management of hepatitis c pma

MANAGEMENT OF MANAGEMENT OF HEPATITIS CHEPATITIS C

Dr Nasir KhokharDr Nasir Khokhar

Professor of Medicine Professor of Medicine

Consultant GastroenterologistConsultant Gastroenterologist

Shifa International Hospital Shifa International Hospital

IslamabadIslamabad

Model of Human Hepatitis C Virus

Lipid Envelope

Capsid Protein

Nucleic Acid

Envelope Glycoprotein E2

Envelope Glycoprotein E1

Reprinted with permission. Henderson LE. Available at http://www.hepcprimer.com.

Model of HCV Replication

Racanelli V, et al. Trends Immunol. 2003;24:456-464.

ER

HCV

Endosome

Uncoating

Translation

Entry

Receptor

NS2NS3/4A NS4B NS5B

NS5A

+-

Replication

Progeny genomes

GolgiE1 E2 Core E1-E2

AssemblyE1-E2

Release

Exocytosis

Nucleus

Cytoplasm

Hepatitis C Virus Infection:Hepatitis C Virus Infection:Population at RiskPopulation at Risk

Centers for Disease Control and Prevention. Available at: http://www.cdc.gov/ncidod/diseases/hepatitis/c/fact.htm. Accessed September 27, 2006.

Transplant or transfusion of blood products before 1992Transplant or transfusion of blood products before 1992

Injection drug useInjection drug use

Nasal inhalation of cocaineNasal inhalation of cocaine

Chronic renal failure on dialysisChronic renal failure on dialysis

IncarcerationIncarceration

Multiple sexual partners, MSMMultiple sexual partners, MSM

Occupational exposure to blood productsOccupational exposure to blood products

Body piercing and possibly tattooBody piercing and possibly tattoo

<1 %

1–2.4 %

2.5–4.9 %

5–10 %

> 10 %

No data available

HCV Has Broad Global PrevalenceHCV Has Broad Global PrevalenceHCV Has Broad Global PrevalenceHCV Has Broad Global Prevalence

Pakistani PerspectivePakistani Perspective

Blood Donors: Replacement 5.14% Non-Blood Donors: Replacement 5.14% Non-remunerated 2.46% remunerated 2.46%

General population: 5.13%General population: 5.13%

Pregnant Women: 4.8% Pregnant Women: 4.8%

Asif, Khokhar, Ilahi. Pak J Med Sci 2004;20:24-28

Khokhar, Gill, Malik. JCPSP 2004;14:127

Khokhar, Raja, Javaid. JPMA 2004;54:135

Natural HistoryNatural History

Hepatitis C VirusHepatitis C VirusFate of Acute InfectionFate of Acute Infection

15%

Chronic85%

Spontaneousresolution

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

0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

0 10 20 30 40 50

F M

ET

AV

IR

Years

Progression of Liver Fibrosis in Progression of Liver Fibrosis in HCV-Infected Patients With Normal ALTHCV-Infected Patients With Normal ALT

Progression of Liver Fibrosis in Progression of Liver Fibrosis in HCV-Infected Patients With Normal ALTHCV-Infected Patients With Normal ALT

Slow

Normal ALT

IntermediateRapid

Matched

Chronic Hepatitis C With Chronic Hepatitis C With Normal Serum ALT: ALT Normal Serum ALT: ALT

Patterns and FlaresPatterns and Flares

ULN

0

20

40

60

80

100

120

0 3 6 9 12 15 18 21 24

Month

AL

T (

IU/m

L)

Single elevationsPeriodic elevationsAlways normal

Illustration by Mitchell L. Shiffman, MD.

Risk FactorsRisk Factors

Summary of Risk FactorsSummary of Risk Factors

Reuse of syringesBlood transfusionContaminated surgical instruments /

Endoscopes / Dialysis machinesDental instruments/ Tooth brushesReuse of infected shaving bladesEar piercing / Tattooing

Clinical FeaturesClinical Features Asymptomatic

Fatigue

Chronic HCV: an indolent Disease extending over many years

Acute attack is usually unrecognized, no clinical features

80% patients will develop chronic hepatitis

Chronic Hepatitis C VirusChronic Hepatitis C VirusExtrahepatic ManifestationsExtrahepatic Manifestations

Nonspecific antibodiesNonspecific antibodies Essential mixed cryoglobulinemiaEssential mixed cryoglobulinemia GlomerulonephritisGlomerulonephritis Porphyria cutanea tardaPorphyria cutanea tarda Leukocytoclastic vasculitisLeukocytoclastic vasculitis Mooren’s corneal ulcerMooren’s corneal ulcer Non-Hodgkin’s lymphomaNon-Hodgkin’s lymphoma Autoimmune thyroiditisAutoimmune thyroiditis Diabetes mellitusDiabetes mellitus

HCV and CryoglobulinemiaHCV and CryoglobulinemiaDermatitisDermatitis

Occurs in Occurs in dependent areasdependent areas

Deposition of Deposition of cryoglobulins in cryoglobulins in small capillariessmall capillaries

Ulcerations may Ulcerations may developdevelop

PruriticPruritic

Zein CO, et al. Am J Gastroenterol. 2005;100:48-55.

Chronic HCV and Diabetes Chronic HCV and Diabetes MellitusMellitus

Prevalence of diabetes Prevalence of diabetes mellitus and insulin mellitus and insulin resistance notedresistance noted

Compared with expected Compared with expected rate based on NHANES rate based on NHANES III study after adjusting forIII study after adjusting for Age, Sex, RaceAge, Sex, Race

Prevalence of DM or Prevalence of DM or insulin resistance higher insulin resistance higher in those with chronic HCVin those with chronic HCV

0

4

8

12

16

20

Females Males

Nu

mb

er o

f C

ases

ObservedExpected

Nagao Y, et al. J Gastroenterol Hepatol. 2004;19:1101-1113.

Extrahepatic Effects of HCVExtrahepatic Effects of HCVLichen PlanusLichen Planus

Occurs in < 1% of the general populationOccurs in < 1% of the general population 10%-30% of patients with chronic HCV10%-30% of patients with chronic HCV AppearanceAppearance

Flat topped, violaceous, pruritic papulesFlat topped, violaceous, pruritic papulesThroughout body Throughout body Oral mucosaOral mucosa

HistologyHistologyDense infiltration of dermis with T lymphocytesDense infiltration of dermis with T lymphocytes

DiagnosisDiagnosis

Determining Who to ScreenDetermining Who to Screen

Primary care physicians are the frontline in Primary care physicians are the frontline in identifying patients with risk factorsidentifying patients with risk factors

Anyone with history of transfusionAnyone with history of transfusion Anyone with a history of IDU Anyone with a history of IDU Persons with a history of noninjection drug Persons with a history of noninjection drug

use and/or multiple sexual partners use and/or multiple sexual partners Persons infected with HIV Persons infected with HIV Any abnormal ALT level Any abnormal ALT level

Normal ALT does not exclude diseaseNormal ALT does not exclude disease

HCV GenotypesHCV Genotypes

USA 1,2,3 Europe 1,2,3

Australia 1,2,3 Far East 1,2

Middle East 4 North Africa 4

South Africa 5 Pakistan 3

HCV Serotypes in PakistanHCV Serotypes in Pakistan

Serotypes

6.005.004.003.002.001.00Missing

Nu

mb

er

of

pa

tie

nts

600

500

400

300

200

100

0

Khokhar et al. Hepatology 2003;38:270-1

Fibrosis EvaluationFibrosis Evaluation

1498552133N =

Fibrosis score

4.003.002.001.00.00

AS

T/A

LT

Ra

tio

2.2

2.0

1.8

1.6

1.4

1.2

1.0

.8

.6

Khokhar. JPMA 2003;53:103-104

Fibrosis EvaluationFibrosis Evaluation

1498552133N =

Fibrosis Score

4.003.002.001.00.00

Pla

tele

t C

ou

nt

300000

200000

100000

0

Khokhar. JPMA 2003;53:103-104

Role of Liver Biopsy in Patient Role of Liver Biopsy in Patient Assessment and ManagementAssessment and Management

NONO YESYES

Patient wants treatment Patient wants treatment regardless regardless of biopsy findings, even if of biopsy findings, even if no fibrosisno fibrosis

HCV treatment absolutely HCV treatment absolutely contraindicatedcontraindicated

Pregnancy, severe Pregnancy, severe depression, ESLD, severe depression, ESLD, severe cardiopulmonary diseasecardiopulmonary disease

Genotype 2 or 3 and willing Genotype 2 or 3 and willing to take treatmentto take treatment

Patient wants treatment if Patient wants treatment if medically necessary as medically necessary as indicated by liver histologyindicated by liver histology

Patient fails to achieve SVR Patient fails to achieve SVR and and no recent biopsy availableno recent biopsy available

Chronic HCVChronic HCVTests UtilizedTests Utilized

Disease SeverityDisease Severity Response to Response to TherapyTherapy

AST/ALTAST/ALT

BilirubinBilirubin

AlbuminAlbumin

Pro-time (INR)Pro-time (INR)

Platelet countPlatelet count

Liver histologyLiver histology

ALTALT

HCV RNAHCV RNA

HCV genotypeHCV genotype

Liver histologyLiver histology

LFTs

Hepatitis C VirusHepatitis C VirusDiagnostic TestingDiagnostic Testing

Diagnostic Test TypeDiagnostic Test Type

SpecificationsSpecifications SerologicSerologic VirologicVirologic

Mode of detectionMode of detection AntibodiesAntibodies VirusVirus

SensitivitySensitivity > 95%> 95% > 98%> 98%

SpecificitySpecificity VariableVariable > 98%> 98%

Detection Detection postexposurepostexposure 2-6 months2-6 months 2-6 weeks2-6 weeks

UseUse ScreeningScreening ConfirmationConfirmation

Testing for Testing for HCV RNAHCV RNA

Confirm HCV infectionConfirm HCV infectionPersistently normal serum ALTPersistently normal serum ALT

HCV antibody positiveHCV antibody positive

Antinuclear antibodiesAntinuclear antibodies

Prior to initiating therapyPrior to initiating therapy

Assess effectiveness of treatmentAssess effectiveness of treatmentPredict likelihood of response before and Predict likelihood of response before and

during therapyduring therapy

Confirm response after therapy completedConfirm response after therapy completed

Testing for HCV PCRTesting for HCV PCRVirologic AssaysVirologic Assays

PCRPCR TMATMA b-DNAb-DNA

Polymerase Polymerase chain reactionchain reaction

Transcription Transcription mediated mediated

amplificationamplification

Branched chain Branched chain DNADNA

Amplifies targetAmplifies target Amplifies targetAmplifies target Amplifies probeAmplifies probe

QualitativeQualitative

QuantitativeQuantitative QualitativeQualitative QuantitativeQuantitative

Hepatitis C Virus InfectionHepatitis C Virus InfectionIdentification of PatientsIdentification of Patients

Found to have elevated serum ALT duringFound to have elevated serum ALT duringRoutine physical examinationRoutine physical examinationRoutine blood testing after starting certain Routine blood testing after starting certain

medicationsmedications Test positive for anti-HCV duringTest positive for anti-HCV during

Volunteer blood donationVolunteer blood donationHealth or life insurance applicationsHealth or life insurance applications

PhysicianPhysician Inquires about previous risk behaviorsInquires about previous risk behaviors

FDA Approved, Marketed HCV Drugs

Generic NameGeneric Name Trade Name (manufacturer)Trade Name (manufacturer) DosingDosing

Interferon alfa-2aInterferon alfa-2a RoferonRoferon®®-A (Roche)-A (Roche) 3 MIU SC TIW 3 MIU SC TIW

Interferon alfa-2bInterferon alfa-2b Intron AIntron A®® (Schering-Plough) (Schering-Plough) 3 MIU SC TIW 3 MIU SC TIW

Interferon alfacon-1Interferon alfacon-1 InfergenInfergen®® (InterMune) (InterMune)9 9 g SC TIW g SC TIW

15 15 g SC TIWg SC TIW**

Peginterferon alfa-2aPeginterferon alfa-2a PegasysPegasys®® (Roche) (Roche) 180 180 g SC QWg SC QW

Peginterferon alfa-2bPeginterferon alfa-2b Peg-IntronPeg-Intron®® (Schering-Plough) (Schering-Plough) 1.01.0––1.5 1.5 g/kg SC QWg/kg SC QW

Ribavirin**Ribavirin**CopegusCopegus®® (Roche) (Roche)RebetolRebetol®® (Schering-Plough) (Schering-Plough)RibasphereRibasphereTM TM (Three Rivers)(Three Rivers)

0.80.8––1.2 g/day, PO1.2 g/day, PO††

0.80.8––1.2 g/day, PO1.2 g/day, PO††

0.80.8––1.2 g/day, PO1.2 g/day, PO††

Pawlotsky JM, et al. Hepatology. 2004;39:554-567.

*Interferon relapsers and nonresponders; **Ribavirin is not approved for monotherapy, but as part of combination with interferon alfa; † Depending on HCV genotype and patient body weight

Treatment RegimenTreatment Regimen

Interferon-alpha 3 MIU TIW SC

Ribavirin 800-1200 mg/day

According to the body weight

for 6-12 months

Type I IFNs:Exhibit Multiple Activities

- Many cell types

B lymphocytes

Immunoregulatory Activity– Proliferation, differentiation, activation of different cell types heavily involved in immune responses

Natural killer cells

T lymphocytes

Activation

Proliferation

Survival

Dendritic cells

Muscle

Fibroblasts

Antifibrotic

Antiviral Activity- Many cell types

Adipocytes

IFN /

Antiangiogenic

Antiproliferative Activity

Stark G, et al. Annu Rev Biochem. 1998;67:227-264.Theofilopoulos AN, et al. Annu Rev Immunol. 2005;23:307-335.Brierley M, et al. J Interferon Cytokine Res. 2002;22:835-845.

Predictors of ResponsePredictors of Response

Younger age (less than 40) Female sex Short duration of disease (less than 5 years) Low HCV-RNA at baseline (Less than 2 million

copies) HCV genotypes other than 1a/1b Absence of fibrosis or cirrhosis No immunosuppression No coinfection with HBV

Time Course of Interferon Side Time Course of Interferon Side EffectsEffects

Sev

erit

y

Flu-like symptoms

Fatigue

Depressive/anxiety symptoms

IFN Treatment(Weeks)

0 2 4 6 8 10 12

What Are Future Therapies What Are Future Therapies for Hepatitis C?for Hepatitis C?

HCV Helicase Unwinds HCV Helicase Unwinds Double-Stranded RNADouble-Stranded RNA

HCV Helicase CrystalHCV Helicase Crystal

Crystallization by vapor Crystallization by vapor diffusion methoddiffusion method

Crystallization conditions: Crystallization conditions: 50 mM Ca acetate, 8% 50 mM Ca acetate, 8% PEG 5000, 20 mM Na PEG 5000, 20 mM Na cacodylate, pH 6.5cacodylate, pH 6.5

3 Domains of HCV-RNA Helicase: 3 Domains of HCV-RNA Helicase: NTPaseNTPase, , RNARNA Binding,Binding, HelicalHelical

Superposition of Two Independent Superposition of Two Independent Molecules Reveals Domain MovementMolecules Reveals Domain Movement

Switch regionSwitch region

TT

AATT

PP

PP

C

520

480

340

N

440

200

620

320

460

300

600

360

380

560

540

220

420

280

500580

400

240

260

DomainDomainrotationrotation

Interactive CaseInteractive Case

HistoryHistory

A 39-year-old male bank executive was A 39-year-old male bank executive was diagnosed 6 months ago with genotype 1 diagnosed 6 months ago with genotype 1 hepatitis C virus (HCV) infection discovered hepatitis C virus (HCV) infection discovered during screening before blood donation. during screening before blood donation. Laboratory studies confirmed the diagnosis of Laboratory studies confirmed the diagnosis of chronic hepatitis C and ruled out other liver chronic hepatitis C and ruled out other liver diseases. diseases.

A liver biopsy demonstrated grade 2 A liver biopsy demonstrated grade 2 inflammation and stage 3 fibrosis and steatosis inflammation and stage 3 fibrosis and steatosis without significant iron accumulation. Abdominal without significant iron accumulation. Abdominal U/S was negative for portal hypertension and U/S was negative for portal hypertension and signs of cirrhosis. His body mass index was 22.8 signs of cirrhosis. His body mass index was 22.8 kg/m2.kg/m2.

Laboratory FindingsLaboratory Findings HCV RNA: 1,500,000 IU/mLHCV RNA: 1,500,000 IU/mL Aspartate aminotransferase (AST): 72 U/LAspartate aminotransferase (AST): 72 U/L Alanine aminotransferase (ALT): 101 U/LAlanine aminotransferase (ALT): 101 U/L Total bilirubin: 0.4 mg/dLTotal bilirubin: 0.4 mg/dL Albumin: 4 g/LAlbumin: 4 g/L Nonfasting glucose: 90 mg/dLNonfasting glucose: 90 mg/dL Hemoglobin (Hb): 15.4 g/dLHemoglobin (Hb): 15.4 g/dL Platelet count: 168,000 cells/mm3Platelet count: 168,000 cells/mm3 Prothrombin time: 10.9 secondsProthrombin time: 10.9 seconds TSH: 2.5 IU/mL (normal: 0.60-3.30 IU/mL)TSH: 2.5 IU/mL (normal: 0.60-3.30 IU/mL) Ferritin: 150 ng/mL (normal: 27-377 ng/mL)Ferritin: 150 ng/mL (normal: 27-377 ng/mL) Alpha-fetoprotein: 2.5 ng/mLAlpha-fetoprotein: 2.5 ng/mL

TreatmentTreatment He was started on interferon alfa-2a TIW plus He was started on interferon alfa-2a TIW plus

ribavirin 1000 mg/day.ribavirin 1000 mg/day. After 4 weeks he presents with Hb: 12.5 g/dL; After 4 weeks he presents with Hb: 12.5 g/dL;

HCT: 37.5% and WBC: 2600; ANC: 1600. The HCT: 37.5% and WBC: 2600; ANC: 1600. The patient's HCV RNA is now 750,000 IU/mL. He is patient's HCV RNA is now 750,000 IU/mL. He is tolerating therapy but initially experienced tolerating therapy but initially experienced fatigue and flu-like symptoms, which have fatigue and flu-like symptoms, which have improved over the past 2 weeks. The patient improved over the past 2 weeks. The patient denies having chest pain, shortness of breath, denies having chest pain, shortness of breath, abdominal pain, chronic fever, vision changes, abdominal pain, chronic fever, vision changes, rashes, depression, suicidal or homicidal rashes, depression, suicidal or homicidal ideation, irritability, or difficulty sleeping. He is ideation, irritability, or difficulty sleeping. He is working full time with some fatigue at the end of working full time with some fatigue at the end of the day.the day.

How will you manage his treatment How will you manage his treatment at 4 week?at 4 week?

A. The patient is a nonresponder and A. The patient is a nonresponder and treatment should be discontinuedtreatment should be discontinued

B.B. Continue current regimen and check viral Continue current regimen and check viral load at treatment Week 12load at treatment Week 12

C.C. Increase ribavirin dose to improve Increase ribavirin dose to improve response and recheck viral count in 4 response and recheck viral count in 4 weeksweeks

The patient continues the The patient continues the current treatment regimen and current treatment regimen and

returns at Week 12 of treatment returns at Week 12 of treatment to undergo further evaluation.to undergo further evaluation.

EvolutionEvolution The patient’s mild adverse effects are The patient’s mild adverse effects are

managed by behavior modification and managed by behavior modification and analgesics. No increases in anemia or analgesics. No increases in anemia or neutropenia severity are noted. He neutropenia severity are noted. He remains motivated to continue therapy and remains motivated to continue therapy and to take full treatment doses as scheduled. to take full treatment doses as scheduled. He has also experienced a mild increase He has also experienced a mild increase in irritability but is still able to work full in irritability but is still able to work full time. The patient’s Week 12 HCV RNA is time. The patient’s Week 12 HCV RNA is negative, his AST is 34 U/mL, and his ALT negative, his AST is 34 U/mL, and his ALT is 28 U/mL.is 28 U/mL.


A. The patient is a nonresponder and A. The patient is a nonresponder and treatment should be discontinuedtreatment should be discontinued

B. Continue on current doses and return at B. Continue on current doses and return at Week 48 for further evaluationWeek 48 for further evaluation

C. Continue on current doses and return at C. Continue on current doses and return at Week 24 for further evaluationWeek 24 for further evaluation

Further EvolutionFurther Evolution

HCV PCR is negative again. He completes HCV PCR is negative again. He completes 48 weeks of therapy and has normal LFT 48 weeks of therapy and has normal LFT and negative HCV PCR. and negative HCV PCR.


Congratulate him on successful treatment Congratulate him on successful treatment and advise him to come back if any further and advise him to come back if any further complaints.complaints.

Follow every month for six months with Follow every month for six months with further tests.further tests.

Advise maintenance interferon for 3-6 Advise maintenance interferon for 3-6 months without ribavirinmonths without ribavirin

The Many Faces of HCV The Many Faces of HCV SummarySummary

Chronic HCV infection leads to cirrhosis Chronic HCV infection leads to cirrhosis and liver failure in a large number of and liver failure in a large number of personspersons

Primary care physicians must recognize Primary care physicians must recognize that chronic HCV is common disorder in that chronic HCV is common disorder in our countryour country

Effective treatment of chronic HCV can Effective treatment of chronic HCV can prevent fibrosis progression and reduce prevent fibrosis progression and reduce complications of HCVcomplications of HCV

THANK YOU FOR THANK YOU FOR YOUR ATTENTIONYOUR ATTENTION

management of hepatitis c pma

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hepatitis c virus infection

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