Approach
Diagnostic tests for hepatitis C virus (HCV) are used to establish a clinical diagnosis, prevent infection through screening of donor blood, and make decisions regarding medical management of patients. Hepatitis C is a notifiable disease in the US and some other countries.
Clinical presentation
Acute infection
Following exposure to the virus, the majority of patients are asymptomatic.[61]
About 30% of patients have features such as fatigue, arthralgia, or jaundice, associated with a transient rise in serum aminotransferases, particularly alanine aminotransferase (ALT).[5] Fulminant hepatic failure is extremely rare.
Some patients may then spontaneously clear the virus. The proportion of people achieving clearance within 3, 6, 12, and 24 months following infection were 19.8%, 27.9%, 36.1%, and 37.1%, respectively. The likelihood of spontaneous clearance was lower in men, HIV co-infection, absence of hepatitis B virus co-infection, asymptomatic infection, black or nonindigenous race, non-genotype 1 infection, older age, and people with alcohol/drug problems. People who do not spontaneously clear the virus within 12 months are unlikely to do so.[41]
The majority of people develop chronic infection.[62]
Chronic infection
Chronic hepatitis C infection is generally defined as persistence of HCV RNA in the blood for at least 6 months.
Patients are usually asymptomatic but may present with features of decompensated cirrhosis (e.g., jaundice, ascites, signs of hepatic encephalopathy) or hepatocellular carcinoma. Occasionally, patients may present with extrahepatic manifestations (e.g., vasculitis, renal complications, porphyria cutanea tarda).
Diagnosis may also be made after routine laboratory tests reveal elevated serum aminotransferases but some patients may have normal levels.
Factors that influence the development of chronic liver disease include older age at time of infection and male sex.[57] Concurrent chronic hepatitis B, HIV infection, or high alcohol intake may also increase the risk of progressive liver disease.[63] Daily cannabis use is strongly associated with moderate-to-severe fibrosis and steatosis.[64][65]
Investigations
An HCV antibody test followed by reflex HCV RNA polymerase chain reaction (PCR) testing is recommended for initial diagnosis.[66]
Dried blood spot samples may be used as an alternative to venous whole blood for HCV antibody and HCV RNA testing. Collection of dried blood spot samples (using a finger stick) allows for assessment of HCV antibodies and reflex HCV RNA testing by testing spots sequentially. An advantage of this method is that cold chain storage is not required for transport of these samples.[66]
HCV antibody test
A negative/nonreactive result indicates no current HCV infection and no further testing is required. A repeat test should be considered 6 months or longer after exposure, in patients with HCV exposure in the past 6 months.[66] It can take several weeks to develop HCV antibodies. Also, patients may spontaneously clear the virus after an acute exposure.
A positive result indicates current infection (either acute or chronic), or a past resolved infection. If the antibody test is positive, it should be followed immediately by sequential HCV RNA testing to confirm HCV viremia.[66] Do not repeat an HCV antibody test in a patient with a previous positive result, as there is no clinical benefit and it contributes to unnecessary costs. A previous positive test in a patient will remain positive for life.[67]
Occasional false-negative results may occur in immunocompromised patients or those undergoing dialysis.[63] False positives are rare, but may occur in the setting of autoimmune disease. Suspicion of a false-positive or false-negative result should lead to HCV RNA testing.
A recombinant immunoblot assay (RIBA) is more specific than an enzyme immunoassay (EIA) and helps rule out false-positive antibody, but is rarely used as a supplemental test. It may be used in nonclinical settings or for those who test positive on EIA and negative for HCV RNA.[63]
Testing with a different HCV antibody assay can help to differentiate between a past, resolved infection and a false-positive result.[66]
HCV RNA testing
Needed to diagnose acute infection; most providers use PCR because it is most readily available.
A negative result indicates no current HCV infection and no further testing is required, unless indicated. Patients with a negative HCV RNA test and a positive antibody test do not have evidence of current infection, but are not protected from reinfection.[66]
A positive result confirms current (or active) HCV infection.
It is important to remember that exposed people may ultimately clear the virus without treatment.[29] In these patients, the HCV antibody test will remain positive, but because they are no longer viremic, the HCV RNA test will become negative.
HCV RNA testing should be considered as the initial test in patients who are immunocompromised or those with possible HCV exposure in the prior 6 months (particularly those with risk factors) as these patients may be HCV-antibody negative due to failed (or delayed) seroconversion.[66]
HCV RNA testing is required to detect reinfection after previous viral clearance as HCV antibody testing will be positive in this situation.[66]
Quantitative HCV RNA testing is recommended prior to initiating antiviral therapy to determine baseline viremia.[66]
Rapid point of care HCV RNA assays are available in some countries, including the US. They may be used as an alternative approach to laboratory-based assays to diagnose viremic infection, and as a test of cure.[68] These tests allow a patient to be linked to care and potentially start on treatment in the same healthcare visit.
HCV core antigen assay
HCV core antigen appears approximately 2-3 weeks after contact with the virus, almost simultaneously with HCV RNA. HCV core antigen testing may be used as an alternative approach to HCV RNA testing to diagnose viremic infection.[66]
As the sensitivity is lower than that for HCV RNA testing, antibody-positive samples that test negative for HCV core antigen should have confirmatory testing with HCV RNA to exclude false-negative core antigen results.[66]
Serum aminotransferases
Serum aminotransferases, particularly alanine aminotransferase, can be used to measure disease activity, although sensitivity and specificity are low.
HCV genotyping
Consider in patients for whom it may alter treatment recommendations (e.g., evidence of cirrhosis, previous unsuccessful treatment). Testing is not recommended in patients who are starting on pangenotypic treatment regimens.[66]
Hepatitis B/HIV testing
Testing for hepatitis B and HIV infection is recommended.[66]
Hepatitis C virus self-testing may be offered as an additional approach to existing testing services.[69]
Noninvasive tests of liver fibrosis
Noninvasive tests of liver fibrosis (fibromarkers in serum and transient elastography that uses ultrasound and low-frequency waves to measure liver elasticity) may be able to suggest or to exclude advanced fibrosis.[66][70]
Simple blood-based noninvasive tests are recommended as an initial test to detect fibrosis or cirrhosis in patients with chronic HCV who require staging prior to antiviral therapy. Simple, readily-available tests such as FIB-4 are recommended over complex proprietary tests. A sequential combination of blood-based markers may perform better than a single biomarker.[71]
Imaging-based noninvasive tests (ultrasound-based or magnetic resonance elastography, depending on local availability and expertise) should be incorporated into the initial fibrosis staging process as they are more accurate than blood-based noninvasive tests.[72]
Blood-based and imaging-based noninvasive tests may be combined, particularly for the detection of significant and advanced fibrosis.[72]
In resource-limited settings, aspartate aminotransferase-to-platelet ratio index (APRI) is recommended as the preferred noninvasive test to assess for significant fibrosis or cirrhosis.[71]
Staging is still important with new antiviral therapies to help determine optimal duration of treatment; however, noninvasive tests for prediction of fibrosis are becoming the standard of care compared with liver biopsy. In the US, liver elastography is now approved and, along with serum tests of fibrosis, has essentially replaced the need for liver biopsy for disease staging. In Europe, noninvasive tests such as elastography have been more accepted as replacements for liver biopsy; however, elastography may not be adequate on its own to rule in or rule out significant fibrosis.[73]
Liver biopsy
Liver biopsy is not used to diagnose hepatitis C infection but is useful in staging fibrosis and the degree of hepatic inflammation. However, because direct-acting antiviral therapy is now considered to be very effective, biopsy is rarely warranted.
Another potential reason to obtain a biopsy is to evaluate the possibility of cirrhosis and thus begin a surveillance program for hepatocellular carcinoma. Physical examination or laboratory values alone may not indicate cirrhosis until its state is advanced.
A biopsy can be considered if the patient and provider want the prognostic information of a fibrosis score or to make a decision regarding treatment.[66]
Risks associated with biopsy include bleeding and puncture of other organs; however, these are rare.
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