NASH: the next liver epidemic in HIV? Dr James Maurice Royal Free Hospital London
NASH: the next liver epidemic in HIV?
Dr James Maurice
Royal Free Hospital London
Disclosures
• Salary funded by Viiv 2017-2019
• Funded to attend HIV Updates Conference
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
What is NAFLD?
Public Doctors NAFLD Specialists
….Depends who you ask
What is it?
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).
Talk Outline
Is it important?
Is HIV relevant?
Who is at risk?
How do we treat it?
What is it?
How does it develop?
How common is NAFLD globally?
5%
15%
25%
What is it?
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
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
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
Talk Outline
Is it important?
Is HIV relevant?
Who is at risk?
How do we treat it?
What is it?
How does it develop?
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
Talk Outline
Is it important?
Is HIV relevant?
Who is at risk?
How do we treat it?
What is it?
How does it develop?
How common is NAFLD in HIV?
Is HIV relevant?
Maurice AIDS 2017
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
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
How common is NAFLD in HIV?
Is HIV relevant?
Steatosis Mono-infection Fibrosis
35% 5-10%
Risk Factors
OBESITY
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
Efavirenz and hepatic steatosis
What is it? Gwag et al J Hep 2019
Translocation and ‘dysbiosis’ is not associated with NAFLD or fibrosis
Is HIV relevant?
Maurice AIDS 2019
Translocation and ‘dysbiosis’ is not associated with NAFLD or fibrosis
Is HIV relevant?
A
≥F2 Fibrosis
Obesity-related monocyte activation in NAFLD and fibrosis
Maurice AIDS Jan 2019
Is HIV relevant?
Obesity-related monocyte activation in NAFLD and fibrosis
Maurice AIDS Jan 2019
Is HIV relevant?
Obesity-related monocyte activation in NAFLD and fibrosis
Maurice AIDS Jan 2019
Is HIV relevant?
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
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
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?
Talk Outline
Is it important?
Is HIV relevant?
Who is at risk?
How do we treat it?
What is it?
How does it develop?
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?
Key risk factor = FIBROSIS NOT NASH
What is it? Angulo Gastro 2015
Whom should we investigate/refer?
Who is at risk?
LFTs Level
ALT>200
ALT>100
ALT
Whom should we investigate?
Who is at risk?
Fib
rosi
s P
rogr
essi
on
Symptomatic
ALT
X
Whom should we investigate?
Who is at risk?
Steatosis Mono-infection Fibrosis
LFTs Refer
Risk Factors
Targeted Screening
Refer for Investigations &
treatment
Who is at risk?
Obesity, metabolic Syndrome
USS/FLI Test
Consider
Talk Outline
Is it important?
Is HIV relevant?
Who is at risk?
How do we treat it?
What is it?
How does it develop?
Weight loss is key
How do we treat it?
5% 7% 10%
Reduced steatosis
NASH Resolution
Fibrosis Regression
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
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
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
Thankyou!