Akut C ve Kronik hepatit C`li hastanın güncel tedavisi
Transkript
Akut C ve Kronik hepatit C`li hastanın güncel tedavisi
HCV’DE GÜNCEL TEDAVİ Dr Murat ALADAĞ 15 Haziran 2003 MALATYA Dünyada HCV Sıklığı WHO. Wkly Epidemiol Rec 2000; 75: 18-9. Dünya’da prevalans % 3 (1) Dünya ölçeğinde 130 - 210 milyon kişi Hepatit C ile infekte (1) Türkiye’de prevalans % 0.5-1(2,3) 1) EASL Clinical Practice Guidelines: Management of hepatitis C virus infection, 2011 2) TKAD 2010 3) VHSD 2010 HCV infeksiyonunun doğal seyri Primer infeksiyon Kronik infeksiyon Viral Klirens Kronik Hepatit C %75-85 Asemptomatik %75 Siroz %20 (20-30 yıl) HCC %1-4 (Sirozdan sonra her yıl) Semptomatik %25 %15-25 Chen ve Morgan Int J Med Sci 2006 Akut HCV enfeksiyonu HCV infeksiyonu %50-90 oranlarında asemptomatik 2-12 hafta içinde kuşkulu HCV bulaşı ALT seviyesinde en az 10 kat ve üzeri artış Total bilirubin seviyesindeki artış +/ Anti-HCV pozitif /negatif olabilir Anti- HCV negatif iken pozitifleşmesi önemli. -Hepatit C kesin tanısı serumda HCV RNA pozitifliği… Akut Akut HCV enfeksiyonu Anti-HCV pozitif /negatif olabilir (Anti- HCV negatif iken pozitifleşmesi önemli) Hepatit C kesin tanısı için serumda HCV RNA’nın pozitifliği gereklidir Akut HCV tedavi Semptomatik olgularda tedavi için 8-12 hafta beklenmeli • spontan iyileşme oranı %15-25 Tedavide • Pegile IFN-alfa • 12. haftada HCV RNA seviyesinde 2 log azalma koşulu aranmaz • Tedavi süresi en az 6 ay (ribavirin kullanımı olgu bazında değerlendirilmeli) AASLD 2004 7 Annual age-adjusted mortality rates from hepatitis B and hepatitis C virus and HIV infections listed as causes of death in the United States between 1999 and 2007.Because a decedent can have multiple causes of death, a record listing more than 1 type of inf... Ly K N et al. Ann Intern Med 2012;156:271-278 ©2012 by American College of Physicians Time is critical The average age of an HCV-infected patient is approximately 55 yrs Perhaps 40% have cirrhosis 10,000-15,000 die each year and is increasing Only 25-30% of HCV patients have been diagnosed Only 11% have been treated Objectives Patterns of response Predictors of response Past therapies Understanding the life cycle of HCV Current treatments Targets for anti-HCV drugs Existing data Future directions Patterns of response HCV RNA NR (null responder) Breakthrough 2 log↓ LVR Relapse RVR eRVR < 25 IU cEVR 0 4 8 pEVR 12 24 36 Time (weeks) 48 72 Standart tedavi pegINF ve ribavirin 48 hafta Genotip 1,4,5,6 SVR %40-50 pegINF ve ribavirin 24 hafta Genotip 2,3 >SVR %80 Virolojik kür YENİ GELİŞME: DİREKT ETKİLİ ANTİVİRAL AJANLAR Genotip 1 için yanıt süresine göre tedavi HVR 4.hafta HCV RNA negatif HCV RNA pozitif (400.000 IU/ML) 24 hafta tedavi EVR 12.hafta negatif 2 log azalma Tedaviyi kes 48 hafta tedavi 24. hafta 2 log azalma negatif 48-72 hafta tedavi pozitif Tedaviyi kes Genotip 1 için yanıt süresine göre tedavi Genotip-1 HCV RNA ≥600 000 IU/ml <600 000 IU/ml 4. Hafta HCV RNA Pozitif Negatif 12. Hafta HCV RNA ≥ 2 log azalma 24 hafta tedavi 24 hafta takip < 2 log azalma 24. hafta PCR HCV RNA Pozitif Negatif 48 hafta tedavi 24 hafta takip Tedaviyi kes (sirotikse idame?) Manns MP, e tal. Gut 2006; 55: 1350-59. Past HCV Therapy (2001-2010) PegIFN + RVN 100 90 80 70 60 % SVR 50 40 30 20 10 0 RVR cEVR pEVR GT 1 and 4 LVR RVR EVR GT 2 and 3 Predictor of Response Favorable Genotype 2 and 3 HCV RNA < 400,000 IU/ml Mild fibrosis (F0-F2) Non-African American Age < 40 IL28B CC Adherence RVR cEVR Unfavorable Genotype 1 HCV RNA > 400,000 IU/ml Advanced fibrosis (F3-F4) African American Age > 40 Steatosis Insulin Resistance Increased BMI IL28B CT or TT Dose reduction > 60% Non-adherence IL28-B POLYMORPHISM IMPACT ON SVR 100 SVR (%) 80 60 40 20 0 TT D Ge et al. Nature 2009; 461:399-401. TC CC IL28-B POLYMORPHISM AND SVR IMPACT OF RACE AND ETHNICITY 100 Asians SVR (%) 80 Caucasians 60 Hispanics 40 20 African Americans 0 30 40 50 60 70 80 IL28B CC HAPLOTYPE (%) D Ge et al. Nature 2009; 461:399-401. 90 100 IL28-B POLYMORPHISM IMPACT OF RACE AND RESPONSE 100 SVR (%) RVR 80 No RVR 60 40 20 0 CC Non-CC Caucasian A Thompson et al. AASLD abstract 2009; LB5. CC Non-CC African American Outdated Strategies Higher doses of PEG or RBV Another kind of ribavirin (taribavirin) Lower anemia rates Similar SVR if dosed properly Another kind of interferon No real improvements on SVR Consensus, albumin-interferon, continuous infusion Longer duration Best for slow responders Difficult to tolerate Where are we now? 24 HCV Life Cycle and DAA Targets Receptor binding and endocytosis Transport and release Fusion and uncoating ER lumen (+) RNA LD LD Translation and NS3/4 protease polyprotein inhibitors processing Membranous web Virion assembly LD ER lumen NS5A* inhibitors *Role in HCV life cycle not well defined Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000. NS5BRNA polymerase inhibitors replication Nucleoside/nucleotide Nonnucleoside HCV Polyprotein Processing and Viral Protein Function McGovern B, Abu Dayyeh B, and Chung RT. Hepatology. 2008; 48:1700-12 New Agents Telaprevir Protease inhibitor (NS3/NS4A) Phase ¾ Boceprevir Protease inhibitor (NS3/NS4A) Phase 3/4 ITMN-191 (R7227) Protease inhibitor (NS3/NS4A) Phase 2 BI12202 Protease inhibitor (NS3/NS4A) Phase 2 TMC435350 Protease inhibitor (NS3/NS4A) Phase 2 MK7009 Protease inhibitor (NS3/NS4A) Phase 2 R1728 Nucleoside Polymerase inhibitor (NS5B) Phase 1 MK-0608 Nucleoside Polymerase inhibitor (NS5B) Phase 1 GS9190 Non-nucleoside Polymerase inhibitor (NS5B) Phase 1 Filibuvir (PF00868554) Non-nucleoside Polymerase inhibitor (NS5B) Phase 1/2 VCH-759 Non-nucleoside Polymerase inhibitor (NS5B) Phase 1 BMS-790052 NS5A inhibitor Phase 1 Nitozoxinide Host-pathway Phase 2 DEBIO-025 Cyclophilin inhibitor Phase 2 NIM811 Cyclophilin inhibitor Phase 1 CTS-1027 Matrix metalloproteinase inhibitor Phase 1/2 Telaprevir in GT 1 ADVANCE and REALIZE trials 90 80 70 60 % SVR 50 T+P+R P+R 40 30 20 10 0 Naïve Relapser Partial Responder Nul Responder Telaprevir Genotype 1a vs. 1b 90 80 70 60 %SVR 50 1a 1b 40 30 20 10 0 Naïve (T12/PR48) Relapser Partial Responder Null Responder Boceprevir in GT1 SPRINT 2 and RESPOND 2 80 70 60 50 %SVR 40 B+P+R P+R 30 20 10 0 Naïve Relapser Partial Responder TREATMENT OF CHRONIC HCV RESPONSE GUIDED THERAPY It is essential that HCV RNA be monitored at regular intervals and that the time the patient becomes HCV RNA negative be defined. The sooner a patient becomes HCV RNA undetectable during treatment the lower the relapse rate and the shorter the course of therapy. The longer it takes for a patient to become HCV RNA undetectable the longer they must remain on treatment to limit relapse. ADVANCE: Telaprevir with Response Guided Therapy in naïve HCV-1 eRVR = HCV RNA(-) @W4,12: Yes 24W, No 48W TPV 750 mg q8h; PEG-2a; WB RBV 100 P < 0.0001 SVR (%) 80 60 P <0.0001 75 69 44 40 20 0 PegIFN/RBV + Placebo 48w (n=361) eRVR, % Relapse, % DC rash, T or Pl/all % DC any AE,% 8 28 1/0 4 TPV 12w+ PegIFN/RBV RGT (n=363) 58 9 7/1.4 7 TPV 8w+ PegIFN/RBV RGT (n=364) 57 9 5/0.5 8 Jacobson I et al, NEJM 2011;364:2405-16 ILLUMINATE: Randomized trial of short vs. long duration Rx after eRVR Gt 1 naive (N=540) Peg2a /WB RBV/TPV x 12 wks Randomize +12 wks P/R (n=162) SVR 92% met noninferiority criteria A truncated PEG/RBV/TPV regimen preserves high rates of SVR following eRVR Wk 4, 12 HCV RNA (-) 65.2% (n=352) +36 wks P/R (n=160) SVR 87% Sherman K et al, AASLD 2010; abstract LB-2 Response Guided Therapy with Boceprevir non-cirrhotic HCV RNA Undetectable < 100 IU/mL Undetectable Lead in BOC + P + R PR 0 4 8 Detectable 12 eRVR, stop at week 28 24 < 100 IU/mL 28 36 48 Undetectable No RVR BOC + P + R PR 0 4 8 12 24 Stop PR 28 If HCV RNA > 100 IU/mL 36 48 Response Guided Therapy with Telaprevir non-cirrhotic naïve or experienced relapsers HCV RNA Undetectable Undetectable Undetectable P+R T+P+R 0 4 8 Detectable 12 24 < 1000 IU/mL eRVR, stop at week 24 28 36 48 Undetectable No RVR T+P+R 0 4 8 PR 12 24 Stop 28 36 If HCV RNA >1000 IU/mL 48 Treatment of Null Responders and Cirrhotics HCV RNA Undetectable < 100 IU/mL Undetectable Non-cirrhotics stop week 36 Cirrhotics continue to week 48 Lead in BOC + P + R PR 0 4 8 12 24 36 48 HCV RNA Undetectable Undetectable P+R T+P+R 0 4 Undetectable 8 12 24 28 36 48 Adverse Events with DAA Telaprevir T/P/R P/R Pruritis 45-50% 28% Nausea 40-43% 31% 56% 34% Anemia 37-39% 19% Diarrhea 28-32% 17% 11% 3% Rash Anorectal discomfort Boceprevir Anemia 50% 30% 35-43% 16% Neutropenia 25% 19% Nausea 46% 42% Dysgeusia Telaprevir Rash Summary In most subjects, the rash was mild-moderate Severe rash in 4% resulting in discontinuation in 6% of subjects Occurred early, usually first 4 weeks but can occur at any time during TVR exposure < 1% had Stevens Johnson Syndrome or DRESS Treated with oral antihistamines, topical and/or systemic steroids No data available on effectiveness Systemic steroids are not recommended Advisory Committee Briefing Document for NDA 201-917 Telaprevir 375 mg tablets. Silver Spring, MD; April 1, 2011. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AntiviralDrugsAdvisoryCommittee /UCM252561.pdf. Accessed May 20, 2011. Drug-Drug Interactions Boceprevir Strong inhibitor of CYP3A Partly metabolized by CYP3A Telaprevir Substrate of CYP3A Inhibitor of CYP3A Important Safety Information Contraindicated Drugs and Other Precautions for Telaprevir Contraindicated Potential for increased toxicity from concomitant medication Not recommended Alfuzosin (UroXatral) Methylergonavine (Methergine) Amiodarone (Cordarone, Pacerone) Midazolam oral* (Versed) Dihydroergotamine (D.H.E. 45 and Migranal) Pimozide (Orap) Ergonvine (Ergonovine Maleate) Propafenone (Rythmol) Ergotamine (Ergomar) Flecainide (Tambocor) Lovastatin (Altocor, Altoprev, Mevacor) Quinidine (Quinaglute Dura-Tabs, Quinidex Extentabs, Cardioquin, Quinora) Budesonide inhaled (Pulmicort Flexhaler, Pulmicort Respules) Use with caution Alprazolam* (Niravam, Xanax) Atorvastatin* (Lipitor) Nifedipine (Adalat, Afeditab CR, Nifediac, Nifedical, Procardia) Bosentan (Tracleer) Nisoldipine (Sular) Clarithromycin (Biaxin) Posaconazole (Noxafil) Colchicine§ (Colcrys) Sildenafil for ED (Viagra) Desipramine (Norpramin) Tadalafil for ED (Cialis) Digoxin* (Lanoxin) Telithromycin (Ketek) Diltiazem (Cardizem, Dilacor, Tiazac) Tenofovir* (Viread) Amlodipine* (Norvasc) Colchicine† (Colcrys) Cyclosporine*‡ (Atopica, Gengraf, Neoral, Sandimmune, Fluticasone inhaled (Flovent) Salmeterol (Serevent) Sildenafil for PAH (Revatio) Sirolimus‡ (Rapamune) Simvastatin (Zocor) Tacrolimus*‡ (Prograf ) Triazolam (Halcion) Tadalafil for PAH (Adcirca) Erthromycin (E.S.P., Eryzole, Pediazole, Sulfimycin) Felodopine (Plendil) Voriconazole (Vfend) Nicardipine (Cardene) Itraconazole (Sporanox) *These interactions have been studied; †Impaired renal/hepatic function; ‡No clinical data are available regarding the treatment of Ketoconazole* organ transplant patients with TRADENAME in combination with peg-IFN/RBV. Therefore, the use of TRADENAME in organ transplant (Feoris, Nizoral) patients is not recommended; §Normal renal/hepatic function. Lidocaine (Xylocaine) Trazadone (Desyrel, Oleptro) Vardenafil (Levitra, Staxyn) Verapamil (Calan, Covera, Isoptin, Verelan) Warfarin (Coumadin, Jantoven, Marfarin) Drugs that are contraindicated Telaprevir and Boceprevir Effect St. Johns Wort May reduce virologic response Rifampicin May reduce virologic response Ergot drug class Potential for ergot toxicity Lovastatin, simvastatin Potential for myopathy Sildinafil (in Tx of pulmonary HTN) Potential for PDE5 associated AE Midazolam (oral) Prolonged sedation Triazolam Prolonged sedation Boceprevir Phenobarbitol, Phenetoin, Carbamezepine May reduce virologic response Oral contraceptives (Drosperinone) Potential for hyperkalemia Monitoring HCV RNA Package inserts for TVR and BOC specific different time points during therapy. TVR weeks 4, 12, and 24 BOC weeks 8, 12 and 24 Different labs use different assays. Different thresholds for using RGT. TVR week 4 1000 IU/mL BOC week 8 100 IU/mL Different thresholds for defining futility. Stopping Rules Telaprevir Time point HCV RNA Action Week 4 or 12 > 1000 IU/mL Stop T/P/R Week 24 Detectable Stop P/R Boceprevir Time point HCV RNA Action Week 8 or 12 > 100 IU/mL Stop B/P/R Week 24 Detectable Stop P/R İLAÇ REZİSTANSMONİTORİZASYONU NS3/4A nın katalitik domaini-mutasyonlar Cross rezistans var Antiviral rezistan varyantlar: Bazal dönemde %7 BOC, %5 TVR. Ancak bu PI ile uzun dönem sonuçları etkilemiyor. Bazal rezistans analizine gerek yok BOC: Naiv olgularda tedavi sırasında %16 olguda direnç. İlk 4 hf lık Peginf+ribavirin ile HCV RNA 1 log dan az düşme BOC için artmış direnç riskidir. TVR: Naiv olguda %12 tedavi almış olguda %22 İnterferon yanıtsızlığı: PI’lerine direnç artar. Genotip 1a>1b ANTİVİRAL İLAÇ DİRENCİ BİR PI/İLACA DİRENÇ VARSA DİĞERİNE GEÇİLMEZ ! So, are we there yet? Not yet, but we are getting there. New Combinations New DAAs Genetic tests EMR Peg RVN DAA Resistance Increasing Complexity Of HCV Management RGT E-scribe Cost Compliance Identifying Candidates For Triple Therapy Host factors Treatment regimen Age, gender, race obesity, co-morbidities Genetic factors (IL28B and ITPA) PEG-IFN Ribavirin DAA Factors to Consider In Treatment Decisions Disease features Fibrosis, steatosis, co-infection (HBV, HIV) Viral factors Genotype / Subtype Quasispecies / Resistance Viral load Conclusions HCV is now more curable than ever. Standard dose ribavirin and PEG interferon will remain as backbone of therapy for now. DAA ? Need for lead in phase to minimize development of resistance and identify those with RVR that may not need additional agents. Newer antiviral agents with few side effects Combining agents of different classes to avoid interferon and/or ribavirin Frequent HCV RNA testing. The Future 0 10 PEG/RBV PI+PEG+RBV PI2+PEG+RBV 20 30 40 % 50 DAA1 + DAA2 + RBV 60 70 80 90 100 2011 2012 2013 2014 2015 2016 2017 2018 2019 Unanswered Questions How does IL28B testing fit in with DAA therapy? Do we still need to biopsy all patients? Will DAA ever be used for GT 2 and 3? Does it make a difference what Peg is used? When will interferon free regimens really be here? Will we ever have a HCV vaccine? SONUÇ OLARAK HCV’nin yeni standart tedavisi olarak düşünülen proteaz inbitörleri her vakada kullanılacak kadar; Çok yüksek etkinlikte, yan etkisiz, tedaviye uyumu kolay ve ucuz değildir. Gelecek tedavileri riske atacak direnç problemleri vardır. Tedavide seçici olunmalıdır. Uyum çok önemli Hem BOC hem de TVR tedavisinde öncü tedavi uygulaması yararlı olabilir. 53 İNÖNÜ ÜNİVERSİTESİ DENEYİMİ-AKUT HCV Toplam 16 hasta Tanı rastlantısal olarak veya diabet ve diğer hastalıkları inceleme esnasında konuldu Tedaviye 4 hastada klasik interferon 12 hastada PEG-INF başlandı Tüm olgularda tedavi sonu cevap alındı 3 ayda ve 6 ayda negatif Tedavi sonu 6ay SVR %100 İNÖNÜ ÜNİVERSİTESİ DENEYİMİ-Kronik HCV Klasik ikili tedavi Tedavi sonu cevap (ERV) SVR 1. yılda nüks 2. yılda nüks 3. yılda nüks %80 %60 %10 %20 %27 İNÖNÜ ÜNİVERSİTESİ DENEYİMİKr HCV Yüksek doz Ribavirin Olgu sayısı 32 Yaş ortalaması 42 (18-65) HCV-RNA 320 (75-1600.000) RVR 23 (%71.8) 12. hafta RNA Negatif 29 (%90.62) 24. hafta RNA Negatif 30 (%93.75) SVR 29 (%90.62 Sadece 2 olguda HCV-RNA>400.000 idi Tedavinin 3. Ayından sonra cevap veren bir olguda tedavi kesilmesindne sonra nüks olduğu görüldü. İNÖNÜ ÜNİVERSİTESİ DENEYİMİ-Tx olguları Toplam 1034 Tx olgumuzun %6.9’ u HCV T x sonrası HCV tedavisi 1. yılın sonunda başlandı Toplam 10 Tx olgusuna tedavi verildi. Tedavi sonu cevap oranı %80 Kalıcı cevap oranı (SVR) %70 Kan transfüzyonu normal hastalardan daha fazla gerekli oldu Halen tedavisi devam eden 2 olgu var İNÖNÜ ÜNİVERSİTESİ DENEYİMİ-DAA deneyimi 16 sirotik olgu alındı Yaş aralığı 53-74 4 hafta HCV-RNA negatifliği %100 12 hafta tamamlayan 9 olgu HCVRNA neg %100 7 olgu tedavi devam ediyor En sık yan etki -Anal ağrı -Ağızda tat bozukluğu -Ciltte kaşıntı ve lezyonlar -Bir olguda pnömoni -Anemi, trombositopeni İNÖNÜ ÜNİVERSİTESİ DENEYİMİ-DAA deneyimi Kan transfüzyonu ihtiyacı çok fazla oldu Bir olguda diş çekimi öncesi trombosit 30.000 olduğu için trombosit aferezi verildi Cilt lezyonları steroidli krem ve güneş koruyucu lar ve antihistaminiklerle tedavi edildi. Tedavi bıraktırılmasını gerektiren yan etki olmadı Bir hasta tedavinin 17 haftasında devam etmek istemedi ve bıraktığında HCV-RNA negatif idi. İNÖNÜ ÜNİVERSİTESİ DENEYİMİ-DAA deneyimi 69