Elementos semánticos en línea

The program of research was initiated by a literature review of factors associated with the response to therapy in patients with genotype 3 HCV infection. A number of studies described response rates in patients from Far Eastern Asia (chiefly Taiwan, China and Korea) and these studies suggested that response rates may be at least equal to response rates reported in pivotal clinical studies from America and Europe[5]. However, many such studies combined data from patients with genotype 2 and 3 HCV making it difficult to determine the contribution of each to the overall response rates. Furthermore more recent work has shown that patients from East Asia have a high likelihood of carrying the IL-28 polymorphism that is favourable to virological response in patients with genotype 1 HCV and it is possible that the excellent response rates seen in this population are unduly influenced by this genetic variation. A few studies have been published which prospectively looked at the impact of age >40 years, low pre treatment viral load, cirrhosis and the impact of rapid virological response (RVR) on predicting response to treatment in Pakistani patients [214-216] but the specific effect of ethnicity was not looked at as an independent factor in those studies. One UK study by Freshwater et al suggested that South

Asian ethnicity reduced the response to therapy and this study is the first to clearly document a reduced response in this ethnic group. However the study involved relatively few patients and was not adequately powered to detect confounding variables, such as age, presence of cirrhosis and insulin resistance. Given data from the United States demonstrating that African Americans have a poor response to antiviral therapy we speculated that the findings of Freshwater et al were correct and we attempted to confirm this with a larger study [169].This involved a retrospective review of over 600 patients treated at various Liver Units throughout the UK. This is the first and largest study to examine the impact of South Asian ethnicity on the response to treatment.We collected a cohort of sufficient size and diversity to determine whether or not South Asian ethnicity per se influences the outcome of therapy. This study included all patients who received therapy and thus there was a limited potential for selection bias. However, there were some missing data (which was largely a consequence of the retrospective nature of the study) but there was no evidence of any systematic bias in the data that was not available. Furthermore analysis of the dataset with and without the missing variables did not lead to different conclusions strongly suggesting that the conclusions are robust. Our data show that South Asian ethnicity is not a major factor in reducing response to therapy but cirrhosis, diabetes and older age are important determinants of the treatment response in patients with Genotype 3 HCV.Our analysis of factors influencing the response to anti-viral therapy show that age and the extent of liver fibrosis dominate the outcome and that diabetes is associated with a significant reduction in the SVR rate. Patients were classified as having diabetes if they were registered as diabetic and those without a mention of diabetes were categorised as non-diabetic. There is a possibility that this may have lead to an underestimation of the prevalence of diabetes and formal tests of insulin resistance were not performed.

It is well established that dose reductions and modifications to the treatment regime as a result of treatment related side effects can reduce the efficacy of therapy and it is conceivable that the impact of age and cirrhosis on treatment outcome was related to reductions in the dose of medication. However, the heterogeneous nature of the dose reductions in the different centres over the long time course of this study precluded a full analysis of the impact of dose reduction so we are unable to comment further on the impact of dose changes.

Data from the four UK treatment centres were included in the study. The centres had used different assays to detect viraemia and the threshold varied with time with a cutoff of less than 615 IU/ml being defined as negative in the first few years, which was later reduced to less than 15 IU/ml. For each laboratory, at each time, the local lower limit of detection was accepted, and samples deemed ‘negative’ by the laboratory were regarded as undetectable. Since studies with Pegylated interferon show that differences in assay sensitivity have minimal impact upon categorisation of outcome we do not believe that these differences were significant in determining the rates of sustained response. However in the determination of RVR it is possible that assay sensitivity did lead to differences in determining whether an RVR had or had not occurred and these data should therefore be treated with some caution.

A number of different treatment regimes were used. In general patients received either 40 kD pegylated interferon  2a combined with 800 mg of ribavirin or 12 kD pegylated interferon  2b combined with weight-adjusted ribavirin. Both treatments were normally given for 24 weeks and response guided therapy with a reduction in treatment duration for rapid and early virological responder was not used at the time of this study. In a few centres, some patients were given extended courses of therapy and these were noted. The use of different dosing regimes across different sites may have blurred the affect of ethnicity in predicting the response to treatment in the cohort. Our dataset also included patients from the Freshwater et al study which was part of the Birmingham centre cohort of patients but as the Freshwater et al cohort was also a retrospective review of patients who had received treatment its inclusion in our study is unlikely to have introduced additional bias.Our results indicate that the role of ethnicity in predicting response to treatment was confounded by older age,diabetes and cirrhosis and that S.Asian ethnicity itself did not play a role in determining response to treatment.

In patients with adverse factors that may reduce the response to antiviral therapy clinicians are often tempted to increase the duration of therapy and a number of patients in this cohort did undergo extended therapy. The number of such patients was small and far too few were studied to allow any meaningful comment on the value of extended therapy. The observation that clinicians are using this unproven regime clearly highlights the need for a clinical trial to examine the value of extended duration therapy in patients with Genotype 3 HCV and adverse prognostic factors.

Our study indicates that Genotype 3 HCV is ‘easy to cure’ provided that the patients are identified when they are young and before they have developed cirrhosis and/or diabetes. These data add further weight to calls for case finding approaches in populations at high risk of Genotype 3 HCV[57].