Patients infected with hepatitis C virus (HCV) who achieve sustained virologic response (SVR) during treatment with direct-acting antivirals (DAAs) are more likely to have an enhanced interferon signature in their liver and blood at baseline compared with patients who experience a virologic breakthrough, according to results published in Hepatology.
These findings suggest that innate immunity may contribute to SVR during DAA therapy for HCV by preventing the emergence of resistance-associated substitutions that can lead to viral breakthrough.
The study included participants with HCV genotype ab in whom a course of peginterferon/ribavirin (n=13) had previously failed. Participants were re-treated with asunaprevir/daclatasvir for 24 weeks. After pretreatment biopsy, participants were randomly assigned to undergo a second biopsy at week 2 or 4 of treatment. The researchers performed microarray and NanoString analyses on paired liver biopsies.
In total, 69% (n=9) of participants achieved SVR and 4 experienced virologic breakthroughs between weeks 4 and 12.
Participants who achieved SVR showed higher interferon-stimulated gene expression levels in baseline liver biopsies compared with participants who did not achieve SVR.
Those who achieved SVR also had a higher frequency of pSTAT1 and TRAIL-expressing, degranulating natural killer cells in baseline blood samples compared with those who experienced virologic breakthrough.
When the researchers compared gene expression levels from baseline and on-therapy biopsies, they found that 408 genes (±1.2-fold, P <.01) were expressed differentially. The genes that were downregulated during treatment were predominantly interferon-stimulated genes.
The researchers found that downregulation of interferon-stimulated genes was rapid and correlated with HCV RNA suppression.
“We speculate that this innate immune response may prevent the emergence of resistance-associated substitutions that lead to viral breakthrough during DAA therapy,” the study authors concluded.
Alao H, Cam M, Keembiyehetty C, et al. Baseline intrahepatic and peripheral innate immunity are associated with hepatitis C virus clearance during DAA therapy [published online April 27, 2018]. Hepatology. doi:10.1002/hep.29921