PGx471: Combined pharmacogenetic analysis of IL28B genotypes in TPL108390 and TPL103922

Trial description: Eltrombopag is a thrombopoietin receptor agonist indicated for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Currently, eltrombopag is also in development for increasing platelet counts in thrombocytopenic patients with chronic hepatitis C (HCV), where standard HCV treatment is contraindicated.Two genetic variants (rs12979860 and rs8099917) mapping near IL28B (IFN-λ3, a type III interferon) have been associated with interferon/ribavirin (IFN/RBV)-induced sustained virologic response (SVR) and spontaneous hepatitis C virus (HCV) clearance in patients carrying HCV genotype 1. In these published studies, patients who carry the `CC’ genotype for rs12979860 have ~2-fold increase in SVR over that achieved by carriers of the CT and TT genotypes, and the difference in SVR rates across ethnic groups was found to align with the frequency of the C allele for rs12979860 in these populations. Furthermore, the association between IL28B and IFN/RBV-induced SVR differs by viral genotype. Reports also suggest that in HIV/HCV co-infected patients, the CC genotype at the rs12979860 locus was associated with IFN/RBV-induced SVR in patients carrying HCV genotypes 1 and 4 infections, while IL28B genotypes were not associated with SVR in patients infected with HCV genotypes 2 and 3. This study includes patients from two clinical trials: TPL103922 which is a randomised, placebo-controlled, multi-centre study to assess the efficacy and safety of eltrombopag in thrombocytopenic subjects with Hepatitis C Virus (HCV) infection who are otherwise eligible to initiate antiviral therapy (peg interferon alfa-2a plus ribavirin) ENABLE 1 (Eltrombopag to INitate and Maintain Interferon Antiviral Treatment to Benefit Subjects with Hepatitis C related Liver DiseasE), and TPL108390, a trial with the same protocol, but where patients received peginterferon alfa-2b plus ribavirin therapy (ENABLE 2) instead. Although IL28B genotypes predict SVR in chronic hepatitis C patients treated with PegIFNalfa-2a (or 2b)/RBV, the clinical studies, TPL103922, and TPL108390, have been conducted in a patient population for which IFN/RBV is normally contraindicated, i.e., in patients with low platelet counts. IL28B variants were investigated for association with treatment response within each study, TPL103922 and TPL108390, in patients who consented to and provided a blood sample for genetics research. However, some parameters could not be evaluated effectively in the individual studies where the number of samples was small. By combining the datasets for TPL103922 and TPL108390, we will increase our sample population. This will enable us to evaluate IL28B genotype associations with antiviral response in more ethnic groups and by specific HCV genotype; the impact of other known predictors of IFN/RBV treatment response such as null or minimal liver fibrosis, age and individual HCV genotypes will also be evaluated.