Changes of serum 2‘,5’‐oligoadenylate synthetase activity during interferon treatment of chronic hepatitis C

Abstract

ABSTRACT— It was our aim to evaluate whether the baseline activity of 2–5 oligoadenylate synthetase (2–5 OAS) in serum and changes induced by the treatment with interferon are relevant factors in remission of chronic hepatitis C. Seventeen out of 30 adult patients with chronic hepatitis C were randomized to receive recombinant alpha‐2b interferon at the dosage of 3 MU three times weekly. By the end of the third month, nine patients had normalized transaminase levels and continued to receive 3 MU of interferon for an additional 3 months, whereas in eight non‐responders the dosage was increased to 6 MU for the same period of time. A single patient responded to the increased dosage. Baseline 2–5 OAS serum activity was significantly higher in patients with chronic hepatitis when compared with normal controls. Follow‐up on the 13 untreated cases showed that 2–5 OAS elevation was stable and unrelated to concomitant infections. Comparison of responders and non‐responders showed that the latter had higher baseline 2–5 OAS activity, tended to have an earlier and higher peak in the enzyme during the first 4 weeks of treatment, and maintained higher levels during the first 3 months of therapy. The increased dosage of interferon in this group led to an additional, although temporary, increase in 2–5 OAS. Our data suggest that HCV infection by itself induces elevated 2–5 OAS levels. The paradoxical increase in non‐responders indicates that monitoring of the enzyme in serum does not predict the response to interferon. The role of the 2–5 OAS pathway in inducing the antiviral state in HCV infection should be further evaluated at tissue level.

Danoprevir Monotherapy Decreases Inflammatory Markers in Patients with Chronic Hepatitis C Virus Infection

“…The median baseline OAS-1 plasma concentration of 580 pM observed in the present study is similar to that in a previous literature report (48). While the significant variability observed in placebo-treated patients over a 2-week period makes it difficult to gauge any danoprevir-related effects on OAS-1 concentration, the variability and lack of discernible correlation with antiviral response may have significant implications for the potential use of OAS-1 as a marker of response to treatment with interferon-free direct-acting antiviral regimens.…”

“…Several studies have reported increased OAS-1 expression during chronic HCV infection (26,38,48). Similar to the case with IP-10 (3,5,8,9,27), the baseline OAS-1 concentration is higher in nonresponders (NRs) to SOC treatment than in those that achieve SVR (48).…”

“…With interferon-based regimens or other activators of immune responses, a significant induction of OAS-1 is observed (48). Therefore, these results suggest that direct inhibition of HCV replication in the liver does not result in a systemically evidenced interferon response.…”

“…2Ј-5Ј-Oligoadenylate synthetase (OAS-1) is an interferonstimulated gene product that is responsible for activation of the RNase L pathway in response to viral RNA. OAS-1 binds to double-stranded RNA and catalyzes the formation of 2Ј-5Ј-linked oligoadenylate, which in turn activates RNase L, an endogenous protein that degrades viral RNA, thereby inhibiting viral protein synthesis and replication (26,32,48). Several studies have reported increased OAS-1 expression during chronic HCV infection (26,38,48).…”

“…OAS-1 binds to double-stranded RNA and catalyzes the formation of 2Ј-5Ј-linked oligoadenylate, which in turn activates RNase L, an endogenous protein that degrades viral RNA, thereby inhibiting viral protein synthesis and replication (26,32,48). Several studies have reported increased OAS-1 expression during chronic HCV infection (26,38,48). Similar to the case with IP-10 (3,5,8,9,27), the baseline OAS-1 concentration is higher in nonresponders (NRs) to SOC treatment than in those that achieve SVR (48).…”