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The Hepatitis B&C Past and Present Martin J Spitz MD FACP AGAF Clinical Professor of Medicine UCSF
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Hepatitis B Geography
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15 - 40% 90% neonates 25–30% children Natural History of Hepatitis B Acute HBV infection <10% adults Progressive chronic hepatitis Cirrhosis HCC Death Decompensated cirrhosis Inactive carrier state Lok and McMahon. Hepatology 2009 Chronic infection Fulminant hepatic failure ~2%
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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
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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.
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AASLD Guidelines on Chronic HBV: Whom to Treat with Antiviral Therapy Elevated HBV DNA levels HBeAg (+): 20,000 IU/mL or 10 5 copies/mL HBeAg (-): 2,000 IU/mL or 10 4 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
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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
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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)
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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
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Post-exposure Prophylaxis www.cdc.gov
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Post-exposure Prophylaxis (non- occupational) www.cdc.gov
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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
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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
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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
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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
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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 canc er in USA
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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
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Glossary (2) Sustained virologic response (SVR): HCV viral load undetectable off of treatment. SVR 12 and SVR 24 considered cure of HCV Response Guided Therapy (RGT): Shortening therapy based on good HCV virologic response over the 1 st 12 weeks of treatment Type of prior response to treatment – Null response: Failure to attain at least 2 log 10 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
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22 Sofosbuvir (SOF) + Ledipasvir (NS5A, LDV) ± RBV for 6 - 8- and 12-Wks for Genotype 1 (phase II trials) SOF + LDV + RBV: NAIVE n=10 n=25 SOF + LDV + RBV: NULL 100% SVR12 SOF + LDV: NAIVE n=21 n=20 SOF + LDV + RBV: NAIVE n=19 SOF + LDV: PI FAILURES SOF + LDV + RBV: PI FAILURES n=21 SOF + LDV: NAIVE Week 8 95% SVR12 100% SVR12 100% SVR4 95% SVR4 ELECTRON LONESTAR SOF + LDV : NULL F4 n=10 SOF + LDV + RBV: NULL F4 80% SVR4 89% SVR4 ELECTRON 68% SVR12 SOF + LDV: NAÏVE F0-3 n=20 Week 6 Week 12 *Gane et al AASLD 2013; ^Lawitz et al AASLD 2013 ELECTRON LONESTAR ELECTRON n=20 SOF + LDV: NAÏVE, difficulty to treat (AA, GT1a) 100% SVR12 SYNERGY Gane E et al, Lawitz E et al, AASLD 2013 Abs 73, 215
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12 N =141 SOF/RBV G2/3 TN N = 6812w SOF/RBV G1 TN 24w 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 Week 048 36 PHOTON-1: Phase 3 SOF+RBV in G1/2/3 Co-infected Patients N = SOF/RBV G2/3 TE 12w N = SOF/RBV G2/3 TE 24w 24 Sulkowski M et al. AASLD 2013 Ab 212 G2 81% SVR12 G3 67% SVR12 G1 76% SVR12 23
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Summary Simeprevir – 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”
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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 – $$$$$
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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
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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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