Direct-acting antiviral therapy slows kidney function decline in patients with Hepatitis C virus infection and chronic kidney disease.

Hepatitis C virus (HCV) infection is common and can accelerate chronic kidney disease (CKD) progression. Direct-acting antiviral (DAA) therapies against hepatitis C have consistently shown rates of sustained viral remission. However, the effect on kidney function is unknown. In a retrospective observational cohort study of HCV-infected patients receiving DAA therapies from 2013 to 2017, the slopes of estimated glomerular filtration rate (eGFR) decline were compared in the three years before DAA therapy to the slope after therapy. Pre- and post-treatment albuminuria values were also compared. In all, 1,178 patients were included; mean age of 56, 64% male, 71% white, 21% were diabetic, and 42% with cirrhosis. In patients with eGFR less than 60ml/min per 1.73m2, the annual decline in eGFR in the three years prior to treatment was -5.98 ml/min per year (95% confidence interval -7.30 to -4.67) and improved to -1.32 ml/min per year (95% confidence interval -4.50 to 1.88) after DAA therapy. In patients with eGFR greater than 60ml/min per 1.73m2 the annual decline in eGFR in the three years prior to treatment was -1.43 ml/min per year (95% confidence interval -1.78 to -1.08) and after DAA therapy was -2.32 ml/min per year (95% confidence interval -3.36 to -1.03). Albuminuria improved significantly in patients without diabetes, but not in those with diabetes. Predictors of eGFR improvement included having CKD at baseline and being non-diabetic. Events of acute kidney injury were rare, occurring in 29 patients, and unrelated to antiviral therapy in 76% of cases. Thus, DAA therapy for HCVs infection may slow CKD progression.

Dynamic changes in innate immune responses during direct-acting antiviral therapy for HCV infection.

The role of the endogenous interferon (IFN) system has been well characterized during IFN-based therapy for chronic hepatitis C virus (HCV) infection; less is known for direct-acting antivirals (DAAs). In this phase 3b open-label study, we assessed changes in IFN-stimulated genes (ISGs) in non-cirrhotic treatment-naïve or pegIFN/RBV-experienced HCV-GT1a-infected patients receiving paritaprevir/ritonavir/ombitasvir + dasabuvir + ribavirin (PrOD + R) for 12 weeks. ISG expression was quantified from peripheral blood mononuclear cells at baseline, treatment weeks (TW)2, TW4, TW8, end of treatment (EOT) and at post-treatment week 12. Paired sera were used to assess IFN-α/IFN-related chemokines/cytokines. Twenty-five patients were enrolled. Overall sustained virologic response (SVR)12 was 92% (no virologic failure [VF]) and 100% for those completing the study protocol. Two patients were excluded from the ISG analysis due to lack of post-treatment samples. The majority of ISGs were downregulated at TW2-TW4 (nadir TW4); however, a relative increase was observed at TW8-EOT, although levels were lower than baseline. This downregulation was accompanied by increases in IFN-α/IFN-related chemokines, a finding not observed with TH 1/2-related cytokines. Following SVR, ISG expression returned to TW2 levels. In conclusion, PrOD + R for 12 weeks was well-tolerated with no VF. Our data demonstrate dynamic alterations in innate immune profiles during highly potent IFN-free DAA therapy. The downregulation of ISG post-therapy suggests reversal of the "exhausted" ISG phenotype following SVR, and the rise in ISGs and IFN-α/IFN-responsive chemokines late during therapy suggests resetting of IFN responsiveness that may be relevant in determining duration of or immunological sequelae from DAA therapy, including HBV reactivation.