Disclosures. I have given sponsored lectures for the following pharmaceutical companies: Gilead, Abbvie and MSD. I own shares of Gilead Sciences.

Transcription

1 Disclosures I have given sponsored lectures for the following pharmaceutical companies: Gilead, Abbvie and MSD. I own shares of Gilead Sciences.

2 Chronic Hepatitis C Prof CL Lai University Department of Medicine Queen Mary Hospital, Hong Kong

3 Epidemiology, esp Asia Pacific areas When and who to treat The Direct Acting Antivirals Treatment for renal failure patients

4 Epidemiology of HCV million people have chronic hepatitis C globally Annual mortality 500,000 WHO 2016

5 Epidemiology of HCV in the Asia-Pacific region Asia, Australia and Egypt Largest population of HCV infected persons ~ million adults are anti-hcv positive China alone has more HCV infected persons than all of Europe or the Americas High prevalence areas in Asia & Africa Especially high in Egypt (15%), Vietnam (6.1%) Pakistan (4.7%) and Taiwan (4.4%) Prevalence rises across age and peaks at age in Asia Sievert W, et al. Liver Int 2011;31 Suppl 2:61 80

6 Prevalence (%) HCV prevalence rises across age and peaks at age in Asia Asia Pacific Asia East Asia Southeast Asia Central Asia South High prevalence necessitates: Age group (years) More efforts in primary prevention (needle usage, transfusion services) Enforcement of early HCC screening and alcohol cessation Changes in treatment strategies for infected carriers *** Hanafiah KM, et al. Hepatology 2013;57:

7 HCV prevalence in Asia Pacific Country Prevalence (%) Vietnam 6.1 Pakistan 5.31 Taiwan 4.4 Mainland China 3.2 Cambodia 2.3 Thailand 2.2 Indonesia 2.1 Korea 1.3 Laos 1.1 Myanmar 0.95 India 0.87 Japan 0.49 Philippines Singapore 0.37 Hong Kong 0.08 Nguyen LH, Nguyen MH. Aliment Pharmacol Ther 2013;37:921 36

8 HCV prevalence and genotype in Asia, Australia and Egypt GT1 GT2 GT3 GT4 GT5 GT6 GT 1: Australia, China, Taiwan and North Asia GT 2: Japan, Korea and Taiwan GT 3: India and Pakistan GT 4: Middle Eastern countries such as Egypt, Saudi Arabia and Syria GT 5: rare in Asia; small number in Syria GT 6: Vietnam and other Southeast Asia Sievert W, et al. Liver Int 2011;31 Suppl 2:61 80

9 HCV in China Incidence 1-1.9% ~13 million people, more than the whole of Europe and the Americas Genotype distribution: GT 1: 67.6% GT 2: 14.4% GT 3: 4.3% GT 6: 13% Others: 0.7% Sievert W, et al. Liver Int 2011;31 Suppl 2:61 80

10 Limitations of epidemiological data Reliable reports on new infections are rare, dependent on the size of the population Considerable variability in the type and quality of prevalence studies among the countries Australia, Egypt and Taiwan have large population studies, while data from other countries, like India and China, only have studies in subgroups Over-representation among men in studies from Egypt, Saudi Arabia and Pakistan make estimates for women less certain Accurate data from individual countries is crucial to developing effective preventive measures Sievert W, et al. Liver Int 2011;31 Suppl 2:61 80

11 Wide variability in prevalence due to variety of risk factors: Egypt Previous use of IV injections for schistosomiasis Pakistan Public shaving of beards and other body hair Tattooing, sexually transmitted HCV infection, acupuncture Japan blood transfusion (before screening), resulting in the bulk of HCV infection in older patients Australia Intravenous drug use most common route Sievert W, et al. Liver Int 2011;31 Suppl 2:61 80

12 Risk factors in HK Study: Incidence % from blood transfusion services ~50% blood transfusion (prior to HCV screening from 1 July 1991) ~25% IV drug users Leung N et al. Intervirology 2006;49.

13 Genotype 6

14 Focus on genotype 6 First identified in SE Asia: 212 HCV blood donors from HK: GT 1a: 6.2% GT 1b: 58.8% GT 2a: 1.4% GT 2b: 1.4% GT 3a: 1.9% GT 6a: 27.0% Prescott LE et al. J Med Virol 1996; 50. Prescott LE et al. J Med Virol 1996;50:68 75

15 Focus on genotype 6 HCV genotype 6 is estimated to be as high as 50% in some regions of Southeast Asia Significantly more common in IV drug users and thalassemia major patients Chao DT et al. Aliment Pharmacol Ther 2011;34:286 96

16 Focus on genotype 6 GT 6 is unique for its extreme subtype diversity, currently 22 recognised subtypes from 6a to 6v Accurate diagnosis of GT 6 requires core sequencing assays or newer INNO-LiPA assays, as older line probe assays often mistaken as GT 1 Chao DT et al. Aliment Pharmacol Ther 2011;34:286 96

17 Phylogenetic relationships among hepatitis C genotypes and genotype 6 subtypes GT 6 shows great diversity with 22 subtypes Chao DT et al. Aliment Pharmacol Ther 2011;34:286 96

18 Genotype 6 prevalence in Southeast Asia As high as ~50% Author Country Prevalence, % Lao et al Hong Kong Nguyen et al Vietnam (south) 36 Kanistanon et al Thailand 18 Lwin et al Burma 49 Oh et al Korea 1.4 Al Namaani K, et al. Can J Gastroenterol 2013;27(1):e8 e12

19 Very high prevalence of genotype 6 variants in southern Vietnam Genotypic distribution of HCV in Ho Chi Minh City, Vietnam 25 23,6 22 Number tested = , ,4 10 8, ,3 3,2 1,8 0,7 0,2 0,2 0,4 0,1 1,2 1,5 0,5 1 0,1 0,1 0,7 1a 1b 1e 2a 2c 2i 2j 2k 6a 6c 6e 6f 6h 6k 6l 6n 6o 6p 6r 6t 256 (30.4%) 128 (15.2%) 458 (54.4%) Pham V, et al. Jpn J Infect Dis. 2011; 64(6):537 39

20 Summary Asia-Pacific region has broad representation of most of the HCV genotypes Need for: Education to prevent spread in those at risk Effective screening to accurately diagnose people who are affected **Access to simple and effective pangenotypic treatment strategies that can be applied across the region

21 HCV Treatment

22 HCV Treatment Potential sites of targets for DAAs: 1. Viral entry into hepatocytes 2. HCV replication with 10 viral proteins 3. Viral assembly and release 4. Host targets on host factors required for replication Rice CM. Topics in Antiviral Med, 2011; 19: 117

23 HCV Treatment Potential sites of targets for DAAs: 1. Viral entry into hepatocytes 2. HCV replication with 10 viral proteins 3. Viral assembly and release 4. Host targets on host factors required for replication Rice CM. Topics in Antiviral Med, 2011; 19: 117

24 Direct Acting Antivirals (DAAs) Protease inhibitors - grazoprevir, paritaprevir, simeprevir, asunaprevir RNA polymerase (NS5B) inhibitor - sofosbuvir, dasabuvir NS5A inhibitors - velpatasvir, ledipasvir, elbasvir, ombitasvir, daclatasvir

25 The Changes in SVR % in HCV Patients 6 IFN 6 m 1986

26 The Changes in SVR % in HCV Patients IFN 6 m IFN + RBV 12 m PEG 12 m PEG + RBV 12 m PI + PEG + RVB 12 m SOF + PEG + RVB 12 wk Pangenotypic 12 wk ORAL DAAs for G1 12 wk

27 Who to Treat and With What Drugs

28 AASLD and EASL Guidelines 2016 The Goal - to reduce all-cause mortality, including end-stage disease and HCC through CURE as evidenced by SVR

29 AASLD and EASL Guidelines 2016 The Goal - proven to be effective: - meta-analysis of 6 studies (n = 443) 137 pts achieved SVR 53% had cirrhosis regression risk ratio of regression 2.69 Aktar E et al. Liver International 2015; Late relapse rate over 4-5 yrs of FU 1-2% - SVR associated with reduction in HCC and liver-related mortality (RR ; ) Smith-Palmer J et al. BMC Infect Dis 2015; 15.

30 AASLD and EASL Guidelines 2016 Who to treat? - ALL patients with chronic HCV, except those with short life expectancy due to non-hcv disease(s) - Patients with end-stage liver disease due to HCV should still be treated

31 AASLD and EASL Guidelines 2016 Pre-treatment assessment - evaluation of fibrosis, by non-invasive methods, e.g., Fibroscan, non-invasive markers (APR index). For treatment strategy and screening for HCC

32 3 Recommended Licensed Agents Harvoni: ledipasvir (90 mg)+ sofosbuvir (400 mg) * licensed by FDA on 10 Oct viekira pak: - paritaprevir (PI) + ritonavir (P450 inhibitor) + ombitasvir (NS5A inhibitor) - dasabuvir (NS5B inhibitor) * licensed by FDA on 19 Dec If patient is on other drugs, check:

33 3 Recommended Licensed Agents Zapatier: grazoprevir (PI) + elbasvir (NS5A inhibitor) Grazoprevir 100mg Elbasvir 50 mg

34 3 Recommended Licensed Agents Zapatier: grazoprevir (PI) + elbasvir (NS5A inhibitor) Grazoprevir 100mg Elbasvir 50 mg * licensed by FDA on 28 Jan 2016 Screening for resistance-associated variants (RAV) recommended before treatment.

35 Recommended Treatment for GT1 a & b Harvoni (ledipasvir + sofosbuvir ) viekira pak (paritaprevir + ritonavir + ombitasvir, and dasabuvir ) Zapatier (grazoprevir + elbasvir) 12 weeks 12 weeks 12 weeks (without RAV) 16 weeks (with RAV for GT!a) Recommended Treatment for GT4 Same 3 combinations, all for 12 weeks

36 Recommended Treatment for GT2 Sofosbuvir + ribavirin (RBV) Daclatasvir + sofosbuvir 12 weeks 12 weeks Recommended Treatment for GT3 Daclatasvir + sofosbuvir Sofosbuvir + RBV + PEG IFN 12 weeks 12 weeks Recommended Treatment for GT5/6 Harvoni (ledipasvir + sofosbuvir ) 12 weeks

37 As-Yet-Unlicensed Pangenotypic Drug

38 Sofosbuvir + Velpatasvir SOF Nucleotide polymerase inhibitor Sofosbuvir (SOF) Potent antiviral activity against HCV GT 1 6 Once-daily, oral, 400-mg tablet SOF VEL NS5A inhibitor VEL Velpatasvir (VEL; GS-5816) Picomolar potency against GT 1 6 Second generation inhibitor with improved resistance profile SOF/VEL FDC Once daily, oral, FDC (400/100 mg)

39 Velpatasvir (VEL) HCV NS5A inhibitor Potent pangenotypic antiviral activity High barrier to resistance in vitro EC 50 Values in HCV Genotype 1-6 Replicons, nm 1a 1b 2a 2a* 2b 3a 4a 5a 6a 6e Cheng, EASL, 2013, Poster #1191

40 Velpatasvir (VEL) HCV NS5A inhibitor Potent pangenotypic antiviral activity High barrier to resistance in vitro EC 50 Values in HCV Genotype 1-6 Replicons, nm 1a 1b 2a 2a* 2b 3a 4a 5a 6a 6e Cheng, EASL, 2013, Poster #1191

41 VEL: Activity Against NS5A RAVs (resistance-associated variants) EC 50 versus genotype 1 RAPs and RAVs EC 50 versus genotypes 2 and 3 RAPs and RAVs Cheng, EASL, 2013, Poster #1191

42 VEL: Activity against other DAA RAVS RAVs of other DAAs including NS3/4a protease inhibitor RAV R155K or D1687, and NS5B RAV S282T Cheng, EASL, 2013, Poster #1191

43 The ASTRAL Studies

44 Available at

45 Study Design: ASTRAL-1 Week 0 Week 12 Week 24 n=500 SOF/VEL SVR12 n=100 Placebo SVR12 5:1 randomization to SOF/VEL or placebo Stratified by HCV genotype and cirrhosis (presence/absence) GT 5 patients not randomized Conducted at 81 sites in US, Canada, UK, Germany, France, Italy, Belgium, and Hong Kong

46 Demographics: ASTRAL-1 Placebo n=116 SOF/VEL n=624 Mean age, y (range) 53 (25 74) 54 (18 82) Male, n (%) 68 (59) 374 (60) White, n (%) 90 (78) 493 (79) Mean BMI, kg/m 2 (range) 26 (18 40) 27 (17 57) US enrolled, n (%) 45 (39) 234 (38) Cirrhosis, n (%) 21 (18) 121 (19) Treatment experienced*, n (%) 33 (28) 201 (32) IL28B CC, n (%) 36 (31) 186 (30) Median HCV RNA, log 10 IU/mL (range) 6.4 ( ) 6.4 ( ) *Includes peg-ifn + RBV failures and PI + peg-ifn + RBV failures.

47 HCV Genotype Distribution: ASTRAL-1 Patients, n (%) Placebo n=116 SOF/VEL n=624 GT 1 65 (56) 328 (53) 1a 46 (40) 210 (34) 1b 19 (16) 118 (19) GT 2 21 (18) 104 (17) GT 4 22 (19) 116 (19) GT 5* 0 35 (6) GT 6 8 (7) 41 (7) *All enrolled to SOF/VEL group.

48 SVR12 (%) Results: SVR Total 1a 1b Genotype

49 SVR12 (%) Results: SVR12 by Genotype Total 1a 1b Genotype

50 SVR12 (%) Results: SVR12 by Genotype relapse 2 lost to follow-up 1 withdrew consent relapse 1 death Total 1a 1b Genotype

51 SVR12 (%) Results: SVR12 by Cirrhosis or Prior Treatment Total No Yes Naïve Experienced Cirrhosis Status Treatment History 51

52 Results: Resistance Analysis (1% cut-off) Total, n= % SVR12 359/359 58% No BL NS5A RAVs n=359 42% BL NS5A RAVs n=257 99% SVR12 255/257

53 Results: Safety A 55 year old white male died in his sleep 8 days Placebo after completing SOF/VEL treatment. The death was assessed Patients, as unrelated n (%) to study n=116 drug by the investigator n=624 AE 89 (77) 485 (78) Grade 3 4 AE 1 (<1) 18 (3) Adverse Events Serious AE 0 15 (2) D/C due to AE 2 (2) 1 (<1) Death 0 1 (<1) Laboratory Abnormalities Grade (12) 45 (7) Hb <10 g/dl 0 2 (<1) Hb <8.5 g/dl year-old white male died in sleep 8 days after completing treatment; death assessed as unrelated to study drug by investigator

54 Conclusions: ASTRAL-1 SOF/VEL for 12 weeks resulted in a 99% SVR12 rate in patients with HCV GT 1, 2, 4, 5, or 6 infection 99% SVR12 rate in patients with cirrhosis 99% SVR12 rate in patients with prior treatment failure Presence of baseline NS5A RAVs did not impact SVR12 SOF/VEL for 12 weeks had a safety profile similar to that of placebo treatment

55 ASTRAL-3 Study

56 Study Design: ASTRAL-3 Week n=250 SOF/VEL SVR12 n=250 SOF + RBV SVR12 1:1 randomization to SOF/VEL or SOF + RBV Stratified by prior treatment (TN/TE) and cirrhosis (presence/absence) Conducted at 76 sites in US, Canada, UK, Germany, France, Italy, Australia, and New Zealand

57 SVR12 (%) Results: SVR12 p < / /275 SOF/VEL 12 Weeks SOF + RBV 24 Weeks

58 SVR12 (%) SVR12 by Cirrhosis or Treatment History SOF/VEL SOF + RBV No Yes Naïve Experienced Cirrhosis Status Treatment History

59 Results: Resistance Analysis Total, n=274 97% SVR12 84% No BL NS5A RAVs n=231 16% BL NS5A RAVs n=43 88% SVR12 225/231 38/43 SVR12 was 84% (21/25) in patients with Y93H 59

60 Conclusions: ASTRAL-3 SOF/VEL for 12 weeks resulted in a 95% SVR12 rate in patients with HCV GT 3 infection Statistically superior to SOF + RBV for 24 weeks (p <0.001) 91% SVR12 rate in patients with cirrhosis SOF/VEL was well tolerated and, compared with SOF + RBV, lacked toxicities commonly associated with RBV

61 SVR12 (%) Pooled Data ASTRAL 1,2,3 SOF/VEL SVR for 12 Weeks GT 1 GT 2 GT 3 GT 4 GT 5 GT 6 Total

62 ASTRAL- 4 Study

63 SOF/VEL ± RBV in Decompensated Liver Disease: GT 1, 2, 3, 4, 6 Week n=90 n=87 n=90 SOF/VEL SOF/VEL + RBV SOF/VEL RBV was weight-based (1000 or 1200 mg daily) Patients SOF/VEL 12 weeks n=90 SOF/VEL+RBV 12 weeks n=87 SOF/VEL 24 weeks n=90 Median MELD (range) 10 (6 24) 10 (6 18) 11 (6 19) MELD < 15, n (%) 86 (96) 83 (95) 85 (84) CTP B, n (%) 86 (96) 77 (89) 77 (86) Ascites, n (%) 74 (82) 65 (75) 75 (83) Encephalopathy, n (%) 52 (58) 54 (62) 59 (66)

64

65 Patients (%) Patients (%) MELD Change from Baseline to Follow Up Week % Improved 27% Worsened Baseline MELD <15 n=208 Change in MELD n= <1 < % Improved 8% Worsened 27 Baseline MELD >15 n= n= Change in MELD

66 Treatment for HCV Patients With Renal Impairment

67 Patients with Creatinine Cl ml/min No dose adjustment required with recommended agents Patients with Creatinine Cl <30 ml/min For GT 1a, 1b and 4: - viekira pak 12 weeks - Zapatier 12 weeks

68 Conclusions

69 Conclusions A substantial proportion of the world s HCV population resides in Asia Public education in prevention and diagnosis, AND greater availability of DAA treatment are urgently required

70 Conclusions SVR has improved from 6% in 1986 to % in 2016 Many DAA combinations can cure genotype 1 and 4 in 12 (-16) weeks Pangenotypic DAA will soon be available