Challenges in HCV Management

Prof Dr Nasir Khokhar
MD FACP FACG
Prof and Chief, Department of
Medicine and Director, Division of
Gastroenterology
Shifa International
Islamaabad
Challenges in Management of HCV-
Infected Patients

clinicaloptions.com/hepatitis
AASLD 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

Non Responders

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%
SVR(%)
 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

34
6
18
32
7
17
43
18
25
38
14
22
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)
SVR(%)
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

Jensen D, et al. Ann Intern Med. 2009;150:528-540.
Patients with
chronic HCV
infection not
responsive to
pegIFN alfa-2b/
RBV therapy
PegIFN alfa-2a 180 µg/wk +
RBV 1000/1200 mg/day
(n = 317)
Wk 48 Wk 96Wk 72
PegIFN alfa-2a
180 µg/wk + RBV
1000/1200 mg/day
(n = 156)
RBV 1000-1200 mg/day
(n = 156)
RBV 1000-1200 mg/day
(n = 313)
PegIFN alfa-2a
360 µg/wk + RBV
1000-1200 mg/day
PegIFN alfa-2a
360 µg/wk + RBV
1000-1200 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

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)
7
14 9
16
0
100
SVR(%)
360/180 µg
72 Wks
360/180 µg
48 Wks
180 µg
72 Wks
180 µg
48 Wks
52/317 11/156
40
22/156 27/313n/N =
20
60
80

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
SVR(%)
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

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 arm
Di 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-2a
90 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

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

HCV with Normal ALT

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.

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 BridgingPortal
Severity of Liver Disease
Patients(%)
Normal ALT (n = 58)
Elevated ALT (n = 37)
23
19
39
19
26 24
6
16
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.

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
SVR(%)
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 0
13
40
0
48 wks of pegIFN + RBV (n = 210)
No treatment (n = 69)
72
78
P < .001
P < .001

Normal ALT:
 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

HCV in children

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.

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
SVR(%)
59
Genotype 1
(n = 46)
Genotypes 2 or 3
(n = 13)
48
100

 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
Children: Summary of Recommendations

HCV HIV Co Infection

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-Related
Diseases
CVD
N = 1246
Deaths(%)
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

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
SVR(%)
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

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
44
38
SVR(%)
All patients
GT1 patients
0
20
60
100
40
80

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.

HIV/HCV Coinfection:
 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

HCV in Renal Disease

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

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.

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
SVR(%)
20
27
21 20 19
56 58
68
33

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*
*Controversial.

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

Race

1. Muir AJ, et al. N Engl J Med. 2004;350:2265-2271.
2. Conjeevaram H, et al. Gastroenterology. 2006;131:470-477.
SVR(%)
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
SVR(%)
0
20
40
60
80
100
196205
RBV 1000-1200 mg/day[2]
n =
Lower SVR Rate in GT1 HCV–Infected
Blacks Receiving PegIFN + RBV vs Whites

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
HCVRNANegative(%)
16
10
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

Black Patients:
 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

HCV Cirrhosis

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.

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
SVR(%)
GT Non-1GT 1
0
40
80
100
13
50
Everson GT, et al. Hepatology. 2005;42:255-262.
60
20

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.
Patients(%)
HCV Free
Posttransplant*
EVR
0
20
40
60
80
100
SVR Patients
Receiving
Transplant
Everson[1]
Forns[2]
Thomas[3]
Crippin[4]
*Regardless of achieving
SVR pretransplantation.

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

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 cirrhotics

Liver Transplant Recipients

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.
Patients(%)
34
45
35 36
44
37
16
20
13
4
7
43
SVR
Discontinued
Mukherjee
et al[1]
Dumortier
et al[2]
Castells
et al[3]
Neuman
et al[4]
Oton
et al[5]
Sharma
et al[6]
0
20
40
60
80
100

Transplantation Recipients:
 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

Acute Hepatitis C

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.

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.

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
SVR(%)
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

Acute HCV Infection:
 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 basis

Obesity and Steatosis

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.

4
3
2
1
0
Association of Hepatic Steatosis and
Fibrosis
Adinolfi L, et al. Hepatology. 2001;33:1358-1364.
HepaticFibrosisScore
Grade of Steatosis
0 1-2 3-4
P < .0001

BMI and Steatosis in Genotype 1
36
30
24
18
0 25 50 75 100
P < .001
BMI(kg/m2)
Normal BMI
Hepatocytes with Steatosis (%)

HCV RNA & Steatosis in Genotype 3a
0 25 50 75 100
P < .001
SerumHCVRNA
(Eq/mLx106)
Hepatocytes with Steatosis (%)
24.0
16.0
8.0
0.2

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.

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 2/3
0
10
20
30
40
50
60
70
80
90
SVR(%)
HCV +
> 33% steatosis
HCV +
< 33% steatosis
P = .01
P = .19
P = .008
n = 39
n = 8
n = 15
n = 59
n = 101
n = 24

Hyperinsulinemia Diminishes
Antiviral Capacity of Interferon
Impact 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.

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

Drugs and Alcohol

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.

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.

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.

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
SVR(%)
SVR
(80:80:80)
SVR
(Overall)
0
20
60
100
60 65
80
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%

Active Injection Drug Users:
 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

HCV in Psychiatric Patients

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
54
59
9
28
15
6
Patients(%)

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.

Patients With Psychiatric Illness:
 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

Management of Other
High-Risk Patients

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.

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.

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.

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
Patients(%)
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.

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.

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

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

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

Reduced Response Rates in Blacks
vs Whites
Black White
50
75
ETR SVR
20
58
19
52
VirologicResponse(%)
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
VirologicResponse(%)

Reduced Response Rates in Blacks
vs Whites (cont’d)
46
40
28
13
32
74 70
52
6
25
0
20
40
60
80
100
Week 24 Week 48 SVR Virologic
Breakthrough
Relapse
Black (n = 196) White (n = 205)
Outcomes in Genotype 1 Patients Receiving Peginterferon
alfa-2a + Ribavirin for up to 48 Weeks
Patients(%)
P < .0001
P < .0001
P < .0001
P < .05
P = NS
Conjeevaram HS, et al. 2006;131:470-477.

Management of Preexisting Neutropenia
Key Data and Controversies
HCV 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

Management of HCV in Patients
With Obesity
Key Data
HCV 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

Improvement in Fibrosis at Week 72
Following Start of HCV Therapy
PatientsWithImprovementin
Fibrosis≥1Stage(%)
MeanFibrosisChange
(MetavirStage)
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
0
SVR Relapse NR
0
10
20
30
40
50
60
SVR Relapse NR
70
80
90
100

At risk 337 261 192 160 124 95 79 49 31
Events 0 5 11 16 20 24 25 28 30
At risk 142 76 48 35 25 14 8 6 5
Events 0 0 0 0 0 1 1 1 1
At risk 337 256 183 155 121 92 74 44 27
Events 0 8 21 24 27 29 31 35 35
At risk 142 76 48 35 25 14 8 6 5
Events 0 0 0 0 0 1 1 1 1
Posttreatment Outcomes in Patients With
Advanced Fibrosis With/Without SVR
Liver FailureLiver-Related Death
Liver-RelatedDeath(%)
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%)
0 81 2 3 4 5 6 7
LiverFailure(%)
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.

Incidence of HCC in Patients With
Advanced Fibrosis With/Without SVR
SVRNo SVR
At risk 337 259 188 153 117 90 71 43 30
Events 0 5 8 13 18 22 27 29 30
SVR
At risk 142 76 48 35 24 14 8 6 5
Events 0 0 1 1 3 3 3 3 3
No SVR
SVR
Years
100
HCC(%)
80
60
40
20
0
80 1 2 3 4 5 6 7
5-yr occurrence
SVR: 9.2% (95% CI: 0.0% to 19.6%)
No SVR: 13.1% (95% CI: 7.6% to 18.6%)
Veldt BJ, et al. Ann Intern Med. 2007;147:677-684. Reproduced with permission.

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

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

Questions

Challenges in HCV Management

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Similar to Challenges in HCV Management

Similar to Challenges in HCV Management (20)

More from drnkhokhar

More from drnkhokhar (8)

Recently uploaded

Recently uploaded (20)

Challenges in HCV Management