Professional Practice Meeting February 2018

Hepatitis C

Hepatitis C Overview

Hepatitis C Virus

Enveloped, single-stranded RNA virus

6 main genotypes: Rapidly mutating virus makes vaccination design difficult

Type 1a and 1b most common in the US

Type 1 most aggressive

Types 2 and 3 most likely to respond to Interferon

Mixed genotype infections in IVDU population

Type, Dose, Duration of treatment depends on genotype

Genotypes 1-6

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC100152/

1a/1b- worldwide (more in US, Europe, Japan) 2: Europe, Japan 3: Asia, India, South America 4: N. Africa (Egypt) 5-6: E. Asia, S. Africa 7-9: E. Asia

Transmission

Via blood products: IV drugs use

Blood transfusions prior to 1992

Clotting factors prior to 1987

Chronic hemodialysis

Needle sticks in hospital settings

Rarely during sexual encounters

Hep C Natural History

30,000 new infections every year in U.S. Acute Phase

This stage lasts up to 6 months approximately 65-75% of people experience no symptoms Symptoms may include fatigue, loss of appetite, jaundice,

nausea, and abdominal pain Symptoms usually clear within several weeks 15-20% undergo spontaneous resolution during this period

(clear all viral RNA)

Chronic Phase 75-80% progress to chronic Hepatitis C Patients likely to be asymptomatic in chronic phase for 20+

years Slow, progressive damage to the liver occurs

Hep C Natural History

Chronic Carriers

Up to 60% develop some liver fibrosis

20% develop cirrhosis within 20-25 years Nausea, loss of appetite, weight loss

Ascites, peripheral edema

Jaundice

Excessive bleeding

Spider veins

Darkening of palms/hands

Mental confusion

Testicular atrophy and/or breast enlargement in men http://www.medpractitioners.com/liver-cirrhosis/

Who to Screen

Universal Screening One time screening for adults born between 1945-1965 75% of those who screen positive were born in this time frame

Selective screening (+1 of the following) Have ever injected illegal drugs Received blood or organs before July 1992 Have received blood products from a donor who later tested positive

for HCV Ever been on chronic hemodialysis Have persistently high ALT Were born to HCV-positive mother Has HIV infection Had needle stick injury or mucosal exposure to HCV infected blood

No recommendation on frequency of selective screening

Hepatitis C Screening Tests

Serum analysis for anti-HCV antibodies Sensitivity >97% AND Specificity of 100% Positive test indicates prior exposure (not necessarily chronic

disease) 3 to 12 weeks for Abs to develop after exposure

If Ab positive, continue with HCV RNA screening Indicates ongoing infection Skip Ab screening and use RNA if suspected recent infection If RNA negative, repeat several months later to confirm

If RNA positive, continue with tests for hepatic fibrosis LFTs, abdominal ultrasound Biochemical markers including APRI

AST/Platelet Ratio Index for information on level of liver fibrosis

To Biopsy or NOT to Biopsy That is the question…

Pre-Treatment Considerations

Vaccination against Hepatitis A+B and Pneumovax23 if not already immunized

Published algorithms to determine type of treatment and duration Based on genotype, cirrhosis status and prior treatments

Additional considerations History of Alcohol Use

Renal impairment

Drug-Drug interactions in those with HIV and HepC co-infection

Hepatitis C Protocol

Pharmacological Treatment Options First Line

Harvoni (ledipasvir/sofosbuvir)

Epclusa (sofosbuvir/velpatasvir)

Zepatier (elbasvir/grazoprevir)

Mavyret (glecaprevir/pibrentasvir)

Alternatives Ribavirin

Peginterferon Alfa-2a

Simeprevir

Daclatasvir

Telaprevir

Viekira Pak (ombitasvir/paritaprevir/ritonavir/dasabuvir)

Technivie (ombitasvir, paritaprevir, ritonavir)

Vosevi (sofosbuvir, velpatasvir, voxilaprevir)

Harvoni

Ledipasvir 90 mg and Sofosbuvir 400 mg

Genotype 1a, 1b, 4, 5, 6

Warnings/Precautions Black Box Warning: Hepatitis B Reactivation

Adverse Reactions Headache; Fatigue; Weakness; Irritability; Nausea

Drug Interactions Amiodarone; Carbamazepine; Rosuvastatin; Proton Pump Inhibitors

Monitoring CBC, INR, LFTs, calculated GFR, HCV genotype and subtype and HCV

viral load at baseline, 4 weeks, and 12 weeks of therapy

Pricing 90-400 mg: $75600 - $113400

Epclusa

Sofosbuvir 400 mg and Velpatasvir 100 mg

Genotype 1a, 1b, 2, 3, 4, 5, 6

Warnings/Precautions Black Box Warning: Hepatitis B Reactivation

Adverse Reactions Headache; Fatigue; Nausea

Drug Interactions Amiodarone; Carbamazepine; Proton Pump Inhibitors; Rosuvastatin;

Atorvastatin

Monitoring CBC, INR, LFTs, calculated GFR, HCV genotype and subtype and HCV

viral load at baseline, 4 weeks, and 12 weeks of therapy

Pricing 400-100 mg: $59808 - $89712

Zepatier Elbasvir 50 mg and Grazoprevir 100 mg

Genotype 1a, 1b, 4

Warnings/Precautions Black Box Warning: Hepatitis B Reactivation

ALT elevations; Hepatic impairment

Adverse Events Fatigue; Headache; Nausea; Insomnia

Drug Interactions Ketoconazole; Rifampin; St John’s Wort; Atazanavir; Cobicistat

Monitoring CBC, INR, LFTs, calculated GFR, HCV genotype and subtype and HCV

viral load at baseline, 4 weeks, and 12 weeks of therapy

Pricing 50-100 mg: $43680 - $54600

Mavyret Glecaprevir 100 mg and Pibrentasvir 40 mg

Genotype 1a, 1b, 2, 3, 4, 5, 6

Warnings/Precautions Black Box Warning: Hepatitis B Reactivation

Hepatic Impairment

Adverse Events Headache; Fatigue; Nausea; Diarrhea

Drug Interactions HMG-CoA reductase inhibitors; Carbamazepine; St John’s Wort

Monitoring CBC, INR, LFTs, calculated GFR, HCV genotype and subtype and HCV

viral load at baseline, 4 weeks, and 12 weeks of therapy

Pricing 100-40 mg: $31680 - $47520

AASLD/IDSA 2017 Guideline Recommendations for Genotype 1 HCV infection

Treatment Naïve Treatment Experienced

Without Cirrhosis With Cirrhosis Without Cirrhosis With Cirrhosis

Harvoni 1 tablet for 8-12 weeks

1 tablet for 12 weeks

1 tablet for 12 weeks

1 tablet + ribavirin for

12 weeks

Epclusa 1 tablet for 12 weeks

1 tablet + ribavirin for 12

weeks Same as naïve

Zepatier 1 tablet for 12 weeks 1 tablet + ribavirin for 16 weeks

Mavyret 3 tablets for 8 weeks

3 tablets for 12 weeks 3 tablets for 12-16 weeks

Limitations to Therapy

Cost

Adherence Patients need to take these medications for 8-12 weeks

Additional Labs/Tests/Monitoring Some drugs require additional steps or therapy modification for

specific genetic make up

Concurrent hepatic impairment

Adverse Reactions

Drug-drug Interactions

Alternatives Drug Name Limitations

Ribavirin Adjunct; Teratogenic; Hemolytic anemia

Peginterferon Alfa-2a “Flu-like” ADR; Several Black Box Warnings

Simeprevir Only treats type 1; No combination; Cannot be used in decompensated cirrhosis

Viekira Pak (ombitasvir/ paritaprevir/ritonavir/dasabuvir)

Cost ($33k/month); Excessive Therapy; Dosage Frequency

Daclatasvir Long Treatment Duration; No combination

Telaprevir Steven-Johnson syndrome; Cannot treat type 1 Technivie (ombitasvir, paritaprevir, ritonavir)

Only for type 4

Vosevi (sofosbuvir/ velpatasvir/ voxilaprevir)

Epclusa showing efficacy without the exposure to voxilaprevir (limiting for hepatic impairment)

Treat Hep C Treat! On the Road to Health Again! Treat Hep C Treat! Because the Meds Really Work this Time!

Get a genotype! A viral load! And no more liver biopsy! Treat, Hep C, Treat! Now at C V I M!

Blood Borne Pathogen Exposure Protocol

CVIM Case Study

“MC” a 25 year old father and patient had a recent exposure.

A friend had been staying at his townhome and MC was cleaning the living room. He went to quickly pick up a hat and felt a sharp prick. That is when he found he had been pricked by a used needle. He then found out his friend had been using drugs at his house. His friend did not know his HIV/Hepatitis

status.

CVIM realized we needed a standard protocol for patients exposed to Blood Borne Pathogens.

Assessing an Exposure

For transmission of a Blood Borne Pathogen (HIV-0.3%, HBV 30%, HCV 1.8%) to occur an exposure must include both of the following: 1. Infectious Body Fluid 2. Portal of Entry

Infectious Body Fluid

Blood, semen, vaginal fluids, amniotic fluids, breast milk, CSF, pericardial fluid, peritoneal fluid, pleural fluid and synovial fluid can transmit HIV, HBV and HCV.

Saliva, urine, feces, sweat, tears, non–bloody emesis and respiratory secretions do not transmit HIV.

Portal of Entry Percutaneous

Increased risk if: hollow bore needles, visibly bloody device, deep injury device used in artery/vein

Mucous membrane Increased risk if large volume exposure

Cutaneous with non intact skin

*you need an infectious body fluid & portal of entry for a risk of transmission to exist

CDC PEP recommendations for Non-occupational Exposures

PEP is Post Exposure Prophylaxis for HIV exposure

CDC recommends prompt initiation of PEP <72 hours after exposure if source is known to be HIV infected and exposure has adequate risk

If exposure <72 hours but source HIV status unknown health care works should assess need for PEP on case by case basis

When patient seeks care >72 hours after exposure PEP is not recommended since window for prevention of transmission has closed

Post Exposure Baseline Labs

Source Person

HIV Ab rapid or HIV Ag/Ab

HCV Ab or HCV RNA

HBS S Ag

RPR

Exposed Person

HIV Ab rapid or HIV Ag/Ab

HCV Ab or HCV RNA

HBV panel

RPR

Follow Up Labs – Exposed Person

Six Weeks (4 weeks in PEP)

HIV 4th gen Ag/Ab

HCV RNA

Four Months

HIV 4th gen Ag/Ab

Anti HCV

**Anti HBV titer if vaccine series was given

Treatment

If a risk of HIV transmission exists patient should receive PEP

If patient has not been vaccinated against HBV they should receive Hep B vaccine and immune globulin, regardless of source status

There is no prophylaxis treatment for HCV Patients should be evaluated the need for

tetanus treatment

Resource

UCSF Needlestick and Exposure Hotline Phone number: 425-353-7842 Hours: 8am-8pm EST

HIV Post Exposure Prophylaxis

For 28 days

Truvada

Tenofovir DF 300 mg and Emtricitabine 200 mg

Warnings/Precautions Black Box Warning: Post-treatment acute exacerbation of Hepatitis B

Decreased bone mineral density; Renal impairment

Adverse Events Headache; Nausea; Dizziness; Insomnia; Weakness; Skin rash

Drug Interactions NSAIDs; Acyclovir; Valacyclovir; Aminoglycosides

Monitoring CBC, renal and hepatic function at baseline and 2 weeks after exposure;

Documented HIV test at baseline and 6 weeks, 12 weeks and 6 months after exposure

Pricing 200-300 mg (30): $2010.95

Raltegravir

Brand Name: Isentress

Warnings/Precautions Myopathy; Skin and hypersensitivity reactions

Adverse Events Headache; Insomnia; Elevations in creatine kinase; Increase serum ALT

Drug Interactions Rifampin

Monitoring CBC, renal and hepatic function at baseline and 2 weeks after exposure;

Documented HIV test at baseline and 6 weeks, 12 weeks and 6 months after exposure

Pricing 400 mg (60): $1800.00

Dolutegravir

Brand Name: Tivicay

Warnings/Precautions Hepatotoxicity; Hypersensitivity reactions

Adverse Events Hyperglycemia; Increase serum ALT; Insomnia; Nausea; Depression

Drug Interactions Carbamazepine; Dofetilide; Phenytoin; Phenobarbital; St. John’s Wort

Monitoring CBC, renal and hepatic function at baseline and 2 weeks after exposure;

Documented HIV test at baseline and 6 weeks, 12 weeks and 6 months after exposure

Pricing 50 mg (30): $1989.13

References

Joshi, SN. Hepatitis C Screening. The Ochsner Journal. 2014; 14(4):664-668. Zein NN. Clinical Significance of Hepatitis C Virus Genotypes. Clinical

Microbiology Reviews. 2000;13(2):223-235. Vercauteren K, de Jong YP, Meuleman P. Animal models for the study of HCV.

Current Opinions in Virology. 2015;13:67-74. Zhao Y-J, Ju Q, Li G-C. Tumor markers for hepatocellular carcinoma. Molecular

and Clinical Oncology. 2013;1(4):593-598. https://www.cdc.gov/hepatitis/hcv/guidelinesc.htm https://www.aafp.org/afp/2014/0915/od1.html http://www.hepctrust.org.uk/information/impact-hepatitis-c-liver/progression-

hepatitis-c/acute-phase-hepatitis-c http://www.hepatitiscentral.com/hepatitis-c/ https://www.uptodate.com/contents/overview-of-the-management-of-chronic-

hepatitis-c-virus-infection?search=hepatitis%20c&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1

http://nvhr.org/sites/default/files/.users/u32/HCV%20Initiating%20Treatment%20Guide.pdf