Case 4: A 61-year-old man with HCV genotype 3 with cirrhosis Ira M. Jacobson, M.D. Weill Cornell Medical College New York, New York USA 1
Genotype 3 case 61-year-old man with HCV genotype 3 Cirrhosis on biopsy in 27 FibroScan 17 kpa in 213 Partial responder to PEG-IFN and RBV (26) cifn + RBV 21: HCV RNA 7, IU/mL at Week 12, discontinued Very poor tolerability ( mental fog, visual changes, cough) Labs early 214: Albumin 3. gm/dl AFP 15.2 ng/dl Platelets 72, ALT 189 U/L, AST 171 U/L Alkaline phosphatase 98 U/L Total bilirubin 1.6 mg/dl Hemoglobin 13.8 gm/dl MRI early 214: small, nodular liver with spleen 16.6 cm; no HCC EGD moderate-sized varices, banded prophylactically 2
How would you have managed this patient (early 214)? (1) No antiviral therapy (2) PEG-IFN + RBV + sofosbuvir 12 weeks (3) Sofosbuvir + RBV alone for 24 weeks (4) Simeprevir + sofosbuvir 12 weeks 3
Course of recent therapy 1/15/14: Started sofosbuvir 4 mg and RBV 12 mg 2/12/14 (week 4): TW4 HCV PCR 177 IU/mL, HgB 12.7 3/13/14 (week 8): TW 8 HCV PCR 18 IU/mL 3/27/214 (week 1): HCV RNA not detected, PEG-IFN added to SOF + RBV 5/8/214: TW16 HCV not detected 5/29/214: TW 19 HCV RNA not detected, HgB 9.6 7/3/14: TW 24 HCV RNA not detected 4
What would you do now? (1) Stop therapy and monitor HCV RNA (2) Continue SOF + RBV for another 12 24 weeks (3) Continue PEG IFN + RBV + SOF for another 12 weeks 5
Post-therapy course Treatment was stopped after 24 weeks At follow up week 4, HCV RNA 18, IU/mL (confirmed) 6
What would you do now? (Assuming unfettered access) No treatment, refer to transplant Retreat with SOF + RBV for 48 weeks Ledipasvir + SOF + RBV for 12 weeks Ledipasvir + SOF + RBV for 24 weeks Daclatasvir + SOF + RBV for 12 weeks Daclatasvir + SOF + RBV for 24 weeks ABT 45/r + ombitasvir + dasabuvir + RBV for 24 weeks 7
Considerations of Natural History of Genotype 3 HCV-Induced Liver Disease 8
HCV genotype 3 in the VA HCV Clinical Case Registry 2-29: Cirrhosis and HCC 88,348 patients with genotype 1 (8%) 13,77 with genotype 2 (12%) 8,337 with genotype 3 (7.5%) Mean follow up 5.4 years After adjustment for demographic, clinical, and antiviral treatment factors, comparison between genotypes 3 and 1: Hazard Ratio Confidence Interval Cirrhosis 1.31 1.22-1.39 HCC 1.8 1.61-2.3 Conclusion: Genotype 3 is associated with a significantly higher risk of cirrhosis and HCC vs genotype 1, independent of age, diabetes, BMI, or antiviral treatment Kanwal F, et al. Hepatology. 214;6:98 15 9
SVR reduced risk of all-cause mortality in a retrospective VA study.3 Genotype 1 (n=12,166) SVR rate: 35%.3 Genotype 2 (n=294) SVR rate: 72%.3 Genotype 3 (n=1794) SVR rate: 62% Cumulative Mortality (%).25.2.15.1.5 P<.1 Non-SVR SVR.25.2.15.1.5 P<.1 Non-SVR 1 2 3 4 5 6 1 2 3 4 5 6 1 2 3 4 5 6 Years Years Years Retrospective analysis of veterans who received PEG-IFN + RBV at any VA medical facility (21-28). SVR=sustained virological response. Backus LI, et al. Clin Gastroenterol Hepatol. 211;9:59-516 SVR.25.2.15.1.5 P<.1 Non- SVR SVR 1
SVR and all-cause mortality in CHC patients with advanced fibrosis 1 year cumulative occurrence rate (%) 53 patients followed for a median of 8.4 years 3 25 2 15 1 5 8.9 SVR patients 26. All cause mortality 1.9 27.4 Liver related mortality or liver transplant Non SVR patients 5.1 HCC 21.8 2.1 29.9 Liver failure Baseline factors significantly associated with allcause mortality: Older age Genotype 3 (2 fold increase in mortality and HCC) Higher Ishak fibrosis score Diabetes Severe alcohol use Van der Meer A, et al. JAMA. 212;38:2584 2593 11
The Foundation for the Phase 3 Trials of Sofosbuvir + Ribavirin 12
ELECTRON: Sofosbuvir + RBV in HCV genotype 2 or 3 infection (n=5) Treatment naïve, no cirrhosis 1 1 1 1 1 SVR12 (%) 8 6 4 2 6 9/9 1/1 11/11 1/1 PEG4 SOF/RBV12 PEG8 SOF/RBV12 PEG12 SOF/RBV12 SOF/RBV 12 6/1 SOF12 63% Genotype 3 7% G3 Gane EJ, et al. N Engl J Med. 213;368:34 44 13
FISSION: Genotype 2, 3 treatment-naive Week 12 24 36 SOF + RBV, n=256 SVR 12 PEG IFN + RBV (SOC), n=243 SVR 12 RBV dose 1 12 mg/day for SOF + RBV and 8 mg/day for PEG IFN + RBV Targeted 3:1 enrollment of genotype 3:genotype 2 patients Expanded inclusion criteria No upper limit to age or BMI Opioid substitution permitted Platelet count >75,/mm 3 (cirrhotic) Randomization 1:1; stratified by genotype, HCV RNA, cirrhosis Lawitz E, et al. N Engl J Med. 213;368:1878 1887 14
FISSION: Virologic response SOF + RBV PEG IFN + RBV Patients with HCV RNA <LLOQ (%) 1 8 6 4 2 92 231/251 32 76/241 >99 249/25 Week 2 Week 4 67 On Treatment 98 89 158/236 249/253 217/243 Last observed 67 67 17/253 162/243 Week 12 Post Treatment Lawitz E, et al. N Engl J Med. 213;368:1878 1887 15
FISSION: SVR12 rates by HCV genotype SOF + RBV PEG IFN + RBV 1 97 SVR12 (%) 8 6 4 67 67 78 56 63 2 17/253 162/243 68/7 52/67 12/183 11/176 Overall GT 2 GT 3 The combination of daclatasvir and asuneprivir has been withdrawn from FDA consideration, but the triple therapy regimen noted above is in trials. Lawitz E, et al. N Engl J Med. 213;368:1878 1887 16
FISSION: SVR12 rates by HCV genotype and cirrhosis status SOF + RBV PEG IFN + RBV 1 8 98 82 91 71 SVR12 (%) 6 4 62 61 34 3 2 58/59 No cirrhosis 44/54 1/11 8/13 89/145 99/139 13/38 11/37 Cirrhosis No cirrhosis GT 2 GT 3 The combination of daclatasvir and asuneprivir has been withdrawn from FDA consideration, but the triple therapy regimen noted above is in trials. Lawitz E, et al. N Engl J Med. 213;368:1878 1887 Cirrhosis 17
FISSION: Multivariate logistic regression Factors associated with SVR12 with SOF+RBV Variable Odds Ratio P value Genotype 2 vs 3 42.5 <.1 Cirrhosis: no vs yes 2.9.5 Baseline HCV RNA 2.3.9 < vs >6 log RBV exposure, mg/kg/day 1.3.2 Lawitz E, et al. N Engl J Med. 213;368:1878 1888 18
POSITRON: Genotype 2, 3 IFN-ineligible, intolerant, or unwilling Week 12 24 SOF + RBV, n=27 Placebo, n=71 SOF dose: 4 mg once daily; RBV dose: 1 12 mg/day. SVR 12 SVR 12 Expanded inclusion criteria Targeted 2% enrollment of patients with cirrhosis No upper limit to age or BMI No lower limit to platelets or neutrophils Stratified by presence or absence of cirrhosis Jacobson IM, et al. N Engl J Med. 213;368:1867 1877 19
POSITRON: SVR12 by HCV genotype 1 93 8 78 SVR12 (%) 6 4 2 161/27 11/19 6/98 Overall GT 2 GT 3 61 Jacobson IM, et al. N Engl J Med. 213;368:1867 1877 2
POSITRON: SVR12 by cirrhosis status No cirrhosis Cirrhosis 1 92 94 8 68 SVR12 (%) 6 4 2 85/92 16/17 57/84 3/14 Genotype 2 Genotype 3 21 Jacobson IM, et al. N Engl J Med. 213;368:1867 1877 21
Safety: Placebo vs SOF+RBV (POSITRON) AEs (>1%) SOF+RBV>PBO Patients Placebo (N=71) % SOF+RBV (N=27) % Any adverse event 77 89 Grade 3 AE 1 8 Serious AE 3 5 Treatment D/C due to AE 4 2 Fatigue 24 44 Insomnia 4 19 Anemia 13 Hemoglobin < 1 gm/dl 7 Hemoglobin < 8.5 gm/dl <1 AE profile of SOF reflects the AE profiles of the drugs with which it is given Jacobson IM, et al. NEJM. 213;368;1867 77 22
FUSION: Genotype 2, 3 with prior treatment failure Week 12 16 24 28 SOF + RBV, n=13 Placebo SVR12 SOF + RBV, n=98 SVR12 SOF dose 4 mg once daily; RBV dose 1 12 mg/day. Expanded inclusion criteria Targeted 3% enrollment of patients with cirrhosis No upper limit to age or BMI Platelet count 5,/mm 3, no neutrophil minimum Randomized (1:1), double blind, placebo controlled Stratified by cirrhosis and genotype Jacobson IM, et al. N Engl J Med. 213;368:1867 1877 23
FUSION: SVR12 by HCV genotype SOF + RBV 12 weeks SOF + RBV 16 weeks 1 8 P <.1 73 86 94 P <.1 SVR12 (%) 6 4 5 3 62 2 5/1 69/95 31/36 3/32 19/64 39/63 Overall GT 2 GT 3 Jacobson IM, et al. N Engl J Med. 213;368:1867 1877 24
FUSION results: SVR12 by HCV genotype and cirrhosis status SOF + RBV 12 weeks SOF + RBV 16 weeks 1 96 1 1 8 78 8 SVR12 (%) 6 4 6 SVR12 (%) 6 4 37 63 61 2 2 19 25/26 23/23 6/1 7/9 14/38 25/4 5/26 14/23 No cirrhosis Cirrhosis No cirrhosis GT 2 GT 3 Cirrhosis Jacobson IM, et al. N Engl J Med. 213;368:1867 1877 Error bars represent 95% confidence intervals. 25
FUSION: Multivariate logistic regression Factors associated with SVR12 in FUSION 12 Weeks Variable Odds Ratio P value Genotype 2 vs 3 21.4 <.1 Baseline weight based RBV dose 1.5.12 Cirrhosis: no vs yes 3.1.46 16 Weeks Variable Odds Ratio P value Genotype 2 vs 3 1.5.3 Sex: Female vs male 3.98.27 Jacobson IM, et al. N Engl J Med. 213;368:1867 1877 26
VALENCE: Genotype 2, 3 Treatment-naïve and treatment-experienced Week 12 24 36 SOF + RBV, n=73 SVR 12 SOF + RBV, n=25 SOF 4 mg; RBV 1 12 mg/day SVR 12 Amended from initial protocol with 12 weeks of therapy for G3 naïve Zeuzem S, et al. N Engl J Med. 214;37:1993 21 27
Sofosbuvir + ribavirin for genotype 3 VALENCE: 24 weeks, n= 25 No cirrhosis Cirrhosis 1 95 92 87 8 6 62 4 2 87/92 12/13 85/98 29/47 Naïve Experienced Zeuzem S, et al. N Engl J Med. 214;37:1993 21 28
VALENCE: Multivariate logistic regression Factors associated with SVR12 (genotype 3) Variable Odds Ratio P value Age < 5 vs >5 2.8.16 Sex: Female vs male 3.2.183 Cirrhosis: no vs yes 2.9.5 Baseline HCV RNA < vs >6 log 2.3.9 Lawitz E, et al. N Engl J Med. 213;368:1878 1887 29
VALENCE: SVR12 by RBV dose reduction or interruption RBV Dose Reduction or Interruption Genotype 2 Genotype 3 Yes 6/6 (1%) 13/13 (1%) No 62/67 (93%) 2/235 (85%) No impact of RBV dose reduction on SVR. Echoes similar theme from many other studies. Lawitz E, et al. N Engl J Med. 213;368:1878 1887 3
PHOTON-I: Study design (co-infected) Week 12 24 36 48 GT 1 Naïve Sofosbuvir + RBV (n = 114) SVR12 SVR24 GT 2, 3 Naïve Sofosbuvir + RBV (n = 68) SVR12 GT 2, 3 Experienced Sofosbuvir + RBV (n = 41) SVR12 Sofosbuvir: 4 mg once daily; RBV: 1 12 mg/day Undetectable HIV RNA on stable ART or no ART with CD4 >5 cells Wide range of ART regimens allowed Compensated cirrhosis permitted (small numbers enrolled) Naggie S, et al. 214; CROI: Boston. #26 31
PHOTON-I: Sofosbuvir + RBV in HCV/HIV co-infected patients 1 88 92 94 8 67 SVR12 (%) 6 4 2 23/26 22/24 28/42 16/17 G2 G2 G3 G3 Experienced Naïve 24 weeks 12 weeks Naïve 12 weeks Experienced 24 weeks Naggie S, et al. 214; CROI: Boston. #26 32
Viral kinetics in GT 3 patients FISSION, POSITRON, and FUSION Mean HCV RNA (log 1 IU/mL) 7 6 5 4 3 2 1 7 6 5 4 3 2 1 LLOQ LLOQ FISSION SVR12 No SVR12 SVR12 No SVR12 Baseline 1 2 4 Week LLOQ LLOQ POSITRON FUSION 12 FUSION 16 Baseline 1 2 4 Week Wyles D, et al. 213; AASLD 33
SVR12 in patients with GT 3 (HCV RNA < or LLOQ TND) LLOQ TND >LLOQ TND (HCV RNA detectable) 1 FISSION + POSITRON FUSION 12 weeks FUSION 16 weeks SVR12 (%) 75 5 25 76 58 69 52 62 48 32 39 28 36 6 62 72 55 65 44 LLOQ TND n/n = Week 1 Week 2 Week 4 19/25 82/118 139/223 9 Week 1 Week 2 Week 4 Week 1 Week 2 Week 4 /1 7/18 18/5 3/5 18/25 35/54 >LLOQ TND n/n = 143/247 8/154 23/48 19/6 12/43 1/11 36/58 21/38 4/9 Wyles D, et al. 213; AASLD 34
VALENCE: Viral kinetics and SVR12 rates Genotype 3 <LLOQ TND <LLOQ (TND+TD) >LLOQ 1 8 1 99 8 94 9 91 87 SVR12 (%) 6 4 61 33 2 7/7 75/76 138/172 64/68 191/212 2/36 178/196 212/245 1/3 Week 1 Week 2 Week 4 Zeuzem S, et al. 214; EASL: London 35
No resistance to SOF in combination therapy for genotypes 2 and 3 S282T is the signature mutation in vitro No SOF resistance mutations in NS5B detected by deep or population sequencing in any subject receiving SOF + RBV or SOF + PEG IFN + RBV in Phase 2 and 3 studies No virologic price to pay for failure Implications for ability to retreat with SOF *n = number of patients analyzed for resistance Study* SOF + RBV FISSION 1 (n=74) % FUSION 2 (n=72) % POSITRON 2 (n=4) % VALENCE 3 % 1. Lawitz E, et al. N Engl J Med. 213;368:1878 1887. 2. Jacobson IM, et al. N Engl J Med. 213;368:1867 1877. 3. Zeuzem S, et al. N Engl J Med. 214;37:1993 21. 36
Sofosbuvir + PEG-IFN + RBV in genotype 3 treatment-experienced patients SOF 4 mg QD + PEG IFN + RBV 1 12 mg for 12 weeks 1 8 83 83 SVR12 (%) 6 4 2 1/12 1/12 No cirrhosis Cirrhosis Lawitz E, et al. N Engl J Med. 213;368:1878 1887 37
Retreatment of genotype 3 sofosbuvir + RBV failures 1 8 PR + SOF 12 Wks 93 74 SOF + RBV 24 Wks 88 SVR12 (%) 6 4 47 2 13/14 17/23 7/8 7/15 No cirrhosis Cirrhosis Esteban R, et al. 214; EASL: London. #8 38
Variable EC 5s for NS5A inhibitors against genotype 3: EC 5 (nm) in replicons Drug 1a 1b 3a 4a Daclatasvir.2.4.15.12 Ledipasvir.34.4 35.11 GS 5816.11.9.12.9 MK 8742.4.3.3.3 ACH 312.2.7 <.2 <.2 IDX 719.62.24.17.2 Gao M. Curr Opin Virol. 213;3:514 52 39
ALLY-3 Study: 12-week combination treatment with DCV + SOF without RBV for HCV G3 Demographic and baseline characteristics Parameter Tx naive (n=11) Tx experienced (n=51) Age, median years 53 (24 67) 58 (4 73) Male, n(%) 58 (57) 32 (63) Race, n (%) White 92 (91) 45 (88) Black 4 (4) 2 (4) Asian 5 (5) 2 (4) Other 2 (4) HCV RNA, n (%) <8, IU/mL 31 (31) 13 (25) 8, IU/mL 7 (69) 38 (75) Cirrhosis, n (%) 19 (19) 13 (25) IL28B genotype, n (%) CC 4 (4) 2 (39) Non CC 61 (6) 31 (61) Nelson DR, et al. 214; AASLD: Boston. #LB 3 4
ALLY-3 study: 12-week combination treatment with DCV + SOF for HCV G3 SVR12 1 9 86 8 SVR12 (%) 6 4 2 91/11 44/51 Treatment naive Treatment experienced Nelson DR, et al. 214; AASLD: Boston. #LB 3 41
ALLY-3 study: 12-week combination treatment with DCV + SOF for HCV G3 (cont) SVR12 in patients without/with cirrhosis 1 Overall Tx naive Tx experienced 8 SVR12 (%) 6 4 96 97 94 63 58 69 2 No Yes No Yes No Yes Cirrhosis Nelson DR, et al. 214; AASLD: Boston. #LB 3 42
Ledipasvir/sofosbuvir ± RBV for treatment-naïve HCV G3 patients LDV/SOF±RBV 12 weeks 1 1 SVR12 (%) 8 6 4 64 2 16/25 26/26 LDV/SOF LDV/SOF/RBV Treatment naive cirrhotic Gane EJ, et al. 214; EASL 43
High efficacy of LDV/SOF regimens for patients with HCV genotype 3 or 6 SVR12 rates Patients (%) 1 8 6 4 2 89 96 82 73 41/5 25/28 16/22 24/25 Overall No cirrhosis Cirrhosis G3 G6 Gane EJ, et al. 214; AASLD: Boston. #LB 11 44
Once-daily SOF with GS-5816 for 8 weeks ± RBV in treatment-naive G3 non-cirrhotics: The ELECTRON-2 study SOF + GS 5816 25 mg SOF + GS 5816 25 mg + RBV SOF + GS 5816 1 mg SOF + GS 5816 1 mg + RBV n 27 24 27 26 RVR n/n (%) SVR4 n/n (%) SVR12 n/n (%) 4 arms: 2 doses of 5816 with/without RBV 26/27 (96) 27/27 (1) 27/27 (1) 22/23 (96) 21/24 (88) 21/24 (88) 24/26 (92) 26/27 (96) 26/27** (96) 25/26 (96) 26/26 (1) 26/26 (1) Relapse n/n (%) () 2* (8) () () LTFU n/n (%) () 1 (4) 1 (4) () Gane EJ, et al. 214; Boston: AASLD. #79 45
Conclusions: Genotype 3 Sofosbuvur + ribavirin for 24 weeks remains the approved regimen in the U.S. Ledipasvir + SOF + RBV appears to be effective against genotype 3 Suboptimal but SVR rates still unexpectedly high in light of poor in vitro activity Probably difficult to access at present Daclatasvir + SOF 24 effective in non cirrhotics, less in cirrhotics Should work because has intrinsic activity vs G3 Perhaps 24 weeks +RBVwould improve SVR in cirrhotics The future of therapy for genotype 3 is likely to be a pangenotypic NS5A (or PI) + a nucleotide 46