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Viral HepatitisViral HepatitisMedicine Student LectureMedicine Student Lecture
David R Nelson, M.D.Associate Professor of Medicine
Director, Hepatology and Liver TransplantationUniversity of Florida
Case 1:Case 1:
29 y/o female came to your clinic with:• Jaundice, Abdominal pain, Nausea / Vomiting• AST-2,000 ALT- 2,500, Total bili 1.8• She denies IVDA or any recent drug/medicine exposure, but
had unprotected sex about 6 weeks ago• Ultrasound shows normal appearing liver and blood flow
• Her diagnosis is……
Causes of Acute HepatitisCauses of Acute Hepatitis
Acute Hepatitis
Viral HepatitisA, B/D, C, E
EBVCMV & HSV
DrugsEthanolTylenol
Halothane
ToxinsJamaica Bush Tea
Mushrooms
VascularHypotensionBudd-Chiari
AutoimmuneHepatitis
MetabolicWilson's Disease
A1AT
Case:Case:
• 38 y/o male with past medical history of abnormal ALT for past 4 years. He had a blood tx as a child due to MVA. Patient came to your clinic with:
– ALT 150, AST 100– HBsAb +, HBcAb +– HCV Ab +– HAV IgG +
• What is your dx?
Causes of Chronic HepatitisCauses of Chronic Hepatitis
Chronic Hepatitis
Viral HepatitisHep BHep C
DrugsMTXINH
Amiodarone
Alcohol NAFLD
AutoimmuneAIHPBCPSC
MetabolicA1ATHHC
Wilson's
Abbreviations: NAFLD: nonalcoholic fatty liver disease; AIH: autoimmune hepatitis; PBC: primary biliary cirrhosisPSC: primary sclerosing cholangitis, A1AT: alpha-1 antitrypsin deficiency, HHC:hereditary hemochromotosis
47%
34%
16%
3%Hepatitis AHepatitis BHepatitis CHepatitis Non-ABC
Source: CDC Sentinel Counties Study on Viral Hepatitis
Acute Viral Hepatitis by Type, USA: 1982-1993 Acute Viral Hepatitis by Type, USA: 1982-1993
27 nm27 nm
Transmission route: fecal-oralTransmission route: fecal-oral
Clinical presentationClinical presentation - Jaundice: Adults- 30%, Children- <5%- Jaundice: Adults- 30%, Children- <5% - Fulminant: <1%- Fulminant: <1%• Diagnostic testsDiagnostic tests - Acute infection: IgM anti-HAV- Acute infection: IgM anti-HAV - Chronic infection: Not applicable- Chronic infection: Not applicable• Immunity: IgG anti-HAVImmunity: IgG anti-HAV• Case-fatality rate: 0.1 – 2.7%Case-fatality rate: 0.1 – 2.7%• Chronic infection:Chronic infection: NoneNone
Transmission route: fecal-oralTransmission route: fecal-oral
Clinical presentationClinical presentation - Jaundice: Adults- 30%, Children- <5%- Jaundice: Adults- 30%, Children- <5% - Fulminant: <1%- Fulminant: <1%• Diagnostic testsDiagnostic tests - Acute infection: IgM anti-HAV- Acute infection: IgM anti-HAV - Chronic infection: Not applicable- Chronic infection: Not applicable• Immunity: IgG anti-HAVImmunity: IgG anti-HAV• Case-fatality rate: 0.1 – 2.7%Case-fatality rate: 0.1 – 2.7%• Chronic infection:Chronic infection: NoneNone
Hepatitis A VirusHepatitis A Virus
Nucleic Acid: 7.5 kb ssRNA
HAV PrevalenceHAV Prevalence
HighHigh
IntermediateIntermediate
LowLow
Very LowVery Low
Global Prevalence of Hepatitis A InfectionGlobal Prevalence of Hepatitis A Infection
FecalHAV
Symptoms
ALTALT
IgM anti-HAVIgM anti-HAV
Total anti-HAVTotal anti-HAV
Months after ExposureMonths after Exposure
Tit
erT
iter
Typical Serologic CourseTypical Serologic Course
0 1 2 3 4 5 6 12 24
Hepatitis A Virus InfectionHepatitis A Virus Infection
Hepatitis A Prevention - Immune GlobulinHepatitis A Prevention - Immune Globulin
PreexposurePreexposure
• Travelers to high HAV-prevalence regionsTravelers to high HAV-prevalence regions
Postexposure (within 14 days)Postexposure (within 14 days)
• RoutineRoutine• Household and other intimate contactsHousehold and other intimate contacts
• Selected situationsSelected situations• Institutions (e.g. daycare centers)Institutions (e.g. daycare centers)• Common source exposure (e.g. food prepared Common source exposure (e.g. food prepared
by infected food handler)by infected food handler)
PreexposurePreexposure
• Travelers to high HAV-prevalence regionsTravelers to high HAV-prevalence regions
Postexposure (within 14 days)Postexposure (within 14 days)
• RoutineRoutine• Household and other intimate contactsHousehold and other intimate contacts
• Selected situationsSelected situations• Institutions (e.g. daycare centers)Institutions (e.g. daycare centers)• Common source exposure (e.g. food prepared Common source exposure (e.g. food prepared
by infected food handler)by infected food handler)
ACIP Recommendations MMWR ACIP Recommendations MMWR 1999; 48(RR12):1
Hepatitis A: Pre-exposure VaccinationHepatitis A: Pre-exposure Vaccination
Persons at increased risk or danger of infectionPersons at increased risk or danger of infection
• Travelers to intermediate and high Travelers to intermediate and high HAV prevalence areasHAV prevalence areas
• Men having sex with menMen having sex with men• Injecting drug usersInjecting drug users• Persons with chronic liver diseasePersons with chronic liver disease
Communities with high rates of hepatitis ACommunities with high rates of hepatitis A(e.g., Alaskan Natives, Native-Americans)(e.g., Alaskan Natives, Native-Americans)Routine pre-school childhood vaccinationRoutine pre-school childhood vaccination
Persons at increased risk or danger of infectionPersons at increased risk or danger of infection
• Travelers to intermediate and high Travelers to intermediate and high HAV prevalence areasHAV prevalence areas
• Men having sex with menMen having sex with men• Injecting drug usersInjecting drug users• Persons with chronic liver diseasePersons with chronic liver disease
Communities with high rates of hepatitis ACommunities with high rates of hepatitis A(e.g., Alaskan Natives, Native-Americans)(e.g., Alaskan Natives, Native-Americans)Routine pre-school childhood vaccinationRoutine pre-school childhood vaccination
Fecal-oral transmission (human to Fecal-oral transmission (human to human)human)
• Contaminated water supplies in tropical Contaminated water supplies in tropical or subtropical developing countriesor subtropical developing countries
• Mainly young adultsMainly young adults• Can infect primates, swine, sheep, ratsCan infect primates, swine, sheep, rats• Swine may be reservoir of infection in Swine may be reservoir of infection in
North America North America • Maternal-infant transmission occurs and Maternal-infant transmission occurs and
is often fatalis often fatal
Fecal-oral transmission (human to Fecal-oral transmission (human to human)human)
• Contaminated water supplies in tropical Contaminated water supplies in tropical or subtropical developing countriesor subtropical developing countries
• Mainly young adultsMainly young adults• Can infect primates, swine, sheep, ratsCan infect primates, swine, sheep, rats• Swine may be reservoir of infection in Swine may be reservoir of infection in
North America North America • Maternal-infant transmission occurs and Maternal-infant transmission occurs and
is often fatalis often fatal
32 nm32 nm
Hepatitis E VirusHepatitis E Virus
Nucleic Acid: 7.5 kb ssRNANucleic Acid: 7.5 kb ssRNA
Hepatitis EHepatitis E
Similar to hepatitis ASimilar to hepatitis A
Dx: IgG anti-HEV (seroconversion)Dx: IgG anti-HEV (seroconversion)
Can cause severe acute hepatitisCan cause severe acute hepatitis
Subclinical infection is commonSubclinical infection is common Attenuated virus from animal reservoirsAttenuated virus from animal reservoirs Low-dose infections often asymptomaticLow-dose infections often asymptomatic
No chronic infectionNo chronic infection
Up to 20% mortality among pregnant women (esp. third Up to 20% mortality among pregnant women (esp. third trimester)trimester)
Similar to hepatitis ASimilar to hepatitis A
Dx: IgG anti-HEV (seroconversion)Dx: IgG anti-HEV (seroconversion)
Can cause severe acute hepatitisCan cause severe acute hepatitis
Subclinical infection is commonSubclinical infection is common Attenuated virus from animal reservoirsAttenuated virus from animal reservoirs Low-dose infections often asymptomaticLow-dose infections often asymptomatic
No chronic infectionNo chronic infection
Up to 20% mortality among pregnant women (esp. third Up to 20% mortality among pregnant women (esp. third trimester)trimester)
Clinical CharacteristicsClinical Characteristics
Hepatitis B VirusHepatitis B Virus
• Hepadnaviridae member that primarily infects liver cells
• 50 to 100 times more infective than HIV
• Multiple genotypes exist (A-H)
• DNA virus found in blood and body fluids– Able to survive in dried blood for longer than 1 week
HBsAgHBsAg
HBV DNAHBV DNA
HBcAgHBcAg42 nm42 nm
Geographic Distribution of Chronic HBV Infection
Geographic Distribution of Chronic HBV Infection
HBsAg Prevalence
8% - High
2-7% - Intermediate
<2% - Low
> 350 million carriers (HBsAg + > 6 months)
10th cause of death(1 million / year)
Cirrhosis in 20% (75 - 100 million)
HCC in 5 - 10% (20 - 40 million)
Son D, Asian Am Pac Isl J Health 2001Slide courtesy of Robert Gish, MD
Hepatitis B PrevalenceHepatitis B Prevalence
• Overall U.S. prevalence: 0.3%
• Asian Americans: ~10-13%
0% 2% 4% 6% 8% 10% 12% 14%
Chinese
Filipino
Japanese
Korean
Vietnamese
Laotians
HBV Sources of InfectionHBV Sources of InfectionHousehold, 3%
Other, 23%
IDU, 20%Multiple sexpartners, 24%
Sexcontact, 23%
MSM, 23%
Centers for Disease Control and Prevention. Hepatitis B. In: Atkinson W et al, eds. Epidemiology & Prevention of Vaccine-Preventable Diseases. 8th ed Washington DC: Public Health Foundation; 2005:191-212.
Many patients do not reveal IDU as source of infection
Signs and Symptoms of Acute Hepatitis BSigns and Symptoms of Acute Hepatitis B
• About 30% of persons have no signs or symptoms
• If symptoms are present, generally nonspecific including:
• Nausea, vomiting• Joint pain• Dark Urine• Clay-colored bowel movements
• Jaundice• Fatigue• Abdominal Pain• Loss of Appetite
Hepatitis B - Clinical FeaturesHepatitis B - Clinical Features
Incubation periodAverage: 60 – 90 daysRange: 45 – 180 days
Clinical illness (jaundice)< 5 yrs of age: <10% 5 yrs of age: 30 – 50%
Acute case-fatality rate 0.5 – 1%
Chronic infection< 5 yrs of age: 30 – 90% 5 yrs of age: 2 – 10%
Mortality from chronic liver disease 15 – 25%
Progression to Chronic Hepatitis B Virus Infection
Progression to Chronic Hepatitis B Virus InfectionTypical Serologic CourseTypical Serologic Course
Weeks after ExposureWeeks after Exposure
TiterTiter
IgM anti-HBc
Total anti-HBc
HBsAg
Acute(6 months)
HBeAg
Chronic(Years)
anti-HBe
0 4 8 12 16 20 24 28 32 36 52 Years
HBV DNA
Acute Acute
hepatitis Bhepatitis B
Recovery Recovery from acute from acute hepatitis Bhepatitis B
Chronic Chronic HBeAg + HBeAg + diseasedisease
Chronic Chronic HBeAG – HBeAG – diseasedisease
Successful Successful VaccinationVaccination
Resistance Resistance to antiviral to antiviral
agentsagents
HBsAg
(may clear)
Anti-HBs
Anti-HBc IgM
Anti-HBc
HBeAg
Anti-HBe
(in some cases)
DNA (PCR if required)
(may be
only marker during
window period)
(sequence pol region)
Interpretation of Serologic MarkersInterpretation of Serologic Markers
Hepatitis B: Disease ProgressionHepatitis B: Disease Progression
Acute Infection
Chronic Infection Cirrhosis Death
1. Torresi J et al. Gastroenterology. 2000.2. Fattovich G et al. Hepatology. 1995.3. Moyer LA et al. Am J Prev Med. 1994.4. Perrillo R et al. Hepatology. 2001.
5%-10% 1
10-30% 1
23% within 5 years
Liver Cancer (HCC)
Chronic HBV is the 6th leading cause of liver transplantation in the US4
Liver Liver TransplantationTransplantation
Liver Failure (Decompensation)
2-6%2-6%
90% in perinatal90% in perinatal30-90% in children<5yrs old30-90% in children<5yrs old
5% in healthy adults5% in healthy adultsHigher in HIV, immune suppressedHigher in HIV, immune suppressed
Targeted Surveillance for HCCTargeted Surveillance for HCC
• Asian males > age 40• Asian females > age 50• All cirrhotic HBV carriers• Family history of HCC• Africans > age 20• High HBV DNA
• Hepatitis C• Alcoholic cirrhosis• Genetic hemochromatosis• Primary biliary cirrhosis• Other (? efficacy)
• A1AT deficiency• NAFLD• Autoimmune hepatitis
Hepatitis B Carriers Non-hepatitis B Cirrhosis
Bruix J and Sherman M. Hepatology 2005;42:1208
Surveillance for HCC should be with ultrasound at Surveillance for HCC should be with ultrasound at 6 to 12 month intervals; AFP is not adequate6 to 12 month intervals; AFP is not adequate
Prevention of Transmission of Hepatitis B Prevention of Transmission of Hepatitis B VaccinationVaccination
1. Vaccinate Sexual and household contacts 2. Newborns of HBV-infected mothers
• HBIG and • hepatitis B vaccine at delivery
3. Test for response to vaccination • infants of HBsAg-positive mothers (9 to 15 months )• health care workers, • dialysis patients, and • sexual partners
4. Follow-up testing of vaccine responders • Annually for chronic hemodialysis patients
1-2 months
Goals of Treatment in HBVGoals of Treatment in HBV
• Reduce the risk of disease progression• Reduce the risk of hepatocellular carcinoma
• Loss of HBeAg, HBeAg HBeAb• Undetectable HBV-DNA
• (<105 copies/ml = 20,000IU/mL)• Normalization of ALT• Histologic Response• HBsAg HBsAb
Virologic Response
Approved TreatmentsApproved Treatments
Lok AND McMahon. .Hepatology, Vol. 45, No. 2, 2007
Nucleic Acid: 1.7 kb ssRNANucleic Acid: 1.7 kb ssRNA
Classification: Classification: unclassified, unclassified, related to viroids; deltavirusrelated to viroids; deltavirus
Transmission: sex, IVDATransmission: sex, IVDA
Clinical featuresClinical features - Fulminant: 2 – 7.5%- Fulminant: 2 – 7.5% - Chronic infection- Chronic infection
Superinfection: 80%Superinfection: 80%Coinfection: < 5%Coinfection: < 5%
• Diagnostic testsDiagnostic tests -Acute infection: IgM anti-HDV-Acute infection: IgM anti-HDV -Chronic infection:IgG anti-HDV, HBsAg +-Chronic infection:IgG anti-HDV, HBsAg +
Nucleic Acid: 1.7 kb ssRNANucleic Acid: 1.7 kb ssRNA
Classification: Classification: unclassified, unclassified, related to viroids; deltavirusrelated to viroids; deltavirus
Transmission: sex, IVDATransmission: sex, IVDA
Clinical featuresClinical features - Fulminant: 2 – 7.5%- Fulminant: 2 – 7.5% - Chronic infection- Chronic infection
Superinfection: 80%Superinfection: 80%Coinfection: < 5%Coinfection: < 5%
• Diagnostic testsDiagnostic tests -Acute infection: IgM anti-HDV-Acute infection: IgM anti-HDV -Chronic infection:IgG anti-HDV, HBsAg +-Chronic infection:IgG anti-HDV, HBsAg +
35-37nm35-37nm
Hepatitis D Virus: Morphology and Hepatitis D Virus: Morphology and CharacteristicsCharacteristics
CoinfectionCoinfection
SuperinfectionSuperinfection
BB
BB
DD
DD
Modes of HDV infectionModes of HDV infection
HCV Life-Cycle and PathogenesisHCV Life-Cycle and PathogenesisHCV Life-Cycle and PathogenesisHCV Life-Cycle and Pathogenesis
Cell Binding Cell Binding and Infectionand InfectionCell Binding Cell Binding and Infectionand Infection
Replication
Immune Immune ResponseResponseImmune Immune
ResponseResponse
CD4CD4CD8CD8NKNKDCDC
CD4CD4CD8CD8NKNKDCDC
HSCHSC
FibrosisFibrosis
Immune Immune RecognitionRecognition
Immune Immune RecognitionRecognition
CytokinesCytokinesCytokinesCytokines
Viral Packaging Viral Packaging and Releaseand Release
Viral Packaging Viral Packaging and Releaseand Release
EffectorEffectorEffectorEffectorHCVHCVHCVHCV
Time After Exposure
Symptoms
0
400
600
800
1000
AL
T (
IU/L
)
0 2 4 6 8 10 12 24 1 2 3 4 5 6
Anti-HCVAnti-HCV
Weeks Months
HCV RNA positive
200
7
Normal ALT
Course of Acute HCV InfectionCourse of Acute HCV Infection
Hoofnagle JH. Hepatology. 1997;26:15S. Carithers RL Jr, et al. Semin Liver Dis. 2000;20:159-171. Pawlosky JM. Hepatology. 2002;36(suppl 1):S65-S73. NIH Management of Hepatitis C Consensus Conference Statement. June 10-12, 2002. Available at: http://consensus.nih.gov/2002/2002HepatitisC2002116html. Accessed April 10, 2007.
Symptoms, or Lack of, in Chronic Symptoms, or Lack of, in Chronic HCV InfectionHCV Infection
Symptomatic37%
Cirrhosis7%
56%Asymptomatic
0
20
40
60
80
100
FatigueP
atie
nts
(%
)
80
ALT Elevations Are Not Indicative of ALT Elevations Are Not Indicative of Chronic HCV InfectionChronic HCV Infection
Inglesby TV, et al. Hepatology. 1999;29:590-596.
42 43
15
0
20
40
60
80
100
PersistentlyNormal ALT
IntermittentlyElevated ALT
Persistently Elevated ALT
Pat
ien
ts*
Wit
h H
CV
infe
ctio
n (
%)
Diagnostic Tests for HCV InfectionDiagnostic Tests for HCV Infection
Diagnostic Test Type
Specifications Serologic Virologic
Mode of detection Antibodies Virus
Sensitivity > 95% > 98%
Specificity Variable > 98%
Detection postexposure 2-6 mos 2-6 wks
Use Screening Confirmation
CDC Morbidity Mortality Weekly Report. 1998;16(RR-19):1-33. NIH Management of Hepatitis C Consensus Conference Statement. June 10-12, 2002. Available at: http://consensus.nih.gov/2002/2002HepatitisC2002116html. Accessed April 10, 2007.
Molecular Virologic AssaysMolecular Virologic Assays
Quantitative assaysQuantitative assaysDetection cutoff > qualitativeDetection cutoff > qualitative
How much HCV is present?
Qualitative assaysQualitative assaysHigh sensitivityHigh sensitivity
(( 50 IU/mL) 50 IU/mL)
Is HCV present?
GenotypeGenotypeassaysassays
What type of HCV is present?
Clinical Significance of HCV GenotypesClinical Significance of HCV Genotypes
Choo QL, et al. Science. 1989;244:359-62. NIH Consensus Development Conference Statement. Bethesda, Md: National Institutes of Health; June 10-12, 2002. Hadziyannis SJ. Ann Intern Med. 2004;140:346-355.
• Great genetic diversity: 2 genotypes (1 through 6)• Multiple subtypes: a, b, c, etc
• Genotype is best pretreatment predictor of response• Genotype 1: least responsive to therapy
• Determines dose and duration of therapy• Genotype 1: 48 weeks of peg-IFN alfa + RBV 1000-1200
mg• Genotype 2/3: 24 weeks of peg-IFN alfa + RBV 800 mg
• All patients should have genotype determined prior to initiating therapy
Prevalence of HCV Dependant on Risk FactorsPrevalence of HCV Dependant on Risk Factors
• Hemophilia 74-90%• IVDA 72-89%• Prison 40%• HIV 30-40%• Blood transfusion prior to 90 5-9%• Infants to HCV+ Mothers 5%• Sexual Partner 0.5-3% • General Population 1.8%
Adapted from MMWR.1998;47:5.
Prevalence of HCV Infection:Prevalence of HCV Infection: United States United States
Alter et al. N Engl J Med. 1999;341:556-562.
An
ti-H
CV
+ (
%)
0
1
2
3
4
5
6
7
Age (yr)6–11 12–19 20–29 30–39 40–49 50–59 70+60–69
MexicanAmerican
Caucasian
3.5%
1.1%
African American
3.2%
1. NIH Consensus Development Conference Statement; March 24-26, 1997. 2. Davis GL et al. Gastroenterol Clin North Am. 1994;23:603-613. 3. Koretz RL et al. Ann Intern Med. 1993;119:110-115. 4. Takahashi M et al. Am J Gastroenterol. 1993;88:240-243.
HCV infectionHCV infection
Chronic HCV Chronic HCV CirrhosisCirrhosis Hepatic FailureHepatic Failure
Liver CancerLiver Cancer Liver TransplantLiver TransplantCandidatesCandidates
60-85%60-85%11
~20%~20%44
~ 20%~ 20%3320%-50%20%-50%22
HCV: Disease ProgressionHCV: Disease Progression
Time: 20-30 yearsTime: 20-30 years
Histologic Progression of HCV Histologic Progression of HCV Monitored by Liver BiopsyMonitored by Liver Biopsy
Inflammation Grade• Measure of severity and ongoing disease activity• 0-4 (METAVIR)• Inflammation leads to scarring/fibrosis
Fibrosis Stage• Amount of fibrous scar tissue• 0-4 (METAVIR)• Stage 4 = cirrhosis• Indicates long-term disease progression
No fibrosis
CirrhosisBrunt EM. Hepatology. 2000;31:241-246.
Identification and Planning
Common Schedule and Type of HCV TestingCommon Schedule and Type of HCV Testing
Identification and PlanningIdentification and Planning TreatmentTreatment
DiagnosisDiagnosis
• Serological • Qual HCV
RNA
PrognosisPrognosis
• Liver biopsy
Treatment Treatment DurationDuration
• Genotyping • Quant HCV
RNA
Assess Response and Resistance
• Quant HCV RNAQuant HCV RNA
Decision to Treat
Stage
Assay
39%42%
34%
16%
54-56%
6%
0
20
40
60
80
100
Sus
tain
ed V
irolo
gic
Sus
tain
ed V
irolo
gic
Res
pons
e (%
)R
espo
nse
(%)
IFNIFN6m6m
IFN/RBVIFN/RBV6m6m
Peg-IFN/ Peg-IFN/ RBV 12mRBV 12m
IFNIFN12m12m
IFN/RBVIFN/RBV12m12m
Peg-IFNPeg-IFN12m12m
Strader DB et al. Hepatology 2004;39:1147-1171
Improvements in Therapy of HCVImprovements in Therapy of HCV
19911991 19981998 20012001 20022002
Current standard treatment duration is Current standard treatment duration is 48 or 24 weeks according to genotype48 or 24 weeks according to genotype
HCV genotypingHCV genotyping
HCV-1 (4,5,6)HCV-1 (4,5,6)Quantitative HCV RNAQuantitative HCV RNA
HCV-2,3HCV-2,3
Peg-IFN +Peg-IFN +RBV 800 mg/dayRBV 800 mg/day for for 24 weeks 24 weeks
Peg-IFN+ RBVPeg-IFN+ RBV1000/1200 mg/day1000/1200 mg/day
Quantitative HCV RNA at week 12Quantitative HCV RNA at week 12
<2 log decline<2 log decline
Stop or re-evaluate Stop or re-evaluate therapytherapy
2 log decline or HCV RNA (–)2 log decline or HCV RNA (–)
48 weeks48 weeks
An estimated 5 million Americans have been infected with HCV, of whom 4 million are chronically infected
Approximately 30,000 people in the US are infected with hepatitis C each year
Hepatitis C is the leading causes of liver disease and cirrhosis in US
12,000 - 15,000 people die of hepatitis C each year in the US
The CDC estimate that the number of annual deaths from hepatitis C will triple in the next 10 - 20 years
The estimated medical and work loss costs per year of hepatitis C is over $600 million
The Burden of Liver Disease Associated The Burden of Liver Disease Associated with HCV is Increasingwith HCV is Increasing
Source: American Liver Foundation