Monday, November 11, 2013

Gender-Oriented Analysis: Who Is More Likely to Respond To Dual Therapy W-PEG-IFN/RBV For Hepatitis C?

Who Is More Likely to Respond to Dual Treatment With Pegylated-Interferon and Ribavirin for Chronic Hepatitis C?

A Gender-Oriented Analysis

V. Di Marco, L. Covolo, V. Calvaruso, M. Levrero, M. Puoti, F. Suter, G. B. Gaeta, C. Ferrari, G. Raimondo, G. Fattovich, T. Santantonio, A. Alberti, R. Bruno, C. Mussini, M. Mondelli, F. Donato, A. Craxì

J Viral Hepat. 2013;20(11):790-800.

Discussion Only
Full Text Available @ Medscape

In this real-life study, we simultaneously assessed the actually known viral and host-related factors that can influence the effectiveness of combined PEG-IFN and RBV therapy. Patients were enrolled in tertiary centres with consolidated experience in the management of hepatitis C infection.

Only roughly one in 10 patients stopped treatment, the majority of whom in the first 12 weeks, because of subjective adverse effects. This low rate of adverse events is similar to that reported by registered trials (5–7), confirming that combination therapy with PEG-IFN and RBV is substantially well tolerated.

Analysis of the entire cohort showed that SVR was independently associated with host factors, such as female gender, younger age and C/C genotype of the rs8099860 SNP, and virologic factors such as virus genotype and low levels of serum HCV-RNA. Therefore, we separately analysed patients according to virus genotype and gender. We further divided females into those under the age of 50, and those 50 or older, in the light of a recent study that suggested that menopause influences SVR and that the average age of spontaneous menopause in Italy is 50.[26]

The characteristics observed in genotype 1 females over the age of 50 were similar to those identified by Villa et al.[26] in menopausal females included in their study. In fact, at baseline, females over 50 years included in our cohort had frequently high BMI and visceral obesity, metabolic alterations and severe histological liver damage, like those observed in the menopausal females in the study by Villa et al. These data confirmed that genotype 1 females over 50 years, especially during menopause, had several factors that reduce the efficacy of interferon-based therapy.[25]

Another host factor analysed in our cohort was the IL28B polymorphism. As reported in other studies, patients who carried the C/C genotype of the rs12979860 SNP had a higher likelihood of responding to dual therapy (12–15). This factor was independent of gender, virus genotype, degree of fibrosis and presence of metabolic cofactors. Age under 50 years and C/C genotype of the rs12979860 SNP were the only two independent favourable factors associated with RVR and SVR in females. Combining the two factors, the rate of RVR in females increased from 15.5% to 73.3%, and the rate of SVR increased from 27.6% to 84.6%. Using these variables, it is possible to identify three groups of naïve females infected with genotype 1. Females with no favourable factors have a very low baseline likelihood of achieving an SVR with dual combination therapy, and this likelihood remains about 50% even in patients who achieve an RVR. Therefore, these patients should be treated with the new therapeutic approach including PEG-IFN, RBV and telaprevir or boceprevir. On the other hand, females with both favourable factors have a very high baseline likelihood of achieving an SVR, and so do not need to be treated with triple therapy as first choice. Finally, in females who have only one of the two favourable factors, RVR predicts patients who have a close to 90% likelihood of achieving an SVR.

In males infected with HCV genotype 1, absence of visceral obesity was an independent host factor associated with SVR, in addition to serum HCV-RNA levels < 400 000 IU/mL and C/C genotype of the rs8099860 SNP. We found no association between age and SVR in genotype 1 males. A possible explanation is that the males, unlike the females, did not experience an increase in inflammation and rapid progression of fibrosis related to menopause. As in the females, in genotype 1 males, we also found an independent association between RVR and SVR. The likelihood of achieving an RVR and an SVR in males with C/C genotype of the rs8099860 SNP, without visceral obesity, and with baseline serum HCV-RNA levels < 400 000 IU/mL, was more than 64% and more than 85%, respectively. These males could be successfully treated with dual therapy. Even males who have 2 or 3 favourable factors have a relatively high likelihood of achieving RVR and SVR, and the presence of RVR predicts patients with a more than 85% likelihood of achieving an SVR. On the contrary, males with no or only one favourable factor have a less than 30% likelihood of achieving SVR, which increases to 57% in those with RVR, a figure lower than that obtained with the triple therapy in all patients with genotype 1. The discriminatory ability of our prediction rule was quite high, with the AUC of the model for predicting SVR in males being near 0.75 and 0.7 in females.

In genotype 2 and genotype 3 patients, we found a very high rate of SVR, and also that host-related factors do not affect the success of therapy. As reported in other studies, RVR was associated with a significantly higher rate of SVR both in females and males infected with genotype 2.[36] We observed a significant difference in SVR among females and males infected with genotype 3. Genotype 3 males who did not achieve an RVR had a rate of SVR of less than 30%. This observation could strengthen the hypothesis that at least males infected with genotype 3 who do not have an RVR should be treated for longer than 24 weeks.[37]

Triple therapy with boceprevir and telaprevir in naive patients infected with HCV genotype 1 obtains an SVR of more than 60%, but the pivotal trials on higher efficacy have also reported a greater number of adverse events and a risk of developing viral resistance.[9,10] AASLD practice guidelines[11] recommend as the optimal therapy for genotype 1 chronic HCV infection the use of boceprevir or telaprevir in combination with PEG-IFN and RBV, but alternative strategies for reducing costs and improving effectiveness using favourable factors associated with the success of dual or triple therapy have also been proposed.[38,39]

Our study suggests that simultaneous analysis of the demographic, genetic and metabolic characteristics of the host that can influence the efficacy of antiviral therapy, and viral factors that may affect the possibility of eradication, may indicate groups of genotype 1 patients with very different likelihoods of achieving an SVR through dual therapy with PEG-IFN and RBV. In males and females, the factors associated with SVR were substantially different, and should, in any event, be combined with the viral variables. In patients who have only a few favourable factors, RVR can significantly predict a successful cure.

This study suggests that factors associated with the efficacy of dual therapy may be different in males and females. However, some possible drawbacks of the research should be mentioned.

First, although the total number of patients included in the cohort was relatively large, we examined many factors possibly associated with response, which reduced considerably the number of subjects according to the combination of some variables and, consequently, the power of statistical tests. For this reason, these results need to be confirmed in a larger data set of patients. Second, several published studies analysed genetic,[12–15] metabolic[19–23] and viral factors,[27,28] which are possibly associated with sustained virologic response, but, to our knowledge, there are not studies that analysed all together the factors assessed in our research so far.

In conclusion, our study suggests that some factors associated with the success of dual antiviral therapy may be different in males and females and that dual therapy with PEG-IFN and RBV can still be used for genotype 1 patients who have favourable clinical, genetic and viral profiles.

  • Abstract and Introduction
  • Patients and Methods
  • Methods
  • Results
  • Discussion

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