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Tratamiento de la hepatitis C en pacientes coinfectados por VIH: importancia de la cinética viral

Tratamiento de la hepatitis C en pacientes coinfectados por VIH: importancia de la cinética viral. Vicente Soriano Servicio de Enfermedades Infecciosas Hospital Carlos III, Madrid. Why to priorize hepatitis C treatment in HIV co-infected patients. Accelerated progression to liver cirrhosis.

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Tratamiento de la hepatitis C en pacientes coinfectados por VIH: importancia de la cinética viral

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  1. Tratamiento de la hepatitis C en pacientes coinfectados por VIH: importancia de la cinética viral Vicente Soriano Servicio de Enfermedades Infecciosas Hospital Carlos III, Madrid

  2. Why to priorize hepatitis C treatment inHIV co-infected patients • Accelerated progression to liver cirrhosis.  50% F3-F4 on average after 25 years of HCV infection • Higher risk of hepatotoxicity of ARV drugs. 12-15% (HCV-pos) versus 5-7% (HCV-neg)

  3. % Martin-Carbonero et al. CID (in press) European Collaborative Study 914 HIV+ patients with chronic hep C and ALT

  4. Fibrosis in Patients with Chronic Hepatitis C and Elevated ALT No. F0 F1 F2 F3 F4 HIV-neg147651% 24% 10% 10% 5% HIV-pos2,31044% 25% 24% 29% 18% 91410% 33% 22% 22% 13% 1 Forns et al. Hepatology 2002; 36: 986-92 2 Berenguer et al. ICAAC 2002: H-1726 3 Martin-Carbonero et al. CID (in press)

  5. Sustained virological response to pegylated interferons No. Overall patients response HCV-1HCV-3 Roche IFN + RBV 444 44% 37% 46% Pegasys 224 29% 21% 56% Pegasys + RBV 453 56% 46%76% Schering-Plough IFN + RBV 505 47% 33% 79% Peg-Intron 1.5/0.5 + RBV 514 47% 34% 80% Peg-Intron 1.5 + RBV 511 54% 42%82% Fried et al. NEJM 2002 Manns et al. Lancet 2001

  6. Draw-backs of anti-HCV therapy in HIV coinfection • Lower response rate. 25-35% SVR using Peg-IFN+RBV • High rate of side effects (mainly due to interactions with ARV drugs) anemia, hyperlactatemia, pancreatitis, severe weight loss

  7. Anti-HCV Treatment in HIV-pos patients IFN+RBV 1Peg-IFN+RBV 2 No. 111 65 Mean age 36 37 Sex (male) 82% 81% IVDUs 80% 94% On ARV 82% 94% HCV gen 1 & 4 62% 70% HCV-RNA >8x105 66% 55% Response EOT 29% 50% Sustained response 22.3%33% Stop due to AEs 12% 14% Soriano et al. ARHR 2003 (in press) Perez-Olmeda et al. AIDS 2003; 17: 1023-8

  8. Peg-IFN + RBV for Hep C in HIV HCV-RNA neg HCV-1/4 HCV-2/3 Stop Study No.HCV-1/4at 24 weksSVRSVRSVR AEs Goelz2545%36%20%??32% Pérez-Olmeda6865%50%33%24%52%15% Perrone100 69% ? 28% 25% 42% 28% Rockstroh 30 73% 57% ? ? ? 13% Hopkins 16 37% 45% ? 0% 62% 6% Chung 133?44%?33%80%? Cargnel 32 ? 56% 34% 20% 80% 25% HCV-HIV Consensus Panel. Updated recommendations AIDS 2003 (in press)

  9. Why lower response rates to anti-HCV therapy in HIV+ patients? • More advanced fibrosis grade. • Higher rate of steatosis (NRTIs, etc) • Unfavorable HCV virological features. • Higher discontinuation due to side effects. • Lower drug compliance. • Lower initial HCV-RNA clearance. • Higher relapse rates.

  10. Early HCV dynamics on Tx 1st phase (clearance of virions) Treatment responders 2nd phase (clearance of infected cells) Neumann et al. Science 1998

  11. Early HCV dynamics on Tx 1st phase (clearance of virions) Non responders 2nd phase (clearance of infected cells) Neumann et al. Science 1998

  12. Early response to anti-HCV therapyWhen to Stop Therapy? • Predictors of sustained response: • Negative serum HCV-RNA at week 24 • >2-log drop HCV-RNA at week 12 a • a NIH Consensus. Gastroenterology2002; 123: 2082-99.

  13. Early response to anti-HCV therapyWhen to Stop Therapy? • Predictors of sustained response • Negative serum HCV-RNA at week 24 • >2-log drop HCV-RNA at week 12 a • Delayed HCV-RNA clearance in HIV/HCV coinfection b • a NIH Consensus. Gastroenterology2002; 123: 2082-99. • b Torriani et al. 9th CROI; Seattle, February 2002. Abstract 121.

  14. 1st phase (clearance of virions) HIV 2nd phase (clearance of infected cells) Neumann et al. Science 1998 Early HCV dynamics on Tx

  15. Patients and Methods • 89 HIV/HCV-coinfected patients who completed a course of pegylated IFN alfa-2b plus ribavirin 800 mg/day. • Elevated serum ALT. • CD4 counts > 300 cells/ul & HIV-RNA < 104 cop/ml. • No active alcohol or drug abuse. • No prior serious psychiatric conditions.

  16. Early virologic response >2 log HCV-RNA drop at week 12 SVR 29 (56%) 52 (58%) 23 89 37 0 neg HCV-RNA at week 24 SVR 29 (67%) 48 (54%) 19 89 41 0 Soriano et al. CID (in press) Negative predictive value: 100%

  17. PRESCO preliminary data Pegylated interferon alfa-2a + RBV 1-1.2 g/day HCV-RNA drop >2 logs Wk No.Disc/lostyesnocomments 4 60 4 35 21 15 G1, 1 G3, 5 G4 (57%) 12 65 7 55 3 2 G1, 1 G4 (95%) On treatment analysis Nuñez et al. CROI (submitted)

  18. Implications for Monitoring • Early virological response to anti-HCV therapy predicts the chance of sustained response in HIV-coinfected patients, as it does in HCV-monoinfected individuals. • The slower decline of HCV-RNA in co-infected patients does not preclude that only those patients showing a reduction in HCV-RNA > 2 logs at week 12 of therapy, will have the chance of attaining sustained virological response. • Therefore, treatment might be discontinued in the rest (in the light of side effects and cost).

  19. 1st phase (clearance of virions) 2nd phase (clearance of infected cells) HIV Neumann et al. Science 1998 More relapses in HIV-HCV coinfection?

  20. Relapses in HIV-HCV coinfected patients with neg HCV-RNA at the end of therapy 19 / 48 (39.6%) neg HCV-RNA relapses at end of therapy HCV gen 1-4 19 / 55 8 42.6% HCV gen 2-3 29 / 34 11 37.9% Perez-Olmeda et al. ARHR (in press)

  21. Predictive value of SVR 65% YES 86% 56% SVR 35% YES 58% no. = 453 NO HCV-RNA drop > 2 logs 44% 3% no. = 89 YES NO 14% 0% SVR 97% 42% NO HIV-neg (Fried et al. NEJM 2002) 100% HIV-pos (our study)

  22. HCV Treatment Algorithm Peg IFN + RBV week 12 HCV-RNA measurement > 2 log  < 2 log  week 24 HCV-RNA stop qualitative neg pos continue until month 12 (HCV 1-4) NIH Consensus. Gastroenterology2002;123:2082-99.

  23. Final considerations • All HIV+ individuals should be screened for HCV antibodies. Active HCV infection should be excluded by PCR. • Coinfected persons should be evaluated for liver disease and for HCV treatment. • Treatment should be offered preferentially to patients with elevated ALT, controlled HIV infection (CD4 >350 cells/mm3 and HIV-RNA <50,000 copies/mL), and lack of contraindications (IVDU, alcohol). • Monitorization of treatment response should be done using a sensitive quantitative virological assay. Assessment of 2 log HCV-RNA drops at week 12 of therapy may permit to identify who will not benefit from extending treatment and therefore may discontinue it, avoiding unnecessary drug exposure and cost. • In early virologic responders, treatment beyond standard periods (6 months for HCV-2/3 and 12 months for HCV-1/4) might reduce the relapse rate. This aspect needs further evaluation.

  24. Use of kinetics for earlier time-point decisions Repeat liver biopsies Variables influencing the decision to treat Hep C in HIV-positives • Genotype: 2/3 vs. 1/4 • ALT: high vs. normal • Age: >40 vs. <40 • Fibrosis: 1-4 vs. 0

  25. Acknowledgments Outclinic Laboratory Marina Nuñez Nuria Camino Pablo Barreiro Mayte Perez-Olmeda Luz Martin-Carbonero Berta Rodés Javier Garcia-Samaniego Carlos Toro Ivana Maida Julie Sheldon Matilde Sánchez-Conde Juan González-Lahoz

  26. A. O´Campo E. Losada C. Miralles A. Prieto P. Arazo M.A. Berdún J. Hernández-Burruezo I. Santos A. Mariño V. Asensi S. Echevarría PRESCO Investigators BIOPSY Investigators Juan BerenguerJosé Mallolas Carmen QueredaAna Arizcorreta Antonio Gonzalez Pilar Miralles Victor Asensi Montse Laguno Leonor MorenoJuan Antonio Girón Santiago Moreno

  27. AVANCE INFORMATIVO Y vosotros ... a correr mañana la MARATON !!! Que me caso!!!!

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