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Alexander Monto, MDProfessor of Clinical Medicine
University of California San FranciscoSan Francisco, California
Review of Issues in Liver Disease for the Nonhepatologist
FORMATTED: 10/19/16
New York, New York: November 4, 2016
Slide 4 of 36
Introduction• Liver is largest internal organ in body (~3‐4 lbs.), and the largest
gland• Receives blood through: a) portal venous system, containing all
nutrients and chemicals taken in through the GI tract, and b) hepatic artery
• Principal jobs: ‐ Protein, lipid, cholesterol synthesis and metabolism‐ Glucose metabolism/glycogen storage‐ Production of bile, which emulsifies lipids, aiding in digestion‐ Detoxifying/metabolizing many medications/foreign substances‐ Unique immune responses
Slide 5 of 36
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Slide 6 of 36
Most Common Causes of Chronic Liver Disease in the United States
#1: NASH/fatty liver disease: 23 million
#2: Alcohol: 8‐10 million
#3: Chronic Hepatitis C: 3‐6 million
#4: Chronic Hepatitis B: 1‐2 million
#5: Hemochromatosis: <100,000
#6: Primary Biliary Cirrhosis: 60,000
Lower: autoimmune hepatitis, PSC
Slide 7 of 36
CIRRHOTIC LIVER
Slide 8 of 36
Risks of Complications of Cirrhosis
Cirrhosis
VaricealBleeding
HCC
Ascites
Encephalopathy
adapted from Bennett WG et al, Ann Intern Med 1997;127:855
0.4%
3-5%2.5%
1.1%
percent per year
Death
Liver Transplant
11%
?20+%
?30+%
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Slide 10 of 36
Fibrosis Assessment
Clinical findings
Physical exam (firm liver edge, splenomegaly, palmar erythema, spider angiomata)
Low platelets (< 100,000/μL)
Abdominal images Surface abnormalities (including dilate portal vein diameter, intraabdominal collaterals, splenomegaly)
Serum markers of fibrosis APRI, FIB‐4, FibroSure (FibroTest)
Liver biopsy Useful in establishing the stage but invasive
Liver fibrosis imaging Ultrasonography (transient elastography, ARFI), MRE, MRI, CT, etc.
APRI = aspartate aminotransferase‐to‐platelet ratio index; ARFI = acoustic radiation force imaging; MRE = magnetic resonance elastography; MRI = magnetic resonance imaging; CT = computed comography.Leroy V, et al. J Hepatol. 2014;S0168‐8278(14)00137‐8; Holmberg SD, et al. Clin Infect Dis. 2013;57(2):240‐246; Chou R, Wasson N. Ann Intern Med. 2013;158(11):807‐820; Poynard T, et al. J Hepatol. 2014;60(4):706‐714; Udell JA, et al. JAMA. 2012;307(8):832‐842; de Lédinghen V, Vergniol J. Gastroenterol Clin Biol. 2008;32(6 Suppl 1):58‐67; Tapper EB, et al. Clin Gastroenterol Hepatol. 2014;S1542‐3565(14)00818‐0; Smith JO, et al. Aliment Pharmacol Ther. 2009;30(6):557‐576; Bonekamp S, et al. J Hepatol. 2009;50(1):17‐35.
Slide 11 of 36
Alternatives to Biopsy• Imaging
– CT/MRI• Good only in the extreme
– cirrhosis vs no cirrhosis• Identification of spleen size, portal vein size, nodularity, heterogeneity, etc.
– US• Contrast enhanced
– Hepatic vein transit time– Reversal of flow – hepatopetal vs hepatofugal
• Fibroscan (transient elastography): a newer method, FDA‐approved in 2015 for staging of liver disease for hepatitis C and for evaluation of severity of steatosis (fat): measures liver stiffness in Kilopascals from very low (<5 KPa) to cirrhotic range (>13.5 KPa)
Slide 12 of 36
Alternatives to Biopsy
• Serologic tests
– APRI (AST to Platelet Ratio Index)
– ELF (European Liver Fibrosis panel)
– FIB‐4
– Fibrotest/Fibrosure (commercial blood test)
A S T s a m p le A S T la b re fe re n c e 1 0 0
P la te le t C o u n t
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Slide 13 of 36
Overview: Hepatitis C
• Hepatitis C therapy as it was from 1998‐2010, with 48 weeks of interferon‐based therapy for most patients and cure rates of 20‐80% is over
• 3 hepatitis C proteins: the protease, the polymerase, and NS5A are under attack with new drugs (all oral, generally 8‐24 weeks)
• 2016 and later belong to all‐oral, IFN‐free, at least 2 drug regimens: often 92+% cure
Slide 14 of 36
Slide 15 of 36
Glossary
• Sof/Led: sofosbuvir/ledipasvir
• PrOD: paritaprevir with ritonavir boosting/ombitasvir/dasabuvir
• GZR/EBR: grazoprevir/elbasvir
• Dcv: daclatasvir
• Sof/Velp: sofosbuvir/velpatasvir
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Slide 16 of 36
2013 2014 2015 2016
Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4
2013 2014 2015 2016
Combination Therapy FDA Approval Timeline
Sofosbuvir + RBV‐‐‐‐‐‐
GT2/3, CPT A‐C
Daclatasvir ‐‐‐‐‐
GT 3a, GT 2
Sof/Led +/‐ RBV‐‐‐‐‐
GT 1, 2, 3, 4, CPT A‐C
PrOD +/‐ RBV‐‐‐‐
GT1b >1a, CPT A
GZR/EBR +/‐ RBV‐‐‐‐
GT 1b >1a, CPT A
Sof/Simeprevir +/‐ RBV‐‐‐‐
GT1, CPT A
* Precise timing TBD
Sof/Velpatasvir +/‐ RBV‐‐‐‐‐
GT 1, 2, 3, 4, CPT A‐ ?C
Slide 17 of 36
Forecast Burden of HCV‐Related Morbidity and Mortality
DCC = decompensated cirrhosis; HCC = hepatocellular carcinoma. Rein DB, et al. Dig Liver Dis. 2011;43(1):66‐72.
Assuming 2,700,000 HCV infected persons are in primary care
1.47 million will develop cirrhosis
350,000 will develop liver cancer
897,000 will die from HCV‐related complications
0
5000
10000
15000
20000
25000
30000
35000
40000
2010
2012
2014
2016
2018
2020
2022
2024
2026
2028
2030
2032
2034
2036
2038
2040
2042
2044
2046
2048
2050
2052
2054
2056
2058
2060
Number
Deaths
DCC
HCC
Time (years)
Slide 17 of 36
Slide 18 of 36
Who Should Be Screened for Hep C?• Anyone born between 1945–1965
• Past or present IV drug use or intranasal drug (cocaine) use, even if used only once
• Received blood/organs prior to 1992
• Received clotting factors prior to 1987
• History of chronic hemodialysis
• Infants born to HCV‐infected mothers
• Unregulated tattoo
• History of incarceration
• Persistently elevated ALT
• HIV‐infected
• Healthcare workers after needle sticks, sharps, or mucosal exposures to HCV‐infected
IV = intravenous; ALT = alanine aminotransferase.MMWR. 2012;61(RR04):1‐18; Moyer VA. Ann Int Med. 2013;159(5):349‐357.
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Slide 19 of 36
Estimated Health Impact of Testing 1945–1965 Birth Cohort for HCV
1,070,840 new cases of HCV identified with birth‐cohort screening
552,000 patients treated
364,000 cured*
• Medical costs averted** $1.5–2.5 billion
• Costs per QALY gained** $15,700–35,000
121,000 deaths
averted**
*With pegIFN and ribavirin + DAA treatment.**Deaths due to decompensated cirrhosis or HCC within 1945–1965 birth cohort.
Rein D, et al. Ann Intern Med. 2012;156(4):263‐270; McGarry LJ, et al. Hepatology. 2012;55(5):1344‐1355.
Slide 20 of 36
The Benefits of Achieving SVR
Yoshida EM, et al. Hepatology. 2014; Thorlund K, et al. Clin Epidemiol. 2014;6:49‐58; van der Meer AJ, et al. JAMA. 2012;308(24):2584‐2593.
Viral Eradication Improved Liver Histology
↓ Mortality
SVR
↓ Extrahepatic Complications
↓ Decompensation ↓ HCC
Improved Clinical Outcomes
Slide 21 of 36
Phase III Studies of Sofosbuvir (Nuc) + Ledipasvir (NS5A) ± RBV in GT1 HCV
ION-1: GT1 treatment-naive pts (16% cirrhotic): SOF/LDV
± RBV for 12 wks
.
ION-3: GT1 treatment-naive pts: SOF/LDV FDC ± RBV
for 8 or 12 wks
SOF/LDV SOF/LDV + RBV
ION-2: GT1 treatment-experienced pts (20% cirrhotic): SOF/LDV FDC
± RBV for 12 or 24 wks
8 Wks 12 Wks
202/215
206/216
201/216
12 Wks 24 Wks
102/109
107/111
108/109
110/111n/N =
209/214
211/217
SV
R1
2 (
%)
12 Wks
98 97100
90
60
40
20
0
94 93 95 94 96 99 99
Afdhal N, et al. N Engl J Med. 2014;370(20):1889‐1898; Kowdley KV, et al. N Engl J Med. 2014;370(20):1879‐1888
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Slide 22 of 36
DAA’s at SFVA
• We have treated over 700 patients in the past 1.5 years with the multidrug regimens (70,000 treated in the VA nationally)
• Treatment will continue to prioritize patients with cirrhosis, who are at risk for complications soon
• Pre‐ or post‐liver transplant patients are also having HCV viremia considered differently
Slide 24 of 36
Chronic HBV Infection, U.S.
• ~1.25 million chronic carriers
– 0.3% of adult population
– 4–5,000 deaths/year related to HBV
complications
• Immigration from endemic areas, including
Asia, impacts the US pattern of disease
Slide 25 of 36
Natural History of Chronic Hepatitis B
Normal liver Chronichepatitis B
ESLD
No furtherprogression
HBV‐related ESLD or HCC are responsible for > 0.5‐1 million deaths/yr, represent 5% to 10% of cases of
liver transplantation in U.S., Europe
Not all patients have progressive disease
Cirrhosis
EASL. J Hepatol. 2012;57:167-185.
HCC
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Slide 26 of 36
Hepatitis B Disease States
HBsAg + HBeAg –
Anti-HBe +/-Normal ALT
HBV DNA -/low(<2,000 IU/mL,
<104 c/mL)
HBsAg + HBeAg –
Anti-HBe +/-Normal ALT
HBV DNA -/low(<2,000 IU/mL,
<104 c/mL)
Antiviral TherapyAntiviral Therapy
Inactive HBsAgCarrier
Inactive HBsAgCarrier
Active Chronic Hepatitis
Active Chronic Hepatitis HBsAg +
HBeAg +Anti-HBe -
Elevated ALTHBV DNA +
(20,000 IU/mL, 105 c/mL)
HBsAg-HBcAb+
HBsAb+/-
HBsAg-HBcAb+
HBsAb+/-
Chronic HBVInfection
Chronic HBVInfection
Past HBV Infection
Slide 27 of 36
AASLD Guidelines on Chronic HBV: Whom to Treat with Antiviral Therapy
• Elevated HBV DNA levels • HBeAg (+): 20,000 IU/mL or 105 copies/mL• HBeAg (‐): 2,000 IU/mL or 104 copies/mL
AND
• Persistently elevated ALT levels >2 x ULN• Normal ALT
– 30 IU/mL for men, 19 IU/mL for women
OR• Moderate/advanced liver disease on biopsy
• Stage 2, 3 or 4 fibrosis
Lok AS and McMahon BJ. Hepatology 2009
Slide 28 of 36
Entecavir is More Potent than LAM
n=354 tx’dw/ Entec 0.5mg,355 tx’d w/ LAM100mg for 52 wks
e-Ag seroconv21% (E) vs 18% (LAM), p=0.33
67% undet DNA (E) vs. 36% (LAM),P<0.001 Chang TT, et al NEJM 2006;354:1011
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Slide 29 of 36
Summary of FDA‐Approved Agents for Chronic HBV Treatment
HBeAg loss
HBeAg seroconversion
HBsAg loss
HBV DNA log10 reduction
Histologic improvement
Resistance
Tolerability
Cost
PEG-IFN TDF ETV LAM ADV35% 24% 22% 13-21% 24%
32% 22% 8-21% 16-18% 12-18%
5-10% 3% 5% <4% 0%
3-4 5-7 5-6.9 5.5 3.6-4.5
41-48% 67-71% 70-72% 49-56% 48-64%
- - -/+ +++ +++ +++ +++ +++ +++
+++ ++ ++ + ++
Slide 30 of 36
Successful Hepatitis B Treatment Reduces Clinical Endpoints
• HBV suppression with nucleos(t)ide analogue therapy reduces risk of hepatic decompensation and HCC in pts with advanced fibrosis or cirrhosis[6]
Pts
Wit
h D
isea
seP
rog
ress
ion
(%
)
P = .001
25
20
15
10
5
030181260 36
n = 198
n = 173
n = 417 n = 385
n = 43
n = 122
24
Lamivudine
Placebo
Kaplan-Meier Estimate of Time to Disease Progression in Asians With CHB (Mos)Liaw YF, et al. N Engl J Med. 2004;351:1521‐1531.
Kaplan-Meier Estimate of Time to Disease Progression in Asians With CHB (Mos)
Slide 31 of 36
Impact of Tenofovir on Liver Fibrosis at Yr 5 in Subjects With Baseline Cirrhosis
• 74% (n/N = 71/96) of subjects had Ishak fibrosis score ≤ 5 at Yr 5
– 73% (n = 70) had decreases of ≥ 2 points
– 25% (n = 24) did not change
– 1% (n = 1) had 1‐point increase in fibrosis score
Chan
ge From Baselin
e
in Fibrosis Score
n = 24
n = 14n = 41
n = 15
n = 1n = 1
-5-4-3-2-10
+1 Subjects With Baseline Cirrhosis (N = 96)
Adapted from Marcellin P, et al. Lancet. 2013;381:468-475.
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Slide 32 of 36
Study ETV‐901: Long‐term Histology Study During Open‐Label Follow‐up
• Pts from 2 phase III studies (HBeAg+ in ETV‐022, HBeAg‐ in ETV‐027)
• Pts entered open‐label rollover study (ETV‐901) and received ETV for total of at least 3 yrs
• Liver biopsies obtained at baseline, Wk 48, Wk 96, and after at least 3 yrs of cumulative ETV therapy
ChronicHBV
patients
Open‐Label ETV 1.0 mg/dayLong‐term histology cohort
(n = 57)
Study Yr
Biopsies
0 1 2 3 4 5 8
HBeAg+ ETV 0.5 mg/day(n = 354)
HBeAg‐ ETV 0.5 mg/day(n = 354)
Chang TT, et al. Hepatology. 2010;52:886-893.*Median time on ETV treatment at the time of long-term biopsy was 280 weeks (~ 6 yrs; range: 3-7 yrs)
*
Median time on ETV treatment at the time of long‐term biopsy was 280 weeks (~ 6 yrs; range: 3‐7 yrs)
Slide 33 of 36
• Genotypic testing for resistance was not performed because all the patients achieved a serum HBV DNA level < 300 copies/mL
Nonhistologic Efficacy Results of ~6 Yrs of Entecavir
*Median duration of ETV therapy at time of long-term biopsy: 6 yrs (range: 3-7 yrs)
Chang TT, et al. Hepatology. 2010;52:886-893.
On Treatment Response, % (n/N) Week 48(n = 57)
Long Term*(n = 57)
HBV DNA < 300 copies/mL on treatment 70% (40/57) 100 (57/57)
ALT ≤ 1 x ULN 67% (38/57) 86 (49/57)
HBeAg loss on treatment 2% (1/41) 55 (22/40)
HBsAg loss 0% (0/57) 0 (0/57)
*Median duration of ETV therapy at time of long‐term biopsy: 6 yrs (range: 3‐7 yrs)
Slide 34 of 36
Summary of Key Conclusions: HBV Therapy
• Long‐term tenofovir and entecavir therapy improved liver histology and fibrosis in nucleoside‐naive HBV patients– Including patients with advanced fibrosis/cirrhosis
• Reversal of liver fibrosis and cirrhosis possible if underlying cause of liver damage continuously suppressed
• These patients still at risk of HCC: continued surveillance is recommended
Chang TT, et al. Hepatology. 2010;52:886-893, Marcellin P, et al. Lancet. 2013;381:468-475
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Slide 35 of 36
Primary Biliary Cholangitis (formerly Cirrhosis)
• What is it?– Immunopathologic injury to lobular bile ducts leading to cholestasis– AMA: hallmark of the diagnosis
– 5% will have AMA negative PBC– Associated with
• Inflammatory arthropathy 5‐10%• Sicca syndrome 40‐65%• CREST syndrome 10‐15% • Thyroid disease 20%• Inflammatory bowel disease
Slide 36 of 36
New PBC Therapy: OBCA
‐ Obeticholic Acid (OBCA)• Obeticholic acid: derivative of the primary human bile acid chenodeoxycholic
acid (CDCA) , FDA approved in 2016 for the treatment of PBC (generally 5‐10mg p.o. qd dose for initiation)
• ligand for the farnesoid X receptor, which plays a role in bile acid homeostasis
• OBCA: more potent agonist of the receptor (approximately 100‐fold higher potency) than CDCA
• OBCA: effective in reducing AP, GGT and aminotransferase levels even in patients already taking Ursodiol with inadequate improvement in LFTs
• Primary side effect is pruritus
Hirschfeld GM, et al. Gastroenterology 2015;148:751
New York, New York: November 4, 2016
