Initial Treatment of the Hepatitis C Virus-Infected Patient

Transcription

1 IDSA/AASLD Initial Treatment of the Hepatitis C Virus-Infected Patient Kristen M. Marks, MD Assistant Professor Weill Cornell Medicine New York, New York Slide FINAL AS 1 of OF: 49 11/15/17 Learning Objectives After attending this presentation, learners will be able to: Describe regimens recommended for initial treatment of HCV infection Recognize when to do testing for HCV resistance Identify the advantages and limitations of newly approved HCV treatment regimens Slide of 49 EASL Slide 4 of 49 Louisville, Kentucky, November 17, 217 1

2 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, glecaprevir ---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, pibrentasvir Slide 5 of 49 Currently used combinations of DAA classes NUC-SPARING HCV Renal insufficiency Drug-drug interactions Duration Affordability/Access Toxicity Resistance NUC NUC + PI + NS5A PI PI +/- RBV +/- RBV NUC + NS5A +/- RBV PI + + NS5A + NS5A + nonnuc NUC-SPARING HIV Toxicity Resistance Renal insufficiency Drug-drug interactions Affordability +/- RBV Slide 6 of 49 Which of the following represents the BEST strategy for treating HCV? 1. drugs for 8 weeks 2. 2 drugs for 8 weeks. 2 drugs for 12 weeks 4. drugs for 12 weeks Slide 8 of 49 56% 25% 19% % drugs for 8 weeks 2 drugs for 8 weeks 2 drugs for 12 weeks drugs for 12 weeks Louisville, Kentucky, November 17, 217 2

3 CASE 1 Treatment duration: when to use 8 v. 12 wks 4 y.o. Caucasian W with HCV Geno 1a, no cirrhosis, HCV RNA 1.2 mil IU/mL HCV Hx: Diagnosed during last pregnancy Treatment naïve Fibrosure F Other med hx includes: Seizure disorder on keppra Slide 9 of 49 Which of the following regimens would NOT be recommended for this patient with HCV g1a and no cirrhosis? 1. Sofosbuvir/velpatasvir/voxilaprevir x 8 wks 2. Sofosbuvir/velpatasvir x 12 wks. Sofosbuvir/ledipasvir x 8 wks 4. Glecaprevir/pibrentasvir x 8 wks 7% 1% % 2% Slide 11 of 49 Sofosbuvir/velpatasvir/vox... Sofosbuvir/velpatasvir x 1... Sofosbuvir/ledipasvir x 8 wks Glecaprevir/pibrentasvir x... G1b vs G1a: G1b Initial Treatment Recommended Regimens IDSA/AASLD NO CIRRHOSIS: Elbasvir/grazoprevir x 12 w Glecaprevir/pibrentasvir x 8 w Ledipasvir/sofosbuvir x 8* or 12 w Sofosbuvir/velpatasvir x 12 w Paritaprevir /ritonavir/ombitasvir + dasabuvir x 12w Simeprevir x sofosbuvir 12w Daclatasvir + sofosbuvir x 12w CIRRHOSIS: Elbasvir/grazoprevir x 12 w Glecaprevir/pibrentasvir x 12 w Ledipasvir/sofosbuvir x 12 w Sofosbuvir/velpatasvir x 12 w Paritaprevir /ritonavir/ombitasvir + dasabuvir x 12w* *8 wk not recommended for Black patients or HIV-infected. Only recommended when RNA< 6 million IU/ml (BOLDED are regimens approved since last year!) Slide 12 of 49 Louisville, Kentucky, November 17, 217

4 G1a Initial Treatment Recommended Regimens IDSA/AASLD NO CIRRHOSIS: CIRRHOSIS: Elbasvir/grazoprevir x 12 w if no hi level NS5A resistance Elbasvir/grazoprevir x 12 w if no hi level NS5A resistance Glecaprevir/pibrentasvir x 8 w Glecaprevir/pibrentasvir x 12 w Ledipasvir/sofosbuvir x 8* or 12 w Sofosbuvir/velpatasvir x 12 w Ledipasvir/sofosbuvir x 12 w Paritaprevir /ritonavir/ombitasvir + dasabuvir x 12w Sofosbuvir/velpatasvir x 12 w Simeprevir x sofosbuvir 12w Daclatasvir + sofosbuvir x 12w (BOLDED are regimens approved since last year!) *8 wk not recommended for Black patients or HIV-infected Slide 1 of 49 Pangenotypic Glecaprevir/pibrentasvir DAA combo naive (TN, PEG/RBV, SOF) & special pops ENDURANCE (Phase ) Co-formulated pills once daily Pangenotypic Next generation Active vs NS RAS at 8, 155, 168 and NS5A RAS at 28, Q, 1, 9 AK associated with failure in GT infection GT 1 no cirrhosis (8 vs 12W) GT 2 no cirrhosis (12W) GT no cirrhosis (8 and 12W) GT 4-6 (12W) Negligible renal excretion EXPEDITION (Phase ) Contains a protease inhibitor GT 1, 2, 4-6 cirrhosis GT 1-6 HIV GT 1-6 Renal impairment Has interaction with acid suppressing meds SURVEYOR (Phase 2) GT 2, 4-6 no cirrhosis 8 weeks GT cirrhosis/te 12 vs 16 W G/P Slides courtesy of S. Naggie Slide 14 of 49 Glecaprevir/pibrentasvir: No Cirrhosis 8 (N=828) vs 12 1 (N=176) weeks TN and TE All GT 1 8 weeks weeks GT 4 GT 5 GT No DAA otherwise 6 Tx emergent RAS PEG, RBV, SOF Relapse <1% Puoti et al. EASL 217 GT 2 GT Slide 15 of 49 Louisville, Kentucky, November 17, 217 4

5 Glecaprevir/pibrentasvir: Cirrhosis 12 weeks in N=146 Compensated cirrhosis TN or TE (25%) with IFN, P/R or SOF+P/R GT1a %, GT1b 27%, GT2 2%, GT4 11%, GT5 1%, GT6 5% 1 relapse- GT1a Forns et al. EASL 217 Slide 16 of 49 Sofosbuvir/velpatasvir x 12 wks in HIV/HCV G1-6, Naïve + Rx-exp N=16 29% Rx-exp 18% cirrhosis 12% NS5a RAVs Of 2 relapses: 1 rx-exp, cirrhosis, baseline RAVS Renal fxn looked unchanged in pts on boosted TDF Slide 17 of 49 POLARIS-2: 8-Wk SOF/VEL/Voxilaprevir vs. 12Wk SOF/VEL Not Non-inferior for DAA-naïve SOF/VEL/VOX 8 wks SOF/VEL 12 wks Treatment difference: -.4% (95% CI: -6.2% to.6%) 1 SVR12 (%) 8-wk SOF/VEL/VOX did not meet criteria for noninferiority vs 12-wk SOF/VEL / 5/ GT / 6 5 7/ / 6 9 1/ T n/n = 47 6/ / 4 4 Overall Relapse, n LTFU, n D/c for AE, n / 7/ GT a 1 1 GT1 2b1 G 5 / 5 8 6/ 8 9 G T Jacobson IM, et al. Gastroenterology / 6 G 5 6/ 5 7 2T41 1 7/ 1 8 G 1T5 / 9/ 9 G T6 2/ 2 Unknow n Slide credit: clinicaloptions.com Slide 18 of 49 Jacobson IM, et al. Gastroenterology Louisville, Kentucky, November 17, 217 5

6 Initial Treatment Algorithm Algorithm HCV genotype/subtype & resistance HIV status Cirrhosis - yes/no - duration If yes, decompensated? (e.g., ascites, encephalopathy, etc) If yes, don t use PIs! Renal function Avoid Sof if CrCl < Medications Address drug interactions Ribavirin is a teratogen Patient preference (8 or 12 w, # pills, packaging) Our case patient 1a, start with 4 recommended regimens resistance testing if elbasvir/grazoprevir only HIV neg Cirrhosis no Potentially eligible for 8 wk regimens Renal function normal so eligible all 4 regimens Medications: Childbearing potential so avoid RBV Anti-epileptics often have interactions Pills and packaging Elbasvir/grazoprevir 1 pill/d x 12 wks Glecaprevir/pibrentasvir pills/d x 8 wks Sofosbuvir/ledipasvir x 8 wks Sofosbuvir/velpatasvir x 12 wks (WHAT PAYER COVERS) Slide 19 of 49 CASE 2 When to do resistance testing and what to use in patients with ESRD 55 y.o. African American M with HCV Geno 1b and cirrhosis, HCV RNA 221, IU/mL HCV Hx: Treatment naïve Cirrhotic based on transient elastographymeasurement of 17 kpa No decompensation events EGD no varices Sono no HCC Other med hx includes: HTN, high cholesterol, renal insufficiency (CrCl 25) Mild GERD on PPI qd HBV sag- cab+ sab- Slide 2 of 49 v (Slide to be updated later this month with guidelines release) Slide 21 of 49 Louisville, Kentucky, November 17, 217 6

7 Glecaprevir/pibrentasvir: Renal Impairment GT 1-6 for 12 weeks Stage 4 or 5 CKD GFR< including HD 82% on HD TN or TE (42%) with IFN, P/R or SOF+P/R Including compensated cirrhosis (19%) GT1a 22%, GT1b 28%, GT2 16%, GT 11%, GT4 19%, GT5 1, GT6 11 Gane et al. EASL 217 Slide 22 of 49 Testing for HCV resistance (RASs) would be indicated in this patient with HCV geno 1b if 1. He had failed PegIFN + RBV in the past 2. You plan to treat with 8 weeks of glecaprevir/pibrentasvir. You plan to treat with 12 weeks of grazoprevir/elbasvir 4. Nope! Resistance testing is not necessary here 5. Hmmm What s a RAS? Slide 24 of 49 He had failed PegIFN + RBV.. You plan to treat with 8 we... 55% 45% % % % You plan to treat with Nope! Resistance testing i... Hmmm What s a RAS? RAS Testing prior to Treatment NS5A RASs are relatively common (1-15%) Significance of NS5A RASs may depend on the RAS, the genotype, the regimen used and whether prior NS5A treatment In initial treatment, use resistance testing prior to: Treatment with grazoprevir/elbasvir for 1a Treatment of G if cirrhosis Slide 25 of 49 Louisville, Kentucky, November 17, 217 7

8 Elbasvir/grazoprevir x12w Results Overall study 95% SVR 144/157 (92%) G1a, 129/11 (99%) G1b, 18/18 G4, 8/1 G6 68/7 (97%) with cirrhosis Baseline NS5A RASs & SVR Slide 26 of 49 Algorithm HCV genotype/subtype & resistance HIV status Cirrhosis - yes/no - duration If yes, decompensated? (e.g., ascites, encephalopathy, etc) If yes, don t use PIs! Renal function Avoid Sof if CrCl < Medications Address drug interactions Ribavirin is a teratogen Patient preference (8 or 12 w, # pills, packaging) Initial Treatment Algorithm Our case patient 1b, no need for resistance testing, start with 4 recommended regimens HIV neg Cirrhosis yes No 8 wk regimens Compensated so ok to use PIs CrCl <, no regimens w/ sofosbuvir, so 2 remaining regimens Medications: PPI qd Elbasvir/grazoprevir no interaction Glecaprevir/pibrentasvir (limit dose) Pills and packaging Elbasvir/grazoprevir 1 pill/d Glecaprevir/pibrentasvir pills/d (WHAT PAYER COVERS) Slide 27 of 49 CASE Treatment and drug interactions in patients with HIV 49 y.o. M with HIV and HCV Geno 2, HCV RNA 12, IU/mL HIV Hx: Well controlled on TDF/FTC + BID darunavir/ritonavir HCV Hx: Treatment naïve Fibroscan 1.1 kpa Other med hx includes: HTN, renal insufficiency (CrCl 5) GERD on PPO Slide 28 of 49 Louisville, Kentucky, November 17, 217 8

9 Which of the following regimens are recommended for genotype 2 infection in a person without cirrhosis? 1. Sofosbuvir/velpatasvir x 12 wks 2. Glecaprevir/pibrentasvir x 8 wks. Both 1 and 2 4. Neither 1 or 2 21% 64% 7% 7% Slide of 49 Sofosbuvir/velpatasvir x 1... Glecaprevir/pibrentasvir x... Both 1 and 2 Neither 1 or 2 G2 INITIAL TREATMENT RECOMMENDED REGIMENS IDSA/AASLD NO CIRRHOSIS: Glecaprevir/pibrentasvir x 8 w Sofosbuvir/velpatasvir x 12 wks CIRRHOSIS: Glecaprevir/pibrentasvir x 12 w Sofosbuvir/velpatasvir x 12 wks Slide 1 of 49 Slide 2 of 49 Louisville, Kentucky, November 17, 217 9

10 Before administering sofosbuvir/velpatasvir in a patient with renal insufficiency (CrCl 5) on TDF/FTC + darunavir/ritonavir, which of the following should be considered? 1. Change darunavir/r dosing from BID to QD 2. Change TDF to TAF. Change darunavir/r to efavirenz 4. No ARV adjustment needed Slide 4 of 49 Change darunavir/r dosing... 18% 18% Change TDF to TAF 64% Change darunavir/r to efav... % No ARV adjustment needed HCVguidelines.org Slide 5 of 49 With SOF/LDV TDF exposures are high in those on PIs NNRTIs Without With LDV/SOF 1,2 LDV/SOF RTV-Boosted PIs Without With LDV/SOF 4-9 LDV/SOF1 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. 6. Zhu. 9th IWCPHT. 28. #2 (ATV+RTV & LPV/r ) 2. Hoetelmans RMW, et al. 6 th IWCPHT 25. Quebec City, Canada. Poster # Kearney B, et al. JAIDS. 26;4():278-8 (LPV/r). German P, et al. ICPHHT 214. #O6 8. Agarwala S, et al. 6th IWCPHT 25. #16. (ATV+RTV) 4. Luber AD, et al. HIV Medicine. 21;11:19-9 (FPV+RTV) 9.. Hoetelmans RMW, et al. BJCP. 27;64(5): (DRV+RTV) 5. Chittick GE, et al. AAC. 26; 5(4):14-1 (SQV+RTV) 1. German P, et al. CROI 215 Slide courtesy of J Kiser Slide 6 of 49 Louisville, Kentucky, November 17, 217 1

11 Guidelines Recommendation about use of LDV or VEL with TDF SOF/LDV + TDF CrCl < 6 ml/min: AVOID SOF/VEL + TDF CrCl < 6 ml/min: AVOID CrCl > 6: MONITOR CrCl > 6: MONITOR SOF/LDV + TDF + cobi- or ritonavir-boosted PI SOF/VEL + TDF + cobi- or ritonavir-boosted PI Any CrCl: AVOID if possible, Consider TAF CrCl < 6 ml/min: AVOID CrCl > 6: MONITOR or consider TAF Slide 7 of 49 Glecaprevir/pibrentasvir DDI with ARV Allowed vs enrolled need clinical data to support safety Enrolled- Raltegravir- 45 Dolutegravir - 67 Rilpivirine - 2 PI/r none ELV/cobi - 1 Rockstroh et al. EASL 217, Kosloski et al. CROI 217 (slide courtesy S. Naggie) Slide 8 of 49 Glecaprevir/pibrentasvir: HIV GT 1-6 Primarily an 8 week study 12 weeks in 16 patients with cirrhosis TN or TE (19%) with IFN, P/R or SOF+P/R VBT on treatment GT with cirrhosis /16 14/15 8 week no cirrhosis 12 week cirhosis Rockstroh et al. EASL 217 Slide 9 of 49 Louisville, Kentucky, November 17,

12 HCVguidelines.org Slide 4 of 49 Which of the following regimens can be used with ANY dose of a proton pump inhibitor? 1. Sofosbuvir/velpatasvir/ voxilaprevir 2. Sofosbuvir/velpatasvir. Elbasvir/grazoprevir 4. Glecaprevir/pibrentasvir 5. Both and 4 Slide 42 of 49 Sofosbuvir/velpatasvir/vox... % % Sofosbuvir/velpatasvir Elbasvir/grazoprevir 4% Glecaprevir/pibrentasvir 27% % Both and 4 Drug-Drug Interactions with DAAS Acid-reducing drugs Anti-epileptics Antiretrovirals Amiodarone Lipid-lowering drugs Slide 4 of 49 Louisville, Kentucky, November 17,

13 Algorithm HCV genotype/subtype & resistance HIV status Cirrhosis - yes/no - duration If yes, decompensated? (e.g., ascites, encephalopathy, etc) If yes, don t use PIs! Renal function Avoid Sof if CrCl < Medications Address drug interactions Ribavirin is a teratogen Patient preference (8 or 12 w, # pills, packaging) Initial Treatment Algorithm Our case patient 2, no need for resistance testing, start with 2 recommended regimens HIV pos watch for drug interactions Cirrhosis no CrCl 5, sofosbuvir ok but Cr Cl> but assess if TDF Medications: TDF, HIV PI, PPI qd need to be addressed ARV adjustment needed Pills and packaging Sofosbuvir/velpatasvir 1 pill/d Glecaprevir/pibrentasvir pills/d (WHAT PAYER COVERS) Slide 44 of 49 CASE 4 Genotype management 71 y.o. W with HCV Geno, HCV RNA 95, IU/mL HCV Hx: Treatment naïve Fibroscan 14.2 kpa (c/w) cirrhosis No symptoms decompensation RAS testing: no mutations Other med hx includes: DM CrCL 55 Slide 45 of 49 Which of the following is recommended for initial treatment of HCV G in a patient with cirrhosis? 1. Sofosbuvir/ledipasvir x 12 wks 2. Sofosbuvir/velpatasvir x 12 wks. Elbasvir/grazoprevir x 12 wks 4. Glecaprevir/pibrentasvir x 8 wks Slide 47 of 49 Sofosbuvir/ledipasvir x % Sofosbuvir/velpatasvir x % Elbasvir/grazoprevir x 12 wks % Glecaprevir/pibrentasvir x... 2% Louisville, Kentucky, November 17, 217 1

14 G INITIAL TREAMENT RECOMMENDED REGIMENS IDSA/AASLD NO CIRRHOSIS: CIRRHOSIS: Glecaprevir/pibrentasvir x 8 w Glecaprevir/pibrentasvir x 12 w Sofosbuvir/velpatasvir x 12 w Sofosbuvir/velpatasvir x 12 w* Sofosbuvir + daclatasvir x 12w Sofosbuvir + daclatasvir +/-RBV x 24w* *RAV testing for Y9H and add RBV if present or use sofosbuvir/velpatasvir/voxilaprevir Slide 48 of 49 Sofosbuvir + Daclatasvir for G (ALLY-) Nelson, Hepatology : Slide 49 of 49 Glecaprevir/pibrentasvir in GT Treatment-naïve without Cirrhosis Non-inferiority 12W vs DAC/SOF X12W 12W vs 8W Viral Failure % G/P 4 in 12W ( relapse, 1 VBT) 1 in DAC/SOF 6 in 8W (5 relapse, 1 VBT) BL Y9H: 5/5 SVR BL dual NS/NS5A 71-86% SVR Tx emergent RAS 5% failures with AK BL AK+Y9 (69-fold R SURVEYOR-II G with Cirrhosis 48 patients received G/P +/- RBV x 12 w = 1% SVR Foster et al. EASL 217 Slide 5 of 49 Louisville, Kentucky, November 17,

15 Glecaprevir/pibrentasvir and RASs -- AK effect? Non-inferiority 12W vs DAC/SOF X12W 12W vs 8W Viral Failure % G/P 4 in 12W ( relapse, 1 VBT) 1 in DAC/SOF 6 in 8W (5 relapse, 1 VBT) Tx emergent RAS 5% failures with AK BL 6% patients overall had a BL AK SURVEYOR-II G with Cirrhosis 48 patients received G/P +/- RBV x 12 w = 1% SVR Foster et al. EASL 217 Krishnan et al. EASL 217 Slide 51 of 49 Sofosbuvir/velpatasvir x 12 wks for G (ASTRAL-2) Most of this % w/ failure had cirrhosis Foster, NEJM, 215, hcvguidelines.org Slide 52 of 49 POLARIS-: SVR12 Rates With 8-Wk SOF/VEL/Voxilaprevir for DAA-naive Cirrhotic GT SVR12 (%) 1 96 SOF/VEL/VOX 8 wks SOF/VEL 12 wks 72/ 75 29/ / 84 76/ / 2 2/ n/n = / / Overall 76/ 77 Treatment Naive 4/ 5 Treatment Experienced No BL RASs Any BL RASs Both regimens: P <.1 for superiority vs prespecified 8% goal Overall VF: SOF/VEL/VOX, n = 2 relapses; SOF/VEL, n = 1 each for relapse and on-treatment failure No treatment-emergent RASs in SOF/VEL/VOX arm; Y9H in both VFs in SOF/VEL arm Jacobson IM, et al. Gastroenterology. 217 Slide credit: clinicaloptions.com Slide 5 of 49 Louisville, Kentucky, November 17,

16 Initial Treatment Algorithm Algorithm HCV genotype/subtype & resistance HIV status Cirrhosis - yes/no - duration If yes, decompensated? (e.g., ascites, encephalopathy, etc) If yes, don t use PIs! Renal function Avoid Sof if CrCl < Medications Address drug interactions Ribavirin is a teratogen Patient preference (8 or 12 w, # pills, packaging) Our case patient Geno, 2 regimens, no AK or Y9H present HIV neg Cirrhosis yes Compensated so PIs ok CrCl 55, sofosbuvir ok Medications: no drug interactions Pills and packaging Sofosbuvir/velpatasvir 1 pill/d x12 wks Glecaprevir/pibrentasvir pills/d x 12 wks (WHAT PAYER COVERS) Slide 54 of 49 Summary : Is this as good as it gets? Remarkable advances in terms of HCV treatment tolerability & efficacy Advances in G2, G, ESRD SVRs for HIV/HCV now mirror monoinfection Still drug interaction issues, but valuable resources to help manage RAS testing prior to initial treatment if: G1a and planned grazoprevir/elbasvir G & cirrhosis and planned sofosbuvir/velpatasvir Successful treatment prevents cirrhosis, end stage liver disease, and hepatocellular cancer Post SVR continue liver disease management/hcc screening, monitor HBV reactivation, and consider HCV screening if ongoing risk Slide 55 of 49 Resources HCVguidelines.org nynjaetc.org THANK YOU Thank you Slide 56 of 49 Louisville, Kentucky, November 17,