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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. Why to treat HCV in HIV patients ?. Why to treat HCV in HIV patients ?. Longer survival Faster progression to cirrhosis Higher mortality due to ESLD

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Treatment of Chronic Hepatitis C in HCV-HIV Infected Patients

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  1. Treatment of Chronic Hepatitis C in HCV-HIV Infected Patients J Mallolas Infectious Diseases Service Hospital Clínic Barcelona

  2. Why to treatHCV in HIV patients ?

  3. Why to treat HCV in HIV patients ? • Longer survival • Faster progression to cirrhosis • Higher mortality due to ESLD • Higher risk of antiretroviral hepatotoxicity • Faster progression of HIV disease

  4. Incidence of Mortality in HIV-Infected Patients at the Hosp. Clinic (Barcelona, Spain) between 1984-1998 HAART: Highly Actibe Antiretroviral Therapy ( 2NRTI plus 1PI/NNRTI)

  5. 4 3 2 1 0 0 10 20 30 40 Effect of HIV on HCV Liver Fibrosis Progression Rate Fibrosis Grades (METAVIR Score) HIV+ (n = 122) 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.

  6. Causes of death per year in HIV patientsHospital Clínic. Barcelona

  7. Author No. ART HCV CD4 Rate Predictors Rodriguez1 132 PI-based 62% 324 11% HCV Alc. Sulkowski2 211 PI-based 51% 109 12% HCV CD4 Saves3 1249 2 NRTIs 44% 234 6% HCV HBV den Brinker4 394 PI-based 22% 150 18% HCV HBV Martínez5 610 NVP-based 51% 279 9.7% HCV ALT Núñez6 222 ART 40% 337 9% HCV age, Alc. Risk factors of Hepatotoxicity in HCV-HIVcoinfected patients: 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.

  8. How to treat HCV in HIV patients ?

  9. Sustained Response to HCV Therapy

  10. 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

  11. 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

  12. Response by Treatment Group, ITT P=0.033 P=0.017 AIDS 2004, 18:F27–F36

  13. Response by Genotype 1-4, ITT P=0.011 P=0.007 AIDS 2004, 18:F27–F36

  14. Response by Genotype 2-3, ITT P=0.914 P=0.730 AIDS 2004, 18:F27–F36

  15. Side effects (I) • 92% of patients developed adverse events.

  16. Side effects (II) • Premature discontinuation: 19% (Peg 23 vs 14%); 15% due to side effects (17 vs 12%) • Severity of the adverse events not shown differences between two arms.

  17. 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

  18. IFN type n. IFN/RBVPEG IFN/RBV ACTG2a133 12% 27% APRICOT 2a 868 12% 40% RIBAVIC2b400 19% 27% Laguno 2b95 21% 44% Crespo 2b 121 26% 55% Superiority of Peg IFN-Ribavirin (Sustained Virological Response)

  19. Differences in Baseline Characteristics Make Difficult a Comparison Face to Face Fibrosis 3-4 IVDU h ALT Geno1 ACTG 10% 50% 67% 78% APRICOT12% 65% 87% 60% RIBAVIC 40% 80% 83% 66% Laguno 30% 85% 100% 63% Crespo ? 79% 100% 48%

  20. Sustained Response to HCV Therapy HIV-neg HIV-pos IFN monotherapy 20% <10% IFN + ribavirin 45% 12-21% Peg-IFN + ribavirin 55% 27-55%

  21. Risk Factors for Failure of HCV Tx • Study of risk factors for failure to achieve EVR to PEG-IFN + RBV • 154 HIV/HCV co-infected patients • EVR: ≥ 2 log10 c/mL ↓HCV RNA • Increased risk of failure with: • Serum HIV RNA • HCV genotypes 1 and 4 • Abacavir use • Increased bilirubin levels • Potential drug interaction between RBV and ABC may be impacting outcomes Bani-Sadr F, et al. 14th CROI, Los Angeles, CA, February 25-28, 2007. Abst. 897.

  22. Abacavir Decreases SVR Rates with HCV Treatment Possible Intracellular Competition Between Abacavir and Ribavirin (Guanosine Analogs) • Retrospective study of 426 HIV/HCV patients (80% on HAART) starting pegIFN + RBV • 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) • 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 • ABC associated with a lower SVR rates possibly due to an inhibitory competition between RBV and ABC which are both guanosine analogs ABV RBV Adenosine kinase ABV-MP Cytosolic deaminase CBV-MP RBV-MP Guanylate kinase CBV-DP RBV-DP Nucleoside diphospho kinase CBV-TP RBV-TP Vispo E, et al. 47th ICAAC; Chicago, IL; September 17-20, 2007. Abstract H-1731.

  23. 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)

  24. Without ABC Without ABC With ABC With ABC Figure 1.Impact of Abacavir use on virologic response to pegylated interferon plus ribavirin in HCV/HIV-coinfected patients 100 90 80 68,89 70 66,04 60 57,14 56,41 % of patients with lack of response 50,42 48,28 50 42,86 38,1 40 35,14 31,58 30 18,18 20 16,67 11,11 10 7,69 0 4 12 24 36 48 60 72 159 45 152 47 52 11 90 24 119 29 195 49 168 42

  25. 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 (2000-2005) • 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 46 45 45 40 35 30 Patient Percent 25 19 20 14 15 10 5 0 G1-4 G2-3 PEG2B-RBV PEG2A-RBV Berenguer J, et al. 47th ICAAC; Chicago, IL; September 17-20, 2007. Abstract V-1897.

  26. 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.esTel. +34-93-2275574FAX. + 34-93-4514438 CROI-2008. Boston. USA

  27. 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.

  28. 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.

  29. Demographics and Baseline Characteristics • Baseline Characteristics of 182included patients: 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. * Mean (Std Desv); # Number (%)

  30. Demographics and Baseline Characteristics • HCV Genotypes PEG 2b PEG 2a Not typ Genot. 1 Genot. 2 Genot. 3Genot. 4

  31. RESULTS • Global vEVR, EVR and SVR: % of response n. 72 77 71 82 86 96 (Primary endpoint)

  32. RESULTS (EVR) • Global PPV and NPV of EVR: n=32 (65%) SVR N=49 (69%) EVR n=17 (35%) No SVR n=71 n=0 PEG 2b SVR n=22 (31%) n=22 (100%) No EVR No SVR n=42 (64%) SVR N=66 (80%) EVR n=24 (36%) No SVR n=82 n=0 PEG 2a SVR n=16 (20%) n=16 (100%) No EVR No SVR

  33. RESULTS • vEVR, EVR and SVR by genotype: % of response n: 39 51 38 52 47 62 29 23 30 27 34 31 Genotype 1 or 4 Genotype 2 or 3

  34. RESULTS • The independent factors related with SVR in the multivariate analysis were: • HCV genotype 2 or 3 • male gender • age ≤40 years

  35. RESULTS (AEs) • 96% of patients presented ≥ 1 side effect. * * * p<0.05

  36. RESULTS (AEs) • Adverse effects Grade III or IV. • 10% (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) * p<0.05 * * % of patients

  37. RESULTS • Cumulative and number of patients with adverse events leading to treatment discontinuation. Number of patients Weeks

  38. 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.

  39. 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 Acknowledments *** To the Patients

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