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TERAPIA PER LA EPATITE DA HBV IFN, LAMIVUDINA, ADEFOVIR ed oltre…….

TERAPIA PER LA EPATITE DA HBV IFN, LAMIVUDINA, ADEFOVIR ed oltre……. Felice Piccinino Dipartimento Malattie infettive II Università Napoli. HBV: End points of treatment. e Ag Neg. ALT NORMAL. Anti e Pos. “HARD” PREVENT FIBROSIS CIRRHOSIS, HCC AND LIVER FAILURE. DNA(HYB.) neg.

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TERAPIA PER LA EPATITE DA HBV IFN, LAMIVUDINA, ADEFOVIR ed oltre…….

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  1. TERAPIA PER LA EPATITE DA HBVIFN, LAMIVUDINA, ADEFOVIR ed oltre……. Felice Piccinino Dipartimento Malattie infettive II Università Napoli

  2. HBV: End points of treatment e Ag Neg ALT NORMAL Anti e Pos “HARD” PREVENT FIBROSIS CIRRHOSIS, HCC AND LIVER FAILURE DNA(HYB.) neg ERADICATION ccc DNA ? DNA(PCR) neg Methods??? Anti HBs Pos HBsAg Neg

  3. Serum HBV DNA and Liver Inflammation in Chronic Hepatitis B Review of 26 prospective studies Correlation between HAI and HBV DNA in untreated patients (r=0.78; P=0.0001) Correlation between change in HBV DNA and HAI with treatment (r=0.96; P<0.0000) Mommeja-Marin H, et al. Hepatology. 2003:37:1309-1319.

  4. Level of DNA suppression • < 50 g/ml • < 1000 g/ml • < 10 4 g/ml • < 10 5 g/ml 1 UI = 5 g

  5. INTERFERONE

  6. Interferon in HBeAg-negative CHB: Sustained Response and HBsAg Clearance SR-12 (ALT normal/HBV-DNA negative by non-PCR assay) HBsAg clearance (with or without anti-HBs) 50 26% to 67% of sustained responders 40 30 % Patients 32% 30% 20 27% 23% 15% 10 15% 10% 9% 10% 6% 0 Manesis, Papatheodoridis (209 cases) Lampertico Colombo (101 cases) Brunetto Bonino (103 cases) FattovichAlberti (88 cases) SantantonioPastore (81 cases)

  7. GLI ANALOGHI

  8. HBV DNA e ALT dopo un anno di terapia con LAM in pazienti HBeAg neg 80 65% 70 60 Patients (%) 50 40 28% 30 20 Missing Data 7% 10 0 HBV DNA -ve, ALT Normal Responders HBV DNA -ve, ALT elevated Partial responders HBV DNA and ALT elevated Non-responders Tassopoulos et al. Hepatology1999

  9. 12% 29% 60% Attività istologica (HAI) dopo un anno di terapia con LAM in pazienti HBeAg neg Improved  2 point reduction No Change  1 point change Worsened 2 point increase Missing data excluded (n=42) Tassopoulos et al. Hepatology1999

  10. Adefovir in naïve HBeAg-neg CHB Median Change of HBV DNA Through 48 Weeks Placebo =61 pts Adefovir Dipivoxil 10 mg/daily = 123 pts 0 - 1.35 log10 copies/ml PLB -1 0% Change in HBV DNA (log copies/ml) HBV DNA < 400 copies/ml p < 0.001 -2 - 3.91 log10 copies/ml 51% -3 ADV -4 Base line 0 4 8 12 16 20 24 28 32 36 40 44 48 4 8 12 16 20 24 28 32 36 40 44 48 Week of study (Hadziyannis et al., NEJM 2003)

  11. 48 weeks of Adefovir dipivoxil (ADV) significantly reduces cccDNA Design: ADV n=22 p=0.002 PLB n=10 Baseline Biopsy Week 48 Biopsy Median -0,8 log reduction from baseline cccDNA in biopsies measured by quantitative real-time PCR Werle, Petersen, Locarnini, Zoulim Gastroenterology 2004

  12. HBV-CH: Cinetica antivirale di LAM ed ADV LAM 8 TERAPIA ADV 7 6 5 HBV DNA Log 4 3 2 1 0 6 12 18 24 MESI

  13. Response to antiviral therapy in HBeAg-negative chronichepatitis B Treatment On-Therapy Sustained HBsAg Response Response loss Interferon >12 months 50-75% 20-30% 10-15% Lamivudine 12 months 60-80% ~10% - 24 months 50-60% ? - >36 months 30-40% ? - Adefovir 12 months 70% ? - (modified from EASL HBV Consensus, J Hepatol 2003)

  14. Long Term Benefit with Adefovir therapy over Time in HBeAg-negative patients HBV DNA < 1000 c/ml ALT Normal 88% 83% 90 79% 73% 80 71% 70 64% 60 Percentage of Patients 50 40 30 20 3% 10 0% 0 Week 0 Week 48 Week 96 Week 144 (3 Yr) Hadziyannis et al., EASL 2004

  15. IL PROBLEMA DELLE RESISTENZE

  16. Limits of new treatments for HBV chronic hepatitis: viral resistance mutations Lamivudine Y inhibition Nucleotides ss (-) DNA M high affinity D D HBV polymerase(wild type) Y = Tyrosine M = Methionine I = isoleucine or V = valine D = Aspartate

  17. Terapia con LAM:Cinetica della resistenza virale Riattivazione Da 5 a 30 mesi LAMIVUDINA 90% Virologica Biochimica ALT HBV DNA Hybridization assay 1 log PCR assay 6 12 mesi Resistenza Genotipica LiPA + + + RLFP + + + Direct sequencing - + + (Santantonio et al, 2002)

  18. Risposta ad ADV in pazienti con epatite cronica da HBV resistenti alla LAMIVUDINA +0.3 log 49 pts Lamivudine + Placebo (compensated) Median HBV DNA (log10 copies/ml) 46 pts Lamivudine + Adefovir (compensated) Lamivudine + Adefovir (decompensated) 40 pts -4.6 log weeks Perrillo et al. Gastroenterology 2004

  19. 0 0 Patients still at risk 28 3 1 0 0 0 0 9 4 2 32 22 14 10 6 5 3 14 13 12 11 10 9 6 4 Livelli di DNA e risposta virologica ad ADV in pazienti Anti- e con resistenza alla LAMIVUDINA 3-6 log HBV-DNA 6-8 log HBV-DNA Pts with undetectable HBV-DNA % >8 log HBV DNA p<0.0001 Months (Lampertico et al., Hepatology 2005, in press)

  20. Therapeutic strategies in HBV Nucleos(t)ide-based treatment  Extended/lifelong treatment On treatment response 1 Lamivudine Adefovir dipivoxil Antiviral C Antiviral with a low frequency of resistance (ADV) 2 Combination of 2 antivirals 3 Years

  21. LAM ADV ETV LdT FTC Reported HBV Polymerase Mutations by Treatment Resistance mutations associated with viral rebound in patients on treatment M204V M250V L180M N236T V173L A184G A181V M204I S202I Selection of YMDD mutants affects future treatment options

  22. Treatment of HBV Resistance

  23. HBV – CH : Azione Analoghi nucleos(t)idici POTENZA Rapidità + Efficacia ETV TEL LdT LAM 3TC TDV PMPA EMT FTC ADV PMEA BARRIERA GENETICA

  24. LE COMBINAZIONI

  25. HCV-CH: Presupposti alla terapia di combinazione • Mutazioni virali preesistono alla terapia • Il cccDNA è l’archivio genetico delle mutazioni resistenti • Il ritrattamento provoca una rapida riemergenza delle mutazioni • Sotto pressione antivirale combinata le varianti genetiche hanno meno probabilità di emergere Zhu AAC 1999; Werle, Gastroenterology 2004; Villeneuve J Hepatol 2003; Richman AASLD 2004; Durantel Hepatology 2004

  26. ADEFOVIR Frequency ?? Lam + ADF -R Prevenzione delle resistenze con terapia di combinazione: la teoria Wild type v LAMIVUDINE Lam-R ADF-R Zoulim, Antiviral research, 2004

  27. 100 80 60 Incidence of resistance* (%) 34% 40 21% 20% 18% 20 12% 11% 5% 2% 1% 0 LAM LAM+ADV LAM LAM+Peg LAM LAM+Peg LAM LAM+LdT LdT Sung 1 Marcellin 2 Lau 3 Lai 4 Prevenzione della resistenza alla LAM con terapie di combinazione * After 1- year therapy 1 Sung et al. J Hepatol 2003 ;38 (suppl 2):25-26 2 Marcellin et al. N EnglJ Med 2004; 351: 1206-17 3 Lau et al. Hepatology 2004;40:171A 4 Lai et al. Hepatology 2003;38:262A

  28. TERAPIA EPATITE CRONICA DA HBV Conclusioni 1 • IFN in prima scelta (PEG IFN > IFN St) • Soppressione stabile dopo sospensione • Possibile perdita HBsAg ( Anti- HBs+ ) • Meno tollerato degli analoghi • Non dà resistenze

  29. TERAPIA EPATITE CRONICA DA HBV conclusioni 2 • Nei non responders o non tolleranti ad IFN terapia continua con LAM o ADV o combinazione. • Nel cirrotico avanzato ADV- monoterapia o combinazione • Nei pazienti in terapia con LAM attento monitoraggio, se riattiva, immediatamente ADV • Nei resistenti ad ADV,LAM o altri analoghi. ??? • Entecavir ! Tenofovir !

  30. GRAZIE DELL’ASCOLTO

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