OBJECTIVE:
There is a need for non-invasive biomarkers that can identify patients with progressive liver fibrosis and monitor response to anti-fibrotic therapy. An equally important need is identification of patients with spontaneous fibrosis regression, since they may not need treatment nor be included in clinical studies with fibrosis as endpoint. Circulating biomarkers, originating from defined fragments of the scar tissue itself, may serve as valuable tools for this aspect of precision medicine.

METHODS:
Plasma samples from patients with moderate stage hepatitis C receiving placebo treatment in a phase II trial of peroxisome proliferator-activated receptor agonist farglitazar were included. The patients had matched liver biopsies at baseline and 52 weeks of follow-up. Serological biomarkers of collagen formation PRO-C3, PRO-C5, P4NP7S, and collagen degradation C3M, C4M, and C6M were analysed.

RESULTS:
Logistic regression analysis including PRO-C3 and C6M identified subjects with progressive liver fibrosis with an AUROC of 0.91 (p<0.0001) and positive and negative predictive values (PPV/NPV) of 75.0%/88.6%. Low levels of PRO-C5 predicted a spontaneous regression phenotype, with an odds ratio of 33.8 times higher compared to patients with low levels (p<0.0025).

CONCLUSION:
Three collagen fragments (PRO-C3, C6M and PRO-C5) identified liver fibrosis progressors. These biomarkers may improve patient stratification and monitor treatment efficacy in studies with fibrosis as clinical endpoint.