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!