Document

Report
The Hepatitis B&C Past and Present
Martin J Spitz MD FACP AGAF
Clinical Professor of Medicine
UCSF
Hepatitis B Geography
Natural History of Hepatitis B
Acute HBV infection
90% neonates
~2%
25–30% children
<10% adults
Chronic infection
15 - 40%
Fulminant
hepatic failure
Progressive chronic
hepatitis
Inactive
carrier state
Cirrhosis
Decompensated
cirrhosis
Death
HCC
Lok and McMahon. Hepatology 2009
Screening High Risk Persons for HBV
•
Persons from high prevalence areas: Asia, Africa, Middle East
•
Household or sexual contacts of HBV+ persons
•
Injection drug users
•
High risk or multiple sexual partners
•
Inmates of correctional facilities
•
Hepatitis C or HIV-infected persons
•
Hemodialysis patients
•
Pregnant women
•
Persons with unexplained, chronically elevated ALT
Lok and McHahon. Hepatology 2009
HCC Screening: Chronic Hepatitis B
(incidence > 0.2% per year)
•
•
•
•
•
•
Asian males > 40 years old
Asian females > 50 years old
Africans > 20 years old
Family history of HCC
Cirrhosis
Non-cirrhosis: varies depending on activity, fibrosis, etc.
Subjects with high HBV DNA, HBeAg or inflammation (ALT)
may be at increased risk.
AASLD Guidelines on Chronic HBV:
Whom to Treat with Antiviral Therapy
• Elevated HBV DNA levels
• HBeAg (+): 20,000 IU/mL or 105 copies/mL
• HBeAg (-): 2,000 IU/mL or 104 copies/mL
AND
• Persistently elevated ALT levels >2 x ULN
• Normal ALT
– 30 IU/mL for men, 19 IU/mL for women
OR
• Moderate/advanced liver disease on biopsy
• Stage 2, 3 or 4 fibrosis
Lok AS and McMahon BJ. Hepatology 2009
Hepatitis B Antiviral Treatment Goals
• Prevent cirrhosis, hepatic failure and HCC
• Normalization of liver function test (ALT)
• Viral suppression
– Undetectable HBV DNA
– HBeAg seroconversion (if originally positive)
• Definition: loss of HBeAg and presence of anti-HBe
– Loss of HBsAg
• Improvement in liver histology
HBV Genotypes Epidemiology
• HBV classified into 7 genotypes
A: North America and Europe
B and C: Asia
D: Southern Europe and India
F: South America
E and G: ?
• Genotype B is associated with less active and more slowly
progressive liver disease than C (?related to earlier e-Ag
seroconversion)
Pharmacologic Options for
Treatment-Naïve Chronic Hepatitis B
• First-line antiviral agents
– Tenofovir (TDF, Viread®) 300 mg daily
– Entecavir (ETV, Baraclude®) 0.5 mg daily
– PEGASYS 180mcg sq qwk x48 wks
• Second-line oral antiviral agents
– Lamivudine (3TC, Epivir-HBV®) 100 mg daily
– Telbivudine (TBV, Tyzeka®) 600 mg daily
– Adefovir (ADV, Hepsera®) 10 mg daily
www.cdc.gov
Post-exposure Prophylaxis
Post-exposure Prophylaxis (nonoccupational)
www.cdc.gov
Summary Chronic HBV Treatment
• Tenofovir, entecavir or peginterferon
– First-line option in treatment-naïve patients
– Tenofovir indicated in lamivudine and/or adefovir resistance
– Entecavir indicated in adefovir resistance
•
Adefovir, lamivudine and telbivudine
– Second line option in treatment-naïve patients
– Resistance increases with continued use as monotherapy
• Dose adjust in renal insufficiency (Clcr <50)
• Treat for at least 12 months
• Consider discontinuing antiviral therapy
– HBeAg or HBSAg seroconversion on 2 separate occasions, at 6-12 months apart
Goals for Antiviral
Treatment-Resistant Chronic HBV
• Normalization of LFTs
• Undetectable HBV DNA
• Avoid hepatic flare & hepatic failure
• HBeAg seroconversion (if originally HBeAg+)
• HBeAg neg & HBeAb pos
• Reduce fibrosis progression & risk of HCC
Review
• Review chronic hepatitis B infection and
interpretation of hepatitis B blood tests
• Identify potential candidates for hepatitis B antiviral
therapy
• Discuss the goals and efficacy of hepatitis B antiviral
treatments
Overview
• Hepatitis C therapy as we have known it, with 48
weeks of interferon-based therapy for most
patients and cure rates of 20-80% is now over
• 3 hepatitis C proteins: the protease, the
polymerase, and NS5A are under attack with new
drugs (all oral, generally 12-16 weeks)
• 2014 was still a year in which SINGLE active drugs
are often being used, at times with IFN/RBV
• The present belongs to all-oral, IFN-free, at least
3 drug regimens: 12 weeks, 90+% cure; at least 3
companies have them
HEPATITIS C
1. Most common blood borne illness in USA
2. 90% of cases become chronic
3.Leading reason for liver transplant in USA
4. Can now be cured with medication in >90%
5. Not as contagious as Hepatitis B
6. Present medications vary between $84,000 to
$168,000 per person treated
7. Major cause of cirrhosis and liver cancer in
USA
Glossary
• DAA: Direct Acting Agent. Anti-HCV
medications that target specific aspects of
HCV viral replication
• PEG (or P): Pegylated interferon
• RBV (or R): Ribavirin
• HCV Genotype: Strains of HCV that affect
treatment response (1-6)
– Genotypes 3 & 1b harder to cure than 2 &
1a
Glossary (2)
• Sustained virologic response (SVR): HCV viral
load undetectable off of treatment. SVR12 and
SVR24 considered cure of HCV
• Response Guided Therapy (RGT): Shortening
therapy based on good HCV virologic response
over the 1st 12 weeks of treatment
• Type of prior response to treatment
– Null response: Failure to attain at least 2 log10 drop in
HCV after 12 weeks of treatment
– Partial responder: Attained 12 week response but
RNA rose again during therapy
– Relapser: HCV RNA undetectable on treatment but
detectable after therapy stopped
Sofosbuvir (SOF) + Ledipasvir (NS5A, LDV) ± RBV
for 6 - 8- and 12-Wks for Genotype 1 (phase II trials)
Week 6
ELECTRON
n=20
SOF + LDV:
NAÏVE F0-3
LONESTAR
n=20
SOF + LDV:
NAIVE
LONESTAR
n=21
SOF + LDV + RBV:
NAIVE
ELECTRON
n=25
SOF + LDV + RBV: NAIVE
100% SVR12
LONESTAR
n=19
SOF + LDV:
NAIVE
100% SVR4
SYNERGY
n=20
SOF + LDV:
NAÏVE, difficulty to treat (AA, GT1a)
100% SVR12
ELECTRON
n=10
SOF + LDV + RBV:
NULL
100% SVR12
ELECTRON
n=10
SOF + LDV :
NULL F4
80% SVR4
ELECTRON
n=10
SOF + LDV + RBV:
NULL F4
89% SVR4
LONESTAR
n=19
SOF + LDV:
PI FAILURES
95% SVR4
LONESTAR
n=21
SOF + LDV + RBV:
PI FAILURES
95% SVR4
22
68% SVR12
Week 8
95% SVR12
Week 12
100% SVR12
Gane E et al, Lawitz E et al, AASLD 2013 Abs 73, 215
*Gane et al AASLD 2013; ^Lawitz et al AASLD 2013
PHOTON-1: Phase 3
SOF+RBV in G1/2/3 Co-infected Patients
12w
N = 68
SOF/RBV G2/3 TN
24w
N =141
SOF/RBV
G1 TN
12w
N=
SOF/RBV
G2/3 TE
24w
N=
SOF/RBV
G2/3 TE
Week
0
G2 81% SVR12
G3 67% SVR12
G1 76% SVR12
4
8
24
12
36
 G2 (n=26) and 3 (n=42) SVR12: 81% and 67%, respectively
 GT1 (n=141): 76% SVR
 2 HIV viral breakthrough:
 1 due to non-adherence
 1 regained control without ART change
 D/C: 3%
 Safe with multiple ART regimens
23
Sulkowski M et al. AASLD 2013 Ab 212
• Simeprevir
Summary
– Protease inhibitor (NS3)
– GT1, Treatment naïve and Treatment-experienced
– TN: 150 mg/day for 12 weeks + PR for 24 weeks
• Stop at W12 if detectable HCV RNA
– Not effective: Q80K mutation (G1a: 40% prevalence)
• Sofosbuvir
–
–
–
–
–
Nucleotide polymerase inhibitor (NS5B)
GT 1, TN: 12 weeks with PR: 90% SVR, est. 75% in TE
GT 2: 12 weeks with ribavirin; 90-95% SVR in TN
GT 3: 24 weeks with ribavirin; 90-95% SVR in TN and TE
“No resistance”
Summary
• Interferon-free
– Multiple DAAs with different targets: 95% SVR, 12 Wk
• HIV/HCV Co-infection
– Sofosbuvir + Ribavirin for 12 weeks
– Simeprevir or Faldaprevir +PR for 24-48 weeks
• Interferon-free timeline for GT 1 (guess)
– Q4 2014: daclatasvir (NS5A)
– Q4 2014 or Q1 2015: Abbvie (4-5 drugs)
– Q4 2014: Gilead (sofosbuvir + ledipasvir)
• Cost
– $$$$$
DAA’s at SFVA
• We are experiencing another wave of HCV
treatment, particularly for GT’s 2 and 3
• Treatment will continue to prioritize patients
with cirrhosis, who are at risk for
complications soon
• Pre- or post-liver transplant patients are also
having HCV viremia considered differently
• 2015-16, with IFN-free regimens for many GT
1 patients, will see even more HCV treatment
ACKNOWLEDGEMENTS
Nursing staff of SFVAMC GIDC for their competence,
patience, compassion and work ethic.
Alex Monto, MD Associate Professor of Medicine
UCSF
Director of Liver Clinic. SFVAMC

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