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 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 https://www.ncbi.nlm.nih.gov/pmc/articles/pmc100152/
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 coinfection
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 Harvoni Epclusa Treatment Naïve Without Cirrhosis With Cirrhosis 1 tablet for 8-12 weeks 1 tablet for 12 weeks 1 tablet for 12 weeks 1 tablet + ribavirin for 12 weeks Treatment Experienced Without Cirrhosis 1 tablet for 12 weeks Same as naïve With Cirrhosis 1 tablet + ribavirin for 12 weeks 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 Ribavirin Peginterferon Alfa-2a Simeprevir Viekira Pak (ombitasvir/ paritaprevir/ritonavir/ dasabuvir) Daclatasvir Limitations Adjunct; Teratogenic; Hemolytic anemia Flu-like ADR; Several Black Box Warnings Only treats type 1; No combination; Cannot be used in decompensated cirrhosis Cost ($33k/month); Excessive Therapy; Dosage Frequency 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 Nonoccupational 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 4 th gen Ag/Ab HCV RNA Four Months HIV 4 th 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.hepatitiscentral.com/hepatitis-c/ http://www.hepctrust.org.uk/information/impact-hepatitis-c-liver/progressionhepatitis-c/acute-phase-hepatitis-c https://www.uptodate.com/contents/overview-of-the-management-of-chronichepatitis-c-virusinfection?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