Hyaluronic acid levels predict risk of hepatic encephalopathy and liver-related death in HIV/viral hepatitis coinfected patients

Lars Peters, Amanda Mocroft, Vincent Soriano, Jürgen Rockstroh, Andri Rauch, Anders Karlsson, Brygida Knysz, Christian Pradier, Kai Zilmer, Jens D Lundgren, for EuroSIDA in EuroCoord, Lars Peters, Amanda Mocroft, Vincent Soriano, Jürgen Rockstroh, Andri Rauch, Anders Karlsson, Brygida Knysz, Christian Pradier, Kai Zilmer, Jens D Lundgren, for EuroSIDA in EuroCoord

Abstract

Background: Whereas it is well established that various soluble biomarkers can predict level of liver fibrosis, their ability to predict liver-related clinical outcomes is less clearly established, in particular among HIV/viral hepatitis co-infected persons. We investigated plasma hyaluronic acid's (HA) ability to predict risk of liver-related events (LRE; hepatic coma or liver-related death) in the EuroSIDA study.

Methods: Patients included were positive for anti-HCV and/or HBsAg with at least one available plasma sample. The earliest collected plasma sample was tested for HA (normal range 0-75 ng/mL) and levels were associated with risk of LRE. Change in HA per year of follow-up was estimated after measuring HA levels in latest sample before the LRE for those experiencing this outcome (cases) and in a random selection of one sixth of the remaining patients (controls).

Results: During a median of 8.2 years of follow-up, 84/1252 (6.7%) patients developed a LRE. Baseline median (IQR) HA in those without and with a LRE was 31.8 (17.2-62.6) and 221.6 ng/mL (74.9-611.3), respectively (p<0.0001). After adjustment, HA levels predicted risk of contracting a LRE; incidence rate ratios for HA levels 75-250 or ≥250 vs. <75 ng/mL were 5.22 (95% CI 2.86-9.26, p<0.0007) and 28.22 (95% CI 14.95-46.00, p<0.0001), respectively. Median HA levels increased substantially prior to developing a LRE (107.6 ng/mL, IQR 0.8 to 251.1), but remained stable for controls (1.0 ng/mL, IQR -5.1 to 8.2), (p<0.0001 comparing cases and controls), and greater increases predicted risk of a LRE in adjusted models (p<0.001).

Conclusions: An elevated level of plasma HA, particularly if the level further increases over time, substantially increases the risk of contracting LRE over the next five years. HA is an inexpensive, standardized and non-invasive supplement to other methods aimed at identifying HIV/viral hepatitis co-infected patients at risk of hepatic complications.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist. The EuroSIDA study has received unrestricted grants from Bristol-Myers-Squibb, GlaxoSmithKline, Roche, Gilead, Pfizer, Merck, Tibotec and Boehringer-Ingelheim. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Figure 1. Distribution of plasma hyaluronic acid…
Figure 1. Distribution of plasma hyaluronic acid levels and any-liver related events during follow-up.
Figure 2. Kaplan Meier progression to any…
Figure 2. Kaplan Meier progression to any liver-related event according to baseline plasma hyaluronic acid level (ng/mL).
Figure 3. Receiver operating characteristic curve for…
Figure 3. Receiver operating characteristic curve for the ability of plasma hyaluronic acid to predict liver-related events.
Figure 4. Adjusted incidence rate ratios of…
Figure 4. Adjusted incidence rate ratios of any liver-related events.
Note: The horizontal lines indicate 95% confidence intervals; HA: hyaluronic acid; HBsAg: hepatitis B surface antigen; HCVab: anti-HCV antibody; Group 1: HBsAg positive and/or anti-HCV/HCV-RNA positive; Group 2: anti-HCV positive/HCV-RNA negative.
Figure 5. Adjusted incidence rate ratios of…
Figure 5. Adjusted incidence rate ratios of any non-liver-related events.
Note: The horizontal lines indicate 95% confidence intervals; HA: hyaluronic acid; HBsAg: hepatitis B surface antigen; HCVab: anti-HCV antibody; Group 1: HBsAg positive and/or anti-HCV/HCV-RNA positive; Group 2: anti-HCV positive/HCV-RNA negative.

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