Traitement de l hépatite C chez le sujet infecté par le VIH Actualités 2004

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2 Traitement de l hépatite C chez le sujet infecté par le VIH Actualités 2004 Pr C. PERRONNE Service des Maladies Infectieuses et Tropicales Hôpital Raymond Poincaré Faculté de Médecine Paris - Ile de France - Ouest 92 GARCHES

3 (Enquête Mortavic) Mortalité par cirrhose et hépato-carcinome liée au VHC chez les patients co-infectés VIH File active VIH Décès totaux (8,15 %) (1 %) Décès par cirrhose ou hépato K (0,12 %) (0,14 %) Décès par cirrhose 21/ /253 ou hépato K (1,4 %) (14,2 %) rapportés au total des décès E. osenthal et al. GERMIVIC Rev. Med. Interne 2002

4 ANRS HC02 (RIBAVIC) : A randomized controlled trial of pegylatedinterferon alfa-2b plus Ribavirin vs interferon alfa-2b plus Ribavirin for the initial treatment of chronic hepatitis C in HIV co-infected patients C. Perronne, F. Carrat, F. Bani Sadr, S. Pol, E. Rosenthal, F. Lunel, P. Morand, D. Salmon, G. Pialoux, P. Cacoub, on behalf of the ANRS HC02 group, ANRS, Paris, France

5 Ribavic : design (1) A multicenter, randomized, parallel-group, open-label trial PEG-IFN alfa-2b 1.5 mg/kg/week + Ribavirin 800 mg/d IFN alfa-2b 3MU x 3/week + Ribavirin 800 mg/d 48 weeks Main inclusion criteria Naive of HCV treatment HCV-RNA positive Liver Biopsy within 18 months before entry Stable HIV-1 RNA (D < 1 log10 over the preceding 3 months) Stable HAART or no HAART CD4 cell count > 200/mL

6 Ribavic : design (2) Primary end-point Long term virologic response (loss of detectable HCV RNA) at week 72 Secondary end-points Safety anf tolerability Quantitative HCV - RNA Alanine aminotransferase serum values CD4 cell count, HIV1-RNA Liver histology (second biopsy sample taken at W72)

7 Ribavic Flow chart 416 randomised 4 excluded 3 HCV RNA negative at D0 1 previous IFN treatment 205 assigned PEG-IFN and ribavirin 207 assigned IFN and ribavirin 11 (5%) never treated 77 (38%) stopped treatment 117 (57%) achieved treatment 18 (9%) never treated 72 (35%) stopped treatment 117 (57%) achieved treatment

8 Ribavic : baseline characteristics (1) Means, (%) PEG-IFN group IFN group General Age yr Male sex (%) (77) (71) Body weight - kg HIV Time from seroconversion yr CD4 cell count - per µl Plasma HIV1-RNA <400 copies /ml (%) log 10 level in > 400 copies/ml (69) 3.6 (63) 3.6 Under HAART (%) (83) (82)

9 Ribavic : baseline characteristics (2) Means (%) PEG-IFN group IFN group HCV Duration of infection - yr Source of infection (%) Intravenous drug use Transfusion Histology (Metavir score) Inflammation Fibrosis F3: bridging fibrosis (%) F4: cirrhosis (%) Genotype 1,4 (%) HCV RNA log 10 copies/ml Aminotransferases ALAT (x ULN*) Sustained ALAT < ULN ( %) (80) (6) (22) (18) (58) (17) (78) (9) (25) (14) (59) (18) * ULN = Upper Limit of Normal

10 Ribavic: Virologic response ITT analysis : sustained virologic response (SVR) PEG : 55/205 (27%) vs IFN : 39/207 (19%) -p=0.03 Virologic response (VR), in patients who did not discontinue treatment (PEG=117, IFN=117 pts) PEG-IFN IFN %VR SVR W4 W12 W24 W48 W72

11 Ribavic: Virologic response Positive and negative predictive values of virologic response at different time-points with regard to SVR in patients who did not discontinue (n=234) PPV NPV W W12 93

12 Sustained virologic response (ITT analysis) 55% 50% 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% p<0.001 p=0.01 p=0.68 PEG-IFN IFN p=0.28 p=0.002 p=0.20 p=0.013 p= ,4 others F0-F2 F3-F4 3N >3N < yes no < Genotype Fibrosis score ALAT (xuln) CD4 (/mm 3 ) Protease Inhibitor HCV RNA (cp/mm 3 )

13 RIBAVIC : Histologic response (preliminary results) SVR yes (n=38) SVR no (n=93) D0 W72 D0 W D0 W72 D0 W72 Metavir A Metavir F Ishak grade Ishak stage

14 Ribavic : safety and tolerability (ITT analysis, at least one dose of study medication PEG=194, IFN=189) Similar adverse event profiles between the two arms * Headache * Fatigue Pyrexia Myalgia Weight Loss Arthralgia General % * Insomnia Depression Irritability Anxiety PEG-IFN IFN Psychiatric Anorexia Diarrhea Nausea GastroIntestinal * Dermatitis Pruritus Injection site reaction Alopecia Dermatological Increased lipodystrophy * p<0.05 Oral candidiasis HIV-related

15 Ribavic : serious adverse events (ITT analysis) Description : 31 % (PEG group) vs 31 % (IFN group) : p = 0.9 PEG-IFN IFN Psychiatric events Sepsis 2 2 Pneumonia 3 7 Hepatic failure Acute pancreatitis 4 1 Hyperlactatemia 5 1 Haematologic disorders 12 3 Mitochondrial toxicity event : Most patients : d4t + ddi Multivariate analysis : Odds ratio for ddi : 44 (95 %, CI : 7.1-Infinity)

16 Ribavic : CONCLUSION In HIV-HCV coinfected patients, PEG-IFN alfa2b plus ribavirin: More effective than IFN alfa2b plus ribavirin Less effective than in HIV negative patients Protocol designed to be close to the real life: High proportion of severe liver disease (40% of bridging fibrosis or cirrhosis) Difficulty to maintain patients under treatment (36% did not complete treatment)

17 PEG IFN alpha 2a + Ribavirin vs IFN alpha 2a + Ribavirin ACTG A 5071 TRIAL 133 patients Cirrhosis : 11 % vs 9 % Sustained virologic response PEG IFN 27 % 12 % Genotype 1 14 % 6 % Genotype % 33 %

18 APRICOT ROCHE TRIAL 860 patients PEG IFN alpha 2a vs PEG IFN alpha 2a + Ribavirin vs IFN alpha 2a + Ribavirin Bridging fibrosis and cirrhosis : % Sustained virologic response PEG IFN 40 % 12 % Genotype 1 29 % 7 % Genotype % 20 %

19 Traitement des patients co-infectés VIH-VHC : facteurs cliniques à prendre en compte Données psycho-sociologiques Souhaits, personnalité, mode de vie Motivation, dépression Dépendances? Alcoolisme Toxicomanie active Observance? Possibilités de suivi, acceptabilité de la PBH (Fibrotest, Actitest?) Tolérance et acceptabilité d autres traitements Cirrhose décompensée?

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