curing hepatitis c: individualized approach and new therapies
TRANSCRIPT
Curing Hepatitis C:
Individualized Approach and
New Therapies
Lorenzo Rossaro, MD
Gastroenterology and Hepatology
University of California Davis Medical Center
R ep r in ted fro m C o h en J. Sc ien ce . 1999 ;285:26 .
H CV Infection:H C V Infection:W orldw ide P revalenceW orldw ide Prevalence
c/o ↑ Liver Cancer (HCC)
HCV History: Outcome FactorsHCV History: Outcome FactorsA c u t e H e p a t i t i s
D e a t h
D e c o m p e n s a t i o n ( 6 % )
D e a t h
H e p a t o m a ( 4 % )
C i r r h o s i s ( 2 - 3 0 % , 2 0 y r s )
C h r o n i c H e p a t i t i s ( 8 5 % ) Male, Age,
3.6%
POSITIVE
ETOH HBV
HIV
Interferon + RibavirinTransplant
NEGATIVE
HCV Screening: HCV Screening: Who is at risk (%)Who is at risk (%) Blood product for clotting problems
produced < 1987 (i.e.hemophilia) ~90 Injected illegal drugs (IVDU) 80
Long-term kidney dialysis 10Blood transfusion or solid organ
transplant < July, 1992 6Born from HCV+ mother 5Tattoos, cocaine, body piercing ?
HCV: diagnosis and stagingHCV: diagnosis and stagingProposed Algorithm
1 Screening: (ALT) and HCV Antibody2 Confirmation: HCV-RNA (not RIBA)3 Predict success: HCV-Genotype 4 Refer to Liver Clinic and/or Request
Liver Biopsy (if appropriate)
Hepatitis C Genotype in U.S.:Hepatitis C Genotype in U.S.: Predict Response to TreatmentPredict Response to Treatment
36%
34%8%
9%8% 5%
1a 1b 2a 2b 3 4 BEST RESPONSE
Type 2
INTERMEDIATE RESPONSE
Type 3 and 4
LOWEST RESPONSE
Type 1
HCV: Severity of Liver DiseaseHCV: Severity of Liver DiseaseSymptoms and Liver “Function”
Tests: usually in late stagesALT levels: often normalUltrasound Examination: not sensitive
for fibrosis/staging Liver Biopsy: gold standardConsider fibrosis markers or
elastography
FibrospectFibrospectLow values (<20) indicative of
mild diseaseHigh values (>80) indicative of
advanced diseaseBetween 20 and 80: can be
anything
Assessing the Severity of Liver Assessing the Severity of Liver DiseaseDisease
LIVER BIOPSY The most accurate method of
determining disease severity and activity Disease severity = Fibrosis (stage: 1-4) Indicator of prognosis Helpful in guiding treatment options
Liver Biopsy by Stage
Cirrhosis
Mild Fibrosis
Treatment Response by Genotype and Duration of Therapy
0
20
40
60
80
100
IFN IFN+RBV PEG+RBV
HCV-1,4 = 48-72 wksHCV-2,3 = 24-48 wks
1987-1997
2002-2011
1998-2001
Hepatitis CHepatitis CThe Goals of TreatmentThe Goals of Treatment
Virus eradication = negative HCV-RNA six months after the end of treatment = CURE
Decrease progression of disease:1. from hepatitis to cirrhosis (or reverse ?)2. risk of cancer (Hepato Cellular
Carcinoma)3. need for liver transplant or retransplant
HCV: Who should be treated ?HCV: Who should be treated ?
Whoever is affected in some way by the chronic disease
AND fully understands the risks and
benefits of therapy
Side effects of InterferonsSide effects of InterferonsFLU-like symptoms (®Tylenol)Behavioral changes:
–Depression, Irritability
Myelosuppression:–Neutropenia–Thrombocytopenia
Skin, GI, Thyroid, Hair loss
Ribavirin:Ribavirin:Risk of TreatmentRisk of Treatment
Hemolytic anemia–Reversible–May require dose reduction or
erythropoietin in selected patientsPregnancy Risks
–Contrtraception required
SustainedResponder
Null Responder
RelapserRelapser
Partial Responder
HCV RNAnegative
Time (weeks)
HCV RNA
12 (EVR)
24 48 (EOT)
72 (SVR)
Patient Profiles During HCV Therapy
Adapted from:Davis GL, et al. Hepatology. 2003;38:645-652.Fried MW, et al. N Engl J Med. 2002;347:975-982. Sanchez-Tapias JM. Gastroenterology 2006;131:451-460
4(RVR)
RVR = HCV RNA (-) at week 4EVR = ? 2log10 drop in HCV RNA or HCV RNA (-) at week 12EOT = HCV RNA (-) at week 48 (genotype 1)SVR = HCV RNA (-) 24 weeks post treatment cessation
C
P
C = Complete EVR; P = Partial EVR
SVR with 48 wks PEG+RIBASVR with 48 wks PEG+RIBAand Patterns of Virological Responseand Patterns of Virological Response
(R=Rapid 4w, E=Early 12w, N=none, c=complete, p=partial)(R=Rapid 4w, E=Early 12w, N=none, c=complete, p=partial)
16%
42%
22%
20%
RVR
cEVRpEVR
NVRRVR 87%
cEVR 68%
pEVR 27%
NR 5%0%
10%20%30%40%50%60%70%80%90%
100%
SVRMarcellin P. AASLD 2007
2 72234-Da y 1-9-On-T reatmen t Response (Shif fm an)-v1 - 186/1/2008 8:15 PM
Slow To R espond PatientsExtending TherapySlow To Respond PatientsExtending Therapy
33
16
5 24 6 4 4
6 9
0
2 0
4 0
6 0
8 0
B er g Sa n ch e z F e re n c i
4 8 w e e ks
7 2 w e e ks
B erg T e t a l. G as troenterology . 2006;130:1086- 1097; S anc hez- Tapias JM et a l. G as troentero logy . 2006;131:451-460;Fer enc i P e t a l. EASL . 2007.
RVN dose = 8 00 m g/d 800 m g/d 1000-1200 mg /d
Patients HCV R NA (-) after week 12
SV
R (
%)
Factors Associated with CureFactors Associated with Cure Viral
– Non-1 Genotype (2,3)– Lower Viral Load– Rapid/Early response
Disease related– No fibrosis/cirrhosis– Higher ALT– Lack of steatosis
Ribavirin dosage (~15 mg/kg)
Adherence– More than 80% of
intended treatment for > 80% of intended duration
Host Factors– Lower body weight– Younger age– Female gender– Race (non-AA, non-
Latino)
January 15, 2009
We evaluated the effect of Latino ethnic background on the response to treatment with peginterferon alfa-2a and ribavirin in patients infected with HCV genotype 1 who had not been treated previously
The rate of sustained virologic response was higher among non-Latino whites than among Latinos (49% vs. 34%, P<0.001).
January 15, 2009
New Studies for Hepatitis C at UC-Davis Fully enrolled*
Roche/
Intermune2bNaïve geno 1
Protease
PEG+RBV
Roche/
Pharmassett2bNaïve geno 1
Polymerase
PEG+RBV
Sciclone2bRelapsersNew IM+RBV
No PEG
Novartis1Non RespondersCyclophillin + *
PEG
Schering3Naïve genotype 1
And Non Respond.Protease * PEG+RBV
Drug Patient Population Phase Sponsor
Protease *
PEG+RBVNaïve geno 1 3 Vertex
NEW drugs for Hepatitis CNEW drugs for Hepatitis C
Will not be approved until 2011-2012 ? Improved efficacy with TRIPLE Rx (~70%)Ribavirin and IFN still platform 3-5 yrsAdded side effects: neutropenia,
lymphopenia, skin toxicitiesBreakthrough and resistance concernsHow many will pass phase 2 and 3 ?
Education for Health ChoicesEducation for Health Choices Moving Mountains
– Train Providers for “Hands on” management of liver disease
Leslie Benson (916) 717-5722
HCV University http://www.hcvu.org HCV University is a project of OASIS, a
not-for-profit community-based clinic located in Oakland, CA (Diana Sylvestre)
SummarySummary Hepatitis C is a serious disease Ask about risk factors and √ HCV Ab Confirm HCV-RNA and Genotype Consider treatment to cure and to halt
progression to cirrhosis and cancer Standard therapy: Pegylated
Interferons and Ribavirin Refer for Clinical Trials with New Rx
GI and Hepatology Clinical GI and Hepatology Clinical Research GroupResearch Group
Thank youThank you Thomas Amankonah Chris Bowlus Juan Carlos Garcia Valentina Medici Thomas Prindiville Lorenzo Rossaro Natalie Torok Shiro Urayama Mark Zern
Laura Lester (Supervisor) Annika Bryant Sandeep Dhaliwal Nicole Ekedahl Mia Minoletti Emanuel Obanor Nina Parks Elizabeth Pickett Monica Ruiz Ann Sanchez Yihey Yuk
How to refer for GI and Hep studiesHow to refer for GI and Hep studies
Laura Lester, NPPhone (916) 734-8696 Fax (916) 734-8666E-mail: [email protected]
Nina Willis, MAPhone (916) 734-8942 Fax (916) 734-8850E-mail: [email protected]