FIGURE 5–2 Results from a flucloxacillin drug-induced liver injury study. Each dot represents an SNP in a genome-wide assay. The x axis represents the position of the SNP on chromosomes. The y axis represents the magnitude of the association of each SNP with liver damage (Cochran-Armitage trend P value) in a case-control study that included 51 liver injury cases and 282 population controls. The high signal peak in chromosome 6 lies in the MHC region and indicates very strong association of injury with that SNP. The horizontal dashed line represents the commonly accepted minimum level for significance in this type of study. (Reproduced, with permission, from Daly AK et al: HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nat Genet 2009;41:816. Copyright 2009 Macmillan Publishers Ltd.) ximelagatran is associated with a HLA-DRB1*07:01 allele. Several drugs used in the treatment of tuberculosis, including isoniazid, rifampin, and ethambutol, also cause liver injury, which appears to be related to HLA polymorphisms.
Interferon lambda-3 (IFN-λ3; also known as interleukin-28B), encoded by the IFNL3 (or IL28B) gene, belongs to the family of type III IFN-λ cytokines. Type III IFNs share many therapeutic effects with type I IFNs, eg, IFN-a (Chapter 55), such as being directly induced by viruses and acting through JAK-STAT signal transduction pathways (via distinct heterodimeric receptor signaling complexes) to produce antiviral activity in cells. Type III IFNs play a role in hepatitis C virus (HCV) infection. Genetic variants near the IFNL3 gene were found to be most significantly associated with HCV treatment response to pegylated-IFN-a (PEG-IFN-a), in combination with ribavirin (RBV). Approximately twofold greater cure rates were observed in patients with a favorable genotype. While the mechanism underlying this association has yet to be fully elucidated, the rs12979860 variant near IFNL3 is considered the strongest baseline predictor of a cure for patients with HCV-1 receiving PEG-IFN-a/RBV. The favorable allele, the rs12979860 variant, is inherited most frequently in Asians (∼90%), and least frequently in Africans (Table 5–1). This frequency distribution is remarkably similar to rates of response to HCV PEG-IFN-a/RBV treatment among the three ethnic groups.
Pegylated interferon with ribavirin: Chronic HCV affects 160 million people worldwide and is a leading cause of cirrhosis of the liver and liver cancer. The goal for HCV antiviral therapy is to resolve the infection, defined clinically as achievement of sustained virologic response (SVR), ie, undetectable HCV RNA measured 6 months after finishing treatment. For patients receiving PEG-IFN-a/RBV regimens, which are associated with many side effects and poor response, clinical decisions of whether to initiate therapy are largely based on likelihood of SVR. Predictors of SVR include viral factors, as well as patient factors. In addition, Europeans homozygous for the favorable genotype (IFNL3 rs12979860/rs12979860; SVR: 69%) are more likely to achieve SVR compared with the unfavorable genotype (IFNL3 reference/reference or reference/rs12979860; SVR: 33% and 27%, respectively), and similar rates are observed in African patients. Guidelines according to CPIC are shown in Table 5–2.