In our study, low threshold of APRI (1) demonstrate moderate performance [AUC 0.72 (95% CI 0.63-0.80)] in diagnosing cirrhosis. This cut-off was lower than cut-off use in Mazzola, et al study (cut-off 2) with moderate performance (AUC 0,77) but almost similar with Merli, et al study (cut off 0.97) with better performance [AUC 0.84 (95% 0.81-0.88)]. One third of population in the Merli, et al study had cirrhosis as in our study, while prevalence of cirrhosis in Mazzola, et al study was 49.6%.[13,14] Low APRI threshold appeared to be better in diagnosis rather than detecting cirrhosis since the positive predictive value was good (79.5%), specificity was excellent (95%), and positive likelihood ratio was good (9.6). Using this threshold, 81.6% of the patients were correctly classified.
The optimal cut-off of FIB-4 in our population 1.66 was much lower than other studies. Merli, et al used FIB-4 cut-off 2.02 and Mazzola, et al used 5.88 for confirming cirrhosis.[13,14] Our new cut-off shown a moderate performance with AUC 0.73 (95% CI 0.65-0.81). This new FIB-4 -cut-off was also better in diagnosis cirrhosis with the positive predictive value, specificity and positive likelihood ratio were good (73.9%, 92.5%, 7.0, respectively). Using this new cut-off, we accurately classified cirrhosis and non-cirrhosis 81.1% of our population.
To achieve elimination goal, there is an urgent need to limit the cost for diagnostic procedure before starting HCV therapy, especially in resource-limited setting. In Indonesia only few TE machines are available, mainly located in big cities, and the cost is still high. Based on previous report from Indonesia, an average cost before starting HCV therapy was USD 191, including USD 74 for TE examination. This high cost could delay treatment initiation for many patients though government provide the drugs. As the majority of HCV infection in Indonesia were driven by unsafe opiate injection around year 2000, we could predict that many untreated HCV-HIV co-infected patients have already in their cirrhosis stage. [15,16] HIV co-infection could accelerate the developing of serious liver disease in one third of persons 20 years or less after infection. About 15% of HCV advanced liver disease patients who did not initiate DAA treatment in the Chronic Hepatitis Cohort Study (CHeCS) had died.
Simple and accurate liver fibrosis assessment other than TE examination that can be done in remote area is essential.[19,20] Since the Indonesian government planned to expand free DAA program for HCV, the result our study could be implemented in many places, as WHO also recommends to use APRI and FIB-4 in resource-constraint countries.[2,14]
This study has several limitations. First, the number of end-stage liver diseases were small. This may be caused by the recruited patients came from outpatient clinic where we rarely found end-stage liver disease stage. Quang Li, et al demonstrated similar limitation among chronic infection of hepatitis B virus (HBV), the sample proportion were inappropriate, merely 7.2% cirrhotic-patient were cirrhosis. Second, we did not use liver biopsy as gold standard in defining liver cirrhosis. However, our study actually shown a real-world data of TE comparison with these indirect biochemical markers, especially in Asia. Although TE is good validated in HCV infected patients, TE result could be interfered by confounding factors such as hepatic inflammation, hepatic congestion, extrahepatic cholestasis, and liver steatosis. Moreover, we did not investigate performance of biochemical markers against liver biopsy. Third, we need to carefully interpret this result in female patients, since men represent majority of the study population (91.5%), as observed in other studies.
Fourth, the use of cut off of APRI and FIB-4 from this study could only be applied among compensated cirrhosis patients. Perez-Latorre, et al mentioned decompensated cirrhosis patients have several activation of neurohormonal mechanism, leading to organ inflammatory damage, and decrease accuracy of TE. Therefore, using TE in liver decompensated must be done carefully.
Fifth, we assessed the diagnostic performances of biochemical markers of fibrosis using TE as a gold standard although we could not validate its performances against liver biopsy in our study population. We recommend further cohort study and larger sample to get new optimal and valid cut-off of APRI and FIB-4.