hepatitis c - rural health association of tennessee, inc. c_2019_11_201… · • 56-yr-old man...

Hepatitis C

Chakradhar M Reddy MD, FACP

Gastrointestinal Associates of North East Tennessee

Assistant Professor

Division of Gastroenterology

Department of Medicine

Quillen College of Medicine, ETSU

Adjunct Assistant Professor

Division of Gastroenterology

Department of Medicine

Vanderbilt University

Disclosure Statement of

Financial Interest

• I, Chakradhar M Reddy MD, DO have a financial interest/arrangement or affiliation with one or more organizations that could be perceived as a real or

apparent conflict of interest in the context of the subject of this presentation, they are:

Affiliation/Financial Interest: Name of Organization (s):

Grant/Research Support:

Consultant:

Speaker's Bureau: Gilead Sciences, Allergan Pharma, Salix Pharma, Echosens, Dova Pharma

Advisory Board: Gilead Sciences, Allergan Pharma

Disclosure Statement of

Unapproved/Investigative Use

I, Chakradhar M Reddy MD

DO NOT anticipate discussing the unapproved/investigative use of a commercial product/device during

this activity or presentation.

Case: Pt With Newly Diagnosed HCV

• 56-yr-old man diagnosed as HCV Ab positive during a new pt visit with PCP

following insurance change

• PMH: HTN, HLP, GERD, Gout, Moderate obesity

– Medications: lisinopril 10 mg QD, rosuvastatin 20 mg QD, omeprazole

40 mg QD, colchicine 0.6 mg QD PRN with gout flairs, ibuprofen PRN

• Married with 2 adult children, does not exercise regularly, drinks 2-4

beers/day, no smoking / illegal drug use

• Referred to hepatitis specialist after positive test results

– Missed initial appointment

Case: 6 Mos After HCV Diagnosis

• Pt returns to PCP for routine appointment and medication refills

• Laboratory values: Hb 15 g/dL, platelets 165/L, creatinine 1.2 mg/dL,

random glucose 122 mg/dL, albumin 4.1 mg/dL, total bilirubin 0.4 mg/dL,

AST 68 IU/L, ALT 64 IU/L, INR 1.0

• Advised to lose weight, stop drinking alcohol

• Referred again to Specialist for Rx

Case: HCV Evaluation

• Completes initial appointment with Specialist

– HCV RNA 5,300,000 IU/mL, GT1a, HAV Ab neg, HBsAb/HBsAg neg

– Liver elastography 10.7 Kpa

– Ultrasound: mild hepatomegaly, fatty infiltration, no mass

• Still drinking 1-2 beers/day on weekend only

• No new medications

Questions

• What does a Hepatitis C mean for patients: Overview ?

• Where is US in caring for these Hepatitis C patients ?

• Whom should be screed: Screening ?

• How to Stage Fibrosis, especially without a Liver Biopsy?

• How are the current treatment regimens ?

• How to establish Linkage to Care and what does that mean ?

• Your role as a Provider ?

Introduction

• A RNA virus that used to be known as non-A, non-B hepatitis until it was discovered in 1988

• No vaccine available

• Hepatitis C Antibody

• Does not mean protection

• Exposure vs Infected vs Cured

• Cure, also known as sustained virologic response (SVR), is defined as no detectable HCV in the blood at 12 or more weeks after therapy is complete

Estimated 70 Million Persons Living With HCV

0% to < 0.6%

0.6% to < 0.8%

0.8% to < 1.3%

1.3% to < 2.9%

2.9% to < 6.7%

Prevalence

(Viremic)

Polaris Observatory HCV Collaborators. Lancet Gastroenterol Hepatol. 2017;2:161-176.

HCV Genotypes by Geographic Region

HCV genotypes in the

United States• GT 1 is most common, accounting

for ~78% of HCV infections2a

• GT 1a subtype is twice as common as GT 1b

GT=genotype. aDerived from HCV RNA–positive participants in NHANES III conducted 1988 to 1994 (N=275)

World Gastroenterology Organisation. Diagnosis, management and prevention of hepatitis C. 2013.

Nainan OV, et al. Gastroenterology. 2006;131:478-484.

Natural History of Hepatitis C Infection

14%-46% <1%

54%-86%

15%-51%

per Year

0.8% per Year

Spontaneous

clearance

Fulminant

hepatitis

Hepatocellular

carcinoma (HCC)

Hepatic

decompensation

Liver cirrhosis

Chronic

hepatitis C

Acute HCV

infection

Annual mortality rate of 2%-4% in

CHC-infected patients with cirrhosis

• In the US, HCV is the leading cause

– Liver Transplantation1

– Liver Cancer2

• HCV-related Liver complications have contributed to shorter lifespan3

1.Kim WR et al. Am J Transplant. 2014;14(suppl 1):69-96.

2.CDC. http://www.cdc.gov/nchhstp/newsroom/docs/2012/HCV-TestingRecsFactSheet_508.pdf. Accessed July

6, 2015.

3.Smith BD et al. MMWR Recomm Rep. 2012;61(RR-4):1-32.

Hepatitis C

Extrahepatic Manifestations of HCV

• Mixed cryoglobulinemia

• Sjögren (sicca) syndrome

• Lymphoproliferative disorders

• Porphyria cutanea tarda

• Neuropathy

• Membranoproliferative glomerulonephritis

• Cryoglobulinemic vasculitis

• Corneal ulcers

(Mooren ulcers)

• Thyroid disease

• Lichen planus

• Pulmonary fibrosis

• Chronic kidney disease

• Type 2 diabetes

• Systemic vasculitis

(polyarteritis nodosa,

microscopic polyangiitis)

• Arthralgias, myalgias,

inflammatory polyarthritis

• Autoimmune

thrombocytopenia

Strongly associated1 Possibly associated1,2

1.Ali A, Zein NN. Cleve Clin J Med. 2005;72:1005-1008; 2. Satapathy SK, et al. Hepatol Int. 2012;6:369-378.

Why HCV Can be Cured

HCV RNA remains in the cytoplasm, while HBV and HIV DNA are incorporated into the nucleus of the cell

Nucleus Host Cell Host DNA

Soriano V et al. J Antimicrob Chemother. 2008;62(1):1-4.

What Defines HCV Cure

• In one study, of those patients who reached SVR, 99% had undetectable levels of HCV RNA more than 4 years after treatment end3

• These patients do not experience viral recurrence3

Cure, also known as sustained

virologic response (SVR), is

defined as no detectable HCV

in the blood at 12 or more

weeks after therapy is

complete1,2

1.US Department of Health and Human Services, Center for Drug Evaluation and Research. Draft Guidance for Industry. Chronic Hepatitis C

Virus Infection: Developing Direct-Acting Antiviral Drugs for Treatment. October 2013.

2.AASLD, IDSA, IAS-USA. Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org.

3.Swain MG et al. Gastroenterology. 2010;139(5):1593-1601.

Comparison: HCV to HIV

1.Ly KN et al. Ann Intern Med. 2012;156(4):271-278.

2.CDC. http://www.cdc.gov/hepatitis/statistics/2010surveillance. Accessed July 6, 2015.

3.Murphy SL et al. http://www.cdc.gov/nchs/data/nvsr/nvsr61/nvsr61_04.pdf. Accessed July 6, 2015.

HCV Has a Mortality Rate That Exceeds HIV1-3

Lee M-H, et al. J Infect Dis. 2012;206:469-477.

REVEAL HCV: Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer (1991-2008) in a prospective Taiwanese cohort. Anti-HCV seronegative (n=18,541); anti-HCV seropositive (n=1095; detectable HCV RNA: 69.4%). Average follow-up: 16.2 years. Among extrahepatic causes of death, 68.5% and 69.3% were noncancer deaths for HCV seronegative and seropositive, respectively. *P<.001 for comparison among all 3 groups and P<.001 for HCV RNA detectable vs undetectable.

HCV Viremia Was Associated with Increased Mortality

All causes Liver cancer Extrahepatic diseases

Anti-HCV+, HCV RNA detectable

Anti-HCV+, HCV RNA undetectable

Anti-HCV−

Follow-up (yr)Follow-up (yr)

(n=2394) (n=115) (n=2199)

Follow-up (yr)

00 2 4 6 8 10 12 14 16 18 20 0 2 4 6 8 10 12 14 16 18 20 0 2 4 6 8 10 12 14 16 18 20

• Cure, or SVR, is associated with improvements in disease complications,

such as rates of hepatocellular carcinoma,

ascites, and variceal bleeding1,2

SVR is also associated

with reduced risk of

all-cause mortality3*

*International, multicenter, long-term follow-up study: 5 large tertiary care hospitals in

Europe and Canada. Patients with chronic HCV infection started an interferon-based

treatment regimen between 1990 and 2003 (n=530).1. Bruno S et al. Hepatology. 2007;45(3):579-587.

2. Singal AG et al. Clin Gastroenterol Hepatol. 2010;8(3):280-288.e1.

3. van der Meer AJ et al. JAMA. 2012;308(24):2584-2593.

Female

Changing Epidemiology of HCV in the US

• Screening → linkage to HCV care → DAA treatment cascade must be operative in all those

at risk

• Treatment of PWIDs plus harm reduction efforts essential part of elimination efforts

Mostly baby

boomers

0 10 20 30 40

Age (Yrs)

050 60 70 80 90 100

0 10 20 30 40

Age (Yrs)

050 60 70 80 90 100

FemalePWIDs: 20-

40 yrs of age

2007 (N = 41,037) 2015 (N = 33,454)

California Department of Public Health. Chronic hepatitis C infections in

California: cases newly reported through 2015. June 2017.

Study Unadjusted RR 95% CI

Hope 2011 1.08 0.31-3.82

Palmateer 2014 0.48 0.24-0.95

Van Den Berg 2007 1.04 0.53-2.05

Overall 0.76 0.44-1.33

Study Unadjusted RR 95% CI

Bruneau 2015 0.63 0.37-1.07

Hope 2011 0.17 0.02-1.54

Palmateer 2014 0.24 0.10-0.59

Van Den Berg 2007 0.15 0.06-0.40

Overall 0.29 0.13-0.65

Country or

Region

No. of

StudiesRR 95% CI

Australia 3 0.42 0.25-0.72

North America 4 0.57 0.42-0.77

Europe 5 0.43 0.27-0.68

Overall 12 0.51 0.40-0.63

HCV Prevention Among PWID:

Harm Reduction and Drug User Health

Platt. Addiction. 2018;113:545. Slide credit: clinicaloptions.com

50% reduction in risk

OST + High Coverage NSP

OST (Methadone/Buprenorphine)

OST + Low Coverage NSP

reduction

in risk

reduction

in risk

Progress Toward HCV Elimination Goals

1. WHO. Global Health Sector Strategy on Viral Hepatitis, 2016-2021. 2.

http://polarisobservatory.org/polaris_view/hepC.htm. 3. Grebely. Addiction. 2019;114:150. 4.

Varan. Public Health Rep. 2014;129:187. Slide credit: clinicaloptions.com

HCV Elimination Targets: 2017[2]

▪ US not among countries on track to eliminate HCV[2]

▪ Missing important population targets

PWID: 30.5% of all HCV infections

in North America are among people

with recent IDU[3]

People who are incarcerated: ~

30% of people with HCV spend at

least part of the yr in a correctional

facility[4]

On track Working toward Not on track

2030 WHO Goals[1]

90% in HCV incidence

65% Reduced mortality

90% Diagnosed

80% Treated

High Burden of HCV Among Incarcerated

Populations • 2.2 million people

incarcerated at end of

2016 in United States

• Nearly 1/3 of

Americans with

HCV spend at least

part of the yr in

correctional facility

• Up to 40% of people

who are incarcerated

in some states are

HCV Ab positive

Bureau of Justice Statistics. www.hepCorrections.org. Varan. Public Health Rep. 2014;129:187. Slide credit: clinicaloptions.com

6.0% to 10.0%

10.1% to 12.4%

12.5% to 17.9%

18.0% to 20.0%

20.1% to 39.7%

HCV Ab

Prevalence in

Corrections

States With Court Cases to Mandate

HCV Treatment Access in Prisons

Adapted and updated from Erica Selig, JD, Florida Justice Institute. March 21, 2018, National Hepatitis

Corrections Network. Houston TX. Slide credit: clinicaloptions.com

Class-action

Litigation for Access

to HCV Treatment

(as of Sept 2019)

Pending

Resolved or settled

(enabling treatment

for some or all,

depending on state)

Projections

• In a study, approximately 45%

of untreated HCV patients were

projected to develop cirrhosis

by 2030

• HCV is a progressive disease.

Patients who develop

cirrhosis are at greater risk

for developing liver cancer

and other liver-related

complications

Increase in liver complications projected to continue

1. CDC. MMWR Morb Mortal Wkly Rep. 2013;62(18):357-361.

2. Davis GL et al. Gastroenterology. 2010;138(2):513-521.

3. El-Serag HB. Gastroenterology. 2012;142(6):1264-1273.e1.

Costs Associated with HCV Are Projected to Increase

• Aggregate US HCV-related healthcare expenditure estimated to be up to $30 billion per year1

─ Higher costs may be attributed to increasing healthcare utilization, such as

hospitalizations and emergency department visits, by HCV-infected patients2

─ The number of serious long-term complications is expected to increase in the next

decade,1 with the majority of peak costs attributable to more advanced liver diseases

(according to a recent system dynamic modeling study)3

1. Younossi ZM, et al. Aliment Pharmacol Ther. 2014;39:518-531; 2. McCombs JS, et al. Clin Ther. 2011;33:1268-1280; 3. Razavi H, et al. Hepatology. 2013;57:2164-2170.

Total cost

Decomp cirrhosis

Comp cirrhosis

Liver transplant

US Estimates of HCV Cascade of Care

Disease

Evaluat

Among Screened Pts

60% of pts

seeing HCV

provider are

not treated

Major gap is in

screening: most

pts unaware of

diagnosis

Chronic

HCV Infected

Diagnosed

and AwareHCV RNA

Testing

Access

Provider

Prescribed

Treatment

Chronic HCV in United States, 2015[1] Linkage to Care in a Southeast

Michigan Health System[2]

1. Bourgi K, et al. PLoS One. 2016;11:e0161241. 2. Yehia BR, et al. PLoS One. 2014;9:e101554.

PROCESS: Testing

HCV Ab: Positive

Hepatitis C PCR

GenotypeNothing to be done

HCV Ab: Negative

Negative

• Spontaneous Clearance

• False Positive test

Not immune to infectionTREAT

Positive

At risk patients

Hepatitis C Antibody

-Liver Enzymes be normal or Abnormal

Post Treatment Hepatitis C Rx

Continuum of Care: Important

Laboratory Calculations &

Special Lab requests

• APRI: AST platelet ratio index

– AST/AST(ULN)/platelet count X 100

• FIB-4 score:

– Age, AST, ALT, PLT

• Fibrosure (USA) or Fibrotest (Internationally):

– Age, Gender Alpha-2-macroglobulin,Haptoglobin,Apolipoprotein

A1, Gamma-glutamyl transpeptidase (GGT), Total bilirubin,

and Alanine transaminase (ALT).

• Formula: AST/AST (ULN) Platelet count X 100

• Meta-analysis: N:40

• APRI cuttoff of 1.0:

– sensitivity (SN): 76% and specificity (SP):72% for predicting cirrhosis.

• APRI cuttoff of 0.7:

– SN: 77% and SP: 72% for predicting significant hepatic fibrosis.

Lin ZH. Hepatology. 2011;53:726-36.

FIB-4 Score

• Formula :( Age x AST ) / ( Platelts x ( sqr ( ALT ) )

• Explanation of Result :

• For NASH :

– Fib4 score < 1.30 = F0-F1

– Fib4 score > 2.67 = F3-F4

• For HCV with or without HIV :

– Fib4 score < 1.45 = F0-F1

– Fib4 score > 3.25 = F3-F4

• SP: 97% specificity

• PPV: 65% for advanced fibrosis.

• Potentially could have avoided liver biopsy with an overall accuracy of 86%.

Sterling RK. Hepatology 2006;43:1317-1325

Martínez SM. Hepatology. 2011 Jan;53(1):325-35.

Fibrosure or Fibrotest

• Age, Gender Alpha-2-macroglobulin, Haptoglobin,Apolipoprotein A1, Gamma-

glutamyl transpeptidase (GGT), Total bilirubin, and Alanine transaminase (ALT).

• Comparison of Stage of Fibrosis to test interpretation

FibroTest METAVIR Knodell Ishak

0.75-1.00 F4 F4 F6

0.73-0.74 F3-F4 F3-F4 F5

0.59-0.72 F3 F3 F4

0.49-0.58 F2 F1-F3 F3

0.32-0.48 F1-F2 F1-F3 F2-F3

0.28-0.31 F1 F1 F2

0.22-0.27 F0-F1 F0-F1 F1

0.00-0.21 F0 F0 F0

Poynard et al. Clin Chem 50 (8): 1344–55. Cacoub P.J Hepatol. 48 (5): 765–73.

Ratziu et al. BMC Gastroenterology 6: 6. Ngo Y. Clin Chem 52 (10): 1887–96.

Radiologic Diagnosis

• Splenomegaly or Hypersplenism

• Increased Echogenicity

• Nodular Liver or Small Nodular Liver

• Atrophy Right lobe

• Hypertrophy of Caudate lobe

• Porto Systemic Collaterals

• Fibroscan

Fibroscan

Liver Stiffness Measurement(LSM)

Transient Elastography (TE)

Fibroscan

Liver Stiffness Measurement(LSM)

Transient Elastography (TE)

Liver Specimen with various Stages

Regardless of Any Symptoms, Screen Patients Who Have Any of These Risk Factors1-2

SCREEN

1. USPSTF. http://www.uspreventiveservicestaskforce.org/uspstf12/hepc/hepcfinalrs.htm/. Accessed July 6, 2015.

2. CDC. http://www.cdc.gov/nchhstp/newsroom/docs/2012/HCV-TestingRecsFactSheet_508.pdf. Accessed July 6, 2015

SCREEN

Baby boomers: born between

1945 and 1965

1. Smith BD et al. MMWR Recomm Rep. 2012;61(RR-4):1-32.

2. USPSTF. http://www.uspreventiveservicestaskforce.org/uspstf12/hepc/hepcfinalrs.htm/. Accessed July 6, 2015.

3. AASLD, IDSA, IAS-USA. Recommendations for testing, managing, and treating hepatitis C.

4. CDC. http://www.cdc.gov/nchhstp/newsroom/docs/2012/HCV-TestingRecsFactSheet_508.pdf. Accessed July 6, 2015

CDC, USPSTF, and AASLD (Liver Society)

Recommend Screening All Baby Boomers, Regardless of Risk Factors1-3

History of ANTI-HCV Rx

Hepatitis C Discovered

Interferon Approved

Ribavirin Approved

15-25 %

Pegylated Interferon Approved

40-45 %

Protease Inhibitor + Pegylated Interferon +

RBV Approved

60-70 %

Directly Acting Anti-viral Approved

• FDA 10/04/2016: Warning

– 24 cases of HBV reactivation reported to FDA1 and from the published

literature in HCV/HBV co-infected patients treated with DAAs during

the 31 months from November 22, 2013 to July 18, 2016

• Please check for / Treat with HBV anti-viral simultaneously or obtain an

expert opinion if you find the follow labs on the patient

– Hepatitis B Surface Antigen

– Hepatitis B Core Total

Risk of Hepatitis B Reactivation

FDA Approved Drugs

Drugs Components Brand Name (Mfr) Genotypes

Grazoprevir NS – 3 Zepatier©

(Merck) 1, 4Elbasvir NS – 5A

Ledipasvir NS – 5A Harvoni©

(Gilead Sciences)1,4, 5, 6

Sofosbuvir NS – 5B

Velapatasvir NS – 5A Epclusa©

(Gilead Sciences)1, 2, 3, 4, 5, 6

Sofosbuvir NS – 5B

Velpatasvir NS – 5AVosevi©

(Gilead Sciences)1, 2, 3, 4, 5, 6Sofosbuvir NS – 5B

Voxelaprevir NS – 3

Glecaprevir NS – 3 Mayvret©

(Abbvie Pharma)1, 2, 3 ,4, 5, 6

Pibrentasvir NS – 5A

AASLD / IDSA Guidelines on HCV Treatment 11/2019

ASCEND: Nonspecialists Can Effectively Treat

HCV Infection

• Nonrandomized phase IV trial of HCV treatment outcomes by DAA prescriber type – Pts (N = 600) from 13 urban, FQHCs in DC, all treated with LDV/SOF per FDA

prescribing info; all providers given 3-hr training in AASLD/IDSA HCV guidance

Kattakuzhy S, et al. Ann Intern Med. 2017;167:311-318.

0NP/PA Primary MD Specialist MD Overall

89 87 84 86

600n/N =

Rapid Shift to Non-Specialty HCV Care in AustraliaA

March April May June July Augus

September Octob

December

Other physicians

General

practitioners

Other specialists

Infectious

diseases

physicians

Gastroenterologis

The Kirby Institute. Monitoring hepatitis C treatment uptake in Australia (Issue 7). Available at:

https://kirby.unsw.edu.au/report/monitoring-hepatitis-c-treatment-uptake-australia-issue-7-july-2017.

Harm Reduction: What It Is and What It Does

Opioid Substituti

on Therapy

Needle-Syringe

Programs

Overdose Prevention/Reversa

HIV and HCV

Testing and

Treatment

• Harm reduction goals: decrease

medical, social, economic harms

resulting from drug use

• Harm reduction outcomes:

– Reduces HIV, HCV transmission

– Prevents overdose death

– Improves health, social service

uptake

Slide credit: clinicaloptions.comSander. J Correct Health Care. 2019;25:105. Kamarulzaman. Lancet. 2016; 388:1115. Hedrich.

Addiction. 2012;107:501.

Treating Patient’s HCV Infection:

SVR Rates High Among PWID, Even With Ongoing IDU

• 90.4% in C-EDGE CO-STAR

(n = 136)[7]

• 94% in SIMPLIFY (n = 102)[8]

– Did not vary by adherence

(90% cut off)

• 98% in pooled analysis from 6

phase III trials (mITT; n = 63)[9]

1Zeuzem. Ann Intern Med. 2015;163:1. 2. Feld. NEJM. 2014;370:1594. 3. Grebely. EASL 2017.

Abstr FRI-236. 4. Grebely. CID. 2016;63:1405. 5. Grebely. CID. 2016;63:1479. 6. Puoti. AASLD

2014. Abstr 1938. 7. Dore. Ann Intern Med. 2016;165:625. 8. Grebely. EASL 2017. Abstr FRI-235. 9.

Foster. AASLD 2017. Abstr 1182.

10095-98

No OST[1-5]

(n > 7000)

OST[3-6]

(n = 627)

SVR12 rates > 90% among

patients with current/recent IDU

Slide credit: clinicaloptions.com

Monitoring in Cured Pts With Advanced Fibrosis

• Routine clinic appointments 1-2 times/yr

– Consider follow up with Hepatologist or Gastroenterologist

• Obtain history and examine for signs of portal HTN

– Thrombocytopenia or Hypersplenism

• HCC surveillance and screening for esophageal varices recommended[1-4]

• Obtain comprehensive metabolic profile, INR, CBC

– Repeat HCV RNA PCR if abnormal LFTs

– Calculate MELD score

• Total bilirubin, creatinine, PT-INR

• Contact specialist if rising

1. AASLD/IDSA Guidelines. September 2017. 2. van der Meer AJ, et al. JAMA. 2012;308:2584-2593. 3. Aleman

S, et al. Clin Infect Dis. 2013;57:230-236. 4. Garcia-Tsao G, et al. Hepatology. 2007;46:922-938.

Hepatocellular Carcinoma (HCC) :

Surveillance in Advanced Fibrosis

• Ultrasound every 6 mos

– Limited data on CT and MRI

– Alpha-fetoprotein not recommended for screening• Poor sensitivity and specificity

• Remains part of the diagnostic approach for a pt with a liver tumor

AASLD/IDSA Guidelines. September 2017.

Bruix J, et al. Hepatology. 2011;53:1020-1022.

Maintaining Liver Wellness for Pts With SVR: Reinfection

• Counsel and educate on risk reduction

– Sexual transmission

• Partner testing

• Safer sex practices

– Pts using injection drugs should

• Referred for treatment

• Counseled on strategies to

avoid HCV transmission

• Vaccinations recommended

– Hepatitis A and B series

– Annual influenza vaccine

– Age appropriate Pneumococcal

vaccination

AASLD/IDSA Guidelines. September 2017.

CDC. Liver Disease/Vaccination. 2014

Maintaining Liver Wellness for Pts With SVR: Alcohol Use

• Most research in pts with ongoing chronic infection

– Alcohol speeds up progression of HCV disease[1-3]

and even replication of HCV[4,5]; abstinence

recommended[6]

• No clear evidence in pts after cure

• Advanced fibrosis: abstinence recommended

• Early fibrosis: mild alcohol use may be permitted[7]

– For men: no more than 4 drinks on any single day AND no more

than 14 drinks per wk

– For women: no more than 3 drinks on any single day AND no

more than 7 drinks per wk

1. Wiley TE, et al. Hepatology. 1998;28:805-809. 2. Corrao G, et al. Hepatology. 1998;27:914-919. 3. Poynard T, et al. Lancet.

1997;349:825-832. 4. Pessione F, et al. Hepatology. 1998;27:1717-1722. 5. Romero-Gomez M, et al. Dig Liver Dis. 2001;33:698-702.

6. AASLD/IDSA Guidelines. February 2016. 7. NIAA. Drinking Levels Defined. 2016.

Maintaining Liver Wellness for Pts With SVR: Obesity

• Fatty liver disease is the next epidemic of cirrhosis

• All pts cured of HCV should try to avoid fatty liver disease and additional

liver fibrosis

• Attempt to lose weight if overweight (BMI > 25)

• If present, gain control of diabetes mellitus and dyslipidemia

Ghany M, et al. Hepatology. 2009;49:1335-1374.

Chalasani N, et al. Hepatology. 2012;55:2005-2023.

Case: Post treatment

• Pt cured: testing for HCV RNA at 12 and 24 wks post treatment HCV PCR : undetectable.

• Considerations

– Hepatoma screening: fibrosis status?

• FibroScan prior to treatment = 10.7 kPa; platelet count normal but in low normal range

– Alcohol use: is 1-2 beers on weekends okay?

– Fatty liver disease risk modification: exercise and diet recommendations

• Follow-up schedule

– PCP vs GI -Hepatology

Summary

• Major societal health burden

• Screening for Baby boomers/PWID is important

• Can be treated easily, completely cured, Check for Hepatitis B co-infection

• Cure can lead to decreased cost burden on the health care system in general

• Everyone in the health care can contribute to cure this infection

• Advocate for your patients in places where you work

• Objectives

– Definition of NAFLD vs NASH

– Pathogenesis

– Burden of the problem

– Treatment

Steatohepatitis

“NASH”

CirrhosisNormal liver Steatosis

“NAFL”

Fatty liver with

inflammation and

hepatocyte ballooning

Increasing fibrosis

leading to cirrhosis,

hepatocellular carcinoma

Worldwide prevalence: ~ 25% 1.50%

to 6.45%

Fatty liver without

inflammation or

hepatocyte ballooning

Definition with Spectrum NAFLD: NAFL + NASH

Chalasani et al. NAFLD: AASLD Practice Guidelines 01/2018

NAFLD Definition:

• Evidence of Hepatic steatosis by Imaging/Biopsy

• Absence of secondary hepatic steatosis or diagnosis of other chronic liver disease

Slide credit: clinical care options

NAFLD: Liver Specimen

Simple Steatosis

Ballooning, Inflammation / Fat Globules

Peri-cellular Fibrosis

Cirrhosis

CIRRHOSIS

Pathogenesis of NASH

Obesity / Over weight

Hypercaloric diet

Metabolic Syndrome

Insulin Resistance

Oxidative Stress

Gut Dysbiogenesis /

Endotoxin

Proinflammatory

Cytokines

Mitochondrial

Dysfunction

Steatosis

• Increase FFA

• De novo

Lipogenesis

• Increased

Inflammation

• Fibrosis

Normal 50%NAFLD

In Patients with

Hyperlipidemia

Normal

In Patients with DM Type-

Normal 20%

NAFLD 80%

In Patients with Morbid

Obesity

Normal 70%

General Population

Epidemiology/Risk Factors

Chalasani et al., Am J Gastro 2012 Jun;107(6):811-26.

Obesity Trends* Among U.S. Adults

BRFSS, 1990, 2000, 2010

(*BMI 30, or about 30 lbs. overweight for 5’4” person)

No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%

Prevalence¶ of Self-Reported Obesity Among U.S. Adults by State and Territory, BRFSS, 2011

¶ Prevalence estimates reflect BRFSS methodological changes started in 2011.

These estimates should not be compared to prevalence estimates before 2011.

*Sample size <50 or the relative standard error (dividing the standard error by the prevalence) ≥ 30%.

*Sample size <50 or the relative standard error (dividing the standard error by the

prevalence) ≥ 30%.

NAFLD Group Relative Risk 95% CI

Interval

P-value

Cardiovascular Events (CVE) 1.77 1.26– 2.48 p < 0.001

Clinical CAD 2.26 1.04 – 4.92 p < 0.001

Ischemic Strokes 2.09 1.46 – 2.98 p < 0.001

Cardiovascular Mortality 1.46 1.31– 1.64 p < 0.001

• Meta-Analysis / Systemic Review of 6 studies

• N: 25,837 patients (NAFLD: 5953; controls: 19,884)

NAFLD with Risk of Cardio-Vascular Events

/Mortality

Haddad TM et al. Diabetes Metab Synd Nov 2017 Vol-2, Sppl-1. S209-216

NASH: Number One Indication for Liver

Transplant in Pts Aged < 50 Yrs

• In 2015 registry of pts listed for liver transplant, NASH surpassed HCV infection

Banini BA, et al. ACG 2016. Abstract 46.

0NASH and

Cryptogenic Cirrhosis

HCV Infection

150124

HCV infectionNASH and cryptogenic cirrhosis P < .0001

Etiology Among Pts Listed for Liver Transplant

Percentage of Weight Loss Associated With Histological

Improvement in NAFLD

• Analysis of data from 4 randomized studies

*Depending on degree of weight loss.

Hannah WN, et al. Clin Liver Dis. 2016;20:339-350.

Weight loss ≥ 5%

Weight loss ≥ 7%

Weight loss ≥ 10%

Weight loss ≥ 3%

Fibrosis

regression

(45% of pts)

NASH resolution

(64% to 90% of pts)*

Ballooning/inflammation

(41% to 100% of pts)*

Steatosis

(35% to 100% of pts)*

PIVENS: Histologic Improvement at

Wk 96 With Vitamin E vs Pioglitazone

*Histologic improvement: ≥ 1-point improvement in hepatocellular ballooning score, no increase in fibrosis score,

and either a decrease in NAS to ≤ 3 or a ≤ 2-point decrease in NAS plus ≥ 1-point decrease in either the lobular

inflammation or steatosis score.

P = .04

P = .001

NNT = 6.9

NNT = 4.2

Vitamin E

800 IU/day

Placebo Pioglitazone

30 mg/day

83 8084

With I

Sanyal AJ, et al. N Engl J Med. 2010;362:1675-1685.

• Double-blind, placebo-controlled, randomized,

• Phase III trial in adults with biopsy-proven NASH and no diabetes or cirrhosis (N = 247)

Pharmacologic Treatment Options Studied in NASH

Agent Good Evidence

for Use[1]

Limited or Insufficient

Evidence for Use[1]

NAFLD/NASH

Recommendation[2]

Vitamin ENASH without

diabetes

NASH with diabetes or

cirrhosisNASH without diabetes

PioglitazoneNASH with or

without diabetesNASH with cirrhosis

Can be used for

steatohepatitis

1. Rinella ME, et al. Gastroenterol Hepatol. 2014;10: 219-227.2. Chalasani et al. NAFLD: AASLD Practice Guidelines 01/2018

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