Pegylated Interferon-alpha2a and Ribavirin in Chronic Hepatitis C Patients
Pegylated Interferon-alpha2a and Ribavirin in Chronic Hepatitis C Patients
In patients with chronic hepatitis C genotype 1, the current algorithm for treatment discontinuation is based on no early virological response (<2 log decline in hepatitis C virus (HCV)-RNA) at 12 weeks. It is important to determine whether prediction of nonsustained virological response (NR) before 12 weeks can be robustly obtained by statistical methods. We used longitudinal discriminant analysis (LDA) to build and cross-validate models including baseline patient characteristics and measurements of serum HCV-RNA in the first 4, 8 or 12 weeks of treatment. The performance of each model was evaluated by the partial AUC (PA) index, exploring the accuracy of prediction in the range of high negative predictive values. Models were compared by computing 95% confidence intervals for the difference in PA indices. NR was best predicted before week 12 by a single HCV-RNA measurement at week 8 taken together with gender, BMI and age (W8 model, PA index = 0.857). This model was not inferior to models that included a measurement at week 12 (PA index = 0.831). The best model obtained with LDA within the first 4 weeks, which included measurements at days 4, 8 and at week 4, was found to be inferior to the week 8 model (PA index = 0.796). These results indicate that lack of sustained viral response is best predicted after 8 weeks of treatment and that waiting until 12 weeks does not improve the prediction.
The introduction of the combination therapy of pegylated interferon (PEG IFN) α-2a or -2b with ribavirin (RBV) considerably improved the rate of sustained virological response (SVR) in patients chronically infected with hepatitis C virus (HCV), but at the expense of higher cost and poorer tolerability. Moreover, half of patients infected with HCV genotype 1 still do not respond to therapy and early treatment withdrawal is desirable to avoid unnecessary side-effects and expense. Thus, one would like to identify as early as possible those patients who will not achieve SVR. Several virus- and host-related predictors of treatment response are known, such as HCV genotype, baseline viral load, age, body weight, race, gender, liver histology, baseline gamma glutamyl transferase level, baseline alanine aminotransferase level and insulin resistance. However, none of these pre-treatment factors can precisely predict response to interferon-based treatments. Monitoring of early viral kinetics has been shown more useful in predicting long-term treatment outcome. In particular, the current algorithm for predicting nonsustained virological response (NR) is based on the absence of an early virological response (EVR) after 12 weeks of combined treatment with PEG IFN and RBV (EVR at week 12 as defined by serum HCV-RNA either <50 IU/mL or decreased by ≥2 log10 after 12 weeks). According to two pivotal studies, patients without an EVR at week 12 are very unlikely to achieve a SVR (negative predictive value, NPV >97%). This finding led the National Institutes of Health Consensus Conference to recommend that in the absence of an EVR at week 12, treatment should be stopped. In HCV genotype 1 patients, it has been confirmed that the absence of an EVR does predict NR accurately (NPV = 98%). One of the current challenges is to be able to predict NR even earlier in these patients.
Recent studies have indeed focused on using the viral response as early as at 4 weeks after the start of treatment to predict the ultimate treatment outcome. It was found that a rapid virological response (RVR as defined by serum HCV-RNA <50 IU/mL after 4 weeks) predicts SVR more accurately than an EVR at week 12. However, NPVs of RVR have been found to be significantly lower than those of an EVR at week 12. Thus, the current practice is still to use the algorithm based on an EVR at week 12 to decide whether to continue or discontinue treatment. However, this algorithm may not be ideal. Indeed, the thresholds used in this algorithm to dichotomize the continuous HCV-RNA variable (i.e. 50 IU/mL for the absolute level of HCV-RNA or 2 for the log10 HCV-RNA decline at week12), and the time points chosen to measure HCV-RNA (baseline and week 12) were determined empirically rather than by a systematic search and optimization method. Moreover, it does not take into account baseline patient characteristics known to correlate with the treatment outcome.
We aimed to use a comprehensive statistical method to determine whether accurate prediction of NR is possible before week 12 of therapy (even within the first month) in HCV genotype 1-infected patients, treated with PEG IFN α-2a and RBV.
Abstract and Introduction
Abstract
In patients with chronic hepatitis C genotype 1, the current algorithm for treatment discontinuation is based on no early virological response (<2 log decline in hepatitis C virus (HCV)-RNA) at 12 weeks. It is important to determine whether prediction of nonsustained virological response (NR) before 12 weeks can be robustly obtained by statistical methods. We used longitudinal discriminant analysis (LDA) to build and cross-validate models including baseline patient characteristics and measurements of serum HCV-RNA in the first 4, 8 or 12 weeks of treatment. The performance of each model was evaluated by the partial AUC (PA) index, exploring the accuracy of prediction in the range of high negative predictive values. Models were compared by computing 95% confidence intervals for the difference in PA indices. NR was best predicted before week 12 by a single HCV-RNA measurement at week 8 taken together with gender, BMI and age (W8 model, PA index = 0.857). This model was not inferior to models that included a measurement at week 12 (PA index = 0.831). The best model obtained with LDA within the first 4 weeks, which included measurements at days 4, 8 and at week 4, was found to be inferior to the week 8 model (PA index = 0.796). These results indicate that lack of sustained viral response is best predicted after 8 weeks of treatment and that waiting until 12 weeks does not improve the prediction.
Introduction
The introduction of the combination therapy of pegylated interferon (PEG IFN) α-2a or -2b with ribavirin (RBV) considerably improved the rate of sustained virological response (SVR) in patients chronically infected with hepatitis C virus (HCV), but at the expense of higher cost and poorer tolerability. Moreover, half of patients infected with HCV genotype 1 still do not respond to therapy and early treatment withdrawal is desirable to avoid unnecessary side-effects and expense. Thus, one would like to identify as early as possible those patients who will not achieve SVR. Several virus- and host-related predictors of treatment response are known, such as HCV genotype, baseline viral load, age, body weight, race, gender, liver histology, baseline gamma glutamyl transferase level, baseline alanine aminotransferase level and insulin resistance. However, none of these pre-treatment factors can precisely predict response to interferon-based treatments. Monitoring of early viral kinetics has been shown more useful in predicting long-term treatment outcome. In particular, the current algorithm for predicting nonsustained virological response (NR) is based on the absence of an early virological response (EVR) after 12 weeks of combined treatment with PEG IFN and RBV (EVR at week 12 as defined by serum HCV-RNA either <50 IU/mL or decreased by ≥2 log10 after 12 weeks). According to two pivotal studies, patients without an EVR at week 12 are very unlikely to achieve a SVR (negative predictive value, NPV >97%). This finding led the National Institutes of Health Consensus Conference to recommend that in the absence of an EVR at week 12, treatment should be stopped. In HCV genotype 1 patients, it has been confirmed that the absence of an EVR does predict NR accurately (NPV = 98%). One of the current challenges is to be able to predict NR even earlier in these patients.
Recent studies have indeed focused on using the viral response as early as at 4 weeks after the start of treatment to predict the ultimate treatment outcome. It was found that a rapid virological response (RVR as defined by serum HCV-RNA <50 IU/mL after 4 weeks) predicts SVR more accurately than an EVR at week 12. However, NPVs of RVR have been found to be significantly lower than those of an EVR at week 12. Thus, the current practice is still to use the algorithm based on an EVR at week 12 to decide whether to continue or discontinue treatment. However, this algorithm may not be ideal. Indeed, the thresholds used in this algorithm to dichotomize the continuous HCV-RNA variable (i.e. 50 IU/mL for the absolute level of HCV-RNA or 2 for the log10 HCV-RNA decline at week12), and the time points chosen to measure HCV-RNA (baseline and week 12) were determined empirically rather than by a systematic search and optimization method. Moreover, it does not take into account baseline patient characteristics known to correlate with the treatment outcome.
We aimed to use a comprehensive statistical method to determine whether accurate prediction of NR is possible before week 12 of therapy (even within the first month) in HCV genotype 1-infected patients, treated with PEG IFN α-2a and RBV.
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