_of treatmentnaive chronic hcv patients天真的治疗慢性丙型肝炎患者的管理课件

Antiviral treatment of chronic hepatitis C in IVDU settings Petr Urbnek Department of Internal Medicine, 1st Medical Faculty Charles University and Central Military Hospital Prague petr.urbanekuvn.cz Goals of Hepatitis C Treatment Primary Eradicate the virus Secondary Prevent progression to cirrhosis Reduce incidence of HCC Reduce need for transplantation Enhance survival Davis GL, et al. J Hepatol. 1995;22(suppl 1):110-114. Lindsay KL. Hepatology. 1997;26(suppl 1):71S-77S. Management of Hepatitis C: NIH Consensus Conference Statement All patients with chronic hepatitis C are potential candidates for antiviral therapy HCV therapy has been successful even when the patients have not abstained from continued drug or alcohol use . . . . Thus, it is recommended that treatment of active injection drug use be considered on a case-by-case basis and that active injection drug use in and of itself not be used to exclude such patients from antiviral therapy. Treatment is recommended for patients with an increased risk of developing cirrhosis NIH Management of Hepatitis C Consensus Conference Statement. June 10-12, 2002. Currently Approved Treatments for HCV Therapy Chronic illness managed with combination of Interferon alfa (subcutaneous injections) Interferon alfa 2aalfa 2bconsensus interferon alfa -1 Pegylated interferon alfa 2aalfa 2b Ribavirin (tablets) Directly acting antivirals (tablets) Telaprevir Boceprevir NIH Recommended HCV Therapies Peg-IFN + RBV more effective than standard IFN + RBV combination or peg-IFN alone Genotype 1 Peg-IFN + RBV 1000-1200 mg/ day 48 weeks Genotype 2 or 3 Peg-IFN + RBV 800 mg/day 24 weeks Goal of treatment is SVR Defined as No detectable serum HCV RNA 24 weeks after the end of treatment Tested using sensitive HCV RNA assay with lower limit of detection of 50 IU/mL NIH Management of Hepatitis C Consensus Conference Statement. June 10-12, 2002. NIH Consensus Statement Recommends Treating IDUs Management of HCV is enhanced by linking to drug- treatment programs Methadone is not a contraindication to HCV treatment HCV treatment of active IDUs should be considered on a case-by-case basis Active IDU in and of itself should not exclude such patients from antiviral therapy NIH Management of Hepatitis C Consensus Conference Statement. June 10-12, 2002 Evaluation of IDUs for Viral Hepatitis Injection drug use HBV serology HAV serology HCV EIA Immunize F/U, counseling; RNA if suspected - HCV RNA + Stop - HCV genotype Lab evaluation ETOH, transmission + Treatment options Liver biopsy? Non-invasive methods Follow-up - Days on Treatment Early Patterns of Response to Initial HCV Therapy Nonresponder Null responder Partial responder Rapid responder 1 2 3 4 5 6 7 0 1 2 37142128 Limit of detection Peg-IFN + RBV 2 log10 decline HCV RNA (log10 IU/mL) 84 (12 weeks) 0 1 2 3 4 5 6 7 06121824303642485460667278 Weeks HCV RNA (log10 IU/mL) 2 log10 decline Peg-IFN + RBV Relapse Breakthrough Different Virologic Responses to HCV Therapy After Week 12 SVR Limit of detection ETR (G3/4)ETR (G1/2) Sanchez-Tapias JM. AASLD 2004. Abstract 125. Heathcote EJ, et al. N Engl J Med. 2000;343:1673-1680. Davis GL, et al. Hepatology. 2003;38:645-652. Virologic monitoring to predict response can provide the following benefits to the patient and clinician Limits unnecessary exposure to therapy Identifies treatment failure Justifies early discontinuation in those responding poorly Limits treatment toxicity Limits cost for those unlikely to respond Identifies optimal duration of treatment Provides incentive to continue therapy Benefits of Virologic Monitoring *Logistic regression analysis: P .002 1. Manns MP, et al. Lancet. 2001;358:958-965. 2. Fried MW, et al. N Engl J Med. 2002;347:975-982. 3. Muir AJ, et al. N Engl J Med. 2004;350:2265-2271. 4. Conjeevaram HS, et al. Gastroenterology. 2006;131:470-477. Baseline FactorSVR Rates Peg-IFN alfa-2a + RBV OR Peg-IFN alfa-2b + RBV HCV RNA, %1,2 2 x 106 copies/mL42-53 Genotype, %1,2 2 or 376-82 142-46 Genotype 1 and high viral load, %30-41 Liver histology, %1,2 Stage 0-255-57 Stage 3-441-44 Age1,2Older age, lower SVR* Weight1,2Higher weight, lower SVR* Race, %3,4 Black19-28 White52 IL28B CC80 Predictors of Sustained Virologic Response: Fixed Factors Mauss S, et al. Hepatology. 2004;40:120-124. HCV GT 1 Treatment Outcomes Are Similar in IDUs Compared With Other Groups P = .16 P = .01 Response Outcomes Patients (%) Patients on methadone maintenance Controls (no history of IDU for 5 years) 76 56 50 42 0 10 20 30 40 50 60 70 80 90 100 ETRSVR 50505050n = 0 10 20 30 40 50 60 70 80 90 100 ETRSVR Sylvestre DL, 2007. HCV Treatment Outcomes Are Similar in IDUs Compared With Other Groups 68 59 40 62 48 32 91 100 64 Completed Street-Recruited Heroin Users Maintained on Buprenorphine 371026n =32112021137 All patients Genotype 1 Non genotype 1 Patients (%) Robaeys G, et al. Eur J Gastroenterol Hepatol. 2006;18:159-166. HCV Treatment Can Be Effective in the Setting of Active Drug Abuse 0 48 31 7.6 61 50 NoncomplianceETRSVR Patients (%) Active IDUs (n = 21) Nonactive IDUs (n = 66) P = NS HCV Treatment Outcomes: Active IDUs vs Nonactive IDUs 0 20 40 60 80 100 P = NS P = NS Sylvestre DL, et al. J Subst Abuse Treatment. 2005;29:159-165. SVR Rate May Increase With IDU Abstinence in a Methadone Program 6 mo 30 Treatment of drug and/or alcohol disorders prior to therapy Treatment of preexisting psychiatric disease Berg T, et al. Gastroenterology 2006;130:1086-1097. Educate IDU Patients Regarding HCV Treatment Before Initiation Characteristics of liver disease Histology, genotype, viral load Goals of HCV treatment Sustained virologic response Adverse effects Provide realistic and balanced information including tools to combat adverse effects Adherence Emphasize that adherence is the key to treatment success Develop Healthcare Network and Support System Establish multidisciplinary team to coordinate care and maximize patient monitoring and support Primary care physician Viral hepatitis specialist Psychiatrist and therapist Addictions specialist Social worker or case manager Support systeminvolve family and friends in treatment plan SVR Increases With Frequency of Visits to Healthcare Providers 45 6 0 20 40 60 80 100 2/3 Appointments 2/3 Appointments SVR (%) Backmund M, et al. Hepatology. 2001;34:188-193. Develop Individualized Medication Adherence Plan Before Treatment Establish daily routine for taking medications Improve delivery of therapy Instruct family member in IFN administration Consider directly administered peg-IFN in health clinic or methadone clinic setting Use pill box for RBV Keep medication diary to track adherence and review with treating provider at appointments Use prompts as reminder to take medications Alarms, calendars, phone calls from friends/family Higher Adherence Associated With Increased SVR Rate Adherence to therapy demonstrates higher SVR when patient Takes 80% of the prescribed IFN dose Takes 80% of the prescribed RBV dose Completes 80% the prescribed duration of therapy Quality of life may determine patient adherence Ferenci P, et al. AASLD 2001. Abstract 716. McHutchison JG, et al. Hepatology. 2000;32:223A. McHutchison JG, et al. Gastroenterology. 2002;123:1061-1069. PegIFN alfa-2b 1.5 g/kg/wk + RBV 800 mg/day for 48 Wks1 PegIFN alfa-2a 180 g/wk + Weight-Based RBV (1000 or 1200 mg/day) for 48 Wks2 1. Manns MP, et al. Lancet. 2001;358:958-965. 2. Fried MW, et al. N Engl J Med. 2002;347:975-982. 46 76 56 OverallGT1GT2/3 298140453 42 82 100 80 60 40 20 0 54 OverallGT1GT2/3 SVR (%) 348147511 100 80 60 40 20 0 n =n = HCV Standard of Care Prior to May 2011 GT1 (most common in US, Europe) least responsive to pegIFN/RBV 3844 1721 NAIVE PATIENTS 6375 5966 Previous non-responders ADVANCE/ SPRINT-21,2 RESPOND-2/ REALIZE3,4 ADVANCE/SPRINT-2/ ILLUMINATE1,5 RESPOND-2/ REALIZE3,4 SVR rate, clinical trials DAAs, HCV 1 SVR (%) 0 20 40 60 80 100 P/R+DAASOC SVR (%) 0 20 40 60 80 100 P/R+DAASOC 1. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 2. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217. 3. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 4. Sherman KE, et al. 2010 AASLD. Abstract LB2. 5. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428. Helpful DrugDrug Interaction Resource Summary of Management of IDU Patients With HCV NIH. Available at: /2002/2002HepatitisC2002116html.htm. Accessed April 11, 2007. Sulkowski M, et al. Clin Pharmacol Ther. 2005;77:214- 224. Mauss S, et al. Hepatology. 2004;40:120-124. Sylvestre DL, et al. J Subst Abuse Treatment. 2005;29:159-165. All HCV-infected drug users should undergo careful risk/benefit assessment for HCV treatment Determine the medical need for treatment Provide best support network possible Determine the probability of SVR Race, HIV status, HCV genotype, and viral load Individualize treatment decision 12-week treatment trials stop if insufficient viral response Summary of HCV Treatment for IDU Patients NIH. Available at: /2002/2002HepatitisC2002116html.htm. Accessed April 11, 2007. Sulkowski M, et al. Clin Pharmacol Ther. 2005;77:214- 224. Mauss S, et al. Hepatology. 2004;40:120-124. Sylvestre DL, et al. J Subst Abuse Treatment. 2005;29:159-165. Active IDU not a contraindication for HCV treatment Patients in methadone maintenance should be considered for HCV treatment No clinically significant drug-drug interaction with peg-IFN or RBV Several case series/studies indicate that HCV treatment may be effective in methadone clinics Response rates comparable to those of traditional patients Benefits of IFN + RBV Therapy Reduction in fibrosis May occur in absence of viral clearance Reduce risk of end-stage liver disease and hepatocellular carcinoma Patient may feel better Public health benefit: reducing transmission of HCV NIH Management of Hepatitis C Consensus Conference Statement. June 10-12, 2002. Available at: /2002/2002HepatitisC2002116html. Accessed April 10, 2007. Advantages of Pegylated Interferon alfa Polyethylene glycol (peg) is bound to interferon Delays clearance of interferon Maintains higher blood levels of interferon Once-weekly injection Avoids “peaks and troughs” of 3-times-weekly dosing Less fatigue and malaise No drug-drug interaction with methadone 1 10 100 1000 15,000 0 10 20 40 60 80 100 120 140 160 180 HoursHours pg/pg/mLmL 20,000 Peg-IFN alfa-2a SC once weekly T1/2 80 hours Peg-IFN -2b SC once weekly T1/2 40 hours IFN TIW T1/2 2-3 hours Pharmacokinetics Why Not Treat Everyone With HCV? In some patients IFN or RBV contraindicated HCV may spontaneously resolve Fibrosis may be absent or nonprogressive Injections may be intolerable Autoimmune conditions or mental illness may be exacerbated Cost/benefit evaluation Peg-IFN toxicity Flu-like and GI symptoms Cytopenias (thrombocytopenia, neutropenia) Depression (including suicidal ideation), somnolence Autoimmune disease Hair loss RBV toxicity Cardiovascular disease Hemolytic anemia Risk of fetal malformations Renal failure Maddrey WC. Semin Liver Dis. 1999;19(suppl 1):67-75. Pawlotsky JM. Hepatology. 2002;36(suppl 1):S65-S73. Sethi A, et al. Clin Liver Dis. 2005;9:453-471. Virologic Definitions of Treatment Response: Early Milestones NonresponseFailure to achieve HCV RNA undetectability at any time point during therapy RVRHCV RNA undetectable by Week 4 EVR 2 log10 decline in HCV RNA by Week 12 Null ResponseHCV RNA decline 2 log10 IU/mL by Week 12 Partial Virologic Response 2 log10 decline in HCV RNA by Week 12, but HCV RNA detectable at Week 24 Possible Changes to Treatment Duration Based on Viral Response EVR ( 2 log10 decline in HCV RNA by Week 12) Predictive of SVR Should be a routine part of monitoring patients1 RVR (HCV RNA undetectable by Week 4) In patients with HCV genotypes 2 and 3 who achieve RVR, 12 weeks of peg-IFN + RBV as effective as 24 weeks2 1. NIH. Available at: /2002/2002HepatitisC2002116html.htm. Accessed April 11, 2007. 2. Mangia A, et al. N Engl J Med. 2005;352:2609-2617. Pawlotsky JM. Hepatology. 2002;36(suppl 1):S65-S73. Sethi A, et al. Clin Liver Dis. 2005;9:453-471. Virologic Monitoring Markers and Definitions of Response to Treatment ETRUndetectable HCV RNA at end of treatment Virologic Breakthrough Decline in HCV RNA to undetectable levels followed by rebound of detectable HCV RNA despite continued treatment SVRHCV RNA negativity 24 weeks after treatment end Relapse E