Management of HCV Tawesak Tanwandee

Transcription

1 Management of HCV 2016 Tawesak Tanwandee

2 Topics Burden of HCV in our countries Natural history and unmet need for HCV treatment Current treatment as for 2016 Conclusion

3 Evolution from HCV infection to HCC.

4 Natural History of Chronic HCV: Liver Fibrosis Progression 20 Years After Infection New Perspective Female gender 1, 2 Younger at age of infection 1, 2 No fibrosis 3 Up to 20% 1 Healthy 1, 2 No confounding comorbidities 1, 2 Chronic HCV 20 Years Postinfection Cirrhosis Male gender 1, 2 Older at age of infection (>40 years) 1-3 History of/or current alcohol abuse 1-3 Fibrosis 2, 3 Up to 70% 1 Obesity 3 Steatosis 3, 4 Metabolic syndrome/ir 2 Diabetes mellitus 1 HIV co-infection 1, 2 IR=insulin resistance. Slide courtesy of Fred Poordad, MD. 1. Marcellin P, et al. Hepatology. 2002;36:S47-S Massard J, et al. J Hepatol. 2006;44(1 suppl):s19-s2. 3. Collier JD, et al. J Viral Hepat. 2005;12: Cholet F, et al. Gastroenterol Clin Biol. 2004;28:

5 Factors Impacting HCV Treatment Response: Before 2015 Viral Factors Host Factors Baseline viral load Age Gender Race HCV genotypes Prior treatment Genetics (IL-28, IP10) Cirrhosis HIV/HCV co-infection Obesity Transplant Hepatic decompensation DAA baseline resistance Diabetes Pharmacokinetics & Drug-Drug interaction HBV/HCV co-infection

6 Factors Impacting HCV Treatment Response: After 2015 Viral Factors Host Factors HCV genotype Cirrhosis Post OLT status Post-treatment DAA RAVs Pharmacokinetics & Drug-Drug interaction

7 Distribution of HCV genotypes in Asean Wasitthankasem R, et al. PLoS One 2015

8 Proportion of patients HCV genotype 3 is associated with accelerated fibrosis progression Markov modeling of biopsies and genotypes in HCV-infected patients in Switzerland (N=1189) Progression to fibrosis stage F3 HCV genotype 1 or 4 (n=630) HCV genotype 2 (n=92) P=0.4 versus genotype 1 or 4 HCV genotype 3 (n=342) P<0.001 versus genotype 1 or Years infected Bochud P-Y et al. J Hepatol 2009;51:

9 HCV genotype 3 is associated with increased risk of late-stage liver morbidities Observational cohort study of 128,769 patients from the Veterans Affairs HCV Clinical Registry, which compiled electronic medical records data from 1999 Cirrhosis Decompensated cirrhosis Liver-related hospitalization Genotype 1 Genotype 2 Genotype 3 Other HCC Hazard ratio McCombs J et al. JAMA Intern Med 2014;174:

10 HCC-free survival HCV genotype 3 is associated with increased risk of HCC in patients with cirrhosis Retrospective study of 353 cirrhotic HCV patients in France, prospectively followed and screened for HCC between 1994 and P=0.001 Genotype 4 Genotype 2 Genotype 1 Genotype Age (years) Nkontchou G t al. J Viral Hepat 2011;18:e516 e522.

11 HCC incidence (%) Achieving SVR is protective against HCC development Retrospective analysis of 1371 HCV-treated patients with a median follow-up of 10 years: all patients Did not achieve SVR Achieved SVR 10 P< Time (years) Purevsambuu T et al. J Hepatol 2014;60:S52 abstract 0125

12 HCC incidence (%) SVR significantly reduces risk of developing HCC even in cirrhotic patients Retrospective analysis of 1371 HCV-treated patients with a median follow-up of 10 years: patients with fibrosis stage F4 30 F4, did not achieve SVR F4, achieved SVR 20 P= Time (years) Purevsambuu T et al. J Hepatol 2014;60:S52 abstract 0125

13 Overall survival (%) Patients who achieve SVR show comparable survival to the general population Cumulative occurrence rates in 530 IFN-treated patients with advanced fibrosis / cirrhosis followed-up for a median of 8.4 years 30 Matched general population % 95% CI ; P= Did not achieve SVR (n=405) Achieved SVR (n=192)* 74.0% 95% CI ; P< Time (years) *204 patients with initial non-svr were retreated and 67 of them achieved SVR after a median of 5.8 years of follow-up. Van der Meer AJ et al. AASLD 2013: poster 1425

14 Goal of Therapy The goal of therapy is to cure HCV infection to prevent hepatic cirrhosis, decompensation of cirrhosis, HCC, severe extra-hepatic manifestations and death The endpoint of therapy is undetectable HCV RNA in a sensitive assay (LOD <15 IU/mL) 12 weeks (SVR12) and/or 24 weeks (SVR24) after the end of treatment Undetectable HCV core antigen 12 weeks (SVR12) and/or 24 weeks (SVR24) after the end of treatment is an alternative endpoint of therapy in patients with detectable HCV core antigen prior to therapy if HCV RNA assays are not available or not affordable EASL 2016

15 Goal of HCV Therapy The goal of treatment of HCV-infected persons is to: reduce all-cause mortality and liver-related health adverse consequences, including end-stage liver disease and hepatocellular carcinoma, by the achievement of virologic cure as evidenced by a sustained virologic response Recommendations for Testing, Managing, and Treating Hepatitis C ( October 2015

16 Treatment is recommended for all patients with chronic HCV infection F0 F1 F2 F3 F4 Decompensate d cirrhosis Treatment should be considered for all patients (treatment-naïve and -experienced) with compensated disease 1,2 1. EASL Recommendations on Treatment of Hepatitis C AASLD and IDSA. Recommendations for Testing Managing and Treating Hepatitis C. 2015

17 HCV Treatment Priority may be useful in resource-limited setting Highest Priority Highest risk for severe complications Advanced fibrosis with compensated cirrhosis (Metavir F3 or F4) Liver transplant recipients Type 2 or 3 essential mixed cryoglobulinemia with end-organ manifestations (eg, vasculitis) Proteinuria, nephrotic syndrome, or MPGN High Priority High risk for complications Fibrosis (Metavir F2) HIV-1 coinfection HBV coinfection Other coexistent liver disease (eg, NASH) Debilitating Fatigue Type 2 Diabetes mellitus (insulin resistant) Porphyria cutanea tarda

18 Universal versus Prioritized HCV Therapy Medical Justification Ethical Justification Administrative Burden Cost Patient/Public Anxiety Pharmaceutical Profit

19 Trends in CHC Treatment in Asia Pacific Countries Sofosbuvir+ Lediprasvir Daclatasvir + Sofosbuvir IFN monotherapy Peg-IFN monotherapy Telaprevir + Peg-IFN + RBV Sofosbuvir+ Peg-IFN + RBV IFN+ RBV Peg-IFN + RBV Boceprevir + Peg-IFN + RBV Simeprevir + Peg-IFN + RBV Adapted from Omata M, et al. Hepatol Int. 2015

20 No role of Peg/Ribavirin 48 weeks in HCV genotype 1 even SVR is higher in Asia SVR in HCV1 patients West: HCV 1 East: HCV 1 East: HCV 1, LVL and RVR (24w) Fried et al Hadzyannis et al Manns et al IDEAL Yu ML, Chuang WL. J Gastroenterol Hepatol 2009;24: Yu et al, Taiwan Kuboki et al, Japan Lee et al, Taiwan Liu et al, Taiwan Liu et al, Taiwan Yu et al, Taiwan

21 Peg/Ribavirin 24 weeks may have role in HCV Genotype 2/3 depending on cost effective West: HCV 2/3 East: HCV 2/3 East: HCV 2/3 and RVR Fried et al Hadzyannis et al Manns et al Yu et al, China Lee et al, Korea Liu et al, Taiwan Yu et al, Taiwan Yu et al, Taiwan Yu ML, Chuang WL. J Gastroenterol Hepatol 2009;24:

22 Multitargeted approach to HCV treatment based on the structure of the HCV protein Velpatasvir Adapted from Wells JT. Clinical Liver Disease 2015

23 Requirements for HCV Therapy SVR > 90% Toxicity Must haves Tolerability Short duration High barrier to resistance Helpful One size fits all: pangenotypic No drug drug interactions Low pill burden Nice bonus

24 SVR12 (%) Peg/RBV+Sofosbuvir 400 mg daily 12 wk: NEUTRINO Study n/n = 295/327 Overall 261/ /28 7/7 GT1 GT4 GT5, /273 43/54 No Cirrhosis Cirrhosis Lawitz E, et al. N Engl J Med. 2013

25 SVR12 (%) HCV Genotype 1 ION 1, 2, and 3: Sofosbuvir/Ledipasvir ± RBV in Tx-Naive Pts and Previous Failures Tx naive Previous Tx (incl PI) failures n/n = 0 211/ 212 S/L 211/ 217 S/L+R 212/ 217 S/L 215/ 217 S/L+R 102/ 109 S/L 107/ 111 S/L+R 108/ 109 S/L 110/ 111 S/L+R 202/ / / 216 S/L S/L+R S/L 12 Wks [1] 24 Wks [1] 12 Wks [2] 24 Wks [2] 8 Wks [3] 12 Wks [3] 8 wks adequate for noncirrhotic treatment-naive pts RBV provides no benefit No SOF resistance observed; most virologic failures have LDV resistance 1. Afdhal N, et al. N Engl J Med. 2014;370: Afdhal N, et al. N Engl J Med. 2014;370: Kowdley KV, et al. N Engl J Med. 2014;370:

26 Sofosbuvir + Daclatasvir in Tx-Naive Pts and PI Failures With GT1 HCV Infection Wk 1 Wk 12 Wk 24 SVR12, % n = 15 SOF SOF + DCV GT1 HCV Treatment Naive (N = 126) n = 14 SOF + DCV n = 15 n = 41 SOF + DCV SOF + DCV + RBV n = 41 SOF + DCV + RBV 95 GT1 HCV TVR/BOC Treatment Failures (N = 41) n = 21 SOF + DCV n = 20 SOF + DCV + RBV 95 Sulkowski MS, et al. N Engl J Med. 2014;370:

27 SVR12 (%) SVR12 (%) VALENCE: SVR12 With 12 or 24 Wks of SOF + RBV in GT2 and GT3 Pts GT 2 12-Wk Treatment (n = 73) GT 3 24-Wk Treatment (n = 250) n/n = 0 29/30 2/2 30/33 7/8 n/n = 0 86/92 12/13 87/ 27/45 Naive, Naive, Exp d Exp d, Naive, Naive, Exp d Exp d, Noncirrhotic Cirrhotic Noncirrhotic Cirrhotic Noncirrhotic Cirrhotic Noncirrhotic Cirrhotic No increase in AEs seen with longer duration treatment AEs seen consistent with RBV 20 Zeuzem S, et al. AASLD Abstract 1085

28 SVR12 (%) PegIFN- /daily weight-based ribavirin/daily sofosbuvir (400mg) for 12 weeks No Cirrhosis Cirrhosis /9 13/14 GT2 10/22 10/12 GT3

29 Treatment options for HCV genotype 2 in both treatment-naïve and PegIFN/RBV-failure Daily sofosbuvir (400mg) / daily weight-based ribavirin for 12 weeks in non-cirrhotic Extended treatment to weeks in patients with cirrhosis SVR 80 * SOF + RBV (12 wks) SOF + RBV (16 wks) Treatment Naive FISSION Treatment Ineligible POSITRON Treatment Experienced FUSION

30 SVR12 (%) BOSON: SVR12 in GT 3 by Tx History and Cirrhosis Status SOF + RBV 16 wks SOF + RBV 24 wks SOF + PegIFN/RBV 12 wks n/n = 0 58/ 70 65/ 72 68/ 71 12/ 21 Treatment Naive 18/ 22 21/ 23 No Cirrhosis Cirrhosis No Cirrhosis Cirrhosis 41/ 54 44/ 54 49/ 52 17/ 36 26/ 34 Treatment Experienced 30/ 35 Foster GR, et al. EASL Abstract LO5.

31 SVR12 (%) LDV/SOF + RBV for 12 Wks in Tx-Experienced Pts With Genotype 3 HCV n/n = 0 41/50 Overall 25/28 No Cirrhosis 16/22 Cirrhosis Gane EJ, et al. AASLD LB-11.

32 SVR12 (%) ALLY-3: SOF + DCV for 12 Wks in Pts With GT 3 HCV Infection 80 No cirrhosis Cirrhosis n/n = 0 105/ / 32 Overall Treatment-Naive Pts Of 16 pts with relapse, 11 had cirrhosis Treatment- Experienced Pts 1 of 16 relapses occurred between posttreatment Wks 4 and 12 73/ 75 Nelson DR, Cooper JN, Lalezari JP, et al. All-oral 12-week treatment with daclatasvir plus sofosbuvir in patients with hepatitis C virus genotype 3 infection: ALLY-3 phase III study. Hepatology. 2015;61: / 19 32/ 34 9/ 13

33 ALLY-3 + ALLY-3+ : SOF + DCV+RBV SVR12: Patients with Advanced Fibrosis a HCV RNA < LLOQ TD/TND (%) Overall 12 Weeks 16 Weeks a Diagnosed by FibroScan 9.6 to < 12.5 kpa (n = 9), FibroScan kpa (n = 4), liver biopsy, (n = 1). 8 8 Leroy V. LB-3 AASLD 2015

34 HCV RNA < LLOQ TD/TND (%) ALLY-3 + : SOF + DCV+ RBV SVR12: Patients with Cirrhosis HCV RNA < LLOQ TD/TND (%) ALLY ITT ANALYSIS Overall Weeks 16 Weeks OBSERVED ANALYSIS Overall VBT a VBT Relapse b Relapse Death c a VBT (virologic breakthrough): confirmed HCV RNA 1 log 10 IU/mL above nadir, or LLOQ if previously < LLOQ TD or TND; b Relapse: confirmed HCV RNA LLOQ at any posttreatment visit following < LLOQ TND at end of treatment; c Dilated cardiomyopathy on Day 72, not related to treatment; cirrhosis status diagnosed by liver biopsy (F4) n = 9; FibroScan 14.6, n = 27. Leroy V. LB-3 AASLD Weeks 16 Weeks

35 SVR12, % LDV/SOF for Genotype 6 Open label for 12 weeks in mostly treatment-naïve patients ( ELECTRON-2 ) 96 Mean age 51 (26 76) Male 64% Asian 88% Cirrhosis 8% Mean HCV RNA log 10 IU/mL Treatment Naïve (%) 6.7 ( ) 92% /2 5 No patients discontinued due to an AE Gane, AASLD, 2014, Poster #LB-11

36 Drug-Drug interaction U Liverpool HEP ichart Use of PPI more than omeprazole 20 mg/day may reduce SVR

37 Treatment of Acute Hepatitis C Acute hepatitis C: Sofosbuvir + NS5A inhibitor 8 weeks No ribavirin Acute hepatitis C, HIV coinfection and/or HCV RNA level > 1 million IU/mL: Same combination regimen 12 weeks EASL 16

38 Special Groups HBV coinfection (screen HBsAg before treatment) Immune-complex mediated manifestations of chronic hepatitis C Comorbidities Renal impairment Non-hepatic solid organ transplant recipients PWIDs Haemoglobinopathies Bleeding disorders

39 DAA Vulnerable to Drug Resistance and Resistance Associated Variants (RAVs) Position of frequently reported resistance mutations North C.S, et al Gen Hosp Psych. 2013

40 Conclusions Treatment of chronic hepatitis C is indicated in all HCV infected patients but treatment can be prioritized Choice of treatment depends on HCV genotype Severity of liver disease Previous treatment Availability of drugs

41 IFN-Free Treatment Options Combination regimen GT1 GT2 GT3 GT4 GT5-6 SOF + RBV No Suboptim al Suboptim al SOF/LDV+RBV Yes No No Yes Yes SOF/VEL+RBV Yes Yes Yes Yes Yes OBV/PTV/r+DSV(3D)+ RBV No No Yes No No No No OBV/PTV/r(2D)+RBV No No No Yes No GZR/EBR+RBV Yes No No Yes No SOF+DCV+RBV Yes Yes Yes Yes Yes SOF+SIM+RBV Suboptim al No No Yes No EASL 2016

42 AASLD,EASL 16 HCV*: Naive or PR experienced GT 1 or 6 compensated cirrhosis Regimen HCV Genotype 1a 1b 6 SOF + PR 12 wks 12 wks SOF/LDV*** 12 wks, no RBV 12 wks, no RBV SOF + DCV 12 wks, no RBV**** 12 wks, no RBV Treatment experience, compensated cirrhosis, DAA naïve Regimen HCV Genotype 1a 1b # 6 SOF + PR 12 wks 12 wks SOF/LDV 12 wks + RBV or 24 wks, no RBV 12 wks + RBV or 24 wks, no RBV SOF + DCV 12 wks + RBV or 24 wks, no RBV 12 wks + RBV or 24 wks, no RBV *Recommendations the same for HCV-monoinfected and HCV/HIV-coinfected pts. ** Decompensated (SOF+LDV or SOF+DCV plus low dose ribavirin 12 week *** Not available as for FEB 2016 **** AASLD 1a, 1b, cirrhosis (SOF+DCV+RBV 24 weeks) # Ib, RBV is not necessary in treatment experienced without cirrhosis(easl 16) AASLD/IDSA 2016 as November 16, EASL HCV Guidelines 16.

43 AASLD,EASL 2015 HCV*: Naive or PR experienced GT 2 or 3 Regimen No Cirrhosis Compensated Cirrhosis (Child-Pugh A) GT2 GT3 GT2 GT3 SOF + PR 12 wks 12 wks 12 wks 12 wks SOF + DCV 12 wks, no RBV 12 wks, no RBV** wks, no RBV** 24 wks + RBV** 12 wks+rbv RxEx*** 12 wks*** 12 wk+rbv 24 wk + RBV RxEx*** *Recommendations the same for HCV-monoinfected and HCV/HIV-coinfected pts. Best first-line option for genotype 2 HCV; other options may be useful in pts with GT 2 HCV who experience tx failure on sofosbuvir plus ribavirin. Suboptimal for genotype 3 HCV, particularly in pts with cirrhosis and previous failure of PR. ** AASLD 16, *** EASL16 EASL HCV Guidelines 16, AASLD 2016

44 HCV Treatment 2016 for Thailand(P/R/SOF/DCV) Anti-HCV + HCV RNA HCV Genotype Cirrhosis? HCV G 2 HCV G 1, 3, 6 No Cirrhosis? Yes No Cirrhosis? Yes SOF+DCV 12 Wks SOF+ DCV Wks SOF+P/R SOF+DCV 12 weeks SOF+P/R SOF+DCV+RBV 12 weeks* 24 wks without RBV 24 wks for HCV G3

45 Challenge in CHC management Decompensated cirrhosis Post-transplantation Chronic renal insufficiency DAAs failure (with RAVs)

46 DAAs in Thailand Regimen SOF+DCV (n=11) SOF+DCV+RBV (n=42) SOF+LDV (n=5) SOF+LDV+RBV (n=12) Sex M/F: 7/4 M/F:21/21 M/F:1/4 M/F:1/11 Mean age Cirrhosis (%) HCV genotype 1/3/6:9/1/1 1/3/6:18/21/3 1/3/6:4/0/1 1/3/6:10/0/2 HCV RNA - at week 12 (n=) 7/7 35/35 4/4 8/8 SVR-12(n=) Genotype1/3/6 1/1 (1/-/-) 9/9 (4/5/-) 2/2 (2/-/-) 4/4 (3/-/1)