Abstract
Background and aims
Although combined antiretroviral treatment (cART) has improved overall survival of HIV infected patients, liver fibrosis and liver related-mortality still constitute major challenges in HIV positive patients. Collagen accumulates in the liver during fibrogenesis. Recent studies showed that circulating levels of extracellular matrix (ECM) fragments might reflect degree of portal hypertension and fibrosis stage in liver disease. In this study, we analyzed the correlation between liver fibrosis assessed by Fibroscan and levels of the formation and degradation markers of type III and IV collagen in HIV positive patients receiving cART.

Methods
116 HIV positive patients (82.7% male, median age 47 years) were enrolled into the study. Liver stiffness and liver fat content were determined using a Fibroscan with integrated CAP function. We quantified ECM formation and degradation fragments of collagen III and IV: PRO-C3, PRO-C4, C3M and C4M. These fragments were measured in peripheral serum by using specific ELISAs.

Results
Fifteen (12.9%) out of the 116 HIV positive patients had relevant fibrosis with a liver stiffness ≥ 7.1 kPa, and 79 patients had relevant steatosis with a CAP value > 248 dB/m. Circulating PRO-C3 levels significantly correlated with increasing degree of liver fibrosis assessed by Fibroscan (p = 0.0005), as well as with APRI score (p = 0.015). Interestingly, circulating PRO-C3 levels were significantly correlated with bilirubin (p = 0.022), reduced platelet count (p = 0.0008) and low albumin levels (p = 0.001), suggesting the association of type III collagen deposition with impaired liver function. None of the other measured ECM components significantly correlated with fibrosis or steatosis.

Conclusion
The formation marker of type III collagen, PRO-C3 not only reflects liver fibrosis, but might also mirror liver dysfunction in HIV positive patients receiving cART. Therefore, the circulating levels of PRO-C3 might be suitable to monitor progression of liver fibrosis and deterioration of liver function in HIV positive patients receiving cART.