HCV Treatment in 2016: is there still a role for IFNa and ribavirin?

HCV Treatment in 2016: is there still a role for IFNa and ribavirin? Heiner Wedemeyer Hannover Medical School Germany 1

Disclosures Honoraria for consulting or speaking (last 5 years): Abbott, AbbVie, Biolex, BMS, Boehringer Ingelheim, Eiger, Gilead, ITS, JJ/Janssen- Cilag, Medgenics, Merck/Schering- Plough, Novartis, Roche, Roche Diagnostics, Siemens, Transgene, ViiV Research grants: Abbott, Abbvie, BMS, Gilead, Merck, Novartis, Roche, Roche Diagnostics, Siemens

Have we really got rid of IFNa? Yes! unless limited financial resources or restrictions in access to DAAs force us to use IFNa Have we really got rid of ribavirin? Not yet!

The hepatitis C-associated disease burden is increasing! GBD-Study: Lancet Jan 2015 HCV-Cirrhosis Mortality Increase 68% Cowie et al.: EASL 2015 Mortality due to HCV 2013 ~ 700.000 HCV-HCC Mortality Increase 292%

Treatment is most important! (not the specific regimen) 100.000 patients 10.000 patients treated 50.000 patients treated SVR 60% SVR 85% SVR 97% SVR 60% SVR 85% SVR 97% Cured 6000 8500 9700 30.000 42.500 48.500

Effects of increasing efficacy (green lines) vs. increasing treatment uptake (blue lines) Germany England France Spain Wedemeyer H, et al. J Viral Hep 2014; 21(Suppl 1):60 89.

Treatment is most important! (not the specific regimen) Restrictions to therapy: - Side effects of drugs - Drug Price Interferons & Ribavirin Novel DAAs

PEG-IFNa for hepatitis C

Pros PEG-IFNa for hepatitis C 15 years of experience Subgroups with SVR rates >90% SVR >90% in IL28B-CC patients and pts. with RVR High response rates in genotype 2/3/6 Very high response rates in acute hepatitis C

percent of patients (%) PEG-IFNa for acute hepatitis C Sustained virological response rates early treatment (arm- A and C) versus delayed treatment (arm-b) 100 90 80 70 60 72% p = 0.071 67% 95% 90% 93% arm-c 50 40 30 54% arm-a arm-b 20 10 0 FU 24 - Intent to treat (ITT) FU 24 patients adherent to therapy (completer) Deterding, et al. Lancet Infect Dis. 2013

Pros 15 years of experience PEG-IFNa for hepatitis C Subgroups with SVR rates >90% Successful PEG-IFNa therapy reduced overall mortality

SVR is associated with reduced mortality ALL CAUSE MORTALITY LIVER RELATED MORTALITY Van der Meer AJ, et al. JAMA 2012

Patients with advanced fibrosis who clear HCV infection have a survival similar to the general population! Recoverd patients Van der Meer et al., JAMA 2014

SVR after PEG-IFNa is associated with reduced HCC incidence Van der Meer AJ, et al. JAMA 2012

HCC incidence after IFN-free cure of chronic hepatitis C? 80 patients with liver cirrhosis 24-36 weeks of observation 5 HCCs Annual HCC incidence: ~9% Higher than after PEG-IFNa?

PEG-IFNa for hepatitis C Pros 15 years of experience Subgroups with SVR rates >90% Successful PEG-IFNa therapy reduced overall mortality We still use PEG-IFNa to treat HBV and HDV infections! IFNa is already upregulated in HCV patients

Plasma cytokine patterns differ between CHC patients and healthy individuals IFNa Owusu-Sekyere etal., Frontiers Immunol 2015.

Pros PEG-IFNa for hepatitis C 15 years of experience Subgroups with SVR rates >90% Successful PEG-IFNa therapy reduced overall mortality We still use PEG-IFNa to treat HBV and HDV infections! IFNa is already upregulated in HCV patients Cheaper than novel DAAs Germany: - PEG-IFN +RBV (24 w): ~12.000 -OBV/PTV/r+DSV 12 weeks: ~ 54.000 - LDV/SOF (12 weeks) ~ 60.000

Treatment is most important! (not the specific regimen) 100.000 patients 10.000 patients treated 50.000 patients treated SVR 60% SVR 85% SVR 97% SVR 60% SVR 85% SVR 97% 5 x more expensive Cured 6000 8500 9700 30.000 42.500 48.500 5 x more expensive

PEG-IFNa for hepatitis C Pros 15 years of experience Subgroups with SVR rates >90% Successful PEG-IFNa therapy reduced overall mortality Cons Side effects! Injections, storage, 24-48 weeks Many contraindications We still use PEG-IFNa to treat HBV and HDV infections! IFNa is already upregulated in HCV patients Cheaper than novel DAAs

Triple Therapy for Hepatitis C: Experiences from the Hannover Medical School Hepatitis clinic PEG-IFNa for hepatitis C: Many patients cannot be treated! 208 Patients Therapyassociated Safety Concerns Poor Chance for SVR No Triple Therapy n=103 Multiple reasons influenced the final decision Maasoumy, Cornberg et al., Plos One 2013 Low Treatment Urgency: Wait for better Options Nonmedical Patient related Reasons

Improvement of liver function parameters in advanced cirrhosis: The Hannover Cohort Changes in MELD Scores baseline-fu-week 12 Deterding et al., AP&T 2015

Improvement of fibroscan values in patients with advanced cirrhosis: The Hannover Cohort FibroScan > 25 kpa at baseline FibroScan 25 kpa at baseline Deterding et al., AP&T 2016

DAAs and DDIs! Keep an eye on DDIs! (Höhner zu Siederdissen, CID Dec 2015)

PEG-IFNa for hepatitis C Pros 15 years of experience Subgroups with SVR rates >90% Successful PEG-IFNa therapy reduced overall mortality We still use PEG-IFNa to treat HBV and HDV infections! IFNa is already upregulated in HCV patients Cheaper than novel DAAs Cons Side effects! Injections, storage, 24-48 weeks Many contraindications Lower cure rates! PEGa therapy is not necessarily cheaper! - Price per SVR? - costs for monitoring - costs of side effect management - secondary costs (productivity, etc.)

PEG-IFNa for hepatitis C Pros 15 years of experience Subgroups with SVR rates >90% Successful PEG-IFNa therapy reduced overall mortality We still use PEG-IFNa to treat HBV and HDV infections! IFNa is already upregulated in HCV patients Cons Side effects! Injections, storage, 24-48 weeks Many contraindications Lower cure rates! PEGa therapy is not necessarily cheaper! Would you use PEG-IFNa? Cheaper than novel DAAs

Ribavirin for hepatitis C

Pros 15 years of experience Ribavirin for hepatitis C Increases SVR rates in subgroups Can shorten treatment duration in IFN-free regimens Why not?

Ribavirin in the treatment of hepatitis C OBV/PTV/r+ DSV: OBV/PRV/r: LDV+ SOF: DCV+ SOF: SOF + RBV: Genotype 1a + RBV Genotype 1b no RBV Genotype 4 + RBV Cirrhosis 12 weeks + RBV no cirrhosis 8-12 weeks no ribavirin Genotype 3, cirrhosis 12-16 weeks + RBV Genotype 3, cirrhosis 24 weeks no RBV Genotype 3, no cirrhosis 12 weeks no RBV Genotype 3 24 weeks Genotype 2 12 weeks

Factors in DAA treatment failure Buti, Riveiro-Barciela & Estaban, J Hepatol 2015

Possible salvage options after DAA treatment failure Buti, Riveiro-Barciela & Estaban, J Hepatol 2015

Ribavirin for hepatitis C Pros 15 years of experience Increases SVR rates in subgroups Can shorten treatment duration in IFN-free regimens Why not? Cons Side effects! Reduced quality of life How does RBV work?

Ribavirin for hepatitis C Ribavirin affects Patient-Reported-Outcomes in sofosbuvir-based therapies Younossi et al., Liver International Jan 2016 (Sirius trial) Younossi et al., Hepatology Jun 2015 (ION-studies) - RBV independent predictor of PRO impairment!

Ribavirin and QoL during OBV/PTV/r+/-RBV therapy Dore et al., J Hepatol 2015

Ribavirin for hepatitis C Pros 15 years of experience Increases SVR rates in subgroups Can shorten treatment duration in IFN-free regimens Why not? Cons Side effects! Reduced quality of life How does RBV work? Would you use ribavirin if an RBV-free option is available?

Treatment as prevention?

SVR >100%? 1000 treated 1045 infections cured/prevented HCV infected patients 1000 950 cured 50 SVR 95% HCV infected patients Transmission HCV infected patients 100 5 95 prevented HCV infecte d patient s Transmission

Treatment as prevention will only be possible with drugs which are almost free of side-effects!