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MANAGEMENT OFMANAGEMENT OF
HEPATITIS CHEPATITIS C
Dr Nasir KhokharDr Nasir Khokhar
Professor of MedicineProfessor of Medic...
Model of Human Hepatitis C Virus
Lipid Envelope
Capsid Protein
Nucleic Acid
Envelope Glycoprotein E2
Envelope Glycoprotein...
Model of HCV Replication
Racanelli V, et al. Trends Immunol. 2003;24:456-464.
ER
HCV
Endosome
Uncoating
Translation
Entry
...
Hepatitis C Virus Infection:Hepatitis C Virus Infection:
Population at RiskPopulation at Risk
Centers for Disease Control ...
<1 %
1–2.4 %
2.5–4.9 %
5–10 %
> 10 %
No data available
HCV Has Broad Global PrevalenceHCV Has Broad Global Prevalence
Pakistani PerspectivePakistani Perspective
 Blood Donors: Replacement 5.14% Non-Blood Donors: Replacement 5.14% Non-
remu...
Natural HistoryNatural History
Hepatitis C VirusHepatitis C Virus
Fate of Acute InfectionFate of Acute Infection
15%
Chronic
85%
Spontaneous
resolution
A...
0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
0 10 20 30 40 50
FMETAVIR
Years
Progression of Liver Fibrosis inProgression of Liver Fib...
Chronic Hepatitis C WithChronic Hepatitis C With
Normal Serum ALT: ALTNormal Serum ALT: ALT
Patterns and FlaresPatterns an...
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 syringes
Blood transfusion
Contaminated surgical instruments /
...
Clinical FeaturesClinical Features
 Asymptomatic
 Fatigue
 Chronic HCV: an indolent Disease extending over many
years
...
Chronic Hepatitis C VirusChronic Hepatitis C Virus
Extrahepatic ManifestationsExtrahepatic Manifestations
 Nonspecific an...
HCV and CryoglobulinemiaHCV and Cryoglobulinemia
DermatitisDermatitis
 Occurs inOccurs in
dependent areasdependent areas
...
Zein CO, et al. Am J Gastroenterol. 2005;100:48-55.
Chronic HCV and DiabetesChronic HCV and Diabetes
MellitusMellitus
 Pr...
Nagao Y, et al. J Gastroenterol Hepatol. 2004;19:1101-1113.
Extrahepatic Effects of HCVExtrahepatic Effects of HCV
Lichen ...
DiagnosisDiagnosis
Determining Who to ScreenDetermining Who to Screen
 Primary care physicians are the frontline inPrimary care physicians a...
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...
HCV Serotypes in PakistanHCV Serotypes in Pakistan
Serotypes
6.005.004.003.002.001.00Missing
Numberofpatients
600
500
400
...
Fibrosis EvaluationFibrosis Evaluation
1498552133N =
Fibrosis score
4.003.002.001.00.00
AST/ALTRatio
2.2
2.0
1.8
1.6
1.4
1...
Fibrosis EvaluationFibrosis Evaluation
1498552133N =
Fibrosis Score
4.003.002.001.00.00
PlateletCount
300000
200000
100000...
Role of Liver Biopsy in PatientRole of Liver Biopsy in Patient
Assessment and ManagementAssessment and Management
NONO YES...
Chronic HCVChronic HCV
Tests UtilizedTests Utilized
Disease SeverityDisease Severity
Response toResponse to
TherapyTherapy...
Hepatitis C VirusHepatitis C Virus
Diagnostic TestingDiagnostic Testing
Diagnostic Test TypeDiagnostic Test Type
Specifica...
Testing forTesting for HCV RNAHCV RNA
 Confirm HCV infectionConfirm HCV infection
Persistently normal serum ALTPersisten...
Testing for HCV PCRTesting for HCV PCR
Virologic AssaysVirologic Assays
PCRPCR TMATMA b-DNAb-DNA
PolymerasePolymerase
chai...
Hepatitis C Virus InfectionHepatitis C Virus Infection
Identification of PatientsIdentification of Patients
 Found to hav...
FDA Approved, Marketed HCV Drugs
Generic NameGeneric Name Trade Name (manufacturer)Trade Name (manufacturer) DosingDosing
...
Treatment RegimenTreatment Regimen
Interferon-alpha 3 MIU TIW SC
 Ribavirin 800-1200 mg/day
According to the body weight...
Type I IFNs:
Exhibit Multiple Activities
- Many cell types
B lymphocytes
Immunoregulatory Activity
– Proliferation, differ...
Predictors of ResponsePredictors of Response
 Younger age (less than 40)
 Female sex
 Short duration of disease (less t...
Time Course of Interferon SideTime Course of Interferon Side
EffectsEffects
Severity
Flu-like
symptoms
Fatigue
Depressive/...
What Are Future TherapiesWhat Are Future Therapies
for Hepatitis C?for Hepatitis C?
HCV Helicase UnwindsHCV Helicase Unwinds
Double-Stranded RNADouble-Stranded RNA
HCV Helicase CrystalHCV Helicase Crystal
 Crystallization by vaporCrystallization by vapor
diffusion methoddiffusion meth...
3 Domains of HCV-RNA Helicase:3 Domains of HCV-RNA Helicase:
NTPaseNTPase,, RNARNA Binding,Binding, HelicalHelical
Superposition of Two IndependentSuperposition of Two Independent
Molecules Reveals Domain MovementMolecules Reveals Domain...
Interactive CaseInteractive Case
HistoryHistory
A 39-year-old male bank executive wasA 39-year-old male bank executive was
diagnosed 6 months ago with geno...
Laboratory FindingsLaboratory Findings
 HCV RNA: 1,500,000 IU/mLHCV RNA: 1,500,000 IU/mL
 Aspartate aminotransferase (AS...
TreatmentTreatment
 He was started on interferon alfa-2a TIW plusHe was started on interferon alfa-2a TIW plus
ribavirin ...
How will you manage his treatmentHow will you manage his treatment
at 4 week?at 4 week?
A. The patient is a nonresponder a...
The patient continues theThe patient continues the
current treatment regimen andcurrent treatment regimen and
returns at W...
EvolutionEvolution
The patient’s mild adverse effects areThe patient’s mild adverse effects are
managed by behavior modifi...
How will you manage his treatmentHow will you manage his treatment
at 12 week?at 12 week?
A. The patient is a nonresponder...
Further EvolutionFurther Evolution
HCV PCR is negative again. HeHCV PCR is negative again. He
completes 48 weeks of therap...
How will you manage his treatmentHow will you manage his treatment
at 48 week?at 48 week?
 Congratulate him on successful...
The Many Faces of HCVThe Many Faces of HCV
SummarySummary
 Chronic HCV infection leads to cirrhosisChronic HCV infection ...
THANK YOU FORTHANK YOU FOR
YOUR ATTENTIONYOUR ATTENTION
Management of hepatitis c pma
Management of hepatitis c pma
Management of hepatitis c pma
Management of hepatitis c pma
Management of hepatitis c pma
Management of hepatitis c pma
Management of hepatitis c pma
Management of hepatitis c pma
Management of hepatitis c pma
Management of hepatitis c pma
Management of hepatitis c pma
Management of hepatitis c pma
Management of hepatitis c pma
Management of hepatitis c pma
Management of hepatitis c pma
Management of hepatitis c pma
Management of hepatitis c pma
Management of hepatitis c pma
Management of hepatitis c pma
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  1. 1. MANAGEMENT OFMANAGEMENT OF HEPATITIS CHEPATITIS C Dr Nasir KhokharDr Nasir Khokhar Professor of MedicineProfessor of Medicine Consultant GastroenterologistConsultant Gastroenterologist Shifa International HospitalShifa International Hospital IslamabadIslamabad
  2. 2. 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.
  3. 3. Model of HCV Replication Racanelli V, et al. Trends Immunol. 2003;24:456-464. ER HCV Endosome Uncoating Translation Entry Receptor NS2 NS3/4A NS4B NS5B NS5A + - Replication Progeny genomes Golgi E1 E2 Core E1-E2 Assembly E1-E2 Release Exocytosis Nucleus Cytoplasm
  4. 4. 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
  5. 5. <1 % 1–2.4 % 2.5–4.9 % 5–10 % > 10 % No data available HCV Has Broad Global PrevalenceHCV Has Broad Global Prevalence
  6. 6. 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
  7. 7. Natural HistoryNatural History
  8. 8. Hepatitis C VirusHepatitis C Virus Fate of Acute InfectionFate of Acute Infection 15% Chronic 85% Spontaneous resolution Alter MJ, et al. N Eng J Med. 1999;341:556-562.
  9. 9. 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 0 10 20 30 40 50 FMETAVIR Years Progression of Liver Fibrosis inProgression of Liver Fibrosis in HCV-Infected Patients With Normal ALTHCV-Infected Patients With Normal ALT Slow Normal ALT IntermediateRapid Matched
  10. 10. Chronic Hepatitis C WithChronic Hepatitis C With Normal Serum ALT: ALTNormal 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 ALT(IU/mL) Single elevations Periodic elevations Always normal Illustration by Mitchell L. Shiffman, MD.
  11. 11. Risk FactorsRisk Factors
  12. 12. Risk FactorsRisk Factors
  13. 13. Risk FactorsRisk Factors
  14. 14. Risk FactorsRisk Factors
  15. 15. Risk FactorsRisk Factors
  16. 16. Risk FactorsRisk Factors
  17. 17. Risk FactorsRisk Factors
  18. 18. Risk FactorsRisk Factors
  19. 19. Summary of Risk FactorsSummary of Risk Factors Reuse of syringes Blood transfusion Contaminated surgical instruments / Endoscopes / Dialysis machines Dental instruments/ Tooth brushes Reuse of infected shaving blades Ear piercing / Tattooing
  20. 20. 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
  21. 21. Chronic Hepatitis C VirusChronic Hepatitis C Virus Extrahepatic 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
  22. 22. HCV and CryoglobulinemiaHCV and Cryoglobulinemia DermatitisDermatitis  Occurs inOccurs in dependent areasdependent areas  Deposition ofDeposition of cryoglobulins incryoglobulins in small capillariessmall capillaries  Ulcerations mayUlcerations may developdevelop  PruriticPruritic
  23. 23. Zein CO, et al. Am J Gastroenterol. 2005;100:48-55. Chronic HCV and DiabetesChronic HCV and Diabetes MellitusMellitus  Prevalence of diabetesPrevalence of diabetes mellitus and insulinmellitus and insulin resistance notedresistance noted  Compared with expectedCompared with expected rate based on NHANESrate based on NHANES III study after adjusting forIII study after adjusting for  Age, Sex, RaceAge, Sex, Race  Prevalence of DM orPrevalence of DM or insulin resistance higherinsulin resistance higher in those with chronic HCVin those with chronic HCV 0 4 8 12 16 20 Females Males NumberofCases Observed Expected
  24. 24. Nagao Y, et al. J Gastroenterol Hepatol. 2004;19:1101-1113. Extrahepatic Effects of HCVExtrahepatic Effects of HCV Lichen 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 papules Throughout bodyThroughout body Oral mucosaOral mucosa  HistologyHistology Dense infiltration of dermis with TDense infiltration of dermis with T lymphocyteslymphocytes
  25. 25. DiagnosisDiagnosis
  26. 26. Determining Who to ScreenDetermining Who to Screen  Primary care physicians are the frontline inPrimary 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 IDUAnyone with a history of IDU  Persons with a history of noninjection drugPersons with a history of noninjection drug use and/or multiple sexual partnersuse and/or multiple sexual partners  Persons infected with HIVPersons infected with HIV  Any abnormal ALT levelAny abnormal ALT level  Normal ALT does not exclude diseaseNormal ALT does not exclude disease
  27. 27. 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
  28. 28. HCV Serotypes in PakistanHCV Serotypes in Pakistan Serotypes 6.005.004.003.002.001.00Missing Numberofpatients 600 500 400 300 200 100 0 Khokhar et al. Hepatology 2003;38:270-1
  29. 29. Fibrosis EvaluationFibrosis Evaluation 1498552133N = Fibrosis score 4.003.002.001.00.00 AST/ALTRatio 2.2 2.0 1.8 1.6 1.4 1.2 1.0 .8 .6 Khokhar. JPMA 2003;53:103-104
  30. 30. Fibrosis EvaluationFibrosis Evaluation 1498552133N = Fibrosis Score 4.003.002.001.00.00 PlateletCount 300000 200000 100000 0 Khokhar. JPMA 2003;53:103-104
  31. 31. Role of Liver Biopsy in PatientRole of Liver Biopsy in Patient Assessment and ManagementAssessment and Management NONO YESYES Patient wants treatmentPatient wants treatment regardlessregardless of biopsy findings, even ifof biopsy findings, even if no fibrosisno fibrosis HCV treatment absolutelyHCV treatment absolutely contraindicatedcontraindicated  Pregnancy, severePregnancy, severe depression, ESLD, severedepression, ESLD, severe cardiopulmonary diseasecardiopulmonary disease Genotype 2 or 3 and willingGenotype 2 or 3 and willing to take treatmentto take treatment Patient wants treatment ifPatient wants treatment if medically necessary asmedically necessary as indicated by liver histologyindicated by liver histology Patient fails to achieve SVRPatient fails to achieve SVR andand no recent biopsy availableno recent biopsy available
  32. 32. Chronic HCVChronic HCV Tests UtilizedTests Utilized Disease SeverityDisease Severity Response toResponse 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
  33. 33. Hepatitis C VirusHepatitis C Virus Diagnostic 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% DetectionDetection postexposurepostexposure 2-6 months2-6 months 2-6 weeks2-6 weeks UseUse ScreeningScreening ConfirmationConfirmation
  34. 34. Testing forTesting for HCV RNAHCV RNA  Confirm HCV infectionConfirm HCV infection Persistently 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 treatment Predict likelihood of response before andPredict likelihood of response before and during therapyduring therapy Confirm response after therapy completedConfirm response after therapy completed
  35. 35. Testing for HCV PCRTesting for HCV PCR Virologic AssaysVirologic Assays PCRPCR TMATMA b-DNAb-DNA PolymerasePolymerase chain reactionchain reaction TranscriptionTranscription mediatedmediated amplificationamplification Branched chainBranched chain DNADNA Amplifies targetAmplifies target Amplifies targetAmplifies target Amplifies probeAmplifies probe QualitativeQualitative QuantitativeQuantitative QualitativeQualitative QuantitativeQuantitative
  36. 36. Hepatitis C Virus InfectionHepatitis C Virus Infection Identification of PatientsIdentification of Patients  Found to have elevated serum ALT duringFound to have elevated serum ALT during Routine physical examinationRoutine physical examination Routine blood testing after starting certainRoutine blood testing after starting certain medicationsmedications  Test positive for anti-HCV duringTest positive for anti-HCV during Volunteer blood donationVolunteer blood donation Health or life insurance applicationsHealth or life insurance applications  PhysicianPhysician Inquires about previous risk behaviorsInquires about previous risk behaviors
  37. 37. 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 TIW3 MIU SC TIW Interferon alfa-2bInterferon alfa-2b Intron AIntron A®® (Schering-Plough)(Schering-Plough) 3 MIU SC TIW3 MIU SC TIW Interferon alfacon-1Interferon alfacon-1 InfergenInfergen®® (InterMune)(InterMune) 99 µµg SC TIWg SC TIW 1515 µµg SC TIWg SC TIW** Peginterferon alfa-2aPeginterferon alfa-2a PegasysPegasys®® (Roche)(Roche) 180180 µµg SC QWg SC QW Peginterferon alfa-2bPeginterferon alfa-2b Peg-IntronPeg-Intron®® (Schering-Plough)(Schering-Plough) 1.01.0––1.51.5 µµg/kg SC QWg/kg SC QW Ribavirin**Ribavirin** CopegusCopegus®® (Roche)(Roche) RebetolRebetol®® (Schering-Plough)(Schering-Plough) RibasphereRibasphereTMTM (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
  38. 38. Treatment RegimenTreatment Regimen Interferon-alpha 3 MIU TIW SC  Ribavirin 800-1200 mg/day According to the body weight for 6-12 months
  39. 39. 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 α/β 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.
  40. 40. 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
  41. 41. Time Course of Interferon SideTime Course of Interferon Side EffectsEffects Severity Flu-like symptoms Fatigue Depressive/anxiety symptoms IFN Treatment (Weeks) 0 2 4 6 8 10 12
  42. 42. What Are Future TherapiesWhat Are Future Therapies for Hepatitis C?for Hepatitis C?
  43. 43. HCV Helicase UnwindsHCV Helicase Unwinds Double-Stranded RNADouble-Stranded RNA
  44. 44. HCV Helicase CrystalHCV Helicase Crystal  Crystallization by vaporCrystallization by vapor diffusion methoddiffusion method  Crystallization conditions:Crystallization conditions: 50 mM Ca acetate, 8%50 mM Ca acetate, 8% PEG 5000, 20 mM NaPEG 5000, 20 mM Na cacodylate, pH 6.5cacodylate, pH 6.5
  45. 45. 3 Domains of HCV-RNA Helicase:3 Domains of HCV-RNA Helicase: NTPaseNTPase,, RNARNA Binding,Binding, HelicalHelical
  46. 46. Superposition of Two IndependentSuperposition of Two Independent Molecules Reveals Domain MovementMolecules Reveals Domain Movement Switch regionSwitch region T A T P P C 520 480 340 N 440 200 620 320 460 300 600 360 380 560 540 220 420 280 500 580 400 240 260 DomainDomain rotationrotation
  47. 47. Interactive CaseInteractive Case
  48. 48. HistoryHistory A 39-year-old male bank executive wasA 39-year-old male bank executive was diagnosed 6 months ago with genotype 1diagnosed 6 months ago with genotype 1 hepatitis C virus (HCV) infection discoveredhepatitis C virus (HCV) infection discovered during screening before blood donation.during screening before blood donation. Laboratory studies confirmed the diagnosis ofLaboratory studies confirmed the diagnosis of chronic hepatitis C and ruled out other liverchronic hepatitis C and ruled out other liver diseases.diseases. A liver biopsy demonstrated grade 2A liver biopsy demonstrated grade 2 inflammation and stage 3 fibrosis and steatosisinflammation and stage 3 fibrosis and steatosis without significant iron accumulation. Abdominalwithout significant iron accumulation. Abdominal U/S was negative for portal hypertension andU/S was negative for portal hypertension and signs of cirrhosis. His body mass index was 22.8signs of cirrhosis. His body mass index was 22.8 kg/m2.kg/m2.
  49. 49. 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
  50. 50. TreatmentTreatment  He was started on interferon alfa-2a TIW plusHe 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. TheHCT: 37.5% and WBC: 2600; ANC: 1600. The patient's HCV RNA is now 750,000 IU/mL. He ispatient's HCV RNA is now 750,000 IU/mL. He is tolerating therapy but initially experiencedtolerating therapy but initially experienced fatigue and flu-like symptoms, which havefatigue and flu-like symptoms, which have improved over the past 2 weeks. The patientimproved 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 homicidalrashes, depression, suicidal or homicidal ideation, irritability, or difficulty sleeping. He isideation, irritability, or difficulty sleeping. He is working full time with some fatigue at the end ofworking full time with some fatigue at the end of the day.the day.
  51. 51. How will you manage his treatmentHow will you manage his treatment at 4 week?at 4 week? A. The patient is a nonresponder andA. The patient is a nonresponder and treatment should be discontinuedtreatment should be discontinued B.B. Continue current regimen and check viralContinue current regimen and check viral load at treatment Week 12load at treatment Week 12 C.C. Increase ribavirin dose to improveIncrease ribavirin dose to improve response and recheck viral count in 4response and recheck viral count in 4 weeksweeks
  52. 52. The patient continues theThe patient continues the current treatment regimen andcurrent treatment regimen and returns at Week 12 of treatmentreturns at Week 12 of treatment to undergo further evaluation.to undergo further evaluation.
  53. 53. EvolutionEvolution The patient’s mild adverse effects areThe patient’s mild adverse effects are managed by behavior modification andmanaged by behavior modification and analgesics. No increases in anemia oranalgesics. No increases in anemia or neutropenia severity are noted. Heneutropenia severity are noted. He remains motivated to continue therapy andremains 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 increaseHe has also experienced a mild increase in irritability but is still able to work fullin irritability but is still able to work full time. The patient’s Week 12 HCV RNA istime. The patient’s Week 12 HCV RNA is negative, his AST is 34 U/mL, and his ALTnegative, his AST is 34 U/mL, and his ALT is 28 U/mL.is 28 U/mL.
  54. 54. How will you manage his treatmentHow will you manage his treatment at 12 week?at 12 week? A. The patient is a nonresponder andA. The patient is a nonresponder and treatment should be discontinuedtreatment should be discontinued B. Continue on current doses and return atB. Continue on current doses and return at Week 48 for further evaluationWeek 48 for further evaluation C. Continue on current doses and return atC. Continue on current doses and return at Week 24 for further evaluationWeek 24 for further evaluation
  55. 55. Further EvolutionFurther Evolution HCV PCR is negative again. HeHCV PCR is negative again. He completes 48 weeks of therapy and hascompletes 48 weeks of therapy and has normal LFT and negative HCV PCR.normal LFT and negative HCV PCR.
  56. 56. How will you manage his treatmentHow will you manage his treatment at 48 week?at 48 week?  Congratulate him on successful treatmentCongratulate him on successful treatment and advise him to come back if any furtherand advise him to come back if any further complaints.complaints.  Follow every month for six months withFollow every month for six months with further tests.further tests.  Advise maintenance interferon for 3-6Advise maintenance interferon for 3-6 months without ribavirinmonths without ribavirin
  57. 57. The Many Faces of HCVThe Many Faces of HCV SummarySummary  Chronic HCV infection leads to cirrhosisChronic HCV infection leads to cirrhosis and liver failure in a large number ofand liver failure in a large number of personspersons  Primary care physicians must recognizePrimary care physicians must recognize that chronic HCV is common disorder inthat chronic HCV is common disorder in our countryour country  Effective treatment of chronic HCV canEffective treatment of chronic HCV can prevent fibrosis progression and reduceprevent fibrosis progression and reduce complications of HCVcomplications of HCV
  58. 58. THANK YOU FORTHANK YOU FOR YOUR ATTENTIONYOUR ATTENTION
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