The role of sofosbuvir/ledipasvir in HCV cure

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1 The role of sofosbuvir/ledipasvir in HCV cure John Koskinas Professor in Medicine-Hepatology 2nd Department of Internal Medicine, Medical School of Athens Hippocration General Hospital 8 th Larissa International Congress of Internal Medicine March 17-19, 2016

2 Conflict of interest Consultant: Gilead, Novartis, Roche, MSD, Bayer, Bristol, Abbvie Talks: Bristol-Myers Squibb, Novartis, Roche, MSD, Bayer, Gilead Grants: Gilead, Roche, MSD, Novartis, Bayer, Abbvie, Bristol Clinical Trials: Novartis, Roche, MSD, Bayer, Gilead, Janssen, Abbvie

Chronic Hepatitis C Brief History 1970: elevated AST/ALT No disease 1980: NonA-NonB hepatitis Mild disease 1990: HCV infection Major Health Problem 2000: Combination

3 Chronic Hepatitis C Brief History 1970: elevated AST/ALT No disease 1980: NonA-NonB hepatitis Mild disease 1990: HCV infection Major Health Problem 2000: Combination therapy (PR) high SVR 2010: New drugs (PIs) for selected patients 2014 : Combination of new drugs with multiple targets 20??: Final victory??? For whom?? With what???

4 The future of HCV infection Parameters Epidemiology new infections risk population Prevention strategies- vaccines Burden of the disease physical history Therapy efficacy- safety - adherence target population Access to drugs Cost of new drugs Health policy- political will

5 Hepatitis C burden of the disease It is estimated that in the next decade 1 it will be a: 50% increase of cirrhosis % increase of decompensated cirrhosis 50% increase of HCC cases 500% increase in the number of patients that they will need transplantation. It is quite clear that chronic HCV infection would have a great impact on health economics the forthcoming years. Ward, Top Antivir. Med, 2013; Davis et al 2010; Pyenson et al 2009

6 Number of Persons 180, ,000 Widespread Use of Effective Therapy Could Significantly Reduce the Need for Transplants Potential Transplant Need 150, , , , , , ,000 80,000 91, ,000 40,000 20, , , , , , , , Year in Model No treatment 25% 50% 75% treated All treated Desai et al. AASLD Poster

7 The race just begun. Both in efficacy and cost BMS Bristol AbbVie Gilead MSD Novartis All with. >90% SVR

8 DAAs choice It needs.. some scientific approach recommendations

9 Θεραπεία με σχήματα χωρίς ΙΦΝ κατά προτεραιότητα σε ασθενείς ανεξαρτήτως γονοτύπου (ΕEMH/ΚΕΕΛΠΝΟ) 1) μη αντιρροπούμενη κίρρωση 2) αντιρροπούμενη κίρρωση (Ishak: 5-6, METAVIR: F4, ελαστογραφία: >12 kpa) που έχουν λάβει σχήματα με ΙΦΝ ή είναι πρωτοθεραπευόμενοι 5) υποτροπή της HCV λοίμωξης μετά από μεταμόσχευση ήπατος ανεξαρτήτως σταδίου ίνωσης 6) σοβαρή εξωηπατική εκδήλωση της HCV λοίμωξης ανεξαρτήτως σταδίου ίνωσης (συμπτωματική κρυοσφαιριναιμία: νεκρωτική αγγειίτιδα, σπειραματονεφρίτιδα, νεφρωσικό σύνδρομο, αισθητικοκινητική αξονική πολυνευροπάθεια) 7) σοβαρή ίνωση (στάδιο Ishak: 4, METAVIR: F3, ελαστογραφία: >9 kpa ) και αντένδειξη στη ΙΦΝ και/η προηγούμενη αποτυχία σε σχήματα με ΙΦΝ 8) σοβαρή ίνωση [(στάδιο Ishak: 4, METAVIR: F3, ελαστογραφία: >9 kpa ) πρωτοθεραπευόμενοι χωρίς αντένδειξη για ΙΦΝ 9) HCV και HIV συλλοίμωξη ανεξαρτήτως σταδίου ίνωσης

10 Treatment at early stages? To prevent progression To prevent transmission newborn, group, sexual partner Feeling of well being Uncertainty about the future Cost? direct, indirect

11 The Advantages of real life studies non-selected population comorbidities (HIV coinfection, renal disease, old age, immune diseases..) broad range of liver disease (early stage decompensated cirrhosis-post OLT) realistic therapy adherence (side effects, number of pills, duration of treatment ) evaluation of complex therapies and drug-drug interactions useful to detect rare or late side effects routine practice setting logistical, ethical feasibility and applicability health policy and health economics

HCV-TARGET Real-World Cohort: LDV/SOF for 8, 12, and 24 Weeks in genotype 1 Efficacy with LDV/SOF by Subgroups LCL (95%) SVR12 Rate (%) UCL (95%) 95.1 96.5 97.6 89.9 93.2 95.7 96.8 98.1 99 95.2 97.

12 HCV-TARGET Real-World Cohort: LDV/SOF for 8, 12, and 24 Weeks in genotype 1 Efficacy with LDV/SOF by Subgroups LCL (95%) SVR12 Rate (%) UCL (95%) * P<0.05 * * * * * Terrault, AASLD, 2015, 94

Efficacy Among Patients with Recurrent HCV Post-Liver Transplant LDV/SOF+RBV 12 wks LDV/SOF+RBV 24 wks LDV/SOF 12 wks 102/ 107 104/ 105 58/ 60 56/ 58 40/ 41 F0 F3 CTP A Kwok, et al. Shoreibah, et al.

13 Efficacy Among Patients with Recurrent HCV Post-Liver Transplant LDV/SOF+RBV 12 wks LDV/SOF+RBV 24 wks LDV/SOF 12 wks 102/ / / 60 56/ 58 40/ 41 F0 F3 CTP A Kwok, et al. Shoreibah, et al. Hassett, et al. 11/ 11 28/ 28 18/ 18 SOLAR-1 and SOLAR-2 Real-World (Non-cirrhotic and cirrhotic) Gane, AASLD, 2015, 1049; Kwok, AASLD 2015, 1101; Shoreibah, AASLD 2015, 1174; Hassett, AASLD, 2015, LB-28

14 Real life data- LDV/SOF ± RBV Efficacy in patients with HCV-1 and compensated cirrhosis Overall SVR wk wk Duration 24 wk Treatment Naïve Treatment Naïve 98% 97% 99% N=161 Treatment Experienced Treatment Experienced 95% 94% 98% N=352 Regimen LDV/SOF LDV/SOF + RBV 96% 99% 95% 96% LDV/SOF 12 wk 96% 90% Duration/± /± RBV LDV/SOF + RBV 12 wk LDV/SOF 24 wk 98% 97% 96% 98% LDV/SOF + RBV 24 wk 100% 100% 12 weeks of LDV/SOF + RBV resulted in similar SVR rates to 24 weeks of LDV/SOF alone Bourliere, AASLD, 2014, Oral #82

15 AASLD, 2015

16 In summary from the clinical studies and real world data in the case of sofosbuvir/ledipasvir Effective in special populations HIV coinfection, old age, immune diseases..) Effective in all the spectrum of liver disease early stage, cirrhosis, decompensated cirrhosis, post OLT) Excellent therapy adherence minor side effects or absence of side effects in the majority of patients one or only a few number of pills daily short duration of treatment 12 wks (8 wks or 24 wks in certain cases)

17 In summary from the clinical studies and the real world data in the case of sofosbuvir/ledipasvir Friedly environment for drug-drug interactions Absence of late side effects Logistical and ethical feasibility relates mostly to cost not related with this combination only general approach and limitations to use DAAs Cost is a major issue for health policy and health economics

18 Treatment of HCV infection The revolution We never had drugs with such and efficacy and safe profile for such a great number of patients Target: To cure all HCV patients with DAAs

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