Current Management of Hepatitis C Virus Infection

Transcription

1 Current Management of Hepatitis C Virus Infection Kristen M. Marks, MD Assistant Professor Weill Cornell Medicine New York, New York FORMATTED: 10/13/16 Financial Relationships With Commercial Entities Dr Marks was awarded research grants, paid to her institution, from Gilead Sciences, Inc, and Merck & Co, Inc. (Updated 11/4/16) Slide 2 of 39 Learning Objectives After attending this presentation, participants will be able to: Describe the options for initial treatment of hepatitis C virus (HCV) infection Describe when resistance testing should be done prior to initial treatment Describe current approaches to posttreatment monitoring Slide 3 of 39 1

2 IDSA/AASLD EASL contributions/clinical practiceguidelines/detail/easl recommendations on treatment of hepatitis c 2016 Slide 4 of 39 Newer strategy for HCV therapy: Direct acting antivirals target life cycle PREVIR Protease inhibitors e.g. telaprevir, boceprevir, faldaprevir, simeprevir, danoprevir, asunaprevir, paritaprevir, grazoprevir, voxilaprevir BUVIR Polymerase inhibitors Nucleos(t)ide analogs: e.g. tegobuvir, sofosbuvir, Non nucs: e.g. deleobuvir, dasabuvir ASVIR NS5A inhibitors e.g. daclatasvir, ledipasvir, ombitasvir, elbasvir, velpatasvir Slide 5 of 39 Currently used combinations of DAA classes Slide 6 of 39 NUC NUC + + PI NS5A +/- RBV +/- RBV PI PI + NS5A + NS5A + nonnuc +/- RBV NUC SPARING HIV Toxicity Resistance Renal insufficiency Drug drug interactions Affordability NUC SPARING HCV Affordability Provider preference Renal insufficiency Drug drug interactions Toxicity Resistance 2

3 CASE 64 y.o. African American W with HIV, HCV Geno 1b and cirrhosis, HCV RNA 88,000 IU/mL Slide 7 of 39 HCV Hx: Treatment naïve Cirrhotic based on Bx 8 yrs ago Transient Elastography 22 kpa No decompensation events EGD no varices MRI no HCC HIV Hx: CD4 256, HIV RNA UD, doing well on TDF/FTC + darunavir/r Other med hx includes: HBVsAg+, eab+ with HBV DNA not detected (had been elevated in distant past) HTN, high cholesterol, renal insufficiency (CrCl 45), past h/o heavy ETOH (none x 8 yrs) LET S CHOOSE AN HCV REGIMEN Q1. Prior to HCV treatment she needs a switch in her ARVs for optimal management with most available HCV regimens. Which of the following switches should NOT be made in this patient? Slide 8 of 39 11% 1. TDF to TAF 43% 2. TDF/FTC to ABC/3TC 12% 3. Darunavir/r to dolutegravir 34% 4. All of the above are fine Q2. Testing for HCV resistance (RAVs) would be indicated in this patient with HIV/HCV geno 1b if 11% 1. She had failed PegIFN + RBV in the past 10% 2. You plan to treat with sofosbuvir/velpatasvir 31% 3. You plan to treat with grazoprevir/elbasvir 37% 4. Nope! Resistance testing is not necessary here 10% 5. Hmmm What s a RAV? Slide 9 of 39 3

4 Q3. A regimen with an 8 week duration SHOULD be used for this patient. (Because it is effective and it saves money.) Slide 10 of 39 20% 1. TRUE 80% 2. FALSE Minimum to Know Pre Treatment HCV genotype/subtype HCV resistance (sometimes) Stage of fibrosis Cirrhosis yes/no If yes, compensated? (e.g., ascites, encephalopathy, etc) Method? Liver biopsy Transient elastography Laboratory biomarkers Imaging Prior HCV treatment? Response? DAA used? Medications To check for drug interactions Interferon eligibility and/or willingness Comorbidities Renal function HIV status Patient preference Child bearing potential of patient/partner Ribavirin is a teratogen HIV/Hepatitis C helpline Slide 11 of 39 Approved Drug Regimens Slide 12 of 39 RBV +/ PEG RBV +/ PTV/r RBV RBV SMV LDV DAC OMV GZR VEL SOF SOF SOF SOF SOF DAS +/ EBV SOF Interferon PegIFN Ribavirin ribavirin ribavirin +/ ribavirin +/ ribavirin Nucs sofosbuvir sofosbuvir sofosbuvir sofosbuvir sofosbuvir sofosbuvir Protease inhibitors simeprevir Paritaprevir /ritonavir grazoprevir velpatasvir NS5A ledipasvir daclatasvir ombitasvir elbasvir Non Nucs dasabuvir G1 X x X X X X X X G2 x X x X G3 X x X X G4 x X x X x X X X 4

5 33/285 8/67 41/207 58/ /289 18/66 56/205 40/64 28/38 77/106 21/23 176/ / /335 49/50 58/63 187/203 54/59 210/218 99/104 11/7/2016 Slide 13 of 39 SUSTAINED VIROLOGIC RESPONSE (%) STUDY REGIMEN Bagwell & Chastain, in press G1b vs G1a: G1b Initial Treatment Recommended Regimens Slide 14 of 39 IDSA/AASLD NO CIRRHOSIS: Elbasvir/grazoprevir x 12 w Ledipasvir/sofosbuvir x 12w Paritaprevir /ritonavir/ombitasvir + dasabuvir x 12w Sofosbuvir/velpatasvir x 12 wks Simeprevir + sofosbuvir x 12 wks Daclatasvir + sofosbuvir x 12w CIRRHOSIS: Elbasvir/grazoprevir x 12 w Ledipasvir/sofosbuvir x 12w Paritaprevir /ritonavir/ombitasvir + dasabuvir x 12w* Sofosbuvir/velpatasvir x 12 wks *Based on TURQUOISE 3 study results of PrOD w/o RBV 100% SVR12 in G1b + cirrhosis (BOLDED are regimens approved since last year!) G1a Initial Treatment Recommended Regimens Slide 15 of 39 IDSA/AASLD NO CIRRHOSIS: CIRRHOSIS: Elbasvir/grazoprevir x 12 w if no high level NS5A Elbasvir/grazoprevir x 12 w if no high level resistance NS5A resistance Ledipasvir/sofosbuvir x 12w Ledipasvir/sofosbuvir x 12w Paritaprevir /ritonavir/ombitasvir + dasabuvir + RBV Sofosbuvir/velpatasvir x 12 wks x 12w Sofosbuvir/velpatasvir x 12 wks Simeprevir + sofosbuvir 12w Daclatasvir + sofosbuvir x 12w 5

6 Elbasvir/grazoprevir x12w Results Overall study 95% SVR 144/157 (92%) G1a, 129/131 (99%) G1b, 18/18 G4, 8/10 G6 68/70 (97%) with cirrhosis Baseline NS5A RAVs & SVR Slide 16 of 39 Ann Intern Med. 2015;163(1):1 13 RAV Testing prior to Treatment NS5A RAVs are relatively common (10 15%) Significance of NS5A RAVs may depend on the RAV, the genotype, the regimen used and whether prior NS5A treatment Use resistance testing prior to: Treatment with grazoprevir/elbasvir for 1a Treatment of G3 if cirrhosis (DAA experienced) Slide 17 of 39 What about 8 wk regimens? Minimum criteria to be eligible: no cirrhosis, VL < 6mil, initial treatment Slide 18 of 39 Preliminary real world (non randomized) cohort data show conflicting results on the comparable effectiveness of 8 and 12 weeks in treatment naïve patients without cirrhosis. Based on available data, shortening treatment to less than 12 weeks is Not Recommended for HIV infected patients, African American patients, or those with known IL28B polymorphism CT or TT. For others, it should be done at the discretion of the practitioner. Wilder 2016, O Brien

7 Slide 19 of 39 Daclatasvir + Sofosbuvir x 8 or 12 wks in HIV/HCV Wyles, NEJM, 2015 Sofosbuvir/velpatasvir x 12 wks in HIV/HCV G1 6, Naïve + Rx exp Slide 20 of 39 N=106 29% Rx exp 18% cirrhosis 12% NS5a RAVs Of 2 relapses: 1 rx exp, 0 cirrhosis, 0 baseline RAVS Renal fxn looked unchanged in pts on boosted TDF Wyles, EASL, 2016 Slide 21 of 39 Hcvguidelines.org 7

8 Drug-Drug Interactions with DAAS Slide 22 of 39 Acid reducing drugs Anti epileptics Antiretrovirals Amiodarone Lipid lowering drugs druginteractions.org/ With SOF/LDV, TFV exposures are high in those on PIs Slide 23 of 39 NNRTIs Without With LDV/SOF 1,2 LDV/SOF 3 RTV Boosted PIs Without With LDV/SOF 4 9 LDV/SOF 10 Range of TFV exposures with available safety data EFV RPV ATR CPA N = FPV SQV LPV/r ATV DRV ATV DRV * 24 17* TFV exposures are higher when TDF is coadministered with LDV/SOF compared to without LDV/SOF, but Compared to the range of TFV exposures with available safety data For EFV or RPV: TFV exposures fall within the range 1 For RTV boosted PIs: TFV exposures partially exceed the range 2 1, Data on File, Gilead Sciences. 2. Hoetelmans RMW, et al. 6 th IWCPHT Quebec City, Canada. Poster # German P, et al. ICPHHT #O6 4. Luber AD, et al. HIV Medicine. 2010;11:193 9 (FPV+RTV) 5. Chittick GE, et al. AAC. 2006; 50(4): (SQV+RTV) 6. Zhu. 9th IWCPHT #023 (ATV+RTV & LPV/r ) * HIV infected subjects in CASTLE study 7. Kearney B, et al. JAIDS. 2006;43(3): (LPV/r) 10. German P, et al. CROI Agarwala S, et al. 6th IWCPHT #16. (ATV+RTV) 9.. Hoetelmans RMW, et al. BJCP. 2007;64(5): (DRV+RTV) Slide courtesy of J Kiser Guidelines Recommendation about use of LDV or VEL with TDF SOF/LDV + TDF CrCl < 60 ml/min: AVOID CrCl > 60: MONITOR SOF/VEL + TDF CrCl < 60 ml/min: AVOID CrCl > 60: MONITOR Slide 24 of 39 SOF/LDV + TDF + cobi or ritonavir boosted PI Any CrCl: AVOID if possible, Consider TAF SOF/VEL + TDF + cobi or ritonavir boosted PI CrCl < 60 ml/min: AVOID CrCl > 60: MONITOR or consider TAF Hcvguidelines.org accessed Aug

9 TAF Possible TDF Alternative in Patients on Cobicistat and Ritonavir Slide 25 of 39 TFV was increased by SOF/LDV in those on F/TAF/ELV/cobi by 27%, but TFV AUC with TAF only ~20% of AUC typically seen with TDF (~400 vs ng*hr/ml) Garrison KL, et al. 16 th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy, Alexandria, VA, May 26 28, 2015, abstract 71. Slide courtesy of J Kiser G4 INITIAL TREATMENT RECOMMENDED REGIMENS IDSA/AASLD Slide 26 of 39 Grazoprevir/elbasvir x 12 w Ledipasvir/sofosbuvir x 12w Paritaprevir/ritonavir/ombitasvir + RBV x 12w (note NO DASABUVIR) Sofosbuvir/velpatasvir x 12 w Sofosbuvir + RBV x 24w G2 INITIAL TREATMENT RECOMMENDED REGIMENS IDSA/AASLD Slide 27 of 39 NO CIRRHOSIS: Sofosbuvir/velpatasvir x 12 wks Sofosbuvir + RBV x 12w Sofosbuvir + daclatasvir x 12w if cannot tolerate RBV CIRRHOSIS: Sofosbuvir/velpatasvir x 12 wks Sofosbuvir + RBV x 16w Sofosbuvir + daclatasvir x 12 24w if cannot tolerate RBV 9

10 Sofosbuvir/velpatasvir x 12 wks for G2 (ASTRAL 2) Slide 28 of 39 14% cirrhosis 14 15% Rx exp Foster, NEJM, 2015 G3 INITIAL TREAMENT RECOMMENDED REGIMENS IDSA/AASLD Slide 29 of 39 NO CIRRHOSIS: Sofosbuvir + daclatasvir x 12w Sofosbuvir/velpatasvir x 12 w Sofosbuvir + PegIFN+ RBV x 12w CIRRHOSIS: Sofosbuvir/velpatasvir x 12 w* Sofosbuvir + daclatasvir +/ RBV x 24w* Sofosbuvir + PegIFN+ RBV x 12w *RAV testing for Y93H and add RBV if present Sofosbuvir + Daclatasvir for G3 (ALLY 3) Slide 30 of 39 Nelson, Hepatology :

11 Slide 31 of 39 Sofosbuvir/velpatasvir x 12 wks for G3 (ASTRAL 2) Most of this 3% w/cirrhosis Foster, NEJM, 2015 Slide 32 of FDA Adverse event reporting 24 cases HBV reactivation associated with DAA treatment 3 decompensated 2 died, 1 transplant. Delays in diagnosis and treatment. Most wks 4 8 of treatment Who s at risk? 7 had detectable HBV at baseline 4 sag+ and undetectable HBV DNA 3 sag and undetectable HBV DNA 10 unknown [RISK: sag+ DNA+/ > sag cab+ sab > sag cab+ sab+ No risk: sag cab sab+] Screen all HBsAg and anti HBc. In patients with serologic evidence of HBV infection, measure baseline HBV DNA prior to DAA treatment. Monitor patients who show evidence of current or prior HBV infection for clinical and laboratory signs (i.e., HBsAg, HBV DNA,serum aminotransferase levels, bilirubin) of hepatitis flare or HBV reactivation during DAA treatment and posttreatment follow up. Counsel patients to contact ahealth care professional immediately if they develop fatigue, weakness, loss of appetite, nausea and vomiting, yellow eyes or skin, or lightcolored stools, as these may be signs of serious liver injury. Q1. Prior to HCV treatment she needs a switch in her ARVs for optimal management with most available HCV regimens. Which of the following switches should NOT be made in this patient? Slide 33 of 39 4% 1. TDF to TAF 51% 2. TDF/FTC to ABC/3TC 12% 3. Darunavir/r to dolutegravir 33% 4. All of the above are fine 11

12 Slide 34 of 39 Q1. Prior to HCV treatment she needs a switch in her ARVs for optimal management with most available HCV regimens. Which of the following switches should NOT be made in this patient? TDF to TAF 4% 11% TDF/FTC to ABC/3TC 43% 51% Darunavir/r to dolutegravir 12% 12% All of the above are fine 34% 33% First Slide Second Slide Q2. Testing for HCV resistance (RAVs) would be indicated in this patient with HIV/HCV geno 1b if 9% 1. She had failed PegIFN + RBV in the past 12% 2. You plan to treat with sofosbuvir/velpatasvir 40% 3. You plan to treat with grazoprevir/elbasvir 40% 4. Nope! Resistance testing is not necessary here 0% 5. Hmmm What s a RAV? Slide 35 of 39 Slide 36 of 39 Q2. Testing for HCV resistance (RAVs) would be indicated in this patient with HIV/HCV geno 1b if She had failed PegIFN + RBV in the past 9% 11% You plan to treat with sofosbuvir/velpatasvir 10% 12% You plan to treat with grazoprevir/elbasvir 31% 40% Nope! Resistance testing is not necessary here 37% 40% Hmmm What s a RAV? 0% 10% First Slide Second Slide 12

13 Q3. A regimen with an 8 week duration SHOULD be used for this patient. (Because it is effective and it saves money.) Slide 37 of 39 2% 1. TRUE 98% 2. FALSE Slide 38 of 39 Q3. A regimen with an 8 week duration SHOULD be used for this patient. (Because it is effective and it saves money.) 20% TRUE 2% 80% FALSE 98% First Slide Second Slide After Successful Treatment: Manage liver disease Monitor for HBV reactivation (sag+ > cab+) HCCs expected (continue screening) Reinfections expected (e.g. MSM) Slide 39 of 39 Lambers AIDS

14 Acute HCV treatment in HIV+ MSM Slide 40 of 39 LDV x SOF x 6wks (n 26) 69% 1a, 31% G4 Any ARVs SVR4 85%, SVR12 77% 4 failures, 2 LTFU by wk 12 Relapses with High baseline RNA 1 reinfection by Wk 12 COMING SOON results from ACTG 5327: SOF/LDV x 8 wks for acute HCV in HIV infected persons Rockstroh, CROI 2016 Slide 41 of 39 Is this as good as it gets? Treatment coverage inadequate Shorter treatment Triples coming e.g. SOF/VEL/voxilaprevir Do we need them for initial treatment? Long acting formulations Will PrEP for HCV ever make sense? Summary Slide 42 of 39 Remarkable advances in terms of HCV treatment tolerability & efficacy SVRs for HCV now mirror monoinfection Continued refinement of therapies without significant drug interactions & those that can be used in varied populations (ESRD, G3+cirrhosis, acute HCV, etc) Successful treatment prevents cirrhosis, end stage liver disease, and hepatocellular cancer Post SVR continue liver disease management and consider HCV screening 14

15 Resources Slide 43 of 39 HCVguidelines.org nynjaetc.org druginteractions.org Thank you 15