R. PARANÁ Universidade Federal da Bahia Faculdade de Medicina Prof Adjunto-Doutor de Gastro-Hepatologia Prof. Livre-Docente de Hepatologia Clinica

Transcrição

1 Tratamento da Hepatite C Em populações especiais R. PARANÁ Universidade Federal da Bahia Faculdade de Medicina Prof Adjunto-Doutor de Gastro-Hepatologia Prof. Livre-Docente de Hepatologia Clinica

2 Hepatitis C in Special Populations Andrew J. Muir, MD MHS Division of Gastroenterology Duke University Medical Center

3 Hepatite C: influência na História Natural infecção Doença avançada Co-fatores,variavéis anos H A HC Fibrose CHC Cirrhose Analise por segmento Progessão variável co-fatores (idade, alcool, obesidade, resistencia a insulina, VHB) Modelo de Progressão

4 Hepatite c: Influência no Tratamento Fatores corrigíveis Esquemas terapêuticos aquém da terapia mais efetiva: Interferon convencional com ou sem ribavirina Falha no reconhecimento do padrão de RVP Redução ou interrupção da dose: Eventos adversos sistêmicos citopenias Uso de álcool ou drogas Disturbios psiquiátrico não tratados (Aderência) Raça Manifestações extra-hepáticas Obesos com SPM

5 Special populations Race/ethnicity Obesity Renal failure Decompensated cirrhosis Psichiatry Disorders Hemophilia Prisons

6 African Americans and HCV More common Genotype 1 predominance Natural history Less cirrhosis? Rising HCC rates

7 HCV in African Americans SVR, % Muir AJ, NEJM 2004 Jeffers LJ, Hepatology 2004 Conjeevaram HS, Gastroenterology 2006

8 Efeito do grau de fibrose e da raça nas chances de RVS PEGASYS 180 μg mais ribavirina RVS (%) African Afro-americanos Americans p= % Tratar precocemente 25% 25% 20% 0 1 ou 2 3 ou 4 5 ou Caucasian Caucasianos Americans 68% p= % 50% 26% 0 1 ou 2 3 ou 4 5 ou 6 n= Conjeevaram H, et al. 56th AASLD 2005; Abstract

9 HCV in African Americans Mechanism of lower response? Pharmacokinetics Inferior phase 1 and 2 decline Immune response Insulin resistance

10 Hepatite C Manifestações Neuro-Psiquiátricas Fadiga Depressão Alteração cognitiva Kremer et al, J Hepatol., 2002

11 Hepatite C: Quem Tratar? indo mais além Desordens de Humor controladas e acompanhado por psiquiátra Esquizofrenia controladas e acompanhado por psiquiátra UDIV e/ou UDIN

12 Hepatite C Manifestações Neuro- Psiquiátricas Depressão precede Rx Depressão se agrava no Rx Qualidade de vida Melhora no HCV- RNA Neg Raramente suspende medicação sindrome ansiedade/depressão Resposta aos IRS Resposta aos ansiolíticos Grupo de estudos em hepatites da Bahia J Med Virol 2008 Hospital Psi, 2008 Liv Int, 2007

13 Injection drug users and HCV Non-compliance (8.2%) in IVDUs was not different from non-ivdus (6.8%) SVR IVDUs (46.6%) non-ivdus (34.6%) (RR =1.35; 95% CI = ) Difference disappeared after adjusting for genotype. No difference in compliance or SVR between active and non-active IVDUs or between IVDU patients in or without a methadone maintenance program. Robaeys G, European Journal of Gastroenterology & Hepatology 2006.

14 O paciente com SPM

15 Obesity Trends* Among U.S. Adults *BMI 30 No Data <10% 10% 14% 15% 19% 20% 24% 25% 29% 30%

16 Obesity and HCV Obesity Insulin resistance IFN bioavailability Fibrosis Response to IFN Adiponectina? Response to HCV therapy

17 Impacto da esteatose na RVS RVS com elevada carga viral em genótipo 1, 4, 5, 6, 60 SVR (%) P < Esteatose Sem esteatose Poynard et al. Hepatology. 2003;38:75-85.

18 Resistência à insulina e Hepatite C RVS em portadores do Genótipo RVS (%) HOMA < 2 HOMA 2-4 HOMA > 4 Romero-Gómez et al. Gastroenterology. 2005;128:

19 Treatment options Obesity and HCV Weight loss Higher doses? Treat insulin resistance (glitazones)

20 Gravidade de efeitos em pacientes F3/F4 F3 F4 Cirrose Hemorragia Insuficiência Hepatica Câncer 3% /a 3% /a 3% /a Mortalidade em 10 anos para cirrose : 50%

21 Decompensated HCV Cirrhosis Rationale for Treating Slow clinical disease progression Improve hepatic synthetic function Reverse complications of liver disease Obviate need for liver transplantation Eradicate HCV RNA To improve histology To reduce post-olt recurrence Reduce severity of posttransplantation liver disease Probably, reduces incidence of CHC

22 Patients Awaiting Liver Transplant Patients Screened 32 Patients Enrolled 15 Plt Ct < 45,000 ul 10 PMN< 1250 ul 4 Hgb < 11 g/dl 2 Characteristics of Treated Patients Mean age 48.6 CPT Score 11.9±1.2 Bilirubin mg/dl 3.3±1.8 INR 1.6±0.4 Crippin, at al. Liver Transpl 2002:8;

23 Patients Awaiting Liver Transplant Treatment Regimen N=3 1MU Interferon alfa-2b tiw N=6 3MU Interferon alfa-2b tiw N=6 1MU interferon alfa-2b qd + 400mg/d ribavirin Patients with On-Treatment RNA clearance 33% Patients with SVR??? Prevention of Post-Transplant Recurrence 0/2 Crippin, at al. Liver Transpl 2002:8;

24 Patients Awaiting Liver Transplant Adverse Events (N = 23) occurred in 13/15 patients 20/23 Adverse Events were severe Thrombocytopenia (< 20, 000/ul) 7 Neutropenia 4 Staph aureus arthritis 1 Hepatic encephalopathy 3 Culture-negative empyema & death 1 Hypothroidism 1 Hyperbilirubinemia 1 Pancreatitis 1 Ventral Hernia 1 Study terminated after 2 nd major infection Crippin, et al. Liver Transpl 2002;8:

25 Low Accelerating Dose Regimen LADR 124 patients male/female ratio 81:43; age range years; 70% genotype 1 63% complications of cirrhosis ascites, spontaneous bacterial peritonitis varices, variceal hemorrhage encephalopathy Everson GT. Hepatology 2005; 42:255-62

26 Low Accelerating Dose Regimen LADR Mean Child-Turcotte-Pugh score: 7.4 +/- 2.3 Class A - 56 Class B - 45 Class C - 23 Mean MELD score was /- 3.7 Everson GT. Hepatology 2005; 42:255-62

27 Low Accelerating Dose Regimen LADR EOT RNA negative 46% RNA negative last follow-up 24% SVR Genotype 1 13% Non-genotype 1 50% Predictors of response: non genotype 1, CTP class A, ability to tolerate full dose and duration Everson GT. Hepatology 2005; 42:255-62

28 Low Accelerating Dose Regimen LADR 12/15 patients HCV RNA-negative before transplantation and remained HCV RNA-negative 6 months or more after transplantation Everson GT. Hepatology 2005; 42:255-62

29 What are the Clinical Limits? Certain preceding clinical events? Refractory Ascites SBP Spontaneous encephalopathy Laboratory Abnormalities? Bilirubin > 4mg/dl Albumin < 2.5g/dl INR > 2.5 Platelet Count < 35,000ul Predictive Clinical-Laboratory Model? Child-Turcotte-Pugh > 11 (absolute) MELD Score > 18 (relative), > 25 (absolute)

30 HCV and Renal Failure > 10% prevalence in dialysis patients Histology often mild in dialysis patients Progression may occur post-transplant Desirable to clear HCV before transplant

31 Kidney Transplant Graft and Recipient Survival Graft Survival Patient Survival HCV infection is associated with lower graft and recipient survival Gentil MA et al. Nephrol Dial Transplant

32 IFN In Dialysis Patients: IFN 3 MU Casanovas Chan Fernandez Pol Degos Izopet Campistol Raptopoulou-Gigi Pooled SVR Russo et al, Am J Gastro 2003 SVR (%)

33 HCV and Renal Failure Romanian center 78 patients on hemodialysis with HCV PEG-IFN alfa -2a 135 mcg s.c. weekly monotherapy. Covic A, Journal of Nephrology 2006.

34 HCV and Renal Failure Romanian center Virologic response Early virologic response 48/78 (61.5%) End-of-treatment response 21/78 (26.9%) to wk 48 15/78 (19.2%) RNA neg Sustained virologic response 11/78 (14.1%) Covic A, Journal of Nephrology 2006.

35 HCV and Renal Failure Romanian center Conclusions: In dialysis patients, PEG-IFN alfa -2a is poorly tolerated is associated with a high number of serious adverse events causes a significant lack of compliance/discontinuation of therapy has low sustained viral response Covic A, Journal of Nephrology 2006.

36 HCV and Renal Failure Dialysis patients may have higher SVR rate with IFN Greater efficacy balanced by greater toxicity There is a rationale for treating patients pretransplant Use ribavirin with extreme caution (investigational)

37 HCV in special populations Many patients in HCV clinics have issues that impact their treatment Understanding more about these special populations is critical to improving treatment responses for all groups.

38 HEPATOLOGIA do MILÊNIO 2008 XI Simpósio Internacional de Terapêutica em Hepatite Viral I monotemático tico sobre correlação histológica/patológica/imaginológica gica/imaginol das sociedades Brasileiras de: Hepatologia, Infectologia e Patologia De 10 a 12 de Julho de 2008 Bahia Othon Hotel Informações e Inscrições: Salvador - Ba A lampertico (ITA) Miguel garassini (VEN) Pirre Bedessa (FRA) Rafael Esteban (ESP) Maria Buti (ESP) Hugo Famboim (ARG) Ricard Sollá (ESP)