Management of HCV in the Correctional Setting

William M. Cassidy, MD

LSU Health Science Center

Baton Rouge, La

Hepatitis C Natural History

Variable

Complications of HCV result from cirrhosis

Question

Do all HCV patient develop cirrhosis

Can HCV be non-progressive

If so, can liver histology differentiate progressive & non-progressive disease

Can Natural History impact treatment decisions

Natural History of HCV

…chronic hepatitis C is a progressive fibrotic disease…

Progression from stage 1 to stage 4 was almost linear according to time.

Rate of fibrosis progression was not normally distributed. There are at least 3 major populations: slow, intermediate and rapid fibrosers.

Poynard T, Bedossa P, Opolon. Natural History of liver fibrosis progression in patients with chronic hepatitis C. Lancet 1997;349:825-832

Staging of Fibrosis on Liver Biopsy

Stage Histology

0 No fibrosis

1 Minimal fibrosis

2 Moderate fibrosis

3 Moderate to Severe fibrosis

4 Cirrhosis

Histologic Progression of HCV

NormalNormal Mild Chronic Mild Chronic HepatitisHepatitis

Moderate Chronic Moderate Chronic HepatitisHepatitis

CirrhosisCirrhosisII-8

Modeling of Liver Fibrosis in Chronic Hepatitis C n=1157 patients

0

1

2

3

4

0 10 20 30 40 50

Years

F M

etav

ir

Rapid progressorsIntermediate progressors

Slow progressors

Poynard et al, Hepatology 1999

Fibrosis Index

Stage of fibrosis seen on liver biopsy

# years infected

Twelve-year Follow-up of 154 Patientswith HCV Compensated Cirrhosis

Patients Mean

Incidence

Clinical decompensation 51 (33%) 3.7%

Ascites 39 (25%) 2.7%

Jaundice 21 (14%) 1.4%

GI bleeding 15 (10%) 1.0%

Hepatocellular carcinoma 48 (31%) 3.3%

Death 44 (28%) 3.0%

Sangiovanni et al. EASL Meeting, Madrid 18-21 April 2002

Ideally

Treat first those with histologically aggressive HCV.

Goal of Treating

Prevent cirrhosis

Not elimination of infection per se.

Approach to Treatment of Chronic Hepatitis C on the Basis of Histologic Findings

Young patients: – aggressive disease - treatment indicated – mild-to-moderate disease - treatment

encouraged

Patients with stage 0 or stage 1– treatment can be safely deferred

III-38Management of Hepatitis C. NIH Consensus Statement..

Sources of Infection for PersonsWith Hepatitis C

Sexual 15%

Other * 1%

Unknown 9%

Injection drug use 60%

*Nosocomial; iatrogenic; PerinatalAdapted from Hepatitis Slide Kit http://www.cdc.gov/ncidod/diseases/hepatitis/slideset.Accessed 07/21/05.

Transfusion 10%(before screening)

Occupational 4%

29%

87%

48%

69%64%

0%

20%

40%

60%

80%

100%

Both Doses 80%

RBV Dose <80%;

PEG Dose 80%

Both Doses <80%

Treatment Factor

PEG Dose <80%;

RBV Dose 80%

Ferenci P et al. J Hepatol. 2005;43:425-433.

SV

R (

%)

All Patients

n=208 n=146 n=40 n=15 n=7

P=0.0143 P=0.0064

Effect of Adherence on SVR Following PEG-IFN

and RBV Therapy in HCV Genotype 1 PatientsPEG-IFN -2a 180 g qwk + RBV 1000-1200 mg/day

Both Doses80%

RBV Dose<80%;

PEG Dose80%

Both Doses<80%

Treatment Factor

PEG Dose<80%;

RBV Dose80%

Davis GL et al. Hepatology 2003;38:645-652.

80%70%

60%

33%

<80%80%

0%

50%

75%

Cha

nce

of E

VR

(%

)

25%

100%

n=324 n=38 n=3 n=15

Adherence During First 12 Wks of PEG-IFN -2b + RBV Therapy Affects Early

Virologic ResponsePEG-IFN -2b Start Dose: 1.5 g/kg Each Wk

RBV Start Dose: 800 mg/d

Adherence: Take-home Messages

Adherence critical for SVR in patients with genotype 1, but role in genotype 2 and 3 less clear– Discontinuations have major impact on SVR

Adherence in first 12 wks of treatment affects EVR– Data do not show a significant negative impact

of late dose reductions (after 12-24 wks) Negative impact of drug reductions on EVR and

SVR are based upon protocol-driven modifications – Impact of smaller and/or temporary dose

reductions on EVR/SVR not studied

SVR and Weight in African Americans

Slide courtesy of Jacobson adapted from Jacobson IM et al. Hepatology. 2004; 40 (suppl 1):217A.Abstract 125.

12% 13%

9%

23%

7%

31%

0%

5%

10%

15%

20%

25%

30%

35%

STD WBD

65-85 >85-105 >105-125 kg

Pat

ient

s A

chie

ving

SV

R (

%)

Overall SVR: 10% FD vs 21% WBD, P=0.004

9/77 7/81 2/30 8/62 18/80 10/32

0

10

20

30

40

50

60

Shiffman ML et al, Hepatology 2005;42:217AShiffman ML et al, Hepatology 2005;42:217AShiffman ML et al, Hepatology 2005;42:217AShiffman ML et al, Hepatology 2005;42:217A

PEG IFN +PEG IFN +RBV 800-1400 RBV 800-1400

PEG IFN +PEG IFN +RBV 800-1400 RBV 800-1400

PEG IFN + PEG IFN + RBV 800-1400 +RBV 800-1400 +

EpoEpo

PEG IFN + PEG IFN + RBV 800-1400 +RBV 800-1400 +

EpoEpo

PEG IFN +PEG IFN +RBV 1000-1600 +RBV 1000-1600 +

EpoEpo

PEG IFN +PEG IFN +RBV 1000-1600 +RBV 1000-1600 +

EpoEpo

Higher Than Conventional RBV Doses Higher Than Conventional RBV Doses May Be More EffectiveMay Be More Effective

Higher Than Conventional RBV Doses Higher Than Conventional RBV Doses May Be More EffectiveMay Be More Effective

• Treatment naïve patients with genotype 1• n=146• PEG 2b 1.5 ug/kg + RBV + epo

• Treatment naïve patients with genotype 1• n=146• PEG 2b 1.5 ug/kg + RBV + epo

19%19%19%19%

49%49%49%49%

29%29% 29%29%

%SVR%SVR%SVR%SVR

Optimizing Therapy

RBV dose is important determinant of SVR Higher doses have benefit in

“more difficult to treat” populations– Genotype 1 – African-Americans– Overweight

Dose-related anemia – Growth factors use appear important in higher dose protocols– Related to renal clearance

HCV: TailoringDuration of Therapy

Patterns of Virologic Response

Vira

l Lo

ad D

ecre

ase

(lo

g co

pie

s/m

L)

ETR SVR

0

72

Rapid Viral Response (RVR)

4 48

ViralRNA (–)

0

PEG-IFNs

Wks of Therapy

Rapid Viral Response (RVR) as a Predictor of SVR

ETR SVR

72

“Complete” Early Viral Response (EVR)

4 48

ViralRNA (–)

0 12

PEG-IFNs

Wks of Therapy

Vira

l Lo

ad D

ecre

ase

(lo

g co

pie

s/m

L)

0

“Complete” Early Viral Response, (EVR) as a Predictor of SVR

ETR SVR

724 48

ViralRNA (–)

0 12 24

≥2 log drop but HCV RNA

(+)

PEG-IFNs

Wks of Therapy

“Partial” Early Viral Response (EVR)

Vira

l Lo

ad D

ecre

ase

(lo

g co

pie

s/m

L)

0

“Partial” Early Viral Response, (EVR) as a Predictor of SVR

Rationale for Evaluating HCV Antiviral Therapy Early

Identify patients in whom therapy should be truncated

Increase chance of SVR with prolongation of therapy in slow responders

Identify nonresponders and discontinue therapy:– Avoids additional morbidity in those

who will not respond – Reduces cost

Goal

Pat

ien

ts W

ith

aP

atie

nts

Wit

h a

Vir

olo

gic

Res

po

nse

(%

)V

iro

log

ic R

esp

on

se (

%)

HCV RNA StatusHCV RNA StatusWeek 4Week 4 Negative Negative ≥2 log 2 log <2 log <2 log ≥2 log <2 log Week 12 Negative Negative Negative ≥2 log ≥2 log Week 24 Negative Negative Negative Negative Negative

Rates of Viral Clearance Predicts SVRPEG-IFN/RBV

PEG-IFN -2a 180 g + RBV 1000–1200 mg

91

72

60

4843

0

20

40

60

80

100

Ferenci P et al. J Hepatol. 2005;43:425.

67%

92%

74%

92%

73%

0%

20%

40%

60%

80%

100%

ITT LVL HVL F0-2 F3-4

Shorter Treatment Duration for HCV-1 and Rapid Virologic Response (RVR)

366 treatment naïve HCV-1 and HCV-4 pts received standard PEG + RBV

79 (22%) W4 HCV RNA – patients received a total of 24 wks of therapy

Ferenci et al. Hepatology 2005;42(suppl 1):218A.

24 wks may suffice for HCV-1 with LVL and

early fibrosis if RVR

PEG-IFN 180 g/wk plus RBV 1,000-1,200 mg/day

24 Wks Tx

Rapid Virologic Response (RVR) of PEG-IFN alfa-2b/RBV Treatment Predicts SVR after 24

Weeks in Genotype 1 CHC Patients

Zeuzem S, et al. Journal of Hepatology. 2006; 44:97-103.

17%25%

89%

0%

20%

40%

60%

80%

100%

4 (n=110) 12 (n=61) 24 (n=24)

Pat

ient

s (%

)

Week at which patient was first RNA negative.

94%89%

97%88%

73% 73%

93% 91%

0%

20%

40%

60%

80%

100%

Pat

ient

s (%

)

17/18 32/33 29/40 51/55n = 16/18 29/33 29/40 50/55

24-LD* 24-SD* 48-LD* 48-SD*

EOT SVR

RVR of PEG-IFNα-2a/RBV in Genotype 1 Patients

*24 and 48 indicate treatment duration in wks; LD indicates 800 mg/day of RBV; SD indicates 1000-1200 mg/day of RBV. Jensen D et al. Hepatology 2006(in press).

Patients With an RVR at Wk 4

63%

16%

70%

23%

35%

56%

44%

63%

0%

20%

40%

60%

80%

100%

EOT SVR

RVR of PEG-IFNα-2a/RBV in Genotype 1 Patients

*24 and 48 indicate treatment duration in wks; LD indicates 800 mg/day of RBV; SD indicates 1000-1200 mg/day of RBV. Jensen D et al. Hepatology 2006(in press).

n = 116/208 133/210 13/81 19/84 72/208 92/21059/8451/81

Patients Without an RVR at Wk 4

Pat

ient

s (%

)

24-LD* 24-SD* 48-LD* 48-SD*

Extended Treatment Duration

in HCV Patients with Genotype 1

48 vs 72 Wks of PEG-IFNα-2a & RBV Tx

52%61%

45%

32%

0%

20%

40%

60%

80%

100%

48 Wks 72 Wks

ETR

SVR

Sanchez-Tapias JM et al. Hepatology 2004;40:218A (Abstract # 126).

n=165 n=162

P=0.0144

48%Relapse

13%Relapse

HC

V R

NA

Neg

ativ

e (%

)90% of Patients HCV-1

66%71%

54%52%

0%

20%

40%

60%

80%

100%

48 Wks 72 Wks

ETR

SVR

n=231 n=225

27%Relapse

18%Relapse

HC

V R

NA

Neg

ativ

e (%

)48 vs 72 Wks of PEG-IFN and RBV Tx

PEG-IFN -2a 180 g/wk + RBV 800 mg/day.Berg T et al. Hepatology 2004;40:238A (Abstract # 169).

All Patients HCV-1

Prolonging Therapy May Decrease Relapse in Late Responders

81%

N = 456 G1 patientsN = 456 G1 patientsPEG-IFN PEG-IFN -2a + RBV 800 mg/day 48 vs 72 wks-2a + RBV 800 mg/day 48 vs 72 wks

Week 12 (+)Week 12 (+)48 weeks48 weeks

44%

Week 12 (+)Week 12 (+)72 weeks72 weeks

Berg et al. Berg et al. Hepatology. 2004;40:238A. Abstract No. 169 2004;40:238A. Abstract No. 169. . (+) HCV RNA positive

% relapse

Extended Duration of Treatment for HCV-1

There are reduced relapse rates with prolonged duration of treatment for patients with chronic HCV and HCV-1

Sanchez-Tapias et al. used a low and fixed dose RBV

Berg et al. only found benefit in a subgroup of patients

Slow responders may respond to prolonged duration

Conclusions

Genotypes2 and 3

Is 12-16 Wks of Therapy Adequate?

Shorter Treatment for HCV Genotypes 2 & 3?

N = 122

Peg-IFN -2b 1.5 g/kg/wk + Riba 800-1400 mg/d

PCR(-) at 4 & 8 weeks?

95 (78%)

YES NO

27 (22%)

Treated x 14 wkSVR90% Treated x 24 wk

SVR56%

h

Peg-IFN -2a (180 g/wk)+ Ribavirin 800-1200 mg/day

Untreated Genotype 2 or 3 (N=153)

*HCV RNA was assessed after 4 weeks with a lower limit of detection of 600 IU/mL.Von Wagner M et al. Gastroenterology 2005;129:522-527

16 vs 24 Weeks of Peg-IFN/RBV in Genotype 2 or 3 HCV Patients

Wk 4 HCV RNA (-)* Wk 4 HCV RNA (+)*

16 wks(n=71)

24 wks(n=68)

24 wks(n=14)

Randomize

SVR 36% SVR

80% SVR 82%

Shorter Treatment for HCV Genotypes 2 & 3?

N = 213

Peg-IFN -2b 1 g/kg/wk + Riba 1,000-1,200 mg/d

PCR(-) at 4 weeks?

133 (62%)

YES NO

80 (38%)

Treated x 12 wkSVR85% Treated x 24 wk

SVR64%

*HCV RNA was assessed after 4 weeks with a lower limit of detection of 50 IU/mL.Mangia A et al. N Engl J Med 2005;352:2609-2617.

HCV Genotype 2 and 3 With High Viral Load: Higher Relapse Rate?

70%

86%91%

95%

23%

8%9%5%

0

20

40

60

80

100

LVL HVL LVL HVL

%

SVR

Relapse

Zeuzem S et al. Hepatology 2004;40:993-999.

Genotype 2 Genotype 3

n=20 n=22 n=99 n=83

n=2 n=7 n=17

n=1

Peg-IFN -2b 1.5g/kg/wk + Ribavirin 800 – 1400 mg/day x 24 Weeks

Viral Factors in Hepatic Steatosis

Chronic Hepatitis C: N=755 Steatosis: 41.7% Independent predictors of steatosis:

– HCV genotype 3, obesity (BMI), ETOH (current), and age

Rubbia-Brandt et al. GUT 2004

HCV genotype 3 is the most important viral factor associated with steatosis

HCV Viral Factors Associated with Steatosis

Host Factors and Hepatic Steatosis

59%

41%

Obese Patients(30 kg/m2; n=37)

Non-obese Patients(<30 kg/m2; n=78)

Present None

Cesario K et al. DDW 2005.

17%

83%

Obesity and Steatosis

HCV and Steatosis: Impact on Fibrosis (cont)

Adinolfi et al. Hepatology 2001

0.00

0.05

0.10

0.15

0.20

0.25

Rat

e o

f P

rog

ress

ion

Fib

rosi

s U

nit

s/yr

0 1 2/3

Grade of Steatosis

Obese Patients(30 kg/m2; n=40)

Non-obese Patients(<30 kg/m2; n=88)

Moderate to Severe None to Mild

Cesario K et al. DDW 2005.

40%

60%

56%

44%

HCV and Steatosis: Impact on Fibrosis (cont)

The Impact of Superimposed Steatosis or Its Risk Factors on HCV Treatment

Obesity may increase the volume of distribution, resulting in lower serum antiviral drug concentrations

Steatosis may alter hepatic structure and function, decreasing the contact between antiviral drug & infected hepatocytes

Leptin resistance may alter the T-cell response, decreasing the potential for viral clearance

Potential Mechanisms for Decreased Response to Antiviral Therapy

The Exact Mechanism is Unknown

The Impact of Superimposed Steatosis or Its Risk Factors on HCV induced liver

disease

Hepatitis C and steatosis (N=19) Three-month weight reduction program

– Weight loss 5.9±3.2 kg – Decrease in waist of 9.0±5.0 cm– Fasting insulin 16±7 to 11±4 mmol/l – ALT improved (16/19)– Patients with paired biopsy (N=10)

9 pts showed reduction in steatosis, improvement in fibrosis (3:1), and activated stellate cells

Hickman et al. GUT 2002