Comparison of transient elastography, APRI, FORNS, and FIB-4 for the assessment of liver fibrosis in HIV/HCV-coinfected

1. Comparison of transient elastography, APRI, FORNS, and FIB-4 for the assessment of liver fibrosis in HIV/HCV-coinfected patients M Sánchez-Conde1, M Montes-Ramírez2, JM Bellón1, JM Castro Alvarez2, M Ramírez1, JR Arribas Lopez2, I Gutiérrez1, P Miralles1, E Alvarez1, J González-Garcia2, and J Berenguer1. 1Hospital Gregorio Marañón, Madrid, Spain, 2Hospital La Paz, Madrid, Spain. msconde@gmail.com OBJECTIVES: To determine the diagnostic accuracy of TE in predicting fibrosis in HIV/HCV-coinfected patients, and to compare it with published non-invasive serum markers. BACKGROUND • Liver biopsy is still considered the gold standard for the assessment of liver fibrosis. • However, this procedure has several limitations, including patient reluctance, adverse events, accessibility, cost, sampling error and interobserver variability. • In recent years, these limitations have led to the development of alternative noninvasive procedures for the assessment of liver fibrosis. • These methods include assays based on serum biomarkers, and transient elastography (TE), a technique that estimates the degree of fibrosis based on liver stiffness. METHODS I: • Patients • HIV outpatient clinic of two large teaching Hospitals from Madrid, Spain. • Patients with documented HIV/HCV coinfection who underwent liver biopsy and TE between January 2007 and January 2008 were included in the study. • Inclusion criteria were: no clinical evidence of hepatic decompensation, detectable HCV RNA by polymerase chain reaction, negative hepatitis B surface antigen, and absence of anti HCV therapy between the date of liver biopsy and the date of TE. • All patients gave their written informed consent for the liver biopsy.

2. METHODS II • Liver stiffness measurements • Liver stiffness was measured using FibroScan ® (EchoSens, Paris, France). • Ten validated measurements were taken for each patient. • Results were expressed in kilopascals (kPa). • The median value was considered representative of liver stiffness • Liver biopsy • Liver biopsy specimens were 25 mm long in most cases and were evaluated at each center by an experienced pathologist who had no knowledge of patient clinical and laboratory data. • 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 and F4, definite cirrhosis. • Noninvasive liver markers of liver fibrosis • We evaluated four recently reported simple models, consisting of routine parameters to predict liver fibrosis: Forn’s fibrosis index; the AST to platelet ratio index (APRI); the FIB-4 index, and the HGM-2 index. • Serum markers were measured from an overnight fasting blood sample taken before liver stiffness was measured. • Statistical analysis • ROC curves were constructed to compare the absence and presence of significant fibrosis and advanced fibrosis (F≤1 vs. F≥2) (F≤2 vs. F≥3). • We also determined optimal cut-off values of TE for F≤ 01 vs. F≥2, F≤2 vs. F≥3 and F≤3 vs. F4. • The diagnostic values of the non-invasive methods (TE, APRI, FIB-4, Forn’s fibrosis index, and HGM-2) were compared by calculating the area under the ROC curves (AUROCs).

3. RESULTS I: 50 40 30 Trasient Elastography 20 10 0 F0 - F1 F2 F3 F4 Fibrosis Score (METAVIR) Table 1: characteristics and the distribution for fibrosis stage and activity grade Liver stiffness measurements ranged from 2.7 to 43.5 kPa. The median (IQR) of liver stiffness according to the different stages of fibrosis (in kPa) was as follows: F0, 4.9 (4.1-6.5); F1, 6.1 (5.3-8.6); F2, 8.4 (5.8-10.5); F3, 11.9 (8.8-16.6); and F4, 31.4 (22.5-40.3) (Fig.1) We assessed the diagnostic accuracy of TE for different categories of fibrosis. Based on the AUROC curves, three cut-off values were chosen to identify F≤1 (<7 kPa), F≥3 (≥ 11.5 kPa), and F4 (≥ 14 kPa). Table 2. Table 2: Accuracy of transient elastography for fibrosis staging Abbreviations: NLR, NPV, negative predictive value; PLR, PPV, positive predictive value. Figure 1: Median (IQR) liver stiffness according to the different stages of fibrosis *N and percentage **Median and IQR

4. RESULTS II: • We compared the accuracy of TE with HGM-2, Forn’s fibrosis index, APRI, and the FIB-4 index for the diagnosis of advanced fibrosis (F≥3). • The AUROCs of TE were significantly higher than the AUROCs obtained with the other four noninvasive indexes (Figure 2 and Table 3). Table 3: AUROCs for non-invasive markers and transient elastography for the diagnosis of advanced fibrosis. CONCLUSIONS: TE accurately identified patients with advanced liver fibrosis and cirrhosis, and patients with mild fibrosis We found that TE outperformed other noninvasive indexes in the diagnosis of liver fibrosis in HIV/HCV-coinfected patients. Our results suggest that TE is a safe, rapid, and accurate tool that can help guide treatment decisions in HIV/HCV-coinfected patients. Figure 2: AUROCs for non-invasive markers and transient elastography for the diagnosis of advanced fibrosis.