Baseline and acquired viral resistance to DAAs: how to test and manage

Baseline and acquired viral resistance to DAAs: how to test and manage Round table discussion by Marc Bourliere, Robert Flisiak, Vasily Isakov, Mark Sulkowsky & Konstantin Zhdanov

Prevalence of baseline polymorphism: east and west Krishnan et al., 2016

Do you aware of prevalence of HCV resistance in your region? Do you aware of baseline resistance of HCV in naïve patients?

Population versus deep sequencing: what tool is better for clinician?

How often in your practice you determine HCV resistance to DAAs? What method do you use: population based or deep sequence?

Impact of Viral Resistance on HCV Treatment Efficacy

SVR12 (%) Impact of Baseline RAVs on Efficacy of OBV/PTV/RTV + DSV ± RBV Analysis of data from 5 phase III trials using NGS; all pts treated with OBV/PTV/RTV + DSV ± RBV on label (based on subgenotype, previous treatment, and cirrhosis) SVR12 rate 100% in pts with GT1b HCV, regardless of BL RAVs 100 With RAVs Without RAVs 100 97 97 97 GT1a (1% NGS detection limit) NS NS 98 98 94 94 NS 96 97 80 60 40 20 n/n = 0 11/ 11 391/ 403 PTV Specific 140/ 145 262/ 269 89/ 95 319/ 325 113/ 120 295/ 300 Q80K OBV Specific NS5A Class Resistance-Associated Variant Type 24/ 25 371/ 382 DSV Specific Sarrazin C, et al. EASL 2016. Abstract LBP503. Reproduced with permission.

Do you think that HCV resistance need to be tested in patients who will be treated with OBV/PTV/RTV + DSV ± RBV? - In naïve patients? - Experienced patients? - In patients with cirrhosis?

SVR12 (%) Impact of Treatment Exp, Q80K Depends on Cirrhosis (12 Wks SMV + SOF in GT1) No Cirrhosis (OPTIMIST-1 [1] ) Cirrhosis (OPTIMIST-2 [2] ) 100 80 97 97 95 96 97 100 80 83 88 79 74 92 60 60 40 40 20 n/n = 0 150/ 155 All pts 112/ 115 Naive 38/ 40 Exp d 44/ 46 1a + Q80K 68/ 70 1a no Q80K 20 n/n = 0 86/ 103 All pts 44/ 50 42/ 53 25/ 34 Naive Exp d 1a + Q80K 35/ 38 1a no Q80K Treatment History HCV GT Treatment History HCV GT 1. Kwo P, et al. EASL 2015. Abstract LP14. 2. Lawitz E, et al. EASL 2015. Abstract LP04.

HCV-TARGET: LDV/SOF and SMV + SOF Efficacy Analysis by Baseline RAVs SMV + SOF: SMV RAVs (aa80, 122, 155, 168, 170) associated with nonsignificant 0% to 9% SVR12 rate difference across pt subgroups Wang GP, et al. EASL 2016. Abstract PS102.

Do you think that HCV resistance need to be tested in patients who will be treated with SMV+SOF? - In naïve patients? - Experienced patients? - In all patients with cirrhosis?

SVR12 (%) Effect of BL NS5A RAVs on Ledipasvir/ Sofosbuvir Efficacy in GT1 HCV Deep sequencing of baseline samples obtained from 1566 pts treated with guideline-based LDV/SOF regimens in clinical trials With RAVs Without Cirrhosis Tx Naive Tx Exp d No RAVs Tx Naive With Cirrhosis Tx Exp d 100 98 99 99 99 90 99 96 96 100 100 88 100 89 96 87 100 80 60 40 20 30/ 107/ 187/ 504/ 79/ 298/ 26/ 65/ 10/ 27/ n/n = 32 108 189 509 88 300 27 68 10 27 0 8 Wks* 12 Wks 12 Wks 12 Wks 12 Wks + RBV *HCV RNA < 6 million IU/mL. 8/ 9 19/ 19 24 Wks 59/ 66 206/ 214 12 Wks + RBV 13/ 15 84/ 84 24 Wks Zeuzem S, et al. AASLD 2015. Abstract 91. Reproduced with permission.

HCV-TARGET: LDV/SOF and SMV + SOF Efficacy Analysis by Baseline RAVs LDV/SOF: LDV RAVs (aa28, 30, 31, 58, 93) associated with nonsignificant 1% to 7% SVR12 rate differences across pt subgroups Y93 LDV RAV infrequent (4%) but associated with significant decrease in SVR12 rate to LDV/SOF: 96% vs 75% (P =.046) Wang GP, et al. EASL 2016. Abstract PS102.

Do you think that HCV resistance need to be tested in patients who will be treated with LDV/SOF? - In naïve patients? - Experienced patients? - In patients with cirrhosis?

How often DAAs treatment failure leads to resistance and what are the options for retreatment?

Real-World Data on Resistance and HCV Retreatment After DAA Regimen Failure Data from large German resistance database: N = 3549 9% of pts with IFN-free DAA regimen failure (n = 310; excludes pts with GT1 HCV treated with SOF + RBV) Resistance analysis for drug class-specific RAVs with > 2-fold EC 50 increase in 195 GT1 and 69 GT3 pts GT1 (n = 195): 90% With RAVs 4% 1% 5% 19% 6% 10% 41% 14% GT3 (n = 69)*: 39% With RAVs 2% 2% 3% 32% 61% No RAVs NS5A NS3 + NS5A NS5A + NS5B NS3 NS5B NS3 + NS5B NS3 + NS5A + NS5B *Previous GT3 tx: SOF + RBV (n = 33); DCV + SOF ± RBV (n = 20); LDV/SOF ± RBV (n = 15); SMV + SOF ± RBV (n = 1). Vermehren J, et al. EASL 2016. Abstract PS103. Reproduced with permission.

Do you think that NS5A resistance after treatment failure is a burning problem?

GT1 Pts With NS5A Failure: Who Needs Resistance Testing? If previous failure of any NS5A inhibitors (including DCV + SOF, LDV/SOF, OMV/PTV/RTV + DSV) and minimal liver disease, deferral preferred pending further data If cirrhosis or other need for urgent treatment, test for NS3 and NS5A RAVs Applies to genotype 1a and 1b HCV infection NS3 and NS5A testing not required for: Previous failure of NS3/4A PIs (including simeprevir, boceprevir, telaprevir) Previous failure of NS5B inhibitors (sofosbuvir) Tx-naive pts (unless considering SMV + SOF in cirrhotic GT1a) AASLD/IDSA/IAS-USA. HCV Guidance.

Real-World Data: Resistance-Based HCV Retreatment After DAA Regimen Failure Previous DAA Regimen Failure Retreatment Regimen SVR12 GT1: SMV + SOF ± RBV NS5A inhibitor containing regimen 91% LDV/SOF ± RBV 12 wks 8/8 LDV/SOF ± RBV 24 wks 9/10 OBV/PTV/RTV + DSV ± RBV 12 wks 3/3 OBV/PTV/RTV + DSV + RBV 24 wks 0/1 GT1: DCV or LDV + SOF ± RBV PI-containing regimen 86% SMV + SOF ± RBV 12 wks 2/2 SMV + SOF ± RBV 24 wks 1/1 OBV/PTV/RTV + DSV ± RBV 12 wks 3/4 GT3: SOF + RBV NS5A inhibitor containing regimen 100% DCV + SOF + RBV 12 wks 2/2 DCV + SOF ± RBV 24 wks 4/4 LDV/SOF + RBV 24 wks 1/1 Vermehren J, et al. EASL 2016. Abstract PS103.

What regimen do you use for the retreatment if the patient failed treatment with any of NS5A containing regimen?

Is Ribavirin Required for Pts With Cirrhosis and NS5A RAVs? Integrated analysis of > 500 pts with cirrhosis treated with LDV/SOF ± RBV Treatment experienced patients had previously received HCV PI SVR12, % (n/n)18 With NS5A RAVs Without NS5A RAVs Overall 91 (86/94) 98 (407/417) 12 wks without RBV 88 (23/26) 95 (86/91) 12 wks with RBV 94 (32/34) 97 (164/169) 24 wks without RBV 85 (17/20) 100 (113/113) 24 wks with RBV 100 (14/14) 100 (44/44) Reddy KR, et al. Hepatology. 2015;62:79-86.

Do you think that ribavirin is necessary to add to DAAs for the retreatment of cirrhotic patients with NS5A RAVs?

Summary Baseline RAVs (especially NS5A) are present in treatment-naive pts Treatment-emergent RAVs (including multidrug-resistant RAVs) seen in treatment failure and in all DAA classes and rarely with SOF NS3 RAVs have low replication efficacy and disappear over 9-18 mos If considering SMV + SOF: In treatment-naive and treatment-experienced pts with both genotype 1a HCV infection and compensated cirrhosis, ensure no Q80K NS5A treatment-emergent RAVs persistent and a clinical challenge If failure with any NS5A inhibitors (including DCV + ASV, DCV + SOF, LDV/SOF, OMV/PTV/RTV + DSV), and treatment is urgent, test for NS3 and NS5A RAVs Use SMV + SOF + RBV if NS5A but no NS3 RAVs Use LDV/SOF + RBV if no NS5A RAVs Treat in clinical trial if both NS5A and NS3 RAVs present Resistance testing may be of benefit in treatment failures