Current advances in the treatment of chronic hepatitis C: does hardto-treat

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1 Current advances in the treatment of chronic hepatitis C: does hardto-treat exist anymore? 4 th ACHA, Xi an China 23 rd May 2015 Date of Preparation: May 2015 PP--CN-0206

2 Disclaimer These presentations and discussion include reference to products in development that have not yet received regulatory approval The views and opinions expressed in the following presentation are those of the presenter and do not necessarily reflect those of AbbVie Ltd AbbVie Ltd does not endorse the use of unregistered products or products outside of their registered indications. Please refer to your country's Product Information for licensed instructions 2

3 Agenda Chair s welcome and introduction Lai Wei IFN-free for HCV: Evolving data in GT1b patients Lim Seng Gee IFN-free for HCV: Treatment of special patient profiles David Iser Q&A and summary Lai Wei 3

4 Welcome and Introduction Lai Wei

5 Anti-HCV Prevalence (mills) The global prevalence of HCV The global anti-hcv prevalence is 1.6%, corresponding to approximately 115 million infections world-wide Serie Gower E, et al. J Hepatol 2014; 61:S45 S57. 5

6 Anti-HCV Prevalence (mills) The global prevalence of HCV The global anti-hcv prevalence is 1.6%, corresponding to approximately 115 million infections world-wide Australia Japan China India Indonesia /Thailand 10 0 Pakistan 15 million infections (anti- HCV+) in China alone Serie Gower E, et al. J Hepatol 2014; 61:S45 S57. 6

7 Relative prevalence of each HCV genotype by region* Globally, GT1 is the predominant HCV genotype and accounts for 46.2% of HCV cases GBD region North Africa and Middle East Western sub-saharan Africa Eastern sub-saharan Africa Central sub-saharan Africa Southern sub-saharan Africa Southern Latin America Andean Latin America Tropical Latin America Central Latin America Caribbean Central Asia South Asia East Asia Southeast Asia High-income Asia Pacific Oceania Australasia High-income North America Western Europe Central Europe Eastern Europe HCV genotype proportion * Size of pie chart is proportional to the number of seroprevalent cases as estimated by Hanafiah M, et al million 14 million 3.9 million 1.7 million 486,000 Messina JP, et al. Hepatology 2015; 61:77 87; Hanafiah M, et al. Hepatology 2013; 57:

8 Relative prevalence of HCV GT1a and GT1b in countries with HCV GT1 High prevalence of HCV GT1b in the Asia-Pacific region HCV 1a vs. 1b GT1a GT1b GT1a/1b equal Unknown subtypes <25% GT1 No data Messina JP, et al. Hepatology 2015; 61:77 87 (+supplement); Sievert W, et al. Liver International 2011; 10:

9 HCV infection in China is predominantly due to GT1b Rao HY, et al. J Gastroenterol Hepatol 2014; 29:

10 HCV infection in China is predominantly due to GT1b In China approximately 8.9 million adult viraemic infections 1 Overall 56.8% of infections due to GT1b 2 1. Gower E, et al. J Hepatol 2014; 61:S45 S57; 2. Rao HY, et al. J Gastroenterol Hepatol 2014; 29:

11 HCV infection in China The main risk factors include IV use of glass syringes/needles and blood transfusions Therapeutic landscape in China Currently approved therapies: IFN + RBV PegIFN + RBV Therapies under evaluation SMV + PR DCV + ASV SOF + RBV OBV/PTV/r with DSV ± RBV LDV/SOF ± RBV Sales Sievert W, et al. Liver International 2011; 10:

12 Why treat HCV? The natural history of infection End-stage liver disease Normal liver Fibrosis Cirrhosis HCC Progression of HCV over time (several decades) Over the course of years, patients chronically infected with HCV can progress to cirrhosis and develop HCC HCV-related mortality and morbidity mainly due to cirrhosis and HCC HCC = hepatocellular carcinoma. Tanaka E, et al. J Gastroenterol Hepatol 2000; 15:E98 E104; Yano M, et al. Hepatology 1996; 23: ; Kobayashi M, et al. J Med Virol 2006; 78:

13 Proportion of patients with HCV and HCC in Asia-Pacific countries Country/region HCV-related HCC, % Japan 79 Australia New Zealand South Korea 20 India 16 Thailand 15 Singapore Mainland China 1 12 Hong Kong 3 6 Philippines 4 Malaysia 2 Yuen MF, et al. J Gastroenterol Hepatol 2009; 24: ; 1. Venook AP, et al. The Oncologist 2010; 15:

14 Cumulative risk for HCC (%) Cumulative risk of HCC by HCV genotype and subtype The cumulative lifetime (30 75 years) risk of HCC is higher for subjects infected with HCV GT1b (29.7%) than those infected with GT1a, 2a and 2b (19.2%) Cumulative lifetime (30 75 years) risk of HCC = 29.7% Subtype 1b Other subtypes (1a, 2a, 2b) Δ10.5% p<0.001 Cumulative lifetime (30 75 years) risk of HCC = 19.2% Age (years) 80 Lee MH, et al. Int J Cancer 2014; 135:

15 Cumulative risk for HCC (%) Cumulative risk of HCC by HCV genotype and subtype The cumulative lifetime (30 75 years) risk of HCC is higher for subjects infected with HCV GT1b (29.7%) than those infected with GT1a, 2a and 2b (19.2%) Subtype 1b Other subtypes (1a, 2a, 2b) With approximately 8.9 million adult viraemic infections 1 Cumulative lifetime (30 75 years) risk of HCC = 29.7% An overall GT1b prevalence of 56.8% 2 Δ10.5% p<0.001 A cumulative lifetime risk for HCC of 29.7% with GT1b 3 Cumulative lifetime (30 75 years) risk of HCC = 19.2% Over 1.5 million future cases of HCC might be expected in China due 10 to HCV GT1b alone Age (years) Gower E, et al. J Hepatol 2014; 61:S45 S57; 2. Rao HY, et al. J Gastroenterol Hepatol 2014; 29: ; 3. Lee MH, et al. Int J Cancer 2014; 135:

16 The evolution of treatment for HCV GT1 infection / PegIFN + RBV 1991 Standard IFN IFN + RBV Only 42 46% of patients treated with PegIFN/RBV achieved virologic cure Manns MP, et al. Lancet 2001; 358: ; Fried MW, et al. N Engl J Med 2002; 347:

17 The evolution of treatment for HCV GT1 infection / BOC or TVR + PegIFN/RBV 66 79% of patients achieved virologic cure SMV or SOF + PegIFN/RBV 80 90% of patients achieved virologic cure BOC = boceprevir; SMV = simeprevir; SOF = sofosbuvir; TVR = telaprevir BOC, TVR, SMV and SOF US prescribing information & EU summary of product characteristics (all accessed April 2015). 17

18 The evolution of treatment for HCV GT1 infection /5 SVR12 rates >85% achieved with IFN-free regimens 1991 LDV/SOF Approved in EU & US SMV + SOF Approved in EU & US DCV + SOF Approved in EU only OBV/PTV/r + DSV Approved in EU & US DCV + ASV Approved in Japan ASV = asunaprevir; DCV = daclatasvir; DSV = dasabuvir; LDV = ledipasvir; OBV = ombitasvir; PTV/r = paritaprevir/ritonavir SMV Summary of Product Characteristics & US prescribing information; DCV Summary of Product Characteristics; LDV/SOF Summary of Product Characteristics & US prescribing information; BMS press release, July 2014; OBV/PTV/r Summary of Product Characteristics & OBV/PTV/r + DSV US prescribing information; All accessed April

19 Summary World wide there are an estimated 115 million HCV infections 15 million in China alone Genotype 1b is widely distributed with a high prevalence in the Asia-Pacific region Newer IFN-free treatment options are associated with high rates of SVR Will the high rates of efficacy mean that traditionally difficult to treat patients will no longer exist? 19

20 Summary World wide there are an estimated 115 million HCV infections 15 million in China alone Genotype 1b is widely distributed with a high prevalence in the Asia-Pacific region Newer IFN-free treatment options are associated with high rates of SVR Will the high rates of efficacy mean that traditionally difficult to treat patients will no longer exist? Let s ask the experts 20

21 IFN-free for HCV: Evolving data in GT1b patients Lim Seng Gee Date of Preparation: May 2015 PP--CN-0206

22 Selected IFN-free HCV treatments of interest in Asia-Pacific OBV/PTV/r + DSV ± RBV LDV/SOF ± RBV SOF + RBV DCV + ASV 22

23 Selected IFN-free HCV treatments of interest in Asia-Pacific OBV/PTV/r + DSV ± RBV LDV/SOF ± RBV SOF + RBV DCV + ASV 23

24 HCV GT1b treatment-naive/-experienced cirrhotic and noncirrhotic patients Treatment naïve non cirrhotic SAPPHIRE-I GT1b (N=204) PEARL-III GT1b (N=419) OBV/PTV/r + DSV + RBV (n=151) Placebo (n=53) OBV/PTV/r + DSV + RBV (n=210) OBV/PTV/r + DSV + Placebo (n=209) OBV/PTV/r + DSV + RBV Treatment experienced non-cirrhotic SAPPHIRE-II GT1b (N=163) PEARL-II GT1b (N=179) OBV/PTV/r + DSV + RBV (n=123) Placebo (n=40) OBV/PTV/r + DSV + RBV (n=88) OBV/PTV/r + DSV + Placebo (n=91) OBV/PTV/r + DSV + RBV Treatment naïve & experienced cirrhotic TURQUOISE-II GT1b (N=119) OBV/PTV/r + DSV + RBV (n=68) OBV/PTV/r + DSV + RBV (n=51) Feld JJ, et al. N Engl J Med 2014; 370: ; Ferenci P et al. N Engl J Med 2014; 370: ; Zeuzem S, et al. N Engl J Med 2014; 370: ; Andreone P, et al. Gastroenterol 2014; 147: ; Poordad F, et al. N Engl J Med 2014; 370:

25 SVR12 (%) Pooled efficacy analysis: phase 3 studies of OBV/PTV/r + DSV ± RBV HCV GT1b-infected, non-cirrhotic patients; SAPPHIRE-I, -II, PEARL-II, -III OBV/PTV/r + DSV OBV/PTV/r + DSV + RBV n N Overall Naive* Relapse Prior partial Prior null * Includes one patient with GT1b infection who was enrolled in the PEARL-IV study. Colombo M, et al. Hepatology 2014; 60(Suppl):1131A. 25

26 SVR12 (%) Efficacy of OBV/PTV/r + DSV in GT1b-infected patients without cirrhosis: PEARL-II & -III pooled efficacy and subgroup analysis Of 301 GT1b patients at BL: Breakthrough = 0 Relapse = n N Prior response to PegIFN/RBV treatment Race Geographic region ROW = rest of world. Colombo M, et al. Hepatology 2014; 60(Suppl):1131A; Vierling J, et al. Hepatology 2014; 60(Suppl):190A. 26

27 SVR12 (%) Data in HCV GT1b-infected patients: pooled efficacy analysis, phase 3 study of OBV/PTV/r + DSV + RBV HCV GT1b-infected, cirrhotic patients; TURQUOISE-II OBV/PTV/r + DSV + RBV, 12 weeks OBV/PTV/r + DSV + RBV, 24 weeks , ,7 Of 68 GT1b patients at BL: Breakthrough = 0 Relapse = 1 20 n N Overall Naive Relapse Prior partial Prior null Colombo M, et al. Hepatology 2014; 60(Suppl):1131A. 27

28 Pooled Safety Analysis: AEs ( 15%) and laboratory abnormalities in patients with HCV GT1b infection ± cirrhosis Without cirrhosis With cirrhosis Event, n (%) OBV/PTV/r + DSV 12 weeks (n=301) OBV/PTV/r + DSV + RBV 12 weeks (n=68) Headache 70 (23.3) 17 (25.0) Fatigue 62 (20.6) 19 (27.9) Asthenia 18 (6.0) 15 (22.1) Pruritus 19 (6.3) 14 (20.6) Cough 12 (4.0) 11 (16.2) Bilirubin Grade 3 (>3X 10X ULN) 1 (0.3) 7 (10.3) Bilirubin Grade 4 (>10X ULN) 0 0 Hb Grade 3/4 (< g/dl) 0 0 ALT Grade 3/4 (>5X ULN) 0 1 (1.5) AST Grade 3/4 (>5X ULN) 1 (0.3) 0 Colombo M, et al. Hepatology 2014; 60(Suppl):1131A. 28

29 Selected IFN-free HCV treatments of interest in Asia-Pacific OBV/PTV/r + DSV ± RBV LDV/SOF ± RBV SOF + RBV DCV + ASV 29

30 HCV GT1b treatment-naive/-experienced, including cirrhotic patients ION-1, phase 3 open-label study; HCV GT1, treatment-naive (including 273 (32%) GT1b) ION-2, phase 3 open-label study; HCV GT1, treatment-experienced (including 93 (21%) GT1b) LDV/SOF (ION-1, GT1b n=66; ION-2, GT1b n=23) LDV/SOF + RBV (ION-1, GT1b n=68; ION-2, GT1b n=23) LDV/SOF (ION-1, GT1b n=68; ION-2 GT1b, n=24) LDV/SOF + RBV (ION-1, GT1b n=71; ION-2, GT1b n=23) Afdhal N, et al. N Engl J Med 2014; 370: ; Afdhal N, et al. N Engl J Med 2014; 370: ; LDV/SOF Summary of Product Characteristics, November 2014 (accessed May 2015). 30

31 SVR12 (%) HCV GT1b treatment-naive/-experienced, including cirrhotic patients ION-1 Treatment-naive ION-2 Treatment-experienced 12 weeks 24 weeks Of 276 GT1b patients at BL: Breakthrough = 1 Relapse = 1 Of 93 GT1b patients at BL: Breakthrough = 0 Relapse = 3 20 n N LDV/SOF LDV/SOF + RBV LDV/SOF LDV/SOF + RBV LDV/SOF Summary of Product Characteristics, November 2014 (accessed May 2015). 31

32 ION-1 & -2: common AEs and laboratory abnormalities in patients with HCV GT1 infection (GT1a/GT1b combined) Patients, n (%) Treatment discontinuations due to AE ION-1 (naive) LDV/SOF, 12 weeks (N=214) ION-2 (experienced) LDV/SOF, 12 weeks (N=109) 0 0 Serious AEs 1 (<1) 0 Any AE 169 (79) 73 (67) AEs in >10% of patients Fatigue 44 (21) 23 (21) Headache 53 (25) 28 (26) Nausea 24 (11) 13 (12) Diarrhea 24 (11) 7 (6) Hemoglobin level <10 g/dl 0 0 Platelet count 25,000 to <50,000/mm 3 1 (<1) 1 (1) Afdhal N, et al. N Engl J Med 2014; 370: ; Afdhal N, et al. N Engl J Med 2014; 370:

33 SVR12 (%) ION-3: HCV GT1b treatment-naive, non cirrhotic patients ION-3, phase 3 open-label study; HCV GT1, treatment-naive, non-cirrhotic, N=647 LDV/SOF (n=43) LDV/SOF + RBV (n=44) LDV/SOF (n=44) Week n 0 N LDV/SOF 8 weeks Of 131 GT1b patients at BL: Breakthrough = 0 Relapse = LDV/SOF + RBV 8 weeks LDV/SOF 12 weeks Overall 4 patients with GT1b infection suffered virologic relapse post-treatment * One patient achieved SVR12, but was not sub-genotyped. Kowdley KV, et al. N Engl J Med 2014; 370: & supplement; LDV/SOF Summary of Product Characteristics, November 2014 (accessed May 2015). 33

34 ION-3: common AEs and laboratory abnormalities in patients with HCV GT1 infection (GT1a/GT1b combined) Patients, n (%) Treatment discontinuations due to AE ION-3 (naive) LDV/SOF, 8 weeks (N=215) ION-3 (naive) LDV/SOF, 12 weeks (N=216) 0 2 (1) Serious AEs 4 (2) 5 (2) Any AE 145 (67) 149 (69) AEs in >10% of patients Fatigue 45 (21) 49 (23) Headache 30 (14) 33 (15) Nausea 15 (7) 24 (11) Hemoglobin level <10 g/dl 0 1 (<1) Neutrophil count 500 to <750/mm (<1) Kowdley KV, et al. N Engl J Med 2014; 370:

35 Integrated analyses: LDV/SOF ± RBV in patients with compensated cirrhosis phase 2/3 study designs Integrated analyses included 513 HCV GT1 patients with compensated cirrhosis Pooled data from phase 2/3 LDV/SOF ± RBV studies LONESTAR, ELECTRON, ELECTRON-2, , ION-1, ION-2, SIRIUS LDV/SOF (n=118) LDV/SOF + RBV (n=204) LDV/SOF (n=133) 12 weeks follow-up 12 weeks follow-up LDV/SOF + RBV (n=58) 12 weeks follow-up 12 weeks follow-up Study Weeks Bourliѐre M, et al. Hepatology 2014; 60(Suppl):239A; Reddy R, et al. Hepatology 2015 doi: /hep.27826; [Epub ahead of print]. 35

36 Integrated analyses: LDV/SOF ± RBV in patients with compensated cirrhosis SVR12 rates in HCV GT1b patients* Total Treatment naive Overall SVR12 96% 98% 95% Genotype GT1b 97% 97% 96% Treatment experienced Genotype/ duration Genotype/ ± RBV GT1b/12 wks 97% 98% 96% GT1b/24 wks 97% 96% 97% GT1b/ RBV 96% 97% 95% GT1b/+ RBV 97% 97% 97% SVR12, % * Of the 513 patients 40% were infected with HCV GT1b. Bourliѐre M, et al. Hepatology 2014; 60(Suppl):239A; Reddy R, et al. Hepatology 2015 doi: /hep.27826; [Epub ahead of print]. 36

37 Integrated analyses: LDV/SOF ± RBV in patients with compensated cirrhosis SVR12 rates in HCV GT1b patients* Total Treatment naive Overall SVR12 96% 98% 95% Genotype GT1b 97% 97% 96% Genotype/ duration Of 207 GT1b patients at BL: GT1b/12 wks 97% 98% 96% Breakthrough = 0 GT1b/24 wks 97% Relapse = 96% 6 97% Treatment experienced Genotype/ ± RBV GT1b/ RBV 96% 97% 95% GT1b/+ RBV 97% 97% 97% SVR12, % * Of the 513 patients 40% were infected with HCV GT1b. Bourliѐre M, et al. Hepatology 2014; 60(Suppl):239A; Reddy R, et al. Hepatology 2015 doi: /hep.27826; [Epub ahead of print]. 37

38 Safety summary: common AEs and laboratory abnormalities in patients with HCV GT1 infection (GT1a/GT1b combined) LDV/SOF LDV/SOF + RBV *AEs occurring in at least 10% of patients in any group 12 weeks (N=118) 24 weeks (N=133) 12 weeks (N=204) Discontinuation of LDV/SOF due to AE (<1) 0 24 weeks (N=58) Any serious AE (SAE) 2 (2) 13 (10) 7 (3) 2 (3) Any AE 76 (64) 114 (86) 171 (84) 54 (93) Common AEs* Headache Fatigue Asthenia Insomnia Nausea Diarrhea Anemia Cough Pruritus Rash Arthralgia Irritability Grade 3 4 hematological abnormalities Hemoglobin concentrations <10 g/dl Hemoglobin concentrations <8 g/dl Lymphocyte count 350 to <500 per mm 3 Lymphocyte count <350 per mm 3 Neutrophil count 500 to <750 per mm 3 Platelet count 25,000 50,000 per mm 3 16 (14) 16 (14) 3 (3) 4 (3) 6 (5) 6 (5) 1 (1) 3 (3) 3 (3) 3 (3) 7 (6) 2 (2) (2) 42 (32) 25 (19) 38 (29) 19 (14) 15 (11) 11 (8) 2 (2) 13 (10) 9 (7) 6 (5) 13 (10) 13 (10) 1 (1) 0 4 (3) 0 1 (1) 5 (4) 39 (19) 27 (13) 32 (16) 28 (14) 30 (15) 14 (7) 24 (12) 16 (8) 22 (11) 16 (8) 8 (4) 10 (5) 19 (9) 3 (1) 1 (<1) 2 (1) (35) 23 (40) 5 (9) 14 (24) 7 (12) 10 (17) 11 (19) 6 (10) 4 (7) 12 (21) 5 (9) 8 (14) 7 (12) Reddy R, et al. Hepatology 2015 doi: /hep.27826; [Epub ahead of print]. 38

39 SVR12 (%) SIRIUS: LDV/SOF in cirrhotic patients who have previously failed PegIFN/RBV and PI-based triple therapy study design and SVR Placebo LDV/SOF + RBV 80 LDV/SOF + Placebo RBV Of 154 GT1b patients at BL: Breakthrough = 0 Relapse = Study Weeks LDV/SOF + RBV 12 weeks LDV/SOF 24 weeks Bourlière M, et al. Lancet Infect Dis 2015;15:

40 Selected IFN-free HCV treatments of interest in Asia-Pacific OBV/PTV/r + DSV ± RBV LDV/SOF ± RBV SOF + RBV DCV + ASV 40

41 DCV + ASV in Japanese patients with GT1b infection study design Phase 3 randomized study All HCV GT1b Japanese patients, (including 22 [10%] patients with cirrhosis), N=222 DCV + ASV IFN ineligible naive/intolerant (n=135) DCV + ASV Non-responders (n=87) Follow-up Follow-up Day 1 TW8 futility rule Week 24 Week 48 TW = treatment week. Kumada H, et al. Hepatology 2014; 59:

42 DCV + ASV in Japanese patients with GT1b infection baseline characteristics IFN-ineligible/intolerant DCV + ASV (n=135) Non-responders DCV + ASV (n=87) Male, n (%) 38 (28) 39 (45) Asian, n (%) 135 (100) 87 (100) Mean age, years (range) 64 (24 75) 60 (42 74) Cirrhosis, n (%) 11 (8) 11 (13) IL28B CC genotype, n (%) 94 (70) 16 (18) HCV genotype, n (%) 1a 0 0 1b 135 (100) 87 (100) Previous response to PegIFN/RBV, n (%) Null N/A 48 (55) Partial N/A 36 (41) Other N/A 3 (3) All patients enrolled were infected with HCV GT1b Kumada H, et al. Hepatology 2014; 59:

43 SVR24 (%) DCV + ASV in Japanese patients with GT1b infection SVR24 rates IFN ineligible/intolerant Non-responders ,4 87,1 80,5 78,9 90,9 90, , , n N Overall No cirrhosis Cirrhosis Baseline (NS5A) L31M/V and/or Y93H DCV + ASV is recommended for 24 weeks in IFN-ineligible/intolerant Japanese patients and non-responders with or without compensated cirrhosis Kumada H, et al. Hepatology 2014; 59:

44 SVR24 (%) DCV + ASV in Japanese patients with GT1b infection SVR24 rates IFN ineligible/intolerant Non-responders ,4 87,1 80,5 78,9 90,9 90, n N Of 222 GT1b patients at BL: Breakthrough = 14 No EOT response = 3 Relapse = Overall No cirrhosis Cirrhosis , , Baseline (NS5A) L31M/V and/or Y93H DCV + ASV is recommended for 24 weeks in IFN-ineligible/intolerant Japanese patients and non-responders with or without compensated cirrhosis Kumada H, et al. Hepatology 2014; 59:

45 Safety summary: Common AEs and grade 3/4 laboratory abnormalities during the treatment period Event or laboratory abnormality, n (%) Interferon ineligible/intolerant N=135 Non-responder N=87 Total N=222 Serious adverse events 9 (6.7) 4 (4.6) 13 (5.9) Adverse event* Nasopharyngitis Increased ALT Increased AST Headache Diarrhea Pyrexia Grade 3 4 laboratory abnormality ALT AST Hemoglobin Lymphocytes Platelets Bilirubin, total Neutrophils Creatinine Lipase, total * Adverse event that occurred in more than 10% of patients in any group 40 (29.6) 24 (17.8) 18 (13.3) 18 (13.3) 12 (8.9) 12 (8.9) 12 (8.9) 10 (7.4) 6 (4.4) 5 (3.7) 2 (1.5) 1 (0.7) 0 1 (0.7) 1 (0.7) 27 (31.0) 11 (12.6) 10 (11.5) 17 (19.5) 10 (11.5) 15 (17.2) 4 (4.6) 2 (2.3) 1 (1.1) 1 (1.1) 2 (2.3) 1 (1.1) 1 (1.1) (30.2) 35 (15.8) 28 (12.6) 35 (15.8) 22 (9.9) 27 (12.2) 16 (7.2) 12 (5.4) 7 (3.2) 6 (2.7) 4 (1.8) 2 (0.9) 1 (0.5) 1 (0.5) 1 (0.5) Kumada H, et al. Hepatology 2014; 59:

46 Selected IFN-free HCV treatments of interest in Asia-Pacific OBV/PTV/r + DSV ± RBV LDV/SOF ± RBV SOF + RBV DCV + ASV 46

47 SVR12 (%) SOF + RBV combined efficacy data from QUANTUM and study SVR24 rates 100 SOF + RBV 24 weeks QUANTUM and n N Overall GT1a GT1b No-cirrhosis Cirrhosis SOF Summary of Product Characteristics, (accessed May 2015). 47

48 Common AEs reported in 10% of subjects in any treatment arm with any HCV genotype Adverse Event, % SOF + RBV 12 weeks N=650 SOF + RBV 24 weeks N=250 Fatigue 38% 30% Headache 24% 30% Nausea 22% 13% Insomnia 15% 16% Pruritus 11% 27% Anemia 10% 6% Asthenia 6% 21% Diarrhea 9% 12% Irritability 10% 10% SOF USPI, (accessed May 2015). 48

49 Percentage of subjects reporting selected hematological parameters Hematological Parameters, % Hemoglobin <10 g/dl <8.5 g/dl Neutrophils 0.5 <0.75 x 10 9 /L <0.5 x10 9 /L Platelets 25 <50 x 10 9 /L <25 x 10 9 /L SOF + RBV 12 weeks N=647 8% 1% <1% <1% <1% 0 SOF + RBV 24 weeks N=250 6% <1% 0 0 1% 0 SOF USPI, (accessed May 2015). 49

50 Summary of EASL recommendations for the treatment of HCV GT1b treatmentnaive or -experienced patients with or without compensated cirrhosis HCV genotype OBV/PTV/r + DSV LDV/SOF SOF + RBV DCV + ASV Non cirrhotic, including treatment-naive or prior PegIFN + RBV treatment failures GT1b 12 weeks 8 12 weeks Not recommended Regimen not approved in Europe Compensated cirrhosis (Child-Pugh A), including treatment naive or prior PegIFN + RBV treatment failures GT1b + RBV 12 weeks + RBV for 12 weeks or RBV for 24 weeks or + RBV for 24 weeks if negative predictors of response Not recommended Regimen not approved in Europe EASL Recommendations on Treatment of Hepatitis C 2015; Available at (accessed May 2015). 50

51 Summary of EASL recommendations for the treatment of HCV GT1b treatmentnaive or -experienced patients with or without compensated cirrhosis HCV genotype OBV/PTV/r + DSV LDV/SOF SOF + RBV DCV + ASV Non cirrhotic, including treatment-naive or prior PegIFN + RBV treatment failures GT1b 12 weeks 8 12 For SOF the Not recommended weeks European Medicines Agency, Summary of Product Compensated cirrhosis (Child-Pugh A), including treatment naive or prior PegIFN + RBV treatment failures GT1b + RBV 12 weeks + RBV for 12 weeks or RBV for 24 weeks or + RBV for 24 weeks if negative predictors of response Characteristics, recommends SOF + RBV for 24 weeks only for patients ineligible or Not recommended intolerant to PegIFN Regimen not approved in Europe Regimen not approved in Europe EASL Recommendations on Treatment of Hepatitis C 2015; Available at (accessed May 2015). 51

52 Summary of EASL recommendations for the treatment of HCV GT1b treatmentnaive or -experienced patients with or without compensated cirrhosis HCV genotype OBV/PTV/r + DSV LDV/SOF SOF + RBV DCV + ASV Non cirrhotic, including treatment-naive or prior PegIFN + RBV treatment failures GT1b GT1b 12 weeks + RBV 12 weeks 8 12 weeks + RBV for 12 weeks or RBV for 24 weeks or + RBV for 24 weeks if negative predictors of response Not recommended Not recommended In Regimen Japan not DCV+ approved ASV is in Europe recommended for 24 weeks in IFNineligible/intolerant + RBV Compensated cirrhosis (Child-Pugh A), including treatment naive or prior PegIFN treatment failures patients and nonresponders with or without compensated Regimen cirrhosis not approved in Europe EASL Recommendations on Treatment of Hepatitis C 2015; Available at (accessed May 2015); BMS press release, July 2015 (accessed May 2015); Available at 52

53 Summary HCV GT1b is the most prevalent genotype worldwide More than 56% of all HCV infections in China are due to HCV GT1b IFN-free regimens achieve high rates of SVR in treatment-naive and treatment-experienced HCV GT1 patients with and without cirrhosis SOF + RBV has lower rates of SVR compared to DAA combinations IFN-free regimens are well tolerated in treatment-naive and treatment-experienced HCV GT1 patients with and without cirrhosis Treatment duration and inclusion of RBV is based on the treatment regimen and patient population 53

54 IFN-free for HCV: Treatment of special patient profiles David Iser Date of Preparation: May 2015 PP--CN-0206

55 Special patient profiles HIV/HCV co-infection Renal disease DDIs 55

56 Special patient profiles HIV/HCV co-infection Renal disease DDIs 56

57 SVR12 (%) TURQUOISE-I: SVR12 rates in HIV/HCV co-infected patients treated with OBV/PTV/r + DSV + RBV OBV/PTV/r + DSV + RBV for 12 or 24 weeks in GT1 treatment-naive and -experienced patients, all with HIV/HCV co-infection HCV GT1, naive or experienced, (N=63)* OBV/PTV/r + DSV + RBV (n=31) OBV/PTV/r + DSV + RBV (n=32) Study weeks 20 0 n N weeks 24 weeks * Including 6 (19%) patients with cirrhosis (F4) in the 12 week arm and 6 (19%) patients with cirrhosis (F4) in the 24 week arm. DSV = dasabuvir; OBV = ombitasvir; PTV/r = paritaprevir/ritonavir. OBV/PTV/r + DSV + RBV Sulkowski MS, et al. JAMA 2015; 313:

58 SVR12 (%) TURQUOISE-I: high SVR12 rates in patients receiving either atazanavir or raltegravir Response in patients on HIV ART Reasons for non-response 12 weeks 24 weeks Atazanavir ART: 1 patient withdrew consent n N Atazanavir Raltegravir Raltegravir ART: 1 patient in the 12-week arm relapsed 1 patient in the 24-week arm experienced viral breakthrough 2 patients in the 24-week arm had recurrence of HCV believed to be due to re-infection ART = anti-retroviral therapy. Eron JJ, et al. J Int AIDS Soc. 2014; 17(Suppl 3):

59 TURQUOISE-I: adverse events and laboratory abnormalities in HIV/HCV co-infected patients treated with OBV/PTV/r + DSV + RBV Parameter, n (%) 12 weeks (n=31) 24 weeks (n=32) Any adverse event (AE) 28 (90) 28 (88) Any serious adverse event (SAE) 0 0 Any AE leading to discontinuation of study drug 0 0 Any severe adverse event 1 (3) 1 (3) AEs in 15% of patients in either arm Fatigue 18 (58) 12 (38) Insomnia 5 (16) 7 (22) Headache 6 (19) 4 (13) Nausea 5 (16) 6 (19) Hemoglobin, <10 8 g/dl 4 (13) 3 (9) Hemoglobin, <8 6.5 g/dl 0 0 Total bilirubin, >3 10X ULN 10 (32) 6 (19) Total bilirubin, >10X ULN 1 (3) 0 ALT, >5X ULN 0 0 AST, >5X ULN 0 1 (3) Sulkowski MS, et al. JAMA 2015; 313:

60 SVR12 (%) ION-4: LDV/SOF in HCV GT1 or 4 patients with HIV co-infection SVR12 rates Study design: GT1 and 4 with HIV/HCV co-infection* Efficacy results: GT1 and 4 with HIV/HCV co-infection LDV/SOF (N=335) Study 12 weeks n N Overall Naive Exp No cirrhosis Cirrhosis * Including 8 (2.4%) patient with GT4 and 67 (20%) patients with cirrhosis. Exp = experienced. Cooper E, et al. EASL-ILC 2015; Poster presentation P

61 ION-4: LDV/SOF in HCV GT1 or 4 patients with HIV co-infection adverse events Patients, n (%) LDV/SOF, 12 weeks (N=335) Headache 83 (25) Fatigue 71 (21) Diarrhea 36 (11) Nausea 33 (10) Arthralgia 22 (7) Upper respiratory tract infection 18 (5) Cooper E, et al. EASL-ILC 2015; Poster presentation P

62 ION-4: LDV/SOF in HCV GT1 or 4 patients with HIV co-infection overall safety summary Event, n (%) Stable CD4 counts throughout treatment and follow-up No patient had confirmed HIV virologic rebound LDV/SOF, 12 weeks (N=335) AE 257 (77) Grade 3 4 AE 14 (4) Serious AE 8 (2) * Treatment discontinuation due to AE 0 Death 1 (<1) Grade 3 4 laboratory abnormality 36 (11) SAEs in >1 patient were HCC (n=2) and portal vein thrombosis (n=2) in patients with cirrhosis; confirmed IV drug user developed Staphylococcus aureus sepsis, endocarditis with associated embolic brain abscesses and multi-organ system failure. Cooper E, et al. EASL-ILC 2015; Poster presentation P

63 SVR12 (%) Randomise 2:1 ALLY-2: DCV + SOF in GT1 6 patients with HIV/HCV co-infection ALLY-2: HCV GT1 treatment-naive and -experienced patients with HIV co-infection* HCV treatment naive DCV + SOF (n=101) Genotype HCV treatment naive DCV + SOF (n=50) 60 HCV treatment experienced DCV + SOF (n=52) Study weeks * Including 9 (8.9%) patients with cirrhosis in the 12 week naive arm, 5 (10.0%) patients with cirrhosis in the 8 week naive arm and 15 (28.8%) patients with cirrhosis in the 12 week experienced arm n N Naive 12 weeks Naive 8 weeks Experienced 12 weeks Wyles DL, et al. EASL-ILC 2015; Poster presentation LP01. 63

64 ALLY-2: DCV + SOF in GT1 6 patients with HIV/HCV co-infection safety summary Event, n (%) Treatment-naive 12 weeks (n=101) Treatment-naive 8 weeks (n=50) Treatment-experienced 12 weeks (n=52) AE 74 (73.3) 29 (58.0) 37 (71.2) Serious AEs a 1 (1.0) 0 3 (5.8) Death b 0 1 (2.0) 0 Grade 3-4 AEs 2 (2.0) 2 (4.0) 4 (7.7) Discontinuations for AEs Common AEs on treatment ( 10% in any treatment group) Fatigue Nausea Headache Dirrhoea 19 (18.8) 14 ( (11.9) 11 (10.9) Treatment-emergent grade 3 4 laboratory abnormalities c INR 2.1xULN AST 5.1xULN Total bilirubin 2.6xULN d Lipase 3.1xULN e 1 (1) 0 5 (5.0) 5 (5.0) 5 (10.0) 4 (8.0) 3 (6.0) 1 (2.0) 0 1 (2.0) 1 (2.0) 1 (2.0) 10 (19.2) 8 (15.4) 8 (15.4) 3 (5.8) 1 (1.9) 0 2 (3.8) 1 (1.9) a SAEs: Priapism, chest pain/presyncope, drug abuse/pulmonary embolism, hypertensive crisis/syncope (all non-related) b Includes pretreatment, on-treatment and during posttreatment follow-up: 52 year old male with cardiac arrest at posttreatment week 4, unrelated to study therapy c No grade 3 4 ALT elevations were detected; all grade 3 4 laboratory abnormalities are listed d All patients were receiving concomitant atazanavir-ritonavir e Transient hyperlipasemia without reported pancreatitis Wyles DL, et al. EASL-ILC 2015; Poster presentation LP01. 64

65 EASL Recommendations for the treatment of patients with HIV/HCV co-infection The same IFN-free treatment regimens can be used in HIV-coinfected patients as in patients without HIV infection, as the virological results of therapy are identical Notwithstanding the respective costs of these options, IFN-free regimens are the best options when available in HIV/HCV-infected patients without cirrhosis or with compensated (Child-Pugh A) or decompensated (Child-Pugh B or C) cirrhosis, because of their virological efficacy, ease of use and tolerability Treatment alteration or dose adjustments may be required due to the potential of DDIs with HIV anti-retrovirals EASL Recommendations on Treatment of Hepatitis C 2015; Available at (accessed May 2015). 65

66 Special patient profiles HIV/HCV co-infection Renal disease DDIs 66

67 RUBY-I: Ongoing study in HCV infected patients with advanced renal disease treated with OBV/PTV/r + DSV ± RBV design Open-label Treatment SVR4 SVR12 GT1a OBV/PTV/r + DSV + RBV GT1b OBV/PTV/r + DSV Day 1 Week 12 Week 24 For GT1a: RBV 200 mg QD For GT1b: No RBV Pockros PJ, et al. EASL-ILC 2015; Oral presentation L01. 67

68 RUBY-I: Ongoing study in HCV infected patients with advanced renal disease treated with OBV/PTV/r + DSV ± RBV baseline demographics OBV/PTV/r + DSV ± RBV N=20 Male; n (%) 17 (85) Black; n (%) 14 (70) Age, years; median (range) 60 (49-69) Hispanic or Latino ethnicity; n(%) 3 (15) Degree of fibrosis*; n(%) F0-F1 10 (50) F2 6 (30) F3 4 (20) HCV viral load, log 10 (IU/mL); median (range) 6.6 ( ) GT1a; n (%) 13 (65) Hemoglobin, g/dl; mean (SD) 12.6 (1.8) CKD stage; n (%) 4 (egfr ml/min/1.73m 2 ) 7 (35) 5 (egfr <15 ml/min/1.73m 2 or requiring dialysis) 13 (65) On dialysis; n (%) 13 (65) egfr, ml/min/1.73m 2 ; median (range) 10.9 ( ) Creatinine, mg/dl; median (range) 6.2 ( ) *Biopsy: 5 patients; Fibroscan: 10 patients; Fibrotest: 5 patients. Pockros PJ, et al. EASL-ILC 2015; Oral presentation L01. 68

69 RUBY-I: Ongoing study in HCV infected patients with advanced renal disease treated with OBV/PTV/r + DSV ± RBV efficacy All patients completing treatment to date had virologic response Virologic response has been sustained in all patients who have reached post-treatment weeks 4 and 12 Time-point N Virologic Response (n) Percent End of Treatment Post-treatment Week Post-treatment Week Pockros PJ, et al. EASL-ILC 2015; Oral presentation L01. 69

70 RUBY-I: Ongoing study in HCV infected patients with advanced renal disease treated with OBV/PTV/r + DSV ± RBV safety GT1b OBV/PTV/r + DSV (N=7) GT1a OBV/PTV/r + DSV + RBV (N=13) Event * (experienced by 2 or more patients), n Anemia 0 8 Fatigue 2 4 Diarrhea 1 4 Nausea 0 5 Dizziness 1 2 Headache 0 3 Decreased appetite 0 2 Irritability 0 2 Edema peripheral 1 1 Weight decreased 0 2 Most adverse events were mild or moderate with no study drug discontinuations No treatment-related SAEs (2 patients with SAEs: diskitis; ileus and respiratory failure) No clinically significant changes in markers of liver or kidney function * Adverse event as reported by investigator. Pockros PJ, et al. EASL-ILC 2015; Oral presentation L01. 70

71 Renal 3 small studies presented at EASL with SOF/SMV P0802, Nazario: Safety and efficacy of SOF + SMV without RBV in HCV GT1-infected patients with end-stage renal disease or GFR <30 ml/min P0878, Czul: First RBV-free SOF + SMV treatment of HCV GT1 patients with severe renal impairment (GFR <30 ml/min or dialysis) LP42, Lin: Safety and efficacy of novel antivirals in kidney transplant recipients with chronic HCV infection Study Patient Population N Regimen SVR12 Nazario et al GT1, ESRD on hemodialysis or with GFR <30 ml/min 17 SOF (400 mg QD) + SMV x 12 weeks 100% (11/11) Czul et al GT1, ESRD on hemodialysis or with GFR <15 ml/min 19 SOF (400 mg QOD) + SMV x 12 weeks SOF (200 mg QD) + SMV x weeks 88% (14/16) Lin et al GT1 or GT2, renal transplant recipients 15 SOF-based regimens (SOF + SMV, SOF + SMV + RBV, SOF + RBV, SOF/LDV) 85% (11/13) Nazario HE, et al. EASL-ILC 2015; Poster presentation P0802; Czul F, et al. EASL-ILC; Poster presentation P0878; Lin MV, et al. EASL-ILC; Poster presentation LP42. 71

72 Real world data: HCV GT1/3 naive and experienced with renal insufficiency SOF-containing regimens Dichotomous = n (%) Continuous = mean (range) egfr 30 n=19 egfr n=63 egfr n=168 SOF not recommended in patients with egfr <30 ml/min egfr >60 n=1643 Female 14 (74) 29 (46) 77 (46) 570 (35) Age 65 years 5 (26) 18 (29) 55 (33) 292 (18) Race White Black or African American HCV genotype 1a 1b 3 15 (79) 4 (21) 45 (71) 12 (19) 140 (83) 13 (8) 1313 (80) 204 (12) 8 (42) 4 (21) 0 (0) 30 (48) 11 (18) 4 (6) 69 (41) 34 (20) 13 (8) 738 (45) 324 (20) 162 (10) Prior HCV Tx 11 (58) 35 (56) 92 (55) 861 (52) Prior PI Treatment failure 1 (5) 5 (8) 13 (8) 163 (10) Cirrhosis History of decompensation MELD 10 8 (42) 6 (32) 5 (26) 43 (68) 30 (48) 26 (41) 95 (57) 55 (33) 33 (20) 844 (51) 380 (23) 227 (14) Liver transplant 7 (37) 34 (54) 57 (34) 136 (8) Kidney transplant 3 (16) 5 (8) 9 (5) 12 (1) Albumin (g/dl) 3.6 ( ) 3.7 ( ) 3.8 (2.0 5) 3.9 (1.2 5) Saxena V, et al. EASL-ILC 2015; Poster presentation LP08. 72

73 SVR12 (%) Real world data: HCV GT1/3 naive and experienced with renal insufficiency SOF-containing regimens SOF + PegRBV SOF + RBV SOF + SMV SOF + SMV + RBV egfr 30 2 (11%) 1 (5%) 5 (26%) Treatment regimen by baseline egfr egfr (19%) 4 (6%) 15 (24%) egfr (10%) 15 (9%) 58 (35%) egfr > (11%) 314 (19%) 618 (38%) 525 (32%) 11 (58%) 22 (51%) 79 (47%) SVR12 by baseline egfr and by treatment regimen egfr 30 egfr egfr egfr >60 Saxena V, et al. EASL-ILC 2015; Poster presentation LP08. 73

74 Real world data: HCV GT1/3 naive and experienced with renal insufficiency SOF-containing regimens Dichotomous = n (%) Continuous = mean (range) Safety outcomes by baseline egfr egfr 30 n=17 egfr n=56 egfr n=157 egfr >60 n=1559 Common AEs Fatigue 3 (18) 19 (34) 56 (36) 543 (35) Headache 1 (5) 9 (16) 19 (12) 274 (18) Nausea 3 (18) 8 (14) 33 (21) 247 (16) Anemia AE 6 (35) 16 (29) 37 (24) 246 (16) Required transfusion (s) 2 (12) 5 (9) 3 (2) 31 (2) EPO start of treatment 1 (6) 8 (14) 14 (9) 50 (3) RBV Reduction in RBV due to 3 (38) 8 (30) 33 (42) 185 (19) anemia RBV discontinuation 0 (0) 4 (15) 1 (1) 12 (1) Worsening renal function 5 (29) 6 (11) 4 (3) 14 (1) Renal or urinary system AEs 5 (29) 6 (11) 13 (8) 84 (5) Any serious AEs 3 (18) 13 (23) 8 (5) 100 (6) Cardiac serious AEs 1 (6) 2 (4) 8 (5) 53 (3) Early treatment 1 (6) 4 (6) 6 (4) 68 (4) discontinuation Early treatment 1 (6) 2 (3) 2 (2) 39 (3) discontinuation AE Death 1 (6) 0 (0) 2 (1) 10 (1) Saxena V, et al. EASL-ILC 2015; Poster presentation LP08. 74

75 Recommended EASL regimens for the treatment of patients with renal impairment Haemodialysis patients An IFN-free and if possible, RBV-free regimen is recommended for 12 weeks (non-cirrhotics) or 24 weeks (cirrhotics) Severe renal disease SMV, DCV, and OBV/PTV/r + DSV are cleared by hepatic metabolism and can be used in patients with severe renal disease End stage renal disease or egfr <30mL/min/1.73m 2 ) SOF should NOT be administered to patients with egfr <30mL/min/1.73m 2 or with end-stage renal disease until more data are available Safety and efficacy data is limited in patients with severe renal disease. Drugs should be used with extreme caution in this population and only in extreme life-threatening situations for patients on haemodialysis egfr= estimated glomerular filtration rate. EASL Recommendations on Treatment of Hepatitis C 2015; Available at (accessed May 2015). 75

76 Special patient profiles HIV/HCV co-infection Renal disease DDIs 76

77 So, in the IFN-free era SVR rates are high with the current and emerging therapies however, DDIs between HCV drugs and other concomitant medications need to be considered when making treatment decisions (Accessed May 2015). 77

78 DDIs should be considered for other co-medications Calcium channel blockers Antiarrhythmics e.g. digoxin, amiodarone Statins HIV antivirals e.g. tenofovir, lopinavir/ ritonavir PPIs/ acid-reducing agents Corticosteroids Diuretics Antifungals Herbal supplements Immunosuppressants Sedatives/ hypnotics 78

79 DDIs should be considered for other co-medications Calcium channel blockers Antiarrhythmics e.g. digoxin, amiodarone Statins HIV antivirals e.g. tenofovir, lopinavir/ ritonavir PPIs/ acid-reducing agents Corticosteroids Diuretics Antifungals Herbal supplements Immunosuppressants Sedatives/ hypnotics 79

80 DDIs with HIV anti-retrovirals; the example of tenofovir Tenofovir containing regimens co-administered with: OBV/PTV/r + DSV ± RBV LDV/SOF SMV No dose adjustments of tenofovir are necessary Tenofovir LDV/SOF in combination with a HIV regimen containing tenofovir disoproxil fumarate and a pharmacokinetic enhancer (ritonavir or cobicistat) should be used with caution, with frequent renal monitoring No dose adjustments of tenofovir are required OBV/PTV/r Summary of Product Characteristics [Accessed May 2015]; LDV/SOF Summary of Product Characteristics [Accessed May 2015]; SMV Summary of Product Characteristics [Accessed May 2015]. 80

81 DDIs with HIV anti-retrovirals; the example of lopinavir (HIV protease inhibitor) Lopinavir/ritonavir co-administered with: OBV/PTV/r + DSV ± RBV LDV/SOF SMV PTV Not studied Not studied: expected to SMV Co-administration is contraindicated The safety of regimens with concomitant administration of lopinavir/ritonavir have not been established It is not recommended to co-administer SMV with any HIV PI, with or without ritonavir Co-administration is not recommended OBV/PTV/r Summary of Product Characteristics [Accessed May 2015]; LDV/SOF Summary of Product Characteristics [Accessed May 2015]; SMV Summary of Product Characteristics [Accessed May 2015]. 81

82 DDIs with PPIs (acid-reducing agents); the example of omeprazole Drugs that modulate gastric acid levels are often prescribed to patients with advanced liver disease to reduce the risk of gastrointestinal bleeding Patients receiving omeprazole in combination with: OBV/PTV/r + DSV ± RBV LDV/SOF SMV If clinically indicated higher doses of omeprazole should be used Proton pump inhibitor doses comparable to omeprazole 20 mg can be administered Proton pump inhibitors should not be taken immediately before LDV/SOF No dose adjustments of omeprazole are required OBV/PTV/r Summary of Product Characteristics [Accessed May 2015]; LDV/SOF Summary of Product Characteristics [Accessed May 2015]; SMV Summary of Product Characteristics [Accessed May 2015]. 82

83 DDIs should be considered for other co-medications Antiarrhythmics e.g. digoxin, Amiodarone Statins PPIs/ acid-reducing agents There is a need for robust data from DDI studies and clinical Calcium channel trials to support the use of concomitant Corticosteroids blockers medication with anti-hcv therapy HIV antivirals e.g. Tenofovir, Lopinavir/ Ritonavir Diuretics Antifungals Herbal supplements Immunosuppressants Sedatives/ hypnotics 83

84 EASL recommendations for monitoring DDIs The efficacy and toxicity of concurrent drugs given for comorbidities and potential DDIs should be monitored during treatment When possible, an interacting co-medication should be stopped during treatment or switched to an alternative drug with less interaction potential EASL Recommendations on Treatment of Hepatitis C 2015; Available at (accessed May 2015). 84

85 Summary HIV/HCV co-infection Renal disease DDIs Patients co-infected with HIV/HCV have SVR rates comparable to HCV mono-infected patients and can be treated the same as HCV monoinfected patients Patients with end stage renal disease remain a challenging patient population Patients with egfr <30 ml/min should not receive SOF Promising new data is emerging for OBV/PTV/r + DSV ± RBV in patients with advanced kidney disease Drug interactions need to be considered for all patients Robust data from DDI studies and clinical trials are needed Resources such as the hep-druginteractions website are available to help guide decision making 85