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

12/13/19 1

Danielle Brandman, MD, MAS

Program director, Transplant hepatology fellowship Director, UCSF Fatty Liver Clinic Associate Professor of Clinical Medicine University of California San Francisco

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¡ Research/clinical trials: Gilead, Allergan

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12/13/19 2

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Drugs and Toxins

– Alcohol – Corticosteroids – Tamoxifen – Amiodarone – Industrial solvents

Inherited Metabolic Diseases

– Lipodystrophy – Abetalipoprotinemia – Wilson Disease

Metabolic Syndrome

– Abdominal Obesity – IGT/Diabetes – Dyslipidemia – Hypertension

Nutritional Syndromes

– JI Bypass – TPN – Rapid weight loss

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Drugs and Toxins

– Alcohol – Corticosteroids – Tamoxifen – Amiodarone – Industrial solvents

Inherited Metabolic Diseases

– Lipodystrophy – Abetalipoprotinemia – Wilson Disease

Metabolic Syndrome

– Abdominal Obesity – IGT/Diabetes – Dyslipidemia – Hypertension

Nutritional Syndromes

– JI Bypass – TPN – Rapid weight loss

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¡ Prevalence of NAFLD: ___ US population ¡ Prevalence of NASH: ___% population

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12/13/19 4 ¡ 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

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Study (year) Country Number of subjects Steatosis assessment Prevalence of NAFLD 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

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▪ NAFLD prevelance: 13% HIV+ vs 19% HIV-, p=0.02 ▪ HIV aOR 0.44, p=0.002

HIV-monoinfected and uninfected women (n=87) and men (n=141)

▪HIV+ women 36% less fat (vs HIV-), p=0.02 ▪HIV+ men 5.3% less fat (vs HIV-), p=0.66 Courtesy of Dr. Jennifer Price, adapted

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12/13/19 6 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 Cumulative ddi exposure MD -15 (-33 to 3.5) OR 1.4 (1.1 to 2.0) p=0.11 P=0.02 CD4 count MD 55 (12 to 98) p=0.01

Courtesy of Dr. Jennifer Price, adapted

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¡ 54yo woman was found to have fatty liver

• n ultrasound done for abdominal pain

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¡ 54yo woman was found to have fatty liver

• n ultrasound done for abdominal pain

¡ The pain has since resolved, but she

wonders how worried she should be about fatty liver

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¡ 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

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¡ 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

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• 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)

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• 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)

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§

Symptoms:

– None: 20 - 77% – Right upper quadrant pain: 25 - 48% – Fatigue: 50 - 75% (Obstructive sleep apnea in 40%)

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Signs:

– Overweight/Obese: 85 - 95% – Acanthosis nigricans: 10 -15% – Hepatomegaly: 25 - 50%

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Laboratory:

– ALT, AST - modest elevation – “Normal enzymes”

– Normal ALT <19-25 for women, <30-35 for men

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12/13/19 10 ¡ 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

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¡ 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

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¡ 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)

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NAFLD NAFL

Steatosis without inflammation

NASH

Steatosis + inflammation

NASH + fibrosis Cirrhosis HCC

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• A. Fibroscan
• B. MR elastography
• C. Liver biopsy

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• A. Fibroscan
• B. MR elastography
• C. Liver biopsy

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¡ 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)

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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

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12/13/19 14 ¡ Suspicious for NASH §

Significant liver enzyme elevation

§

Diabetes

¡ Suspicious for advanced fibrosis or

cirrhosis

• Thrombocytopenia
• Imaging (e.g., splenomegaly)
• Noninvasive assessment: FIB-4, Fibroscan
• Diabetes
• Older age

§ Unable to rule out other diseases

Chalassani, Hepatology 2017. Chalassani, Hepatology 2012.

NASH Advanced fibrosis

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NASH 7 years per 1 stage ~28 years 0à cirrhosis

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NASH 7 years per 1 stage ~28 years 0à cirrhosis NAFL 14 years per 1 stage ~56 years 0à cirrhosis

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AUROC Any fibrosis ≥F2 F3-4 Cirrhosis Transient elastography 0.74-0.78 0.79-0.84 0.83-0.88 0.86-0.93 MR elastography 0.83 0.91 0.89 0.97 NAFLD fibrosis score 0.82 0.72-0.82 0.73-0.86 0.77-0.92 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.

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Hagstrom, J Hep, 2017.

Overall mortality Liver-related event

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12/13/19 17 ¡ The patient was reluctant to undergo liver biopsy and

• pted instead for Fibroscan

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¡ The patient was reluctant to undergo liver biopsy and

• pted instead for Fibroscan

§ Liver stiffness measurement: 13kPa (IQR 0.9) § CAP score: 330 (IQR 13)

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12/13/19 18 ¡ The patient was reluctant to undergo liver biopsy and

• pted instead for Fibroscan

§ Liver stiffness measurement: 13kPa (IQR 0.9) § CAP score: 330 (IQR 13) § Interpretation: Cirrhosis (F4), though LSM could be

• verestimated due to the presence of severe steatosis

(CAP>300)

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¡ The patient was reluctant to undergo liver biopsy and

• pted instead for Fibroscan

§ Liver stiffness measurement: 13kPa (IQR 0.9) § CAP score: 330 (IQR 13) § Interpretation: Cirrhosis (F4), though LSM could be

• verestimated due to the presence of severe steatosis

(CAP>300)

§ NFS -0.4 (indeterminate), FIB-4 1.24 (90% NPV for

advanced fibrosis)

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¡ Because of the concern for cirrhosis, you

again recommend liver biopsy for more definitive diagnosis and staging

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¡ 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

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12/13/19 20 ¡ 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

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• A. Cardiovascular disease
• B. Malignancy
• C. Liver disease
• D. Kidney disease

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• A. Cardiovascular disease
• B. Malignancy
• C. Liver disease
• D. Kidney disease

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Hagstrom, J Hep, 2018.

43 Steatosis NASH ± F1-F2 fibrosis HCC Death/ LTx Cirrhosis Advanced F3 fibrosis 12-40% 5-10% 0-50% 8% 13% 25-50% 14% 25% 7%

Day, J Hep, 2008.

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Wong, Gastroenterology, 2015.

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¡ 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

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• A. Bariatric surgery
• B. Vitamin E
• C. Ursodiol
• D. Lifestyle modifcation for weight loss
• E. B & D

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• A. Bariatric surgery
• B. Vitamin E
• C. Ursodiol
• D. Lifestyle modifcation for weight loss
• E. B & D

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• Diet & Exercise

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Combination is best

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Avoid fructose-sweetened beverages, added sugars

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Loss of >7 - 10% weight to improve NASH+fibrosis

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Exercise alone reduces liver fat

• Aerobic >150-250 minutes per week
• Resistance training 45 minutes/day x 3 days/week
• Harrison. Hepatology, 2009.

Promrat, Hepatology , 2010 Vilar-Gomez, Gastro, 2015 Chalasani , Hepatology 2012 .

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12/13/19 26 ¡ Currently available

§ Vitamin E, pioglitazone (PIVENS trial; NEJM 2011)

¡ Potentially available in the future

§ Obeticholic acid § Elafibranor § Cenicriviroc § Many others in phase 2 trials

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¡ Tesamorelin

▪ Synthetic growth hormone-releasing hormone, targets visceral fat ▪ 60 HIV+ patients randomized to tesamorelin 2 mg or placebo SC daily x 6 months, followed by all receiving tesamorelin 2mg ▪ Modest but significant reduction in liver fat in tesamorelin group vs placebo

¡ Aramchol

▪ Fatty acid-bile acid conjugate ▪ Reduction in liver fat in phase 2 trial in primary NAFLD ▪ 50 HIV+ patients with lipodystrophy and NAFLD ▪ Failed to meet primary endpoint of improvement in liver fat at 12 weeks

Stanley TL, JAMA, 2014. Stanley TL, Lancet HIV, 2019. Safadi R, Clin Gastroenterol Hepatol, 2014. 52

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Rotman, Gut, 2017.

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¡ Statins

§ Safe for use in NAFLD § Potential benefits of NAFLD/liver enzyme improvement and

reduced risk of liver death or HCC ▪ Not proven in randomized controlled trials

¡ Metformin

§ Safe for use in NAFLD § Some studies show improvement in liver biopsy and liver

enzymes ▪ Not proven in randomized controlled trials

§ Possible anti-neoplastic effects

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¡

NAFLD is common, and most patients with metabolic syndrome comorbidities will have NAFLD, with ~16 million in the US having NASH

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NAFLD is an umbrella term that includes NAFL and NASH

§ NASH>>>NAFL has risk of progression to cirrhosis § Biopsy is needed to characterize NAFLD

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Management hinges on weight loss, exercise, avoiding added carbohydrates, metabolic syndrome control

§ Vitamin E only for biopsy-proven NASH § Many drugs in the pipeline for NASH and fibrosis

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