Prof Dr Nasir Khokhar MD FACP FACGProf and Chief, Department of Medicine and Director, Division of GastroenterologyShifa InternationalIslamaabad
Challenges in Management of HCV-Infected Patients
clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update
Management of Special Populations of HCV-Infected Patients Nonresponders
Patients with normal ALT levels
Children
Patients with HIV coinfection
Patients with renal disease
Patients with compensated and decompensated cirrhosis
Patients with solid organ transplantation
Acute infection
IV drug users
Patient with psychiatric illness
Black patients
clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update
Non Responders
clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update
NR: IFN + RBV[1-6] Relapse: IFN + RBV[1,5,6] NR: IFN[1,3,5]
8% to 18%
40% to 50%
20% to 30%SV
R (
%)
Previous HCV RNA reduction predicts response
High relapse rate
PegIFN + RBV for Previous IFN ± RBV Nonresponders/Relapsers
1. Jacobson IM, et al. Am J Gastroenterol. 2005;100:2453-2462. 2. Lawitz E, et al. DDW 2003. Abstract T1293. 3. Shiffman M, et al. Gastroenterology. 2004;126:1015-1023. 4. Gross JB, et al. AASLD 2005. Abstract 60. 5. Krawitt E, et al. J Hepatol. 2005;43:243-249. 6. Poynard T, et al. Gastroenterology. 2009;136:1618-1628.
100
90
70
50
30
10
0
80
60
40
20
clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update
34
6
18
32
7
17
43
1825
38
1422
EPIC3: SVR by Previous Treatment and Response
Poynard T, et al. Gastroenterol. 2009;136:1618-1628.
0
20
40
PegIFN alfa-2a + RBV (n = 375)
All(N = 2293)
SV
R (
%)
100
IFN/RBV(n = 1423)
PegIFN alfa-2b + RBV (n = 488)
All Previous nonresponders Previous relapsers
Previous Regimen
PegIFN alfa-2b 1.5 µg/kg/wk + Weight-Based RBV 800-1400 mg/day for 48 Wks
Note: results from EPIC3 study led to expanded indication for nonresponders to nonpegylated interferon and RBV.
60
80
clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update
Jensen D, et al. Ann Intern Med. 2009;150:528-540.
Patients with chronic HCV infection not
responsive topegIFN alfa-2b/
RBV therapy
PegIFN alfa-2a 180 µg/wk + RBV 1000/1200 mg/day
(n = 317)
Wk 48 Wk 96 Wk 72
PegIFN alfa-2a 180 µg/wk + RBV 1000/1200 mg/day
(n = 156)
PegIFN alfa-2a 180 µg/wk + RBV 1000-1200 mg/day
(n = 156)
PegIFN alfa-2a 180 µg/wk + RBV 1000-1200 mg/day
(n = 313)
PegIFN alfa-2a360 µg/wk + RBV1000-1200 mg/day
PegIFN alfa-2a360 µg/wk + RBV1000-1200 mg/day
Wk 12
Follow-up
Follow-up
Follow-up
Follow-up
2:1:1:2 randomization
REPEAT: PegIFN alfa-2a Treatment of PegIFN alfa-2b Nonresponders
clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update
REPEAT: 72-Wk Treatment Duration Associated With Higher SVR Rate
Jensen D, et al. Ann Intern Med. 2009;150:528-540.
P = .006; OR: 1.8 (95% CI: 1.17-2.77)
714 9
16
0
100
SV
R (
%)
360/180 µg72 Wks
360/180 µg48 Wks
180 µg 72 Wks
180 µg48 Wks
52/317 11/156
40
22/156 27/313n/N =
20
60
80
clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update
DIRECT Trial: Comparison of 2 Doses of cIFN + RBV in Previous Nonresponders
Bacon B, et al. Hepatology. 2009;49:1838-1846. Copyright © 2009 . Reproduced with permission of John Wiley & Sons, Inc.
cIFN + RBV
SV
R (
%)
P = .141
7(17/245)
11(26/242)
9 μg 15 μg
100
80
60
40
20
0
Highest rates of SVR in noncirrhotics with substantial previous HCV RNA reductions
ITT Analysis
clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update
HALT-C: Final Results of Maintenance PegIFN alfa-2a in Nonresponders No significant difference between arms in any primary outcome
– 34.1% vs 33.8%; HR: 1.01 (95% CI: 0.81-1.26)
Low-dose pegIFN alfa-2a 90 µg/wk vs control group had
– Greater reductions in HCV RNA and ALT (P < .0001)
– Greater reductions in necroinflammation (P < .001)
No reduction or difference in fibrosis in either armDi Bisceglie AM, et al. N Engl J Med. 2008;359:2429-2441.
Study Arm Baseline Fibrosis
Any Primary Outcome, %
Death, % HCC, % CTP Score ≥ 7, %
PegIFN alfa-2a90 µg/wk (n = 517)
3/4 36.7 2.6 2.6 3.2
5/6 30.2 2.4 1.9 17.8
Control (n = 533)3/4 35.5 0.6 1.6 3.2
5/6 31.2 2.7 4.6 14.6
clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update
Ghany MG, et al. Hepatology. 2009;49:1335-1374.
Nonresponders: Summary of Recommendations PegIFN + RBV can be considered for nonresponders or
relapsers to either standard IFN ± RBV or pegIFN monotherapy
PegIFN + RBV retreatment not recommended for patients without an SVR after previous full course of pegIFN + RBV
Maintenance therapy not recommended for patients with bridging fibrosis or cirrhosis who have failed a previous course of pegIFN + RBV
clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update
HCV with Normal ALT
clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update
Updated Limits for Determining Normal ALT ALT values differ by age, race, sex, and body mass index Updated healthy ALT ranges determined from low-risk
individuals[1]
– Males: 30 IU/L
– Females: 19 IU/L
Common definition for normal ALT– ALT < 40 IU/L on 2-3 occasions separated by ≥ 1 mo over
period of 6 mos
1. Prati D, et al. Ann Intern Med. 2002;137:1-10.
clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update
Persistently Normal ALT an Imperfect Marker of Liver Disease Severity Significantly less liver fibrosis generally observed in patients with
persistently normal ALT[1-2]
However, fibrosis and cirrhosis observed in patients with normal ALT[3]
0
20
40
60
80
100
No fibrosis Mild BridgingPortalSeverity of Liver Disease
Pat
ien
ts (
%)
Normal ALT (n = 58)Elevated ALT (n = 37)
2319
39
1926 24
616
Cirrhosis
6
22
1. Martinot-Peignoux M, et al. Hepatology. 2001;34:1000-1005. 2. Nutt AK, et al. Am J Med. 2000;109:62-64. 3. Shiffman ML, et al. J Infect Dis. 2000;182:1595-1601.
clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update
Efficacy of PegIFN in HCV-Infected Patients With Normal ALT Patients with ≥ 3 normal ALT measurements over 18 mos randomized to pegIFN
alfa-2a 180 µg/wk + RBV 800 mg/day or no treatment
0
20
40
60
80
100
All Patients
SV
R (
%)
24 wks of pegIFN + RBV (n = 212)
30
52
Zeuzem S, et al. Gastroenterol. 2004;127:1724-1732.
Genotype 1 Genotypes 2 or 3
0 013
40
0
48 wks of pegIFN + RBV (n = 210)
No treatment (n = 69)
7278
P < .001P < .001
clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update
Normal ALT: Summary of Recommendations Regardless of serum ALT levels, decision to initiate
therapy with pegIFN + RBV should be individualized based on
– Liver biopsy results
– Potential for serious adverse effects
– Likelihood of response
– Presence of comorbid conditions
Treatment regimen for HCV-infected patients with normal ALT same as that for persons with elevated serum ALT
Ghany MG, et al. Hepatology. 2009;49:1335-1374.
clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update
HCV in children
clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update
HCV Infection Among Children
23,048-42,296 children in United States chronically infected [1]
– 7200 new cases/yr
– Mother-to-child transmission most common mode of HCV transmission in US children
Children more likely to spontaneously clear HCV than adults[2]
Minimal progression of liver disease over 5- to 10-yr period[3]
– However, since average child likely to be infected > 50 yrs, routine treatment may still be appropriate
1. Jhaveri R, et al. J Pediatr. 2006;148:353-358. 2. Guido M, et al. Gastroenterol.1998;115:1525-1529. 3. Camarero C, et al. Eur J Pediatr .2008;167:219-224.
clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update
PegIFN alfa-2b + RBV Effective in Children and Adolescents Open-label study of 62 children receiving pegIFN alfa-2b 1.5 µg/kg/wk + RBV
15 mg/kg/day for 48 wks
Dose modification of pegIFN due to adverse events in 31% of patients; discontinuation in 7% of patients
Wirth S, et al. Hepatology. 2005;41:1013-1018.
0
20
40
60
80
100
Overall
SV
R (
%) 59
Genotype 1(n = 46)
Genotypes 2 or 3(n = 13)
48
100
clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update
Routine anti-HCV testing not recommended at birth in children born to HCV-infected mothers due to high rate of positive antibody transfer from mother
– HCV RNA testing may be considered at 1-2 mos if early diagnosis desired
– Anti-HCV testing may be performed at ≥ 18 mos
Children aged 2-17 yrs should be considered appropriate candidates for treatment using same criteria as those used for adults
– Appropriate treatment: pegIFN alfa-2b 1.5 µg/1.73 m2/wk + RBV 15 mg/kg/day
Ghany MG, et al. Hepatology. 2009;49:1335-1374.
Children: Summary of Recommendations
clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update
HCV HIV Co Infection
clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update
Liver Disease a Leading Cause of Death in HIV-Infected Patients D:A:D study (N = 23,441)
– Median FU: 3.5 yrs
Baseline characteristics
– Previous AIDS: 26.4%
– HCV positive: 22.5%
– Active HBV infection: 6.8%
– Receiving antiretrovirals: 88.7%
Mortality over 3.5 yrs median FU
– Total: 5.3%
– Incidence: 1.62/100 patient-yrs
– Median age: 44 yrs
AIDS Liver-RelatedDiseases
CVD
N = 1246
Dea
ths
(%)
31
15 11
Weber R, et al. Arch Intern Med. 2006;166:1632-1641.
0
20
40
80
100
10
30
60
70
50
90
clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update
PegIFN ± RBV vs Standard IFN in HIV/HCV-Coinfected Patients 868 HCV/HIV-coinfected patients randomized to standard IFN alfa-2a + RBV,
pegIFN alfa-2a + placebo, or pegIFN alfa-2a + RBV for 48 wks
0
20
40
60
80
100
Overall
SV
R (
%)
12
Baseline HCV RNA ≤ 800,000 IU/mL
Baseline HCV RNA > 800,000 IU/mL
PegIFN alfa-2a + placebo (n = 286)PegIFN alfa-2a + RBV (n = 289)
IFN alfa-2a + RBV (n = 285)
20
40
22
34
61
7 15
33
P < .001
P < .001
Torriani F, et al. N Engl J Med. 2004;351:438-450.
n = 82 79 79 203 206 208
clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update
1. Torriani F, et al. N Engl J Med. 2004;351:438-450. 2. Chung R, et al. N Engl J Med. 2004;351:451-459. 3. Carrat F, et al. JAMA. 2004;292:2839-2848. 4. Laguno M, et al. AIDS. 2004;18:F27-F36.
Efficacy of PegIFN + RBV in HCV/HIV-Coinfected Patients
PegIFN alfa-2a +RBV 800[1]
PegIFN alfa-2a +RBV 600-1000[2]
PegIFN alfa-2b + RBV 800[3]
Peg IFN alfa-2b +RBV 800-1200[4]
40
29 27
14
27
17
4438S
VR
(%
)
All patients
GT1 patients
0
20
60
100
40
80
clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update
Safety Considerations When Managing HCV/HIV-Coinfected Patients RBV-related anemia more common in HCV/HIV-coinfected
patients than in HCV-monoinfected patients[1]
– Particularly common in patients also receiving the anti-HIV drug zidovudine[2]
RBV potentiates the toxic effects of the anti-HIV drug didanosine[3]
– Can result in fatal lactic acidosis
– Combination contraindicated
1. Moore RD. Clin Infect Dis. 1999;29:44-49. 2. Alvarez D, et al. J Viral Hepat. 2006;13:683-689. 3. Lafeuillade A, et al. Lancet. 2001;357:280-281.
clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update
HIV/HCV Coinfection: Summary of Recommendations Anti-HCV testing should be performed in all HIV-infected
persons
HCV should be treated in the coinfected patient if the risk of serious liver disease and likelihood of treatment response are judged to outweigh morbidity of therapy
– Initial treatment of coinfected patients should be pegIFN + RBV for 48 wks at standard doses
Patients on zidovudine, and particularly those on didanosine, should be switch to an equivalent antiretroviral agent before beginning RBV therapy
Ghany MG, et al. Hepatology. 2009;49:1335-1374.
clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update
HCV in Renal Disease
clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update
HCV Therapy in Patients With Kidney Disease Kidney important for catabolism and filtration of both IFN
and RBV
– Reduced doses warranted
Standard IFN vs pegIFN for persons with kidney failure
– Reduced excretion of pegIFN
– Higher rate of adverse events with pegIFN vs standard IFN
– Management of adverse events more difficult with pegIFN vs standard IFN
Ghany MG, et al. Hepatology. 2009;49:1335-1374.
clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update
PegIFN Monotherapy Not Superior to Standard IFN Monotherapy in Dialysis Pts 78 hemodialysis patients treated with pegIFN alfa-2a 135
µg/wk[1]
– SVR obtained in 14% of patients
– Adverse events reported in 83% of patients (flu-like syndrome, mild to moderate thrombocytopenia, leukopenia, and anemia)
– 32% of patients noncompliant
Randomized trial of 16 patients receiving pegIFN alfa-2b 1.0 or 0.5 µg/kg/wk discontinued due to adverse events and modifications[2]
– 56% of patients in 1 µg/kg/wk group and 28% in 0.5 µg/kg/wk experienced serious adverse events requiring therapy discontinuation
1. Covic A, et al. J Nephrol 2006;19:794-801. 2. Russo MW, et al. Nephrol Dial Transplant. 2006;21:437-443.
clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update
IFN Monotherapy 3 MU TIW in Dialysis Patients
Russo MW, et al. Am J Gastroenterol. 2003;98:1610-1615.
100
80
60
40
20
0
SV
R (
%)
2027
21 20 19
56 58
68
33
CasanovasChan
FernandezPol
DegosIzopet
Campistol
Raptopoulou-Gigi
Pooled SVR
clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update
Patients With Renal Disease:Summary of Recommendations (I)Description GFR,
mL/min*1.73 m2
Recommended Treatment
Kidney damage with normal or increased GFR
≥ 90 Routine combination therapy
Kidney damage with mildly decreased GFR
60-90
Moderately decreased GFR 30-59 PegIFN alfa-2b 1 µg/kg/wk or pegIFN alfa-2a 135 µg/wk + RBV 200-800 mg/day (starting with lowest dose and increasing
if adverse effects manageable)
Severely decreased GFR 15-29
Kidney failure < 15
Dialysis Standard IFN 3 mU 3x/wk or pegIFN alfa-2b 1 µg/kg/wk or pegIFN alfa-2a
135 µg/wk ± markedly reduced daily RBV dose*
Ghany MG, et al. Hepatology. 2009;49:1335-1374.
*Controversial.
clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update
Patients With Renal Disease:Summary of Recommendations (II) HCV treatment not recommended for patients who have
undergone kidney transplantation, unless fibrosing cholestatic hepatitis develops
Patients with cryoglobulinemia, mild to moderate proteinuria, and slowly progressive kidney disease can be treated with standard IFN or reduced doses of pegIFN + RBV
Patients with cryoglobulinemia and marked proteinuria with evidence of progressive kidney disease or an acute flare of cryoglobulinemia can be treated with rituximab, cyclophosphamide + methylprednisolone, or plasma exchange followed by IFN-based treatment once the acute process has subsided
Ghany MG, et al. Hepatology. 2009;49:1335-1374.
clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update
Race
clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update
1. Muir AJ, et al. N Engl J Med. 2004;350:2265-2271. 2. Conjeevaram H, et al. Gastroenterology. 2006;131:470-477.
SV
R (
%)
0
20
40
60
80
100
PegIFN alfa-2b 1.5 µg/kg/wk + RBV 800-1000 mg/day[1]
Non-Hispanic whites
Blacks
n =
52
19
P < .001
100100
52
28
P < .0001
SV
R (
%)
0
20
40
60
80
100
196205
PegIFN alfa-2a 180 µg/wk + RBV 1000-1200 mg/day[2]
n =
Lower SVR Rate in GT1 HCV–Infected Blacks Receiving PegIFN + RBV vs Whites
clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update
WIN-R Trial: Weight-Based RBV Dosing Superior to Flat Dosing in HCV GT1 Blacks Randomized trial compared pegIFN alfa-2b 1.5 µg/kg/wk + either flat dosing of RBV
(800 mg/day) or weight-based RBV (800-1400 mg)
Jacobson IM, et al. Hepatology. 2007;46:982-990.
P = .004
36/17430/188 50/174
HC
V R
NA
Neg
ativ
e (%
)
1610
21
29
0
20
40
60
80
100
End of Treatment SVR (Wk 24 Posttreatment)
Flat dosing (n = 188)
Weight-based dosing (n = 174)
P = .006
10
30
50
70
90
clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update
Black Patients: Summary of Recommendations Blacks who are appropriate HCV treatment candidates
should be treated with current optimal regimen of pegIFN + RBV
Blacks with baseline neutropenia (ANC < 1500/mm3) should receive HCV treatment
Ghany MG, et al. Hepatology. 2009;49:1335-1374.
clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update
HCV Cirrhosis
clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update
Observations in HCV-Infected Patients With Cirrhosis Lower SVR rates in compensated cirrhotics vs patients without
cirrhosis in registrational treatment trials[1-3]
– 41% to 44% vs 57% to 63%, respectively
Treatment still strongly indicated in compensated cirrhotics
– Serious adverse events common and should be closely monitored
Screening for varices and for HCC must be standard in cirrhotics
– HCC risk declines but still exists after SVR in cirrhotics; must continue screening indefinitely
HCV recurrence after transplantation is almost universal
Treatment more difficult posttransplantation (more adverse events, lower SVR rates)
1. Manns MP, et al. Lancet. 2001;358:958-965. 2. Fried MW, et al. N Engl J Med. 2002;347:975-982. 3. Hadziyannis SJ, et al. Ann Intern Med. 2004;140:346-355.
clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update
Low Accelerating Dose Regimen in Patients With Advanced Cirrhosis 124 patients with advanced
cirrhosis treated with IFN + RBV or pegIFN + RBV
– Treatment began with half doses of both IFN and RBV that were increased incrementally as tolerated
Frequent adverse events requiring dose reduction or discontinuation
Among patients HCV RNA negative before transplantation, 80% remained HCV RNA negative 6 mos later
19/3811/86
SV
R (
%)
GT Non-1GT 10
40
80
100
13
50
Everson GT, et al. Hepatology. 2005;42:255-262.
60
20
clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update
HCV Therapy in Decompensated Cirrhotics Awaiting Liver Transplantation
1. Everson GT, et al. Hepatology. 2005;42:255-262. 2. Forns X, et al. J Hepatol. 2003;39:389-396. 3. Thomas RM, et al. Liver Transpl. 2003;9:905-915. 4. Crippin JS, et al. Liver Transpl. 2002;8:350-355.
Pat
ien
ts (
%)
HCV FreePosttransplant*
EVR0
20
40
60
80
100
SVR Patients Receiving Transplant
Everson[1]
Forns[2]
Thomas[3]
Crippin[4]
*Regardless of achieving SVR pretransplantation.
clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update
Lessons of Low Acclerating Dose Regimen SVR can be achieved in some well-selected patients with
HCV and decompensated cirrhosis
If a patient achieves SVR before transplantation, posttransplantation recurrence of HCV is prevented
Risk of sepsis, hepatic failure, and death must be balanced against potential benefits
Risks usually outweigh benefits in Child’s C cirrhotics
Transplantation evaluation should be completed before treatment begins in case patient should decompensate further on treatment
Ghany MG, et al. Hepatology. 2009;49:1335-1374.
clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update
Cirrhosis: Summary of Recommendations
Compensated cirrhotics can be treated with standard regimen of pegIFN + RBV but require close monitoring for adverse events
Decompensated cirrhotics should be considered for liver transplantation
IFN-based therapy may be initiated at a lower dose in decompensated cirrhotics if
– Treatment is administered by experienced clinician with vigilant monitoring
– Preferably in patients already accepted as candidates for transplantation
Growth factors can be used for anemia and leukopenia to
– Improve quality of life
– May limit need for dose reductions in decompensated cirrhoticsGhany MG, et al. Hepatology. 2009;49:1335-1374.
clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update
Liver Transplant Recipients
clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update
PegIFN + RBV Treatment for Recurrent HCV Post–Liver Transplantation
1. Mukherjee S. Transplant Proc. 2005;37:4403-4405. 2. Dumortier J, et al. J Hepatol. 2004;40:669-674. 3. Castells L, et al. J Hepatol. 2005;43:53-59. 4. Neumann U, et al. Transplantation. 2006;82:43-47. 5. Oton E, et al. Am J Transplant. 2006;6:2348-2355. 6. Sharma P, et al. Liver Transpl. 2007;13:1100-1108.
Pat
ien
ts (
%)
34
45
35 3644
37
1620
13
4 7
43
SVR
Discontinued
Mukherjee et al[1]
Dumortieret al[2]
Castellset al[3]
Neumanet al[4]
Otonet al[5]
Sharmaet al[6]
0
20
40
60
80
100
clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update
Transplantation Recipients: Summary of Recommendations Treatment of HCV-related liver disease following liver
transplantation should be initiated with caution in appropriate candidates after demonstration of recurrent histologic disease
– PegIFN ± RBV the preferred regimen when treating HCV post–liver transplantation
IFN-based therapies should not be used in recipients of heart, lung, and kidney grafts
– Except for patients who develop fibrosing cholestatic hepatitis
Ghany MG, et al. Hepatology. 2009;49:1335-1374.
clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update
Acute Hepatitis C
clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update
Spontaneous Clearance for Symptomatic Acute HCV High, Justifies Treatment Delay 60 patients with acute HCV (36 genotype 1) followed[1]
– Spontaneous clearance in 52% of 51 symptomatic cases
– No asymptomatic patient cleared virus spontaneously
– SVR achieved in 81% of symptomatic patients without spontaneous clearance who were treated > 3 mos after symptom onset with IFN ± RBV
Recent study showed similar SVR rates in symptomatic adherent patients who delayed therapy for 12 wks vs those who received immediate treatment[2]
1. Gerlach JT, et al. Gastroenterol. 2003;125:80-88. 2. Deterding K, et al. EASL 2009. Abstract 1047.
clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update
Very High Rate of SVR With IFN Monotherapy for Acute HCV 44 patients with acute HCV infection
– 61% genotype 1
– 68% with icterus
Treated with IFN alfa-2b 5 MU/day x 4 wks, followed by IFN 3 MU TIW x 20 wks
– Average time from infection to signs/symptoms: 54 days
– Average time from infection to start of therapy: 89 days
43 of 44 (98%) had SVR
Jaeckel E, et al. N Engl J Med. 2001;345:1452-1457.
clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update
Randomized Trial of Treatment for Acute Hepatitis C at Variable Times After Onset 129 patients entered
treatment for lack of spontaneous clearance within 8 wks of presentation
– 37% genotype 1
– 41% genotype 4
Randomized to treatment at Wk 8, 12, or 20
Treatment with pegIFN alfa-2b 1.5 µg/kg/wk x 12 wks
Kamal SM, et al. Gastroenterol. 2006;130:632-638.
Time of Treatment Initiation
43 4343
95* 92
76
SV
R (
%)
n =
*SVR rates significantly higher for genotype 1 patients who received treatment after 8 wks vs either 12 or 20 wks (P = .01 and P = .004, respectively).
0
20
40
60
80
100
8 wks 12 wks 20 wks
clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update
Acute HCV Infection: Summary of Recommendations Patients with acute HCV infection should be considered for
IFN-based therapy
Treatment can be delayed 8-12 weeks after acute onset to allow for spontaneous resolution
Although standard IFN monotherapy effective in this population, pegIFN can be considered due to greater ease of administration
No definitive recommendation about optimal duration of treatment for acute hepatitis C; however, it is reasonable to treat for ≥ 12 weeks, and 24 weeks may be considered
Decision to use RBV made on a case-by-case basisGhany MG, et al. Hepatology. 2009;49:1335-1374.
clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update
Obesity and Steatosis
clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update
Steatosis and HCV
2/3 of HCV patients have some steatosis
Steatosis is more common with obesity and genotype 3 infection
Increased steatosis may be associated with increased fibrosis progression, particularly in non-genotype 3 HCV
In genotype 3, the presence of steatosis correlates with viral replication
Adinolfi L, et al. Hepatology. 2001;33:1358-1364. Hu K, et al. J Hepatol. 2004;40:147-154.
clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update
4
3
2
1
0
Association of Hepatic Steatosis and Fibrosis
Adinolfi L, et al. Hepatology. 2001;33:1358-1364.
Hep
atic
Fib
rosi
s S
core
Grade of Steatosis
0 1-2 3-4
P < .0001
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BMI and Steatosis in Genotype 1
36
30
24
18
0 25 50 75 100
P < .001
BM
I (k
g/m
2 )
Normal BMI
Hepatocytes with Steatosis (%)
Adinolfi L, et al. Hepatology. 2001;33:1358-1364.
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HCV RNA & Steatosis in Genotype 3a
0 25 50 75 100
P < .001
Ser
um
HC
V R
NA
(Eq
/mL
x 1
06 )
Hepatocytes with Steatosis (%)
24.0
16.0
8.0
0.2
Adinolfi L, et al. Hepatology. 2001;33:1358-1364.
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Steatosis and HCV
Viral Factors: Genotype 3 Steatosis correlated with
intrahepatic viral replication Eradication of HCV improves
steatosis
Host Factors: Steatosis associated with
obesity and insulin resistance
Associated with decreased response to IFN
Other Factors: Alcohol Medications
Steatosis> 50% of all HCV patients
Negro F. Hepatology. 2002;36:1050-1052. Adinolfi L, et al. Hepatology. 2001;33:1358-1364.
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Decreased Response to Therapy in Obese CHC Patients with Coexistent Steatosis
Harrison SA, et al. Hepatology. 2003;38(Suppl 1):626A.
Overall Genotype 1 Genotype 2/30
10
20
30
40
50
60
70
80
90
SV
R (
%)
HCV + > 33% steatosis
HCV + < 33% steatosis
PP = .01 = .01
PP = .19 = .19
PP = .008 = .008
n = 39
n = 8
n = 15
n = 59
n = 101
n = 24
clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update
Hyperinsulinemia Diminishes Antiviral Capacity of InterferonImpact of insulin level on interferon antiviral activity examined
in HCV replicon system:
Interferon resulted in a rapid, sharp, stable decrease in HCV RNA
Interferon induced PKR and IRF-1 protein expression
Insulin prevented IFN-mediated HCV suppression:
– Blocked the effects of key intra-hepatic proteins
Sanyal AJ, et al. AASLD 2004. Abstract 39.
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Body Weight and HCV
BMI and steatosis are independent predictors of fibrosis progression
Weight loss may improve HCV disease progression in obese, steatotic individuals.
IFN response decreases with high body weight and is not necessarily overcome with higher IFN doses
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Drugs and Alcohol
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Drug Use and HCV
Methadone or buprenorphine use does not decrease interferon responsiveness
Continued IDU is a concern in treatment candidates:
– Greater rate of depression
– Risk of noncompliance
– Should be an individualized decision
Strader DB, et al. Hepatology. 2004;39:1147-1171.
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Alcohol and HCV
Increases the fibrosis progression rate
Increases HCV mortality rate
Threshold amount of alcohol necessary is unknown, but probably around 30-50 g/day
Alcohol may interfere with interferon responsiveness
Poynard T, et al. Lancet. 1997;349:825-832. Oshnishi K, et al. Am J Gastroenterol. 1996;91:1374-1379. Sawada M, et al. Alcohol Alcohol Suppl. 1993;1B:85-90. Degos F. J Hepatol 1999;31 Suppl 1:113-118.
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Treatment of HCV in Methadone-Maintained Patients 71 patients on methadone treated with IFN + RBV
SVR rate higher in the 68% of patients who were adherent
– 42% in adherent patients
– 4% in nonadherent patients
Adherence in occasional drug users similar to abstinent patients
Predictors of nonadherence
– Relapse to regular drug use (P = .03)
– Preexisting psychiatric diagnosis (P = .04)
Sylvestre DL, et al. Eur J Gastroenterol Hepatol. 2007;19:741-747.
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Impact of IV Drug Use on HCV Therapy:Swiss Hepatitis C Cohort Study
Bruggmann P, et al. J Viral Hepat. 2008;15:747-752.
19/38
SV
R (
%)
SVR (80:80:80)
SVR (Overall)
0
20
60
100
60 6580
40
69 76
Controls
IVDUs
500 patients treated, most with pegIFN and RBV
– 199 active IV drug users (30% GT1, 62% GT3)
– 301 controls (47% GT1, 29% GT3)
IVDUs equally adherent vs controls
– 66% vs 60% received ≥ 80% cumulative drug dose
– 87% vs 86% received ≥ 80% treatment duration
Overall SVR: 63%
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Active Injection Drug Users: Summary of Recommendations Treatment of HCV infection can be considered in persons
who currently use illicit drugs or who are in a methadone maintenance program
– Must be willing to undergo therapy and maintain close monitoring
– Benefit must be judged to outweigh risks
Persons who use illicit drugs should receive continued support from drug abuse and psychiatric counseling services as an important adjunct to treatment
Ghany MG, et al. Hepatology. 2009;49:1335-1374.
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HCV in Psychiatric Patients
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SVR and Dropout Rates Similar Between Psychiatric Patients and Controls 70 HCV-infected patients prospectively evaluated for response to HCV
therapy based on presence of psychiatric disease or drug addiction
– PegIFN alfa-2b + RBV administered for 24 wks (GT 2/3) or 48 wks (GT 1/4)
Schaefer M, et al. Hepatology. 2007; 46:991-998.
0
20
40
60
80
100
SVR Dropout
Psychiatric (n = 22)
Methadone (n = 18)
Former drug abuse (n = 13)
Control (n = 17)
50
72
5459
9
28
156
Pat
ien
ts (
%)
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Approach to Managing Psychiatric Issues During HCV Treatment Education, monitoring, and support
– Information and psychoeducation before and during treatment
– Monitoring of patients and past/current psychiatric issues
– Assessment of current or previous substance abuse
– Supportive psychotherapy and counseling
– Management of sleep disturbances
Pharmaceutical strategies
– Antidepressant treatment
– Other treatments: antipsychotics, benzodiazepines (mood stabilizers, amphetamines, naltrexone, tryptophan, etc)
– Antiviral therapy dose reduction, discontinuation if needed
Schaefer M, et al. Curr Drug Abuse Rev. 2008;1:177-187.
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Patients With Psychiatric Illness: Summary of Recommendations Patients with HCV infection and controlled mental and
psychiatric disorders can be considered for treatment using currently approved regimens
– Only with support of multidisciplinary team that should include psychiatric counseling services
Ghany MG, et al. Hepatology. 2009;49:1335-1374.
Management of OtherHigh-Risk Patients
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Seizure Disorders
Interferon may be associated with decreased seizure threshold leading to potential increased risk
– Risk ~ 1 in 13,000 persons (no seizure history)
Uncontrolled seizure is absolute contraindication
Stable, controlled seizure disorder or remote seizure history may be considered for HCV treatment
Neurologic evaluation pretreatment may be indicated
Shakil AO, et al. J Hepatology. 1996;24:48-51.
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Management of Hepatitis C in Patients With Coronary Artery Disease Direct cardiac toxicity with interferon/ribavirin rare
– Rare cases of cardiomyopathy
Ribavirin associated hemolytic anemia is primary concern
– May precipitate cardiac ischemia
Assess cardiac risk in all persons prior to HCV treatment
– Smoking, DM, HTN, family history, prior cardiac event
– In persons at risk, consider exercise or pharmacologic stress test prior to treatment
McHutchison JG, et al. Liver Int. 2006;26:389-398.
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Management of Hepatitis C in Patients With Coronary Artery Disease (cont’d) Monitor hemoglobin closely in persons at increased risk
for cardiac ischemia
Follow ribavirin dose reduction guidelines for this group
Consider hematopoietic growth factors to prevent severe anemia
– Epoetin alfa 40,000 IU SC weekly
– Darbepoetin alfa 200 µg SC every other week
– Use before therapy?
Monotherapy is an option
McHutchison JG, et al. Liver Int. 2006;26:389-398.
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HCV and Hemophilia
HCV common among those receiving human-derived blood products before 1987
Increasing rates of liver disease among older men with bleeding disorders
Role of biopsy is controversial due to need for aggressive management peri-procedure
– Biopsy can be performed safely
– Noninvasive markers may be useful
HCV treatment is NOT contraindicated
– No increased bleeding risk observed in trials
22
43
57
0
20
40
60
80
100
IFN IFN+ RBV
PegIFN + RBV
Pat
ien
ts (
%)
SVR Rates Among HCV-Infected Hemophiliacs
Posthouwer D, et al. Haemophilia. 2006;12:473-478. Maor Y, et al. Haemophilia. 2006;12:372-379. Manns MP, et al. Lancet. 2001;358:958-965. Fried MW, et al. N Engl J Med. 2002;347:975-982.
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Managements of Thalassemias and Hemoglobinopathies Thalassemia major/minor
Sickle cell anemia
RBV-associated hemolysis may increase blood transfusion requirements
Management in HCV
Limited data from case series suggest HCV treatment may be effective
Key data
Management in HCV
Limited data from case series suggest HCV treatment may be effectiveKey data
Avoid precipitation of crisis
Butensky E, et al. Ann N Y Acad Sci. 2005;1054:290-299. Inati A, et al. Br J Haematol. 2005;130:644-646. Li CK, et al. Br J Haematol. 2002;117:755-758. Hassan M, et al. J Natl Med Assoc. 2003;95:872-874.
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Autoimmune Disease
Interferon may exacerbate underlying autoimmunity
– Limited data on safety
Autoimmune hepatitis is a contraindication to interferon
– However, patients who are ANA positive but do not fit the “typical” profile may have a positive ANA through complex HCV-immune interaction
Patients with RA, SLE or other conditions may be considered on a case-by-case basis only if disease is well controlled
Patients with sarcoid should not be treated due to risk of flare
Yee HS, et al. Am J Gastroenterol. 2006;101:2360-2378.
Managing Difficult-to-Treat Patients at Low Risk for
Complications
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Managing Older Patients With Hepatitis C
Management considerations for HCV patients older than 70 yrs of age
Consider treatment on a case-by-case
basis
Watch for excessive RBV-associated
hemolysis
Medical comorbidities
Liver disease
HCV genotype
RBV is cleared by the kidneys and age-related
reduction in CrCl leads to its accumulation
Estimate GFR and consider lower
dose RBV
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Management of HCV Infection in Blacks
Lower SVR rates not explained by differences in HCV genotype, viral load, liver disease, body weight, or adherence
Multiple studies under way to analyze the genetics of interferon responsiveness in this patient group
Although SVR rates are relatively low, individual patients may respond
– Treat all black patients in whom the potential benefits of therapy outweigh the risks
– Week 12 EVR rule applies: stop therapy if ≥ 2 log10 reduction in HCV RNA is not achieved
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Reduced Response Rates in Blacks vs Whites
Black White
50
75
ETR SVR
2020
5858
1919
5252
Vir
olo
gic
Res
po
nse
(%
)
30
52
26
39
ETR SVR
PegIFN Alfa-2a + RBV[2]PegIFN Alfa-2b + RBV[1]
1. Muir AJ, et al. N Engl J Med. 2004;350:2265-2271.2. Jeffers L, et al. Hepatology. 2004;39:1702-1708.
25
0
50
75
25
0
Vir
olo
gic
Res
po
nse
(%
)
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Reduced Response Rates in Blacks vs Whites (cont’d)
4640
28
13
32
74 70
52
6
25
0
20
40
60
80
100
Week 24 Week 48 SVR VirologicBreakthrough
Relapse
Black (n = 196) White (n = 205)
Outcomes in Genotype 1 Patients Receiving Peginterferon alfa-2a + Ribavirin for up to 48 Weeks
Pat
ien
ts (
%)
P < .0001P < .0001
P < .0001
P < .05
P = NS
Conjeevaram HS, et al. 2006;131:470-477.
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Management of Preexisting Neutropenia
Key Data and ControversiesHCV Management Strategies in
Patients With Neutropenia
Typically seen in blacks and cirrhotics Typically excluded from therapy
– How low is too low? Intratherapy declines expected
– How low is too low?– Relative drop vs percentage drop– Is there a higher risk of infection?
Value of pretreatment GCSF not studied
Close attention to white blood cell counts/ANCs
Report any signs of infection/injury immediately
Judicious use of antibiotics Use of GCSF Discontinuation of therapy if SAE
occurs such as pneumonia, urosepsis, or if hospitalization is required
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Management of HCV in Patients With Obesity
Key DataHCV Management Strategies in
Obese Patients
Epidemic in the US, common among persons with HCV infection
High BMI > 30 is associated with lower SVR rates
Insight into causes– Obesity is an active inflammatory
state– Insulin resistance– Presence of steatosis – Increased fibrosis
Fixed dosing vs weight-based dosing– Can more interferon overcome
impact of higher BMI? Weight loss program BEFORE
hepatitis C treatment– Diet, exercise, surgery
Insulin-sensitizing agents have been studied but remain experimental
Bressler BL, et al. Hepatology. 2003;38:639-644. Brown RS Jr, et al. EASL 2006. Abstract 41. Hadziyannis SJ, et al. Ann Intern Med. 2004;140:346-355. Sanyal AJ, et al. Clin Gastroenterol Hepatol. 2004;2:1107-1115.
Impact of Treatment on Natural History of Hepatitis C
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Improvement in Fibrosis at Week 72 Following Start of HCV Therapy
Pat
ien
ts W
ith
Imp
rove
men
t in
F
ibro
sis
≥ 1
Sta
ge
(%)
Mea
n F
ibro
sis
Ch
ang
e (M
etav
ir S
tag
e)
Everson GT, et al. Aliment Pharm Ther. 2008;27:542-551.
Varied With Response to Treatment
-1.2
-1.0
-0.8
-0.6
-0.4
-0.2
0SVR Relapse NR
0
10
20
30
40
50
60
SVR Relapse NR
70
80
90
100
clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update
At risk 337 261 192 160 124 95 79 49 31Events 0 5 11 16 20 24 25 28 30
At risk 142 76 48 35 25 14 8 6 5Events 0 0 0 0 0 1 1 1 1
At risk 337 256 183 155 121 92 74 44 27Events 0 8 21 24 27 29 31 35 35
At risk 142 76 48 35 25 14 8 6 5Events 0 0 0 0 0 1 1 1 1
Posttreatment Outcomes in Patients With Advanced Fibrosis With/Without SVR
Liver FailureLiver-Related Death
Liv
er-R
elat
ed D
eath
(%
)
Year
50 5-yr occurrence
SVR: 4.4% (CI: 0% to 12.9%)No SVR: 12.9% (CI: 7.7% to 18.0%)
P = .024 (log likelihood)
Year
5-yr occurrence
SVR: 0%No SVR: 13.3% (CI: 8.4% to 18.2%)
P = .001 (log likelihood)
0 81 2 3 4 5 6 7
Liv
er F
ailu
re (
%)
50
40
30
20
10
0
0 1 2 3 4 5 6 7 8
No SVR
SVR
40
30
20
10
0
Veldt BJ, et al. Ann Intern Med. 2007;147:677-684. Reproduced with permission.
clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update
Incidence of HCC in Patients With Advanced Fibrosis With/Without SVR
SVRNo SVRAt risk 337 259 188 153 117 90 71 43 30Events 0 5 8 13 18 22 27 29 30
SVRAt risk 142 76 48 35 24 14 8 6 5Events 0 0 1 1 3 3 3 3 3
No SVR
SVR
Years
100
HC
C (
%)
80
60
40
20
0
80 1 2 3 4 5 6 7
5-yr occurrenceSVR: 9.2% (95% CI: 0.0% to 19.6%)No SVR: 13.1% (95% CI: 7.6% to 18.6%)P = .192 (log likelihood)
Veldt BJ, et al. Ann Intern Med. 2007;147:677-684. Reproduced with permission.
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Progression of HCV Liver Disease: Summary Chronic HCV infection leads to cirrhosis and liver failure in
a large number of persons
– Clinical complications of advanced liver disease include portal hypertension, ascites, variceal bleeding, and HCC
Rates of progression dependent on modifiable and nonmodifiable factors
Effective treatment of chronic HCV infection can prevent fibrosis progression and reduce complications of HCV
– Treatment outcomes impacted by baseline fibrosis and cirrhosis
clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update
Conclusion
HCV infection is common among persons with comorbid medical and psychiatric conditions
Successful treatment is possible
– Requires a team oriented approach
– Experienced clinician in the management of chronic hepatitis C
Many other individuals could benefit from treatment
– HIV, HBV
– Cirrhosis, cryoglobulinemia
– Prior relapsers and nonresponders
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Questions