Treatment of Chronic Hepatitis C in HCV-HIV Infected Patients

Treatment of Chronic Hepatitis C in HCV-HIV Infected Patients J Mallolas Infectious Diseases Service Hospital Clínic Barcelona to treat HCV in HIV patients ? 1. Why Why to treat HCV in HIV patients ? 1. Longer survival 2. Faster progression to cirrhosis 3. Higher mortality due to ESLD 4. Higher risk of antiretroviral hepatotoxicity 5. Faster progression of HIV disease Incidence of Mortality in HIV-Infected Patients at the Hosp. Clinic (Barcelona, Spain) between 1984-1998 Incidence of Mortality in HIV-Infected Patients at the Hosp. Clinic (Barcelona, Spain) between 1984 - 1998 40 NO. x100 EXPOSED PATIENTS xYEAR No Tx 1NRTI 2NRTI HAART 30 20 10 0 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 YEAR HAART: Highly Active Antiretroviral Therapy (2NRTI plus 1PI/NNRTI) HAART: Highly Actibe Antiretroviral Therapy ( 2NRTI plus 1PI/NNRTI) Effect of HIV on HCV Liver Fibrosis Progression Rate 4 Fibrosis Grades (METAVIR Score) 3 2 HIV+ (n = 122) 1 0 0 10 20 30 40 Matched controls (n = 122) Simulated controls (n = 122) Duration of HCV Infection (years) Increase with CD4 <200/mm3, ETOH, age Benhamou et al. Hepatology 1999;30:1054. Causes of death per year in HIV patients Hospital Clínic. Barcelona 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Cardiovascular causes Accidental causes Neoplasias End-stage liver disease AIDS-related illnesses 1997 1998 1999 2000 2001 Risk factors of Hepatotoxicity in HCVHIVcoinfected patients: Author No. ART HCV CD4 Rate Predictors Rodriguez1 Sulkowski2 Saves3 den Brinker4 132 211 1249 394 PI-based PI-based 2 NRTIs PI-based 62% 51% 44% 22% 324 109 234 150 11% 12% 6% 18% HCV Alc. HCV CD4 HCV HBV HCV HBV Martínez5 Núñez6 610 222 NVP-based ART 51% 40% 279 337 9.7% 9% HCV ALT HCV age, Alc. 1. Rodriguez-Rosado et al. AIDS 1998;12:1256. 2. Sulkowski et al. JAMA 2000;283:74. 3. Saves et al. AIDS 1999;13:F115. 4. den Brinker et al. AIDS 2000;14:2895. 5. Martínez et al. AIDS 2001;15:1261. 6. Núñez et al. J AIDS 2001;27:426. 2. How to treat HCV in HIV patients ? Sustained Response to HCV Therapy HIV-neg IFN monotherapy 20% HIV-pos 10% IFN + ribavirin Peg-IFN + ribavirin 45% 55% 20% ? Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for treatment of HIV/HCV co-infected patients AIDS 2004, 18:F27–F36 Methods • Randomized, single-centre, open-label clinical trial including patients with: • HCV: – detectable HCV-RNA, – alanine aminotransferase >1.5-fold upper limit of normal – abnormal liver histology • HIV: – CD4 cell count >250 x106 cell/L – HIV- RNA , <10,000 copies/ml AIDS 2004, 18:F27–F36 Response by Treatment Group, ITT PEG + RBV (n=52) 100 IFN + RBV (n=43) P=0.033 80 P=0.017 52 44 30 21 % of patients 60 40 20 0 VR SVR AIDS 2004, 18:F27–F36 Response by Genotype 1-4, ITT PEG + RBV (n=52) 100 IFN + RBV (n=43) P=0.011 80 P=0.007 % of patients 60 41 40 38 20 11 7 SVR 0 VR AIDS 2004, 18:F27–F36 Response by Genotype 2-3, ITT PEG + RBV (n=19) 100 IFN + RBV (n=15) P=0.914 P=0.730 68 80 % of patients 67 53 47 60 40 20 0 VR SVR AIDS 2004, 18:F27–F36 % of patients 1= 100 20 40 60 80 0 Side effects (I) • 92% of patients developed adverse events. Adverse Events fl u -li 2= ke as Sd 3= the n a 4= n o ia de rex pr i es a 6= 5= si ga al on str ope oi nt cia es 7= t ina ce l 8= fal m ea ia 9= l gia 10 s a =l n e 11 e m =p uco ia laq pe ue nia t 13 12 o pe n = =i r 14 re rita ia = a b hy ctio ili ty pe n rl a l oc 15 ct at a l e = ins mia om 16 nia = ot he r Side effects (II) • Premature discontinuation: 19% (Peg 23 vs 14%); 15% due to side effects (17 vs 12%) 20 Premature cumulative discontinuation% 15 10 5 0 2 4 8 12 16 40 PEG+RBV INF+RBV – Severity of the adverse events not shown differences between two arms. PEG+RBV INF+RBV TOTAL p-value Grade 1-2 Grade 3-4 290 (84%) 56 (16%) 189 (85%) 33 (15%) 479 (84,4%) 89 (15.6%) NS NS Conclusions • PEG-INF  2b + RBV was significantly more effective than IFN  2b + RBV for the treatment of chronic hepatitis C in HIV co-infected patients, mainly of genotype 1 or 4. • Side effects were very frequent, the majority of them were mild or moderate. • Total CD4 fell in both arms but no evidence of deleterius effect on HIV control were seen. AIDS 2004, 18:F27–F36 Superiority of Peg IFN-Ribavirin (Sustained Virological Response) IFN type n. IFN/RBV PEG IFN/RBV ACTG 2a 133 12% 27% APRICOT RIBAVIC Laguno 2a 2b 2b 868 400 95 12% 19% 21% 40% 27% 44% Crespo 2b 121 26% 55% Differences in Baseline Characteristics Make Difficult a Comparison Face to Face Fibrosis 3-4 ACTG APRICOT RIBAVIC Laguno Crespo 10% 12% 40% 30% ? IVDU 50% 65% 80% 85% 79% h ALT 67% 87% 83% 100% 100% Geno1 78% 60% 66% 63% 48% Sustained Response to HCV Therapy HIV-neg IFN monotherapy 20% HIV-pos <10% IFN + ribavirin Peg-IFN + ribavirin 45% 55% 12-21% 27-55% Risk Factors for Failure of HCV Tx • Study of risk factors for failure to achieve EVR to PEG-IFN + RBV – – Univariate OR Serum HCV RNA HCV GT 2/3 HCV GT 1/4 d4T ABC GGT (x ULN) Bilirubin (x ULN) 2.12 1 9.82 0.55 3.62 1.21 2.52 Multivariate OR 2.11 P value 0.022 154 HIV/HCV co-infected patients EVR: ≥ 2 log10 c/mL ↓HCV RNA Serum HIV RNA HCV genotypes 1 and 4 Abacavir use Increased bilirubin levels • Increased risk of failure with: – – – – 12.13 <0.0001 • 4.92 0.0083 Potential drug interaction between RBV and ABC may be impacting outcomes 4.52 0.0064 Bani-Sadr F, et al. 14th CROI, Los Angeles, CA, February 25-28, 2007. Abst. 897. Abacavir Decreases SVR Rates with HCV Treatment • Retrospective study of 426 HIV/HCV patients (80% on HAART) starting pegIFN + RBV Possible Intracellular Competition Between Abacavir and Ribavirin (Guanosine Analogs) • • ABV Adenosine kinase ABV-MP Cytosolic deaminase CBV-MP Guanylate kinase CBV-DP Nucleoside diphospho kinase CBV-TP 72% did not achieve SVR Lack of SVR associated with: – – – Higher HCV-RNA (1.92 [1.33-2.78] <0.001) GT 1/4 (4.76 [2.78-8.33] <0.001) ABC use (OR 2.04 [1.08-3.85] 0.03) RBV RBV-MP • ABC not associated with lower SVR if higher RBV levels – RBV level >2 µg/ml: 53.3% with ABC vs 38.5% without ABC, p=0.32 RBV-DP • ABC associated with a lower SVR rates possibly due to an inhibitory competition between RBV and ABC which are both guanosine analogs RBV-TP Vispo E, et al. 47th ICAAC; Chicago, IL; September 17-20, 2007. Abstract H-1731. Abacavir does not influence the rate of sustained virological response in HIV-HCV co-infected patients treated with pegylated interferon and weight adjusted ribavirin Authors: Laufer N1, Laguno M1, Perez I2, Cifuentes C3, Murillas J4, Vidal F5, Bonet L4, Veloso S5, Gatell JM1; Mallolas J1. *** Antiviral Therapy (submitted for publication) Figure 1.Impact of Abacavir use on virologic response to pegylated interferon plus ribavirin in HCV/HIV-coinfected patients % of patients with lack of response 100 90 80 70 60 50 40 30 20 10 0 4 12 24 7,69 18,18 11,11 16,67 38,1 31,58 66,04 68,89 Without ABC With ABC 56,41 57,14 50,42 42,86 35,14 48,28 36 48 60 72 Without ABC With ABC 159 45 168 42 152 47 52 11 90 24 119 29 195 49 Comparison of Pegylated Interferons SVR by HCV Genotypes • Cohort study of PEG2A (n=315) and PEG2B (n=242) with RBV in HIV/HCV+, HCV Tx naïve pts (20002005) – – Well matched except more F3-F4 in PEG2B (32.8% vs 42.0%; p < 0.05) No differences dose RBV or duration Tx • • No differences in efficacy or safety PEG2A vs. PEG2B Factors independently associated with SVR – – CDC clinical category (A/B vs C: 3.30 95%CI: 1.38 - 7.89, p = 0.007) HCV genotype (GT 2/3 vs 1/4: 3.05 95%CI: 1.67 - 5.56, p<0.001) 50 45 40 35 30 25 20 15 10 5 0 46 45 Patient Percent 19 14 G1-4 G2-3 PEG2B-RBV PEG2A-RBV Berenguer J, et al. 47th ICAAC; Chicago, IL; September 17-20, 2007. Abstract V-1897. Poster: 1018 b A randomized trial to compare the efficacy and safety of PEG-interferon (PEG) alfa-2b plus ribavirin (RBV) vs PEG alfa-2a plus RBV for treatment of chronic hepatitis C in HIV co-infected patients. Laguno M1, Cifuentes C2, Murillas J3, Vidal F4, Bonet L3, Veloso S4, Tural C5, Perez I1, Gatell JM1, Mallolas J1. 1Hospital Clínic. Barcelona. Spain. 2Hospital Son Llàtzer. Mallorca. Spain. 3Hospital Son Dureta. Mallorca. Spain. 4Hospital Joan XXIII. Tarragona. Spain. 5Hospital Germans Trias i Pujol. Badalona. Spain. E-mail: mallolas@clinic.ub.es Tel. +34-93-2275574 FAX. + 34-93-4514438 CROI-2008. Boston. USA METHODS • Prospective, randomized, multi-centre, open-label clinical trial • Inclusion criteria: – – – – Detectable HCV-RNA Alanine aminotransferase >1.5-fold upper normal limit Abnormal liver histology CD4 counts >250 cells/mm3 and HIV-RNA <50000 copies/mL. • Treatment arms: PEG 2b (80-150 µg/wk adjusted to body weight) or PEG 2a (180µg/wk) + RBV (800-1200 mg/d adjusted to body weight) in both arms • Duration of treatment: 48 weeks. METHODS • Primary endpoint: – Sustained Virological Response • (SVR= HCV-RNA negative at week 72). • Sample size was calculated to detect, with 80% power, differences above 20 percentual points if they exist. Demographics and Baseline Characteristics • Baseline Characteristics of 182 included patients: Interferon (nº patients) PEG 2b (86) Male gender # Age (years)* Age at HCV infection time (years) * Baseline weight (Kg) * Time with HCV infection (years) * HCV Genotype # 1 2 3 4 Baseline HCV-RNA >600.000 IU/ml # Baseline HCV-RNA >800.000 IU/ml # Fibrosis score # 0-2 3-4 Baseline ALT (IU/mL)* HIV risk group # IDU HMX HTX Others Baseline CD4 cell count (cell/mL) * Baseline CD4 cell count >300 # HIV viral load < 200copies/mL # * Mean (Std Desv); # Number (%) PEG 2a (96) 64 (66.7) 40,6 (5,4) 22,2 (6,6) 67.3 (10,8) 18.3 (6,0) 47 (50,5) 3(3,2) 28(30,1) 15 (16,3) 54 (58,1) 50 (53,7) 64 (71,1) 26 (28,9) 89.1 (47,4) 68 (70,8) 7 (7,3) 20 (20,8) 1 (1) 602.3 (279,6) 88 (91,7) 70 (72,9) All (182) 132 (72.5) 40,7 (5,2) 22,8 (6,8) 68.3 (11,5) 17.8 (6,2) 79 (45,4) 6(3,4) 59 (33,9) 30 (17,2) 104 (59,1) 98 (55,7) 115 (70,9) 47 (29,1) 99.4 (62,9) 137 (75,7) 11 (6,1) 29 (16) 4 (2,1) 597.7 (274,0) 166 (91,7) 133 (73,5) 68 (79.1) 40,7 (5,0) 23,3 (6,9) 69.4 (12,3) 17.3 (6,4) 32 (39,5) 3 (3,7) 31 (38,3) 15 (18,5) 50 (60,2) 48 (57,8) 51 (70,8) 21 (29,2) 111.2 (75,3) 69 (81,2) 4 (4,7) 9 (10,6) 3 (3,5) 592.5 (269,2) 78(91,8) 63 (74,1) Both groups were well balanced: – – – – – 72,5% males 76% former drug users 63% HCV genotype 1 or 4 29% bridging fibrosis or cirrhosis 56% HCV viral load > 800000 IU/mL. Demographics and Baseline Characteristics • HCV Genotypes PEG 2b PEG 2a 16.28 5.81 37.21 15.63 3.13 29.17 36.05 4.65 48.96 3.13 Not typ Genot. 1 Genot. 2 Genot. 3 Genot. 4 RESULTS • Global vEVR, EVR and SVR: % of response PEG 2b 100 90 80 70 60 50 40 30 20 10 0 PEG 2a 80,49 69,01 34,72 35,06 41,86 45,83 vEVR (week 4) EVR (week 12) SRV (week 72) n. 72 77 71 82 86 96 (Primary endpoint) RESULTS (EVR) • Global PPV and NPV of EVR: SVR EVR N=49 (69%) n=32 (65%) n=17 (35%) n=0 n=22 (100%) PEG 2b n=71 No SVR SVR n=22 (31%) No EVR No SVR SVR EVR N=66 (80%) n=42 (64%) PEG 2a n=82 No SVR SVR n=16 (20%) n=24 (36%) n=0 No EVR No SVR n=16 (100%) RESULTS • vEVR, EVR and SVR by genotype: PEG 2b 100 96.3 71.15 56.76 27.66 32.26 15.69 55.17 78.26 83.33 61.76 70.97 PEG 2a % of response 90 80 70 60 50 40 30 20 10 0 20.51 vEVR (w eek4) EVR (w eek 12) SRV (w eek 72) vEVR (w eek 4) EVR (w eek 12) SRV (w eek 72) n: 39 51 38 52 47 62 29 23 30 27 34 31 Genotype 1 or 4 Genotype 2 or 3 RESULTS • The independent factors related with SVR in the multivariate analysis were: – HCV genotype 2 or 3 – male gender – age ≤40 years Effect Odds Ratio Estimate Lower 95% Confidence Limit for Odds Ratio 1.308 0.813 1.241 2.317 Upper 95% Confidence Limit for Odds Ratio variable 5.317 age 3.171 Interferon 6.447 gender 9.202 genotype Pr > Chi-Square 0.0067 0.1725 0.0134 <.0001 Age: <= 40 years vs > 40 years 2.637 1.606 2.828 4.618 PEG 2a vs PEG 2b Gender: male vs female HCV Genotype: 2+3 vs 1+4 % of patients 100 30 40 50 60 70 80 90 10 20 0 Ge ne ra l Di so rd er s Ph yc hia tri cd iso rd er s alo pe c ia dig es tiv e dis or de rs An em ia Le uc op en ia * • 96% of patients presented ≥ 1 side effect. RESULTS (AEs) * p<0.05 Th ro mb op en ia * Lo ca l re ac Hy pe rla cta tio n PEG 2b te mi a Ot h PEG 2a er s RESULTS (AEs) • Adverse effects Grade III or IV. 100 90 80 * p<0.05 % of patients 70 60 50 40 30 20 10 0 * * PEG 2b PEG 2a • 10% AE ≥ 1 AE= grade III ≥ 1 AE= grade IV ≥ 1 AE= grade III or IV (n=19) of patients discontinuated the treatment due to adverse effects 8% (n=7) in PEG 2b and 13% (n=12) in PEG 2a arm, (p=0.56) RESULTS • Cumulative and number of patients with adverse events leading to treatment discontinuation. 20 18 16 14 12 10 8 6 4 2 0 2 4 8 12 16 20 24 28 32 36 40 44 48 Weeks Number of patients n patients cumulative CONCLUSION • In HIV infected patients, treatment of chronic HCV with RBV plus PEG 2b or PEG 2a had no statistically significant differences in tolerance and efficacy. Acknowledments Infections Diseases Service: Laguno M Murillas J León A Blanco JL García-Gasalla M Martínez E Milinkovic A Loncá M Callau P Miró JM Poal M Rodriguez A Casadesus C García F Gatell JM Mallolas J Radiology Service: Bianchi L Vilana R Gilabert R García-Criado A Bargalló X Hepatology Service: Sánchez-Tapias JM Pathology Service: Miquel R Biostatistics: de Lazzari E Pérez I Phyquiatry Service: Blanch J *** To the Patients