Sofosbuvir Therapy and IFNL4 Genotype

In: Medical Genetics Summaries [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2012.


Sofosbuvir is an antiviral agent used in the treatment of chronic hepatitis C virus (HCV) infection. Sofosbuvir is FDA-approved to treat patients infected with HCV genotypes 1, 2, 3, and 4, as part of a combination antiviral treatment regimen (1). HCV genotype 1 is the most prevalent worldwide and HCV genotype 3 is the next most prevalent (2). Sofosbuvir may also be used as part of the treatment regimen of HCV genotypes 5 or 6 (3).

About 180 million people worldwide are infected with chronic hepatitis C, which is a major cause of chronic liver disease, cirrhosis, and liver cancer. Viral eradication is suboptimal with peginterferon plus ribavirin-based therapy, with only about half of patients with HCV genotype 1 infection achieving a sustained virological response (SVR) after 24 weeks (4). A SVR is defined as undetectable HCV RNA by the end of treatment or at a specific number of weeks after the initiation of treatment, e.g., undetectable HCV RNA at 12 weeks is annotated (SVR12).

Direct-acting antivirals (DAAs), such as sofosbuvir, were developed to improve viral eradication rates. They target HCV-encoded proteins involved in viral replication and infection. Sofosbuvir, the first and thus far only DAA, targets NS5B polymerase, the viral enzyme required for HCV RNA replication.

Sofosbuvir may be used in combination with peginterferon. The genetic variant rs12979860, located in the INFL4 gene, is a strong predictor of response to peginterferon-based therapies. The variant is a C to T change—individuals with the favorable “C/C” genotype have about a 2-fold higher likelihood of achieving SVR compared to individuals with CT or TT genotypes (5). (Note, because the association of rs12979860 with treatment response was reported several years before the discovery of IFNL4, the variant is commonly, but mistakenly, referred to as IL28B, which is the previous name for the IFNL3 gene.)

For specific treatment regimens that include sofosbuvir, although the IFNL4 variant still influences treatment outcomes, the SVR remains relatively high for all IFNL4 genotypes. For example in the NEUTRINO study, which is referred to in the FDA-approved drug label for sofosbuvir, the SVR12 rate was 99% in individuals with baseline C/C alleles and 87% in individuals with baseline non-C/C alleles. The individuals in this study had HCV genotype 1 or 4 infection, and were receiving sofosbuvir plus peginterferon plus ribavirin therapy (1, 6).

The drug label for sofosbuvir also discusses viral resistance. In cell culture, the amino acid substitution S282T in the viral NS5B polymerase is associated with reduced susceptibility to sofosbuvir (7). During the ELECTRON trial, this substitution was transiently detected in one individual who relapsed during sofosbuvir monotherapy. However, the clinical significance of such substitutions remains unknown (1).

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