April 10, 2015

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By Will Boggs MD

April 02, 2015

NEW YORK (Reuters Health) - Fibroblast growth factor-2 (FGF-2) and other non-interferon mediators contribute to hepatitis C virus (HCV) reinfection after liver transplantation, researchers from Germany report.

"We have identified FGF-2 and the signaling cascade triggered by it as an unexpected novel driver of HCV replication," Dr. Sandra Ciesek from Medizinische Hochschule Hannover told Reuters Health by email. "Hence, it is important to be aware that modulation of host signaling cascades (e.g., certain novel anti-cancer drugs, such as brivanib, that block FGF signaling) may have unexpected effects on viral replication."

While orthotopic liver transplantation is the only treatment for end-stage liver disease due to HCV infection, it is not a cure, and nearly all patients develop graft reinfection.

Dr. Ciesek and colleagues set out to determine how the inflammatory response that occurs in the peritransplantation period modulates the HCV replication cycle and whether it contributes to the poor outcome of HCV-positive individuals after liver transplant.

All 13 transplant recipients (three of whom had HCV) showed marked rises in C-reactive protein levels between pre-transplant and post-transplant sera, but there was heterogeneity in the changes of serum chemokines and no apparent association with the etiology of liver disease.

Among 27 non-interferon inflammatory mediators examined by the researchers, FGF-2 alone enhanced HCV RNA replication and release of infectious particles, they report in Gut, online March 23.

In contrast, FGF-1, a close relative of FGF-2, did not enhance HCV RNA replication.

The effects of FGF-2 appeared to be mediated by signaling through FGF receptor 3 (FGFR3).

In 70 individuals with chronic HCV infection, serum FGF-2 levels were significantly higher in those with high viral load than in those with low viral load.

The investigators are now studying which exact downstream events triggered by FGF-2 and FGFR3 are required for HCV replication.

"Right now there is an enormous opportunity to prevent the majority of post-transplant HCV reinfection events by using direct antiviral agent combinations that have reached the market during the past 15 months," Dr. Ciesek said. "We do not anticipate that modulation of the host serum milieu (or FGF2 signaling) will play a major role here."

"There remains a minority of patients -- those with very advanced liver disease and concomitant renal failure -- that cannot be treated with the currently available regimens," she added. "Thus, new approaches may be needed for this subgroup of patients. It is conceivable that modulation of host factors or host signaling pathways might play a role here."

SOURCE: http://bit.ly/1GgGAwe

Gut 2015.

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