1. results of the METAFIB study
24th July 2017
Metabolic syndrome and obesity are the cornerstones of liver fibrosis in HIV-monoinfected patients:
results of the METAFIB study
Maud Lemoine1, Karine Lacombe2, Jean Philippe Bastard4, Manuela Sébire2, Laurent Fonquernie2, Nadia Valin2, Soraya Fellahi4, Jacqueline Capeau4, , Pierre-Marie Girard2, Jean-Luc Meynard2
1 Liver unit, St Mary’s Hospital, Imperial College London, UK,
2 Department of Infectious and Tropical Diseases, Saint-Antoine Hospital, Paris, France
3 Department of Biochemistry and Hormonology, Tenon hospital, INSERM, Paris, France.

2. Disclosure Consultancies and lectureships: MSD, Viiv
Research grants and clinical trials: Gilead, BMS, Viiv

3. Rational
1- Metabolic syndrome and its hepatic manifestation, nonalcoholic fatty liver disease (NAFLD), have emerged as new concerns in HIV subjects (prevalence: 25% and 35%, respectively)
2- Liver fibrosis and its pathophysiology have been poorly assessed in HIV-monoinfected patients
Nguyen KA et al. Plos One 2016
Maurice, J et al. AIDS 2017

4. METAFIB study- Objectives
1. To assess the impact of MetS on the proportion and severity of liver fibrosis in HIV-monoinfected patients
2. To analyze the association between MetS, liver fibrosis and markers of adipose tissue and macrophage activation.

5. METAFIB study- Methods
Single center, exposed – nonexposed cohort of HIV1- monoinfected patients without excessive alcohol consumption, HBV/HCV coinfections or other causes of chronic liver disease
Exposure defined as the presence of MetS (IDF criteria)
Patients nonexposed to MetS matched to exposed patients,
on age, sex and duration of HIV infection
Liver fibrosis: liver stiffness measurement (LSM,Fibroscan)
Circulating inflammatory markers:
- Adipokines: leptin, adiponectin, IL6
- HsCRP
- sCD163 and CD14 (macrophage activation)

6. Results Number of screened patients: n = 478
Number of included patients:
n=468
(246 MetS+, 222 MetS-)
63 patients with invalid LSM results
(19 failures and 44 unreliable results)
Number of patients with valid LSM:
n=405
(203 MetS+, 202 MetS-)

7. Study population (1) Study population n=405 Patients with MetS, n=203
Patients without
MetS, n=202
P value
Mean age, years, (SD)
53 (9)
54 (9)
52 (8)
0.02
Males, n (%)
359 (89)
183 (90)
176 (87)
0.4
Duration of HIV infection (years)
17.0 (7.0)
16.9 (6.8)
17.0 (7.3)
0.9
CD4 cells count (per mm3)
617 (257)
628 (239)
607 (273)
0.2
HIV1-VL<20 copies/mL (n,%)
323 (79.8)
160 (78.8)
163 (80.7)
0.7
Metabolic parameters
Mean BMI, kg/m2, (SD)
24.6 (5.3)
26.0 (4.7)
23.2 (5.5)
0.0001
Obesity: BMI ≥30kg/m2 n (%)
34 (8.4)
27 (13.3)
7 (3.5)
Type 2 Diabetes (n=404), n (%)
33 (8.2)
31 (15.3)
2 (1.0)
HOMA score ≥2.5 (n,%),
116 (29)
99 (49)
17 (8.5)
HDL-cholesterol (mmol/L)
1.21 (0.37)
1.06 (0.30)
1.36 (0.37)
LDL-cholesterol (mmol/L)
2.95 (1.04)
2.80 (1.25)
3.11 (0.74)
Triglycerides (mmol/L)
1.89 (1.78)
2.40 (1.65)
1.37 (1.75)
Fasting glucose (mmol/L)
5.47 (1.20)
5.85 (1.48)
5.09 (0.64)

8. Study population (2) Study population n=405 Patients with MetS, n=203
Patients without
MetS, n=202
P value
Hepatic parameters
AST (IU/L)
29 (20)
31 (19)
27 (20)
0.0001
ALT (IU/L)
34 (27)
41 (34)
28 (15)
GGT (IU/L)
52 (52)
62 (64)
42 (33)
Serum inflammatory markers
n=396
n=199
n=197
Hs CRP (mg/L)
3.50 (4.94)
3.69 (4.88)
3.32 (5.01
0.07
Hs IL-6 (pg/mL)
2.22 (4.33)
2.16 (3.40)
2.28 (5.12)
0.4
Leptin (ng/mL)
7.99 (11.48)
10.52 (13.19)
5.44 (8.76)
Total adiponectin (µg/mL)
4.39 (2.83)
3.36 (2.27)
5.44 (2.95)
HMW adiponectin (µg/mL)
2.13 (1.95)
1.39 (1.44)
2.87 (2.12)
Leptin/adiponectin ratio
2.56 (4.76)
3.92 (6.16)
1.19 (1.87)
sCD14 (ng/mL)
(736.0)
(1019.3)
sCD163 (ng/mL)
(293.82)
778.1 (298.6)
643.3 (273.4)

9. Prevalence of liver fibrosis

10. Inflammatory markers and fibrosis
Fibrosis ≥ F2
n=66
Fibrosis<F2
n=330
P value
Cirrhosis
n=17
No cirrhosis
n=388
Hs CRP (mg/L)
4.56 (5.17)
3.29 (4.88)
0.0008
5.32 (4.38)
3.41 (4.96)
0.002
Hs IL6 (pg/mL)
2.22 (4.66)
2.42 (2.02)
0.03
2.51 (1.60)
2.21 (4.43)
0.02
Leptin (ng/mL)
12.86 (16.92)
7.02 (9.80)
0.0001
18.0 (18.0)
7.49 (10.84)
Total adiponectin (µg/mL)
3.72 (2.86)
4.53 (2.81)
0.004
3.18 (2.16)
4.45 (2.84)
0.01
HMW adiponectin (µg/mL)
1.71 (2.09)
2.22 (1.92)
0.003
1.30 (1.59)
2.17 (1.96)
Leptin/adiponectin ratio
5.36 (9.68)
2.00 (2.60)
8.16 (10.41)
2.28 (4.11)
sCD14 (ng/mL)
(765.2)
(915.8)
0.3
(626.9)
(903.2)
0.8
sCD163 (ng/mL)
797.5 (301.1)
693.7 (289.7)
893.7 (300.6)
701.8 (290.9)
Levels of inflammatory except CD14 significantly differ with the degree of liver fibrosis

11. Risk factors of liver fibrosis (1)
Liver fibrosis ≥ F2
OR (95%CI)
Liver fibrosis ≥ F3
Cirrhosis
BMI (kg/m2)
1.13 (1.05 – 1.21)
1.07 (1.02 – 1.13)
1.09 (1.03 – 1.16)
Waist circumference (cm)
1.03 (0.99 – 1.06)
1.05 (1.009 – 1.09)
1.09 (1.03 – 1.15)
Obesity: BMI ≥30kg/m2
3.13 (1.45 – 6.73)
3.59 (1.52 – 8.49)
5.29 (1.88 – 14.94)
Type 2 diabetes
1.46 (0.64 – 3.32)
2.09 (0.85 – 5.17)
3.44 (1.18 – 10.06)
HOMA score (mU/mmol)
1.09 (1.02 – 1.17)
1.12 (1.04 – 1.21)
1.012 (1.03 – 1.23)
GGT (IU/L)
1.005 (1.00 – 1.009)
1.005 ( – 1.01)
1.005 ( – 1.01)
Leptin (ng/mL)
1.03 (1.005 – 1.05)
1.02 (1.001 – 1.05)
1.03 (1.006 – 1.06)
Leptin/adiponectin ratio
1.12 (1.04 – 1.20)
1.05 (0.99 – 1.11)
1.08 (1.01 – 1.15)
sCD163 (ng/mL)
1.01 (1.00 – 1.00)
1.01 (1.00 – 1.001)
1.001 (1.0 – 1.002)
Association between levels of liver fibrosis and covariates after adjustment on the presence of MetS (bivariate analysis)
Liver transaminases levels, ART exposure or HIV parameters were not associated with liver fibrosis

12. Risk factors of liver fibrosis (2)
Liver fibrosis ≥ F2
OR (95%CI)
Liver fibrosis ≥ F3
Cirrhosis
Parameters
unadjOR (CI95%)
adjOR (CI95%)
P value
MetS
3.9 (2.1 – 7.1)
2.3 (1.1 – 4.8)
0.02
6.1 (2.5 – 15.0)
4.3 (1.6 – 11.8)
0.05
9.1 (2.1 – 40.1)
7.9 (1.5 – 42.2)
Obesity (BMI≥30kg/m2)
4.2 (2.0 – 8.8)
3.2 (1.3 – 7.5)
0.009
5.1 (2.2 – 11.7)
3.0 (1.1 – 8.4)
0.03
7.8 (2.8 – 21.3)
4.3 (1.1 – 16.7)
Mutivariate analysis of risk factors for fibrosis and cirrhosis

13. Conclusion
HIV-monoinfected patients with MetS are at risk of liver fibrosis and should be systematically screened for liver fibrosis irrespective of transaminases levels or HIV parameters
2. Mass fat measured by BMI and circulating level of leptin is strongly associated with liver fibrosis independently of HIV parameters and ART exposure.
3. Adipose tissue (leptin), insulin resistance (leptin/adiponectin ratio) and macrophage activation (sCD163) are probably key players in the development of liver fibrosis in HIV-monoinfected patients

14. Discussion
Liver fibrosis assessment based on noninvasive marker (fibroscan)
No liver histology
No analysis of liver steatosis and NASH

15. The medical team Saint-Antoine Hospital, Paris
Acknowledgment
The medical team Saint-Antoine Hospital, Paris
Hayette Rougier
Prof. Lawrence Serfaty
The patients
INSERM/ANRS
IMEA