Treating Hepatitis C-HIV Coinfected Patients Welcome to the Real World H. Nina Kim, MD MSc Associate Professor of Medicine University of Washington Division of Allergy & Infectious Diseases April 21, 2017
Learning Objectives Upon completion of this presentation, learners should be better able to: Discuss some real-world HCV treatment issues related to choice of direct-acting antiviral (DAA) therapy in HIV-HCV coinfected patients Identify relevant drug interactions with DAAs and antiretroviral therapy Recognize the potential for adverse events in selected patients undergoing DAA therapy Highlight the importance of HCC surveillance even after HCV clearance in patients with cirrhosis
Milestones in HCV Treatment 100 HCV HIV/HCV Patients with SVR 12 (%) 80 60 40 20 35 18 44 27 75 74 85 85 96 96 0 IFN/RBV PegIFN/RBV Telaprevir or Boceprevir + PR SMV or SOF + PR IFN-free DAAs
HIV-HCV Coinfected Responses to DAA Therapy Comparable to HCV Monoinfected Genotype 1 Regimen (12 weeks) HIV-HCV Coinfected HCV Monoinfected Study SVR Study SVR Daclatasvir + Sofosbuvir ALLY-2 97% AI444040 100% Ledipasvir-Sofosbuvir ION-4 96% ION-1 99% Paritaprevir-ritonavirombitasvir + Dasabuvir TURQUOISE-I 94% PEARL-III, IV 96% Elbasvir-Grazoprevir C-EDGE Coinf 95% C-EDGE TN 95%
HCV Targets for Direct-Acting Antivirals (DAAs) Receptor binding and endocytosis Transport and release Fusion and uncoating Virion assembly (+) RNA Translation NS3/4 and polyprotein protease processing inhibitors Membranous web NS5A inhibitors replication and assembly Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000. NS5B polymerase RNA replication inhibitors Nucleos(t)ide Non-nucleoside
Currently Available DAAs Class Drug Dosing Activity FDA Approved NS5B inhibitor Sofosbuvir (Solvadi) QD Pangenotypic 2013 NS3A protease inhibitor (PI) NS5A-NS5B inhibitor combo NS5A, NS5B inhibitors with PI ( 3D ) NS5A inhibitor + PI NS5A inhibitor Simeprevir (Olysio) QD GT 1, 2, 4, 5, 6 2013 Ledipasvir-Sofosbuvir (Harvoni) Paritaprevir/ ritonavir/ombitasvir + dasabuvir (Viekira Pak) Ombitasvirparitaprevir/ritonavir (Technivie) Daclatasvir (Daclinza) NS5A inhibitor + PI Elbasvir-Grazoprevir (Zepatier) QD NS5A-NS5B inhibitor combo Sofosbuvir-Velpatasvir (Epclusa) QD GT 1 2014 BID GT 1 2014 QD GT 4 2015 QD Pangenotypic 2015 GT 1, 4 (pangenotypic) 2016 QD Pangenotypic 2016
Case 1 A 52 year-old HIV-infected man presents to your clinic for routine follow-up. On emtricitabine/tenofovir (FTC/TDF), ritonavir and atazanavir with a recent CD4 count 560 cells/mm 3 and HIV RNA <40 copies/ml. He has chronic hepatitis C, with HCV RNA level of 1.5 million IU/mL, genotype 1A, treatment naïve. His exam is notable for a firm liver edge and scattered spider angiomata. Labs show ALT 50, AST 60, platelets 110K; his CrCl is 75. His ultrasound demonstrates a nodular contoured liver and normal-sized spleen. He wants treatment for his hepatitis C infection.
Which of the following would you do next? A. Set him up for a liver biopsy for disease staging. B. Consider switching his antiretroviral regimen in anticipation of treatment with ledipasvir-sofosbuvir. C. Start elbasvir-grazoprevir once daily. D. Start ledipasvir-sofosbuvir plus ribavirin (weightbased dosing).
Factors to Consider in Choice of DAA Regimen Genotype (and subtype: 1A vs 1B) Cirrhosis? Decompensated or compensated? Treatment experience? Failure with peginterferon/ribavirin or prior DAAs? If HIV-coinfected: what is their antiretroviral therapy?
DAA Regimens: Genotype 1 GT 1A No cirrhosis GT 1A Cirrhosis, Naïve GT 1A Cirrhosis, PR Experienced GT 1B No cirrhosis GT 1B Cirrhosis, Naïve GT 1B Cirrhosis, PR Experienced EBR-GRZ LDV-SOF PrOD SOF-VEL SMV + SOF DCV + SOF 12 weeks (*16 weeks + RBV if +NS5A RAV) 12 weeks (*16 weeks + RBV if +NS5A RAV) 12 weeks (*16 weeks + RBV if +NS5A RAV) 12 weeks 12 weeks + RBV 12 weeks 12 weeks 12 weeks 12 weeks --- 12 weeks --- --- 12 weeks + RBV (or 24 weeks alone) (24 weeks + RBV) 12 weeks (24 weeks (+RBV if Q80K)) (24 weeks +/- RBV) 12 weeks 12 weeks 12 weeks 12 weeks --- --- 12 weeks 12 weeks 12 weeks 12 weeks --- --- 12 weeks (*16 weeks + RBV if +NS5A RAV) 12 weeks + RBV (or 24 weeks alone) 12 weeks 12 weeks (24 weeks +/- RBV) (24 weeks +/- RBV)
Ledipasvir-Sofosbuvir (Harvoni) Indications and Usage - HCV genotypes 1, 4, 5, and 6 in adults - Patients co-infected with HIV and HCV Class & Mechanism - Ledipasvir: NS5A inhibitor - Sofosbuvir: Nucleotide analog NS5B polymerase inhibitor Dosing: Ledipasvir-Sofosbuvir (fixed dose 90 mg/400 mg): 1 tablet orally once daily with or without food Drug Interactions: Yes, but to a lesser extent than HCV protease inhibitors Adverse Effects (AE): Fatigue, headache Wholesale Cost: $94,500 for a 12-week course Source: Harvoni Prescribing Information. Gilead Sciences
Drug Interactions: ART and DAAs
Ledipasvir-Sofosbuvir & Tenofovir DF Ledipasvir increases tenofovir DF exposure by 30-60% when coadministered with boosted PI (which independently increases TDF levels). Avoid LDV and TDF if CrCl <60 Co-administered with r/pi Renal toxicity monitoring: Cr and UA at week 2, 4 and further as indicated Consider switch to TAF/FTC Source: Harvoni Prescribing Information. Gilead Sciences German P, CROI 2015, Abstract 82.
Case 2 A 60 year-old HIV-infected man presents to your clinic. On abacavir, dolutegravir and rilpivirine with a recent CD4 count 350 cells/mm 3 and HIV RNA <40 copies/ml. PMH: Burkitt s lymphoma in 2008 in remission. Hx TDF nephrotoxicity, hx M184V, and unable to tolerate PIs. He has chronic hepatitis C, with HCV RNA level of 800,000 IU/mL, genotype 1A, treatment naïve. FibroScan reveals F2 fibrosis. He has an isolated hep B core Ab and is immune to hepatitis A. You plan to prescribe ledipasvir-sofosbuvir (LDV/SOF). His insurance denies authorization of LDV-SOF but has elbasvirgrazoprevir (EBR-GRZ) on formulary.
Elbasvir-Grazoprevir (Zepatier) Indications and Usage - Chronic HCV genotypes 1 or 4 in adults - Patients with HIV-HCV coinfection Class & Mechanism - Elbasvir: HCV NS5A inhibitor - Grazoprevir: HCV NS3/4A protease inhibitor Dosing: Elbasvir-Grazoprevir (fixed dose 50 mg/100 mg) One tablet orally once daily, with or without food Drug Interactions: Yes substrate of CYP3A4 and PgP Adverse Effects (AE): - Fatigue, headache, nausea, rash (4%) - Increase in ALT > 5x normal in 1% of subjects Wholesale Cost: $54,600 for a 12-week course Source: Zepatier Prescribing Information. Merck & Co., Inc.
Drug Interactions: ART and DAAs
DAA Regimens: Genotype 1 GT 1A No cirrhosis GT 1A Cirrhosis, Naïve GT 1A Cirrhosis, PR Experienced GT 1B No cirrhosis GT 1B Cirrhosis, Naïve GT 1B Cirrhosis, PR Experienced EBR-GRZ LDV-SOF PrOD SOF-VEL SMV + SOF DCV + SOF 12 weeks (*16 weeks + RBV if +NS5A RAV) 12 weeks (*16 weeks + RBV if +NS5A RAV) 12 weeks (*16 weeks + RBV if +NS5A RAV) 12 weeks 12 weeks + RBV 12 weeks 12 weeks 12 weeks 12 weeks --- 12 weeks --- --- 12 weeks + RBV (or 24 weeks alone) (24 weeks + RBV) 12 weeks (24 weeks (+RBV if Q80K)) (24 weeks +/- RBV) 12 weeks 12 weeks 12 weeks 12 weeks --- --- 12 weeks 12 weeks 12 weeks 12 weeks --- --- 12 weeks (*16 weeks + RBV if +NS5A RAV) 12 weeks + RBV (or 24 weeks alone) 12 weeks 12 weeks (24 weeks +/- RBV) (24 weeks +/- RBV)
Impact of Baseline NS5A RAVs in GT1a HCV treated with EBR-GRZ Patients without RAVs Patients with RAVs SVR12 (%) 98 98 98 98 86 72 58 91 405/ 414 14/ 24 345/ 352 74/ 86 389/ 396 31/ 43 284/ 289 136/ 150 EBR RAVs NS5A RAVs EBR RAVs NS5A RAVs Population Sequencing Next Generation Sequencing Jacobson I, et al. Gastroenterology. 2017, E-pub ahead of print.
Case 2 continued You send NS5A genotype 1 resistance testing. It returns showing Y93H mutation. You decide to start EBR-GRZ + ribavirin 600 mg BID for a planned duration of 16 weeks. Patient misses his week 2 CBC and returns 4 weeks into therapy with complaint of fatigue, irritability and malaise. Week 4 Labs: Hemoglobin 10 g/dl (from a baseline of 14). Total bilirubin is 3.2, ALT has risen to 365 (from 55) and AST 250 (from 40).
Which would you do next? A. Reduce the ribavirin from 1200 mg to 800 mg daily. B. Discontinue the ribavirin and continue elbasvirgrazoprevir. C. Send HBV DNA level. Consider stopping therapy pending these results. D. Wait for HCV RNA results to return before deciding what to do.
Factors to Consider in Choice of DAA Regimen Genotype (and subtype: 1A vs 1B) Cirrhosis? Decompensated or compensated? Treatment experience? Failure with peginterferon/ribavirin or prior DAAs? If HIV-coinfected: their antiretroviral therapy? Can they tolerate ribavirin? What is their insurance?
FDA Warning Oct 2016 HBV Reactivation on DAA Therapy Unexpected ALT and AST elevations 4-8 weeks (mean 53 days) from DAA initiation. Multiple kinds of DAA. Hospitalization in at least 6 patients. Severe clinical decompensation in 3 cases à 2 deaths and 1 liver transplantation. Among the 29 cases of HBV reactivation, 13 (45%) were chronic HBV carriers (+HBsAg). Some had absent HBsAg and anti-hbs, i.e. an isolated anti- HB core profile. https://www.fda.gov/drugs/drugsafety/ucm522932.htm
VA Cohort HBV Reactivation on DAA Therapy DAA treatment Hep B status HBV DNA tested on DAA HBV reactivation (>3 log 10 ) ALT peak not normal 62,920 HBsAg+ 377 (0.7%) Isolated core 7295* 84 (22%) 7 (8%) 6 173 (2.4%) 1 (0.6%) 0 *18% of the 62% tested for core Ab (as well as sag/ab) Belperio, Hepatology. 2017. E-published ahead of print.
Case 2 A 60 year-old HIV-infected man presents to your clinic. On abacavir, dolutegravir and rilpivirine with a recent CD4 count 350 cells/mm 3 and HIV RNA <40 copies/ml. PMH: Burkitt s lymphoma in 2008 in remission. Hx TDF nephrotoxicity and unable to tolerate PIs. He has chronic hepatitis C, with HCV RNA level of 800,000 IU/mL, genotype 1A, treatment naïve. FibroScan reveals F2 fibrosis. He has an isolated hep B core Ab and is immune to hepatitis A. You plan to prescribe ledipasvir-sofosbuvir (LDV/SOF). His insurance denies authorization of LDV-SOF but has elbasvirgrazoprevir (EBR-GRZ) on formulary.
Paritaprevir-Ritonavir-Ombitasvir + Dasabuvir ( 3D, Viekira Pak) Indication: HCV Genotype 1 infection, including compensated cirrhosis Class & Mechanism - Ombitasvir: NS5A inhibitor - Paritaprevir: NS3/4A protease inhibitor - Ritonavir: HIV PI used as booster - Dasabuvir: NS5B inhibitor Dose: 2 tablets Ombitasvir-Paritaprevir-Ritonavir once daily with food plus Dasabuvir 1 tablet twice daily with food Adverse Effects (AE): Fatigue, pruritus, and insomnia Wholesale Cost: $83,319 for 12-week course Source: Viekira Pak Prescribing Information. Abbvie, Inc.
Coformulated DAAs for GT1 HCV Drug Pros Cons Ledipasvir-sofosbuvir (LDV-SOF) (Harvoni) Simplicity, even for cirrhotics Can use without RBV in most Few drug interactions Data in decompensated cirrhotics Cost Restrictive drug access program Approved only vs GT 1 Paritaprevir-ritonavirombitasvir + dasabuvir (PrOD) (Viekira Pak) Elbasvir-grazoprevir (EBR-GRZ) (Zepatier) Activity vs GT 4 (Technivie) Data in ESRD Simplicity in most patients Extensive data in ESRD Activity vs GT 4 Lower cost Works for PI-experienced pts Pill burden (esp + RBV) BID dosing w/ food Drug interactions Necessity of RBV with GT 1A Hepatoxicity (rare) avoid in decompensated pts Drug interactions NS5A resistance testing in GT 1A 16 week duration in some Hepatotoxicity (rare) avoid in decompensated pts RBV = ribavirin, IDUs = injection drug users, ESRD = end-stage renal disease
Case 3 A 45 year-old HIV-infected man presents to your clinic for routine follow-up. On FTC/TDF, ritonavir and darunavir with a recent CD4 count 560 cells/mm 3 and HIV RNA <40 copies/ml. Past Medical Hx: Diabetes mellitus, type 2 A1C 7% on metformin and GERD well controlled on omeprazole 20 mg BID Chronic hepatitis C, genotype 1A, stage 2 fibrosis on recent fibroscan. Has hx viral non-response to peginterferon + ribavirin in 2004.
DAA Regimens: Genotype 1 GT 1A No cirrhosis GT 1A Cirrhosis, Naïve GT 1A Cirrhosis, PR Experienced GT 1B No cirrhosis GT 1B Cirrhosis, Naïve GT 1B Cirrhosis, PR Experienced EBR-GRZ LDV-SOF PrOD SOF-VEL SMV + SOF DCV + SOF 12 weeks (*16 weeks + RBV if +NS5A RAV) 12 weeks (*16 weeks + RBV if +NS5A RAV) 12 weeks (*16 weeks + RBV if +NS5A RAV) 12 weeks 12 weeks + RBV 12 weeks 12 weeks 12 weeks 12 weeks --- 12 weeks --- --- 12 weeks + RBV (or 24 weeks alone) (24 weeks + RBV) 12 weeks (24 weeks (+RBV if Q80K)) (24 weeks +/- RBV) 12 weeks 12 weeks 12 weeks 12 weeks --- --- 12 weeks 12 weeks 12 weeks 12 weeks --- --- 12 weeks (*16 weeks + RBV if +NS5A RAV) 12 weeks + RBV (or 24 weeks alone) 12 weeks 12 weeks (24 weeks +/- RBV) (24 weeks +/- RBV)
Case 3 A 45 year-old HIV-infected man presents to your clinic for routine follow-up. On FTC/TDF, ritonavir and darunavir with a recent CD4 count 560 cells/mm 3 and HIV RNA <40 copies/ml. Past Medical Hx: Diabetes mellitus, type 2 A1C 7% on metformin and GERD well controlled on omeprazole 20 mg BID Chronic hepatitis C, genotype 1A, stage 2 fibrosis on recent fibroscan. Has viral non-response to peginterferon + ribavirin in 2004. You decide that ledipasvir-sofosbuvir is the simplest treatment option for patient at this time.
Question What medication changes would you want to make before starting ledipasvir-sofosbuvir in this patient? A. No changes current medications are fine. B. Discontinue metformin and switch to sulfonylurea. C. Reduce his omeprazole to 20 mg once daily or discontinue. D. Discontinue his ritonavir, darunavir and start dolutegravir. E. C and D.
Ledipasvir-Sofosbuvir & Proton Pump Inhibitors 100 98 98 95 93 93 SVR12 (%) 90 No PPI PPI 85 80 8 wks LDV-SOF 12 wks LDV-SOF Terrault, N et al. HCV-TARGET. Gastroenterol 2016;151:1131.
Tapper, N et al. TRIO Network. Hepatology 2016;64:1893.
Case 3 (continued) A 45 year-old HIV-infected man presents to your clinic for routine follow-up. On FTC/TDF, ritonavir and darunavir with a recent CD4 count 560 cells/mm 3 and HIV RNA <40 copies/ml. Past Medical Hx: Diabetes mellitus, type 2 A1C 7% on metformin and GERD well controlled on omeprazole 20 mg BID Chronic hepatitis C, genotype 1A, stage 2 fibrosis on recent fibroscan. Has viral non-response to peginterferon + ribavirin in 2004. Starts on dolutegravir (DTG), FTC/TDF. Omeprazole reduced to 20 mg once daily to be taken on empty stomach with LDV-SOF. Metformin was dose reduced for coadministration with DTG à A1C 10% on repeat testing.
Case 4 A 50 year-old HIV-infected man comes in for routine care after missing a few interval visits. He has been on FTC/TDF and dolutegravir, last CD4 count 630 cells/mm 3 and HIV undetectable in 2016. PMH: Obesity BMI 35 kg/m 2. Hx chronic hepatitis C genotype 3, stage 4 fibrosis who cleared with sofosbuvir + daclatasvir in 2015. At this visit, he is found to have ALT 200 and AST 350 (ALT and AST in 20s in Jan 2016). He notes some fatigue, anorexia and nausea. Denies any alcohol use, IVDU or sexual activity. His hepatitis A Ab (total) and Hep B surface Ab were both positive on entry into care.
For this patient, which of the following would you do next? A. Counsel patient that he should stop his ART given likely hepatotoxicity. B. Obtain ultrasound and serum alpha-fetoprotein. C. Arrange for CT or MRI liver protocol. D. Send hepatitis C antibody with reflexive RNA level. E. Send hepatitis A IgM antibody.
HCC in cirrhotic HCV patients Maintain surveillance after HCV clearance Risk of HCC in HCV cirrhotics à 1-3% per year. SVR associated with 76% reduction in HCC risk in long-term studies. But reduction in HCC risk is not immediate post-svr Possible risk in tumor recurrence or more diffuse/aggressive HCC post-daa suggested by a few recent European series. Morgan, Ann Intern Med. 2013;158:329-37. Reig, J Hepatol. 2016;65:719 26. Conti, J Hepatol. 2016;65:727-33.
Beste, Gastro. 2015;149:1471-82.
HCC in cirrhotic HCV patients Risk Factors Age Severity of cirrhosis Diabetes, metabolic syndrome, obesity à NASH/NAFLD Male gender Alcohol Chronic hepatitis B coinfection HIV infection (low CD4) AASLD 2011 HCC Practice Guidelines. Akuta, Oncology. 2016;91:341-47. Gjaerde, Clin Infect Dis. 2016;63:821-9.
www.hepatitisc.uw.edu
Nina Kim, MD MSc University of Washington Harborview Liver Clinic hyangkim@uw.edu Questions?