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A New Era in Hepatitis C

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A New Era in Hepatitis C 11/1/2014 Objectives • Describe the natural history of HCV infection • Be able to diagnose HCV Hepatitis C: The new era of • Know the factors which predict progression to fibrosis and cirrhosis screening and treatment • Know that HCV therapy is rapidly changing, and that most patients now have > 95% cure rate with 8-12 David Crabb, M.D. weeks of oral therapy Department of Medicine, Indiana • Understand the genomic organization of the HCV as it University and relates to new direct acting antivirals • Contemplate that this breakthrough ranks with the Eskenazi Health development of treatment for syphilis, TB, and HIV History of HCV diagnosis and screening Worldwide prevalence of chronic HCV More people have HCV than HIV! • Post-transfusion hepatitis: as HBsAg Egypt 15% discovered and screened we had: Henan province, China 9% – Non-A, Non-B hepatitis (NANB) • Identification and cloning of virus 1989 • Testing for blood supply 1992 • Screening recommendations 2013 Distribution of HCV genotypes The risk of HCV from blood transfusion 1 11/1/2014 Routes of transmission Acute HCV infection Take home point: perhaps 15% or more of patients infected recover without treatment They generally remain anti-HCV positive Long term consequences of HCV Chronic HCV infection infection and risk of cirrhosis Genotype 3 is only viral factor to affect progression We don’t know slope of progression Take home point: Chronic HCV is diagnosed by persistent presence of HCV RNA. beyond 20 years Once you have made this dx, there is no need to test for RNA outside of treatment. The history of the natural history of More Americans die of HCV than HIV HCV (1968-2009) Take home points: Infection at older age, male sex, post-transfusion infection, co-infection with HBV/HIV, heavy alcohol use, NAFLD, obesity, insulin resistance linked to more likely progression A majority of patients may not develop significant fibrosis Better means to assess fibrosis (other than bx) would be very valuable to assess individual patients. 2 11/1/2014 CDC screening recommendations What good is eradication of the virus? • Persons for Whom HCV Testing Is Recommended • Adults born during 1945 through 1965 should be tested once (without prior ascertainment of HCV risk factors) • HCV-testing is recommended for those who: • Stops progression to fibrosis/cirrhosis – Currently inject drugs – Ever injected drugs, including those who injected once or a few times many years ago – Have certain medical conditions, including persons: • who received clotting factor concentrates produced before 1987 • Stops development of portal hypertension in • who were ever on long-term hemodialysis • with persistently abnormal alanine aminotransferase levels (ALT) • who have HIV infection cirrhotic patients – Were prior recipients of transfusions or organ transplants, including persons who: • were notified that they received blood from a donor who later tested positive for HCV infection • received a transfusion of blood, blood components or an organ transplant before July 1992 • Decreases risk of hepatoma development • HCV- testing based on a recognized exposure is recommended for: – Healthcare, emergency medical, and public safety workers after needle sticks, sharps, or mucosal exposures to HCV-positive blood • – Children born to HCV-positive women Eliminates effects of type II cryoglobulinemia • Note: For persons who might have been exposed to HCV within the past 6 months, testing for HCV RNA or follow-up testing for HCV antibody is recommended. (renal injury, skin rash, neuropathy) • ? Effect on risk of diabetes, lymphoma, fatigue • Should reduce transmission to others Improved outcomes with SVR From HCVGuidelines.org SVR = Sustained viral response Goal of treatment 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 an SVR. Rating: Class I, Level A Recommendations for when and in whom to initiate treatment Treatment is recommended for patients with chronic HCV infection. Rating: Class I, Level A Treatment is assigned the highest priority for those patients with advanced fibrosis (Metavir F3), those with compensated cirrhosis (Metavir F4), liver transplant recipients, and patients with severe extrahepatic hepatitis C (Table 1). Note decompensation from early HCV cirrhosis may occur at ~7%/year. Based on available resources, treatment should be prioritized as necessary so that patients at high risk for liver- related complications and severe extrahepatic hepatitis C complications are given high priority (Table 1). Recommendations for pretreatment assessment An assessment of the degree of hepatic fibrosis, using noninvasive testing or liver biopsy, is recommended. Rating: Class I, Level A Recommendation for repeat liver disease assessment Ongoing assessment of liver disease is recommended for persons in whom therapy is deferred. Rating: Class I, Level C Settings of Liver-Related Complications and Extrahepatic Disease in Which HCV Treatment is Most Likely to Provide the The HCV genome and viral proteins Most Immediate and Impactful Benefits Highest Priority for Treatment Owing to Highest Risk for Severe Complications Advanced fibrosis (Metavir F3) or compensated cirrhosis (Metavir F4) Rating: Class I, Level A Organ transplant Rating: Class I, Level B Type 2 or 3 essential mixed cryoglobulinemia with end-organ manifestations (eg, vasculitis) Rating: Class I, Level B Proteinuria, nephrotic syndrome, or membranoproliferative glomerulonephritis Rating: Class IIa, Level B 3 11/1/2014 Treatment of NANB hepatitis up to Brief history of treatment 2011 • Interferon: Initially 3 MU TIW (very difficult) • Initially (mid 1970’s) steroids- reduced ALT • Interferon with ribavirin • IFN tested based on responses of HBV in 1986 • PEG interferon: weekly injection • First generation protease inhibitors (Pis) (2011) • PIs were first direct acting antiviral (DAA)- drug directed specifically against a viral enzyme/protein • The explosion of treatment (2013 onward) Effect of first generation protease Effect of DAAs on GT 1 responses inhibitors DAA= boceprevir or telaprevir What do the DAAs do? P= PEG-IFN R, RBV = ribavirin SOF= sofosbuvir Currently: simeprevir ledipasvir sofosbuvir 4 11/1/2014 Highlights From EASL 2014 clinicaloptions.com/hepatitis COSMOS: Simeprevir + Sofosbuvir ± RBV in Genotype 1 HCV Patients COSMOS . Randomized phase IIa study Wk 12 Wk 24 Patients With GT1 HCV Simeprevir + Sofosbuvir + RBV (n = 30) Cohort 1: Previous null responders, F0-F2[1] Simeprevir + Sofosbuvir (n = 16) (N = 80) Simeprevir + Sofosbuvir + Cohort 2: RBV (n = 27) October 10, 2014 Naives and previous null responders, F3-F4[2] (N = 87) Simeprevir + Sofosbuvir (n = 14) Simeprevir 150 mg QD; sofosbuvir 400 mg QD; weight-based RBV 1000-1200 mg/day. 1. Sulkowski M, et al. EASL 2014. Abstract O7. 2. Lawitz E, et al. EASL 2014. Abstract O165. Highlights From EASL 2014 clinicaloptions.com/hepatitis Evidence of drug effectiveness: SOF+ COSMOS: SVR12 in Cohorts 1 and 2 by Ledipasvir in treatment-naïve patients HCV Subgenotype and Baseline Q80K SVR12 (%) GT1b GT1a without Q80K GT1a with Q80K Cohort 1 (F0-F2 Nulls)*[1] Cohort 2 (F3-F4 Naives/Nulls)*[2] 100 100 100100 100 100 100 100 100 100 100 100 100 100 100100 100 100 100 100 100 100 93 95 96 89 89 89 88 88 83 80 60 40 20 4/ 7/ 8/ 3/ 7/ 3/ 6/ 12/ 8/ 4/ 4/ 5/ 7/ 30/ 24/ 6/ 11/ 11/ 4/ 7/ 4/ 5/ 13/ 7/ 3/ 7/ 3/ 18/ 38/ 25/ 4 7 9 3 7 3 6 12 9 4 4 6 17 30 27 6 11 11 4 7 4 5 14 8 3 8 3 18 40 26 0 SMV/SOF + SMV/SOF SMV/SOF+ SMV/SOF SMV/SOF ± SMV/SOF + SMV/SOF SMV/SOF + SMV/SOF SMV/SOF ± RBV RBV RBV RBV RBV RBV 24 Wks 12 Wks Overall 24 Wks 12 Wks Overall *Excluding patients who discontinued for nonvirologic reasons. 1. Sulkowski M, et al. EASL 2014. Abstract O7. 2. Lawitz E, et al. EASL 2014. Abstract O165. Patients were previously untreated, GT1, 16% cirrhosis (well compensated) Evidence of drug effectiveness: SOF+ Evidence of drug effectiveness: SOF+ Ledipasvir in treatment-naïve, non-cirrhotic patients Ledipasvir in IFN +/- protease inhibitor failures Patients with GT1 HCV, ~20% cirrhosis; did not include those who withdrew from Rx 5 11/1/2014 Direct-Acting Antiviral Agents: Many more Direct-Acting Antiviral Key Characteristics Agents on the Way 5’UTR Core E1 E2 NS2 NS3 NS4B NS5A NS5B 3’UTR C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B p7 Protease Polymerase NS3/4A Protease Inhibitors (PI) NS5B Nucleos(t)ide Inhibitors (NI) High potency Intermediate potency NS5A NS3 NS5B NS5B Ribavirin Replication Complex Protease Inhibitors NUC Inhibitors Non-NUC Inhibitors Limited genotypic coverage Pangenotypic coverage Inhibitors Low barrier to resistance High barrier to resistance Telaprevir Daclatasvir(DCV) Sofosbuvir Dasabuvir (DBV) Boceprevir Ledipasvir(LDV) (SOF) BMS-791325 Simeprevir (SIM) Ombitasvir (OMB) VX-135 PPI-383 NS5A Inhibitors NS5B Nonnucleoside Inhibitors (NNI) Asunaprevir (ASV) MK-8742 IDX21437 GS-9669 ABT-450 (Paritprevir) GS-5885 ACH-3422 TMC647055 High potency Intermediate potency MK-5172 GS-5816 Faldaprevir ACH-3102 BUVIRs BUVIRs Sovaprevir PPI-668 Multigenotypic coverage Limited genotypic coverage ACH-2684 GSK2336805 Samatasvir Low barrier to resistance Low barrier to resistance PREVIRs ASVIRs Genotype 1 Choices Cost Assumptions Using WAC Prices and Patient Regimen Options SVR Cost per Estimates of Clinical Costs Characteristics SVR Naïve , no cirrhosis Wait until 2015 ? ? Drug Cost Assumptions SOF/Peg-IFN/RBV
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