What Should We Do With Difficult to Treat HCV Populations?

Transcription

1 What Should We Do With Difficult to Treat HCV Populations? Norah Terrault, MD Professor of Medicine and Surgery Director, Viral Hepatitis Center University of California San Francisco Disclosures Norah Terrault, M.D. Grants/Research Support AbbVie, Gilead, BMS, Biotest, Eisai Consultant: Genentech, BMS, Cryocrystal, Achillion Stock/Shareholder: Speakers Bureau: Royalties: None None Up to date 1

2 Disappearance of Difficult to Cure Groups PAST Era of Peginterferon and Ribavirin Genotype 1 African Americans Treatment experienced Cirrhosis HIV coinfection Transplant patients Decompensated cirrhosis PRESENT Era of Direct Antiviral Drug Combinations Genotype 3 End stage renal disease/dialysis Decompensated cirrhosis, CP B/C DAA failures Genotype 3 2

3 Genotype 3: Key Studies VALENCE (TN, TE) Week SOF + RBV, n=250 SVR12 Week SOF + RBV, n=180 SVR12 SOF + RBV, n=178 SVR12 SOF +Peg IFN + RBV, n=179 SVR12 Week SOF + DCV n=152 SVR12 Week SOF + DCV n=24 SVR12 SOF + DCV n=26 Leroy V, AASLD 2015:LB 3; Nelson DR, et al. Hepatology 2015;61: ; Zeuzem S, et.al. NEJM 2014;370: ; Foster GR, et.al.gastroent.2015;149: SVR Rates by Treatment Regimen No Cirrhosis VALENCE ALLY 3 BOSON Not head to head comparisons Nelson DR, et al. Hepatology 2015;61: ; Zeuzem S, et.al. NEJM 2014;370: ; Foster GR, et.al.gastroent.2015;149:

4 SVR Rates by Treatment Regimen With Cirrhosis VALENCE ALLY 3 BOSON ALLY 3+ Not head to head comparisons Nelson DR, et al. Hepatology 2015;61: ; Zeuzem S, et.al. NEJM 2014;370: ; Foster GR, et.al.gastroent.2015;149: Key Points: Genotype 3 Genotype 3 is currently the most difficult to cure genotype SOF/P/R or SOF/DCV for 12 weeks in non cirrhotics achieve >90% SVR; no head to head comparisons Cirrhotics are more challenging, need to extend treatment or add RBV; SVR rates ~80 85% Benefits of RBV plus extension unclear If decompensated cirrhosis, adding RBV and extend to 24 weeks best strategy LDV/SOF plus RBV may be alternative, except if decompensated cirrhosis 4

5 Sofosbuvir/Velpatasvir for HCV Patients With Genotype 3 HCV ASTRAL 3 1:1 randomization to SOF/VEL or SOF + RBV Stratified by prior treatment (TN/TE) and cirrhosis (presence/absence Week n=250 n=250 SOF/VEL SOF + RBV SVR12 SVR12 p <0.001* 4 relapse 2 others 16 relapse 4 others 7 relapse 22 relapse 6 others 191/ /187 73/80 55/83 No Cirrhosis Cirrhosis 12 Weeks 24 Weeks Mangia A, AASLD 2015, Abstract 249 Another Pangenotypic DAA Combo: ABT ABT 530 ±RBV for 8 Weeks SURVEYOR I and II Genotypes 1 and 2: TN and TE 97% 98% 97% Genotype 3: TN 100% 100% SVR12 (%) SVR12 (%) Genotype 1 (n=34) All patients non cirrhotic No virologic failures Genotype 2 (n=54) No RBV No Cirrhosis 8 Weeks (n=29) No RBV (n=24) Cirrhosis 12 Weeks RBV (n=24) Muir AJ, et al. J Hepatol. 2016;64(suppl 2):S186. Abstract PS098. Kwo PY, et al. J Hepatol. 2016;64(suppl 2):S208. Abstract LBO1. Poordad F, et al. J Hepatol. 2016;64(suppl 2):S768. Abstract SAT

6 Advanced or End Stage Renal Disease Sofosbuvir in Patients with Severe Renal Impairment SOF AUC (ng h/ml) 10, SOF and GS Pharmacokinetics Severe RI (200 mg) SOF Historical (400 mg) Severe RI (200 mg) GS Historical (400 mg) Dots indicate patients with SVR4 (blue dots) or viral relapse (red dots). 100,000 10,000 Comparable SOF and ~ 4 fold higher GS exposures compared with historical HCV infected population 1000 GS AUC (ng h/ml) Adverse Events SOF 200 mg + RBV N=10 Anemia 5 Headache 4 Pruritus 3 Rash 3 Muscle spasms 2 Hypoesthesia 2 Insomnia 2 Irritability 2 No treatment emergent clinically significant ECG results SOF 200 mg + RBV was safe and relatively well tolerated in patients with severe renal impairment with exacerbation of anemia via RBV induced hemolysis as primary AE Gane, AASLD, 2014, Poster #966 6

7 Safety of Sofosbuvir Based Regimens in Patients egfr <30 ml/min HCV Target Experience Change in egfr over time in patients with egfr<30 at baseline N=18, 5 on HD All received SOF 400 mg daily Higher rates of renal safety events than patients with egfr 45 ml/min Anemia (30%) Serious AEs (18%) Worsening renal failure (30%) Saxena V, Liver Int Feb 29 Guidance for Treating HCV in the Setting of Renal Impairment Recommendations if CrCl 30 ml/min: AASLD IDSA and EASL Guidelines No dosage adjustment needed for any of the approved HCV DAAs Recommendations if CrCl < 30 ml/min or ESRD* GT subtype Regimen Duration GT1a, 1b or 4 Grazoprevir Elbasvir 12 wks GT1b Omibitasvir/Paritaprevir/ritonavir + 12 wks Dasabuvir GT2, 3, 5 or 6 PEG IFN + dose adjusted RBV (200 mg/d) None of the all oral combinations of direct antiviral drugs available in India are approved for use in patients with CrCl <30 ml/min *For patients in whom the urgency to treat is high and kidney transplant is not an immediate option. RBV should be discon nued if hemoglobin levels decline by more than 2 g/gl despite use of erythropoie n. Updated 2/24/16 7

8 Efficacy of Approved DAAs in Genotype 1 Patients with Stage 4 5 CKD, Including Dialysis Ombitasvir/paritaprevir/r + dasabuvir (GT1B) + RBV (GT1A) for 12 wks, non cirrhotic RUBY 1 Elbasvir/grazoprevir for 12 wks, G1, only 6% cirrhosis C SURFER 1 relapse 6 discontinued (not due to AE) 9/13 anemia requiring dose reduction None discontinued 1 death 1 relapse 115/ /122 Pockros P, Gastroenterology Mar 11. Roth D, Lancet 2015;386: Decompensated Cirrhosis 8

9 Spectrum of Advanced HCV Disease Concurrent evaluation for liver transplant Compensated cirrhosis Child Pugh A MELD <10 No portal hypertensive complications Decompensated cirrhosis Child Pugh B Less severe portal HT MELD>10 Decompensated cirrhosis Child Pugh C Severe/refractory portal hypertensive complications MELD typically >20 Risk of dying of liver related complications Goals of Treatment in Patients with Decompensated Cirrhosis Primary: Improve patient survival Other Potential Benefits: Avoid need for liver transplantation Reduce progression whilst waiting Improve portal hypertension Improve quality of life Prevent post transplant recurrence 9

10 Unique Aspects of Treating Patients with Decompensated Cirrhosis DAA treatment options are more limited SVR rates are lower as severity of liver disease increases Potential harms of therapy Reduced survival on waiting list SVR does not prevent disease progression in the sickest patients (POINT OF NO RETURN) DAA toxicity & side effects cause progression Reduced access to liver transplantation Small improvements in MELD post SVR do not prevent need for transplant (MELD PURGATORY) Drug Options More Limited in Decompensated Cirrhosis DAAs Sofosbuvir ± Ledipasvir Primary Metabolic Pathway Suitable in Patients With Cirrhosis CP A CP B CP C Suitable if Renal Impairment Renal Yes Yes Yes Not if CrCl < 30 ml/min Daclatasvir Hepatic Yes Yes Yes Yes, but not studied in dialysis Simeprevir Hepatic Yes No No Not if CrCl < 15 ml/min Ombitasvir/Pari taprevir/r Hepatic Yes No No Yes but not if dialysis Dasabuvir Hepatic Yes No No Yes but not if dialysis Elbasvir/grazop revir Hepatic Yes No No Yes Ribavirin Renal Yes Yes Yes Yes, adjusted Bifano M, et al. AASLD Abstract Garimella K, et al. Clin Pharm P43. Sofosbuvir [package insert]. Simeprevir [package insert]. Khatri A, et al. AASLD Abstract 758. German et al. AASLD Abstract 467. Kirby R, et al. 8th International Workshop on Clinical Pharmacology of Hepatitis Therapy PO20 10

11 SVR Rates are Lower in Patients with CP C versus CP B Cirrhosis LDV SOF + RBV (for 12 or 24 weeks) in decompensated cirrhotics Genotypes 1 and % 81% 80 SVR12 (%) relapses 3 deaths 6 relapses 9 deaths 20 0 CPT B CPT C Overall: 96/108 75/91 GT1: 91/102 73/86 GT4: 5/6 2/5 Gane E, APASL 2016 SOF + DCV plus RBV for Decompensated Cirrhosis: ALLY 1 N=48 Child Pugh Class 67% CP B 33% CP C G1 4 included (71% G1) 60% Rx experienced MELD range % MELD >15 Median RBV dose 445 mg/day CP B 398 mg/day CP C 10 relapses No deaths 30/32 22/24 3/3 9/16 5/10 2/3 Poordad F. Hepatology Jan

12 What About Safety? Serious AEs During Treatment with SOF + NS5Ai Number of events (% of total SAEs) Number of patients (% of total population) Total SAEs (25.5%) Likely related to liver disease 138 (78.9%) 100 (21.4%) and/or HCV therapy Likely unrelated to liver disease 37 (21.1%) 37 (7.9%) and/or HCV therapy Ascites 55 (31.4%) 38 (8.1%) Hepatic encephalopathy 28 (16%) 23 (4.9%) Variceal bleed 6 (3.4%) 6 (1.3%) Infection 26 (14.9%) 23 (4.9%) Liver transplantation 16 (3.4%) New HCC 7 (1.5%) Discontinuation of DAAs 42 (9%) Deaths 14 (3.0%) Foster G, J Hepatol 2016, in press Safety of DAA Therapy in Patients with Decompensated Cirrhosis Overall, DAAs appear to be safe and AEs consistent with clinical sequelae of advanced liver disease, RBV toxicity Ribavirin associated anemia is common and more problematic to manage: best to start with 600 mg daily Difficult to determine if DAAs increases risk of adverse events as majority of studies are uncontrolled In few controlled studies, AEs predicted by severity of liver disease and not treatment per se Saxena V, Hepatology, 2015 Lactic acidosis occurred in 5/35 (14%) patients during therapy, while no event of lactic acidosis was observed prior to therapy Welker T J Hepatol

13 Is There a Point of No Return? Probably Insufficient time to improve Inability to recovery/reverse Some clues: Older age regenerative capacity? Significant portosystemic shunting? Severity of liver synthetic dysfunction: CP C? Need better tools to assess regenerative/repair capacity Summary Who Should We Treat? Compensated cirrhosis Child Pugh A MELD <10 HCC as indication for LT Decompensated cirrhosis Child Pugh B Less severe portal HT Decompensated cirrhosis Child Pugh C Severe/refractory portal hypertensive complications Harm vs benefits associated with HCV treatment Treat all patients Treat most patients Consider age, severity of PHT complications, CP ( 8) and MELD scores ( 16 20) Focus on getting to LT Treat selectively and only if expect survival at least 6 months 13

14 DAA Failures Antiviral Resistance: A Fact of Life.Especially Among Treatment Failures Good news No integration into host DNA In contrast to HBV RAVs are not archived No cellular reservoir known In contrast to HIV and HBV Bad News Resistance variants exist pre treatment All classes of DAAs can be predicted to select for further RAVs Risk varies with: Drug used Duration of therapy?use of ribavirin 14

15 Baseline versus Selected Resistance Associated Variants (RAVs) Baseline Selected Single variants Multiple variants Variable fold change Variable prevalence in viral population Any patient High fold change High prevalence in viral population Difficult to treat populations Kitrinos K. #1949 EASL Wyles D. EASL Cooper C CROI 2016 Differing Rates of RAV Persistence Post Therapy Median time to disappearance of NS3 RAVs = ~8 months Majority of NS5A RAVs remain detectable at 2 years Soriano V, AIDS Rev

16 Not All RAVs are Created Equal Fold change in EC50 1a 1b Position M28T Q30R L31M/V Y93H/N L31V Y93H/N Ledipasvir 20x >100x Ombitasvir >1000x >100x Daclatasvir >100x >1000x Elbasvir 20x >100x >100x/ >100x >1,000x/ >10,000 <3x >10,000x/ >100x >10,000x >100x/ >1000x Velpatasvir <10x <3x 20x/50x >1,000x/ >10,000x >10x >1,000x/ >100x >1,000x 100x/ >1000x 20X >100x/? <10x 20x/50x <10x 20x/50x <10x >100x/ <3x/ <3x/ Cross resistance at positions Q30R, L31M/V, Y93H/N (G1A) >100 fold change appears to be clinically significant Cross resistance and persistence over time limits use of NS5A inhibitors in retreatment regimens Wang C. AAC Cheng G. #1172. EASL Zhao Y. #A845 EASL Yang G. EASL Ng T. #639 CROI General Approach to Patient Who Has Failed DAA Therapy How urgent is retreatment? Virologic evaluation Exclude genotype shift Exclude HCV reinfection Assess for RAVs Strategic plan: add RBV, use non cross resistance drug class, extend treatment Genotypic Resistance Testing No RAVS NS5A RAVs alone (even if Q80K) NS3 RAVs (R155, A156, D168) 2 RAV Classes As treatmentexperienced SOF + SMV + RBV 24 weeks SOF/LDV or DCV + RBV 24 wks Defer retreatment 16

17 Treatment of Elbasvir/Grazoprevir Failures with EBR/GZR + SOF + RBV X 12 Wks C SWIFT RETREATMENT N=25 GT1 patients who failed a prior short course (4 8wks) Mean time from virologic failure to retreatment = 214 days (range ) SVR12* * *Including: NR5A: N=4 Y93C/H/N NS3: n=1 D168E AEs related to RBV Dose reductions in 2 patients for anemia No ALT elevations *Excludes 2 patients lost to follow up at day 3 and week 4 Lawitz E, AASLD 2015, LB12 Summary: Difficult to Treat Populations Genotype 3 if with cirrhosis, and especially if treatmentexperienced have lowest SVR rates among all patients Ribavirin ± extended duration therapy needed to optimize SVR rates ESRD is no longer a difficult to treat population for genotypes 1 and 4, if compensated disease Non 1/4 genotypes and decompensated cirrhosis still without DAA option DAA failures: most have treatment emergent RASs Represent a small % of treated patients but more challenging to treat SVR rates lower in decompensated patients, in part related to competing risk of death from progressive disease Next generation DAA combinations offer advances for several of these difficult to treatment groups 17

18 Thank you 18