nash: the next liver epidemic in hiv?...2019/06/11 · nafl n=2 normal n=1 ≥f2 fibrosis n=5 ≥...
TRANSCRIPT
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NASH: the next liver epidemic in HIV?
Dr James Maurice
Royal Free Hospital London
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Disclosures
• Salary funded by Viiv 2017-2019
• Funded to attend HIV Updates Conference
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Talk Outline
Is it important?
Is HIV relevant?
Who is at risk?
How do we treat it?
What is it?
How does it develop?
Epidemiology
Pathophysiology
Management
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What is NAFLD?
Public Doctors NAFLD Specialists
….Depends who you ask
What is it?
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Histological Definitions
What is it?
Simple Steatosis Non-alcoholic Steatohepatitis (NASH)
Fibrosis Cirrhosis
Macrovesicular hepatic steatosis in the absence of a secondary cause (e.g. alcohol, steroids).
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Talk Outline
Is it important?
Is HIV relevant?
Who is at risk?
How do we treat it?
What is it?
How does it develop?
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How common is NAFLD globally?
5%
15%
25%
What is it?
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Is it important?
Yes…
• It is common • Global prevalence of 25%
• It is associated with increased mortality
• It is a (soon ‘the’) leading cause of liver transplantation (in the USA) • 2004-13, new listing with NASH increased
by 175% (vs 45% ALD & 14% HCV)
Is it important?
Hagstrom J Hep 2018
Wong Gastroenterology 2015
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Is it important?
Yes…
• Increasing hospital admissions
• The proportion with advanced disease is increasing
• Possible increased risk of de novo HCC
Is it important?
Williams Lancet 2014
Estes J Hep 2018
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Is it important?
….But
• 40% die from cardiac disease vs 4% from cirrhosis
• It takes 7-14 years for 1 stage fibrosis progression (probably an overestimate)
• Absolute numbers of liver transplant for NAFLD are relatively low in Europe
Is it important?
Belli J Hep 2018
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Talk Outline
Is it important?
Is HIV relevant?
Who is at risk?
How do we treat it?
What is it?
How does it develop?
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Normal Liver NAFL NASH Fibrosis Cirrhosis
Genetics e.g. PNPLA3 Diet (saturated fat, fructose, ?red meat) Sedentary Lifestyle
Central obesity Insulin resistance/ Type 2 DM Dyslipidaemia Hypertension
Innate Immunity
• Monocyte infiltration • Kupffer cell activation
and pro-inflammatory mediators
Hepatocellular injury & Death
• Apoptosis • Impaired
autophagy • Necrosis
Microbiome • ↑Energy Harvest • Bile acids/FXR
signalling • Translocation • ↑ethanol • ↓choline
Lipotoxicity
↓ Harmful lipids
eg palmitic acid ↓
Lipotoxicity
Disease Mechanism
Clinical Features
Genetics & Environment
HCC
Insulin Resistance ↓
Increased lipid availability (FFA)
↓ Inert lipids (TG)
↓ Steatosis
Adapted from Maurice & Manousou Clin Med 2018
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Talk Outline
Is it important?
Is HIV relevant?
Who is at risk?
How do we treat it?
What is it?
How does it develop?
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How common is NAFLD in HIV?
Is HIV relevant?
Maurice AIDS 2017
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Who is at risk of NAFLD in HIV?
Is HIV relevant?
Study Country Year n Population Diagnostic Test
NAFLD Prevalence
Fibrosis Prevalence
RF Steatosis RF Fibrosis
Pembroke Canada 2017 726 Prospective screening
Mono-infection n=538
Fibroscan/ CAP
36% 18% (LSM>7.1
kPa)
BMI, Triglycerides Time since HIV Dx, steatosis
Perazzo Brazil 2018 395 Prospective Mono-infection
only
Fibroscan/ CAP
35% 9% (LSM >8kPa)
Obesity, T2DM, Dyslipidaemia,
hypertension, MS, male gender, duration
of ART/HIV
Age, CD4
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New patients seen n=176 March 2016- October 2018
Yes N=141
No Steatosis n=35
Excluded n=36 HCV n=4 HBV n=1
Alcohol n=27 Anabolic steroids n=2
Drug reaction n=1 Acute CMV n=1 TE failure n=1
CAP≥250 and/or Steatosis on USS
Fibroscan ≥7.1kPa N=26
Fibroscan
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How common is NAFLD in HIV?
Is HIV relevant?
Steatosis Mono-infection Fibrosis
35% 5-10%
Risk Factors
OBESITY
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Does HIV impact NAFLD development?
Is HIV relevant?
• Meta-analysis: ? More steatosis in HIV populations (~35% vs ~25%)
• Price Am J Gastro 2014 and Price Hepatology 2017: MACS (2014) and WIHS/VAHH cohorts (2017), Steatosis less common in HIV+ vs HIV-
• Vodkin AP&T 2015: NASH more common in HIV 63% vs 37% (**major limitations**)
• But data is limited, no longitudinal data with hard outcomes
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Efavirenz and hepatic steatosis
What is it? Gwag et al J Hep 2019
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Translocation and ‘dysbiosis’ is not associated with NAFLD or fibrosis
Is HIV relevant?
Maurice AIDS 2019
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Translocation and ‘dysbiosis’ is not associated with NAFLD or fibrosis
Is HIV relevant?
A
≥F2 Fibrosis
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Obesity-related monocyte activation in NAFLD and fibrosis
Maurice AIDS Jan 2019
Is HIV relevant?
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Obesity-related monocyte activation in NAFLD and fibrosis
Maurice AIDS Jan 2019
Is HIV relevant?
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Obesity-related monocyte activation in NAFLD and fibrosis
Maurice AIDS Jan 2019
Is HIV relevant?
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Does HIV contribute to metabolic syndrome and obesity?
Is HIV relevant?
Quickest change in fat mass in first 96 weeks Slower increase after but >HIV neg controls Similar effect PI vs II (McComsey CID 2016)
Grant AIDS 2016
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Does HIV contribute to metabolic syndrome and obesity?
Is HIV relevant?
• More co-morbidities vs age- and sex-matched HIV- controls
• Diabetes 26vs13% • Heterogenous data on
the role of drug exposure (Systematic review Nansseu Epidemiology 2018)
Ruzicka J Infec Chemo 2018
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Is HIV relevant?
- Possible increased prevalence of steatosis- ? Drug-related
- ? potentiating obesity-related pathophysiology
- More research in larger cohorts with biopsy-proven disease required (watch this space) to assess relevant outcomes
Is HIV relevant?
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Talk Outline
Is it important?
Is HIV relevant?
Who is at risk?
How do we treat it?
What is it?
How does it develop?
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What is the most important prognostic marker for patients with NAFLD?
NASH on liver biopsy
Grade 3 steatosis
At least F3 fibrosis
What is it?
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Key risk factor = FIBROSIS NOT NASH
What is it? Angulo Gastro 2015
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Whom should we investigate/refer?
Who is at risk?
LFTs Level
ALT>200
ALT>100
ALT
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Whom should we investigate?
Who is at risk?
Fib
rosi
s P
rogr
essi
on
Symptomatic
ALT
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X
Whom should we investigate?
Who is at risk?
Steatosis Mono-infection Fibrosis
LFTs Refer
Risk Factors
Targeted Screening
Refer for Investigations &
treatment
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Who is at risk?
Obesity, metabolic Syndrome
USS/FLI Test
Consider
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Talk Outline
Is it important?
Is HIV relevant?
Who is at risk?
How do we treat it?
What is it?
How does it develop?
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Weight loss is key
How do we treat it?
5% 7% 10%
Reduced steatosis
NASH Resolution
Fibrosis Regression
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Emerging drug therapies
How do we treat it?
Drug Trial Mechanism of Action
Obeticholic Acid Regenerate (NCT02548351)
FXR Ligand
Elafibrinor RESOLVE-IT (NCT02704403)
PPAR-α/δ agoinist
Selonsertib STELLAR-3 and STELLAR-4 (NCT03053050 and NCT03053063)
ASK-1 Inhibitor
Cenicriviroc AURORA (NCT03028740)
CCR2/CCR5 antagonist
Rotman Gut 2017
Drugs in Phase 3 Development
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Emerging drug therapies (HIV population)
How do we treat it?
MavMet Trial (Sarah Pett, UCL) A multicentre, 48 week randomised controlled factorial trial of adding maraviroc and/or metformin for hepatic steatosis in HIV-1-infected adults on combination antiretroviral therapy. Design: 2x2 randomised placebo-controlled Primary Endpoint: Liver fat reduction by MRI PDFF after 48 weeks of MVC, MVC + Metformin, Metformin or placebo MASH Trial (Maud Lemoine) Maraviroc Add-On therapy for steatohepatitis in HIV Design: Single arm proof-of-concept Primary Endpoint: immune cell reduction on liver biopsy after 48 weeks MVC
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Summary
• NAFLD is an increasingly common cause of chronic liver disease
• Consequence of the obesity and the metabolic syndrome
• Only a minority develop chronic liver disease
• The role of HIV has not been clearly defined
• Longitudinal data on long term outcomes is needed
• Risk stratify using non-invasive markers
• Weight loss is central
• Enrol in clinic trials
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Thankyou!