5/12/2016

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Alex Monto, MDProfessor of Clinical Medicine

University of California San Francisco

San Francisco, California

Hepatology for the Nonhepatologist

FLOWED: 04/28/2016

San Francisco, California: May 5, 2016

Slide 2 of 45

Introduction

• Liver is the 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 3 of 45

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Slide 4 of 45

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 5 of 45

Overview

• Only ~20-30% of pts with chronic HCV will develop cirrhosis (even if untreated)

• 2015 was the year with the most HCV treatment ever; 2016 may have even more

• October 2014: FDA approval of Sof/Led

• December 2014: FDA approval of PrOD

• August 2015: FDA approval of Daclatasvir (NS5A inhibitor)

• January 2016: FDA approval of Elb/Grz

Slide 6 of 45

Overview

• 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 12-24 weeks)

• 2016 and later belong largely to all-oral, IFN-free, at least 2 drug regimens: 8-12 weeks, 92+% cure

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Glossary

• Sof/Led: sofosbuvir/ledipasvir

• PrOD: paritaprevir with ritonavir boosting/ombitasvir/dasabuvir

• GZR/EBR: grazoprevir/elbasvir

• Dcv: daclatasvir

• Sof/Velp: sofosbuvir/velpatasvir (expected FDA approval late 6/2016)

Slide 9 of 45

New General Points

• “Cure” is now very genotype and sub-type specific: GT 2 > GT 1b > GT 1a > GT 3

• SVR12 (negative HCV RNA 12 weeks after treatment): standard outcome (SVR 24 was the old standard

• SVRs in non-cirrhotics generally > cirrhotics

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Slide 10 of 45

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

Grazoprevir/Elbasvir +/- 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 11 of 45

CIRRHOTIC LIVER

Slide 12 of 45

Risks of Complications of Cirrhosis

Cirrhosis

Variceal

Bleeding

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 13 of 45

Cirrhosis Natural History Studies Summary

• No decompensation: 80% 10-year survival

• Decompensation is variable, imperfectly predicted. Portal HTN vs. synthetic dysfunction

• HCC, ascites: the 2 principal forms of decompensation

• Risk of decompensation: roughly 4-5% per year in a patient with Child’s A cirrhosis

• After decompensation, probability of 5-yr survival without transplant: 35-50%

Slide 14 of 45

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

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25000

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Nu

mb

er

Time (years)

Deaths

DCC

HCC

Slide 15 of 45

Projected HCV Sequelae Cost U.S. 1950–2030

$10

$8

$6

$4

$2

$0

19601950 1980 2020 20302000 201019901970

$3.0

$4.0

$5.0

$1.0

$0.0

$2.0

Tota

l Co

st (b

illio

ns)

Seq

uel

ae C

ost

(bill

ions

)

Total Cost

Decomp Cirrhosis HCC

F0-F3

Liver Transplant

Comp Cirrhosis

Razavi H, et al. Hepatology. 2013;57(6):2164-2170.

The Total Cost of Chronic HCV Is Expected to Peak in 2024 at $9.1 Billion

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Slide 16 of 45

Who Should Be Screened?• 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.

Slide 17 of 45

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 18 of 45

Real-World Findings of the Burden of Liver Disease Among Baby Boomers with HCV in the US

• CDC analysis of nearly 9.8 million HCV-related tests conducted during 2010–2013

• 273,207 people had positive HCV RNA test results

• Of these, 186,416 (68.2%) were born from 1945–1965

Stage Fibrosis Before 1945 1945–1965 After 1965 All

None 1.2% 9% 55% 19.5%

Moderate 20% 39% 28.5% 35%

Severe 38% 26% 6.7% 22%

Cirrhosis 36% 21% 4% 18%

Missing 5% 4.5% 5.5% 4.8%

Total 8,521 86,741 29,814 125,076

81% of persons with advanced fibrosis and cirrhosis were from birth cohort

Klevens M, et al. CROI 2015. Abstract 145.

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Opportunities to Improve Care and Outcomes in HCV

100% 50% 43% 27% 16% 9%0%

20%

40%

60%

80%

100%

Chronic HCV-Infected

Diagnosed andAware

Access toOutpatient Care

HCV RNAConfirmed

Prescribed HCVTreatment

Achieved SVR

Per

cen

tage

of P

atie

nts

HCV Care Cascade3,500,00

Yehia BR, et al. PLoS One. 2014;9(7):e101554.

Slide 20 of 45

The Benefits of Achieving SVR

Yoshida EM, et al. Hepatology. 2014; Epub ahead of print; 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 45

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.

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Invasive and Nonivasive Fibrosis Compared

Liver Biopsy Serum Markers Transient Elastography

MethodologyDirect observation Measures direct and indirect

serum markers* of fibrosis

Liver stiffness by detection of ultrasound-propagated shear waves

Accuracy for detecting cirrhosis

HighModerate (APRI) to high (FibroSURETM, ELF)

High

Accuracy for detecting intermediate fibrosis

HighLow (APRI) to moderate (FibroSURETM, ELF)

Moderate to high

Risk of complications Risk of pain/bleeding Minimal Minimal

Contraindications Coagulopathy Minimal Obesity; narrow rib spaces

Limitations Sampling errorObserver variation

False-positives with hemolysis, inflammation, Gilbert’s syndrome

False-positives with inflammation, congestion

Longitudinal monitoring

UnsuitableIndices may change with disease progression/therapy

Liver stiffness changes with disease progression/therapy

Cost Highest per-treat cost Low per-test cost High initial equipment cost

Serum tests that incorporate markers of fibrogenesis are generally more accurate. AST = aspartate aminotransferase; ELF = enhanced liver fibrosis.Nguyen D, Talwalkar JA. Hepatology. 2011;53:2107-2110.

Slide 23 of 45

“Highest” Priority for Treatment

F0 F1 F2 F3 F4

Highest Priority Owing to Highest Risk for Severe Complications:

• Advanced fibrosis (Metavir F3) or compensated cirrhosis (Metavir 4)

• Organ transplant

• Type 2 or 3 essential mixed cryoglobulinemia with end-organ manifestations (eg, vasculitis)

• Proteinuria, nephrotic syndrome, or membranoproliferative glomerulonephritis

Afdhal NH. Gastroenterol Hepatol. 2012;8(9):605-607; Bonder A, et al. Curr Gastroenterol Rep. 2014;16(2):372; AASLD, IDSA. Recommendations for testing, managing, and treating HCV. www.hcvguidelines.org. Accessed 3/27/15.

Slide 24 of 45

“High” Priority for TreatmentOwing to High Risk for Complications

• Fibrosis (Metavir F2)

• HIV-1 coinfection

• HBV coinfection

• Other coexistent liver disease (eg, NASH)

• Debilitating fatigue

• T2DM (insulin resistant)

• Porphyria cutanea tarda

HIV = human immunodeficiency virus; HBV = hepatitus B virus; NASH = nonalcoholic steatohepatitis; T2DM = type 2 diabetes mell itus. AASLD, IDSA. Recommendations for testing, managing, and treating HCV. www.hcvguidelines.org. Accessed 3/27/15.

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Most Patients Meet “High” or “Highest” Priority for HCV Treatment

Priority Status N = 8,504

“HIGHEST PRIORITY” 32.9%

F3 or higher by biopsy or FIB-4 score ≥ 2.5 30.0%

˂ F3 with chronic kidney disease 2.9%

“HIGH PRIORITY” 28.9%

F2 by biopsy or FIB-4 score ≥ 1.6 or < 2.5 22.7%

˂ F2 with HIV coinfection 0.7%

˂ F2 with HBV coinfection 0.2%

˂ F2 with NASH 0.4%

< F2 with DM 4.9%

NOT MEETING “HIGHEST” or “HIGH PRIORITY” 38.2%

Results from Chronic Hepatitis Cohort Study (CHeCS). Xu F, et al. AASLD The Liver Meeting 2014, Boston, MA. LB-29.

Slide 26 of 45

Communication, Coordination, and Collaboration among Providers

Initial

• Verification of diagnosis, dose, and comorbidities

• Regimen conformity with guidelines

• Patient/caregiver counseling

• Services and support

Follow-Up

• On-treatment monitoring

• Viral load evaluation

• Response to therapy

• Barriers to compliance

• Adverse effects, administration, cost, complex therapy

• Follow-up after treatment completion

Specialty Pharmacy Times. Managing hepatitis C costs, improving patient outcomes. www.specialtypharmacytimes.com/publications/specialty-pharmacy-times/2014/august-2014/managing-hepatitis-c-costs-improving-patient-outcomes/P-1. Accessed 3/27/15.

Slide 27 of 45

Barriers to Older Therapies

IFN/pegIFN

• Flu-like symptoms

• Leukopenia, thrombocytopenia

• Depressed mood

• Insomnia

RBV

• Significant anemia

• Rash

• Cough and dyspnea

• Teratogenicity

• Multiple daily dosing

First DAAs

• Complicated regimens

• Anemia, neutropenia, thrombocytopenia

• Rash

• Significant pill burden

• Drug interactions

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Slide 28 of 45 Lawitz E et al, Jacobson I et al, NEJM May 2013

POSITRON TN, PEG-IFN-unable

SOF + RBV, n=207

PBO, n=71

SVR12

FUSION Treatment Experienced

SOF + RBV, n=103 PBO

SOF + RBV, n=98

SVR12

SVR12

NEUTRINO Treatment Naïve

SOF + PEG-IFN+RBV, n=327 SVR12

GT 2/3

GT 1/4/5/6

0 12 16 24 36Week

FISSION Treatment Naïve

SOF+ RBV, n=256

PEG-IFN+RBV, n=243

SVR12

SVR12

Sofosbuvir Phase 3 Study Designs

SVR2489% GT 1, 9% GT 4, 2% GT 6

Slide 29 of 45

NEUTRINO: Sofosbuvir + P/R for 12 weeksSVR12 according to Genotype and Cirrhosis

Lawitz E et al, NEJM May 2013

SVR

12

(%

)

92

80

100

80

60

40

20

0No

CirrhosisCirrhosis

252/273 43/54

SVR12 According to Fibrosis Level

SVR

12

(%

)

8996

100100

80

60

40

20

0GT 1 GT 4 GT 5,6

261/292 27/28 7/7

SVR12 According to Genotype

n/N =

Slide 30 of 45

Sofosbuvir + RBV in HCV GT 2/3Impact of Genotype on SVR12

62

30

61

56

94

86

93

97

0 20 40 60 80 100

Fusion 16 Wk

Fusion 12 Wk

Positron 12 Wk

Fission 12 Wk

GT-2 GT-3

SVR 12 in G2/3 (%)Lawitz E et al, Jacobson IM et al, NEJM May 2013

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Slide 31 of 45

Sofosbuvir + RBV in HCV Genotype 2Impact of Treatment Status and Cirrhosis on SVR12

989192 9496

60

100

78

0

10

20

30

40

50

60

70

80

90

100

No Cirrhosis Cirrhosis

Fission 12 (TN) Positron 12 (TN) Fusion 12 (TE) Fusion 16 (TE)

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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

R12 (

%)

12 Wks

98 97100

90

60

40

20

0

94 93 95 94 96 99 99

Slide 33 of 45

ION-2: Ledipasvir/Sofosbuvir for Tx-Exp GT 1

Characteristic 12-Wk Regimen 24-Wk RegimenLDV–SOF LDV–SOF + RBV LDV-SOF + RBV(N = 109) (N = 111) (N = 109) (N = 111)

Age: yr, mean 56 57 56 55

Post-treatmentAt 4 wk 103 (94) 107 (96) 109 (100) 110 (99)At 12 wk 102 (94) 107 (96) 108 (99) 110 (99)Virologic breakthr: 0 0 0 1 Relapse 7 (6%) 4 (4%) 0 0* One of the 109 patients who received 12 weeks of ledipasvir–sofosbuvir had an HCV RNA level of 42 IU per milliliter

N Afdhal et al, NEJM Apr 17 2014;370:16

20% of pts had cirrhosis79% GT 1a, 21% GT 1b55% of pts had previously failed PEG-RBV-protease inhibitor

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Slide 34 of 45 TW=treatment week FUW=follow up week

C-EDGE TN: GZR/EBR for 12 Weeks in TN GT 1, 4, or 6

Slide 35 of 45

Impact of Baseline NS5A Variants on Efficacy in GT 1 Patients

C-EDGE TN: GZR/EBR for 12 Weeks in TN GT 1, 4, or 6

GT 1a GT 1b

9299

58

22

0

20

40

60

80

100

Overall No NS5AVariant

AnyNS5A

Variant

BaselineRAV with> 5-fold

shift

SV

R12,

%

144/157 133/135 11/19 2/9

99 10094 94

0

20

40

60

80

100

Overall No NS5AVariant

AnyNS5A

Variant

BaselineRAV with> 5-fold

shift

129/131 112/112 17/18 16/17

Zeuzem, EASL, 2015, G07Zeuzem, et al. Ann Intern Med Published Online April 2015

Slide 36 of 45

Efficacy by Prior Relapse vs. Prior Partial or Null ResponsePer-Protocol Analysis

Kwo, EASL, 2015, P0886

• Relapse: primarily in prior partial or null responders treated for 12 weeks

10091

1009192 94

100 100

0

20

40

60

80

100

Prior relapse Prior partial or null response

SV

R12,

%

GZR/EBR 12 weeks GZR/EBR+RBV 12 weeks

GZR/EBR 16 weeks GZR/EBR+RBV 16 weeks

35/35 37/37 35/38 39/39 61/67 58/64 62/66 62/62

C-EDGE TE: GZR/EBR±RBV for 12 and 16 Weeks in TE GT 1, 4, or 6

• Open-label trial: patients failing prior PEG/RBV randomized 1:1:1:1. Demographics: median age 57 years (range: 19 to 77); 64% male; 67% White; 18% Black or African American; 9% Hispanic or Latino; mean BMI 28 kg/m2; 78% HCV RNA levels > 800,000 IU/mL; 34% had cirrhosis; 79% had non-C/C IL28B alleles (CT or TT); 60% GT 1a, 39% GT 1b, 1%: genotype 1-other.

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SAPPHIRE-1: PrOD +RBV, Placebo-controlled, Ph 3, Tx-Naïve, Non-cirrhotic

RBV 1000mg-1200mg Wt < 75kg vs. >=75kgJJ Feld et al, NEJM 2014;370:1594

Slide 38 of 45

SAPPHIRE-1: PrOD+RBV, Placebo-controlled, Ph 3, Tx-Naïve,Non-cirrhotic

JJ Feld et al, NEJM 2014;370:1594

Slide 39 of 45

PrOD +/-RBV SVR12, Ph 3, Tx Naïve, Non-Cirrhotic

JM Pawlotsky, Gastro 2014;146:1176

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PrOD +/-RBV SVR12, Ph 3, Tx Exp, Non-Cirrhotic

JM Pawlotsky, Gastro 2014;146:1176

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TURQUOISE-II: PrOD +RBV, Ph 3, Tx-Naïve/Exp, Cirrhotic

PrOD+ RBV (n=208)

PrOD+RBV (n=172)

Wk 12 Wk 24 SVR 12-24

RBV 1000mg-1200mg Wt < 75kg vs. >=75kg

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TURQUOISE-II: PrOD +RBV SVR12, Ph 3, Tx Naïve and Exp, Compensated Cirrhosis

F Poordad et al, NEJM 2014;370:1973

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TURQUOISE-II: PrOD +RBV SVR12, Ph 3, Tx Naïve and Exp, Compensated Cirrhosis

F Poordad et al, NEJM 2014;370:1973

GT 1a, prior null: 80% 12 wks,93% 24 wks

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DAAs at SFVA

• We have treated over 400 patients in the past 1.5 years with the regimens described, particularly GT’s 1 and 2

• 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 45 of 45

Summary

• Many HCV patients will be fine without therapy

• Sof/Led +/- RBV for GT 1: 95+% cure rates in most patients. Tx-exp cirrhotics benefit from RBV and may require 24 weeks. Sof+/- Led is safe even in decompensated cirrhotics, post-liver transplant

• GT 3: consider Sof/Led/RBV vs. Sof/Dcv vs. wait

• GT 2 has high SVR with SOF/RBV for 12-16 weeks

• Elb/Grz: outstanding (>93% SVR) 1b>1a, test GT 1a for resistance at baseline to ensure 12 wks vs. 16 weeks with RBV