John Scott, MD, MScJohn Scott, MD, MSc

Infectious Diseases Fellows CourseInfectious Diseases Fellows Course

July 7, 2011July 7, 2011

Outline Outline

Hepatitis BHepatitis B– biologybiology– epidemiologyepidemiology– natural historynatural history– treatmenttreatment– HIV coinfectionHIV coinfection

Hepatitis CHepatitis C– biologybiology– epidemiologyepidemiology– natural historynatural history– treatmenttreatment– HIV coinfectionHIV coinfection

Alphabet soup of viral hepatitisAlphabet soup of viral hepatitis

Hepatitis A: contaminated food and water, ~1% fatality with Hepatitis A: contaminated food and water, ~1% fatality with acute form, no chronic infection, vaccine availableacute form, no chronic infection, vaccine available

Hepatitis B: Blood borne and sexual transmission, most Hepatitis B: Blood borne and sexual transmission, most common world wide, can become chronic, vaccine and common world wide, can become chronic, vaccine and treatment availabletreatment available

Hepatitis C: primarily blood borne, chronic in 60-85%, Hepatitis C: primarily blood borne, chronic in 60-85%, treatment availabletreatment available

Hepatitis D: rare, only seen w/ Hep B, severe disease w/ Hepatitis D: rare, only seen w/ Hep B, severe disease w/ cirrhosis in 70% casescirrhosis in 70% cases

Hepatitis E: contaminated food and water, acute only, rare Hepatitis E: contaminated food and water, acute only, rare in US, severe in pregnant women (~10% fatality)in US, severe in pregnant women (~10% fatality)

Hep B BiologyHep B Biology partially ds DNA partially ds DNA

virus, 3200 bpvirus, 3200 bp HepadnavirusHepadnavirus 42 nm42 nm 8 genotypes (A-H)8 genotypes (A-H) Covalently closed Covalently closed

circular (ccc) DNAcircular (ccc) DNA

Geographic DistributionGeographic Distributionof Chronic HBV Infectionof Chronic HBV Infection

HBsAg PrevalenceHigh (>8%)

Intermediate (2%-8%)

Low (<2%)

Mast EE, et al. MMWR Recomm Rep. 2006;55(16):1-33.Custer B, et al. J Clin Gastroenterol. 2004;38(10 suppl):S158-S168.

Natural history of chronic hep B in Natural history of chronic hep B in AsiaAsia

25-40% of 25-40% of malemale carriers will die from sequelae (either carriers will die from sequelae (either cirrhosis or HCC)cirrhosis or HCC)

~15% of female carriers~15% of female carriers Additional risk factors for adverse outcome include:Additional risk factors for adverse outcome include:

– Male sexMale sex– Older ageOlder age– SmokingSmoking– AlcoholAlcohol– Cirrhosis (as a risk factor for HCC)Cirrhosis (as a risk factor for HCC)

Liver cancer is the most common cause of cancer Liver cancer is the most common cause of cancer death among men in Asiadeath among men in Asia

REVEAL: Relationship BetweenREVEAL: Relationship BetweenHBV DNA Level and All-Cause MortalityHBV DNA Level and All-Cause Mortality

Iloeje UH, et al. Gastroenterology. 2006;130:678-686.

Viral load presented as copies/mL.

0.8

0.85

Baseline HBV DNA(copies/mL)

<300300-9,99910,000-99,999100,000-999,999>1 million

0 1 2 3 4 5 6 7Year of follow-up

P<0.001

8 9 10 11 12 13 14

0.9

0.95

1.0

Su

rviv

al

4 Phases of Chronic HBV 4 Phases of Chronic HBV InfectionInfection

Immune tolerant phase*Immune tolerant phase*– HBeAg positiveHBeAg positive– HBV DNA 10HBV DNA 105-105-10

– ALT normalALT normal

Non-replicative phase Non-replicative phase (inactive HBsAg carrier)(inactive HBsAg carrier)– HBeAg negativeHBeAg negative– HBV DNA <10HBV DNA <1044

– ALT normalALT normal– HBsAg may later become HBsAg may later become

undetectableundetectable

Immune active Immune active HBeAg positive chronic HBeAg positive chronic HBVHBV– HBV DNA 10HBV DNA 105-105-10

– ALT levels high or fluctuatingALT levels high or fluctuating– Active inflammation on liver Active inflammation on liver

biopsybiopsy

HBeAg negative HBeAg negative – HBeAg negative chronic HBVHBeAg negative chronic HBV– HBV DNA 10HBV DNA 104-84-8 – ALT levels high or fluctuatingALT levels high or fluctuating– Active inflammation on liver Active inflammation on liver

biopsybiopsy

Candidates for TherapyNot Candidates for Therapy

Yim HJ, et al. Hepatology. 2006;43:S173-S181.

*Not seen in adult-onset infection.

Treatment of chronic hepatitis BTreatment of chronic hepatitis B

<1999 1999 2001 2002 2005 2008

interferonlamivudinetenofovir(HIV)

adefovir•Peginterferon•entecavir

•tenofovir•telbivudine

Treatment endpointsTreatment endpoints

Loss of HBeAg Loss of HBeAg Development of HBeAb (seroconversion)Development of HBeAb (seroconversion) Loss of sAgLoss of sAg HBV DNA suppressionHBV DNA suppression Improve liver histologyImprove liver histology Reduce rates of progression to cirrhosis or Reduce rates of progression to cirrhosis or

hepatocellular carcinomahepatocellular carcinoma

HBeAg Positive

Treat

Monitor

Chronic HBV Treatment:Chronic HBV Treatment:Simplified Flow ChartSimplified Flow Chart

Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962.

HBeAg Negative

HBV DNA >20,000 IU/mL HBV DNA >2,000 IU/mL

Normal ALT

Liver Biopsy

Abnormal Histology

Elevated ALT

ALT Evaluation

Chronic HBV Treatment: Simplified Chronic HBV Treatment: Simplified Flow Chart for Patients With CirrhosisFlow Chart for Patients With Cirrhosis

Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962.

Compensated Decompensated

HBV DNA <2,000 IU/mL

Detectable HBV DNA

Observe or Treat

Wait List for Transplant

HBV DNA >2,000 IU/mL

Treat

Undetectable

HBV DNA

Treat Observe

Q: All of the following are candidates Q: All of the following are candidates for HBV therapy except:for HBV therapy except:

35 yo Asian eAg+, HBV DNA 10 million 35 yo Asian eAg+, HBV DNA 10 million IU/ml and ALT over 60 (x 6 mos)IU/ml and ALT over 60 (x 6 mos)

45 yo Somali man eAg-, HBV DNA 17k, ALT 45 yo Somali man eAg-, HBV DNA 17k, ALT 35, cirrhosis on ultrasound35, cirrhosis on ultrasound

29 yo Asian woman eAg+, HBV DNA 20 29 yo Asian woman eAg+, HBV DNA 20 million, ALT 22million, ALT 22

65 yo Asian woman eAg-, HBV DNA 700k, 65 yo Asian woman eAg-, HBV DNA 700k, ALT 100ALT 100

HBV Combination TherapyHBV Combination Therapy

Consider de novo combination therapy in:Consider de novo combination therapy in:– Decompensated HBV cirrhosisDecompensated HBV cirrhosis– Patients with prior resistance to HBV Patients with prior resistance to HBV

medicationsmedications– Patients with prior exposure to HBV Patients with prior exposure to HBV

medications (i.e HIV+ pts)medications (i.e HIV+ pts)– Post-transplant patientsPost-transplant patients– Patients requiring long-term therapyPatients requiring long-term therapy

Updated from Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962.

HBV Treatment Options inHBV Treatment Options inHIV/HBV-Coinfected PatientsHIV/HBV-Coinfected Patients

PreferredPreferredOther Other

OptionsOptions CommentsComments

HIV and HBV HIV and HBV need treatmentneed treatment

HBVHBVtreatment- treatment- naïvenaïve

Tenofovir/emtricitabineTenofovir/emtricitabineTenofovir + lamivudineTenofovir + lamivudine

Entecavir + Entecavir + HAARTHAART

Avoid single-agent HBV therapy Avoid single-agent HBV therapy with lamivudine, emtricitabine, orwith lamivudine, emtricitabine, ortenofovir due to the increasedtenofovir due to the increased risk of HBV resistancerisk of HBV resistance

LamivudineLamivudineresistantresistant

Tenofovir/emtricitabineTenofovir/emtricitabineTenofovir + entecavirTenofovir + entecavir

Emtricitabine not active againstEmtricitabine not active against lamivudine-resistant HBVlamivudine-resistant HBV

HBV only needs HBV only needs treatmenttreatment

Peginterferon 2aPeginterferon 2aAdefovirAdefovir

Adefovir + Adefovir + telbivudinetelbivudine

(monitor HBV (monitor HBV DNA at week DNA at week

24)24)

Initiate HAARTInitiate HAARTMonitor HBV DNAMonitor HBV DNAMonitor liver functionMonitor liver function

Lok AS, et al. Hepatology. 2007;45:507-539.European AIDS Clinical Society Guidelines. Available at: http://www.eacs.eu.

HIV/HBV CoinfectionHIV/HBV Coinfection

Liver-related disease is a major cause of Liver-related disease is a major cause of death among HIV-infected individualsdeath among HIV-infected individuals11

Up to 10% of HIV+ patients may be HBV Up to 10% of HIV+ patients may be HBV carrierscarriers

1Smith, et al. J Urban Health. 2003 Dec;80(4):676-88.

Hep B case 2:Hep B case 2:

43 year old Somali man sent to you because 43 year old Somali man sent to you because he is sAg+he is sAg+

What labs do you order next?What labs do you order next?

Hep B case 2:Hep B case 2:

eAg-, eAb+eAg-, eAb+ ALT 63 (slightly above normal)ALT 63 (slightly above normal)

Hep B: Case 2Hep B: Case 2

HBV DNA = 240 copies/mlHBV DNA = 240 copies/ml Your diagnosis?Your diagnosis?

Inactive hepatitis B carrier

Hep B: Case 2Hep B: Case 2

HBV DNA = 1.6 million copies/mlHBV DNA = 1.6 million copies/ml Your diagnosis?Your diagnosis?

Chronic hepatitis B, precore mutant

What would be the best choice for What would be the best choice for treatment?treatment?

Tenofovir 300 mg dailyor

Entecavir 0.5 mg daily

Because of need for prolonged treatment (no endpoint) and low rate of resistance

Outline Outline

Hepatitis BHepatitis B– biologybiology– epidemiologyepidemiology– natural historynatural history– treatmenttreatment– HIV coinfectionHIV coinfection

Hepatitis CHepatitis C– biologybiology– epidemiologyepidemiology– natural historynatural history– treatmenttreatment– HIV coinfectionHIV coinfection

BiologyBiology

ss RNA virusss RNA virus RNA-dependent RNA RNA-dependent RNA

polymerase, lacks polymerase, lacks proofreading functionproofreading function

FlaviviridaeFlaviviridae 6 genotypes, type 1 6 genotypes, type 1

accounts for 70% of accounts for 70% of infections in US, types 2,3 infections in US, types 2,3 account for restaccount for rest

No easy culture system!No easy culture system!

www.hepcprimer.com/3dmodel.html

HCV problem persists because…HCV problem persists because…

Source: 2010 Institute of Medicine Report on Viral Hepatitis

Occupational ExposuresOccupational Exposures

Blood borne exposures (i.e needlestick)Blood borne exposures (i.e needlestick) Greatest risk comes from hollow bore Greatest risk comes from hollow bore

needle w/ deep puncture from patient w/ needle w/ deep puncture from patient w/ high viral loadhigh viral load

Rule of 3’sRule of 3’s HIV 1/300HIV 1/300 HCV 1/30HCV 1/30 HBV 1/3HBV 1/3

Summary of HCV TestsSummary of HCV TestsDiagnosisDiagnosis TreatmentTreatment

TestTest ScreenScreen ConfirmationConfirmation ResponseResponse Predicting Predicting responseresponse

EIAEIA XX

RIBARIBA X (?)X (?)

RNA qualRNA qual ?? XX XX

RNA RNA quantquant

X (if real time X (if real time PCR)PCR)

XX XX

GenotypeGenotype XX

Who to test?Who to test?

Persons who ever have injected illicit drugsPersons who ever have injected illicit drugs Persons with high prevalence of HCVPersons with high prevalence of HCV

– HIV+HIV+– Hemophiliacs who received clotting factor Hemophiliacs who received clotting factor

concentrates before 1987concentrates before 1987– Persons who were ever on hemodialysisPersons who were ever on hemodialysis– Persons with unexplained abnormal Persons with unexplained abnormal

aminotransferase levelsaminotransferase levels Children born to HCV-infected mothersChildren born to HCV-infected mothers

CDC guidelines. MMWR 1998;47(RR-19):1-39

Liver BiopsyLiver Biopsy

Currently the best way to determine how Currently the best way to determine how much scarring is presentmuch scarring is present

Needle, local anestheticNeedle, local anesthetic Risks: bleedingRisks: bleeding Scar Stages: 0-1-2-3-4 (Batts-Ludwig)Scar Stages: 0-1-2-3-4 (Batts-Ludwig)

Progression of Fibrosis on BiopsyProgression of Fibrosis on Biopsy

No FibrosisNo Fibrosis

Stage 1: Fibrous Stage 1: Fibrous expansion of expansion of some portal areassome portal areas

Stage 3: Stage 3: Fibrous Fibrous expansion of expansion of most portal most portal areas areas with occasional with occasional portal to portal portal to portal bridgingbridging

Stage 4: Fibrous Stage 4: Fibrous expansion of expansion of portal areas with portal areas with marked bridging marked bridging (portal to portal (portal to portal and portal to and portal to central)central)

Stage 4: CirrhosisStage 4: Cirrhosis

Cirrhotic liver: Cirrhotic liver: Gross anatomy Gross anatomy of cadaverof cadaver

Courtesy of Gregory Everson, MD.Courtesy of Gregory Everson, MD.

0102030405060708090100

0 2 4 6 8 10 12 14 16 18 20

Years

% p

rogr

essi

on t

o ci

rrh

osis

Stage 3Stage 2Stage 1

Likelihood of progression to cirrhosis based on stage of fibrosis

Liver Disease has Emerged as a Major Liver Disease has Emerged as a Major Cause of Death in the HAART EraCause of Death in the HAART Era

Bica Clin Infect Dis 2001; Puoti JAIDS 2000; Soriano Eur J Epidemiol 1999; Soriano PRN Notebook 2002; Martin-Carbonero AIDS Res Human Retrovirus 2001

0

10

20

30

40

50

60

Mo

rtal

ity

(%)

Death from end-stage liver disease (ESLD) as a% of all deaths among HIV patients

Italy (Brescia) Spain (Madrid) USA (Boston)

13%

35%

5%

12%

45%

50%Pre-HAART era

HAART era

Evolution of treatment for Evolution of treatment for hepatitis Chepatitis C

Side Effects of PegIFN/RibavirinSide Effects of PegIFN/Ribavirin

• Depression ranging from mild to suicidality• Irritability, aggressive behavior• Worsening of mania• Fatigue• Insomnia• Myalgias, fever, flu-like symptoms• Hair loss• Cytopenias“Interferon Man”

Protease InhibitorsProtease Inhibitors

Approved May 2011Approved May 2011 Boceprevir (Victrellis) and Telaprevir (Incivek)Boceprevir (Victrellis) and Telaprevir (Incivek) PotentPotent Rapid antiviral resistance if used by itselfRapid antiviral resistance if used by itself

– Will still need peginterferon and ribavirinWill still need peginterferon and ribavirin

More side effectsMore side effects– Anemia, GI, rashAnemia, GI, rash

Drug interactions! Cyp 3a/4Drug interactions! Cyp 3a/4

-Boceprevir: SPRINT-2 -Telaprevir: ADVANCE

Key Phase III Clinical Trial Data for Protease InhibitorsTreatment-Naïve HCV G1 Patients

All of the following are TRUE about All of the following are TRUE about protease inhibitors EXCEPT:protease inhibitors EXCEPT:

Telaprevir may be administered in combination with Telaprevir may be administered in combination with boceprevir in order to prevent antiviral resistanceboceprevir in order to prevent antiviral resistance

Protease inhibitors must be used together with Protease inhibitors must be used together with PegIFN/RBVPegIFN/RBV

The addition of a protease inhibitor to PegIFN/RBV The addition of a protease inhibitor to PegIFN/RBV increases the chance of SVR for GT 1 patientsincreases the chance of SVR for GT 1 patients

Telaprevir and boceprevir increase the rate of rapid Telaprevir and boceprevir increase the rate of rapid virologic response when used with PegIFN/RBVvirologic response when used with PegIFN/RBV

IFN sparing regimens?IFN sparing regimens?

Roche: protease + polymerase inhibitor Roche: protease + polymerase inhibitor (phase II)(phase II)

Merck/Schering: protease + polymerase Merck/Schering: protease + polymerase inhibitors (phase II)inhibitors (phase II)

BMS: NS5a + protease + polymerase BMS: NS5a + protease + polymerase inhibitor (phase II)inhibitor (phase II)

Kinder, gentler IFN?Kinder, gentler IFN?

Peginterferon lambdaPeginterferon lambda ZymogeneticsZymogenetics More restricted host range of receptorsMore restricted host range of receptors Phase 1: equivalent antiviral potency but Phase 1: equivalent antiviral potency but

minimal neuropsychiatric side effectsminimal neuropsychiatric side effects

2002-11

Peginterferon

+

Ribavirin

~50% cure rate

Peginterferon

+

Ribavirin

+

Protease Inhibitor

~70% cure rate

Now

PI

+

Poly Inh

+

IFN?

>80% cure rate?

2014?

Web ResourcesWeb Resources www.aasld.org www.hivandhepatitis.org www.hepwebstudy.org www.cdc.gov/ncidod/disea

ses/hepatitis/c/index.htmindex.htm

jdscott@u.washington.edu