Análisis de las características basales y cinéticas virolipídicas durante las primeras semanas de terapia antiviral dual en pacientes con hepatitis crónica C genotipo 1diseño de un modelo predictivo costo-eficiente para la detección muy precoz de pacientes que no van a responder a la biterapia antiviral

  1. Jiménez Macías, Fernando Manuel
Supervised by:
  1. Emilio Pujol de la Llave Director
  2. Carlos Ruiz Frutos Director

Defence university: Universidad de Huelva

Fecha de defensa: 16 October 2014

  1. José Aguilar Reina Chair
  2. Manuel Montero Pérez-Barquero Secretary
  3. Mariano Aguayo Canela Committee member

Type: Thesis


INTRODUCTION Until 2011 the only therapeutic regimen for genotype 1 was dual therapy (pegylated interferón + Ribavirin), being approved the use of the first direct antiviral agents (DAA): Boceprevir or Telaprevir combined with dual therapy, increasing the rate of sustained and rapid virological responses (SVR and RVR): (first generation triple therapy). Thus, during 2014 it is possible that other DAA could be approved (Second generation triple therapy): Simeprevir, Sofosbuvir and Faldaprevir, which could increase the rate of SVR, using shorter therapies. The reduction of viremia obtained after administration of interferon is dose-dependent and show the degree of sensitivity to this drug, which could be evaluated, using a first induction-dose of pegylated interferón in order to observe if the reduction of viremia is higher with a higher dose. The lipid Metabolism plays an important role, having associated higher levels of LDL-cholesterol with higher rates of SVR. In the other hand, actually the daily dose of Ribavirin is dosage depend on body weight. However, Lindahl informed about the importance of making a daily adjustment of Ribavirin dosage according with Creatinine clearance. HYPOTHESIS Use of a combination of independent predictors of SVR associated with viral and lipid kinetics could be useful to design prognostic scales based on scores obtained from patients with chronic hepatitis C genotype 1, allowing to develop futility rules, which could help us in making-decision process in early moments of therapy (personalized and costefficient therapy). AIMS To design a novel diagnostic tool as help for therapeutic making-decision in patients with chronic hepatitis C genotype 1, depending on scores obtained from 3 prognostic scales with high positive and negative predictive value (Baseline Scale, Virologic Scale and Lipid Scale), which would classify to our patients before beginning new antiviral regimens in patients in subjects with low, medium and high risk of treatment failure to dual therapy (Primary Endpoint). MATERIAL & METHODS A prospective, randomized, double-blind, placebo-controlled study that included 99 patients CHC genotype 1, who were randomized to receive a first induction-dose (FID) of pegylated interferon alfa-2a (40 KD) (360 micrograms/subcutaneous) (Pegasys; Roche, Basel, Switzerland) against a first standard dose of pegylated interferon(180 micrograms/subcutaneous) plus ribavirin (1000 mg/day, if body weight < 75 kg, or ribavirin 1200 mg/day if body weight 75 kg), followed, after the second week, by standard bitherapy (pegylated Interferon 180 mcg/sc/week + ribavirin (weight-based), during 47 weeks more. We considered that in order for them to achieve SVR they would need a higher maximum reduction of viral load within the first week of bitherapy (VR1 value), whether at the third or seventh day, than individuals with a lower degree of fibrosis (METAVIR F0�F3) and/or lower BVL. Once patients were assigned their LFVR, we would determine that First Week Virological Response (FWVR) was achieved if the level of maximum reduction of viral load achieved during the first week of bitherapy (VR1 value) was equal or higher than the previously assigned LFVR. We designed 5 Levels of Lipid Exigency, depending on the degree of liver fibrosis, baseline viremia and the value of infectivity ratio, being our patients assigned to them. We selected different cutoff points for mLDLc variable in each Level of Lipid Exigency, using the COR curve, establishing that those subjects who achieve at least the value of mLDLc variable established in that level, had a favorable lipid metabolism, and obtaining a positive score in Lipid Scale, being negative if this value was not achieved. The comparison between the groups (presence of SVR) and (absence of SVR) was performed using the Student T test, or U Mann-Whitney test for continuous variables; 2 (Chi square), or Fisher's exact test was used for categorical variables. Those variables with a p value < 0.05 were considered statistically significant. Odds ratio and 95% Confidence Interval (CI) were calculated by univariate logistic regression analysis. Box-plox and scatter diagram were used. Later, a multivariate logistic regression analysis was performed in order to determine which variables were statistically related to "FWVR" variable, with a significance level < 0.05. RESULTS Subjects who reached the First Week Virological Response and a Favorable Lipid Metabolism achieved higher rates of SVR. The first futility rule (total score obtained in Baseline Scale + Virologic Scale) allowed us to detect those patients with lower possibilities of achieving SVR (candidates to therapies with higher efficacy). The second futility rule defined if a patient could be cured only with dual therapy (total score of three scales), generating a potential saving cost of 498724 �. The value of VR1 was statistically higher in patients with SVR, without taking in consideration whether a FID was given or not: (-2.06 ± 0.98 log10 UI/ml) versus (-0.87 ± 0.71 log10 UI/ml): odds ratio (OR) 5.9; 95% confidence interval (IC) (2.9�12.4); p < 0.0001. First Week Virological Response was achieved in 94.2% of patients with SVR, not being observed in 82.9% of patients with absence of SVR: OR 79.6; 95% CI (19.7�320.3); p < 0.0001; it showed a higher negative predictive value than the RVR or IL-28B ones. Patients with liver fibrosis F3-F4 who had higher baseline levels of LDL-cholesterol achieved higher rates of SVR. Those patients who had a lower value of infectivity ratio and median levels of LDL-cholesterol during the first month of bitherapy achieved higher rates of SVR too: �SVR group� 100 + 23 mg/dl against �absent of SVR�: 89 + 28 mg/dl; OR 1.1; CI 95% (1.0-1.2); p < 0.05, being these differences more significant in genotype IL-28B-CC (p = 0.013). Patients with SVR had higher rates of FLM. In subjects with CT/TT IL-28B genotype, lower degree of liver fibrosis and histologic inflammation, absent of insulin resistance, higher plasma concentration of Ribavirin at the first month of dual therapy were associated with higher rates of SVR. In multivariate analysis, urinary pH higher than 6 at the first month and an increasement of erythrocyte median corpuscular volume higher than 6 fentolitres were found associated statistically with higher plasma concentration of Ribavirina. CONCLUSIONS We developed a cost-efficient diagnostic tool for making-decision in chronic hepatitis C. First Week Virological Response is a biomarker of interferón-sensitivity as an independent predictor of response to dual therapy with a high negative predictive value. All patients did not have the same lipid kinetics during the first month of dual therapy, being necessary to achieve a favorable lipid Metabolism and/or achieve SVR to keep higher plasma median concentration of LDL-cholesterol during this period. Those subjects with absent of favorable lipid metabolism could benefit from use of statins. The adjustment of the daily dose of Ribavirin before and during antiviral therapy should be monitoring the erythrocyte median corpuscular volume, urinary pH and Lindahl´s formula.