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Updates in Hepatitis C MIMI NGUYEN, MD

FIRST HILL FAMILY MEDICINE

JUNE 2016

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Disclosures None

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Key objectives 1) Discuss screening and diagnosis of hepatitis C

2) Discuss hepatitis C counseling

3) Identify who to treat and when to treat

4) Discuss monitoring after cure.

Will not cover: • Hepatitis C drugs regimens

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Why do we care?

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Denniston MM et al Ann Intern Med. 2014;160:293-300

Prevalence of Hepatitis C

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Hepatitis C Mortality Change in Mortality Rates From 1999 to 2007

Rate

pe

r 1

00

,00

0 P

eo

ple

7

6

5

4

3

2

1

0

1999 2000 2001 2002 2003 2004 2005 2006 2007

Year

HIV

Hepatitis C

Hepatitis B

15,106

12,734

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

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Screening 1998: Risk based screening

2012: Risk based + Birth cohort screening

27%

27% + 68%

http://www.cdc.gov/knowmorehepatitis

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CDC Recommendations

Everyone born from 1945 through 1965 (one-time)

Persons who ever injected illegal drugs

Persons who received clotting factor concentrates produced before 1987

Chronic (long-term) hemodialysis

Persons with persistently abnormal ALT levels.

Recipients of transfusions or organ transplants prior to 1992

Persons with recognized occupational exposures

Children born to HCV-positive women

HIV positive persons

USPSTF Grade B Recs*

Everyone born from 1945 through 1965 (one-time)

Past or present injection drug use

Sex with an IDU; other high-risk sex

Blood transfusion prior to 1992

Persons with hemophilia

Long-term hemodialysis

Born to an HCV-infected mother

Incarceration

Intranasal drug use

Receiving an unregulated tattoo

Occupational percutaneous exposure

Surgery before implementation of universal precautions

CDC Screening Recommendations and USPSTF Screening Recommendations

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Meet Bill Bill is a 57 year old male, born in 1959, with HTN, DM2, and obesity.

• He comes in for a follow up visit for his chronic problems

• You decide to screen him for Hepatitis C because he falls into the 1945-1965 birth cohort. • You order a Hepatitis C Ab per guidelines.

CDC Hepatitis C Flowsheet

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CDC Hepatitis C Guidelines

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Bill: 1,006,090 copies

CDC Hepatitis C Guidelines

Quantitative RNA Assay

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Back To Bill – Patient Counseling •Bill’s medications include: Lisinopril, metformin, ibuprofen, and acetaminophen.

Max of 2g of acetaminophen daily. 1g for active drinkers.

Avoid NSAIDs in cirrhosis.

•Bill is now on disability due to severe osteoarthritis.

•He has been trying to lose weight but it’s been hard.

Goal BMI of 25.

•He drinks 2 glasses of wine a night.

Limit alcohol use.

http://www.eattoperform.com/wp-content/uploads/2013/06/Alcohol.jpg

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Patient Counseling •Does not recall if he’s ever been vaccinated with Hepatitis B.

Hepatitis A and B vaccination if no evidence of prior exposure

•He worries about his wife getting hepatitis C.

Do not share toothbrushes, razors, or other personal care items

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“What now?” .

Not necessarily the FibroSure, any test for fibrosis

Not commonly tested

Swedish Hepatitis C Epic Smartset

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Fibrosis Assessment Gold standard is liver biopsy but that is becoming less favorable.

UW Hepatitis C Module

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Fibrosis Assessment: Blood Tests FibroSure/Test™:

6 serum markers: alpha-2-macroglobulin, haptoglobin, GGT, apolipoprotein A1, total bilirubin, ALT

Metavir Fibrosis Scores

F4 = (Severe) Cirrhosis

F3 = (Severe) Numerous septa without cirrhosis

F2 = (Significant) Portal fibrosis with few septa

F1 = (Mild) Portal fibrosis without septa

F0 = (Normal) No Fibrosis

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Fibrosis Assessment: Blood Tests Using commonly obtained laboratory tests

<0.70: Low risk of fibrosis >2.0: Cirrhosis

<1.45: Low risk of fibrosis >3.25: Cirrhosis

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Fibrosis Assessment: Blood Tests

Biomarker Cutoffs AUROC

FIB-4 >1.45 0.74 (0.61 to 0.81)

APRI >0.5 0.77 (0.58 to 0.95)

FibroTest >0.10 to >0.22 0.79 (0.70 to 0.79)

Adapted from: Chou et al2013;159(4):308

Biomarker Cutoffs AUROC

FIB-4 >1.45 0.87 (0.83 to 0.92)

APRI >1.0 0.84 (0.54 to 0.97)

FibroTest >0.56 or >0.66 0.86 (0.71 to 0.92)

Mo

der

ate

-Sev

ere

Fib

rosi

s C

irrh

osi

s

AUROC .90-1 = excellent (A) .80-.90 = good (B) .70-.80 = fair (C) .60-.70 = poor (D)

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Comparing Blood Tests

Test A Test B Studies Median AUROC for Test A (Range)

Median AUROC for Test B (Range)

Median Difference (Range)

APRI FibroTest 18 0.76 (0.69 to 0.82) 0.79 (0.70 to 0.85) -0.03 (-0.10 to 0.07)

APRI FIB-4 11 0.77 (0.65 to 0.83) 0.78 (0.61 to 0.85) 0 (-0.13 to 0.12)

FibroTest FIB-4 5 0.79 (0.62 to 0.81) 0.79 (0.61 to 0.83) 0.01 (-0.03 to 0.07)

Adapted from: Chou et al2013;159(4):308

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Fibrosis Assessment: Blood Tests •APRI and FIB4 scores are roughly equivalent tests to the FibroSure/Test for determining low risk of fibrosis and cirrhosis.

•FibroSure/Test costs $300-$400.

•If there is no other way to assess fibrosis, getting the FibroSure/Test would be helpful.

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Fibrosis Assessment: Imaging •Hepatic Ultrasound

•Transient Ultrasound Elastography

•MR Elastography

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Fibrosis Assessment: FibroScan •Measures propagation of elastic waves through the liver

•Velocity of the waves = directly correlated with liver stiffness

•More fibrosis – higher measurement

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Castera L et al Gastroenterology. 2005;128:343-50

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Sheehan et al. 2007 Nov;102(11):2589-600

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Fibroscan Increased stiffness can be caused by:

•Fat

•Inflammation

•Fibrosis

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Who should be treated? All except those short life expectancies that cannot be remediated by treating HCV.

However must take into account:

•Patient readiness

•Compliance with follow up and drug adherence

•Fibrosis stage

•Cost

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Highest priority High priority May be deferred

F0-F1 F2 F3 F4 Post-Transplant

• Type 2 or 3 essential mixed cryoglobulinemia with end-organ manifestations

• Proteinuria, nephrotic syndrome, glomerulonephritis

• HIV Coinfection • HBV Coinfection • Other coexisting

liver diseases (e.g. NASH)

• Debilitating fatigue • Type 2 DM (insulin

resistant) • Prophyria cutanea

tarda

EASL Guidelines 2015; http://www.hep-druginteractions.org/ (Accessed May 2015)

• Active injection drug users

• MSMs • Prisoners • Women of child

bearing age • Hemodialysis

patients

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Highest priority High priority May be deferred

F0-F1 F2 F3 F4 Post-Transplant

• Type 2 or 3 essential mixed cryoglobulinemia with end-organ manifestations

• Proteinuria, nephrotic syndrome, glomerulonephritis

• HIV Coinfection • HBV Coinfection • Other coexisting

liver diseases (e.g. NASH)

• Debilitating fatigue • Type 2 DM (insulin

resistant) • Prophyria cutanea

tarda

EASL Guidelines 2015; http://www.hep-druginteractions.org/ (Accessed May 2015)

• Active injection drug users

• MSMs • Prisoners • Women of child

bearing age • Hemodialysis

patients

Medicaid: F2 only with extrahepatic manifestations, F3, F4

Medicare Part D, Group Health, Regence: all regardless of fibrosis

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UW Hepatitis C Module

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Treatment Unlike HIV and HBV infection, HCV infection is a curable disease

What does cure mean?

• SVR or sustained virologic response

◦ Undetectable HCV RNA 12 weeks after completion of antiviral

therapy for chronic HCV infection

◦ Best predictor of long term response to treatment.

◦ Can reverse hepatic inflammation and fibrosis

www.gossipextra.com

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Treatment is rapidly changing •2011 “Breakthrough direct acting antivirals approved (Victrellis™ & Incivek™)

•November 2013 simeprivir (Olysio™) approved GT1

•December 2013 sofosbuvir (Sovaldi™) approved GT1-4

•October 2014 ledipasvir/sofosbuvir (Harvoni™) GT1

•December 2014 paritaprevir/r/ombitasvir/dasabuvir (Viekira Pak™) approved GT1

•January 2015 elbasvir and grazoprevir (Zapetier ™) GT1, GT4

•June 2016 sofosbuvir/velpatasvir will be approved for all genotypes

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Monitoring after SVR Metavir stage F0-F2: Follow up same as if they were never infected

Metavir stage F3-F4: twice yearly ultrasound examination for hepatocellular carcinoma surveillance

If cirrhotic: Baseline endoscopy to screen for varices

Rescreening for HCV: only if patient has ongoing risk for HCV or unexplained hepatitis dysfunction

Get HCV RNA assay instead of anti-HCV serology

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Monitoring Untreated Patients Metavir stage F0-F2: Follow up at least yearly

•Counseling: healthy diet, weight control, limiting intake of hepatoxic medications and abstaining from or limiting alcohol intake.

•Yearly CBC, CMP

•Every 1-2 years: Noninvasive fibrosis assessment

Metavir stage F3-F4: Follow up at least twice yearly

•Address psychosocial issues

•Hepatocellular carcinoma surveillance with a hepatic ultrasound every 6 months.

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Revisiting Bill •F4 Cirrhosis and started on Harvoni treatment

•12 weeks into treatment- HCV RNA negative

•Cured!

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Take Away Points •Do not forget to do risk based screening

•Counseling is important to prevent further fibrosis.

•Noninvasive tests have good evidence for identifying minimal fibrosis and severe fibrosis/cirrhosis and can be used in lieu of biopsy. • APRI score is cheaper and equivalent than the proprietary Fibrosure

• Fibroscan is an evidence-based alternative.

•Hepatitis C treatment is constantly changing and so is payment.

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Epic SmartSet Content

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http://www.hepatitisc.uw.edu/

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Special Acknowledgements Drs. Belinda Fu and Maureen Brown

Dr. Kris Kowdley and the Swedish Liver Clinic

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References Castera L, Vergniol J, Foucher J, et al. Prospective comparison of transient elastography, Fibrotest, APRI, and liver biopsy for the

assessment of fibrosis in chronic hepatitis C. Gastroenterology. 2005;128:343-50.

Centers for Disease Control. Viral Hepatitis – Hepatitis C Information (2015). http://www.cdc.gov/hepatitis/hcv/index.htm. May 31 2015. Accessed May 15, 2016.

Chandok N, Watt KDS. Pain Management in the Cirrhotic Patient: The Clinical Challenge. Mayo Clinic Proceedings. 2010;85(5):451-458. doi:10.4065/mcp.2009.0534.

Chou R, Wasson N. Blood tests to diagnose fibrosis or cirrhosis in patients with chronic hepatitis C virus infection: a systematic review. Annals of Internal Medicine, 2013;159(4):308.

Denniston MM, Jiles RB, Drobeniuc J, Klevens RM, Ward JW, McQuillan GM, Holmberg SD. Chronic hepatitis C virus infection in the United States, National Health and Nutrition Examination Survey 2003 to 2010. Ann Intern Med. 2014;160:293-300.

HCV epidemic in North America peaked between 1940 and 1965 with medical procedures likely source of most infections. Infohep. http://www.infohep.org/page/3047867/. April 4 2016. Accessed March 23, 2016.

Hepatitis C Kills More Americans than Any Other Infectious Disease Centers for Disease Control and Prevention website http://www.cdc.gov/Environmental/. Updated January 9, 2012. Accessed March 2, 2016.

Joy JB et al. The spread of hepatitis C virus genotype 1a in North America: a retrospective phylogenetic study. Lancet Infectious Diseases. Online edition, dx.doi.org/10.1016/S1437-3099(16)00124-9.

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References

Ly, K. N., Xing, J., Klevens, R. M., Jiles, R. B., Ward, J. W., & Holmberg, S. D. (2012). The increasing burden of mortality from viral hepatitis in the United States between 1999 and 2007. Annals of internal medicine, 156(4), 271-278.

Mahajan R, Liu SJ, Klevens RM, Holmberg SD. Indications for testing among reported cases of HCV infection from enhanced hepatitis surveillance sites in the United States, 2004-2010. Am J Public Health. 2013;103(8):1445-1449.

Razavi H, ElKhoury AC, Elbasha E, et al. Chronic Hepatitis C Virus (HCV) Disease Burden and Cost in the United States. Hepatology (Baltimore, Md). 2013;57(6):2164-2170. doi:10.1002/hep.26218.

Shaheen AA, Wan AF, Myers RP. FibroTest and FibroScan for the prediction of hepatitis C-related fibrosis: a systematic review of diagnostic test accuracy. Am J Gastroenterol. 2007 Nov;102(11):2589-600.

University of Washington. Hepatitis C Online (2016). http://www.hepatitisc.uw.edu/. Accessed May/June 2016.