HEPATITIS C and METABOLIC MANIFESTATIONShasld.org/images/gianhang/document/item_l87.pdf · BODY...
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HEPATITIS C and
METABOLIC MANIFESTATIONS
HUY N. TRINH, MD, AGAF SAN JOSE GASTROENTEROLOGY, MC
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Prevalence of Hepatitis C in VN
• HCV prevalence was estimated at 2%–9% among adults
• Higher prevalence rates in special populations
– IVDA - 55.6%
– Dialysis – 26.6%
– Sex workers – 8.7%
– Blood transfusion – 6%
Nakata S et al. J Gastro Hepatol, 1994
Tran HT et al. Hepatol Res. 2003; 26:275-280
Dunford, Linda et al. Plos One, Vol 7, Aug 2012
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Genotype of Hepatitis C in VN
Ho Chi Minh City
• Genotype 6: 53%
• Genotype 1: 32.6%
• Genotype 2: 18.6%
• Genotype 3: 0%
Ha Noi and Central
• Genotype 1: 60%
• Genotype 6: 35.8%
• Genotype 3: 1.8%
• Genotype 2: 0.4%
Dunford, Linda et al. Plos One, Vol 7, Aug 2012
Virology, 2014 November; 0:197-206
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BODY MASS INDEX
Overweight Obese
Caucasian BMI 25-29.9 kg/m2 >30 kg/m2
Asian BMI 23-27.4 kg/m2 >27.5 kg/m2
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Prevalence of Obesity in VN
VIETNAM Overweight % Obesity %
Males 9.5 1.2
Females 10.9 2.1
USA 34.5 34.9
Ashtari S; World J Hepatol, 2015 July8: 1788-1796
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Insulin Resistance
• A condition in which organs do respond properly to body produced insulin
• insulin resistance score (HOMA-IR)= fasting plasma glucose (mmol/l) X fasting serum insulin (mU/l)/ 22.5.
• Low HOMA-IR values indicate high insulin sensitivity
• High HOMA-IR values indicate low insulin sensitivity (insulin resistance).
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Metabolic Syndrome
a group of risk factors increases risk for heart disease, diabetes and stroke
• Abdominal Obesity
– Waist circumference > 102cm in men
– Waist circumference > 88cm in women
• Hypertriglyceridemia >150mg/dl
• Low HDL level: <40 mg/dl in men; <50mg/dl in women
• High blood pressure (>130/85mm/Hg)
• High fasting glucose (>110mg/dl)
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Prevalence of Metabolic Syndrome in VN
• 15.8% in age >54
• 16.3% in Red River Delta Region
Binh et al. Endocrine Disorders, 2014, 14:77
Huy Tran. J Geriatric Cardiology, Dec 2004
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Fatty Liver Disease
NALDF NASH Normal
• Perisinusoidal fibrosis
• Lobular inflammation
• Mallory hyaline
•Ballooning degeneration
• Steatosis
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Fatty Liver Disease
Steatosis alone
NASH
10%-20%
HCV
By itself
Cirrhosis
Benign
Aggressive
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Risk factors for NALDF/NASH
• Diabetes
• Metabolic Syndrome
• Hyperlipidemia
• Obesity (high BMI)
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Metabolic Effects of Hepatitis C
• Insulin Resistance
• Diabetes
• Metabolic Syndrome
• Steatosis
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Prevalence of IR in HCV
1. Prospective, single-center, observational cohort study of 500 CHC patients1
• 32.4% overall prevalence of IR excluding diabetic patients (n=38%)
• 40.1% prevalence of IR in GT 1 and 4 patients
2. Retrospective, single-center, study of 69 CHC, genotype 1 patients2
• 64% prevalence of IR
3. Prospective, single-center, study of 201 CHC, genotype 1 patients3
• 52.7% prevalence of IR
1Moucari R, et al. Gastroenterology. 2008;134:416-423. 2 Harrison SA. Hepatology 2006; 3 Petta S, et al. Am J Gastroenterol 2008;103;1136-1144.
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Insulin Resistance and HCV Viral Load
• IR defined as a HOMA > 3
• High viral load > 600,000 IU/mL
• HVL associated with IR 55.3% versus 42.3% for LVL, p=0.009
Moucari et al, Gastroenterology 2008;134:416-423.
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Association of Insulin Resistance and Fibrosis Progression
• IR associated with moderate to severe inflammation
• HOMA increased significantly with fibrosis stage (p<0.001)
• By logistic regression, IR independently associated with significant fibrosis
Moucari et al, Gastroenterology 2008;134:416-423.
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Association of Insulin Resistance and Fibrosis Progression
• 260 patients with CHC, 48% GT 1
• Single Center experience
• IR is a predictor of the stage of fibrosis and rate of fibrosis progression
Hui et al, Gastroenterology 2003;125;1695-1704
GT 3
GT non-3
Mean HOMA:
GT 1: 3.2 GT 3: 2.4
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Diabetes in non-cirrhotic HCV patients
Knobler H et al, Mayo clin Proc 2000, 75:355-359
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HCV and Diabetes
• After adjustment for confounders, patients with HCV (>40 yrs) were more likely to have type 2 DM: OR 3.77 (95% CI, 1.80-3.87)
0
5
10
15
20
25
30
35
40-49 50-59 60-69
Pre
va
len
ce
of
typ
e 2
DM
(%
)
+HCV
-HCV
NHANES III
N=9841
Mehta et al. Annals of Int Med 2000
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Chronic HCV Infection: Insulin Resistance and Diabetes
• HCV infection is associated with the development of insulin resistance (precursor of type 2 diabetes mellitus)
• HCV infection predisposes to insulin resistance regardless of liver disease severity
• Though the relationship is not understood, the incidence of diabetes is increased in patients with HCV. In fact, it is greater than 3 fold greater if the HCV-infected patients are also over 40 years old.
• Prevalence of diabetes mellitus
– Increasing in HCV-infected subjects compared to general population, and to patients with other etiologies of liver disease
• Further, HCV associated with diabetes and/or insulin resistance increases the risk for HCC and accelerated liver fibrogenesis
• Treatment of HCV in diabetics is associated with reduced risk of end stage
renal disease and ischemic stroke
Aghemo A,et al. Hepatology. 2012;May 22. [Epub ahead of print].
White DL, et al. J Hepatol. 2008;49:831-844.
Ko HM, Hernandez-Prera JC, Zhu H, et al. Morphologic Features of Extrahepatic Manifestations of Hepatitis C Virus Infection.
Clinical and Developmental Immunology. 2012; Article ID 740138.
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HCV and Metabolic Syndrome
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
50%
HCV NHANES III
MS%
SVR GT 1:
MS: 21.6%
No MS: 42.7% p=0.009
Hanouneh IA, et al. Clin Gastro Hepatol 2008;6:584-589.
*NS
26% 22%
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HCV and Metabolic Syndrome
0
0.2
0.4
0.6
0.8
1P
rev
ale
nc
e o
f M
eta
bo
lic
Sy
nd
rom
e (
%)
)N=69(HCV/NAFLD
)N=75(HCV Controls
Sanyal A et al Am J of Gastro 2003
P<0.001
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Metabolic Syndrome vs HCADS
Ballestri S et al. Int. J. Mol. Sci 2016,17,355
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HCV and Steatosis
• Sources of Steatosis in HCV
– In chronic hepatitis C, steatosis is common (40%-70%)
– Sources of steatosis:
• Viral factors
• Host factors
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Source of Steatosis in HCV
• BMI / obesity
• Diabetes / insulin resistance
• Increased leptin (?)
Host Factors Affecting Steatosis in HCV
Hourigan 1999, Ong 2001, Adinolfi 2001,
Westin 2002, Hickman 2003, Hui 2003,
Poynard 2003, Rubbia-Brandt 2004,
Hu 2004, Younossi 2004
Giannini 1999, Ellidokuz 2003,
Romero-Gomez 2003, Piche 2004
Mason 1999, Caronia 99, Mehta 2000,
Ong 2001, Hui 2003, Sanyal 2003
Metabolic syndrome
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Source of Steatosis in HCV
• HCV genotype 3
• HCV core protein (?)
HCV Viral Factors Associated with Steatosis
Fayyzi M et al. Hepatology 1997
Adinolfi et al. E J Gastro Hepatology 2000
Rubbia-Brandt et al. J Hepatology 2000
Rubbia-Brandt et al. Histopatology 2001
Westin J et al. J Heptaology 2002
Hui J et al. Gastro 2003
Asseleh T et al. Gut 2003
Poynard T et al. Hepatology 2003
Sharma P et al. DDS 2004
Rubbia-Brandt et al. Gut 2004
Younossi Z et al. J Clin Gastro 2004
Moriya K et al. J of Gen Virology 1997
Fujie H et al. J of Med Virology 1999
Perlemuter G et al. FASEB 2002
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Viral Factors in Hepatic Steatosis
• Chronic Hepatitis C: N=755
• Steatosis: 41.7%
• Independent predictors of steatosis:
– HCV genotype 3, obesity (BMI), ETOH (current), and age
Rubbia-Brandt et al. GUT 2004
HCV genotype 3 is the most important viral factor
associated with steatosis
HCV Viral Factors Associated with Steatosis
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Interactions of HCV on steatosis
Patel A, Gastro and Hepatol 2012, vol 8, 305-312
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Proposed pathogenesis for hepatic steatosis in patients with CHC
Harrison SA, Clin Gastro Hepatol 2008
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Metabolic Effects of HCV and HCC
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Insulin Resistance and Incidence of HCC
Hayashi et al. Infectious Agents and Cancer (2016) 11:9
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HCC Risk Remains High After SVR
With PegIFN ± RBV • Retrospective VA cohort study of HCV-infected pts treated with
pegIFN ± RBV from 1999-2009 (N = 22,028)
• HCC incidence rate 3.27/1000 PY with SVR vs 13.2/1000 PY
without SVR (HR: 0.358)
El-Serag HB, et al. AASLD 2015. Abstract 90. Reproduced with permission.
Predictor of HCC Following SVR* HR (95% CI) P Value
Cirrhosis at time of SVR 4.45 (2.53-7.82) < .0001
Age at SVR, yrs (vs younger than 55 yrs)
55-64 2.40 (1.53-3.77) .0002
65 or older 4.69 (2.04-10.78) .0003
Diabetes 2.07 (1.35-3.20) .0010
HCV GT (vs GT1)
2 0.56 (0.32-1.01) .0522
3 1.91 (1.14-3.18) .0131
*Cox proportional hazards model adjusted for competing risk of death.
Slide credit: clinicaloptions.com
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Metabolic Effects of HCV and HCC
• Insulin Resistance has a strong impact on the development of HCC in non-cirrhotic patients
• Type II Diabetes is established factor for cirrhosis and HCC especially with chronic HCV patients
• NALDF patients can develop HCC without evidence of cirrhosis
Hayashi et al. Infectious Agents and Cancer 2016, 11:9
Ertle, J et al. Int. J. cancer 2011, 128,2436-2243
Raff, E.J. et al. J. clin. Tranl. Hepatol. 2015, 3, 9-16
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Metabolic Effects on HCV Treatment Response with Peg Interferon
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SVR Decreased in Insulin Resistant Patients with HCV Genotype 1
61%
40%
20%
0%
20%
40%
60%
80%
100%
SV
R%
Homa <2 Homa 2-4 Homa >4
Romero-Gomez et al. Gastroenterology 2005;128:636-41.
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SV
R (
%)
44 42 44
30 28 33
0
20
40
60
80
PEG-2b 1.5 mcg/kg/wk
PEG-2b 1.0 mcg/kg/wk
PEG-2a 180 mcg/wk
Normal High
Normal = fasting glucose < 100 mg/dL; High = fasting glucose >100 mg/dL.
Subjects through fasting glucose > 140 mg/dL were excluded.
Sulkowski M, et al. EASL 2008
PEG-IFN/RBV Treatment of Hepatitis C by Baseline
Glucose Intolerance: SVR Results from IDEAL
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The Impact of Superimposed Steatosis or Its Risk Factors on HCV Treatment (cont)
Treatments: IFN -2b 3 MU TIW + RBV 1000 –1200 mg/day for 48 wks or Peg-IFN -2b 1.5
g/kg/wk for 4 wks followed by 0.5 g/kg/wk for 44 wks + RBV 1000 – 1200 mg/day or Peg-IFN -
2b 1.5 g/kg/wk + RBV 800 mg/day for 48 wks
Poynard T et al. Hepatology 2003;38:75-85.
Geno 2
F0-1
SV
R (
%)
96%
59%
F2,3,4
59%
High Viral
Load
57% 51% 39%
Geno
1,4.5.6
Geno
1,4.5.6
High V Load
Geno
1,4.5.6
High V Load
F2,3,4
No steatosis
n=364
86%
41% 40% 35% 24%
21%
Steatosis
n=670
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Why Is There A Decreased Response with PegInterferon?
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The Impact of Superimposed Steatosis or Its Risk Factors on HCV Treatment (cont)
• Insulin may prevent IFN-mediated HCV suppression
• Obesity may inhibit IFN signaling in the liver
Sanyal AJ et al. AASLD 2004
Walsh M et al. Gut 2005
Potential Mechanisms for Decreased
Response to Antiviral Therapy
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Obesity
Inflammation
Oxidative
Stress
Impaired IFN-
Signaling1
Increased/altered
cytokine release and
function2,3
1 Di Bona D, et al. J Hepatol. 2006;45:271-279.
2 Larrea E, et al. Hepatology. 1996;23:210-217.
3 Walsh MJ, et al. Gut. 2006;55:529-535.
4 Lin W, et al. Gastroenterology. 2005;128:1034-41.
5 Luquin E, et al. Antiviral Res. 2007;76:194-197.
HCV core protein disrupts
JAK/STAT pathway as well 4,5
SVR
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The Impact of Superimposed Steatosis or Its Risk Factors on HCV Treatment (cont)
• Hepatitis C and steatosis (N=19)
• Three-month weight reduction program – Weight loss 5.9±3.2 kg
– Decrease in waist of 9.0±5.0 cm
– Fasting insulin 16±7 to 11±4 mmol/l
– ALT improved (16/19)
– Patients with paired biopsy (N=10) • 9 pts showed reduction in steatosis, improvement in
fibrosis (3:1), and activated stellate cells
Hickman et al. GUT 2002
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Metabolic Effects on HCV treatment with DAA
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The ASTRAL Phase 3 Program (N=1408)
43
ASTRAL-1
GT 1, 2, 4‒6
TN, TE
NC, CC
ASTRAL-2
GT 2
TN, TE
NC, CC
ASTRAL-3
GT 3
TN, TE
NC, CC
ASTRAL-4
GT 1‒6
TN, TE
CTP-B Cirrhosis
‡
Primary endpoints
– SVR12
– Discontinuations due to AEs
n=624
n=116
Wk 0 Wk 12
n=134
n=132
Wk 0 Wk 12
n=277
n=275
Wk 0 Wk 12
SOF + RBV
SOF/VEL
Wk 24 Wk
0
Wk 12
SOF/VEL
Wk 24
n=90
n=87
n=90
SOF/VEL + RBV
SOF/VEL
SOF/VEL
Placebo
SOF/VEL
SOF+RBV
ASTRAL-5
GT 1‒4
TN, TE
NC, CC
HIV/HCV Co-Infection
n=106
Wk 0 Wk 12
SOF/VEL
Feld, AASLD, 2015, LB-2. Feld JJ, et al. N Engl J Med. 2015; Sulkowski, AASLD, 2015, 205. Foster GR, et al. New Engl J Med. 2015.; Mangia, AASLD, 2015, 249. Foster GR,
et al. New Engl J Med. 2015, Charlton, AASLD, 2015, LB-13. Curry MP, et al. New Engl J Med.2015. Wyles, EASL 2016, PS104
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Integrated Efficacy Analysis of SOF/VEL for 12 Weeks
Agarwal, EASL 2016, Poster SAT-195 44
ASTRAL-1, -2, -3
Retrospective integrated analysis of data from 1,035 SOF/VEL patients in
ASTRAL-1, -2, and -3
Baseline Demographics
The ASTRAL-1, -2, and -3 studies enrolled patients with baseline characteristics
historically associated with poor response
Patients, n (%) GT1
n=328
GT2
n=238
GT3
n=277
GT4
n=116
GT5
n=35
GT6
n=41
Total
N=1035
Cirrhosis 73 (22) 29 (12) 80 (29) 27 (23) 5 (14) 6 (15) 220 (21)
Platelets <100 x 103/µL 21 (6) 4 (2) 25 (9) 8 (7) 1 (3) 3 (7) 62 (6)
Albumin <3.5 mg/dL 6 (2) 1 (<1) 8 (3) 6 (5) 0 0 21 (2)
Fibroscan ≥15 kPa 30 (16) 9 (7) 40 (20) 17 (19) 4 (17) 5 (19) 105 (16)
HCV RNA ≥800,000 IU/mL 255 (78) 186 (78) 191 (69) 74 (64) 26 (74) 31 (76) 763 (74)
Treatment experienced 110 (34) 44 (18) 71 (26) 52 (45) 11 (31) 3 (7) 291 (28)
Black race 25 (8) 19 (8) 3 (1) 14 (12) 0 0 61 (6)
Age ≥65 years 36 (11) 53 (22) 7 (3) 11 (10) 16 (46) 0 123 (12)
BMI ≥35 kg/m2 20 (6) 18 (8) 21 (8) 8 (7) 3 (9) 0 70 (7)
HbA1c ≥6.5% 21 (6) 9 (4) 13 (5) 10 (9) 3 (9) 4 (10) 60 (6)
NS5A RAVs (15% cut off) 50 (15) 146 (61) 31 (11) 69 (59) 3 (9) 19 (46) 318 (31)
‡
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Integrated Efficacy: SVR12
Agarwal, EASL 2016, Poster SAT-195 45
ASTRAL-1, -2, -3
SV
R12 (
%)
98 99 95 100 97 100
0
20
40
60
80
100 98
Total
1015
1035
323
328
264
277
116
116
34
35
41
41
237
238
GT 1 GT 2 GT 3 GT 4 GT 5 GT 6
‡
2 relapse
2 LTFU
1 D/C 1 D/C
11 relapse
2 D/C 1 death
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Patients,
n(%)
SVR% (n/n)
GT1
n=328
GT2
n=238
GT3
n=277
GT4
n=116
GT5
n=35
GT6
n=41
Total
n=1035
Cirrhosis Yes 99 (72/73) 100 (29/29) 91 (73/80) 100 (27/27) 100 (5/5) 100 (6/6) 96 (212/220)
No 98 (251/255) 99 (207/208) 97 (191/197) 100 (89/89) 97 (28/29) 100 (35/35) 99 (801/813)
Platelets <100 x 103/μL 95 (20/21) 100 (4/4) 88 (22/25) 100 (8/8) 100 (1/1) 100 (3/3) 94 (58/62)
≥100 x 103/μL 99 (303/307) 99 (233/234) 96 (242/252) 100 (108/108) 97 (33/34) 100 (38/38) 98 (957/973)
Albumin <3.5 mg/dL 100 (6/6) 100 (1/1) 88 (7/8) 100 (6/6) 0 0 95 (20/21)
≥3.5 mg/dL 98 (317/322) 99 (236/237) 96 (257/269) 100 (110/110) 97 (34/35) 100 (41/41) 98 (995/1014)
FibroScan ≥15 kPa 100 (30/30) 100 (9/9) 90 (36/40) 100 (17/17) 100 (4/4) 100 (5/5) 96 (101/105)
<15 kPa 98 (154/158) 99 (118/119) 97 (152/156) 100 (74/74) 95 (19/20) 100 (22/22) 98 (539/549)
Treatment
experienced
Experienced 99 (109/110) 100 (44/44) 90 (64/71) 100 (52/52) 100 (11/11) 100 (3/3) 97 (283/291)
Naïve 98 (214/218) 99 (193/194) 97 (200/206) 100 (64/64) 96 (23/24) 100 (38/38) 98 (732/744)
NS5A RAVs
(15% cut off)
With RAVs 96 (48/50) 100 (146/146) 87 (27/31) 100 (69/69) 100 (3/3) 100 (19/19) 98 (312/318)
Without RAVs 99 (275/278) 99 (89/90) 96 (236/245) 100 (46/46) 97 (31/32) 100 (21/21) 98 (698/712)
SVR12 per negative predictor
Agarwal, EASL 2016. Poster #SAT-195 46
ASTRAL-1, -2, -3 ‡
GILEAD CONFIDENTIAL
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Diabetes and Hyperlipidemia Compromise SVR with DAA treatment
Nasrollah L et al
Gastroenterology 2015;
148 (Suppl 1): S-1087
[DOI:n10.1016
• Overall SVR: 81%
• Lower SVR if
pretreatment fasting
glucose >126mg/dl
hyperlipidemia
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Does Eradication of HCV improves its Metabolic Effects
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Treatment Response Improves IR
• HOMA-IR decreased in HCV patients who achieved SVR but not in non reponders and relapsers
Kwaguchi T et al. Am J Pathol 2004: 165:1499-1508
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SVR With PegIFN + RBV Reduces Development of New-Onset Insulin Resistance
• Extended follow-up sub-study of the MIST study – Non-diabetic, white HCV-infected
patients treated with pegIFN + RBV (n=399)
• Male: 58%
• Age: 51.8 years
• BMI >25 kg/m2: 46%
• Genotype 1/4: 50%
• Fibrosis stage >4: 29%
• HOMA score: 1.15
• SVR rate: 63%
• New-onset insulin resistance (matched measurements) – 10.7% (n=38/354)
MIST Study Cohort:
Rate
(%
)
SVR (n=230)
Non-SVR (n=124)
17%
Rate of De-Novo Insulin Resistance
7%
Aghemo A,et al. Hepatology. 2012;May 22. [Epub ahead of print].
P=0.007
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51 ©2016 GILEAD ǀ CONFIDENTIAL
SVR May Lower Cumulative Incidences of
HCV-Related Comorbidities
Two retrospective studies in Japan showed that SVR reduced the cumulative incidences of type 2
diabetes mellitus1 and hemorrhagic stroke2
1. Arase Y, et al. Hepatology. 2009;49:739-744.
2. Arase Y, et al. J Med Virol. 2014;86:169-175.
3. Arcaini L, et al. Ann Oncol. 2014;25:1404-1410.
4. Hsu YC, et al. Hepatology. 2014;59:1293-1302.
Cu
mu
lati
ve
In
cid
en
ce
(%
)
Non-SVR/SVR
HRa=2.78 (1.75-4.41); P<0.001
40
30
20
10
0 0 10 20
Non-SVR
(N=1667)
SVR
(N=1175)
Follow-up (y)
P<0.001
Type 2 Diabetes1
HCV nonclearance/clearance
HRa=3.22 (1.22-8.53); P=0.018
Cu
mu
lati
ve
In
cid
en
ce
(%
)
8
6
4
2
0 0 10 30
HCV nonclearance
(N=2577)
HCV clearance
(N=2125)
Follow-up (y)
P=0.020
20
0.4%
0.1%
1.1%
0.4%
1.1%
2.0%
Hemorrhagic Stroke2
Patient cohorts from the Toranomon Hospital, Japan: 2842 CHC patients were treated with an IFN-based regimen between September 1990
and March 20071; 4649 CHC patients were treated between September 1990 and May 2010.2
HCV clearance was defined as clearance of HCV RNA at 6 months after the cessation of therapy. aCox regression analysis.
Antiviral treatment has shown benefit for other comorbidities, such as lymphoma,3 end-stage renal
disease,4 and ischemic stroke4
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Treatment Response Improves Steatosis
Genotype 3 Other Genotype
Improvement of at least one grade
77% 29%
Disappearance of steatosis 46% 29%
T. Poynard et al. Hepatology, Jully 2003, 75-85
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Eradication of Hepatitis C
• Improve and resolve Insulin resistance and Diabetes
• Improve and resolve steatosis especially in genotype 3
• Reduce and prevent HCC
T. Poynard et al. Hepatology, Jully 2003, 75-85
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SUMMARY
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Hepatitis C
Insulin Resistance
Diabetes ObesityMetabolic Syndrome
Steatosis
CirrhosisLiver
Cancer
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Summary
• Treat hepatitis C - treat early!
• Eradication of HCV may reduce Insulin Resistance and prevent Diabetes, Metabolic syndrome and Steatosis
• Weight reduction before treatment if patients are treated with Interferon and have BMI greater than 27kg/m2
• HCC surveillance in treatment response cirrhotic and diabetic patients
• Alcohol reduction
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