Embed Size (px)
Citation preview
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
