Hepatitis C

Epidemiology, Diagnosis, & Current treatment options

Amir Butt, MD
Assistant Professor Medical Director Pancreatico-biliary Service Division of Gastroenterology, Hepatology, & Nutrition Brody School of Medicine East Carolina University

Disclosures

Objectives

Hepatitis C: Prevalence, transmission & symptoms Making the diagnosis Current treatment options

Help
While suturing a HCV infected patient at 8pm on a Saturday evening, a surgical resident receives a needle stick injury. He shows up to occupational health on Monday morning and after lab work, he is told to be HCV Ab positive. That afternoon he is in your clinic. Which of the following is the most appropriate response? A. Almost all surgeons get HCV Ab sometime in their life B. You have contracted HCV from the needle stick C. HCV infection not entirely curable D. You should have stuck to Internal Medicine E. You have Hepatitis C from a prior exposure

Epidemiology

NANB - Hepatitis

Isolation of a cDNA clone derived from a bloodborne non-A, non-B viral hepatitis genome
A random-primed complementary DNA library was constructed from plasma containing the uncharacterized non-A, non-B hepatitis (NANBH) agent and screened with serum from a patient diagnosed with NANBH. A complementary DNA clone was isolated that was shown to encode an antigen associated specifically with NANBH infections. This clone is not derived from host DNA but from an RNA molecule present in NANBH infections that consists of at least 10,000 nucleotides and that is positive-stranded with respect to the encoded NANBH antigen. These data indicate that this clone is derived from the genome of the NANBH agent and are consistent with the agent being similar to the togaviridae or flaviviridae. This molecular approach should be of great value in the isolation and characterization of other unidentified infectious agents.
QL Choo et al. Chiron Corporation, Emeryville, CA - 1989

Hepatitis C virus: The major causative agent of viral non-A, non-B hepatitis
A blind recombinant immunoscreening approach, of general application to studies of infectious diseases, was used to clone and identify the genome of the previously uncharacterized nonA, non-B hepatitis (NANB) virus. This agent is a positivestranded RNA virus that appears to be distantly related to the flaviviridae family. Data obtained using this assay indicate that this agent, termed the hepatitis C virus (HCV), is the major cause of post-transfusion, community-acquired and cryptogenic, NANB.

QL Choo, et al. Chiron Corporation, Emeryville California, USA - 1990

Hepatitis C Virus

Single stranded, positive sense, RNA

Flaviviridae family Spherical, enveloped

Great genetic diversity

Six genotypes: 1 through 6 Multiple subtypes: a, b, c, etc Viral sequences can be used to track a ~ 50 nm

common source of infection

HCV: Magnitude of the Problem

Nearly 4 million persons in United States infected Approximately 35,000 new cases yearly 85% of new cases become chronic Leading cause of

Chronic liver disease Cirrhosis Liver cancer Liver transplantation

Centers for Disease Control and Prevention. Hepatitis C fact sheet. February 1, 2006.

Advanced Liver Disease in Chronic HCV-Infected US Population, 2009-2028

Assuming No Changes in SOC
250,000 200,000 150,000 100,000 50,000 0 2009 2012 2015 2018 2021 2024 2027

Liver transplant Hepatocellular carcinoma Decompensated cirrhosis

Individuals

Year

The total number of patients with advanced liver disease in 20 yrs is projected to be > 4-fold greater than it is today

The Milliman Report. Consequences of Hepatitis C Virus (HCV): May 2009.

Annual US Medical Costs for Chronic HCV Infection From 2009-2028

Assuming No Changes in SOC
100 USD$, Billions 80 60

40
20 0 2009 2012 2015 2018 2021 2024 2027

Medicare Uninsured VA Medicaid Commercial

Year

Total medical costs for patients with HCV infection are expected to more than double, from $30 billion to more than $85 billion USD over the next 20 yrs

The Milliman Report. Consequences of Hepatitis C Virus (HCV): May 2009.

Hepatitis C: A Worldwide Epidemic

Estimated ~ 170 million (3.1%) globally (2003)

1, 2, 3
The Americas 13.1 million (1.7%)

Europe 8.9 million 1 (1.03%)

Asia: 6 1,3 Southeast Asia

32.3 million (2.15%)

Western Pacific 1, 3 62.2 million (3.9%)

Africa 31.9 million (5.3%)

4 4,5

Eastern Mediterranean 21.3 million (4.6%)

Common Genotype

Worldwide: 6

World Health Organization. Hepatitis C: global prevalence: update. 2003. Farci P, et al. Semin Liver Dis. 2000;20:103-126. Wasley A, et al. Semin Liver Dis. 2000;20:1-16.

HCV: Genotypes in the USA

Type 2 17%

Type 1 72%

Type 3 10% All others 1%

McHutchinson JG, et al. N Engl J Med. 1998;339:1485-1492.

Determination of HCV Genotype INNOLiPA Assay

PCR
1b 2a

1a

HCV genotype
Best pretreatment predictor of

response
Determines duration of

2b 3a 3b 4 5

therapy

All patients should have genotype determined prior to initiating therapy

Large Population Underscreened and HCV Patients Under diagnosed

Current screening practices fail to identify a large proportion of patients with chronic HCV infection[1]
As few as 25% of patients are diagnosed

Survey of 4000 primary care physicians[2]

Only 59% of 1412 respondents asked all patients about

HCV risk factors

AASLD recommends that as part of a comprehensive health evaluation, all persons should be screened for behaviors that place them at high risk for HCV infection[3]

1. Kim WR. Hepatology. 2002;36:S30-S34. 2. Shehab TM, et al. J Viral Hepat. 2001;8:377-383. 3. Ghany MG, et al. Hepatology. 2009;49:1335-1374.

HCV Infection: High-Risk Populations in Which Screening Is Indicated

Injection drug use Nasal inhalation of cocaine Chronic renal failure on dialysis Incarceration Multiple sexual partners, MSM, HIV positive

Transplantation or transfusion of blood products before 1992 Occupational exposure to blood products Body piercing and possibly tattoo Children born to HCVpositive women

Centers for Disease Control and Prevention. April 10, 2007. Verucchi G, et al. Infection. 2004;32:33-46.

High Prevalence of HCV Among IDUs

Amsterdam Bulgaria Russia New Zealand Baltimore New York 63 67 74

80

64
89

20

40
HCV (%)

60

80

100

Thomas DL, et al. Medicine (Baltimore). 1995;74:212-220. Des Jarlais DC, et al. AIDS. 2005;19(suppl 3):S20-S25. Vassilev ZP, et al. Int J STD AIDS. 2006;17:621-626. Kemp R, et al. N Z Med J. 1998;111:50-53.

Reasons for High HCV Risk Among Injection Drug Users

Contaminated needles Contaminated works

Syringes, cookers, cottons, rinse water

Old (infected) mentor transmits to young initiate

Villano SA, et al. J Clin Microbiol. 1997;35:3274-3277. Garfein RS, et al. J Acquir Immune Defic Syndr Hum Retrovirol. 1998;18(suppl 1):S11-S19. Thorpe LE, et al. Am J Epidemiol. 2002;155:645-653. Hagan H, et al. Public Health Rep. 2006;121:710-719.

Modes of HCV Transmission

HCV can probably survive on environmental surfaces at room temperature for 16-72 hours Do not exchange blood
Razors, toothbrushes, nail clippers

Sexual transmission rate is low

Condoms recommended for multiple sexual partners

Not transmitted by casual contact (eg, hugging)

HCV Prevalence
Anti-HCV Positive (%)

4.0
3.0 2.0 1.0 0
1.8%

All

Race

Sex

Alter MJ, et al. N Eng J Med. 1999;341:556-562.

Prevalence in 2006
NH White 10 9 8 7 6 5 4 3 2 1 0 6-19 20-29 30-39 40-49 50-59 60-69 70+ Age group
Armstrong GL, Ann Intern Med 2006;144:705-714

NH Black

Mex Amer

Percent Anti-HCV Positive

Prevalence rates of HCV - 2008

Diagnosis

Making the diagnosis

Natural History - Acute Infection

Symptoms
Are uncommon (body aches, flu-like symptoms, etc) On average, appear 6 to 7 weeks after infection.

Testing
6 to 8 weeks: Average time antibodies can be detected.
1 to 3 weeks: Average time virus can be detected. 4 to 12 weeks: Often elevation in ALT

Serologic Pattern of Acute HCV Infection with Recovery

Symptoms +/-

antiHCV

HCV RNA Titer

ALT

Normal 0 1 2 3 4 Months 5 6 1 2 3 Years 4

Time after Exposure

Chronic HCV Symptoms

Percentage of Patients
Symptomatic 37% Cirrhosis 7% 100 80 60 40 20

56% Asymptomatic

Fatigue
Unpublished data from MCV Hepatitis Program, 1995.

Serologic Pattern of Acute HCV Infection with Progression to Chronic Infection

Symptoms +/HCV RNA Titer

anti-HCV

Normal 0 1 2 3 4 Months 5 6 1 2 3 Years 4

Time after Exposure

HCV Response: Acute vs Chronic

200
150

+/-

HCV RNA

+ Resolution

ALT (IU/l)

100
50 0 0 6 12 18 24

Chronic

Month

Hepatitis C Virus Diagnostic Testing

Diagnostic Test Type

Specifications
Mode of detection Sensitivity Specificity Detection postexposure Use

Serologic
Antibodies > 95% Variable 2-6 months Screening

Virologic
Virus > 98% > 98% 2-6 weeks Confirmation

Hepatitis C Virus Host Production of HCV Antibodies

HCV infects cell HCV proteins expressed on surface of hepatocytes Antibodies to HCV proteins produced by host HCV antibodies do NOT confer immunity

Y YY

Natural History
Acute HCV Resolved 15% Stable 75% to 95% Chronic HCV 85% Cirrhosis 5% to 25%

Stable 97% to 99%/yr

HCC or Decompensation 1% to 3%/yr

Thomas DL, et al. Clin Liver Dis. 2005;9:383-398 Strader DB, et al. Eur J Gastroenterol Hepatol. 1996;8:324-328. Seeff LB, et al. Hepatology. 2002;36(suppl):S1-S2. Seeff LB, et al. Hepatology. 2002;36(suppl):S35-S46. Liang TJ, et al. Ann Intern Med. 2000;132:296-305. Fattovich G, et al. Gastroenterology. 1997;112:463-472.

Are laboratory data helpful?

Serum HCV RNA Level Stability Over Time

8

Log HCV RNA (IU/mL)

6 4 2 0 Baseline 1 2 3 4

Patient 1 2 3 4 5
Limit of detection

Time (Years)
Ferreira-Gonzalez A, et al. Semin Liver Dis. 2004;24:9-18.

HCV RNA effect on Liver Histology & Fibrosis

Serum HCV RNA does not correlate with level of fibrosis
8

Log HCV RNA (copies/mL)

6 4 2 0

Genotype 1 2 3 4

No Portal Bridging Cirrhosis Fibrosis Fibrosis Fibrosis

Ferreira-Gonzalez A, et al. Semin Liver Dis. 2004;24:9-18.

HCV RNA effect on Liver Histology & Inflammation

Serum HCV RNA does not correlate with level of inflammation
8

Log HCV RNA (copies/mL)

6 4 2

Genotype 1 2 3 4

0
0 2 4 6 8 10 12

Inflammation Score
Ferreira-Gonzalez A, et al. Semin Liver Dis. 2004;24:9-18.

Chronic HCV Infection Normal vs Elevated Serum ALT

Portal 26%

Bridging 6%
Cirrhosis 6%

Bridging 13% Portal 20%

Cirrhosis 18%

No fibrosis 23%

Mild 39%

No fibrosis 16%

Mild 33%

Normal ALT
Shiffman ML, et al. J Infect Dis. 2000;182:1595-1601.

Elevated ALT

HCV Infection - Liver Biopsy

Only test that can accurately assess

Severity of inflammation Degree of fibrosis

Determines the following

Risk for developing cirrhosis in future
Need for therapy Need for ongoing therapy when initial treatment has failed

Is Liver Biopsy Necessary?

NO
Patient wants treatment even if no fibrosis Patient does not want treatment or treatment contraindicated even if advanced fibrosis Labs and radiographic studies do not suggest cirrhosis Patient achieves SVR

YES
Patient would only accept treatment if advanced fibrosis Labs or radiographic studies suggest cirrhosis may be present Patient fails to achieve SVR and no recent biopsy available

Chronic HCV: Progression to Cirrhosis

Proportion of Patients Developing Cirrhosis According to Initial Level of Fibrosis

Approximate Percentage of Patients With Cirrhosis

100

80
60

40
20 0 0 5 10 15 20

Bridging Portal None

Time (Years)
Yano M, et al. Hepatology. 1996;23:1334-1340.

I hope I dont have Hepatitis C

HCV and Alcohol

100

Cirrhosis (%)

80 60 40 20 0 10 20 30 40 HCV HCV + alcohol

Years Following Exposure

Excessive alcohol intake characterized as > 40 g/day for women and > 60 g/day for men.
Wiley TE, et al. Hepatology. 1998:28:805-809.

HCV Fibrosis Progression: Effect of Age

4.0

Fibrosis Score

3.0 2.0 1.0 0

Age at time of infection > 40 years < 40 years

< 10

11-20

21-30

31-40

> 40

Duration of Infection (Years)

Poynard T, et al. Lancet. 1997;349:825-832.

Viral Kinetics

Definitions of On-Treatment Response

Response RVR Complete EVR Partial EVR

Definition HCV RNA negative (< 50 IU/mL) at Wk 4 HCV RNA positive at Wk 4 but negative at Wk 12 HCV RNA positive at WK 4 and 12 but 2 log10 IU/mL drop from baseline at Wk 12

EVR

Non-EVR

< 2 log10 IU/mL drop from baseline at Wk 12

SVR Holy Grail

SVR Sustained virologic response

Undetectable viral load measured at 24 weeks after

completing therapy Patients achieving SVR are considered Cured

RVR

Achieving RVR is highly predictive of SVR[1]

Independent of genotype and treatment regimen
RVR achieved by 15% to 20% with genotype 1; 66% with

genotypes 2/3[1,2]

1. Ferenci P, et al. J Hepatol. 2005;43:425-433. 2. Shiffman ML, et al. N Engl J Med. 2007;357:124-134.

SVR in Patients Who Achieved an RVR

100 80 SVR (%) 60 40 20 n= 0

100 88

86

86

90 GT 1

282

257

9 GT 4

GT 2 GT 3 Patients With an RVR

RVR: HCV RNA negative (< 50 IU/mL) at Wk 4 Fried MW, et al. EASL 2008.

EVR as Predictor of SVR in Genotype 1 Patients

Failure to achieve EVR strongly correlates with nonresponse[1,2]

97% to 100% who do not achieve EVR also fail to achieve SVR Patients without EVR can discontinue therapy

Achieving EVR is less accurate in predicting SVR[3]

65% to 72% of patients with EVR go on to achieve SVR

cEVR is a better predictor of SVR than pEVR[3]

83% vs 21%, respectively, achieved SVR[2]

1. Fried MW, et al. N Engl J Med. 2002;347:975-982. 2. Davis GL, et al. Hepatology. 2003;38:645-652. 3. Ghany MG, et al. Hepatology. 2009;49:1335-1374.

Viral Kinetics and Outcome Importance of Rapid Virologic Response

100 Virologic Response (%) 80 60 40 20 0
13 2
HCV RNA Status Wk 4 Wk 12 Wk 24 Neg Neg Neg > 2 log Neg Neg < 2 log Neg Neg > 2 log > 2 log Neg < 2 log > 2 log Neg Any Pos Pos

91 91

94 72

90

86

90 PegIFN alfa-2a + RBV (N = 453) EOT response SVR 48 43

60

Ferenci P, et al, Predicting sustained virological responses in chronic hepatitis C patients treated with peginterferon alfa-2a (40 KD)/ribavirin, 425-433, 2005.

Factors Associated With Increased SVR Rates

Useful for advising patients on their likelihood of an SVR Absence of favorable factors should not be used to deny therapy

Major Predictors[1-3] Viral genotype (nongenotype 1) Less Consistently Reported[1,2,4] Dose of pegIFN (1.5 vs 0.5 g/kg/wk) Dose of RBV (> 10.6 mg/kg) Female sex Younger age (younger than 40 yrs) Nonblack race
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. 4. Nguyen MH, et al. Am J Gastroenterol. 2008;103:1131-1135.

Pretreatment HCV RNA ( 600,000 IU/mL)

Lower body weight ( 75 kg) Absence of insulin resistance Elevated ALT levels (3 x ULN) Absence of bridging fibrosis or cirrhosis

Current Treatment

Recommended Regimens for Initial HCV Treatment

Optimal duration of treatment should be based on the viral genotype

PegIFN alfa-2a 180 g PegIFN alfa-2b 1.5 g/kg

Genotype 2/3 PegIFN dose (weekly)

RBV dose (daily)

Planned duration

800 mg
24 wks

800 mg
24 wks

Genotype 1 PegIFN dose (weekly)

PegIFN alfa-2a 180 g

PegIFN alfa-2b 1.5 g/kg

RBV dose (daily)

1000 mg if 75 kg 1200 mg if > 75 kg

800 mg if 65 kg 1000 mg if > 65 to 85 kg 1200 mg if > 85 to 105 kg 1400 mg if >105 kg

48 wks

Planned duration

48 wks

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

The Future is now

Before 2011
PegIFN/RBV constituted standard of care for patients

infected with all major HCV genotypes until 2011

Genotypes 1 and 4: 48 wks of therapy Genotypes 2 and 3: 24 wks of therapy

2011
Patients with genotype 1 HCV have new options with the

FDA approval of 2 protease inhibitors: telaprevir and boceprevir

Each agent used in combination with pegIFN/RBV

Patients with genotype 2, 3, or 4 HCV continue to receive

pegIFN/RBV

Treatment of Chronic HCV: Peginterferon and Ribavirin this was then

100

Sustained Virologic

Response (%)

80 60 40 20 0 1 Genotype 2-3
PegIFN-2a/RBV PegIFN-2b/RBV

Fried MW, et al. N Eng J Med. 2002;347:975-982. Manns MP, et al. Lancet 2001;358:958-965.

GT1 SVR Whites vs Blacks this was then

100
80 P < .001 SVR (%) SVR (%) 60 40 20 n= 0 PegIFN alfa-2b 1.5 g/kg/wk + RBV 800-1000 mg/day[1] 100 19 100 0 PegIFN alfa-2a 180 g/wk + RBV 1000-1200 mg/day[2] 52 60 52 Non-Hispanic whites 100 80 P < .0001

Blacks

40
20 n= 205

28

196

1. Muir AJ, et al. N Engl J Med. 2004;350:2265-2271. 2. Conjeevaram H, et al. Gastroenterology. 2006;131:470-477.

Boceprevir and Telaprevir

Boceprevir, a potent inhibitor of HCV NS3 protease Telaprevir, a potent inhibitor of HCV NS3/4A protease
Both agents are to be used in combination with current standard-of-care (peginterferon alfa-2/ ribavirin)

Trials reported at AASLD 2010

Boceprevir
SPRINT-III: naive GT1 patients
RESPOND-2: nonresponder GT1 patients

Telaprevir
ADVANCE: naive GT1 patients

Phase III SPRINT-2: Boceprevir + PegIFN/RBV in GT1 Tx-Naive Patients

Randomized, placebo-controlled trial
Wk 4 PR* (n = 316, 52) Treatment-naive patients with genotype 1 HCV (2 cohorts: N = 938 nonblack and 159 black) PR* (n = 311, 55) BOC + PR* (n = 316 nonblack, 52 black) Wk 28
No RVR RVR

Wk 48

Wk 72

Follow-up PR* Follow-up

BOC + PR* (n = 311 nonblack, 55 black)

Follow-up

PR* (n = 311 nonblack, 52 black)

Follow-up

*BOC 800 mg q8h; pegIFN alfa-2b 1.5 g/kg/wk; weight-based RBV 600-1400 mg/day. Undetectable HCV RNA at Wk 4 of BOC treatment (ie, at Wk 8) and at all subsequent assays. Poordad F, et al. AASLD 2010.

SPRINT-2: Response Rates According to Race

4-wk PR + response-guided BOC + PR 100 80 67 Patients (%) 60 40 20 9 0 n = 211 213 125 SVR 40 23 68 Patients (%) 4-wk PR + 44 weeks BOC + PR 100 80 48-wk PR

Nonblack Patients
P < .0001

Black Patients
P = .044 P = .004

60
42 40

53

20
22 29 SVR

23

8
0 12

12
3

17 6

14 2

21 18 37 Relapse

Relapse

Poordad F, et al. AASLD 2010.

Phase III ADVANCE: Telaprevir + PegIFN/RBV in GT1 Tx-Naive Patients

Randomized, placebo-controlled trial
Wk 8 Wk 12 Wk 24 Wk 48 Follow-up PR* Follow-up Follow-up PR* Follow-up Wk 72

TVR + PR* (n = 364) Treatment-naive patients with genotype1 HCV (N = 1088)

eRVR: PR*

TVR + PR* (n = 363)

eRVR: PR*

PR* (n = 361)
*TVR 750 mg q8h; pegIFN alfa-2a 180 g/wk; weight-based RBV 1000-1200 mg/day. eRVR: extended rapid virologic response = undetectable HCV RNA at Wks 4 and 12. Jacobson IM, et al. AASLD 2010.

Follow-up

ADVANCE: Overall SVR and Relapse Rates

8-wk TVR + PR + 16/40-wk PR (n = 364) 100 80 Patients (%) 69 60 44 40 20 0
n= 250 271 158 n=

P < .0001 for both treatment arms vs control 75

48-wk PR (n = 361) 12-wk TVR + PR + 12/36-wk PR (n = 363)

28 9
28

9
27 64

SVR

Relapse

Jacobson IM, et al. AASLD 2010.

ADVANCE: SVR with Telaprevir according to Race & Ethnicity

Phase III: genotype 1, treatment naive
100 80 SVR (%) 60 46 40 25 20 0
n = 325 315 318 26 40 28 35 44 38 328 320 323

T12PR T8PR PR48 74 75 66 69

75

70 62 58

39

44

White

Black

Latino

Non-Latino

Race/Ethnicity
Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.

Phase III RESPOND-2: Boceprevir in GT1 Prior Nonresponders to PegIFN/RBV

Wk 8
If detectable at Wk 8

Wk 36

Wk 48

BOC + PR*

PR*

Follow-up

Treatmentexperienced patients with GT1 HCV (N = 403)

PR* (n = 162) PR* (n = 161)

BOC + PR*

Follow-up Follow-up Follow-up

BOC + PR*
PR* (n = 80)

*BOC 800 mg TID; pegIFN alfa-2b 1.5 g/kg/wk; weight-based RBV 600-1400 mg/day. Follow-up for 24 wks after completion of therapy. Bacon BR, et al. AASLD 2010. Abstract 216.

RESPOND-2: SVR Rates According to Treatment Arm and Prior Response

100 80 66 SVR (%) 60 59* 52 40 29 20 0 21
95/ 107/ 17/ 162 161 80 23/ 30/ 57 58 2/29

P < .0001 vs control (both arms) 75

4-wk PR + response-guided BOC + PR (n = 162) 4-wk PR + 44-wk BOC + PR (n = 161)

69

48-wk PR (n = 80)

40

72/ 77/ 15/ 105 103 51

Overall

Previous Nonresponders

Previous Relapsers

Bacon BR, et al. AASLD 2010. Abstract 216.

PegIFN adverse effects

AE Occurring in > 20% of Pts, % Fatigue/insomnia Headache Nausea Anemia Rash Neutropenia Irritability/depression Chills Injection-site reactions PegIFN alfa-2a/RBV (n = 1035) 64/41 41 34 34 34 31 25/20 23 23 PegIFN alfa-2b/RBV (n = 1019) 67/38 50 40 35 29 26 25/25 39 34

Myalgia/arthralgia
Dyspnea Pyrexia Anorexia Alopecia

22/22
22 21 21 17

27/21
21 35 29 23

RBV adverse effects

Adverse events occurring more frequently when RBV added to pegIFN vs pegIFN alone
Hemolytic anemia Headache

Cough/SOB
Gastrointestinal upset Rash Insomnia Teratogenicity

Adverse Events Reported More Frequently With TVR and BOC vs PegIFN/RBV
Telaprevir[1]
Adverse Event, %
Pruritus Nausea Rash Anemia Diarrhea

TVR-Containing Arms (n = 727)

45-50 40-43 35-37 37-39 28-32

PegIFN/RBV Arm (n = 361)

36 31 24 19 22

Boceprevir[2]
Adverse Event, % Anemia BOC-Containing Arms (n = 734) 49 PegIFN/RBV Arm (n = 363) 29

Dysgeusia

37-43

18

1. Jacobson IM, et al. AASLD 2010. Abstract 211. 2. Poordad F, et al. AASLD 2010. Abstract LB4.

Everyone is special !!!

97

100
Probability of Achieving an SVR 80 60 40

89 74 52 36 19

14
7

20
0

Cirrhosis ALT quotient Age in years BMI HCV RNA, IU/mL x 103

No 7 20 20 40

No 2 20 20 40

No 2 43 26 40

No No No No Yes 2 2 2 1 1 43 43 60 60 60 26 26 30 30 30 1200 9000 9000 9000 9000

HCV and Renal Disease

Description Kidney damage with normal or increased GFR GFR, mL/min*1.73 m2 90 Recommended Treatment Routine combination therapy

Kidney damage with mildly decreased GFR

Moderately decreased GFR Severely decreased GFR Kidney failure Dialysis

60-90
30-59 15-29 < 15 PegIFN alfa-2b 1 g/kg/wk or pegIFN alfa-2a 135 g/wk + RBV 200-800 mg/day (starting with lowest dose and increasing if adverse effects manageable) Standard IFN 3 mU 3x/wk or pegIFN alfa-2b 1 g/kg/wk or pegIFN alfa-2a 135 g/wk markedly reduced daily RBV dose*

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

HCV and Renal Disease

HCV treatment not recommended for patients who have undergone kidney transplantation, unless fibrosing cholestatic hepatitis develops

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

Renal Disease: pegIFN not superior to IFN

78 hemodialysis patients treated with pegIFN alfa-2a 135 g/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 g/kg/wk discontinued due to adverse events and modifications[2]
56% of patients in 1 g/kg/wk group and 28% in 0.5 g/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 in Dialysis Patients

100 80 68 SVR (%) 60 40 27 20 0 20 21 56 58

33

20

19

Russo MW, et al. Am J Gastroenterol. 2003;98:1610-1615.

Current Contraindications to Treatment

Characteristics Major uncontrolled depressive illness Most solid organ transplantation (renal, heart, or lung) Autoimmune hepatitis or other autoimmune condition known to be exacerbated by peginterferon and ribavirin Untreated thyroid disease Pregnant or unwilling to comply with adequate contraception Severe concurrent medical disease such as Severe hypertension, heart failure, significant coronary heart disease, poorly controlled diabetes, chronic obstructive pulmonary disease Younger than 2 yrs of age Known hypersensitivity to drugs used to treat HCV
Ghany MG, et al. Hepatology. 2009;49:1335-1374.

Summary

Chronic HCV infection leads to cirrhosis and liver failure in a large number of persons Health care providers must recognize that chronic HCV is common in IDU and high risk behaviors Effective treatment of chronic HCV can prevent fibrosis progression and reduce complications New treatment modalities in genotype 1 patients show improved SVR

Thank you
Email: butta@ecu.edu