leevy, carroll
TRANSCRIPT
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