Diapositiva 1

1
INTERFERON ALPHA AND RIBAVIRIN THERAPY FOR
CHRONIC HEPATITIS C IN HIV-INFECTED PATIENTS
(GESIDA 28-02 STUDY) J. Berenguer1, J. Gonzalez2,
P. Miralles1, C. Quereda3, M.A. Von-wichman4, P.
Labarga5, B. Mahillo6, and the GESIDA 28/02
Study Group. 1Hosp Gregorio Marañón, 2Hosp La
Paz, 3Hosp Ramón y Cajal, 4Hosp Donostia, 5Hosp
La Rioja, 6Agencia de Ensayos Clínicos de GESIDA,
SPAIN
OBJECTIVE OBJECTIVE
To analyze the therapeutic efficacy and the safety of conventional interferon a (IFN) and ribavirin (RBV) for chronic hepatitis C (CHC) in HIV-infected patients To analyze the therapeutic efficacy and the safety of conventional interferon a (IFN) and ribavirin (RBV) for chronic hepatitis C (CHC) in HIV-infected patients
PATIENTS AND METHODS PATIENTS AND METHODS
Design Observational multicenter cohort study
Patients 132 patients from 6 hospitals affiliated to GESIDA with HIV infection and confirmed CHC
Treatment IFN a-2b 114 patients IFN a-2a 18 patients. IFN 3MU 3 times/wk 119 patients, IFN gt 3MU 3 times/wk (for induction) 13 patients. The median dose of RBV administered was 14.63 mg/Kg. A PCR for serum HCV-RNA was performed at 24 wk if () IFN-RBV therapy was stopped if (-) therapy was prolonged to 48 wk.
Assessment End of treatment response (ETR) (-) HCV-RNA at the end of IFN RBV therapy. Sustained virologic response (SVR) (-) HCV-RNA 24 wk after the finalization of IFN RBV. Safety was assessed by laboratory tests and evaluation of adverse events (AE) at least monthly during IFN-RBV therapy.
Statistical Analysis All analyses were done in an ITT basis and included all patients who received at least one dose of IFN-RBV . Logistic-regression models were used to explore base-line factors predicting a SVR and discontinuation of therapy due to adverse events (AE)
TABLE 3. EVOLUTION OF CD4 CELLS AND HIV VIRAL LOAD DURING IFN-RBV THERAPY TABLE 3. EVOLUTION OF CD4 CELLS AND HIV VIRAL LOAD DURING IFN-RBV THERAPY TABLE 3. EVOLUTION OF CD4 CELLS AND HIV VIRAL LOAD DURING IFN-RBV THERAPY TABLE 3. EVOLUTION OF CD4 CELLS AND HIV VIRAL LOAD DURING IFN-RBV THERAPY TABLE 3. EVOLUTION OF CD4 CELLS AND HIV VIRAL LOAD DURING IFN-RBV THERAPY TABLE 3. EVOLUTION OF CD4 CELLS AND HIV VIRAL LOAD DURING IFN-RBV THERAPY
Variable WK 0 WK 12 WK 24 WK 48 WK 60
CD4 cells/uL, median (IQR) 510 (366- 755) 344 (246 598) 360 (263 554) 437 (261 651) 586 (435 758)
Nº of patient studied 131 108 102 66 65
patients with VL lt LOD 52 57 55 41 56
Nº of patients studied 129 107 98 74 57
APPENDIX In addition to the authors, the
following members of the GESIDA 28-02 Study Group
participated in this study J.A. Pérez Molina,
J.C. López, J. Cosín, B. Padilla, F. Fernández
and M. Ramírez-Schacke from Hosp. Gregorio
Marañón, Madrid. J.D. Pedreira and J. Juega from
Hosp. Juan Canalejo, La Coruña. J.R. Arribas, A.
Lorenzo and S. Hernández from Hospital La Paz,
Madrid. L. Moreno, A. Moreno and S. Moreno from
Hosp. Ramón y Cajal, Madrid. J.A. Iribarren, J.
Arrizabalaga and F. Rodríguez-Arrondo from Hosp.
Donostia, San Sebastián. J. Pinilla from Hosp. La
Rioja, Logroño. H. Esteban from Agencia de
Ensayos Clínicos de GESIDA, Madrid.
TABLE 1. CHARACTERISTICS OF THE PATIENTS AT BASE LINE. PART I TABLE 1. CHARACTERISTICS OF THE PATIENTS AT BASE LINE. PART I
Characteristic Value
Sex M/F ( male) 103/29 (78.0)
Age yr. Median (IQR) 37 (34 41)
Weight kg. Median (IQR) 69 (61 77)
Mode of HIV infection no. () Injection of drugs Heterosexual relations Homosexual relations Other 116 (87.9) 10 (7.6) 2 (1.5) 4 (3.0)
CDC clinical category no. () A B C 66 (50.0) 36 (27.3) 29 (21.9)
Nadir CD4 cells/uL. Median (IQR) 216 (121 354)
Baseline CD4 cells/uL. Median (IQR) 510 (366 755)
Baseline HIV viral load lt 200 c/ml no. () 67/129 (51.9)
ART no. () 110 (83.3)
HAART no. () 98 (74.2)
Drugs included in the regimen AZT ddI d4T ddI d4T 16 (12.1) 18 (13.6) 53 (40.2) 21 (15.9)
TABLE 2. CHARACTERISTICS OF THE PATIENTS AT BASE LINE. PART II TABLE 2. CHARACTERISTICS OF THE PATIENTS AT BASE LINE. PART II
Characteristic Value
Years with HCV, median (IQR) 17 (12 20)
ALT U/liter, median (IQR) 127 (83 - 191)
History of alcohol gt 50 g/d no. () Never Before Current No data 68 (51.5) 50 (37.9) 8 (6.1) 6 (4.5)
HCV genotype no. () 1 2 3 4 Unknown 65 (49.2) 4 (3.0) 52 (39.4) 10 (7.6) 1 (0.7)
HCV RNA level gt 2 x 106 c/ml or 850,000 IU no. () lt 2 x 106 c/ml or 850,000 IU no. () Unknown 70 (53.0) 57 (43.2) 5 (3.8)
Stage of fibrosis no. () F0 F1 F2 F3 F4 Unknown (biopsy not performed) 6 (4.5) 27 (20.5) 25 (18.9) 43 (32.6) 15 (11.4) 16 (12.1)
ABSTRACT Objective To analyze therapeutic
efficacy and safety of interferon a (IFN) and
ribavirin (RBV) for chronic hepatitis C (CHC) in
HIV-infected patients (pt). Patients and Methods
Design Observational multicenter cohort study.
Patients 132 pt (from 6 hospitals affiliated to
GESIDA) with HIV and confirmed CHC (increased
ALT, () PCR for HCV and (-) HBsAg). Male/female
103/29. Median age 37 y. Median wgt 69 kg. HIV
data IVDA 116 pt. CDC category, A 66 pt, B 36
pt, C 29 pt. Median nadir CD4 216/uL. Median
baseline CD4 510/uL. HIV viral load lt 50
copies/ml 66 pt. HAART 98 pt (AZT 16 pt, ddI
18 pt, d4T 53 pt, ddId4T 21 pt). CHC data
Genotypes, 1 65 pt, 2 4 pt, 3 52 pt, 4 10 pt,
unknown 1 pt. HCV viral load gt 850,000 UI 70 pt.
Never drinked alcohol (gt 50 g/d) 68 pt. Liver
biopsy (116 pt), F0 4,5, F1 20,5, F2 18,9,
F3 32,6, F4 11,4. Treatment IFN a-2b 114
pt IFN a-2a 18 pt. IFN 3MU 3 times/wk 119 pt,
and IFN gt 3MU 3 times/wk (for induction) 13 pt.
RBV median dose 14.63 mg/kg. HCV PCR was
performed at 24 wk, if () IFN-RBV therapy was
stopped, if (-) therapy was prolonged to 48 wk.
Results Efficacy Sustained virologic response
(SVR) by ITT analysis all genotypes 28 pt
(21.2), genotypes 1-4 9 pt (12), genotypes
2-3 18 pt (32). By logistic regression,
genotype was the only variable associated with
SVR OR of not achieving SVR by ITT for genotypes
1-4 vs. 2-3 3.4 (CI 95 1.21 9.58) p 0.021.
Safety Severe adverse events (AE) developed in
19 pt (14) psychiatric disorders 4 pt,
pancreatitis/lactic acidosis 4 pt, hepatic
decompensation 3 pt, lipoatrophy 2 pt, other AE 6
pt. Fifteen 15 pt (11) discontinued IFN-RBV due
to AE. Two pt died during IFN-RBV therapy sepsis
and lactic acidosis, one each. By logistic
regression, d4TddI therapy was the only variable
associated with discontinuation of IFN-RBV due to
AE OR for d4TddI vs. no d4TddI 4.44 (CI 95
1.38 14.27) p 0.012. Conclusions Our data
suggest that the therapeutic efficacy of IFN-RBV
for CHC in HIV-infected pt is substantially lower
than that reported in clinical trials in HIV-non
infected pt. Genotype was the only baseline
predictor of treatment outcome. The combination
of IFN-RBV may cause severe AE due to drug
interactions with antiretrovirals particularly in
patients treated with d4T ddI.
TABLE 4. INCIDENCE OF SEVERE AE, DOSE MODIFICATION, AND CONCOMITANT MEDICATION TABLE 4. INCIDENCE OF SEVERE AE, DOSE MODIFICATION, AND CONCOMITANT MEDICATION
Variable Number ()
Adverse event Psychiatric disorders Pancreatitis Lactic acidosis Liver decompensation Severe lipoatrophy AIDS defining condition (PML) Fever, weight loss, and malaise Thrombocytopenia Right heart failure (COPD PHT) 19 (14.4) 5 3 2 (1 died) 2 (1 died) 1 1 1 2 1
Dose reduction of RBV Dose reduction of IFN Use of psychiatric medication Use of G-CSF  Use of erythropoietin  Changes in ART 13 (9,8) 4 (3) 23 (17,4) 4 (3) 0 (0) 17 (15,5)
TABLE 5. PREDICTORS OF SUSTAINED VIROLOGIC RESPONSE (SVR) AND OF DISCONTINUATION DUE TO ADVERSE EVENTS (AE) TABLE 5. PREDICTORS OF SUSTAINED VIROLOGIC RESPONSE (SVR) AND OF DISCONTINUATION DUE TO ADVERSE EVENTS (AE) TABLE 5. PREDICTORS OF SUSTAINED VIROLOGIC RESPONSE (SVR) AND OF DISCONTINUATION DUE TO ADVERSE EVENTS (AE) TABLE 5. PREDICTORS OF SUSTAINED VIROLOGIC RESPONSE (SVR) AND OF DISCONTINUATION DUE TO ADVERSE EVENTS (AE)
Independent Factors Associated with SVR Independent Factors Associated with SVR Independent Factors Associated with SVR Independent Factors Associated with SVR
Variable OR of not achieving SVR 95 CI p
Genotype 1-4 3.4 1.21 9.58 0.021
In multivariable analyses to identify predictors of SVR among patients who received IFNRBV, our final model including the following factors was entered in the final regression analysis sex, weight, stage of fibrosis (F0-F2 vs F3-F4), pre-treatment ARN-HCV ( 2 x 106 c/ml or 850,000 UI/ml vs gt 2 x 106 c/ml or 850,000 UI/ml), genotype (1-4 vs 2-3), pre-treatment ALT, nadir CD4 cells/uL, dose of RBV ( 10.4 mg/kg vs gt 10.4 mg/kg) and induction therapy with IFN. One factor independently and significantly increased the odds of not achieving a SVR an HCV genotype 1 or 4. In multivariable analyses to identify predictors of SVR among patients who received IFNRBV, our final model including the following factors was entered in the final regression analysis sex, weight, stage of fibrosis (F0-F2 vs F3-F4), pre-treatment ARN-HCV ( 2 x 106 c/ml or 850,000 UI/ml vs gt 2 x 106 c/ml or 850,000 UI/ml), genotype (1-4 vs 2-3), pre-treatment ALT, nadir CD4 cells/uL, dose of RBV ( 10.4 mg/kg vs gt 10.4 mg/kg) and induction therapy with IFN. One factor independently and significantly increased the odds of not achieving a SVR an HCV genotype 1 or 4. In multivariable analyses to identify predictors of SVR among patients who received IFNRBV, our final model including the following factors was entered in the final regression analysis sex, weight, stage of fibrosis (F0-F2 vs F3-F4), pre-treatment ARN-HCV ( 2 x 106 c/ml or 850,000 UI/ml vs gt 2 x 106 c/ml or 850,000 UI/ml), genotype (1-4 vs 2-3), pre-treatment ALT, nadir CD4 cells/uL, dose of RBV ( 10.4 mg/kg vs gt 10.4 mg/kg) and induction therapy with IFN. One factor independently and significantly increased the odds of not achieving a SVR an HCV genotype 1 or 4. In multivariable analyses to identify predictors of SVR among patients who received IFNRBV, our final model including the following factors was entered in the final regression analysis sex, weight, stage of fibrosis (F0-F2 vs F3-F4), pre-treatment ARN-HCV ( 2 x 106 c/ml or 850,000 UI/ml vs gt 2 x 106 c/ml or 850,000 UI/ml), genotype (1-4 vs 2-3), pre-treatment ALT, nadir CD4 cells/uL, dose of RBV ( 10.4 mg/kg vs gt 10.4 mg/kg) and induction therapy with IFN. One factor independently and significantly increased the odds of not achieving a SVR an HCV genotype 1 or 4.
Independent Factors Associated with Discontinuation due to AE Independent Factors Associated with Discontinuation due to AE Independent Factors Associated with Discontinuation due to AE Independent Factors Associated with Discontinuation due to AE
Variable OR of discontinuation 95 CI p
ddI d4T therapy 4.44 1.38 14.27 0.012
Our final multiple logistic-regression model to identify predictors of discontinuation of IFN-RBV therapy due to AE included the same factors as in efficacy analysis plus type of HAART. One factor independently and significantly increased the odds of achieving a sustained virologic response ddI d4T therapy. Our final multiple logistic-regression model to identify predictors of discontinuation of IFN-RBV therapy due to AE included the same factors as in efficacy analysis plus type of HAART. One factor independently and significantly increased the odds of achieving a sustained virologic response ddI d4T therapy. Our final multiple logistic-regression model to identify predictors of discontinuation of IFN-RBV therapy due to AE included the same factors as in efficacy analysis plus type of HAART. One factor independently and significantly increased the odds of achieving a sustained virologic response ddI d4T therapy. Our final multiple logistic-regression model to identify predictors of discontinuation of IFN-RBV therapy due to AE included the same factors as in efficacy analysis plus type of HAART. One factor independently and significantly increased the odds of achieving a sustained virologic response ddI d4T therapy.