Beginner HCV Management

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1 Disclosures Beginner HCV Management None Rachel Rutishauser, MD, PhD University of California, San Francisco Zuckerberg San Francisco General Hospital and Trauma Center When to treat? Treatment is recommended for all patients with chronic HCV infection, ecept those with short life epectancies that cannot be remediated by treating HCV, by transplantation, or by other directed therapy. Patients with short life epectancies owing to liver disease should be managed in consultation with an epert. Outline Review HCV medications Focus: recommended regimens* for treatment-naïve individuals with no (or compensated) cirrhosis Recommendations are the same for HCV mono- or HCV-HIV co-infected (but specific considerations in HIV+) Framework for choosing HCV therapy Pre-treatment evaluation How to monitor your patient during and after therapy *AASLD/IDSA HCV guidelines. Updated September

2 ARS: I am ready to start treating the HCV-infected patients on my panel on my own? A) True B) False ARS: When I think about treating patients for HCV I am the most worried about A) Keeping the names of the medications straight B) Counseling my patients C) Avoiding interactions with anti-retrovirals D) Monitoring my patients while they are on therapy E) My high-risk patients will get re-infected F) All of the above Direct Acting Agents Recommended regimens (fied-dose combination) à -ASVIR Ledipasvir Velpatasvir Elbasvir Pibrentasvir NS5a NS5b Protease Harvoni Ledipasvir Sofosbuvir Zepatier Elbasvir Grazoprevir Epclusa Velpatasvir Sofosbuvir Mavyret Pibrentasvir Glecaprevir Vosevi* Velpatasvir Sofosbuvir Voilaprevir -PREVIR Grazoprevir Glecaprevir Voilaprevir -BUVIR Sofosbuvir * = for treatment-eperienced (including with NS5a inhibitors) Adopted from Gane, E.J., et al. American Journal of Transplantation

3 A framework for HCV evaluation and choosing therapy Genotype 1a, 1b, 2, 3, 4, 5, 6 Treatment-eperience Prior eperience with IFN/ribavirin or DAAs Cirrhosis Yes/probable (compensated vs decompensated) or No Co-morbidities e.g., CKD/ESRD Drug-drug interactions e.g., PPI, ART, statin Insurance coverage Recommended regimens for treatment-naïve patients +/- compensated cirrhosis Genotype GT1a GT1b 12 (vs 8)** wks 12 wks*** 12 wks GT wks 12 wks* GT3 - - GT4 12 wks 12 wks GT5/6 12 wks - 12 wks if compensated cirrhosis * GT3 cirrhotic only, perform NS5a RAS testing: If Y93H, ribavirin recommended ** 8 wks ok if: non-black, HIV-uninfected, HCV RNA < 6 million IU/mL *** GT1a perform NS5a RAS testing: If resistance, 16 weeks + ribavirin AASLD/IDSA. HCV guidelines. September Patient 1 45 year old man with HIV (CD4 480, VL <40) on DTG/ABC/3TC. Other meds include methadone 80mg daily, omeprazole 20mg BID. He is seually active with men and uses methamphetamine (injects and snorts). He was first told he had HCV in 2009 but has never been evaluated for treatment. Pre-treatment evaluation Confirm HCV infected HCV RNA within the last 6-12 months (spontaneous clearance uncommon after 1 st yr, but can happen, <5%/yr) Evaluate for cirrhosis If cirrhotic, HCC screening (q6mo u/s) and EGD referral Any history of hepatic decompensation? E.g., varices, ascites, encephalopathy Review medications ART regimen Drug interactions (especially H2 blockers, PPIs, statins) Confirm stable on ART Confirm HAV & HBV immune If not, vaccinate Select appropriate treatment Counsel regarding risk for reinfection 3

4 12/8/17 Fibrosis assessment APRI = AST to Platelet Ratio Inde Physical Eam Palmar erythema, telangectasia, gynecomastia, splenomegaly Serologic markers Platelets, INR, Albumin APRI, Fib-4, FibroSure/Test > 0.7 à possible significant fibrosis (F2+ fibrosis) Sens. 77% Spec. 72% >1.0 à possible cirrhosis (F4) Sens. 76% Spec. 72% >2.0 à probable cirrhosis Sens 46%, Spec 91% FIB-4 (fibrosis-4) Lin ZH et al. Hepatology Fibrosis assessment Physical Eam Palmar erythema, telangectasia, gynecomastia, splenomegaly Serologic markers < 1.45 à low likelihood of advanced fibrosis/cirrhosis NPV 90% > 3.25 à advanced fibrosis/cirrhosis Spec 97%, PPV 65% Platelets, INR, Albumin APRI, Fib- 4, FibroSure/Test Imaging Ultrasound for signs of cirrhosis CT and MRI usually unnecessary- would avoid radiation and save as follow-on tests Transient Elastography: Fibroscan Ecellent option when available Biopsy: rarely necessary Sterling RK et. al. Hepatology

5 FibroScan (transient elastography) Non-invasive assessment of liver stiffness Match stiffness score (median of 10 measurements) to fibrosis stage High correlation with cirrhosis Less accurate in intermediate fibrosis, obese patients Afdhal, Gastroenterology & Hepatology, Degos et al, Journal of Hepatology, HCV Ab HCV RNA HCV genotype Pre-treatment laboratory testing NS5a RAS testing LFTs (AST, ALT, Alk Phos, Tbili) CBC INR Albumin Cr HAV IgG HBV: sag, sab, cab HIV RNA Within last 6-12mo GT1a: if considering Zepatier GT3: if cirrhosis + Epclusa (HBcAb+=evidence of prior infection, risk for reactivation) Back to our patient Genotype 1a or 1b HCV viral load 3.7 million IU/mL HIV RNA <40, Cr 0.93 (egfr > 60) AST 45, ALT 76 Albumin 4.1 Hgb 14, Platelets 170 APRI: 0.65 (i.e., cirrhosis unlikely) Abdominal ultrasound: coarse, heterogeneous and hyperechoic liver, no evidence of cirrhosis or portal hypertension HAV and HBV immune Genotype GT1a GT1b Genotype 1a or 1b, without cirrhosis 8 wks 12 wks* 12 (vs 8)** wks 12 wks*** 12 wks GT2 - - GT3 - - GT4 12 wks 12 wks GT5/6 12 wks - 12 wks if compensated cirrhosis * GT3 cirrhotic only, perform NS5a RAS testing: If Y93H, ribavirin recommended ** 8 wks ok if: non-black, HIV-uninfected, HCV RNA < 6 million IU/mL *** GT1a perform NS5a RAS testing: If resistance, 16 weeks + ribavirin AASLD/IDSA. HCV guidelines. September

6 There are so many options! How do I choose a regimen? Duration Cost (or whatever insurance will pay for) Comorbidities Potential drug-drug interactions ART-DAA interactions are a unique concern in HIV/HCV co-infected patients Comorbidities important to HCV treatment Renal disease Avoid SOF for CrCL < 30 or are ok for CrCl < 30 & ESRD GERD/Gastritis PPI not compatible with LDV or VEL (in Harvoni, Epclusa) Anemia If ribavirin-containing regimen is indicated HBV Risk for re-activation if HBV core Ab+ lower if on HBVactive ART (3TC/FTC/TDF/TAF) Checking DDI: Run the list! Most common drug interactions Ledipasvir and Velpatasvir (part of Harvoni and Epclusa) with acid blocking meds (antacids, H2 blockers, PPIs) reduced drug levels Note: Mayvret package insert in Europe-Omeprazole NTE 20mg/day, but clinical data suggest no meaningful impact Sofosbuvir with amiodarone Black Bo! Elbasvir/Grazoprevir and Glecaprevir/Pibrentasvir have many interactions with anti-retrovirals Some are contraindicated, especially ritonavir-boosted HIV PI 6

7 DAA-ART interactions (treatment-naïve recommended regimens) ATV/r VEL, ATZ LDV, ATZ ELB,GRZ,ATZ DRV/r * VEL, DRV LDV, DRV ELB,GRZ, DRV LPV/r * VEL, LPV ELB,GRZ, LPV EFV LDV, EFV RPV RPV, G/P VEL, RPV LDV, RPV ELB,GRZ,RPV ETV RAL RAL, G/P VEL, RAL LDV, RAL ELB,GRZ, RAL ELV/c GLE, PIB, COB VEL, COB LDV, COB ELB,GRZ,COB DTG GLE,PIB DTG VEL, DTG LDV, DTG ELB,GRZ, DTG MVC TDF VEL, TFV LDV, TFV ELB,GRZ, TFV TAF GLE, PIB, TFV VEL, TFV LDV, TFV no data; RED=avoid, GREEN=safe, YELLOW=dose change/monitor ORANGE/* PK data support co-administration GT1a or 1b, treatment-naïve, non-cirrhotic, on Triumeq & BID PPI Back to the patient The patient strongly desires to continue taking PPI at current dose and are out : clinical data suggest ok to coadminister Options: 8 weeks 12 weeks (GT1a/b genotype so, if 1a => resistance testing) His insurance will approve Glecaprevir/Pibrentasvir Approved August, 2017 Genotypes: 1-6 Duration: 8 weeks 12 weeks if compensated cirrhosis ART Interactions: Cannot co-administer with boosted ATV, efavirenz, or etravirine ATV/r DRV/r LPV/r EFV RPV ETV RAL ELV/c DTG MVC TDF TAF * * RPV RAL GLE, PIB, COB GLE,PIB DTG GLE, PIB, TAF = no data * PK data support co-administration Genotype 1 summary Four options; SVR12 (w/o cirrhosis): 99% % 2 98% 3 1a: 92% 1b: 99% 4 If considering in Genotype 1a, send testing for baseline NS5A RAS If present etend treatment to 16 weeks and add ribavirin In 2017, is a good option in many cases (for GT1a/b as well as other genotypes!) 8 weeks (unless compensated cirrhosis: 12 weeks) Watch out for DDI with ATV, EFV, ETV 1. EURANCE-1 (Zeuzem, 2016) 2. ASTRAL-1 (Feld, 2015) 3. ION-1 (Afdhal, 2014) 4. C-EDGE (Zeuzem, 2017) 7

8 Genotype 3 52M with well-controlled HIV on FTC/TDF + ATV/r, diabetes, HTN, and chronic HCV genotype 3 Doesn t want to stop ATV/r No cirrhosis, no prior treatment history Normal CBC, Cr, LFTs HAV and HBV immune Other medications include metformin, lisinopril, and pravastatin Genotype 3, no cirrhosis, on ATV/r Genotype GT1a GT1b 12 (vs 8)** wks 12 wks*** 12 wks GT2 - - GT3 8 wks 12 wks* - - GT4 12 wks 12 wks GT5/6 12 wks - 12 wks if compensated cirrhosis * GT3 cirrhotic only, perform NS5a RAS testing: If Y93H, ribavirin recommended ** 8 wks ok if: non-black, HIV-uninfected, HCV RNA < 6 million IU/mL *** Gt1a perform NS5a RAS testing: If resistance, 16 weeks + ribavirin AASLD/IDSA. HCV guidelines. September DAA-ART interactions (treatment-naïve recommended regimens) ATV/r VEL, ATZ LDV, ATZ ELB,GRZ,ATZ DRV/r * VEL, DRV LDV, DRV ELB,GRZ, DRV LPV/r * VEL, LPV ELB,GRZ, LPV EFV LDV, EFV RPV RPV, G/P VEL, RPV LDV, RPV ELB,GRZ,RPV ETV RAL RAL, G/P VEL, RAL LDV, RAL ELB,GRZ, RAL ELV/c GLE, PIB, COB VEL, COB LDV, COB ELB,GRZ,COB DTG GLE,PIB DTG VEL, DTG LDV, DTG ELB,GRZ, DTG MVC TDF VEL, TFV LDV, TFV ELB,GRZ, TFV TAF GLE, PIB, TFV VEL, TFV LDV, TFV no data; RED=avoid, GREEN=safe, YELLOW=dose change/monitor ORANGE/* PK data support co-administration Sofsobuvir/Velpatasvir Approved June, 2016 Genotypes: Pangenotypic Baseline RAS testing for GT3 w/cirrhosis Duration: 12 week course for all GT3 + cirrhosis: RAS testing, if Y93H => +ribavirin Drug-Drug Interactions: CANNOT give with EFV, ETR Tenofovir elevated 20-80% with TDF Also increase with TAF but well below concentrations seen w/tdf Caution with PPIs, H2 Avoid if possible and don t eceed 20 mg PPI **Not recommended for CrCL <30 ATV/r DRV/r LPV/r EFV RPV ETV RAL ELV/c DTG MVC TDF TAF VEL, ATZ VEL, DRV VEL, LPV VEL, RPV VEL, RAL VEL, COB VEL, DTG VEL, TFV VEL, TFV = no data 8

9 Genotype 3 Summary Historically, individuals with GT3 had worse prognosis if untreated and were also harder to treat In 2017: 8w (12w if compensated cirrhosis) and 12w are recommended therapies with SVR12 (w/o cirrhosis): 95% 1 98% 2 Some reasons for not choosing Mavyret: Insurance coverage, DDI: cannot give with boosted ATV, EFV, ETV (but note that also can t be given with EFV, ETV) 1. EURANCE-1 (Zeuzem, 2016) 2. ASTRAL-3 (Foster, 2015) Genotype 4 case 57 yo M with well-controlled HIV on Atripla (TDF/FTC/EFV) and genotype 4 HCV Does not want to stop Atripla No other major comorbidities Normal labs and no cirrhosis on imaging Genotype GT1a GT1b Genotype 4, no cirrhosis 12 (vs 8)** wks 12 wks*** 12 wks GT2 - - GT3 - - GT4 8 wks 12 wks* 12 wks 12 wks GT5/6 12 wks - 12 wks if compensated cirrhosis GT4, treatment naïve, non-cirrhotic, Atripla ARS: What do you recommend? A) Switch ART to Triumeq and start Mavyret () B) Continue Atripla, start Epclusa () C) Continue Atripla, start Zepatier (GZR/EBR) D) Continue Atripla, start Harvoni () * GT3 cirrhotic only, perform NS5a RAS testing: If Y93H, ribavirin recommended ** 8 wks ok if: non-black, HIV-uninfected, HCV RNA < 6 million IU/mL *** Gt1a perform NS5a RAS testing: If resistance, 16 weeks + ribavirin AASLD/IDSA. HCV guidelines. September

10 DAA-ART interactions (treatment-naïve recommended regimens) ATV/r VEL, ATZ LDV, ATZ ELB,GRZ,ATZ DRV/r * VEL, DRV LDV, DRV ELB,GRZ, DRV LPV/r * VEL, LPV ELB,GRZ, LPV EFV LDV, EFV RPV RPV, G/P VEL, RPV LDV, RPV ELB,GRZ,RPV ETV RAL RAL, G/P VEL, RAL LDV, RAL ELB,GRZ, RAL ELV/c GLE, PIB, COB VEL, COB LDV, COB ELB,GRZ,COB DTG GLE,PIB DTG VEL, DTG LDV, DTG ELB,GRZ, DTG MVC TDF VEL, TFV LDV, TFV ELB,GRZ, TFV TAF GLE, PIB, TFV VEL, TFV LDV, TFV no data; RED=avoid, GREEN=safe, YELLOW=dose change/monitor * PK data support co-administration Ledipasvir/Sofosbuvir Genotypes: 1, 4, 5/6 Duration: Generally 12 weeks 8 wk if non-black + HIV neg + HCV < 6 million Add RBV if decomp cirrhosis or retreatment in cirrhosis Drug-Drug Interactions: Ledipasvir tenofovir levels, particularly in setting of PI/r + TDF Consider change from TDF + PI/r if giving SOF/LDV If giving TDF with SOF/LDV, monitor for nephrotoicity Tenofovir levels from TAF also raised but overall much lower Caution with PPIs & H2 Avoid if possible and don t eceed 20 mg PPI ** Not recommended for CrCL <30 ATV/r DRV/r LPV/r EFV RPV ETV RAL ELV/c DTG MVC TDF TAF LDV, ATZ LDV, DRV LDV, EFV LDV, RPV LDV, RAL LDV, COB LDV, DTG LDV, TFV LDV, TFV Genotype 4 summary Four options; SVR12 (w/o cirrhosis): 99% 1 100% 2 100% 3 97% 4 Treatment choice will be influenced by duration of therapy, drug-drug interactions, co-morbidities, insurance coverage 1. EURANCE-4 (Asselah, 2016) 2. ASTRAL-1 (Feld, 2015) 3. SYNERGY (Kohli, 2015) 4. Asselah, 2015 Monitoring on/after therapy Monitoring much more minimal with newer agents, but pharmacy and adherence support still essential Monitor CBC, LFT, BUN/Cr, HCV RNA at week 4, then repeat as needed More frequent labs in more challenging patients: +cirrhosis, CKD, anemia on RBV, patients on regimens that will boost TDF, etc Detectable HCV RNA may be marker of non-adherence LFTs at week 8 if on If new transaminitis think about HBV flare! After therapy, HCV RNA check 12 weeks after completion of therapy for SVR For cirrhotics: remember to continue HCC screening (q6m) Assess for recurrence (HCV-RNA) if continued risk for reinfection or uneplained hepatic dysfunction 10

11 12/8/17 Cumulative incidence of HCC 0% 5% 10% 15% 20% 25% HCV cure reduces but does not eliminate HCC risk in cirrhotics Counsel about Re-Infection Drug use: shared needles, works, straws used for snorting Seual contact through men having se with men (MSM) Risk highest in HIV+ men Continue to screen cirrhotic patients for HCC after SVR Cirrhosis negative Cirrhosis positive Years after SVR 7 Continue monitoring HCV RNA screening! 8 El-Serag Hepatology Hill AASLD 2014 Abstract 44 Resources Management guidelines from IDSA and AASLD Free downloadable app Patient information: Doc, I ve got a question. What s the difference between Hepatitis A, B, and C? But I heard you can t cure it? What are the side effects? I was told I can t get treated for Hep C because my T cells are too low Is it too late? How many pills? Can I get it again? When can I start??? 11

12 Summary Treatment regimens influenced by GT, prior treatment, +/- cirrhosis, DDI, co-morbidities, insurance In treatment-naïve, baseline resistance testing generally only necessary if GT1a and considering Zepatier or GT3 w/cirrhosis and considering Epclusa Other medications may need to be adjusted If making changes, make sure stable on ART regimen for 3-4 weeks prior to starting therapy Minimal lab monitoring for most, but closer attention for those at risk for complications Educate about risk for re-infection Continue imaging surveillance for HCC in patients with cirrhosis Thank you!! Annie Luetkemeyer Parya Saberi Lillian Brown Bryn Boslett Val Robb Janet Grochowski Diane Havlir Monica Gandhi Ward 86 HIV/HCV clinic patients Hepatitis C Consultation Services (844) AM-8PM EST, M-F nccc.ucsf.edu The Clinician Consultation Center (CCC) provides up-to-date epert advice to support clinicians managing patients with hepatitis C (HCV) and co-morbidities such as HIV or substance use. Guidance is based on national treatment guidelines, current scientific findings, and best clinical practices. Consultation topics include: HCV transmission & prevention HCV screening & diagnostic testing HCV evaluation & monitoring Regimen selection Re-treatment strategies Co-infection (HCV-HIV, HCV-HBV) HCV and special populations (chronic kidney disease, cirrhosis, pregnancy) The Clinician Consultation Center is a free telephone advice service for clinicians by clinicians. Receive epert clinical advice on HIV, hepatitis C, substance use, PrEP, PEP, and perinatal HIV. See nccc.ucsf.edu for more information. HIV treatment, ARV decisions, complications, and co-morbidities HCV testing, staging, monitoring, treatment Pregnant women with HIV or at-risk for HIV & their infants Pre-eposure prophylais for persons at risk for HIV This project is supported by the Health Resources and Services Administration (HRSA) of the U.S. Department of Health and Human Services (HHS) under grant number U1OHA (AIDS Education and Training Centers National Clinician Consultation Center) awarded to the University of California, San Francisco. (updated 10/24/17) Substance use evaluation and management Occupational & non-occupational eposure management 12