Brilliant Answers Brilliant Answers Jennifer Price, MD, PhD - PDF document

12/8/18 10 Important Liver Care 10 Important Liver Care Questions and 10 Questions and 10 × Brilliant Answers Brilliant Answers Jennifer Price, MD, PhD Jennifer Price, MD, PhD UCSF Hepatology UCSF Hepatology December 7, 2018 December 7, 2018 Disclosures Outline • Grant support: Gilead, Merck • HBV • NAFLD/NASH • Advisory board: Surrozen • Cirrhosis and HCC screening • Ownership interest: Bristol-Myers Squibb, Johnson and Johnson, Merck, Abbvie

12/8/18 HBV HBV 1. What does an isolated anti-HBc+ mean? 1. What does an isolated anti-HBc+ mean? • Potential scenarios: a) “Window phase” of acute HBV recovery b) Occult HBV ─ Rates vary depending on study ─ Check HBV DNA (I reserve for HIV+, ESRD on HD, cirrhosis, immunocompromised) c) Prior exposure with loss of anti-HBs ─ Most common scenario if risk factors for prior exposure d) False positive ─ Higher suspicion if no risk factors for exposure HBV HBV 2. Should I vaccinate my isolated anti-HBc+ patients? 1. What does an isolated anti-HBc+ mean? 362 pts (110 HIV+) with isolated anti-HBc+ (Paris) anti-HBc IgM 1 “Window phase” (0.3%) 11 false Repeat anti-HBc positive (3%) 10 HBV DNA+ HBV DNA (3%) 341 HBV DNA- (94%) Launay O, J Viral Hep, 2011. Terrault N, AASLD 2018 Hepatitis B Guidance

12/8/18 HBV HBV 3. How do you manage anti-HBc+ patients during HCV 2. Should I vaccinate my isolated anti-HBc+ patients? treatment? Yes if HIV+ Terrault N, AASLD 2018 Hepatitis B Guidance HBV HBV 3. How do you manage anti-HBc+ patients during HCV 3. How do you manage anti-HBc+ patients during HCV treatment? treatment? • Test for HBsAg, anti-HBs, anti-HBc prior to treatment start • Test for HBsAg, anti-HBs, anti-HBc prior to treatment start HBsAg Positive Meets HBV treatment criteria Start HBV treatment before HCV treatment AASLD/IDSA 2018 HCV Guidance AASLD/IDSA 2018 HCV Guidance; Terrault N, AASLD 2018 Hepatitis B Guidance

12/8/18 HBV HBV 3. How do you manage anti-HBc+ patients during HCV 3. How do you manage anti-HBc+ patients during HCV treatment? treatment? • Test for HBsAg, anti-HBs, anti-HBc prior to treatment start • Test for HBsAg, anti-HBs, anti-HBc prior to treatment start HBsAg Negative HBsAg Positive HBsAg Positive Anti-HBc Positive Meets HBV Does not meet HBV Meets HBV Does not meet HBV treatment criteria treatment criteria treatment criteria treatment criteria Start HBV HBV DNA every 4-8 Start HBV HBV DNA every 4-8 treatment before wks on treatment treatment before wks on treatment HCV treatment for 12 wks after HCV treatment for 12 wks after Start HBV treatment if HBV DNA increases Start HBV treatment if HBV DNA increases >10-fold OR is >1000 IU/mL if undetected >10-fold OR is >1000 IU/mL if undetected or unquantifiable prior to HCV treatment or unquantifiable prior to HCV treatment AASLD/IDSA 2018 HCV Guidance; Terrault N, AASLD 2018 Hepatitis B Guidance AASLD/IDSA 2018 HCV Guidance; Terrault N, AASLD 2018 Hepatitis B Guidance HBV HBV 3. How do you manage anti-HBc+ patients during HCV 3. How do you manage anti-HBc+ patients during HCV treatment? treatment? • Test for HBsAg, anti-HBs, anti-HBc prior to treatment start • What if they are HIV+ and on 1-2 HBV active agents? HBsAg Negative HBsAg Positive Anti-HBc Positive Meets HBV Does not meet HBV Monitor ALT at baseline, treatment criteria treatment criteria EOT, and follow-up Start HBV HBV DNA every 4-8 If ALT increases or fails to treatment before wks on treatment normalize, test HBV DNA HCV treatment for 12 wks after and HBsAg Start HBV treatment if HBV DNA increases HBV treatment if >10-fold OR is >1000 IU/mL if undetected evidence of HBV or unquantifiable prior to HCV treatment reactivation AASLD/IDSA 2018 HCV Guidance; Terrault N, AASLD 2018 Hepatitis B Guidance

12/8/18 HBV HBV 3. How do you manage anti-HBc+ patients during HCV 3. How do you manage anti-HBc+ patients during HCV treatment? treatment? • What if they are HIV+ and on 1-2 HBV active agents? • What if they are HIV+ and on 1-2 HBV active agents? HBsAg Positive HBsAg Positive HBV DNA undetected, HBV DNA+ HBV DNA+ unquantifiable Additional Follow AASLD Follow AASLD monitoring not necessary guidelines for guidelines for virologic virologic breakthrough breakthrough HBV HBV 4. In whom should I use the new HEPLISAV 3. How do you manage anti-HBc+ patients during HCV treatment? vaccine? • What if they are HIV+ and on 1-2 HBV active agents? HBsAg Negative HBsAg Positive Anti-HBc Positive HBV DNA undetected, Additional HBV DNA+ unquantifiable monitoring not necessary Additional Follow AASLD monitoring not necessary guidelines for virologic breakthrough

12/8/18 HEPLISAV-B HEPLISAV-B Clinical Trials • Contains CpG 1018 + recombinant HBsAg (20 mcg) Study HEPLISAV-B Engerix-B (HEPLISAV-B minus Engerix-B) – Binds to TLR9 (sensing receptor for innate immune Population SPR (95% CI) SPR (95% CI) Difference in SPR (95% CI) responses) expressed on dendritic cells and memory B 95% (94, 96) 81% (78, 85) 14% (10, 18)* cells Ages 18-55 N=1511 N=521 – Leads to enhanced T and B memory for HBsAg 90% (88, 92) 71% (66, 75) 20% (15, 25)* Ages 40-70 • Given at 0, 1 month N=1121 N=353 Diabetes, 90% (87, 92) 65% (60, 70) 25% (19, 31)* Ages 18-70 N=640 N=321 SPR= Seroprotection rate; *Non-inferiority met HEPLISAV-B package insert. A5379 B-Enhancement of HBV HEPLISAV-B Clinical Trials Vaccination in PLWH (BEe-HIVe) Study HEPLISAV-B Engerix-B (HEPLISAV-B minus Engerix-B) • Randomized controlled trial of HEPLISAV-B vs Engerix-B Population SPR (95% CI) SPR (95% CI) Difference in SPR (95% CI) in HIV+ vaccine non-responders or vaccine naïve 95% (94, 96) 81% (78, 85) 14% (10, 18)* Ages 18-55 • Vaccine non-responders N=1511 N=521 90% (88, 92) 71% (66, 75) 20% (15, 25)* – HBSLISAV-B 2 and 3 doses compared to Engerix 3 doses Ages 40-70 N=1121 N=353 • Vaccine naïve Diabetes, 90% (87, 92) 65% (60, 70) 25% (19, 31)* Ages 18-70 N=640 N=321 – HBSLISAV-B 2 doses SPR= Seroprotection rate; *Non-inferiority met Hasn’t been studied in HIV+ HEPLISAV-B package insert.

12/8/18 NAFLD/NASH NAFLD/NASH 5. What is your evaluation for NAFLD/NASH? How useful are noninvasive markers or tests to make the diagnosis? ~30% ~3-10% ~0.3-2% NAFLD/NASH NAFLD/NASH 5. What is your evaluation for NAFLD/NASH? How useful are noninvasive markers or tests to make the diagnosis? ~30% HIV+ similar to HIV- ~3-10% Likely higher in HIV+ (42% NASH, 22% ≥F2) ~0.3-2% Is it higher in HIV?

12/8/18 NAFLD/NASH NAFLD/NASH 5. What is your evaluation for NAFLD/NASH? How useful 5. What is your evaluation for NAFLD/NASH? How useful are noninvasive markers or tests to make the diagnosis? are noninvasive markers or tests to make the diagnosis? • Noninvasive tests can estimate: • Noninvasive tests can estimate: – Presence +/- severity of steatosis – Presence +/- severity of steatosis – Presence +/- severity of fibrosis – Presence +/- severity of fibrosis • Especially advanced fibrosis or cirrhosis • Especially advanced fibrosis or cirrhosis • Noninvasive tests cannot distinguish simple steatosis vs NASH Non-invasive Imaging of Steatosis Non-invasive Imaging of Steatosis • Magnetic resonance spectroscopy (MRS) • Magnetic resonance spectroscopy (MRS) • MRI with proton density fat fraction (MRI-PDFF) • MRI with proton density fat fraction (MRI-PDFF) • Ultrasound • Ultrasound • Non-contrast CT • Non-contrast CT • Fibroscan with • Fibroscan with Controlled attenuation Controlled attenuation parameter (CAP) parameter (CAP) Ultrasound and CAP are more commonly used clinically Younossi Z, Hepatology, 2018. Stefan N, Lancet Diabetes Endocrinol, 2018. Younossi Z, Hepatology, 2018. Stefan N, Lancet Diabetes Endocrinol, 2018.

12/8/18 Non-invasive Imaging of Fibrosis in Serum Markers of Fibrosis in NAFLD NAFLD • Fibroscan/Vibration controlled transient elastography Liver enzymes correlate (VCTE) poorly with histology • Magnetic resonance elastography (MRE) AUROC ≥F2 AUROC ≥F2 Fibrosis test HIV- (N=104) HIV+ (N=59) Fibroscan/VCTE 0.86 (0.77-0.95) 0.93 (0.85-0.99) MRE 0.89 (0.83-0.96) Park CC, Gastroenterology, 2017. Morse CG, AIDS, 2015. Serum Markers of Fibrosis in NAFLD/NASH NAFLD 5. What is your evaluation for NAFLD/NASH? How useful are noninvasive markers or tests to make the diagnosis? Liver enzymes correlate poorly with histology • AST:ALT ratio AST/ALT AST/ upper limit of nl x 100 • AST-to-plt ratio index (APRI) Platelet count (10 9 /L) Age (years) x AST • FIB-4 Platelet count (10 9 /L) x √ALT nafldscore.com • NAFLD fibrosis score Giannini E, Arch Intern Med, 2003. Wai CT, Hepatology, 2003. Sterling RK, Hepatology, 2006. Angulo P , Hepatology, 2007.