Once a diagnosis of chronic HCV infection has been established, further investigation should be directed toward assessing for the presence or absence of cirrhosis. Although all people with chronic HCV infection are eligible for treatment, regardless of liver fibrosis stage, the presence of cirrhosis influences treatment duration and regimen (see Treatment for chronic hepatitis C), and a person’s cirrhosis status must be provided at the time of seeking PBS authority to write a prescription for the new HCV medicines. The presence of cirrhosis also identifies people who require lifelong surveillance for HCC and portal hypertension.
Clinical risk factors for cirrhosis include male sex, older age at infection, prolonged duration of HCV infection (> 20 years) and comorbidities including excessive alcohol consumption, diabetes, obesity, the metabolic syndrome and coinfection with HBV or HIV. Clues to the presence of advanced liver disease include peripheral stigmata of chronic liver disease (eg, leukonychia, spider naevi) and markers of portal hypertension, including splenomegaly and thrombocytopaenia. Low albumin levels, raised bilirubin levels and a raised international normalised ratio (INR) are markers of reduced liver functional reserve and decompensated liver disease.
Formal evaluation for cirrhosis with a non-invasive test is recommended for all individuals with chronic HCV infection. Evaluation of liver fibrosis stage should be performed before commencing treatment. None of the non-invasive tests have been validated for diagnosing cirrhosis after SVR, and there is a risk of false negative results when performed after treatment. Transient elastography, or FibroScan® (EchoSens, Paris), measures liver stiffness and is the most common method used for diagnosing cirrhosis. It has been extensively evaluated and validated in people with chronic HCV infection  and outperforms serum biomarkers for detecting cirrhosis.  FibroScan® is available in most metropolitan centres. A liver stiffness of > 12.5 kPa measured using FibroScan® is a reasonable threshold for identifying people with cirrhosis for treatment decision making. [27,28] Alternative elastography methods for measuring liver stiffness include shear wave elastography and acoustic radiation force impulse (ARFI) technology. These techniques can be offered as an add-on to liver ultrasound using many machines but have been less well validated for the assessment of fibrosis stage in the setting of chronic HCV infection, and the cut-offs for identification of cirrhosis are different.
Serum biomarkers for liver fibrosis have also been developed, such as the APRI (aspartate aminotransferase [AST] to platelet ratio index), Hepascore, FibroGENE, Enhanced Liver Fibrosis (ELF) test and FibroTest. The APRI is a simple biochemical marker that can be calculated from routine blood test results. Hepascore and the ELF test are alternative serum fibrosis markers that are available in Australia but not currently reimbursed. FibroGENE is a biomarker panel based on age, biochemical markers and IFNL3 genotype.  FibroTest is not yet available in Australia. Serum biomarkers may be used to exclude the presence of cirrhosis in settings where other tools, such as transient elastography, are not accessible in a timely fashion. Supplementary Table 1 presents further information and key clinical thresholds for excluding the presence of cirrhosis in people using the serum biomarkers for liver fibrosis that are available in Australia.
It is important to remember that none of the methods for non-invasive assessment of liver fibrosis are perfectly accurate, and the results must be interpreted in the context of the pre-test probability based on other clinical information. For example, a 50-year-old obese man with a 30-year duration of HCV infection, a past history of heavy alcohol consumption, spider naevi evident on examination and a platelet count of 90 × 109/L is very likely to have cirrhosis, even if the liver stiffness measures 9.0 kPa using FibroScan®. If there is concern about the accuracy of the liver fibrosis assessment, referral for further assessment for the presence of cirrhosis by a specialist with experience in assessing liver disease severity and managing patients with advanced liver disease is recommended. There is no routine role for liver biopsy. Liver biopsy is generally reserved for people in whom there is uncertainty about the underlying cause of liver disease, or where there is uncertainty about the liver fibrosis stage. Liver histology is not required for accessing antiviral therapy.
All individuals with cirrhosis should have a liver ultrasound to examine for features of portal hypertension (splenomegaly, reversal of portal vein flow) and to exclude HCC. Guidelines recommend gastroscopy for all people with cirrhosis to exclude the presence of clinically significant oesophageal varices before commencing therapy. Bone densitometry is recommended to screen for osteoporosis. Performance of these tests should not delay treatment for HCV infection, but may be scheduled simultaneously or after treatment.
In the setting of cirrhosis, it is also important to evaluate for markers of hepatic decompensation. Two key groups among those with cirrhosis are: i) people with Child–Pugh A cirrhosis who have a low albumin level (< 35 g/L) and/or platelets < 100 × 109/L (NS3 protease inhibitors should be avoided in these people due to concerns about increased intrahepatic drug concentrations and secondary toxicity); and ii) people with true decompensated liver disease — this group should be considered a special population (see Special populations: treatment of decompensated liver disease). All individuals with decompensated liver disease should be assessed by a specialist with experience in managing chronic liver disease and, where appropriate, referred to a liver transplant centre. Indications for assessment by a liver transplant centre include Child–Pugh score ≥ B7, Model for End-Stage Liver Disease (MELD) score ≥ 13 or one of the following clinical events: refractory ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, recurrent or chronic hepatic encephalopathy, small HCC or severe malnutrition (Supplementary Table 2 ).
Due to the complexity of managing cirrhosis, it is recommended that these people are referred for assessment by a specialist who is an expert in the care of patients with chronic liver disease, and that they are treated in active collaboration with HCV treatment experts.