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1
Paper H-2320
Diagnostic Accuracy of Serum Hyaluronic Acid for
Advanced Fibrosis/Cirrhosis in Patients
Coinfected with HIV and HCV S. Resino,1 P.
Miralles,2 D. Micheloud,1 J. M. Bellón,2 A.
Vargas,2 P. Catalán,2 E. Álvarez,2 J. Cosín,2 R.
Lorente,2 M. Sánchez-Conde,2 M. A.
Muñoz-Fernández,2 And J. Berenguer 2 1 Instituto
de Salud Carlos III, Majadahonda, Madrid 2
Hosp.General Universitario Gregorio Marañón,
Madrid, Spain
OBJETIVE
RESULTS

• Hyaluronic acid (HA), an essential component of
  the extracellular matrix of the liver is produced
  by hepatic stellate cells and degraded by
  sinusoidal endothelial cells. HA levels increase
  with the development of liver fibrosis in
  patients with HCV. We evaluated serum HA to
  predict advanced fibrosis (F3) and cirrhosis
  (F4) in HIV/HCV patients.

Our study cohort included 201 patients whose
characteristics at the time of liver biopsy are
shown in Table 1. Overall, HA increased
significantly with the advanced stage of hepatic
fibrosis (Figure 1). Moreover, the differences
were higher between F0-F1 and F4 in AH levels
distribution. For purposes of comparison, we also
evaluated three reported simple models consisting
of routine parameters to predict liver fibrosis
a) Forns index b) the APRI index c) FIB-4. The
AUROC values of the HA for significant fibrosis
(F2), advanced fibrosis (F3) and cirrhosis (F4)
were similar to FIB-4, APRI, and Forns indexes
(Figure 2). The 95 confidence interval of AUROC
of HA for significant fibrosis (0.676 CI95
0.603 0.750) and cirrhosis (0.863 CI95 0.795
0.931) are not overlapped and there is difference
statistically significant (plt0.05). Next, we
calculated the Se, Sp, PPV and NPV of several
cutoff points to evaluate the diagnostic accuracy
of HA for significant fibrosis (F2), advanced
fibrosis (F3) and cirrhosis (F4) (Table 2). For
significant fibrosis (F2) and with the low AH
cut-off (lt430 ng/mL), 13 of 84 (15.5) patients
without significant fibrosis were correctly
identified, and only 6 of 117 (5.1) patients
with significant fibrosis were misclassified
(61.0 PPV and 68.4 NPV). When we applied the
high AH cut-off (gt 1800 ng/mL), 36 of 117 (30.8)
patients with significant fibrosis were correctly
identified, and only 4 of 84 (4.8) of the
patients without significant fibrosis were
misclassified (90 PPV and 49.7 NPV) (Table
2). For advanced fibrosis (F3) and with the low
AH cut-off (lt687 ng/mL), 49 of 137 (35.8)
patients without advanced fibrosis were correctly
identified, and only 3 of 64 (4.8) patients with
advanced fibrosis were misclassified (40.9 PPV
and 94.2 NPV). When we applied the high AH
cut-off (gt 2290 ng/mL), 18 of 64 (28.1) patients
with advanced fibrosis were correctly identified,
and only 7 of 137 (5.1) of the patients without
advanced fibrosis were misclassified (72 PPV and
73.9 NPV) (Table 2). For cirrhosis (F4) and with
the low AH cut-off (lt1182 ng/mL), 100 of 178
(56.2) patients without cirrhosis (F4) were
correctly identified, and only 1 of 23 (4.3)
patients with cirrhosis (F4) were misclassified
(22.2 PPV and 99 NPV). When we applied the high
AH cut-off (gt 2400 ng/mL), 11 of 23 (47.8)
patients with cirrhosis (F4) were correctly
identified, and only 9 of 178 (5.1) of the
patients without cirrhosis (F4) were
misclassified (55 PPV and 93.4 NPV) (Table 2).
PATIENS AND METHODS
Patients The patients for this study came from
the Hospital Gregorio Marañón in Madrid (Spain).
They all had documented HIV-HCV coinfection and
underwent liver biopsy prior to therapy with
interferon and ribavirin. Laboratory data A
fasting serum sample was immediately stored and
frozen (at a temperature of -70ºC) for further
assays, after the patient gave a written consent.
Hyaluronic acid (HA) was tested in serum samples
mentioned before by a commercially available
quantitative ELISA (HA-ELISA Echelon Biosciences
Inc., Salt Lake City, UT, USA). Concentrations
were assayed in duplicate. Liver fibrosis was
estimated following the criteria established by
the METAVIR Cooperative Study Group. Fibrosis was
scored as follows F0, no fibrosis F1, portal
fibrosis F2 periportal fibrosis or rare
portal-portal septa F3, fibrous septa with
architectural distortion no obvious cirrhosis
(bridging fibrosis) and F4, definite
cirrhosis. Statistics Results are presented by
median and percentiles, and as frequencies and
percentages for categorical data. We calculated
the diagnostic values of HA, Forns, APRI and
FIB-4 indexes and assessed their diagnostic
accuracy by using the area under the receiver
operating characteristic curves (AUROCs). Next,
we calculated the sensitivity (Se) and
specificity (Sp) of several cut-off points to
evaluate the diagnostic accuracy for advanced
fibrosis. Thus, we chose the one with the 95 Se
(low cut-off) and the one with the 95 Sp (high
cut-off). We also calculated the positive
predictive value (PPV) and negative predictive
value (NPV) for these two cut-off points.
Comparison between HA and fibrosis stage were
analysed using Mann-Witney U-test. All tests were
two-tailed with P values 0.05 considered
significant. Statistical analysis was performed
by SPSS 14.0 software (SPSS INC, Chicago, IL,
USA) and STATA 9.1.
CONCLUSION
HA appears to be and accurate non-invasive method
for detection of of advanced fibrosis and
cirrhosis in HIV/HCV-coinfected patients.
Corresponding author Salvador Resino, Unidad de
Investigación, Instituto de Salud Carlos III
(Campus Majadahonda), Carretera Majadahonda-
Pozuelo, Km 2.2 28220 Majadahonda (Madrid)
Telf. 34 918 223 266 Fax [phone]
e-mail sresino_at_isciii.es