Update on Hepatitis C. Francesco Negro Hôpitaux Universitaires de Genève Berne, November 15, 2017

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1 Update on Hepatitis C Francesco Negro Hôpitaux Universitaires de Genève Berne, November 15, 2017

2 The global prevalence of HCV was 1 0% (95% uncertainty interval ) in 2015: 71 1 million ( ) viremic infections The Polaris Observatory HCV Collaborators. Lancet Gastroenterol Hepatol 2017;2:161-76

3 Most viral hepatitis deaths are due to end-stage liver-related complications

4 How many persons are still infected with HCV in Switzerland? Anti-HCV+ Low-risk population (2015)* 58,000 Viremic, low-risk population** ~46,230 Viremic, high-risk population (PWID)*** 4,270 Others, high-risk, viremic* ~800 Total estimated viremic population (discount due to overlap is not considered) ~51,300 Treated and cured as of end of 2017**** ~17,000 Deceased* 4,000 Residual viremic pool (end of 2017) ~30,300 *Situation analysis (KEISER et al 2017) **Anti-HCV+ x (ARMSTRONG et al 2006) ***42% of 10,160 (BRUGGMANN et al 2017) ****Situation analysis (KEISER et al 2017), updated assuming 2,000 treated py

5 Mortality associated with HBV, HCV, HIV (Switzerland, ) HCV = 2.5 / 100,000 py HBV = 0.5 / 100,000 py HIV = 0.5 / 100,000 py KEISER O et al, communication personnelle

6 4,556 persons enrolled in the SCCS until December 31 st reported deaths 421 with a date of death 363 persons linked to SFSO 133 deaths were HCV-related (according to SCCS ecrf) 4,113 persons alive as of December 31 st persons with missing date of death 58 persons not linked to SFSO 230 died of causes unrelated to HCV However, HCV was not mentioned on the SFSO death certificate of 60 (45%) of them KEISER O et al, J Viral Hepatitis (in press)

7 Treatment Indications All treatment-naïve and treatment-experienced patients with compensated or decompensated chronic liver disease due to HCV must be considered for therapy UNIVERSAL ACCESS TO THERAPY EASL Recommendations on Treatment of Hepatitis C. J Hepatol 2017;66:

8 Patients Who Should be Treated Without Delay Significant fibrosis or cirrhosis (METAVIR score F2, F3, F4), including decompensated cirrhosis Clinically significant extra-hepatic manifestations HCV recurrence after liver transplantation Individuals at risk of transmitting HCV Active injection drug users MSM with high-risk sexual practices Women of child-bearing age who wish to get pregnant Hemodialysis patients Prison inmates EASL Recommendations on Treatment of Hepatitis C. J Hepatol 2017;66: In low-risk populations, prioritization is medically and ethically justifiable: treating everyone as they come may delay treatment of the most advanced cases, negatively affecting the beneficial impact of SVR on mortality

9 Direct acting antivirals (DAA) against HCV Without IFN Asunaprevir + Daclatasvir G2/3 Sofosbuvir + RBV Paritaprevir/r + Ombitasvir + Dasabuvir ± RBV Sofosbuvir + Ledipasvir ± RBV Inhibitors of NS3/NS4A serine protease NS3/4A Nucleotide inhibitors of NS5B polymerase Inhibitors of NS5A Non-nucleoside inhibitors of NS5B polymerase Grazoprevir + Elbasvir Sofosbuvir + Velpatasvir Sofosbuvir + Velpatasvir +? Voxilaprevir Glecaprevir + Pibrentasvir? With IFN Sofosbuvir (G1,4,5,6) Simeprevir (G1, 4) Daclatasvir (G1, 2, 3, 4)

10 The good and the bad about direct-acting antivirals GOOD BAD Very effective (>90% SVR) High cost at the population level (?) Very safe Simple to administer (1-4 pills a day) Pangenotypic regimens available Unclear relationship with HCC risk Coformulation is a barrier for problematic patients (e.g. NS5A RAS and Child B) Efficacy in genotype 3 still not optimal

11 Special populations: do they still exist? Subgroup SVR Reference Liver graft recipients 93% Manns 2016 End-stage liver disease 99% Roth 2015 Kidney graft recipients 100% Colombo 2017 Inherited blood disorders 94% Hezode 2017 HIV+ PWID 96% Dore 2015 Children 6-17 y.o. 97% Schwarz 2016

12 Cost of 4 weeks of treatment with available DAAs (Compendium, November 10, 2017) CHF Sovaldi 14, Harvoni 14, Daklinza (30 mg = 60 mg) 9, Viekirax 9, Exviera Zepatier 10, Epclusa 10,317.40

13 Treatment regimens Cost per cure (HCV-1)* MeanSVR % (95% CI) Mean cost per SVR (USD) (95% CI) IFN-α monotherapy 12 (5 19) 81,026 (74,128 87,925) IFN-α and RBV 35 (28 41) 65,018 (58,120 71,916) pegifn-α and RBV 48 (44 52) 72,013 (68,030 75,996) First PI, pegifn-α and RBV 75 (71 79) 61,151 (57,169 65,134) DAA ± pegifn-α and RBV 96 (92 100) 65,422 (61,440 69,405) Current pangenotypic DAA 99 (95 100) 31,382 (31,068 32,703) *Excluding costs of management of side effects and surveillance Adapted from VERNAZ et al, PLoS One 2016

14 The estimated costs of HCV (Switzerland, up to 2030) Estimate (Billion CHF) Direct costs Cost of treating all viremics (~30,300 patients x 31,000 CHF) ~0.94 Indirect costs MULLHAUPT et al, PLoS One 2015;10:e and 50% prevalence sensitivity analysis 2. VIETRI et al, BMC Gastroenterology 2013, 13:16

15 HCV cascade of care in the OST setting (Aargau) Questionnaires sent to 161 physicians treating 631 OST patients Only 205 (32.5%) patients were recruited: 49 (24%) had never been screened for HCV 18/95 (19%) of those anti-hcv+ had never been tested for HCV RNA 12/61 (20%) with chronic hepatitis C had never been genotyped 32/61 (53%) had never undergone a liver biopsy 33/61 (54%) had never been treated for HCV, and those treated had never received DAA BREGENZER et al, Swiss Med Wkly (in press)

16 Efficacy of 8 (n=252) vs. 12 (n=574) weeks of ledipasvir + sofosbuvir in real-world, treatment-naïve, non-cirrhotic HCV-1 patients 97% ION-3 (<6 E 06) CURRY et al, Aliment Pharmacol Ther 2017;46:540-8 KOWDLEY et al, N Eng J Med 2014;370:

17 Efficacy of 8 weeks of Grazoprevir/Elbasvir Treatment-naive, non-cirrhotic HCV-1b: a multicenter French trial ABERGEL et al, AASLD

18 Efficacy of 8- vs 12-week Glecaprevir/Pibrentasvir Treatment-naive or IFN/RBV/SOF-experienced, non-cirrhotic PUOTI et al, EASL

19 Efficacy of 8 vs. 12 weeks of Glecaprevir/Pibrentasvir Integrated analysis in treatment-naive, non-cirrhotic HCV-3 FLAMM et al, AASLD

20 Efficacy of 8 vs. 12 weeks of Glecaprevir/Pibrentasvir Integrated analysis in treatment-naive, non-cirrhotic HCV-3 FLAMM et al, AASLD

21 Easy-to-treat patients may be treated with 8 weeks of G/P

22 Efficacy of 12 weeks of Glecaprevir/Pibrentasvir Integrated analysis in treatment-naive / IFN/RBV/DAA-experienced 308 cirrhotics genotype GANE et al, AASLD

23 Pibrentasvir and Glecaprevir Antiviral Activity Against Common GT1 Resistance-Associated Variants In Vitro Pibrentasvir retains activity against GT1 Y93 variants against which many current NS5A inhibitors have low potency NS3 A156T/V variants confer resistance to Glecaprevir, but the fitness of these variants is low PIB: Pibrentasvir; VEL: Velpatasvir ; EBR: Elbasvir GLE: Glecaprevir; GZR: Grazoprevir; PTV: Paritaprevir Ng T, et al. Hepatology 2016; 64(suppl):417A-418A (poster presentation 849).

24 Glecaprevir (ABT-493) + Pibrentasvir (ABT-530) HCV-1 failures to DAA-containing regimens, MAGELLAN-1 Study (Part 1) SVR12 by key NS3 and NS5A baseline substitution Key baseline NS3 and NS5A substitutions were only present in patients with prior failure to both PI and NS5A inhibitors 5/9 of these patients achieved SVR12 Key NS3 positions: 155, 156, 168 Key NS5A positions: 24, 28, 30, 31, 58, 92, 93 OTVF: on-treatment virologic failure Y93H/N at baseline: 100% (13/13) SVR12 in patients with NS5A inhibitor experience (PI-naïve) POORDAD et al, EASL 2017

25 Voxilaprevir (formerly GS-9857) Pan-genotypic NS3 protease inhibitor Pharmacokinetics supports once a day dosing Robust viral RNA decline when given to patients with HCV genotypes 1-4 Additive antiviral activity when tested in vitro with SOF or VEL Cannot be used in cirrhosis Child-Pugh B or C

26 SOF/VEL/VOX, 1 cpr QD, 12 weeks Phase III, salvage study (POLARIS-1) % SVR Virological failures to NS5AI-containing regimens (n=263, 46% cirrhosis Child A) 6 virological failures (relapses, HCV-1a and -3, all cirrhotics) HCV-3 may still need RBV BOURLIERE et al, AASLD 2016

27 How frequent is post-svr reinfection? If you are not having reinfection cases, you are not treating high-risk populations... C-EDGE CO-STAR study, part B All patients treated with elbasvir/grazoprevir receiving opioid agonist therapy were followed every six months after cure (n=191 at start, n=118 at 24 months) Reinfection rate: 2.6 person-years Persistent reinfection rate: 1.6 person-years DORE et al, AASLD 2017

28 DAA therapy: clinical impact UNOS monthly liver transplant listing for non-hcc HCV during the years was reduced by 35% compared to the years CHOLANKERIL et al, AASLD 2017 (abstract 123) Mortality in SOLARIS studies on patients with hepatic decompensation was compared with mortality predicted by survival models DAA therapy was associated with a 60% decrease in the mortality risk within the first year after DAA treatment (SMR 0.39, observed vs. expected) KIM et al, AASLD 2017(abstract LB27)

29 Survival free of HCC by cirrhosis and SVR status after DAA-only therapy (retrospective study on 21,948 Veterans; HCC diagnosed 6 mos. from DAA start) Overall HR (SVR vs. non-svr) 0.29, 95% CI IOANNOU et al, AASLD 2017 and J Hepatol 2017 (in press)

30 Unexpected HCC occurrence in a VA cohort after DAA-induced SVR MONTO et al, AASLD 2017 (abstract 1412)