Natural History of HCV P-DS-D-150. HCV Characteristics Family Flaviviridae 1 Family Flaviviridae 1 Enveloped 2 Enveloped 2 Positive-sense single-stranded

Natural History of HCVNatural History of HCV

P-DS-D-150P-DS-D-150

HCV CharacteristicsHCV Characteristics

Family FlaviviridaeFamily Flaviviridae11

EnvelopedEnveloped22 Positive-sense single-stranded RNA (9.6 kb)Positive-sense single-stranded RNA (9.6 kb)1,31,3

3000–amino acid polyprotein3000–amino acid polyprotein33

No RNA polymerase proofreading abilityNo RNA polymerase proofreading ability44

– Quasispecies– Quasispecies44

Half-life: Half-life: 2.7 hours2.7 hours22

Daily production: 10 trillion (10Daily production: 10 trillion (101212) virions) virions22

1 Purcell R. NIH Consensus Conference on Hepatitis C. 1997. 2 Neumann A et al. Science. 1998;282:103-107. 3 Rosenberg S. J Mol Biol. 2001;313(3):451-464. 4 Lauer G et al. N Engl J Med. 2001;345(1):41-52. P-DS-D-148P-DS-D-148

Natural History of HCV InfectionNatural History of HCV Infection

TimeTime(yr)(yr)

ExposureExposure(Acute Phase)(Acute Phase)

ResolvedResolved

20%20%

15% 15% 85%85%

ESLDESLD HCCHCC

Transplant/deathTransplant/death

6%/yr6%/yr 4%/yr4%/yr

33––4%/yr4%/yr

~20 year ~20 year progression rate progression rate accelerated with accelerated with HIV, HBV, alcoholHIV, HBV, alcohol

HCC = hepatocellular carcinomaHCC = hepatocellular carcinoma

ESLD = end-stage liver diseaseESLD = end-stage liver disease

5-year 5-year survival in survival in

patients with patients with HCC is < 5%HCC is < 5%22

1010 2020 3030

CirrhosisCirrhosis

ChronicChronic

Di Bisceglie A, et al. Di Bisceglie A, et al. HepatologyHepatology. 2000;31:1014-1018.. 2000;31:1014-1018.P-DS-D-041P-DS-D-041

Clinical ManifestationsClinical Manifestationsof HCV Infectionof HCV Infection

Acute infection Majority asymptomatic but jaundice may occur

Chronic infection

No symptoms or fatigue, depression, abdominal discomfort, others

Advanced chronic infection

Portal hypertension with ascites, encephalopathy, gastrointestinal bleeding, jaundice and decompensation

CDC. CDC. MMWRMMWR. 1998;47(RR-19):1-38.. 1998;47(RR-19):1-38. P-DS-D-151P-DS-D-151

Complications of CirrhosisComplications of Cirrhosis

SBP = Spontaneous bacterial peritonitis

Sleisenger & Fordtran's Gastrointestinal and Liver Disease. 6th Ed. 1998 Feldman M, Sleisenger & Fordtran's Gastrointestinal and Liver Disease. 6th Ed. 1998 Feldman M, Scharschmidt BF, Sleisenger MH. WB Saunders, Philadelphia, PA.Scharschmidt BF, Sleisenger MH. WB Saunders, Philadelphia, PA.

Hepatic encephalopathy

Ascites/SBP

Portal hypertension

Hepatorenal syndrome

Cirrhosis

{


11NIH. NIH. NIH Consens State Sci StatementsNIH Consens State Sci Statements. 2002;19(3):1-46.. 2002;19(3):1-46.22Sene D et al. Sene D et al. Metab Brain DisMetab Brain Dis. 2004;19(3-4):357-381. . 2004;19(3-4):357-381.

Extrahepatic Manifestations Associated with Extrahepatic Manifestations Associated with HCVHCV

HematologicHematologic• Mixed cryoglobulinemiaMixed cryoglobulinemia11

• Aplastic anemiaAplastic anemia22

• ThrombocytopeniaThrombocytopenia22

• Non-Hodgkin's b-cell lymphomaNon-Hodgkin's b-cell lymphoma22

DermatologicDermatologic• Porphyria cutanea tardaPorphyria cutanea tarda11

• Lichen planusLichen planus22

• Cutaneous necrotizing Cutaneous necrotizing • vasculitis2vasculitis2

RenalRenal• GlomerulonephritisGlomerulonephritis11

• Nephrotic syndromeNephrotic syndrome22

EndocrineEndocrine• HypothyroidismHypothyroidism22

• Diabetes mellitusDiabetes mellitus22

OcularOcular• Corneal ulcerCorneal ulcer22

• UveitisUveitis22

VascularVascular• Necrotizing vasculitisNecrotizing vasculitis22

• Polyarteritis nodosaPolyarteritis nodosa22

NeuromuscularNeuromuscular22

• Weakness/myalgiaWeakness/myalgia• Peripheral neuropathyPeripheral neuropathy• Arthritis/arthralgiaArthritis/arthralgia

Autoimmune Autoimmune PhenomenaPhenomena22

• CREST syndromeCREST syndromeNeuropsychiatricNeuropsychiatric• DepressionDepression11


HistologyHistology

Stage 1 Stage 2

Stage 3 Stage 4


Factors AssociatedFactors AssociatedWith Disease ProgressionWith Disease Progression

Associatedwith disease progression1

Not Associatedwith disease progression1

Alcohol consumption 30 g/day for males 20 g/day for females

Alanine aminotransferase level

Viral load

Transmission mode

Genotype

~2 drinks/da

y

11Poynard T et al. Poynard T et al. Lancet.Lancet. 1997;349:825-832. 1997;349:825-832.22NIH. NIH. NIH Consens State Sci StatementsNIH Consens State Sci Statements. 2002;19(3):1-46.. 2002;19(3):1-46. P-DS-D-153P-DS-D-153

Type of Factor

Well Established Factors

Host

• Age at infection• Duration of

infection• Male gender• Baseline fibrosis

Viral • HIV infection• HBV infection

External • Heavy alcohol use

Factors AssociatedFactors Associatedwith Advanced Fibrosiswith Advanced Fibrosis

Bialek SR, et al. Clin Liver Dis. 2006;10:697-715. P-DS-D-047P-DS-D-047

Risk of Fibrosis Progression Risk of Fibrosis Progression Increases with AgeIncreases with Age

0

1

2

3

4

5

6

7

8

9

10

(19- 24) (25 - 29) (30 34) (35 - 39) (40 - 44) (45 - 49) (50 - 54) (55 - 59) (60 - 64) (65 - 69) (70 +)

Rela

tive r

isk o

f p

rog

ressio

n

Ryder S et al. Gut .2004;53:451-55.P-DS-D-099P-DS-D-099

Projected Prevalence of HCV-Related Cirrhosis Projected Prevalence of HCV-Related Cirrhosis and Complications in US by 2020and Complications in US by 2020

HCV infections 2.7 million

Cirrhosis 0.86 million

Decompensated Cirrhosis 0.14 million

Hepatocellular Carcinoma 13,390

Liver-related Deaths 36,483

Davis GL. Rev Gastroenterol Disord. 2004;4:7-17.P-DS-D-042P-DS-D-042

Liver TransplantationLiver Transplantationfor Hepatitis C in the USfor Hepatitis C in the US

0

500

1000

1500

2000

1991 1992 1993 1994 1995 1996 1997 1998 1999 2000

16791679

343343

Tra

nsp

lan

ts (

No.)

Year

Kim W et al. Kim W et al. HepatologyHepatology. 2002;36:S30-S34.. 2002;36:S30-S34. P-DS-D-435P-DS-D-435

Hepatitis C is Leading IndicationHepatitis C is Leading Indicationfor Liver Transplantfor Liver Transplant

0

1000

2000

3000

4000

5000

6000

7000

1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007

Year

Nu

mb

er o

f T

ran

spla

nts

HCV

Alcoholic Cirrhosis

All Other Diagnoses

Based on OPTN data as of August 15, 2008.HCV diagnosis defined as cirrhosis type C or acute hepatic necrosis (AHN) type CMixed diagnoses with HCV as a contributing factor are included under “All Other Diagnoses”

Organ Procurement and Transplantation Network. Available at www.optn.org.

HCV: 21-30% of LTHCV: 21-30% of LT

Alcoholic cirrhosis: 10-12% of LTAlcoholic cirrhosis: 10-12% of LT


Financial Burden of HCV-Related Financial Burden of HCV-Related Liver Transplant Liver Transplant

HCV-Related Liver Transplants Accountfor 40% of Total Transplants1

Number2 ~2000/year

Procurement, Hospital/Physician Charges3 ~$300,000

Evaluation, Follow Up3 ~$100,000

Total Transplant Cost ~$400,000

Immunosuppressant medication3 ~$30,000/year

Total cost (transplant + immunosuppressant tx) ~$430,000/ first year

11Kim W et al. Kim W et al. HepatologyHepatology. 2002;36:S30-S34.. 2002;36:S30-S34.22Available at: www.unos.org. Accessed March 13, 2006.Available at: www.unos.org. Accessed March 13, 2006.33Ortner N. Ortner N. 2005 US Organ and Tissue Transplant Cost Estimates and Discussion2005 US Organ and Tissue Transplant Cost Estimates and Discussion, June 2005, 1-28., June 2005, 1-28.


None

10% -4.9%

50% -24.5%

75% -34.2%

All -48.9%

TreatedEffect

at 20 yr

Davis G, et al. Davis G, et al. Liver TransplLiver Transpl. 2003;9:331-338.. 2003;9:331-338.

Identification and Treatment of PatientsIdentification and Treatment of Patients

with CHC Reduces the Number of Caseswith CHC Reduces the Number of Cases

of Decompensated Cirrhosisof Decompensated Cirrhosis

Decom

pen

sate

d C

ases

(X1

00

0)

Year

0

20

40

60

80

100

120

140

160

2000 2010 2020 2030 2040 2050


Carcinogenicity of Hepatitis VirusesCarcinogenicity of Hepatitis Viruses

• HCV & HBV added in 2005 to DHHS* list of cancer-HCV & HBV added in 2005 to DHHS* list of cancer-causing agents-“Report on Carcinogens” causing agents-“Report on Carcinogens”

• Listed in “known to be human carcinogens”Listed in “known to be human carcinogens”¹ ¹ category, since human studies demonstrated chronic category, since human studies demonstrated chronic HCV and HBV infections can lead to liver cancerHCV and HBV infections can lead to liver cancer

• Some evidence suggests chronic HCV infection might increase B-cell lymphoma risk¹¹

. *DHHS=Department of Health and Human Services 1NIH News. http://ntp.niehs.nih.gov/files/11thROC_factsheet_1-31-05.pdf P-DS-D-P-DS-D-21272127

http://ntp.niehs.nih.gov/files/11thROC_factsheet_1-31-05.pdf

Epidemiology of Hepatocellular Carcinoma Epidemiology of Hepatocellular Carcinoma (HCC): US(HCC): US HCV accounts for approximately one third of HCC casesHCV accounts for approximately one third of HCC cases

in the USin the US11

Incidence of HCV-related HCC continues to riseIncidence of HCV-related HCC continues to rise11

− Increase in number of persons who have had HCV for decadesIncrease in number of persons who have had HCV for decades

− Presence of comorbid factorsPresence of comorbid factors

− Longer survival of persons with advanced liver diseaseLonger survival of persons with advanced liver disease

Risk factors for HCC are same as those for decompensated Risk factors for HCC are same as those for decompensated cirrhosiscirrhosis11

Studies suggest treatment of HCV with pegylated interferon + Studies suggest treatment of HCV with pegylated interferon + ribavirin (PEG IFN + RBV) may reduce risk of developing HCC ribavirin (PEG IFN + RBV) may reduce risk of developing HCC but further studies are neededbut further studies are needed22

11NIH. NIH. NIH Consens State Sci StatementsNIH Consens State Sci Statements. 2002;19(3):1-46.. 2002;19(3):1-46.22Fattovich G et al. Fattovich G et al. GastroenterologyGastroenterology.1997;112:463-472..1997;112:463-472. P-DS-D-155P-DS-D-155

Increase in Liver Cancer Mortality Rate Increase in Liver Cancer Mortality Rate for 1995-2004 is Among the Highestfor 1995-2004 is Among the Highest

1.2

1.1

0.6

0.3

0.2

0.1

-1.2

-1.5 -1 -0.5 0 0.5 1 1.5

All Cancers (Average)

Testis

Esophagus

Lung and Bronchus (Females)

Liver

Thyroid

*Represents the annual percent change over the time intervalNational Cancer Institute Web site.

U.S. Cancer Mortality Rates Annual Percent Change (1995-2004)*

Uterus


Incidence of HCC by RaceIncidence of HCC by Race

El-Serag HM, et al. El-Serag HM, et al. N Engl J Med.N Engl J Med. 1999;340:745-750. 1999;340:745-750.

Incid

en

ce p

er

10

0,0

00

Incid

en

ce p

er

10

0,0

00

AgeAge

Black

White

75-7

9

20-2

425

-29

30-3

435

-39

40-4

445

-49

50-5

455

-59

60-6

465

-69

70-7

4

80-8

4≥

85+

8

6

4

2

0

10

12

14

16

20

18


AASLD RecommendationsAASLD RecommendationsHCC SurveillanceHCC Surveillance

Patients at risk for HCC should be entered into Patients at risk for HCC should be entered into surveillancesurveillance

Surveillance for HCC should be with ultrasoundSurveillance for HCC should be with ultrasound

AFP alone should not be used for screening unless AFP alone should not be used for screening unless imaging is unavailableimaging is unavailable

Patients should be screened at 6 to 12 month intervalsPatients should be screened at 6 to 12 month intervals

Surveillance interval does not need to be shortened for Surveillance interval does not need to be shortened for patients at higher risk for HCCpatients at higher risk for HCC

Bruix J and Sherman M. Hepatology. 2005;42:1208-1236.P-DS-D-091P-DS-D-091

Counseling Counseling about HCV about HCV status and status and risk factorsrisk factors

Timing of Timing of HCV HCV

treatmenttreatment

Optimal dose of Optimal dose of therapiestherapies

Addiction-related Addiction-related problems and problems and socioeconomic socioeconomic

issuesissues

Liver Liver transplantationtransplantation

Addressing Addressing adverse eventsadverse events

Vaccinations for Vaccinations for HBV, HAV (if HBV, HAV (if

needed)needed)

Counseling for Counseling for transmission risk transmission risk

and alcohol and alcohol abstinenceabstinence

Avoidance Avoidance of drugs that of drugs that

increase increase hepatotoxicity riskhepatotoxicity risk

Obtain psychiatrichistory

HCV InfectionHCV InfectionPatient-related IssuesPatient-related Issues

Adapted from Soriano V, et al. AIDS. 2004;18:1-12. P-DS-D-036P-DS-D-036

Multidisciplinary ApproachMultidisciplinary Approachto HCV Treatmentto HCV Treatment

Active collaboration with specialists

Resource Identification: Financial and psychosocial

Increased adherence --> effective treatment

Patient education

and support

Effective side-effect management

Gujral H, et al. Clev Clin J Med. 2004;71(suppl 3):S33-S37. P-DS-D-035P-DS-D-035

Genotype and Viral LoadGenotype and Viral Loadin US Patientsin US Patients

Genotype 1 Genotype 1 HVL 49.5%HVL 49.5%

Other Other HVL 17.4%HVL 17.4%

Genotype 1 Genotype 1 LVL LVL

24%24%

Other Other LVL 9.1%LVL 9.1%

LVL LVL Patients Patients

33%33%22

HVL HVL Patients Patients

67%67%22

11Alter M et al. Alter M et al. N Engl J MedN Engl J Med. 1999;341:556-562.. 1999;341:556-562.22Blatt L et al. Blatt L et al. J Viral HepatitisJ Viral Hepatitis. 2000;7:196-202.. 2000;7:196-202.

Two Thirds of HCV Patients in the US Have Two Thirds of HCV Patients in the US Have HVL 49.5% of US Patients Have Genotype HVL 49.5% of US Patients Have Genotype

1, HVL1, HVL11


Epidemiology of HCVEpidemiology of HCV


92.5 91

70 67

0

20

40

60

80

100

Chronicity Prevalence

African-American Non-Hispanic White

Prevalence of HCV by RacePrevalence of HCV by Race

•HCV is 2-3 HCV is 2-3 fold more fold more common common among among African African Americans Americans than among than among NHW NHW AmericansAmericans

•African African Americans Americans have a higher have a higher rate of rate of cirrhosis, cirrhosis, HCC, and HCC, and death due to death due to HCVHCV

Howell C et al. Howell C et al. GastroenterologyGastroenterology. 2000;119(5):1385-1396.. 2000;119(5):1385-1396.

HCV HCV Genotype Genotype

11

HCV HCV InfectionInfection

(Perc

en

t)

%

%

%

%


Seroprevalence of Hepatitis C: Seroprevalence of Hepatitis C: 170 to 200 Million Worldwide170 to 200 Million Worldwide

AmericasAmericas12-15 M12-15 M

Africa Africa 30-40M30-40M AustraliaAustralia

.2 M.2 M

Western Western PacificPacific60 M60 MWestern Western

Europe Europe 5 M5 M

Eastern Eastern Europe Europe

10 M10 M

Southeast Southeast AsiaAsia

30-35 M30-35 M

1. World Health Organization. 1. World Health Organization. Wkly Epidemiol RecWkly Epidemiol Rec. 2000;75:17-28.. 2000;75:17-28.

2. Edlin B et al. AASLD; November 11-15; 2005 San Francisco, California. Oral Presentation #44. 2. Edlin B et al. AASLD; November 11-15; 2005 San Francisco, California. Oral Presentation #44.

3. Fontanet A. Annual Report of Emerging Diseases for Year 2005. Accessed 03/13/06 at3. Fontanet A. Annual Report of Emerging Diseases for Year 2005. Accessed 03/13/06 at

http://www.pasteur.fr/recherche/RAR/RAR2005/Epimal-en.html http://www.pasteur.fr/recherche/RAR/RAR2005/Epimal-en.html

United StatesUnited States5M5M

Highest Highest Prevalence: Prevalence:

Egypt-4MEgypt-4M(45% adults (45% adults

>>40y)40y)


Chronic Hepatitis C in the United States:Chronic Hepatitis C in the United States:Genotype DistributionGenotype Distribution

Genotype 1 74%

Genotype 2,3 22%

Genotype 4,5,6 4%

Alter M et al. N Engl J Med. 1999;341(8):556-562.

Blatt, L et al. J Viral Hepatitis. 2000;7:196-202.

P-DS-D-1226P-DS-D-1226

Genotypes 1,2,3

Worldwide Distribution

Prevalent Genotype in US Infections

Genotype 4

Middle East, Africa

Genotype 5

South Africa

Genotype 6

Southeast Asia

HCSP FactSheet. Version 2.0.February (2006) Accessed via www.hcvadvocate.org

HCV Infection: HCV Infection: Worldwide Genotype DistributionWorldwide Genotype Distribution


HCV HBV HIV

Infected Persons (US) Undiagnosed Persons (US)

HCV, HBV, and HIV: PrevalenceHCV, HBV, and HIV: Prevalencevs Undiagnosed Casesvs Undiagnosed Cases

** Extrapolated from small population study.Extrapolated from small population study.

1. American Liver Foundation. 1. American Liver Foundation. Hepatitis C FactsheetHepatitis C Factsheet. Available at: www.liverfoundation.org. Accessed March 14, 2005.. Available at: www.liverfoundation.org. Accessed March 14, 2005.

2. NIAID. 2. NIAID. HIV/AIDS StatisticsHIV/AIDS Statistics. Available at: www.niaid.nih.gov.. Available at: www.niaid.nih.gov.

3. Lok A et al. 3. Lok A et al. HepatologyHepatology. 2004;39:1-5.. 2004;39:1-5.

4. Thompson J et al. 4. Thompson J et al. J Cancer EducJ Cancer Educ. 2002;17(4):222-226.. 2002;17(4):222-226.

*

3.5 M

2.5 M

1.5 M

.5 M

0


HCV Screening and HCV Screening and DiagnosisDiagnosis


Transmission of HCVTransmission of HCV

Tattoos, Tattoos, body body

piercingpiercing

IVDU or IVDU or intranasal intranasal

drug usedrug use

Clotting Clotting factors before factors before

19871987

Blood Blood product/ product/

organ/tissuorgan/tissue e

transplant transplant

before 1992before 1992

High-risk High-risk sexual sexual

activityactivity

Mother- Mother- to-infantto-infant

Shared Shared personal items personal items with infected with infected individualsindividuals

Nosocomial Nosocomial or or

occupational occupational exposureexposure

Modes of Modes of TransmissiTransmissi

onon

NIH. NIH. NIH Consens State Sci StatementsNIH Consens State Sci Statements. 2002;19(3):1-46.. 2002;19(3):1-46. P-DS-D-165P-DS-D-165

2004 AASLD Practice Guidelines:2004 AASLD Practice Guidelines:Who Should Be Tested?Who Should Be Tested? Persons who have injected illicit drugs in the recent Persons who have injected illicit drugs in the recent

or remote past, or remote past, including those who have injected only including those who have injected only once and do not consider themselves drug usersonce and do not consider themselves drug users

Persons with conditions associated with high Persons with conditions associated with high prevalence of infectionprevalence of infection− Persons with HIVPersons with HIV

− Hemophiliacs who received clotting factor concentrates Hemophiliacs who received clotting factor concentrates prior to 1987prior to 1987

− Persons who ever received hemodialysisPersons who ever received hemodialysis

− Persons with unexplained ALT elevationsPersons with unexplained ALT elevations

Strader D et al. Strader D et al. HepatologyHepatology. 2004;39 (4):1147-1171.. 2004;39 (4):1147-1171. P-DS-D-167P-DS-D-167

2004 AASLD Practice Guidelines:2004 AASLD Practice Guidelines:Who Should Be Tested?Who Should Be Tested?

Prior recipients of transfusions or organ transplants including:Prior recipients of transfusions or organ transplants including:− Persons notified that they received blood from an HCV+ donorPersons notified that they received blood from an HCV+ donor

− Persons who received transfusions prior to 1992Persons who received transfusions prior to 1992

− Persons who received organ transplants prior to 1992Persons who received organ transplants prior to 1992

Children born to HCV+ mothersChildren born to HCV+ mothers− Should not be tested until at least 18 months of age due to Should not be tested until at least 18 months of age due to

viral clearance of HCVviral clearance of HCV

Health care/emergency/public healthcare personnel Health care/emergency/public healthcare personnel who have had who have had a needle-stick injury or mucosal exposure to HCV+ blooda needle-stick injury or mucosal exposure to HCV+ blood

Current sexual partners of HCV-infected personsCurrent sexual partners of HCV-infected persons− Although prevalence of infection is low, a negative test in the partner Although prevalence of infection is low, a negative test in the partner

provides reassurance, making testing of sexual partners beneficial in provides reassurance, making testing of sexual partners beneficial in clinical practiceclinical practice

Strader D et al. Strader D et al. HepatologyHepatology. 2004;39 (4):1147-1171.. 2004;39 (4):1147-1171. P-DS-D-168P-DS-D-168

Opportunity to Diagnose: Opportunity to Diagnose: The Role of the Primary Care PhysicianThe Role of the Primary Care Physician

Often has first opportunity to make the initial diagnosisOften has first opportunity to make the initial diagnosis− The PCP often has a long-term relationship with the patient, The PCP often has a long-term relationship with the patient,

and is more likely to obtain an honest assessment of riskand is more likely to obtain an honest assessment of risk

Knowledge of risk factors vitalKnowledge of risk factors vital− Especially in those with a normal ALT Especially in those with a normal ALT

Has an opportunity to refer for treatment early Has an opportunity to refer for treatment early − Prior to development of symptomsPrior to development of symptoms

Two factors that PCP can help influence areTwo factors that PCP can help influence are− Treatment at an earlier age Treatment at an earlier age − Treatment at an earlier histology stageTreatment at an earlier histology stage

All persons with CHC should be evaluated for potential candidacy All persons with CHC should be evaluated for potential candidacy for HCV therapyfor HCV therapy11

Of note: as of 2012, CDC has now recommended that all Of note: as of 2012, CDC has now recommended that all individuals born between 1945 and 1965 be screened for individuals born between 1945 and 1965 be screened for Hepatitis CHepatitis C

22Adapted from Shehab T et al. Adapted from Shehab T et al. J Viral HepatolJ Viral Hepatol. 2001;8(5):377-383.. 2001;8(5):377-383.

11NIH. NIH. NIH Consens State Sci StatementsNIH Consens State Sci Statements. 2002;19(3):1-. 2002;19(3):1-46.46.


Patient Education: Lowering Patient Education: Lowering Transmission RiskTransmission Risk

RecommendedRecommended::

− Avoid sharing Avoid sharing toothbrushes, dental toothbrushes, dental equipment, razorsequipment, razors

− Cover bleeding woundsCover bleeding wounds

− Avoid sex during menses, Avoid sex during menses, or use barrier methodor use barrier method

− Harm reductionHarm reduction

− Do not donate organs, Do not donate organs, blood, semenblood, semen

Not RecommendedNot Recommended

− Barrier method for those in Barrier method for those in monogamous sexual monogamous sexual relationshipsrelationships

− Breast feeding is not Breast feeding is not discourageddiscouraged

− No change needed in No change needed in normal work or activitiesnormal work or activities

Terrault N. Hepatology 2002; 36(suppl 1):S99-S105.

Strader D et al. Hepatology. 2004;39:1147-1171.P-DS-D-170P-DS-D-170

Barriers to ScreeningBarriers to Screening


HCV Disease Progression in Patients With HCV Disease Progression in Patients With Normal ALTNormal ALT

No fibrosis 23%

Cirrhosis 6%

Bridging 6%

Portal fibrosis

26%Mild 40%

Normal ALTNormal ALT

Despite ‘persistently Despite ‘persistently normal’ ALT levels, normal’ ALT levels, >75% have some >75% have some degree of liver damage degree of liver damage on biopsy, with 32% on biopsy, with 32% having portal and having portal and bridging fibrosisbridging fibrosis

Shiffman M et al. Shiffman M et al. J Infect Dis.J Infect Dis. 2000;182:1595-1601. 2000;182:1595-1601. P-DS-D-175P-DS-D-175

NegativeObtain HCV genotype, CBC, hepatic function Obtain HCV genotype, CBC, hepatic function

panel, basic metabolic panel, PT, PTT, panel, basic metabolic panel, PT, PTT, ferritin, iron, transferrin SAT, TSH, pregnancy ferritin, iron, transferrin SAT, TSH, pregnancy

test. Consider abnormal ultrasound. test. Consider abnormal ultrasound. Consider liver biopsy.Consider liver biopsy.

Consider therapy: PEG IFN + RBVConsider therapy: PEG IFN + RBV

Quantitative HCV RNAQuantitative HCV RNA

Medical EvaluationMedical EvaluationPositive

No No further further

evaluation evaluation

HCV Testing AlgorithmHCV Testing Algorithm11

11Adapted from Strader D et al. Adapted from Strader D et al. HepatologyHepatology. 2004;39(4)1147-1171.. 2004;39(4)1147-1171.22Adapted from Adapted from NIH. NIH. NIH Consens State Sci StatementsNIH Consens State Sci Statements. 2002;19(3):1-46.. 2002;19(3):1-46.

Negative PositiveIndeterminate

Additional Additional laboratory laboratory evaluationevaluation(PCR, ALT)(PCR, ALT)

A single A single negative assay negative assay

does not does not exclude viremia exclude viremia – follow-up HCV – follow-up HCV

RNA may be RNA may be consideredconsidered22

Anti-HCV screening assay (EIA, ELISA)Anti-HCV screening assay (EIA, ELISA)


Overall Prevalence of HCV Among Overall Prevalence of HCV Among HIV-Infected Persons in the USHIV-Infected Persons in the US

11Sulkowski M, et al. Sulkowski M, et al. Ann Intern Med.Ann Intern Med. 2003;138:197-207. 2003;138:197-207. 22Thomas D. Thomas D. Hepatology.Hepatology. 2002;36:S201-S209. 2002;36:S201-S209.

HCV/HIV Coinfected HIV Monoinfected

30%

70%


HCV TREATMENT GUIDELINESHCV TREATMENT GUIDELINES

Reproduced with Permission. John Wiley & Sons, Inc. All rights reserved.

Modified From: Ghany MG, et. al. Hepatology. 2009;49:1335-74.

Definitions for HCV Treatment Responses

HEPATITIS C: TREATMENT

Rapid Virologic Response (RVR) HCV RNA undetectable at treatment week 4

Extended Rapid Virologic Response (eRVR) HCV RNA undetectable at treatment weeks 4 and 12

Early Virologic Response (EVR) **an old definition only used for genotypes 2 & 3

≥ 2 log10 reduction in HCV RNA level compared to baseline HCV RNA level (partial EVR) or HCV RNA undetectable at treatment week 12 (complete EVR)

End-of-Treatment Response (ETR)HCV RNA undetectable at the end of 24 or 48 weeks of treatment

Sustained Virologic Response (SVR) Cure

HCV RNA undetectable 24 weeks after cessation of treatment

Nonresponder Failure to clear HCV RNA after 24 weeks of therapy

Null ResponderFailure to decrease HCV RNA by at least 2 log10 after 24 week of therapy

Partial Responder2 log10 decrease in HCV RNA but HCV RNA still detectable at week 24

Breakthrough Reappearance of HCV RNA while still on therapy

RelapseReappearance of HCV RNA after therapy isdiscontinued

Telaprevir (Incivek)• Dosage is 750 mg (two 375 mg tablets) by mouth every eight hours for twelve

weeks

• Must be taken with 20 grams of fat

• Examples of food with 20 grams of fat include 1 cup whole fat yogurt with olive oil,1/2 cup nuts,1 avocado, 2 cups whole milk, or 3 tablespoon peanut butter

• Compliance is most important with this medication as skipping doses can lead to mutations of the virus

• This medication should be stopped immediately if patient’s start having skin peeling as there is a risk of Steven-Johnsons syndrome which has been seen in patients in Japan

• Contraindicated meds: Sustiva (Efavirenz), -statin's, St. John’s Wort

• Note: Viagra/Cialis require dose reduction

**Anemia is severely increased when Ribavirin + Incivek given together. Note: Reduce Ribavirin to 600mg & give Procrit

*In clinical trials, HCV-RNA in plasma was measured using a COBAS® TaqMan® assay with a lower limit of quantification of 25 IU/mL and a limit of detection of 10 IU/mL.

Source: Telaprevir (Incivek) Prescribing Information. Vertex Pharmaceuticals.

Telaprevir (Incivek)Response Guided Therapy


Telaprevir Response-Guided TherapyTreatment Naïve and Prior Relapse Patients


Telaprevir: Response Guided Therapy (RGT) for Treatment Naïve and Prior Relapse Patients

Undetectable

Telaprevir-12 wksTelaprevir-12 wks

Peginterferon + Ribavirin-24 wksPeginterferon + Ribavirin-24 wks

Telaprevir-12 wksTelaprevir-12 wks


RGTRGT

TPV w/ P/R: Adverse ReactionsClinical Adverse Reactions Reported with at Least 5% Higher Frequency Among Subjects Receiving Telaprevir

Telaprevir [package insert]. Table 4. Vertex Pharmaceuticals.

Event, %

Telaprevir, peginterferon alfa, and RBV combination treatment

n=1797 peginterferon alfa and RBV

n=493

Rash* 56 34

Fatigue 56 50

Pruritus 47 28

Nausea 39 28

Anemia* 36 17

Diarrhea 26 17

Vomiting 13 8

Hemorrhoids 12 3

Anorectal discomfort 11 3

Dysgeusia 10 3

Anal pruritus 6 1

*Rash and anemia based on SSC (Special Search Category) grouped terms.

© 2013 Genentech, Inc. All rights reserved


Response to Treatment•If a patient has a viral load of 0 at 4 weeks, and they are treatment naïve, their treatment time can be cut from 48 weeks to 24 weeks

•If a patient has a viral load >1,000 at anytime between 12 weeks and the end of treatment, patient is considered a non-responder and treatment should be stopped at that time

•If a patient has a viral load of zero at 48 weeks, are they cured of hepatitis C?

TPV w/ P/R: Treatment-Naïve Adults

ILLUMINATE: Results

Telaprevir [package insert]. Vertex Pharmaceuticals.

352*540

162 160N= 540


TPV w/ P/R: Previously Treated Adults

REALIZE: SVR Rate by Prior Response

Telaprevir [package insert]. Data from Table 11. Vertex Pharmaceuticals.

246286

1568

5797

47147

427

2/37

* Lead-in and immediate start T12/PR regimens pooled.



SVR at Posttreatment Week 24 (SVR24)

TVR Plus P/R in HIVHCV Co-infected Patients

a Prior to Week 24 visit, 1 patient in this cohort was lost to follow-up. SVR24 was imputed based on SVR12 for this patient. HCV RNA assessed by Roche COBAS® TaqMan® HCV test v2.0, LLOQ of 25 IU/mL.

57

1116

1215

2838

26

48

48

1022

nN

a a


Boceprevir Boceprevir VictrelisVictrelis

Used for treatment of HCV genotype 1Used for treatment of HCV genotype 1

Dosing info: 800mg PO TID (four 200mg Dosing info: 800mg PO TID (four 200mg capsules) with a light mealcapsules) with a light meal

Restrictions:Restrictions:− Contraindicated medications: Alfuzosin HCL, Contraindicated medications: Alfuzosin HCL,

Atorvastatin, Ergo Containing meds eg Methyler Atorvastatin, Ergo Containing meds eg Methyler Gonovine, Lovastatin, Primodide, Rifampin, Gonovine, Lovastatin, Primodide, Rifampin, Sildenafil & Tadalafil (for pulm HTN), Sildenafil & Tadalafil (for pulm HTN), Simanvastatin, St. John’s Wort or products Simanvastatin, St. John’s Wort or products containing St. John’s Wortcontaining St. John’s Wort

Source: Boceprevir (Victrelis) Prescribing Information. Merck & Co.

Boceprevir (Victrelis)Response Guided Therapy


Early ResponderEarly Responder

Late ResponderLate Responder

Early ResponderEarly Responder

Late ResponderLate Responder

Boceprevir Response-Guided TherapyPreviously Untreated Patients


Boceprevir: Response Guided Therapy (RGT) for Previously Untreated Patients

Undetectable

Boceprevir-24 wksBoceprevir-24 wks


Boceprevir-32 wksBoceprevir-32 wks


Early Responder

Early Responder

Late Responder

Late Responder

Peginterferon alfa-2a (Pegasys)• A large molecule medication so dosage is independent of patient’s

weight

• Dosage is 180 mcg (1 mL vial, 0.5 mL prefilled syringe, or 0.5 mL disposable autoinjector)

• Given subcutaneously once weekly for 48 weeks

• Dose can be reduced to 135 mcg if patient experiences thrombocytopenia

Peg-Intron α-2B• A small molecule medication, dosing is dependent on patient’s weight

• Dosage is 0.15mcg/kg/week

• Redipen available in single use vial 50mcg, 80, 120, or 150 mcg per 0.5mL

RibavirinRibavirin

• Weight adjusted dose- 13-15 mg/kg/day divided Weight adjusted dose- 13-15 mg/kg/day divided into two dosesinto two doses

• Taken by mouth twice a day for 48 weeksTaken by mouth twice a day for 48 weeks

• Dose can be reduced if patient develops anemiaDose can be reduced if patient develops anemia

• If patient’s hemoglobin drops below 10 g/dL, If patient’s hemoglobin drops below 10 g/dL, patient should be started on Procrit at a dose of patient should be started on Procrit at a dose of 40,000U/wk until hemoglobin goes above 12 40,000U/wk until hemoglobin goes above 12 g/dLg/dL

Side Effect Treatment

Rash TOPICAL Steroids, derm consult, mild soap, avoid sun

Fatigue Take med @ bedtime, low impact exercise, inc fluid

Anorectal Discom. (capsaicin) Hydrocortisone preparation

GI Upset Take w/food, ginger, oral hygine, anti-emetic

Flu-like Sx Aspirin (for arthralgia)

Hair loss Avoid frequent brushing or combing

Headache Aspirin + hydration

Insomnia Avoid caffeine

Dehydration 8-10 glasses/day (wt. (lbs) / 2 = # of oz to consume)

Vision changes Baseline eye exam, ophthalmology consult

Depression & Anxiety Group therapy, consider med therapy, psych consult, SSRI, Klonopin

Teratogenicity ♂ & ♀ Use 2 forms of birth control

Weight loss/ Dec appetite (~20lbs wt loss After Incivek with Interferon)

Periactin, megace, nutritional supplements

Non-hematologic Side Effects


• Anemia (HGB <10 g/dL) Transfusion (if necessary), Dose reduction Ribivarin, Procrit 40,000 units/wk

• Thrombocytopenia (Plt <50,000)

Dose reduction IFN

• Neutropenia (ANC <750) Dose reduction IFN, Neupogen if ANC <500 (480 mcg/wk)

Hematological Side Effects


• Thyroid Alterations *Autoimmune thyroiditis is the only nonreversible SE of Hep C treatment

Life long hormone replacement

Endocrine Side Effects

PREGNANCY!!PREGNANCY!!

Ribavirin is teratogenic to both female and Ribavirin is teratogenic to both female and male spermmale sperm

Any pregnancy that occurs while being treated Any pregnancy that occurs while being treated with Ribavirin will result in medical terminationwith Ribavirin will result in medical termination

Pregnancy is contraindicated while either male Pregnancy is contraindicated while either male and female are treated and 6 months post and female are treated and 6 months post treatmenttreatment

Strange labsStrange labs

Why is ANA done?Why is ANA done?− + ANA may be associated with Auto-immune + ANA may be associated with Auto-immune

hepatitis, interferons can make autoimmune hepatitis, interferons can make autoimmune hepatitis worse even in patients with hepatitis C. hepatitis worse even in patients with hepatitis C. These individuals deserve to have an evaluation These individuals deserve to have an evaluation with hepatologistswith hepatologists

Why is TSH a part of screening?Why is TSH a part of screening?− There is only 1 non reversible side effect from There is only 1 non reversible side effect from

Hepatitis C treatment Hepatitis C treatment

− Autoimmune thyroiditis, initial: low TSH, later: Autoimmune thyroiditis, initial: low TSH, later: inc TSH with need for thyroid hormone inc TSH with need for thyroid hormone replacementreplacement

Special PopulationsSpecial PopulationsIndividuals with HIV nationwide have a 25% co-Individuals with HIV nationwide have a 25% co-

infection with hep Cinfection with hep C

Hep C is now the #1 cause of death in HIV Hep C is now the #1 cause of death in HIV patients patients

Some programs in Inner cities have co-Some programs in Inner cities have co-infection up to 90%infection up to 90%

Alcohol is now contraindicated for at least 6 Alcohol is now contraindicated for at least 6 months as studies show a 20% less response months as studies show a 20% less response to Txto Tx

I require patients show me a 6 month period of I require patients show me a 6 month period of abstinence from alcohol abstinence from alcohol

2009 AASLD Guidelines: Treatment of 2009 AASLD Guidelines: Treatment of Genotypes 2 and 3 HCV InfectionGenotypes 2 and 3 HCV Infection

Optimal therapy for CHC infection (Class I, Level A):Optimal therapy for CHC infection (Class I, Level A):− PEG-IFN alfa + RBV 800 mg/day PEG-IFN alfa + RBV 800 mg/day

Treatment duration: 24 weeks (Class I, Level A)Treatment duration: 24 weeks (Class I, Level A)

Retest for HCV RNA 24 weeks post end of treatment to evaluate Retest for HCV RNA 24 weeks post end of treatment to evaluate for SVR (Cure) (Class I, Level A) or Curefor SVR (Cure) (Class I, Level A) or Cure

No change in guidelines since 2009No change in guidelines since 2009

Ghany MG, et al. Hepatology. 2009;49:1335-1374.P-DS-D-2458P-DS-D-2458

2009 AASLD Guidelines: 2009 AASLD Guidelines: Treatment of Treatment of Genotypes 4 HCV InfectionGenotypes 4 HCV Infection

Optimal therapy for CHC infection (Class I, Level A):Optimal therapy for CHC infection (Class I, Level A):− PEG-IFN alfa + RBVPEG-IFN alfa + RBV

Treatment duration: 48 weeks (Class I, Level A)Treatment duration: 48 weeks (Class I, Level A)− PEGASYS sc dose: 180 PEGASYS sc dose: 180 µµg/wk + weight-based RBV:g/wk + weight-based RBV:

• ≤ ≤ 75kg: 1000mg/day75kg: 1000mg/day• >75kg: 1200mg/day>75kg: 1200mg/day

− PEG-IFN alfa-2b sc dose: 1.5µg/kg/wk + weight-based RBV: PEG-IFN alfa-2b sc dose: 1.5µg/kg/wk + weight-based RBV: − RBV dosing:RBV dosing:

• <65kg: 800mg/day<65kg: 800mg/day• >65-85kg: 1000mg/day>65-85kg: 1000mg/day• >85-105kg: 1200mg/day>85-105kg: 1200mg/day• >105kg: 1400mg/day >105kg: 1400mg/day

Retest for HCV RNA 24 weeks post end of treatment to evaluate for SVR (Cure) Retest for HCV RNA 24 weeks post end of treatment to evaluate for SVR (Cure) (Class I, Level A)(Class I, Level A)

No change in guidelines since 2009No change in guidelines since 2009Ghany MG, et al. Hepatology. 2009;49:1335-1374.

P-DS-D-2456P-DS-D-2456

2011 AASLD Guidelines: Treatment of Genotype 1 HCV Infection

Optimum therapy for chronic HCV: Boceprevir or Telaprevirn + PegINF-alpha + Ribavarin(Class 1, Level A )

Treatment naïve Patients:1) Boceprevir (800 mg) with food TID (Q 7-9 H) + peginterferon alfa + weight-based ribavirin for 24-44 weeks preceded by 4 weeks of lead-in treatment with peginterferon alfa and ribavirin alone (Class 1, Level A).

2) Without cirrhosis treated with boceprevir, peginterferon, and ribavirin, preceded by 4 weeks of lead-in peginterferon and ribavirin, with undetactable HCV RNA level at weeks 8 and 24,may be considered for a shortened treatment duration of 28 weeks in total (4 weeks lead-in with peginterferon and ribavirin followed by 24 weeks oftriple therapy) (Class 2a, Level B).

3) Treatment with all three drugs (boceprevir,peginterferon alfa, and ribavirin) should be stopped if the HCV RNA level is >100 IU/mL at treatment week 12 or detectable at treatment week 24 (Class2a, Level B).

2011 AASLD Guidelines: Treatment of Genotype 1 HCV Infection Contd...

4) Telaprevir (750 mg) with food TID (Q7-9 H) + peginterferon alfa + weight -based ribavirin for 12 weeks followed by an additional 12-36 weeks of peginterferon alfa and ribavirin (Class 1, Level A) .

For treatment-experienced patients:

5) Re-treatment with boceprevir or telaprevir, togetherwith peginterferon alfa and weight-based ribavirin,can be recommended for patients who had virological relapse or were partial responders after a prior course of treatment with standard interferon alfa or peginterferon alfa and/or ribavirin (Class Level A).

6) Re-treatment with telaprevir, together with peginterferon alfa and weight-based ribavirin, may be considered for prior null responders to a course of standard interferon alfa or peginterferon alfa and/or weight-based ribavirin (Class 2b, Level B.)

7) Response-guided therapy of treatment-experienced patients using either a boceprevir- or telaprevir-based regimen can be considered for relapsers(Class 2a, Level B for boceprevir; Class 2b, Level C for telaprevir), may be considered for partial responders (Class 2b, Level B for boceprevir; Class 3,Level C for telaprevir), but cannot be recommended for null responders (Class 3, Level C).

Documents

Natural History of HCV P-DS-D-150. HCV Characteristics Family Flaviviridae 1 Family Flaviviridae 1 Enveloped 2 Enveloped 2 Positive-sense single-stranded