challenges in hcv management

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


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%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


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


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


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


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


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


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 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.


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


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



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

SV

R (

%) 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-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


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


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


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: 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



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

SV

R (

%)

2027

21 20 19

56 58

68

33

CasanovasChan

FernandezPol

DegosIzopet

Campistol

Raptopoulou-Gigi

Pooled SVR


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.

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


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


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



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

SV

R (

%)

GT Non-1GT 10

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.

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.


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 cirrhoticsGhany MG, et al. Hepatology. 2009;49:1335-1374.


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.

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


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



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

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


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.


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.

Hep

atic

Fib

rosi

s S

core

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

BM

I (k

g/m

2 )

Normal BMI

Hepatocytes with Steatosis (%)



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



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 2/30

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


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.


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

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%


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



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

5459

9

28

156

Pat

ien

ts (

%)


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: 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


Management of OtherHigh-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

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.


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

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

(%

)


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.


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


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


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


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.


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.


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

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