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HCV - MSD Italia
Il paziente HIV “difficile”: il ruolo delle coinfezioni Franco Maggiolo USC di Malattie Infettive, US di terapia antivirale, Ospedali Riuniti, Bergamo Argomenti • • • • • • Epidemiologia Diagnosi Effetti HIV Effetti virus epatitici Effetti HAART Terapia epatite cronica Overlapping HCV & HIV epidemics HIV HCV 25% of HIV 40 million 10 million 175 million Argomenti Epidemiologia Diagnosi Effetti HIV Effetti virus epatitici Effetti HAART Terapia epatite cronica Fibroscan Diagnostic Performance of Transient Elastography Similar in HBV and HCV Study comparing diagnostic performance of transient elastography (TE) for assessment of liver fibrosis in chronic HBV and HCV (N=613) Liver biopsy and TE on same day METAVIR score used for histological analysis HBV (n=202) HCV (n=363) P 80% 60% <0.001 41 49 <0.001 BMI (kg/m2) 24.2 24.6 0.199 Obesity 7% 6% 0.838 Insulin Resistance 20% 27% 0.215 Diabetes 5% 5% 0.700 ALT 52 75 <0.001 Prothrombin Time 90 94 <0.001 Significant Steatosis (>30%) 14% 26% 0.001 Significant fibrosis (F≥2) 42% 54% 0.005 Advanced Fibrosis (≥3) 17% 24% 0.0048 6.3 6.6 0.095 Male Age (yrs) Liver Stiffness, kPa Cardoso T, et al. 45th EASL; Vienna, Austria; April 14-18, 2010; Abst. 390. Diagnostic Performance of Transient Elastography Similar in HBV and HCV TE performance in HBV and HCV Patients HBV HCV Accuracy Sensitivity Specificity Positive LR Negative LR F≥2 82 74 88 6.19 0.29 F≥3 82 88 81 4.63 0.14 F≥2 77 68 88 5.98 0.35 F≥3 86 67 92 8.51 0.35 Conclusions: TE reliably predicts absence or the presence of significant and advanced liver fibrosis in HBV and HCV Cutoff values previously proposed for HBV and HCV patients appear valid Cardoso T, et al. 45th EASL; Vienna, Austria; April 14-18, 2010; Abst. 390. Percentage of HCV clearance by rs12979860 genotype OR 3.0 OR 2.6 OR 3.1 DL Thomas et al. Nature 461, 798-801 (2009) doi:10.1038/nature08463 Inosine Triphosphatase Variants and Anaemia 50 45 40 35 30 25 20 15 10 5 0 %Hb decline>3g/dl AA CA CC rs1127354 50 45 40 35 30 25 20 15 10 5 0 Hb<10 g/dl CC AC AA rs7270101 Fellay Nature 2010 Argomenti • • • • • • Epidemiologia Diagnosi Effetti HIV Effetti virus epatitici Effetti HAART Terapia epatite cronica Rate ratio of Cirrhosis between HIV/HCV and HCV: HAART era Model Study name N 381 Verma, 2006a 160 Di Martino, 2001 656 Brau, 2006 Gaslightwala & Bini, 2006 708 464 Monto, 2005 208 Mohsen, 2003 Martinez-Sierra, 2003 188 Macias, 2005 234 Fixed Random Statistics for each study Risk Lower Upper ratio limit limit Z-Valuep-Value 2.015 1.421 2.858 3.928 0.000 2.245 0.581 8.683 1.172 0.241 1.404 1.010 1.951 2.019 0.044 7.289 4.93810.760 9.998 0.000 0.778 0.327 1.854 -0.566 0.572 1.814 0.958 3.434 1.830 0.067 4.195 1.66510.567 3.042 0.002 1.698 0.911 3.165 1.666 0.096 2.290 1.919 2.732 9.197 0.000 2.181 1.285 3.703 2.887 0.004 Risk ratio and 95% CI 0.1 0.2 Meta-Analysis 0.5 1 2 5 10 Causes of death (116 events) NHL KS Primary cerebral lymphoma Respiratory tract 35,3 GE tract Cerebral Liver renal genital 6 41,4 6 21,6 58,6 6 ADEs 16 Non ADE 9 6,9 18,1 AIDS related Cancer Wasting Other causes Infections Other causes Hepatopathy Unknown Cardiovascular 15 8 2 4 4 2 2 1 2 Prevalence of patients living with disease % of subjects 6 5 4 3 2 1 0 diabetes cardiovascular diseases general population cirrhosis Bergamo cohort neoplastic disease Argomenti • • • • • • Epidemiologia Diagnosi Effetti HIV Effetti virus epatitici Effetti HAART Terapia epatite cronica Fracture Rate (per 1,000 patient-years) Fracture Rates in HIV and HIV/HCV Patients 4.5 4.06 4 3.5 3 3.35 2.86 2.54 2.5 2 1.5 1 0.5 0 HIV HIV/HCV HAART Era ('96-'09): 258,326 PY HIV HIV/HCV Entire Period ('88-'09): 303,678 PY HAART Era ('96-'09): 258,326 PY HIV HAART Era ('96-'09): 258,326 PY HIV/HCV Entire Period ('88-'09): 303,678 PY HIV Entire Period ('88-'09): 303,678 PY HIV/HCV Risk of AMI and CVD Among HIV and HIV/HCV Patients in the HAART era Events Acute Myocardial Infarction Cerebrovascular Disease HIV HIV/HCV HIV HIV/HCV Event Rate/1000 Patient-Years 3.36 4.19 11.12 12.47 Unadjusted Hazard Ratio (95% CI; P value) 1.25 (0.98-1.59) p=0.075 1.12 (0.98 - 1.29) p=0.105 Adjusted Hazard Ratio (95% CI; P value) 1.25 (0.98-1.61) P=0.072 1.20 (1.04 - 1.38) p=0.013 Insulin Resistance and Diabetes Mellitus in HCV/HIV coinfected Unadjusted Adjusted Merchante N, et al., Gut 2009 Hep C negative 1 1 Hep C positive 1.12 1.32 (O.94-1.33) (1.04-1.69) Adjusted for sex,age,risk,ethnicity, previous AIDS,smoking,family history,ART drug exposure,cohort,year Rainer CROI 2008 Argomenti • • • • • • Epidemiologia Diagnosi Effetti HIV Effetti virus epatitici Effetti HAART Terapia epatite cronica Most Common Grade 4 Events: CPCRA Cohort per 100 Person-Years 3 Incidence Liver 2.6 2 Neutropenia 1.5 Anemia 1.1 1 CVD 0.9 Pancreatitis 0.9 Psychiatric 0.8 Renal 0.6 0 Hazard Ratio For Death by Grade 4 Event (95% CI) 3.49 (2.38-5.12) P=0.0001 1.02 (0.61-1.72) P=0.93 1.76 (0.99-3.09) P=0.051 n=2947; CPCRA=Terry Beirn Community Programs for Clinical Research on AIDS. 7.08 (4.14-12.05) P=0.0001 3.40 (1.82-6.33) P=0.0001 1.91 (0.79-4.63) P=0.15 4.60 (2.45-8.66) P=0.0001 Reisler RB, et al. JAIDS. 2003;34:379-35:182-189. Mechanism of HAART related Hepatotoxicity Drugs Direct Toxicity HSR Mitochondrial Toxicity IRIS NNRTI/PI Abacavir, NNRTIs, Fosamprenavir/ Darunavir NRTI All (AZT,D4T, DDI ) Dose Dependance Yes No Yes No Onset 2-12m <6 weeks Late Early Fever,Rash, AST>ALT HBV,HCV Eosinophilia Lactic Acidosis Other HAART and Liver Enzyme Elevations Meta-analysis of 20 publications of HIV-infected patients ± HCV coinfection Grade 2 or higher liver elevations noted % LEE in HCV-Coinfected Patients by Drug Class Patients With LEE,% P = .025 40 P = .004 32.00 P = .009 30 18.44 20 15.96 14.67 13.62 10 5.26 0 NNRTI PI Mixed BPI Drug Class Benhamou Y, et al. CROI 2006. Abstract 88. NRTI Overall Drugs available for HIV therapy NRTIs • Abacavir • Didanosine • Emtricitabine • Lamivudine • Stavudine • Tenofovir • Zidovudine Mitochondrial toxicity 1. Lichterfeld M, Haasen S, Fischer HP, Voigt E, Rockstroh JK, Spengler U: Liver histopathology in human immune deficiency virus/hepatitis C coinfected patients with fatal liver disease. J Gastrol Hepatol 20: 739-745, 2005 Risk of Mitochondrial Toxicity: NRTI + Ribavirin in HIV/HCV-Coinfected Patients US FDA Adverse Event Reporting System (2002) — HIV/HCV patients • Ribavirin + NRTIs Mitochondrial Toxicity Risk Ribavirin + 12.4 31 cases (58 adverse events) suggestive of mitochondrial toxicity — Pancreatitis and/or increased lipase (n=21) — Lactic acidosis (n=20) — Elevated LFTs (n=8) — Hepatic steatosis (n=6) — Elevated creatinine, neuropathy, multiorgan failure (n=1 each) 8.0 Didan Didano stav 3.3 Stav 1.1 Ab 0.2 Lamiv 0.06 0.01 0.1 Zidov 1.0 10 100 Odds Ratio (95% CI) Fleischer R, et al. 2004. Didanosine associated portal Hypertension Often non-cirrhotic but associated with nodular hyperplasia Associated with portal vein thrombosis Often present late with variceal bleed Drugs available for HIV therapy NNRTIs • Efavirenz • Nevirapine • Etravirine Prospective study on the incidence severe hepatotoxicity (grade 3 or 4 AST/ALT) Johns Hopkins HIV cohort (n=568) HCV (43%) and HBV (7.7%) Overall incidence of severe hepatotoxicity Nevirapine: 15.6% Efavirenz: 8.0% Hepatotoxicity risk was significantly greater in: Hepatitis coinfection NNRTI + PI Cases/100 Person-Exposed 25 Cases/100 Person-Exposed Incidence of Severe Hepatotoxicity of NNRTIs in Hepatitis Coinfection 25 20 Nevirapine (n=256) HCVHCV+ 18.1 14.4 15 10 5 0 20 18.1 6.1 No PI PI Added Efavirenz (n=312) HCVHCV+ 20.9 15 10 5.8 5 0 9.7 0 No PI PI Added Sulkowski MS, et al. Hepatology. 2002:35:182-189. Time to Onset of Asymptomatic ALT or AST >5 x ULN on NVP in Controlled Trials 0-12 Months 20 3-12 Months 6 weeks 20 NVP Control 15 NVP Control 15 Probability10 (%) 5 10 0 0 5 0 2 4 6 8 10 Months of Treatment NVP (n = 1731) 12 3 4 5 6 7 8 9 10 11 12 Months of Treatment Control (n = 1912) Stern JO et al. XIV International AIDS Conference; July 7-12, 2002; Barcelona, Spain. Discussion Impact of NVP on HCV-RNA viral load It has been shown that HCV patients receiving NNRTIs, especially NVP, have lower HCVRNA levels1,2. Mean HCV-RNA (Log10 IU/mL) level HIV can induce HCV replication through TGF-beta1, which is produced in the liver in response to proinflamatory cytokines3. NVP has been associated with higher decreases in levels of TNF-alpha receptor than other antiretroviral drugs4, which might decrease TGF-beta1 secretion in the liver and reduce HCV replication. HCV-RNA level among individuals receiving PI-, EFV- or NVP-based ART2 9 p=0.012 8 7 6 5 4 3 N= 19 108 106 NVP EFV PI Antiretroviral drug 1) Bani-Sadr F et al. AIDS 2007; 21: 1645 2) Mata R et al. EACS Conference 2009, Cologne, Germany. 3) Lin W et al. Gastroenterology 2008; 134:803–811 4) Virgili N et al. J Acquir Immune Defic Syndr 2009; 50: 552-553 Drugs available for HIV therapy Protease Inhibitors • Atazanavir • Darunavir • Fos-Amprenavir • Indinavir • Lopinavir • Nelfinavir • Ritonavir • Saquinavir • Tipranavir Incidence of Severe Hepatotoxicity During Therapy With PI-Based Regimens Incidence (%) 40 HIV monoinfection Hepatitis coinfection 30 26.2% 20 15.8% 14.8% 12.8% 10.0% 10 6.5% 11.4% 6.0% 0 Nelfinavir n=605 (1250 mg bid) Kaletra n=89 (400/100 mg bid) Indinavir + RTV n=94 (100-200/200 mg bid) Saquinavir + RTV n=273 (400/400 mg bid) Sulkowski MS, et al. AIDS. 2004;18:1-8. Hepatotoxicity with Newer PIs KLEAN 20 18 16 14 12 10 8 6 4 2 0 % Grade 3/4 % Grade 3/4 CASTLE ATZr LPVr FPVr TITAN LPVr RESIST % Grade 3/4 % Grade 2/4 20 18 16 14 12 10 8 6 4 2 0 Drugs available for HIV therapy New Classes Fusion Inhibitors • Enfuvirtide R5 Inhibitors • Maraviroc Integrase Inhibitors • Raltegravir Hepatotoxicity and New Agents Motivate 1 and 2 Benchmark 1 Rates of Grade ¾ rises in ALT Bonn cohort (1990-2002) Liver-related mortality rates per 100 person-years 285 HIV/HCV coinfected patients HAART: 0.45 ART: 0.69 No therapy: 1.70 Predictors for liver-related mortality No HAART Low CD4 cell count Increasing age Overall Mortality 1 HAART* 0.8 0.6 ART 0.4 *P<0.001 0.2 0 1 Cumulative Survival Cumulative Survival Impact of ART on Overall Liver Mortality in HIV/HCV-Coinfected Patients 1000 2000 No therapy 3000 4000 Days 5000 6000 Liver-Related Mortality 0.8 HAART* ART 0.6 No therapy 0.4 0.2 *P=0.018 0 1000 2000 3000 4000 Days 5000 6000 Qurishi N, et al. Lancet. 2003:362:1708-1713. QUANDO COMINCIARE • PAZIENTI CON CD4+ <200 cells/ µL : è fortemente raccomandato (AI) • PAZIENTI CON CD4+ 200 -350 cells/ µL è fortemente raccomandato (AII) il paziente va ben preparato all’inizio della terapia • PAZIENTI CON CD4+ 350 - 500 cells/ µL • moderatamente raccomandato (BII) • fortemente raccomandato : • decremento di CD4+ ≥100 cells/ µL ogni anno (AII) • carica virale > 100000 copie /ml (AII) • età > 50 (AII) • epatite cronica da HCV (AII) • rischio CV elevato : diabete mellito o pregressi eventi CV, o rischio>20% nei succ.10 anni (Framingham) (BIII) Renato Maserati • PAZIENTI CON CD4+ > 500 cells/ µL non raccomandato Argomenti Epidemiologia Diagnosi Effetti HIV Effetti virus epatitici Effetti HAART Terapia epatite cronica Anti-HBV Therapies Immune modulators Polymerase Inhibitors IFN-alpha Lamivudine Pegylated-Interferonalpha Adefovir Entecavir Telbivudine Tenofovir Emtricitabine LAM MonoTherapy: Major Issues A181T/V X Adefovir ? LAM MonoTherapy T184S X Entecavir X Telbivudine/ Clevudine X Adefovir X Tenofovir X Adefovir T184G/S202I/M250V L180M M204V/I L80V/I A181T/V A194T V214A/Q215S HCV/HIV TREATMENT OUTCOMES Genotype 1 SVR 14-38% Genotype 3 SVR 44-73% QoL Scores Decline in Pts Receiving HCV Therapy • Posttreatment 90 SF-36 Domain Score SF-36 Domain Score Standard IFN alfa + RBV Treatment 90 60 30 BL4 12 Week 24 48 60 72 BP RE GH MH PF VT RP SF 412 HCV-infected pts randomized to open-label treatment with pegIFN alfa-2a vs IFN alfa-2b + RBV PegIFN alfa-2a Treatment 60 30 BL4 12 Week 24 Comparison of quality of life, work productivity and medical resource utilization of peginterferon alpha 2a vs the combination of interferon alpha 2b plus ribavirin as initial treatment in patients with chronic hepatitis C, Perrillo R, et al. J Viral Hepat. 2004;11:157-165. Copyright © 2004. Reproduced with permission of Blackwell Publishing, Ltd. 48 60 72 New HCV Treatments in Development Nucleosidic Interferons polymerase inhibitors Immune Cyclophiline B inhibitors modulators Oligonucleotides Analogues Non-nucleosidic of ribavirin Therapeutic polymerase Protease Inhibitors Vaccines inhibitors Glucosidase α inhibitors RNA interference Disclaimer Servizio scientifico offerto alla Classe Medica da MSD Italia S.r.l. Questa pubblicazione riflette i punti di vista e le esperienze dell’autore [o degli autori] e non necessariamente quelli della MSD Italia S.r.l. Ogni farmaco menzionato deve essere usato in accordo con il relativo riassunto delle caratteristiche del prodotto fornito dalla ditta produttrice. 01-13-RTG-2010-IT-4769-AV