management of hepatitis c pma
TRANSCRIPT
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
Risk FactorsRisk Factors
Risk FactorsRisk Factors
Risk FactorsRisk Factors
Risk FactorsRisk Factors
Risk FactorsRisk Factors
Risk FactorsRisk Factors
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.
How will you manage his treatment How will you manage his treatment at 12 week?at 12 week?
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.
How will you manage his treatment How will you manage his treatment at 48 week?at 48 week?
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