Best of AASLD 2010 For IAGH April 2011 Reza Malekzadeh M.D. AGAF Professor of Medicne DDRC/TUMS
DAAs Direct-Acting Antivirals Understanding of HCV life cycle Identification of potential targets of antivirals that directly interrupt HCV replication. 1)Binding of the virus to the plasma membrane 2) endocytosis through the membrane, 3)uncoating 4)generating the membranous web to translation 4) replication,5)viral assembly, 6) transport 7) release again into the extracellular space, The most obvious targets are the NS3/4 serine protease and the NS5B HCV polymerase.
HCV Life Cycle and DAA Targets Receptor binding and endocytosis Fusion and uncoating Transport and release (+) RNA LD ER lumen LD Virion assembly Translation and NS3/4 protease polyprotein inhibitors processing ER lumen Membranous web LD NS5B RNA polymerase replication inhibitors Nucleoside/nucleotide Nonnucleoside NS5A* inhibitors *Role in HCV life cycle not well defined Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.
A new era of HCV Therapy Direct-Acting Antivirals (DAAs): First generation Protease inhibitors: Boceprevir and telaprevir Second -generation protease Inhibitors Danoprevir,Vaniprevir Nucleoside polymerase inhibitors. Nonnucleoside polymerase inhibitors. Filibuvir NS5A inhibitors.
Select DAAs in Clinical Development
Evolution of HCV Therapy 2001 2011 Beyond PegIFN/RBV Protease inhibitor Nucleos(t)ide polymerase inhibitor Nonnucleoside polymerase inhibitor NS5A inhibitor
Boceprevir and Telaprevir Boceprevir, a potent inhibitor of HCV NS3/4A protease Telaprevir, a potent inhibitor of HCV NS3/4A protease Both being tested in combination with standard-ofcare pegifn alfa-2/rbv in phase III studies in chronic HCV infection Boceprevir SPRINT-2: naive GT1 patients RESPOND-2: nonresponder GT1 patients (partial responders and relapsers) Telaprevir ADVANCE: naive GT1 patients ILLUMINATE: response-guided therapy in naive GT1 paitents REALIZE: nonresponder GT1 patients (null responders, partial responders, relapsers)
Definitions for virologic response Rapid virologic response (RVR). Early virologic response (EVR). End of treatment response (ETR). Sustain Viral Response (SVR).
Extended RVR (ervr) is defined as undetectable HCV RNA at Week 4 of therapy by a sensitive molecular test that is maintained through a later time point. The definitions may be different: some define ervr over a period of 12 weeks, others over 24 weeks, but ervr indicates that the patient does not relapse after having achieved undetectable HCV RNA results.
Evolving Response Definitions in Patients Receiving HCV Therapy With DAAs Term Time Point HCV RNA Level RVR NEW: ervr Wk 4 of therapy NEW: Wk 4 of triple therapy Wk 4 and later time point Undetectable Undetectable EVR Wk 12 of therapy Undetectable (complete EVR) ETR End of therapy Undetectable 2 log decrease from baseline (partial EVR) SVR 6 mos posttherapy Undetectable Adapted from Ghany MG, et al. Hepatology. 2009;49:1335-1374.
SVR (%) SVR (%) SVR Rates With BOC and TPV in GT1 Treatment-Naive and -Experienced Pts 100 Current Standard of Care 100 SOC + Protease Inhibitors (Approval Anticipated in 2011) 80 80 63-75 [1-2] 59-66 [3-4] 60 60 38-44 [1-2] 40 40 20 17-21 [3-4] 20 0 Treatment-Naive Pts Treatment- Experienced 0 Treatment-Naive Pts Treatment- Experienced 1. Poordad F, et al. AASLD 2010. Abstract LB-4. 2. Jacobson IM, et al. AASLD 2010. Abstract 211. 3. Bacon BR, et al. AASLD 2010. Abstract 216. 4. Foster GR, et al. APASL 2011. Abstract 1529.
Similarities and Differences in Phase III Studies of TVR and BOC in GT1 Naive Pts Parameter TVR [1] BOC [2] PR lead-in? No Yes: 4 wks PegIFN alfa formulation 2a 2b PI dosing requirements TID; administer with fatty meal TID Duration of PI triple therapy 8-12 wks followed by 12-40 wks PR 24-44 wks after 4 wks PR lead-in Qualification for shortened therapy (response guided) Undetectable HCV RNA until Wk 12 of triple therapy Undetectable HCV RNA until Wk 24 of triple therapy Qualified for shortened therapy, % 58 (24 wks) 44 (28 wks) SVR, % 69-75 63-66 Relapse, % 9 9 Adverse events more frequent in PI arms Rash, anemia, pruritus, nausea Anemia, dysgeusia 1. Jacobson IM, et al. AASLD 2010. Abstract 211. 2. Poordad F, et al. AASLD 2010. Abstract LB-4.
Second -generation protease Inhibitors Danoprevir,Vaniprevir Have been presented mainly at the AASLD and EASL 2010 Generally with these protease inhibitors, excellent RVR rates and very good early virologic response rates are achieved. Sustained virologic response data are not currently available for these compounds In AASLD 2011 more data will become available.
Benefit of Second -generation protease Inhibitors Danoprevir,Vaniprevir Better side-effect profiles Single or double dosing requirements.
HCV Life Cycle and DAA Targets Receptor binding and endocytosis Fusion and uncoating Transport and release (+) RNA LD ER lumen LD Virion assembly Translation and NS3/4 protease polyprotein inhibitors processing ER lumen Membranous web LD NS5B RNA polymerase replication inhibitors Nucleoside/nucleotide Nonnucleoside NS5A* inhibitors *Role in HCV life cycle not well defined Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.
Activity of Other Protease Inhibitors Combined With PR in Phase II Studies Protease Inhibitor Trial, Phase Patients Meeting Efficacy Measure, % (SOC) BI 201335 [1] SILEN-C2, II RVR: 62-69 (NR) EVR: 54-59 (NR) Danoprevir (RG7227) [2] ATLAS, II RVR: 73-86 (7) cevr: 88-92 (43) TMC435 [3] PILLAR, IIb SVR4: 91-93 (NR) SVR12: 88-97 (NR) Vaniprevir (MK-7009) [4] Protocol 007, IIa RVR: 67-84 (5)* cevr: 74-85 (47)* SVR: 61-84 (63) *Significant difference. 1. Sulkowski M, et al. EASL 2010. Abstract 1190. 2. Terrault N, et al. AASLD 2010. Abstract 32. 3. Fried M, et al. AASLD 2010. Abstract LB-5. 4. Manns MP, et al. AASLD 2010. Abstract 82.
Polymerase inhibitors Two nonnucleoside polymerase inhibitors ANA598 and Filibuvir have reported data with peginterferon/ribavirin. Advanced program has been developed for a nucleoside polymerase inhibitor, RG7128. SVR data is still quite limited. We will need to wait probably 1-1.5 years to see whether this class of DAAs may achieve different SVR rates than the protease inhibitors.. s
Activity of Polymerase Inhibitors Combined With PR in Phase II Studies Polymerase Inhibitor Nonnucleoside Trial, Phase Patients Meeting Efficacy Measure, % (SOC) ANA 598 [1] II cevr: 73-75 (63) Filibuvir [2] II RVR : 60-75 (0) cevr: 63-88 (50) EOT: 60-75 (50) SVR 12: 30-50 (50) Relapse: 20-50 (0) Nucleoside RG7128 [3] PROPEL, IIb cevr: 80-88 (49) 1. Lawitz E, et al. AASLD 2010. Abstract 31. 2. Jacobson I, et al. EASL 2010. Abstract 2088. 3. Jensen DM, et al. AASLD 2010. Abstract 81.
NS5A inhibitor One NS5A inhibitor, BMS-790052, has reported data in combination with peginterferon/ribavirin A number of other NS5A inhibitors in clinical development. This is a very potent class; very low doses achieve very potent antiviral efficacy. As with the other newer drugs, SVR rates are awaited. This drug class will be an important addition to the armamentarium for HCV therapy.
HCV Life Cycle and DAA Targets Receptor binding and endocytosis Fusion and uncoating Transport and release (+) RNA LD ER lumen LD Virion assembly Translation and NS3/4 protease polyprotein inhibitors processing ER lumen Membranous web LD NS5B RNA polymerase replication inhibitors Nucleoside/nucleotide Nonnucleoside NS5A* inhibitors *Role in HCV life cycle not well defined Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.
Activity of NS5A Inhibitors Combined With PR in Phase II Studies Polymerase Inhibitor Trial, Phase Patients Meeting Efficacy Measure, % (SOC) BMS- IIa RVR: 42-92 (8) 790052 [1] ervr: 42-83 (8) cevr: 58-83 (42) 1. Pol S, et al. EASL 2010. Abstract 1189.
Genotype 1 Boceprevir and Telaprevir, have their major activity against genotype 1. They both have activity against genotype 2. Boceprevir and telaprevir clearly have no activity against HCV genotypes 3 and 4. No data are available for other genotypes, such as 5 and 6.
Extended spectrum of activity Some of the next-generation protease inhibitors, s (MK-5172 and TMC435), may have an extended spectrum of activity. We hope that future drug candidates in the protease inhibitor class have potent activity against all genotypic subtypes so that we may not need to subtype our patients before starting therapy.
Activity of DAAs by HCV Genotype Agent Protease Inhibitors Potential Activity Boceprevir [1,2] 1, 2 Telaprevir [3,4] 1, 2 BI 201335 [5] 1, 2? Danoprevir [6] 1, 2? MK-5172 [7] 1-6 TMC435 [8] 1, 2, 4, 5, 6 Vaniprevir [9] 1, 2? 1. Poordad F, et al. AASLD 2010. Abstract LB-4. 2. Pawlotsky JM, et al. Gastroenterology. 2011[epub ahead of print]. Abstract 820. 3. Jacobson IM, et al. AASLD 2010. Abstract 211. 4. Foster G, et al. EASL 2010. Abstract 57. 5. Sulkowski M, et al. EASL 2010. Abstract 1190. 6. Terrault N, et al. AASLD 2010. Abstract 32. 7. Petry A, et al. AASLD 2010. Abstract 807. 8. Fried M, et al. AASLD 2010. Abstract LB-5. 9. Manns MP, et al. AASLD 2010. Abstract 82.
Activity of DAAs by HCV Genotype Agent Potential Activity Polymerase Inhibitors Nonnucleoside ANA598 [1] 1 Filibuvir [2] 1 Nucleoside IDX184 [3] 1-4 (5, 6?) RG7128 [4] 1-6 NS5A Inhibitors BMS -790052 [5] 1+ (not fully pangenotypic) 1. Lawitz E, et al. AASLD 2010. Abstract 31. 2. Jacobson I, et al. EASL 2010. Abstract 2088. 3. Standring DN, et al. EASL 2009. Abstract 91. 4. Jensen DM, et al. AASLD 2010. Abstract 81. 5. Pol S, et al. EASL 2010. Abstract 1189.
Pros and Cons of Treating vs Deferring Therapy Once PIs Are Available Treat Protease inhibitors substantially increase chance of SVR Successful treatment may arrest progression of liver disease (including potential for cirrhosis, HCC, etc) Many patients already warehoused awaiting DAAs, but when is the right time to exit the warehouse? Defer Current regimens complex, challenging adverse events Potential for better treatment options in future, eg, better response rates, fewer adverse events, shorter duration Risk of resistance if therapy fails; impact on future options?
Adherence
SVR (%) Adherence to PegIFN/RBV: Essential but Challenging Retrospective analysis of pegifn alfa-2b/rbv trials (N = 511) [1] 100 n = 80 60 40 20 0 35 17 24 54 72 53 75 63 305 10 30 50 70 90 Adherence Rate (%) Only ~ 60% of US patients adhere to HCV therapy [2] Drug exposure correlates with SVR; 80% adherence correlates with SVR [1,3] Patient self-report overestimates adherence [4] 1. McHutchison JG, et al. Gastroenterology. 2002;123:1061-1069. 2. Mitra D, et al. Value Health. 2010;13:479-486. 3. Raptopoulou M, et al. J Viral Hepat. 2005;12:91-95. 4. Smith SR, et al. Ann Pharmacother. 2007;41:1116-1123.
Dosing Frequency of DAAs (All Plus PegIFN/RBV) in Current Trials in Naive Pts QD BI 201335 BMS-790052 TMC435 *With RTV boosting. BID BI 201335 Telaprevir Danoprevir* Vaniprevir ANA598 RG7128 Filibuvir TID Boceprevir Telaprevir Danoprevir
Common AEs of DAAs in Current Trials in Naive Pts Agent AEs More Frequent in Experimental Arm vs PR Discontinuations due to AEs, % (Wk) Boceprevir [1] Anemia, dysgeusia 14 (48) Telaprevir [2] Rash, anemia, pruritus, nausea 10 (48) ANA598 [3] Rash incidence and severity increased with 400-mg dose 2 (12) BI 201335 [4] Gastrointestinal events, jaundice, and rash* 5 (12) BMS-790052 [5] None reported 8 (12) Danoprevir [6] ALT elevation, neutropenia, nausea diarrhea 4 (12) Filibuvir [7] None reported 0 (4) RG7128 [8] None reported 2 (12) TMC435 [9] Mild bilirubin increases in first 2 wks of therapy 7 (24) Vaniprevir [10] Vomiting with 600-mg dose 0 (6) *Higher in BID dosing than QD. 1. Poordad F, et al. AASLD 2010. Abstract LB-4. 2. Jacobson IM, et al. AASLD 2010. Abstract 211. 3.Lawitz E, et al. AASLD 2010. Abstract 31. 4. Sulkowski M, et al. EASL 2010. Abstract 1190. 5. Pol S, et al. EASL 2010. Abstract 1189. 6. Terrault N, et al. AASLD 2010. Abstract 32. 7. Jacobson I, et al. EASL 2010. Abstract 2088. 8. Jensen DM, et al. AASLD 2010. Abstract 81. 9. Fried M, et al. AASLD 2010. Abstract LB-5. 10. Manns MP, et al. AASLD 2010. Abstract 82.
Resistance
What Do We Currently Know About Resistance to Protease Inhibitors? Minor resistant populations preexist at baseline in virtually all HCVinfected patients [1] Resistant variants rapidly selected with monotherapy [2] R155K requires 1 nucleotide change in GT1a but 2 nucleotide changes in GT1b; virtually all resistance has been seen in GT1a [3] Emergence of resistance reduced when protease inhibitor combined with potent antivirals without cross-resistance, such as pegifn, or pegifn plus RBV [3,4] Failure to achieve SVR during triple-combination therapy associated with selection of resistant HCV variants [3] 1. Bartenschlager R, et al. J Gen Virol. 2000;81:1631-1648. 2. Ozeki I. J Hepatol. 2009;50:S350. 3. McHutchison JG, et al. N Engl J Med. 2009;360:1827-1838. 4. Kwo PY, et al. Lancet. 2010;376:705-716.
Viral Load Development of Viral Resistance Treatment begins Drug-susceptible quasispecies Drug-resistant quasispecies Incomplete suppression Inadequate potency Inadequate drug levels Inadequate adherence Preexisting resistance Selection of resistant quasispecies Time
Looking Further Into the Future of HCV Therapy Combined three oral therapy with no major side effects!
AI447011: BMS-790052 + BMS-650032 Alone or With PR in GT1 Null Responders Open-label, randomized, placebo-controlled phase IIa trial of BMS-790052 (NS5A inhibitor) and BMS-650032 (NS3 protease inhibitor) Wk 24 Wk 72 Prior null responders with GT1 HCV (N = 21) BMS-790052 60 mg QD + BMS-650032 600 mg BID (n = 11) BMS-790052 60 mg QD + BMS-650032 600 mg BID + PegIFN/RBV* (n = 10) Follow-up Follow-up *PegIFN alfa-2a 180 µg/wk; weight-based RBV 1000-1200 mg/day. Lok A, et al. AASLD 2010. Abstract LB-8.
Patients (%) AI447011: BMS-790052 + BMS-650032 Alone or With PR: Wk 12 Interim Analysis 100 80 60 40 BMS-790052 + BMS-650032 BMS-790052 + BMS-650032 + PegIFN/RBV 64 60 60 36 46 90 All viral breakthroughs occurred in patients with GT1a No serious adverse events, or treatment-related discontinuations of DAAs 6/21 patients experienced transient transaminitis that improved or resolved without discontinuation of drug 20 0 7/11 6/10 4/11 6/10 5/11 9/10 RVR ervr cevr Lok A, et al. AASLD 2010. Abstract LB-8.
Summary 2 new protease inhibitors, boceprevir and telaprevir, with activity against GT1 HCV in combination with pegifn/rbv are expected to become available in 2011 Substantial increases in SVR rates in naive and previous nonresponder GT1 patients Require pegifn/rbv, increased adverse events, risk of resistance. adherence challenges HCV therapy expected to continue to evolve during coming yrs Potential for different patterns of adverse events, dosing, duration of therapy, barrier to resistance; wider genotypic efficacy; potential to eliminate pegifn and/or RBV
Important Link for you Look at the following link for all information in AASLD 2010 http://trs.scivee.tv/node/986
Wilson s Disease and Liver Transpalnation Wilson s disease is a rare indication (<1%) of LT with a good long-term outcome at 87.5% at 5 years. Results of LT for neurological indication of WD are mitigated and need more experience.
Outcome of exclusive zinc monotherapy for symptomatic Wilson disease may be unfavourable, Although short term clinical outcome is often satisfactory, hepatic Wilson disease tends to progress during long term zinc monotherapy, even after initial penicillamine decoppering.
Lifestyle modification is effective in improving liver histology in NAFLD and NASH Prospective analysis confirms that lifestyle modification is effective in improving liver histology in NAFLD and NASH, particularly when a low fat diet is combined with moderate exercise. However, further analysis is needed to confirm these preliminary findings.
NASH patients have greater liverrelated mortality than non-nash. Over a median follow up length 15 years from 290 NAFLD (140 NASH) subjects, NASH patients developed significantly higher rate of liver-related mortality as compared to patients with non-nash NAFLD (15.9% of all NASH subjects vs. 2.5% of all non-nash NAFLD subjects, p=0.0002). A long-term follow-up of NAFLD patients confirms that NASH patients have greater liver-related mortality than non-nash. Additionally, patients with NAFLD and DM have higher risk of overall and liver-related mortality. Zobair_Younossi AASLD, 2010
The Significance of Autoantibodies in Non-alcoholic Fatty Liver Disease The prevalence of autoantibodies in our NAFLD cohort was 11% more in female and older ages One quarter of autoantibody positive patients have histological features of AIH. One quarter of autoantibody positive patients have elevated IgG and this subgroup has a high prevalence of fibrosis. Further studies are warranted to determine whether these subgroups have a worse prognosis.
High prevalence of IgG4 positive immunohistochemical cholangitis in liver explants from patients with PSC A large number of patients undergoing transplantation for PSC (48.0% )have marked histological IgG4 plasmacytic cholangitis. Further characterization of the significance of this histological observation is required, as it raises the question of whether steroids may have a role in a sub-population of patients with PSC.
Infliximab as third-line therapy for difficult-to-treat autoimmune hepatitis Report of nine patients (6 female) with difficult-to-treat AIH who were treated off-lable with infliximab at a dose of 5mg/kg bodyweight. Patients were followed 3 to 90 months (median 11 months). Treatment was stopped in three out of nine patients: One patient tolerated treatment poorly, one patient developed a flare after 17 months of treatment and one patient (suffering from PBC/AIH Overlap syndrome) did not respond adequately to treatment. Six patients are currently continuing treatment with excellent response. Five patients developed infectious complications during therapy, Infliximab is an effective treatment for patients with difficult to treat AIH but may lead to serious infectious complications.
Prevalence and Diagnostic Performance of Elevated IgG4 in Liver Disease Patients IgG4 level in patients attending liver clinics, imunoglobulins and subclasses were determined in 1409 consecutive patients. The frequency of IgG4 elevation was 23 %, where 7.2% of patients had IgG4 levels above 200 mg/dl. The most frequent diagnosis among the latter group was liver cirrhosis
IgG4 choangiopathy Only 6 of these 101 patients has evidence for IgG4 disease (5 patients IgG4 associated cholnagiopathy and 1 patient with IgG4 pancreatitis). Based on these data the prevalence of IgG4 choangiopathy is 5 % and IgG4 pancreatisi is 1 % in patients with IgG4 > 200 mg/dl. In conclusion, elevated IgG4 serum concentration is a non specific finding and is frequently present in patients with liver cirrhoses, where an excellent correlation with total IgG can be found. When patients with elevated total IgG are excluded, no increase in specificity of IgG4 could be found