DOI: 10.1097/FPC.0000000000000158
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PMID: 26111151
Issn Print: 1744-6872
Publication Date: 2015/09/01
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Excerpt
HCV infection affects 170–200 million people worldwide and is the leading cause of cirrhosis and hepatocellular carcinoma 2. Although the prevalence of HCV appears to be decreasing in most developed nations, mortality due to liver diseases secondary to HCV infection is expected to continue to rise over the next 20 years 3. Although a minority of patients with acute HCV infections are able to clear the virus spontaneously, 55–85% of patients develop chronic HCV infection, defined as detectable HCV RNA for longer than 6 months 4. Chronic infection, once established, rarely resolves spontaneously 5. The primary goal of treatment is achievement of sustained virologic response (SVR), characterized by undetectable serum viral RNA 24 weeks after the end of therapy, which is considered clinically as cure of infection and is associated with lower morbidity and mortality 6. HCV is divided into seven recognized genotypes (1–7), which differ at 30–35% of nucleotide sites 7. HCV genotypes are differentially distributed globally, with genotype 1 being most prevalent in North America, South America, and Europe 8. Further, the HCV genotype is highly associated with response to PEG-IFN-α/RBV combination therapy, and the rates of treatment-induced SVR are lowest for patients infected with HCV genotypes 1 and 4 9.
Before 2011, the standard-of-care for patients with chronic HCV was a combination of PEG-IFN-α and RBV therapy (either PEG-IFN-α 2a or 2b) administered for either 48 weeks, for HCV genotypes 1, 4, 5, and 6, or 24 weeks, for genotypes 2 and 3. However, these combination therapies yield SVR rates of only 40–50% in HCV genotype 1 patients 10. In contrast, SVR rates for patients with genotypes 2 and 3 are ~70–80%, although these rates apply to selected populations without the comorbidities that often accompany HCV 10–14. Further, combination therapy is costly, is associated with several moderate-to-severe side effects (influenza-like symptoms, depression, thrombocytopenia, and hemolytic anemia) 15, and is contraindicated in many patients (hepatic decompensation, portal hypertension, hypersplenism, severe psychiatric depression, major systems impairment, and pregnancy) 16. Positive predictive factors for achieving SVR include young age, female sex, and low pretreatment HCV-RNA levels 17. Conversely, SVR is less likely in HCV patients with high baseline HCV-RNA levels (>800 000 IU/ml), steatosis, insulin resistance, coinfection with HIV, and more advanced liver fibrosis 5,17.
The strongest pretreatment predictor of SVR rate is variations in IFNL3 (formerly known as IL28B), which is located on chromosome 19. The gene encodes IFN-λ 3, a member of the type 3 IFN-λ family that exhibits antiviral, antiproliferative, and immunomodulatory activities 18. The strongest and most commonly tested polymorphisms are rs12979860 and rs8099917, which are located 3 and 8 kb upstream of IFNL3, respectively, and exhibit strong linkage disequilibrium 19. As described in detail below, patients with the favorable rs12979860 CC or rs8099917 TT genotype have a greater than two-fold increased likelihood of achieving treatment-induced SVR. The Clinical Pharmacogenetics Implementation Consortium, which advises clinicians on how to utilize genetic information in treatment decisions, has produced detailed guidelines on the basis of IFNL3 genotyping for PEG-IFN-α/RBV-based treatment regimens 20.
