12/9/16 Disclosures • None Managing Hepatitis C: a Case-based Approach December 9, 2016 Bryn A Boslett, MD Outline Case 1 • 36M with well-controlled HIV, chronic HCV, and intermittent IV • Pre-treatment evaluation heroin abuse. His HCV has never been treated. • Impact of illicit drug use • He states that he’s been clean for 8 months • Newest regimens and how they work • Patient wonders, “Can I qualify for one of those fancy new • Management of concomitant medications hepatitis treatments that I keep hearing about?” • How to monitor your patient during and after therapy 1
12/9/16 Question 1 Effect of HCV genotype • Worldwide, genotypes 1 – 6 What studies are necessary in pre-treatment assessment for a patient with HCV? • Predicts response to HCV therapy A) Hepatitis C genotype • May predict progression of disease (eg, GT 3 à steatohepatitis) • In the US : B) Hepatitis C resistance testing • GT 1a and 1b (70%) C) FibroScan (transient elastography) • GT 2 and 3 (30%) D) All of the above • GT 4 (1%) US Distribution of HCV Genotypes GT3 GT2 GT1 Genotype 1 Genotype 2 Genotype 3 Genotype 4 Messina JP . Hepatology. 2015 Jan;61(1):77-87. Fibrosis Evaluation Back to our patient • Physical Exam: palmar erythema, • HCV viral load ~ 5 million, genotype 1b telangectasia, splenomegaly, etc • HAV immune, HBV non-immune (sAb, core Ab and sAg neg) à • Non-invasive markers: AST ÷ AST (Upper limit of normal) • HIV RNA <40, ND VACCINATE!!! • AST, ALT, INR, albumin, platelets APRI = x 100 Platelet count (10⁹ /L) • FIB-4, APRI, FibroSure/FibroTest • Cr 0.80 (GFR >60) • Transient elastography • AST 55, ALT 90 (Fibroscan) • Hgb 14, Platelets 180 • Imaging: Ultrasound for HCC, • APRI: 0.64, FIB-4: 1.9 à Fibrosis stage 2 (non-cirrhotic) splenomegaly, nodularity, etc • Biopsy: rarely needed AST ÷ AST (Upper limit of normal) Further discussion of liver disease evaluation: APRI = x 100 Platelet count (10⁹ /L) Marion Peters, MD 9:50 – 10:30 am (Next talk!) 2
12/9/16 Question 2 Review of Medications List • Antiretroviral therapy may need to be adjusted Before initiating HCV therapy for the patient, what other • Least interactions: TDF/FTC (Truvada), TAF/FTC (Descovy), information is needed? ABC/3TC (Epzicom), rilpivirine, raltegravir, dolutegravir A) Current antiretroviral therapy • Other NNRTIs, PIs also OK for certain regimens B) Psych evaluation • Others with potential drug interactions: antacids, anticonvulants, antiarrhythmics, statins C) Evaluation for varices D) At least three months of negative urine tox screens Workshop on HCV pharmacology: Parya Saberi, PharmD, MAS Pharmacology for All HCV Clinicians Breakout Session B, 4:10 – 4:55 pm Incidence of acute HCV, age <30 People who inject drugs (PWID) • Estimated that 60% of HCV cases in the US exist in current or former PWID • Approx 30,000 new HCV infections related to IVDU in 2013 – 80% of all new cases that year Non-urban • Growing HCV epidemic in persons age <30 years • Surveillance data from four states (Kentucky, Tennessee, Virginia, West Urban Virginia) showed 364% increase in the number of cases of acute HCV infection from 2006 to 2012 among persons aged ≤30 years. • Similar trends in other states, concurrent with rise in opiate abuse Litwin AH, et al. Clin Infect Dis . 2005;40:S339-S345.; Grebely J, et al. Clin Infect Dis . 2013;57:1014-1020; CDC. MMWR . CDC. MMWR . 2015:64:1-7. 2012;61:1-43; SAMHSA. National Survey on Drug Use and Health Report. September 4, 2014.; CDC. MMWR . 2015:64:1-7. 3
12/9/16 Real-life data for PWID Ready…set… • 121 HCV+ patients accessing primary care from a federally- qualified health center (FQHC) in the Bronx, NY in 2014-2015 • Your patient is motivated to start HCV therapy • 46/121 patients (52%) were PWID • Abacavir/Lamivudine/Dolutegravir (Triumeq) for ART • Methadone maintenance therapy • HCV care coordinator on-site for scheduling, reminder calls, education, prior authorizations But what to start??? Norton BL, et al. #585. CROI 2016 DAA Mechanisms of Action Guidelines Help • http://www.hcvguidelines.org Protease inhibitors NS5b Inhibitors NS5a Inhibitors • Management guidelines from IDSA and AASLD à Target viral à Target viral protease à Target viral RNA assembly and à “-previr” polymerase • http://www.hep-druginteractions.org Simeprevir release à “-buvir” Paritaprevir à “-asvir” • Free downloadable app Grazoprevir Ledipasvir NS5b Nucleotide Ombitasvir Sofosbuvir Daclatasvir • www.hcvadvocate.org NS5b Non-nucleotide Elbasvir Dasabuvir • Great patient information Velpatasvir 4
12/9/16 Red box: Combo pill or pack Available regimens Best options NS3 protease NS5A inhibitors NS5B NS5B Non- inhibitors nucleos(t)ide nucleoside Genotype 1, treatment naïve, +/- cirrhosis polymerase polymerase inhibitors inhibitors Regimen Dose Duration Velpatasvir Sofosbuvir Elbasvir/Grazoprevir 1 tab daily 12 -16* wks ( Zepatier ) +/- RBV* EBR (50mg)/GZR (100mg) Grazoprevir Elbasvir Daclatasvir Sofosbuvir Ledipasvir/Sofosbuvir 1 tab daily 12 wks ( Harvoni ) LDV (90mg)/SOF (400mg) Paritaprevir Ombitasvir Dasabuvir Velpatasvir/Sofosbuvir 1 tab daily 12 wks Ledipasvir Sofosbuvir ( Epclusa ) VEL (100mg)/SOF (400mg) Simeprevir Sofosbuvir *16 wks + RBV needed in GT 1a with NS5A RAS http://www.hcvguidelines.org/ Gt 1b, treatment Question 3 Elbasvir (EBR)/Grazoprevir (GRZ) naïve, non-cirrhotic, ABC/3TC/DTG (Triumeq) PROs CONs What additional steps need to happen before this regimen • Approved for GT 1 and 4 • GT1a: If NS5A resistance, (elbasvir/grazoprevir) is started? needs ribavirin and 16 wks • Can be used in renal failure, A) Change needs to be made to ART incl HD (C-Surfer) • Cannot use with PI-based regimens, cobicistat or EFV B) Change needs to be made to methadone therapy • Single pill • Activity against resistance- C) Resistance testing should be sent associated substitutions (RAS) D) No additional steps – we’re ready! with 1st gen PI • Lower cost ($54,600) 5
12/9/16 22% ELB/GRZ failures: resistance ELB/GRZ in treatment naive compensated cirrhotics impacts GT 1a C-EDGE: SVR12 Results by Genotype • High HCV RNA + baseline 100 100 99 NS5a resistance predicts 95 Patients with SVR12 (%) 92 lower SVR for GT 1a only 80 • For GT 1a, must perform 60 baseline resistance testing prior to use! 40 • If NS5A resistance present, must extend therapy to 16 20 weeks and add ribavirin 299/316 144/157 129/131 18/18 0 All GT1a GT1b GT4 <800K >800K YES NO Genotype IU/mL IU/mL Overall SVR12 results includes the 10 patients with GT 6, 8 of whom achieved SVR12. Baseline HCV Baseline NS5A Zeuzem, et al. Ann Intern Med. 2015 Jul 7;163(1):1-13. RNA Resistance Zeuzem, et al. Ann Intern Med. 2015 Jul 7;163(1):1-13 Kwo, et al. J Hepatol. 2015 Apr;62, Supplement 2:S674–5. 35% ELB/GRZ in patients on opiate ELB/GRZ in HIV co-infection compensated cirrhotics agonists C-EDGE CO-INFECTION: SVR12 Results by Genotype 100 • 92% SVR in C-EDGE CO-STAR 93 93 93 93 trial of PWID Patients with SVR12 (%) 80 • High adherence despite 60% of patients with Utox+ during the 60 study >80% >90% >95% • Methadone and 40 buprenorphine do not appear to significantly interact with % Adherence 20 ELB/GRZ 203/218 134/144 41/44 26/28 0 All GT1a GT1b GT4 Genotype Overall SVR12 results includes the 2 patients with GT 6, who both achieved SVR12. Dore AIM 2016 Rockstroh JK, et al. Lancet HIV. 2015;2:e319-27. 6
12/9/16 ELB/GRZ + ART interactions Elbasvir/Grazoprevir Summary HIV Drug Class Medication Interaction Treatment naïve or experienced*, including compensated cirrhosis Atazanavir/r HIV protease inhibitors ↑ ELB/GRZ, ATV Genotype NS5A Ribavirin Duration Darunavir/r resistance Rilpvirine Compatible 1a No No 12 weeks HIV NNRTI Efavirenz ↓ ELB/GRZ, EFV Etravirine No data 1a Yes Yes 16 weeks Dolutegravir Compatible Integrase inhibitors Raltegravir 1b N/A No 12 weeks Elvitegravir/cobi ↑ ELB/GRZ CCR5 Inhibitors Maraviroc No data 1b N/A No 12 weeks ABC, TAF, 3TC/FTC Compatible HIV NRTIs 4 N/A No 12 weeks TDF Compatible *If prior PI failure (telaprevir, boceprevir, simeprevir), need to add RBV Take Home Points from Case 1 Case 2 • 72M with well-controlled HIV, chronic HCV genotype 1a with • Pre-treatment: genotype, fibrosis assessment (ultrasound, compensated cirrhosis, hypertension and peptic ulcer disease serologic markers +/- transient elastography), accurate medication list, check HAV/HBV status and vaccinate! • Failed interferon + ribavirin + telaprevir in 2012 (relapsed) • Recent or active IVDU not a contraindication to HCV • Cr 1.2 (eGFR 55), Hgb 11.0 therapy, and opiate agonists compatible with all regimens • HAV immune and HBV sAb pos, core Ab pos, sAg neg • Elbasvir/Grazoprevir (ELB/GRZ) - Zepatier • He is willing to try HCV Rx again – ”Second time’s a charm?” • Can be used in ESRD • Compensated cirrhosis does not affect regimen • GT1a: need to check NS5A resistance, may need to add ribavirin and extend course • Contraindicated with PIs, cobicistat, NNRTIs except rilpivirine 7
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