Kristen M Marks MD Assistant Professor Weill Cornell Medical College New York New York Financial Relationships With Commercial Entities Dr Marks was awarded research grants paid to her institution from BristolMyers Squibb Gilead Sciences ID: 1043646
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1. Newly Approved Hepatitis C Virus Drugs: Approach to Initial TherapyKristen M. Marks, MDAssistant ProfessorWeill Cornell Medical College New York, New York
2. Financial Relationships With Commercial EntitiesDr Marks was awarded research grants, paid to her institution, from Bristol-Myers Squibb, Gilead Sciences, Inc, and Merck. (Updated 10/16/17)
3. Learning ObjectivesAfter attending this presentation, learners will be able to: Describe regimens recommended for initial treatment of HCV infectionRecognize when to do testing for HCV resistanceIdentify the advantages and limitations of newly approved HCV treatment regimens
4. IDSA/AASLDwww.hcvguidelines.orgEASLhttp://www.easl.eu/research/our-contributions/clinical-practice-guidelines/detail/easl-recommendations-on-treatment-of-hepatitis-c-2016
5. Newer strategy for HCV therapy:Direct acting antivirals target life cycle---PREVIRProtease inhibitorse.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---ASVIRNS5A inhibitors e.g. daclatasvir, ledipasvir, ombitasvir, elbasvir, velpatasvir, pibrentasvir
6. NUCPI+NUCNS5A+PINS5A+PINS5A+nonNuc+NUC-SPARING HCVRenal insufficiencyDrug-drug interactionsDurationAffordability/AccessToxicityResistance+/- RBV+/- RBV+/- RBVCurrently used combinations of DAA classesNUC-SPARING HIVToxicityResistanceRenal insufficiencyDrug-drug interactionsAffordabilityNUC+NS5A+/- RBVPI+
7. Minimum to Know Pre-TreatmentHCV genotype/subtypeHCV resistance (sometimes)Stage of fibrosis Cirrhosis - yes/noIf yes, decompensated? (e.g., ascites, encephalopathy, etc)If yes, don’t use PIs!Method?Liver biopsyTransient elastographyLaboratory biomarkersImagingPrior HCV treatment?Response?DAA used? HIV/Hepatitis C helpline1-866-637-2342MedicationsTo check for drug interactionsComorbiditiesRenal functionHIV statusPatient preferenceChild-bearing potential of patient/partnerRibavirin is a teratogen
8. PEG RBVSOFRBVSOFSOFRBVSMV+/-SOFRBV+/-LDVOMVDASInterferonPegIFNRibavirinribavirinribavirin+/-ribavirin+/-ribavirinNucssofosbuvirsofosbuvirsofosbuvirsofosbuvirsofosbuvirsofosbuvirProtease inhibitorssimeprevirParitaprevir/ritonavirgrazoprevirvelpatasvirglecaprevirNS5AledipasvirdaclatasvirombitasvirelbasvirpibrentasvirNon-NucsdasabuvirSOFDACPTV/r+/-G1XXXXXXXXXG2XXXXXG3XXXXXG4XXXXXXXXXGZREBVSOFVELApproved Drug Regimens for Initial TreatmentGLEPBV
9. IDSA/AASLDwww.hcvguidelines.orgNO CIRRHOSIS:Elbasvir/grazoprevir x 12 wGlecaprevir/pibrentasvir x 8 wLedipasvir/sofosbuvir x 8* or 12 wSofosbuvir/velpatasvir x 12 wParitaprevir /ritonavir/ombitasvir + dasabuvir x 12wSimeprevir x sofosbuvir 12w Daclatasvir + sofosbuvir x 12w*8 wk not recommended for Black patients or HIV-infectedCIRRHOSIS:Elbasvir/grazoprevir x 12 w Glecaprevir/pibrentasvir x 12 wLedipasvir/sofosbuvir x 12 wSofosbuvir/velpatasvir x 12 wParitaprevir /ritonavir/ombitasvir + dasabuvir x 12w*G1b vs G1a:G1b Initial Treatment Recommended Regimens (BOLDED are regimens approved since last year!)
10. IDSA/AASLDwww.hcvguidelines.orgNO CIRRHOSIS:Elbasvir/grazoprevir x 12 w if no hi level NS5A resistance Glecaprevir/pibrentasvir x 8 wLedipasvir/sofosbuvir x 8* or 12 wSofosbuvir/velpatasvir x 12 wParitaprevir /ritonavir/ombitasvir + dasabuvir x 12wSimeprevir x sofosbuvir 12w Daclatasvir + sofosbuvir x 12w*8 wk not recommended for Black patients or HIV-infectedCIRRHOSIS:Elbasvir/grazoprevir x 12 w if no hi level NS5A resistance Glecaprevir/pibrentasvir x 12 wLedipasvir/sofosbuvir x 12 wSofosbuvir/velpatasvir x 12 wG1a Initial Treatment Recommended Regimens (BOLDED are regimens approved since last year!)
11. Pangenotypic Glecaprevir/pibrentasvirDAA combo naive (TN, PEG/RBV, SOF) & special popsENDURANCE (Phase 3)GT 1 no cirrhosis (8 vs 12W)GT 2 no cirrhosis (12W)GT 3 no cirrhosis (8 and 12W)GT 4-6 (12W)EXPEDITION (Phase 3)GT 1, 2, 4-6 cirrhosisGT 1-6 HIVGT 1-6 Renal impairmentSURVEYOR (Phase 2)GT 2, 4-6 no cirrhosis 8 weeksGT 3 cirrhosis/TE 12 vs 16 WCo-formulated – 3 pills once dailyPangenotypicNext generationActive vs NS3 RAS at 80, 155, 168 and NS5A RAS at 28, Q30, 31, 93A30K associated with failure in GT3 infectionNegligible renal excretionContains a protease inhibitorHas interaction with acid suppressing meds but ?clinically significantG/P Slides courtesy of S. Naggie
12. Glecaprevir/pibrentasvir: No Cirrhosis8 (N=828) vs 12 (N=1076) weeksTN and TEPEG, RBV, SOFNo DAA otherwiseRelapse <1%Tx emergent RASPuoti et al. EASL 2017
13. Glecaprevir/pibrentasvir: CirrhosisForns et al. EASL 201712 weeks in N=146Compensated cirrhosisTN or TE (25%) with IFN, P/R or SOF+P/RGT1a 33%, GT1b 27%, GT2 23%, GT4 11%, GT5 1%, GT6 5%1 relapse- GT1a
14. Sofosbuvir/velpatasvir x 12 wks in HIV/HCV G1-6, Naïve + Rx-expWyles, EASL, 2016N=10629% Rx-exp18% cirrhosis12% NS5a RAVsOf 2 relapses:1 rx-exp, 0 cirrhosis, 0 baseline RAVSRenal fxn looked unchanged in pts on boosted TDF
15. 9398POLARIS-2: 8-Wk SOF/VEL/Voxilaprevir vs. 12-Wk SOF/VEL Not Non-inferior for DAA-naïveRelapse, nLTFU, nD/c for AE, n 2140 34116002201400110200110200000010021230100100000000000GT1GT1bGT2GT4100806040200SVR12 (%)n/N =9598476/501432/440217/233228/232SOF/VEL/VOX 8 wksSOF/VEL 12 wks9299155/169170/172979761/6357/5910061/6353/5397999791/9286/899858/6356/579217/1809410030/309/91002/21000OverallGT1aGT3GT5GT6UnknownJacobson IM, et al. Gastroenterology. 2017.8-wk SOF/VEL/VOX did not meet criteria for noninferiority vs 12-wk SOF/VELTreatment difference: -3.4% (95% CI: -6.2% to -0.6%)Jacobson IM, et al. Gastroenterology. 2017.Slide credit: clinicaloptions.com
16. HCVguidlines.org accessed 9/29/17
17. Glecaprevir/pibrentasvir: HIV 136/136 14/15Rockstroh et al. EASL 2017GT 1-6Primarily an 8 week study12 weeks in 16 patients with cirrhosisTN or TE (19%) with IFN, P/R or SOF+P/RVBT on treatment – GT3 with cirrhosis
18. RAS Testing prior to TreatmentNS5A RASs are relatively common (10-15%)Significance of NS5A RASs may depend on the RAV, the genotype, the regimen used and whether prior NS5A treatmentIn initial treatment, use resistance testing prior to:Treatment with grazoprevir/elbasvir for 1aTreatment of G3 with sofosbuvir/velpatasvir if cirrhosis
19. Elbasvir/grazoprevir x12w ResultsOverall study 95% SVR144/157 (92%) G1a, 129/131 (99%) G1b, 18/18 G4, 8/10 G668/70 (97%) with cirrhosisAnn Intern Med. 2015;163(1):1-13Baseline NS5A RASs & SVR
20. v(Slide to be updated later this month with guidelines release)HCVguidlines.org accessed 9/29/17
21. Glecaprevir/pibrentasvir: Renal ImpairmentGane et al. EASL 2017GT 1-6 for 12 weeksStage 4 or 5 CKDGFR<30 including HD82% on HDTN or TE (42%) with IFN, P/R or SOF+P/RIncluding compensated cirrhosis (19%)GT1a 22%, GT1b 28%, GT2 16%, GT3 11%, GT4 19%, GT5 1, GT6 11
22. Drug-Drug Interactions with DAASAcid-reducing drugsAnti-epilepticsAntiretroviralsAmiodaroneLipid-lowering drugshttp://www.hep-druginteractions.org/
23. Guidelines Recommendation about use of LDV or VEL with TDFSOF/LDV + TDFCrCl < 60 mL/min: AVOIDCrCl > 60: MONITORSOF/LDV + TDF + cobi- or ritonavir-boosted PIAny CrCl: AVOID if possible, Consider TAFSOF/VEL + TDFCrCl < 60 mL/min: AVOIDCrCl > 60: MONITORSOF/VEL + TDF + cobi- or ritonavir-boosted PICrCl < 60 mL/min: AVOIDCrCl > 60: MONITOR or consider TAFHCVguidlines.org accessed 9/29/17
24. IDSA/AASLDwww.hcvguidelines.orgNO CIRRHOSIS:Elbasvir/grazoprevir x 12 wGlecaprevir/pibrentasvir x 8 wLedipasvir/sofosbuvir x 12 wSofosbuvir/velpatasvir x 12 wParitaprevir /ritonavir/ombitasvir + dasabuvir x 12wCIRRHOSIS:Elbasvir/grazoprevir x 12 w Glecaprevir/pibrentasvir x 12 wLedipasvir/sofosbuvir x 12 wSofosbuvir/velpatasvir x 12 wParitaprevir /ritonavir/ombitasvir + dasabuvir x 12w*G4 INITIAL TREATMENT RECOMMENDED REGIMENS(BOLDED are regimens approved since last year!)
25. IDSA/AASLD/IAS–USAwww.hcvguidelines.orgNO CIRRHOSIS:Glecaprevir/pibrentasvir x 8 w Sofosbuvir/velpatasvir x 12 wksG2 INITIAL TREATMENT RECOMMENDED REGIMENSCIRRHOSIS:Glecaprevir/pibrentasvir x 12 wSofosbuvir/velpatasvir x 12 wks
26. IDSA/AASLD/IAS–USAwww.hcvguidelines.orgNO CIRRHOSIS:Glecaprevir/pibrentasvir x 8 wSofosbuvir/velpatasvir x 12 wSofosbuvir + daclatasvir x 12wG3 INITIAL TREATMENT RECOMMENDED REGIMENSCIRRHOSIS:Glecaprevir/pibrentasvir x 12 wSofosbuvir/velpatasvir x 12 w*Sofosbuvir + daclatasvir +/-RBV x 24w* *RAV testing for Y93H and add RBV if present or use sofosbuvir/velpatasvir/voxilaprevir
27. Sofosbuvir + Daclatasvir for G3 (ALLY-3)Nelson, Hepatology 2015 61:1127-35.
28. Glecaprevir/pibrentasvir in GT3 Treatment-naïve without CirrhosisFoster et al. EASL 2017Non-inferiority12W vs DAC/SOF X12W12W vs 8WViral Failure 3% G/P4 in 12W (3 relapse, 1 VBT)1 in DAC/SOF6 in 8W (5 relapse, 1 VBT)BL Y93H: 5/5 SVRBL dual NS3/NS5A 71-86% SVRTx emergent RAS50% failures with A30K BLA30K+Y93 (69-fold R)SURVEYOR-II – G3 with Cirrhosis48 patients received G/P +/- RBV x 12 w = 100% SVR
29. Glecaprevir/pibrentasvir in GT3 Treatment-naïve without Cirrhosis – A30K effect?Foster et al. EASL 2017 Krishnan et al. EASL 2017Non-inferiority12W vs DAC/SOF X12W12W vs 8WViral Failure 3% G/P4 in 12W (3 relapse, 1 VBT)1 in DAC/SOF6 in 8W (5 relapse, 1 VBT)Tx emergent RAS50% failures with A30K BL6% patients overall had a BL A30KSURVEYOR-II – G3 with Cirrhosis48 patients received G/P +/- RBV x 12 w = 100% SVR
30. Sofosbuvir/velpatasvir x 12 wks for G3 (ASTRAL-2)Foster, NEJM, 2015, hcvguidelines.orgMost of this 3% w/ failure had cirrhosis
31. POLARIS-3: SVR12 Rates With 8-Wk SOF/VEL/Voxilaprevir for DAA-naive Cirrhotic GT3 Both regimens: P < .001 for superiority vs prespecified 83% goalOverall VF: SOF/VEL/VOX, n = 2 relapses; SOF/VEL, n = 1 each for relapse and on-treatment failureNo treatment-emergent RASs in SOF/VEL/VOX arm; Y93H in both VFs in SOF/VEL armTreatment NaiveTreatment ExperiencedNo BL RASsAny BL RASsOverall100806040200SVR12 (%)SOF/VEL/VOX 8 wks SOF/VEL 12 wks106/110105/10972/7576/7734/3529/3280/8476/8023/2323/239696969997919595100100n/N =Slide credit: clinicaloptions.comJacobson IM, et al. Gastroenterology. 2017
32. Initial Treatment AlgorithmAlgorithmHCV genotype/subtype & resistance HIV statusCirrhosis - yes/no - durationIf yes, decompensated? (e.g., ascites, encephalopathy, etc)If yes, don’t use PIs!Renal functionAvoid Sof if CrCl <30MedicationsAddress drug interactions Ribavirin is a teratogenPatient preference (8 or 12 w, # pills, packaging)Our case patient1b, no need for resistance testing, start with 4 recommended regimensHIV negCirrhosis – yes No 8 wk regimensCompensated so ok to use PisCrCl <30, no regimens w/ sofosbuvir, so 2 remaining regimensMedications: PPI qdElbasvir/grazoprevir – no interactionGlecaprevir/pibrentasvir (limit dose)Pills and packagingElbasvir/grazoprevir – 1 pill/d Glecaprevir/pibrentasvir 3 pills/d(WHAT PAYER COVERS)
33. Remarkable advances in terms of HCV treatment tolerability & efficacyAdvances in G2, G3, ESRDSVRs for HIV/HCV now mirror monoinfectionStill drug interaction issues, but valuable resources to help manageRAV testing prior to initial treatment if:G1a and planned grazoprevir/elbasvir G3 & cirrhosis and planned sofosbuvir/velpatasvirSuccessful treatment prevents cirrhosis, end stage liver disease, and hepatocellular cancerPost SVR – continue liver disease management/HCC screening, monitor HBV reactivation, and consider HCV screening if ongoing riskSummary : Is this as good as it gets?
34. HCVguidelines.orgnynjaetc.orghttp://www.hep-druginteractions.orgTHANK YOUResources