The current standard of care for hepatitis C virus (HCV) infection is pegylated interferon and ribavirin. Unfortunately, treatment cures at best only 40% to 50% of patients infected with genotype 1 HCV, the most common HCV genotype in Western countries. Treatment is also expensive and is often poorly tolerated. Therefore, the identification of patients most likely to benefit from treatment is clinically important. Genome-wide association studies have recently identified genetic variants, most notably IL28B and ITPA, which will enhance the ability of clinicians to personalize antiviral therapy for HCV infection.
"Recently, some countries have incorporated IL28B genotyping as a diagnostic criterion in clinical practice . In those patients with unfavorable IL28B genotypes, which result in response rates of less than 40%, clinicians may consider deferral of treatment until novel therapies are licensed, something likely to occur soon . However, IL28B genotype is not solely responsible for therapy response. "
[Show abstract][Hide abstract] ABSTRACT: Background
Since 2009, several studies have identified single-nucleotide polymorphisms (SNPs) near the gene encoding for interleukin (IL)-28 (IL28B) that are strongly associated with spontaneous and treatment-induced hepatitis C virus (HCV) clearance. Because this large amount of data includes some inconsistencies, we consider assessment of the global estimate for each SNP to be essential.
Relevant studies assessing IL28B polymorphisms associated with sustained virologic response (SVR) and spontaneous clearance (SC) were identified from a literature search of PubMed up to 9 July, 2012. Studies were eligible studies if they included patients infected with HCV or HCV/HIV, or assessed any SNP located within or near the IL28B gene, SVR data available under standard treatment, and/or SC data in patients with acute HCV infection. Pooled odds ratios were estimated by fixed or random effects models when appropriate. Variables such as HCV genotype, ethnicity, and type of co-infection were studied.
Of 282 screened studies, 67 were selected for SVR and 10 for SC. In total, 20,163 patients were studied for SVR and 3,554 for SC. For SVR, we found that all SNPs showed strong associations in patients with HCV genotypes 1 and 4, whereas the pooled ORs were almost three times lower for genotypes 2 and 3 (rs12979860 and rs8099917). Regarding ethnicity, the SNP most associated with SVR was rs12979860 in white patients, whereas in East Asians it seemed to be rs8099917. The most studied SNP (rs12979860) showed similar results for patients co-infected with HCV/HIV, as for those infected with HCV only. Finally, rs12979860 and rs8099917 both appeared to be associated with SC.
IL28B polymorphisms influence both the outcome of interferon treatment and the natural clearance of HCV. However we did not identify a universal predictor SNP, as the best genetic markers differed depending on patient ethnicity, genotype, and type of infection. Nevertheless, our results may be useful for more precise treatment decision-making.
BMC Medicine 01/2013; 11(1):6. DOI:10.1186/1741-7015-11-6 · 7.25 Impact Factor
"Predictive biomarkers predict the likely response of a patient to a special treatment in terms of efficacy and/or safety and thus support clinical decision-making (Table 1). For example, GWAs conducted by three independent groups from North America, Australia/Northern Europe, and Japan (Holmes et al. 2011) demonstrated that the IL28B gene is a strong indicator for response to standard treatment in patients with hepatitis C virus-1 (HCV-1) infection. Further, there is evidence for population stratification in the IL28B gene, such that treatment response varied across different ethnic groups. "
[Show abstract][Hide abstract] ABSTRACT: Biomarkers are of increasing importance for personalized medicine, with applications including diagnosis, prognosis, and selection of targeted therapies. Their use is extremely diverse, ranging from pharmacodynamics to treatment monitoring. Following a concise review of terminology, we provide examples and current applications of three broad categories of biomarkers-DNA biomarkers, DNA tumor biomarkers, and other general biomarkers. We outline clinical trial phases for identifying and validating diagnostic and prognostic biomarkers. Predictive biomarkers, more generally termed companion diagnostic tests predict treatment response in terms of efficacy and/or safety. We consider suitability of clinical trial designs for predictive biomarkers, including a detailed discussion of validation study designs, with emphasis on interpretation of study results. We specifically discuss the interpretability of treatment effects if a large set of DNA biomarker profiles is available and the number of therapies is identical to the number of different profiles.
Human Genetics 07/2012; 131(10):1627-38. DOI:10.1007/s00439-012-1188-9 · 4.82 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Biobanks are currently archiving human materials for medical research at a hitherto unprecedented rate. These valuable resources will be essential for developing ‘personalized’ medicines and for a better understanding of disease susceptibilities. However, for such scientific advances to benefit everyone, it is crucial that biobanks recruit donations from all sections of the community. Unfortunately, other initiatives, such as transplant programmes, have clearly demonstrated that ethnic minorities are under-represented. Here we suggest that this issue deserves serious consideration to avoid biobanks evolving into ethnically biased archives which unwittingly promote race-specific research. Specifically, this necessitates research ethics committees engaging in a re-assessment of the relative merits of individual personal sovereignty and the common good.
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