Diagnostic performance of APRI and FIB-4 for confirming cirrhosis in Indonesian HIV/HCV co-infected patients

Hepatitis C virus (HCV infection) is one of global health problem that can increase morbidity and mortality in HIV-infected population. In 2017, about 71 million people living with chronic HCV infection globally, of which only 19% (13.1 million) knew their diagnosis. The estimated prevalence in South-East Asia was 0.5% with incidence 14.8 (95% CI 12.5–26.9) per 100,000 population in 2015 [1]. In Indonesia, HCV infection prevalence is estimated at 1%, of which 90% comes from intravenous drug user [2]. World Health Organization (WHO) recently released targets for HCV elimination by 2030, targeting 80% HCV-infected patients being treated [1]. A large gap between HCV-diagnosed patients and HCV-treated patients still exist to achieve this global target since only around 10% of HCV-infected patients in South East Asia have been treated [3]. Achieving global elimination of HCV need major increase in service all populations along the entire cascade of care, including testing, linkage to care, retention in care, treatment, chronic care and prevention of primary infection and reinfection [4]. In 2017, Indonesian government started free direct acting antiviral (DAA) program for HCV, mainly sofosbuvir and daclatasvir combination [2, 5]. This 12 weeks combination for non-cirrhotic patients and 24 weeks for cirrhotic-patients shown similar success rate for both HIV/HCV co-infected patients and HCV mono-infected patients [6]. Despite these facts, there are still many barriers to start HCV treatment, especially in defining liver fibrosis phase. Liver biopsy has been gold standard for liver fibrosis assessment for a long time. This invasive procedure carries some serious side effects and can only be done in specialized care. Transient elastography (TE) is a non-invasive method that measures liver stiffness using both ultrasound and low-frequency elastic waves to define liver fibrosis phase [7]. This method has been validated in viral hepatitis with equal performance in HCV and HIV/HCV co-infection [8]. However, it is not widely available in Indonesia and still carries a high-cost examination.

Several laboratory tests, scores, and indices have been developed for non-invasive prediction of cirrhosis (F4) in HCV mono-infected patients. Aspartate aminotransferase (AST)-to- platelet ratio (APRI), fibrosis-4 (FIB4), modified APRI, Forns, and Göteborg University Cirrhosis Index (GUCI) are based on routine laboratory parameters and readily available in clinical practice. The two most common and validated used are APRI and FIB-4. WHO ranked these two scores as preferred non-invasive markers of fibrosis in resource-limited setting [9].

Since the determination of liver cirrhosis significantly influences the decision for treatment duration of sofosbuvir and daclatasvir, optimal cut-off of APRI and FIB-4 to diagnose cirrhosis need to be defined in our HIV/HCV co-infected population. We aimed to assess the diagnostic performance of APRI and FIB-4 for diagnosing liver cirrhosis in Indonesian HIV/HCV co-infected patients using hepatic TE (Fibroscan®) as a gold standard.

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 [2]. 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 [17]. About 15% of HCV advanced liver disease patients who did not initiate DAA treatment in the Chronic Hepatitis Cohort Study (CHeCS) had died [18].

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 [20]. 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 [19]. 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 [14].

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 [21]. 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.

APRI and FIB-4 have moderate performance with high specificity in diagnosing cirrhosis. These biochemical markers could be used as diagnosis while TE is not available. In situation where TE is not available, our data support the use of these low-cost biochemical markers as diagnostic tools before DAA treatment.