1. The Hepatitis B&C Past and Present Martin J Spitz MD FACP AGAF Clinical Professor of Medicine UCSF

3. Hepatitis B Geography

4. 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%

5. 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

6. 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.

7. 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

8. 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

9. 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)

10. 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

11. Post-exposure Prophylaxis www.cdc.gov

12. Post-exposure Prophylaxis (non- occupational) www.cdc.gov

13. 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

14. 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

15. 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

17. 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

18. 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

19. 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

20. 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

22. 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

23. 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

24. 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”

25. 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 – $$$$$

26. 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

27. 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