This section contains excerpted
1
information on gene-based dosing recommendations. Neither this section nor other parts of this review contain the complete recommendations from the sources.
Statement from the US Food and Drug Administration (FDA):
NEUTRINO was an open-label, single-arm trial that evaluated 12 weeks of treatment with sofosbuvir in combination with peginterferon alfa 2a and ribavirin in treatment-naïve subjects with genotype 1, 4, 5 or 6 HCV infection compared to pre-specified historical control. [...] SVR12 rates were 99% (89/90) in subjects with genotype 1 or 4 HCV and baseline IL28B C/C allele and 87% (200/230) in subjects with genotype 1 or 4 HCV and baseline IL28B non-C/C alleles2
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It is estimated that the SVR12 in patients who previously failed pegylated interferon and ribavirin therapy will approximate the observed SVR12 in NEUTRINO subjects with multiple baseline factors traditionally associated with a lower response to interferon-based treatment. The SVR12 rate in the NEUTRINO trial in genotype 1 subjects with IL28B non-C/C alleles, HCV RNA greater than 800,000 IU/mL and Metavir F3/F4 fibrosis was 71% (37/52).
[…]
In a pooled analysis of 982 subjects who received sofosbuvir in Phase 3 trials, 224 subjects had post- baseline NS5B genotypic data from next generation nucleotide sequencing (assay cutoff of 1%).
Treatment-emergent substitutions L159F (n=6) and V321A (n=5) were detected in post-baseline samples from GT3a-infected subjects across the Phase 3 trials. No detectable shift in the phenotypic susceptibility to sofosbuvir of subject isolates with L159F or V321A substitutions was seen. The sofosbuvir-associated resistance substitution S282T was not detected at baseline or in the failure isolates from Phase 3 trials. However, an S282T substitution was detected in one genotype 2b subject who relapsed at Week 4 post-treatment after 12 weeks of sofosbuvir monotherapy in the Phase 2 trial P7977-0523 [ELECTRON]. The isolate from this subject displayed a mean 13.5-fold reduced susceptibility to sofosbuvir. For this subject, the S282T substitution was no longer detectable at Week 12 post-treatment by next generation sequencing with an assay cutoff of 1%.
Please review the complete therapeutic recommendations that are located here:
(1).
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The FDA labels specific drug formulations. We have substituted the generic names for any drug labels in this excerpt. The FDA may not have labeled all formulations containing the generic drug.
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Note: Recent studies report that the rs12979860 variant is in the IFNL4 gene, and not the IFNL3 gene (previously called IL28B). Therefore, a more accurate term for describing an individual’s genotype would be “rs12979860 C/C”, instead of “IL28B C/C”.