Diagnosis & treatment of NAFLD - ICAR 2019
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Diagnosis & treatment of NAFLD
ICAR 2019
Milano, June 6th 2019
Luca Valenti
Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Italy
Translational Medicine - Transfusion Medicine and Hematology
Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico
Disclosures
Speaking fees: MSD, Gilead, AlfaSigma,
AbbVie
Consulting: Gilead, Pfizer, Astra Zeneca, Novo
Nordisk
Research grants: Gilead
Acknowledgements
MILAN
Serena Pelusi Francesca Truglio
Guido Baselli Irene Zanoni
Alice Taliento Annalisa Cespiati
Luigi Santoro
Daniele Prati
Gothenburg Dallas Palermo
Stefano Julia Kozlitina Salvo Petta
Romeo Newcastle
Quentin Anstee London
Helen Reeves
Neil Youngson
Surgery Finland
Stefano Gatti Jussi Pihlajamaki
Verona Humanitas
INGM
Domenico Girelli Massimo Colombo
Raffaele Defrancesco
Pathology Alessio Aghemo
Torino Valentina Vaira
New York
Elisabetta Bugianesi Marco Maggioni Modena Domenico
Ramy Younes Silvano Bosari Elena Corradini
Accili
Udine Roma Zurich Utpal Pajvani
Giorgio Soardo Luca Miele, Anna Alisi Felix Stickel Ira Tabas
Outline Epidemiology Diagnosis and staging Treatment Peculiarities of NAFLD in HIV+ individuals
The global prevalence of NAFLD
Type 2 Diabetes, Obesity >65%
Both >85%
Younossi, Gastroenterology 2016
The epidemic of NAFLD: data from the
general population in Italy (Sicily)
3%
No NAFLD
NAFLD
NAFLD + fibrosis
NAFLD defined
as CAP >248
Petta, Liv Int 2018
Histological spectrum of NAFLD:
From simple steatosis to NASH and HCC
Steatosis Ballooning Lobular inflammation
Peri-cellular/venular fibrosis Cirrhosis HCC
Distribution of NAFLD population by
fibrosis stage 2016 & 2030
NASH
Steatosis
1.9%
Estes, J Hepatol 2018
Liver transplantation Italy
Decompensated
23,4
22,9
HCC
20,8
18,3
16,5
14,7
%
11
8,9 8,9
8 8,2
7
6,8
4,9
4,6 4,6
3,6
2,3
1,8
1,3
0,2 0,2 0 0
HCV ALD HBV NASH AI/Chol Other HCV ALD HBV NASH AI/Chol Other
Pre-DAAs (2006-2013) Post-DAAs (2014-2017)
Ferrarese, World J Gastroenterol 2018
Outline Epidemiology Diagnosis and staging Treatment Peculiarities of NAFLD in HIV+ individuals
Flow-chart Legend: 1 Steatosis biomarkers: Fatty Liver Index, SteatoTest, NAFLD Fat score (see Tables) 2 Liver tests: ALT AST, gGT 3Any increase in ALT, AST or gGT 4 Serum fibrosis markers: NAFLD Fibrosis Score, FIB- 4, Commercial tests (FibroTest, FibroMeter, ELF) 5 Low risk: indicative of no/mild fibrosis; Medium/high risk: indicative of significant fibrosis or cirrhosis EASL-EASD-EASO 2016
Increased mortality by fibrosis stage
in NAFLD: a meta-analysis
OVERALL MORTALITY
LIVER-RELATED MORTALITY
Dulai, Hepatology 2017Nonivasive assessment of fibrosis in NAFLD:
a meta-analysis
Formula Threshold >F2
AST / PLTs x 100 >1.5
Clinical scores age x AST/PLTs x ✔ALT >3.25
-1.675 + 0.037 × age + 0.094 × BMI + 1.13 × < -1.455 = F0-F2
IFG/diabetes + 0.99 × AST/ALT – 0.013 × > +0.675 = F3-F4
PLTs – 0.66 × albumin
>7/7.9
Liver Stiffness
Measurement
Xiao, Hepatology 2017Accuracy of Fibroscan
Eddowes, Gastroenterology 2019What to do in clinical practice?
Vilar-Gomez & Chalasani J Hepatol 2018Outline Epidemiology Diagnosis and staging Treatment Peculiarities of NAFLD in HIV+ individuals
Current management of NASH
Lifestyle
interventions
Vitamin E Pioglitazone
800 IU/d 30-45 mg/d
Weight loss
5-10% of body
weight
• No long term data on these
Bariatric intervention and clinical outcomes
surgery • No specifically approved drug for
this indication
ExerciseTherapeutic approaches for NASH
ADIPOSE TISSUE
Glitazones
BRAIN GLP1 agonists
FFAs - adiponectin
Food intake
PPAR agonists TRHβ agonists
FXR agonists
ACC inhibitors
Klotho/FGFR4
Fat accumulation Aramchol
Vitamin E
FGF19 Lipotoxicity Selonsertib
FGF21 agonists Cenicriviroc
GUT Inflammation
FXR agonists
Fibrosis
Microbiome based-therapies (LOXL2 inhibitors)
GR-MD-02
Pts (%)
100
20
40
60
80
0
Vitamin E
54
800 IU/day
72
22/
Pioglitazone
69
30 mg/day
Obeticholic Acid
61
25 mg/day
Liraglutide
83
1.8 mg/day
NGM282 3mg/day
74
+ rosuvastatin
Elafibranor
35
Results from separate studies, not head to head
120 mg/day
Cenicriviroc
19
– Time points and populations may differ among studies
150 mg/day
Selonsertib 6 or 18
31
mg/day
Key NASH therapies:
30
PLACEBO
Improvement in histological steatosisKey NASH therapies:
Improvement in histological fibrosis
Results from separate studies, not head to head
– Time points and populations may differ among studies
100
80
* *
60
*
Pts (%)
41
44
35 * 42
*
37
20
40 ?
26
20
20
22/
72
0
Selonsertib 6 or 18
Obeticholic Acid
NGM282 3mg/day
150 mg/day
Cenicriviroc
120 mg/day
+ rosuvastatin
Pioglitazone
Elafibranor
1.8 mg/day
800 IU/day
PLACEBO
25 mg/day
Liraglutide
30 mg/day
Vitamin E
mg/dayOngoing Phase III Trials in NASH
Name Mechanism
Duration Primary Outcomes Inclusion criteria n
Drug of action
NASH resolution w/o fibrosis
72 W (biopsy) progression NAS score ≥4 (at least 1
RESOLVE-IT
in every component)
ELAFIBRANOR PPAR α/δ ag. ca. 4 Y (event All-cause mortality, cirrhosis, 2000
+
120 mg driven – biopsy) and liver-related clinical Fibrosis 1 - 3
outcomes
72 W (biopsy) NASH resolution w/o fibrosis
REGENERATE progression NAS score ≥4 (at least 1
OBETICHOLIC ca. 4 Y (event in every component)
ACID FXR agonist driven – biopsy) All-cause mortality, cirrhosis, 2000
+
10 mg/25 mg and liver-related clinical Fibrosis 1 - 3
outcomes
48 W (biopsy) ≥ 1-Stage Fibrosis
STELLAR 3 and 4 improvement
Anti –apoptosis NASH and F3 or F4 800
SELONSERTIB ca. 5 Y (event
Anti -fibrotic fibrosis each
6 mg/18 mg driven) Event Free Survival
48 W (biopsy) NASH resolution w/o fibrosis
CCR2 and progression
AURORA
CCR5 inhibitor ca. 5 Y (event
(ex STELLARIS) NASH and F2 or F3
(macrophages driven – biopsy) All-cause mortality, cirrhosis, 2000
CENICRIVIROC fibrosis
activation, and liver-related clinical
150 mg
fibrogenesis) outcomesREGENERATE Primary Endpoint:
Fibrosis Improvement
Study met fibrosis primary endpoint at the interim analysis at 18 mos (ITT)
Fibrosis Improvement
by ≥ 1 Stage With No NASH Worsening
100 In post hoc analysis, OCA 25 mg
associated with steatohepatitis
80 P = .0002 resolution* (placebo, 12.2%;
Patients (%)
60 OCA 10 mg, 16.3%; OCA 25 mg,
P = .04 23.1%; P = .0004 for OCA 25 mg
40 vs placebo)
23.1
17.6
20 11.9 In PP analysis, OCA 25 mg
n= 311 312 308 also associated with fibrosis
0
improvement across subgroups
Placebo OCA 10 mg OCA 25 mg defined by fibrosis stage, NAS
score, T2DM status
Younossi. EASL 2019. Abstr GS-06.Outline Epidemiology Diagnosis and staging Treatment Peculiarities of NAFLD in HIV+ individuals
HIV and risk of NAFLD/NASH
Prevalence of NAFLD/NASH in HIV+:
a meta-analysis
Maurice, AIDS 2017Key messages:
1. NAFLD is projected to become the leading
cause of ESLD and HCC by 2025
2. Diagnosing and staging rely on a combination
of non-invasive approaches to select patients
for liver biopsy
3. Lifestyle changes are the cornerstone of
treatment; initial P3 study results may lead to
the first approval of OCA for this indication
4. NAFLD is a leading cause of liver damage in
HIV+, with some distinct featuresMilan city center – Ospedale Policlinico
Marangoni pavilion Velasca tower Piazza Duomo
Ancient Ospedale Maggiore Ca’ Granda -
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