYSPEGASYS(40 kDa) + (40 kDa) + PlaceboPlacebo

PEGASYSPEGASYS(40 kDa) + COPEGUS(40 kDa) + COPEGUS

End of treatmentEnd of treatment End of follow-upEnd of follow-up

FatigueFatigue 40%40% 41%41% 44%44%

PyrexiaPyrexia 35%35% 43%43% 44%44%

HeadacheHeadache 41%41% 38%38% 39%39%

MyalgiaMyalgia 29%29% 33%33% 36%36%

NauseaNausea 25%25% 27%27% 30%30%

DiarrhoeaDiarrhoea 24%24% 26%26% 28%28%

InsomniaInsomnia 29%29% 21%21% 26%26%

AstheniaAsthenia 24%24% 22%22% 28%28%

DepressionDepression 22%22% 20%20% 26%26%

ArthralgiaArthralgia 18%18% 20%20% 20%20%

Weight decreasedWeight decreased 14%14% 18%18% 20%20%

Adverse events Adverse events 20% 20%irrespective of causalityirrespective of causality

RoferonRoferon®®-A -A PEGASYS PEGASYS®® PEGASYSPEGASYS®®

+ COPEGUS+ COPEGUS®® + placebo + placebo + COPEGUS+ COPEGUS®®

(n = 285)(n = 285) (n = 286)(n = 286) (n = 288)(n = 288)

Torriani et al. 11th CROI, 2004; abstract 112

Patients withPatients withserious adverse events (SAEs)serious adverse events (SAEs)

Pat

ien

ts (

%)

Pat

ien

ts (

%)

*Possibly or probably related*Possibly or probably related

RoferonRoferon®®-A-A+ COPEGUS+ COPEGUS®®

PEGASYSPEGASYS®®

+ + placeboplaceboPEGASYSPEGASYS®®

+ COPEGUS+ COPEGUS®®

15%

21%

17%

5%

10%8%

0

5

10

15

20

25All SAEs Related*

Torriani et al. 11th CROI, 2004; abstract 112

Withdrawal from treatmentWithdrawal from treatment

Pat

ien

tsP

atie

nts

RoferonRoferon®®-A-A+ COPEGUS+ COPEGUS®®

PEGASYSPEGASYS®®

+ + placeboplaceboPEGASYSPEGASYS®®

+ COPEGUS+ COPEGUS®®

Torriani et al. 11th CROI, 2004; abstract 112

0%

5%3%

14%12% 12%

24%

15%

10%

0%

5%

10%

15%

20%

25%

30%Laboratory abnormality Adverse event Non-safety

Median change fromMedian change frombaseline in CD4 countsbaseline in CD4 counts

Med

ian

ch

ang

e fr

om

bas

elin

eM

edia

n c

han

ge

fro

m b

asel

ine

in C

D4

cou

nt

(cel

ls/m

min

CD

4 co

un

t (c

ells

/mm

33 ))

Time (weeks)Time (weeks)

Patients receiving 48 weeks of treatmentPatients receiving 48 weeks of treatment

-160-140-120-100-80-60-40-20

0204060

Roferon®-A + COPEGUS® (n = 174)PEGASYS® + placebo (n = 196)PEGASYS® + COPEGUS® (n = 217)

Torriani et al. 11th CROI, 2004; abstract 112

BL 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76

Median change from baselineMedian change from baselinein CD4 percentage of lymphocytesin CD4 percentage of lymphocytes

Patients receiving 48 weeks of treatmentPatients receiving 48 weeks of treatment

Med

ian

ch

ang

e fr

om

Med

ian

ch

ang

e fr

om

bas

elin

e in

CD

4 b

asel

ine

in C

D4

(( %)

%)

BL

-2

-1

0

1

2

3

4

5

4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76

Torriani et al. 11th CROI, 2004; abstract 112

Roferon®-A + COPEGUS® (n = 174)PEGASYS® + placebo (n = 196)PEGASYS® + COPEGUS® (n = 217)

Time (weeks)Time (weeks)

Mean change from baseline in Mean change from baseline in HIV RNA: all patients treatedHIV RNA: all patients treated

Patients receiving 48 weeks of treatmentPatients receiving 48 weeks of treatment

Ch

ang

e in

lo

gC

han

ge

in l

og

1010 H

IV R

NA

HIV

RN

A

BL

-2.0

-1.5

-1.0

-0.5

0.0

0.5

1.0

1.5

2.0

4 8 12 24 36 48 52 60 72

Torriani et al. 11th CROI, 2004; abstract 112

Roferon®-A + COPEGUS® (n = 174)PEGASYS® + placebo (n = 196)PEGASYS® + COPEGUS® (n = 217)

Time (weeks)Time (weeks)

Mean change from baseline in HIV RNA: Mean change from baseline in HIV RNA: patients with detectable HIV RNA at baselinepatients with detectable HIV RNA at baseline

Patients receiving 48 weeks of treatmentPatients receiving 48 weeks of treatment Torriani et al. 11th CROI, 2004; abstract 112

Roferon®-A + COPEGUS® (n = 174)PEGASYS® + placebo (n = 196)PEGASYS® + COPEGUS® (n = 217)

BL

-2.0

-1.5

-1.0

-0.5

0.0

0.5

1.0

1.5

2.0

4 8 12 24 36 48 52 60 72

Time (weeks)Time (weeks)

Ch

ang

e in

lo

gC

han

ge

in l

og

1010 H

IV R

NA

HIV

RN

A

Effects of HCV treatmentEffects of HCV treatmenton HIV therapyon HIV therapy

In APRICOT, PEGASYS® plus COPEGUS® did not negatively affect the control of HIV infection:

– Absolute CD4 counts decreased during treatment (a known effect of interferon therapy)

– Absolute CD4 counts returned to baseline levels during follow-up

– Percentage CD4 count increased during therapy

– HIV RNA levels remained almost unchanged during treatment

– Patients with detectable HIV RNA at baseline had a 0.7 log10 copies/ml reduction in HIV RNA during treatment Torriani et al. 11th CROI, 2004; abstract 112

Nested pharmacokineticsNested pharmacokinetics

In patients with HIV–HCV co-infection:– COPEGUS® did not appear to disrupt the intracellular

metabolism of lamivudine, stavudine or zidovudine or their corresponding nucleoside triphosphates

– COPEGUS® did not appear to modify the plasma concentration-time profile of lamivudine, stavudine or zidovudine (data not shown)

– PEGASYS® plus COPEGUS® at 800 mg/day can be prescribed in HIV–HCV co-infected patients receiving antiretroviral therapy without undue concern for pharmacokinetic interactions between COPEGUS® and lamivudine, stavudine and/or zidovudine

Gries et al. 11th CROI, 2004; abstract 136LB

Rationale:– Ribavirin affects intracellular nucleotide pools– Ribavirin reduces phosphorylation of pyrimidine

analogues (lamivudine, stavudine, zidovudine)

Intracellular stavudineIntracellular stavudinetriphosphate time profiletriphosphate time profile

Gries et al. 11th CROI, 2004; abstract 136LB

0 2 4 6 8 10 12

0 2 4 6 8 10 12

Sta

vud

ine

trip

ho

sph

ate

con

cen

trat

ion

(p

mo

l/106

cells

)

-0.05

0.0

0.05

0.10

0.15

0.20

0.25PEGASYSPEGASYS®® + COPEGUS + COPEGUS®®

PEGASYSPEGASYS®® + placebo + placebo

Baseline Week 8

Time (hours)

Intracellular zidovudineIntracellular zidovudinetriphosphate time profiletriphosphate time profile

3 8 13

PEGASYSPEGASYS®® + COPEGUS + COPEGUS®®

PEGASYSPEGASYS®® + placebo + placebo

3 8 13

-0.1

0.0

0.1

0.2

Zid

ovu

din

e tr

iph

osp

hat

e co

nce

ntr

atio

n(p

mo

l/106

cells

)

Baseline Week 8

Gries et al. 11th CROI, 2004; abstract 136LB

Time (hours)

Time (hours)

SummarySummary

SVR was significantly higher for PEGASYS (40 kDa) + COPEGUS compared to conventional combination therapy

– Overall: 40% vs 12%; P <0.0001– Genotype 1: 29% vs 7%– Genotype 2/3: 62% vs 20%

Adverse event profile of PEGASYS (40kDa) + COPEGUS is generally similar to IFN + RBV therapy

Only 15% of patients discontinued for adverse events or laboratory abnormalities

Combination therapy with PEGASYS® plus COPEGUS® appears to have a favourable benefit-to-risk ratio in patients with HIV–HCV co-infection