Research/clinical trials: Gilead, Allergan 2 1 12/13/19 3 - PDF document

12/13/19 Danielle Brandman, MD, MAS Program director, Transplant hepatology fellowship Director, UCSF Fatty Liver Clinic Associate Professor of Clinical Medicine University of California San Francisco 1 ¡ Research/clinical trials: Gilead, Allergan 2 1

12/13/19 3 Drugs and Toxins Metabolic Syndrome – Alcohol – Abdominal Obesity – Corticosteroids – IGT/Diabetes – Tamoxifen – Dyslipidemia – Amiodarone – Hypertension – Industrial solvents Inherited Metabolic Nutritional Syndromes Diseases – JI Bypass – Lipodystrophy – TPN – Abetalipoprotinemia – Rapid weight loss – Wilson Disease 4 2

12/13/19 Drugs and Toxins Metabolic Syndrome – Alcohol – Abdominal Obesity – Corticosteroids – IGT/Diabetes – Tamoxifen – Dyslipidemia – Amiodarone – Hypertension – Industrial solvents Inherited Metabolic Nutritional Syndromes Diseases – JI Bypass – Lipodystrophy – TPN – Abetalipoprotinemia – Rapid weight loss – Wilson Disease 5 ¡ Prevalence of NAFLD: ___ US population ¡ Prevalence of NASH: ___% population 6 3

12/13/19 ¡ Prevalence of NAFLD: 16-29% US population ¡ Prevalence of NASH: 2-7% population Farrell, Hepatology , 2006. Younoussi, Hepatology , 2015. 7 ¡ Prevalence of NAFLD: 16-29% US population § 2/3 of obese adults § 84-96% bariatric surgery population § Up to 76% of diabetics ¡ Prevalence of NASH: 2-7% population § 10-30% of NAFLD § 20% of obese adults Farrell, Hepatology , 2006. Younoussi, Hepatology , 2015. 8 4

12/13/19 Number of Study (year) Country Steatosis assessment Prevalence of NAFLD subjects Hadigan, C (2007) USA 33 MR spectroscopy 42% Moreno-Torres, A (2007) Spain 29 MR spectroscopy 58% Mohammed, SS (2007) Canada 26 Liver biopsy 45% Guaraldi, G (2008) Italy 225 CT 37% Crum-Cianflone, P (2009) USA 216 Ultrasound 31% Ingiliz, P (2009) France 30 Liver biopsy 60% Nishijima, T (2014) Japan 435 Ultrasound 31% Price, JC (2014) USA 465* CT 13% Macias, J (2014) Spain 505* CAP** 40% Lui, G (2016) Japan 80 MR spectroscopy 29% Lombardi, R (2016) Greece 125 Ultrasound 55% Vuille-Lessard, E (2016) Canada 300 CAP 48% Price, JC (2017) USA 122 MR spectroscopy 28% *Includes HIV + HCV or HBV; **CAP= controlled attenuation parameter, obtained with Fibroscan Slide courtesy of Dr. Jennifer Price 9 HIV-monoinfected and uninfected women (n=87) and men (n=141) ▪ HIV+ women 36% less fat (vs HIV-), p=0.02 ▪ NAFLD prevelance: 13% HIV+ vs 19% HIV-, p=0.02 ▪ HIV+ men 5.3% less fat (vs HIV-), p=0.66 ▪ HIV aOR 0.44, p=0.002 Courtesy of Dr. Jennifer Price, adapted 10 5

12/13/19 Variable Mean Difference (MD) or Odds Ratio (OR) P-value BMI MD 2.9 (2.4 to 3.7) p<0.001 Waist circumference MD 8.0 (5.5 to 10.6) p<0.001 Type 2 diabetes OR 1.6 (1.1 to 2.4) p=0.02 Hypertension OR 1.8 (1.3 to 2.4) p=0.001 Triglycerides MD 62 (24 to 99) p=0.001 HDL MD -4.2 (-6.8 to -1.6) p=0.002 Duration of HAART MD -15 (-33 to 3.5) p=0.11 Cumulative ddi exposure OR 1.4 (1.1 to 2.0) P=0.02 CD4 count MD 55 (12 to 98) p=0.01 Courtesy of Dr. Jennifer Price, adapted 11 ¡ 54yo woman was found to have fatty liver on ultrasound done for abdominal pain 12 6

12/13/19 ¡ 54yo woman was found to have fatty liver on ultrasound done for abdominal pain ¡ The pain has since resolved, but she wonders how worried she should be about fatty liver 13 ¡ Her weight has fluctuated within the past few years, during which time her BMI has ranged from 30-33 ¡ PMH: HIV, prediabetes (HbA1c 5.9), dyslipidemia (HDL 36, TGs 180), HTN ¡ Meds: DRV/c/TAF/FTC atorvastatin, lisinopril ¡ Family history: Parents with diabetes 14 7

12/13/19 ¡ Labs: AST 38, ALT 71, albumin 4.1, INR 1.0, platelets 200 ¡ Upon review of prior lab results, she has largely had AST 20s-40s and ALT 40s-80s since 2015 15 A. Liver biopsy B. Counsel her on lifestyle modification to try to lose weight and repeat liver tests again in 6 months C. Evaluate for other causes of chronic liver disease D. Transient elastography (Fibroscan) 16 8

12/13/19 A. Liver biopsy B. Counsel her on lifestyle modification to try to lose weight and repeat liver tests again in 6 months C. Evaluate for other causes of chronic liver disease D. Transient elastography (Fibroscan) 17 § Symptoms: – None: 20 - 77% – Right upper quadrant pain: 25 - 48% – Fatigue: 50 - 75% (Obstructive sleep apnea in 40%) § Signs: – Overweight/Obese: 85 - 95% – Acanthosis nigricans: 10 -15% – Hepatomegaly: 25 - 50% § Laboratory: – ALT, AST - modest elevation – “ Normal enzymes ” – Normal ALT <19-25 for women, <30-35 for men 18 9

12/13/19 ¡ Diagnostic criteria § Hepatic steatosis on imaging or liver biopsy § No “significant” alcohol intake § Absence of other causes of liver disease § No medications known to cause hepatic steatosis 19 ¡ Diagnostic criteria § Hepatic steatosis on imaging or liver biopsy § No “significant” alcohol intake § Absence of other causes of liver disease § No medications known to cause hepatic steatosis NAFLD is a diagnosis of exclusion 20 10

12/13/19 ¡ Liver tests ¡ Abdominal ultrasound ¡ Other serologic evaluation: § HBsAg, sAb, cAb § HCV Ab § [AMA, IgM (for PBC)] § ASMA, ANA, IgG § A1AT phenotype § Iron, Tsat, ferritin § Ceruloplasmin age < 45 § HAV Ab (for vaccination status) 21 NAFL Steatosis without inflammation NAFLD Cirrhosis NASH + NASH fibrosis HCC Steatosis + inflammation 22 11

12/13/19 A. Fibroscan B. MR elastography C. Liver biopsy 23 A. Fibroscan B. MR elastography C. Liver biopsy 24 12

12/13/19 ¡ Liver biopsy is the only method to reliably distinguish between NAFL and NASH ¡ Noninvasive assessment of fibrosis § Fibroscan § Clinical prediction rules (e.g., FIB-4, NAFLD fibrosis score) 25 NAFLD fibrosis score = -1.675 + 0.037*age + 0.094*BMI + 1.13*IFG/DM + 0.99*AST:ALT – 0.13*platelets – 0.66*albumin 26 13

12/13/19 ¡ Suspicious for NASH Significant liver enzyme elevation § Diabetes § NASH ¡ Suspicious for advanced fibrosis or cirrhosis Advanced fibrosis - Thrombocytopenia - Imaging (e.g., splenomegaly) - Noninvasive assessment: FIB-4, Fibroscan - Diabetes - Older age Chalassani, Hepatology 2017. § Unable to rule out other diseases Chalassani, Hepatology 2012. 27 NASH 7 years per 1 stage ~28 years 0 à cirrhosis 28 14

12/13/19 NASH 7 years per 1 stage ~28 years 0 à cirrhosis NAFL 14 years per 1 stage ~56 years 0 à cirrhosis 29 AUROC Any fibrosis ≥F2 F3-4 Cirrhosis Transient 0.74-0.78 0.79-0.84 0.83-0.88 0.86-0.93 elastography MR 0.83 0.91 0.89 0.97 elastography NAFLD fibrosis 0.82 0.72-0.82 0.73-0.86 0.77-0.92 score FIB-4 0.8 0.72-0.83 0.78-0.86 0.78-0.88 Siddiqui, . . .Brandman et al. Clin Gastro Hep, 2018. Boursier, J Hepatol 2016. Imajo, Gastroenterology 2016. Hsu, Clin Gastro Hep , 2018. 30 15

12/13/19 31 Overall mortality Liver-related event Hagstrom, J Hep, 2017. 32 16

12/13/19 ¡ The patient was reluctant to undergo liver biopsy and opted instead for Fibroscan 33 ¡ The patient was reluctant to undergo liver biopsy and opted instead for Fibroscan § Liver stiffness measurement: 13kPa (IQR 0.9) § CAP score: 330 (IQR 13) 34 17

12/13/19 ¡ The patient was reluctant to undergo liver biopsy and opted instead for Fibroscan § Liver stiffness measurement: 13kPa (IQR 0.9) § CAP score: 330 (IQR 13) § Interpretation: Cirrhosis (F4), though LSM could be overestimated due to the presence of severe steatosis (CAP>300) 35 ¡ The patient was reluctant to undergo liver biopsy and opted instead for Fibroscan § Liver stiffness measurement: 13kPa (IQR 0.9) § CAP score: 330 (IQR 13) § Interpretation: Cirrhosis (F4), though LSM could be overestimated due to the presence of severe steatosis (CAP>300) § NFS -0.4 (indeterminate), FIB-4 1.24 (90% NPV for advanced fibrosis) 36 18

12/13/19 ¡ Because of the concern for cirrhosis, you again recommend liver biopsy for more definitive diagnosis and staging 37 ¡ Because of the concern for cirrhosis, you again recommend liver biopsy for more definitive diagnosis and staging ¡ The patient is now amenable to liver biopsy 38 19

12/13/19 ¡ Impression: steatohepatitis § >20 portal tracts present, no fragmentation § Severe steatosis (>66%) § Ballooned hepatocytes § Moderate lobular inflammation § Fibrosis: stage 3, with bridging fibrosis and areas of centrizonal fibrosis 39 40 20

12/13/19 A. Cardiovascular disease B. Malignancy C. Liver disease D. Kidney disease 41 A. Cardiovascular disease B. Malignancy C. Liver disease D. Kidney disease 42 21

12/13/19 Hagstrom, J Hep, 2018. 43 Steatosis 8% NASH ± 12 - 40% F1 - F2 fibrosis 13% Advanced 5 - 10% 14% F3 fibrosis 0 - 50% Death/ Cirrhosis LTx 25% 25 - 50% 7% HCC Day, J Hep, 2008. 44 22

12/13/19 Wong, Gastroenterology , 2015. 45 ¡ This 54F with HIV, metabolic syndrome (BMI 33, pre-DM, HTN, HL), and biopsy- proven NASH with advanced fibrosis is interested to know what can be done to treat disease and prevent or reverse fibrosis 46 23

12/13/19 A. Bariatric surgery B. Vitamin E C. Ursodiol D. Lifestyle modifcation for weight loss E. B & D 47 A. Bariatric surgery B. Vitamin E C. Ursodiol D. Lifestyle modifcation for weight loss E. B & D 48 24