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Viral Hepatitis: Laboratory Support of Diagnosis and Management

Viral Hepatitis: Laboratory Support of Diagnosis and Management

Clinical Focus

Viral Hepatitis

Laboratory Support of Diagnosis and Management

  

Contents:

Clinical Background  - Table 1 - Table 2

Individuals Suitable for Testing - Table 3

Test Availability

Test Selection and Interpretation - Table 4 - Table 5

Acute Viral Hepatitis Infection: Diagnosis and Follow Up -
Figure 1 - Figure 2 - Table 6 - Table 7

Chronic Viral Hepatitis: Diagnosis - Figure 3 - Table 8

Chronic Viral Hepatitis: Treatment Decisions and Monitoring -
Figure 4 - Table 9 - Table 10 - Figure 5 - Table 11

Chronic Viral Hepatitis: Demonstrate Recovery

References
 

Clinical Background [return to contents]

Viral hepatitis is a common form of liver disease that affects roughly 1% to 2% of the United States population. It is caused by a diverse group of hepatotropic agents that lead to liver inflammation and cell death. Five hepatitis viruses have been well characterized: hepatitis A (HAV), B (HBV), C (HCV), D (HDV), and E (HEV). HAV, HBV, and HCV are the most frequent causes of viral hepatitis in the United States (Table 1). HDV infection is rare in the United States, except among HBV-infected individuals. HEV is considered an uncommon form of viral hepatitis in the developed world and is not discussed further in this Clinical Focus. Other viruses that cause hepatitis include cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus (HSV), and varicella zoster virus (VZV). Hepatitis may also be due to other diseases or medications.

Table 1. Incidence and Prevalence of Viral Hepatitis in the United States1
Virus

New Infections in US,
2012 Estimate

Chronically Infected People in US, 2012 Estimate

HAV 3050 NA
HBV 18,760 0.7–1.4 million
HCV 21,870 2.7–3.9 million
HDV Unknown

Rare in United Statesa

HEV2 Unknownb NA

NA, not applicable
a
Risk is elevated in individuals with chronic HBV infection and risk factors such as intravenous drug use.3,4
b US seroprevalence, indicating past exposure, is 21%.
5

Clinical manifestations vary widely between different forms of viral hepatitis (Table 2). HAV manifests as acute or asymptomatic disease, has no chronic carrier state, and seldom causes serious sequelae, although some patients may develop acute fulminant liver failure. HBV, HCV, and HDV can also cause asymptomatic or acute infection, but often establish chronic infection resulting in significant morbidity and mortality. Chronic infection with HBV or HCV may lead to liver cirrhosis and hepatocellular carcinoma (HCC). HDV is a "defective" virus in that it can replicate only in the presence of HBV. HBV/HDV coinfection (simultaneous acquisition of HBV and HDV) and superinfection (acquisition of HDV by a person with chronic HBV infection) significantly increase the severity of disease relative to HBV infection alone.4,6,7 Acute HBV/HDV coinfection may be severe, but it tends to resolve spontaneously. In contrast, HBV/HDV superinfection has a high likelihood of progressing to chronic infection.

Table 2. Clinical Spectrum of Viral Hepatitis
Virus Transmission Route Incubation Period

Mortality1

Likelihood of
Carrier State
Likelihood of Chronic Disease Associated with HCC
HAV Fecal-oral 2-6 wk 1% None None No
HBV Parenteral, perinatal, sexual 4-26 wk 1-2% (3000/y) 5% (adults)a 90% (infants) 1%-10% Yes
HCV Parenteral, perinatal, sexual 2-23 wk 1-5% (12,000/y) 50%-80%
 
80%-90% Yes
HDV Parenteral, sexual, perinatal 6-26 wk 2-20%

Variableb
 

80% in

superinfectiona

Yesb

HEV2 Fecal-oral 2-9 wk 1%c Rared Rarec No

a Higher in immunocompromised patients.
b Requires co-infection with HBV. Simultaneous infection with HBV is associated with severe acute disease and low likelihood of chronic infection (<5%); superinfection with HBV carries high likelihood of fulminant disease (2%-20%), chronic HDV infection (up to 80%), and cirrhosis (60%-70%), and may progress to hepatocellular carcinoma (HCC).
c 10%-30% in pregnant women.
d Chronic carriage may be more common in immunocompromised individuals, including those with HIV and transplant recipients. There have also been anecdotal reports of reactivation of resolved infection.5

Treatment for HAV is supportive, whereas specific antiviral therapies are available for HBV and HCV infection. Prompt and accurate diagnosis of chronic HBV and HCV is needed to avoid complications. Timely diagnosis of all forms of viral hepatitis is useful for preventing transmission (especially in the case of fecal-orally transmitted viruses) and understanding outbreak patterns. Vaccines are available for only HAV and HBV.

Quest Diagnostics offers a variety of immunologic and molecular assays for diagnosing viral hepatitis, monitoring disease course and treatment response, and identifying candidates for HAV and HBV vaccination. This Clinical Focus provides an overview of available tests and indications for their use. The tables and figures are provided for informational purposes only and are not intended as medical advice. A physician's test selection and interpretation, diagnosis, and patient management decisions should be based on his/her education, clinical expertise, and assessment of the patient.

Individuals Suitable for Testing [return to contents]

Table 3 provides a summary of individuals who are suitable for screening and diagnostic testing.

Table 3. Individuals Suitable for Laboratory Diagnostic Testing2,8-11
Risk Group HAV HBV HCV HDV
Individuals with clinical symptoms or elevated liver enzyme levels  
Individuals born in highly or moderately endemic areas     
Children of immigrants from highly endemic areas (if the children were not vaccinated as infants)      
Individuals with HIV or HCV infection a    
Household and sexual contacts of infected persons      

Pregnant womenb

     
Children born to infected women    
Intravenous drug users (current or past)    
Men who have sex with men a  
Health-care workers after percutaneous exposurec    
Individuals receiving immunosuppressive therapy, including recipients of organ transplants or cancer chemotherapy    
Hemodialysis patients    
Individuals born 1945 through 1965 (baby boomer population)d      
Individuals who received a transfusion before 1992 or clotting factor concentrates produced before 1987      
Individuals who have received an unregulated tattoo or used drugs intranasally    
Individuals who have a history of sexually transmitted infections or participate in high-risk sexual activities      
Inmates of correctional facilities      
Individuals with HBV infection a     e

In addition to the diagnostic indications above, patients with diagnosed viral hepatitis may be candidates for ongoing monitoring with chemistry, serologic, and molecular tests.
a Assess immunity prior to HAV vaccination.
b HCV testing is also indicated for pregnant women at high risk for HCV infection.
c HBV testing for immunity may be desirable prior to vaccinating healthcare workers.
dThe Centers for Disease Control and Prevention (CDC) and the US Preventive Services Task Force recommends one-time HCV antibody testing for all individuals born 1945 through 1965.9,10 This group accounts for up to 75% of adult HCV cases in the United States. Those with positive antibody results should be tested using an HCV nucleic acid test to determine whether there is active infection.
e If HDV coinfection or superinfection is clinically suspected.

Test Availability [return to contents]

  • Routine blood tests (eg, albumin; alkaline phosphatase; ALT; AST; bilirubin; complete blood count, including platelets; prothrombin time [INR]; FibroTest-ActiTest) are used to monitor therapy and to assess liver damage.
  • Serologic tests include immunoassays for antibodies and antigens. Targets are available to assess:

    –  Presence of infection

    –  Immune status

    –  Disease status

  • –  Need for treatment

  • Nucleic acid-based tests, including real-time polymerase chain reaction (PCR) and transcription-mediated amplification (TMA), are used to:

    –  Detect viremia (confirm infection or document resolution of infection)

    –  Measure viral load (assess prognosis, need for treatment, and treatment response)

  • Genotyping tests, including hybridization and sequencing-based assays, are used to determine:

    –  HBV genotype (for epidemiological and prognostic purposes) and HCV genotype (to assess prognosis and inform treatment decisions)

    –  Presence of HBV or HCV mutations associated with resistance to antiviral agents

Test Selection and Interpretation [return to contents]

Multiple tests may be required to appropriately characterize an individual's viral hepatitis infection. The sections below summarize the use and interpretation of some of the major serologic (Table 4) and molecular (Table 5) tests available for diagnosis and disease management.

Table 4. Clinical Application of Serologic Laboratory Tests for Hepatitis
Test Codes

CPT Codesa

Test Clinical Application
Viral Hepatitis Screening Panels  
10306b

80074

Hepatitis Panel, Acute with Reflex to Confirmation

Includes HAV IgM, HBsAg w/rfl confirmation,

HBcAb, HCV Ab.

Screen for acute hepatitis caused by hepatitis A, B, or C
6462b

86708

86706

87340

86704

86803

Hepatitis Panel, General

Includes total HAV Ab, qualitative HBsAb,
HBsAg w/rfl confirmation, HBcAb, HCV Ab.

Detect hepatitis caused by hepatitis A, B, or C
Hepatitis A Virus (HAV)  
512 86709 Hepatitis A Antibody (IgM) First-line diagnostic test for acute hepatitis A
508 86708 Hepatitis A Antibody, Total Screen for immunity prior to vaccination

36504b

86708 Hepatitis A Antibody, Total with Reflex
to IgM
Indicate prior or acute infection with, or immunization to, HAV
Hepatitis B Virus (HBV)  
4848 86705

Hepatitis B Core Antibody (IgM)

First-line diagnostic test for acute hepatitis B

Indicate recent infection (within preceding 4-6 months)

501 86704

Hepatitis B Core Antibody, Total

Indicate current or prior infection
37676b 86704

Hepatitis B Core Antibody, Total with

Reflex to IgM

Indicate current or prior infection; differentiate recent infection (within preceding 4-6 months) from chronic or prior infection
556 86707 Hepatitis Be Antibody Indicate convalescence/treatment response
555 87350 Hepatitis Be Antigen Indicate active viral replication and high infectivity

Assess likelihood of chronic hepatitis and HBV carriage

27 87350 86707

Hepatitis Be Panel

Includes HBeAg, HBeAb.
 

Indicate likelihood of chronic infection

Indicate response to therapy and level of infectivity (disappearance of HBeAg and appearance of HBeAb)

499 86706 HBV Surface Antibody, Qualitative Indicate resolved infection or vaccine response
8475 86317 Hepatitis B Surface Antibody, Quantitative

Indicate immunity post-infection, vaccination, or HBIG; levels

≥10 mIU/mL are suggestive of a protective response

37132 86317 Hepatitis B Surface Antibody Quantitative, Liver Transplant Assess HBV immunoglobulin pre- and post-infusion of HBIG
498b 87340 Hepatitis B Surface Antigen with Reflex
to Confirmation
First-line diagnostic test for HBV infection

Indicates chronic hepatitis when still positive 6 months after diagnosis of HBV infection

17375b 87340 Donor, Hepatitis B Surface Antigen with Reflex to Confirmation Screen for HBV infection in donors of human cells, tissues, and tissue-based products
Hepatitis C Virus (HCV)  
91438b 86803 Hepatitis C Antibody with Reflex to HCV RNA, Quantitative Real-Time PCR Detect HCV antibody and confirm active HCV infection

Establish baseline viral load for treatment monitoring

8472 86803 Hepatitis C Antibody First-line screening test for detection of acute and chronic hepatitis C
91408b 86803 Donor, HCV Antibody Screen with Reflex to 2nd Antibody Screen Screen for HCV infection in donors of human cells, tissues, and tissue-based products
Hepatitis D Virus (HDV)  
4990(X) 86692 Hepatitis D Virus (HDV) Antibody, Total Diagnose HDV infection in patients with fulminant hepatic failure or known previous HBV infection
35664(X) 86692 Hepatitis D Virus (HDV) IgM Antibody, EIA Detect HDV infection in patients with fulminant hepatic failure or known previous HBV infection, including those with reactive HDV total antibody results and suggestive clinical features but negative HDV RNA results12

HBIG, hepatitis B immune globulin.
Refer to the Quest Diagnostics Test Center (QuestDiagnostics.com/TestCenter) for additional testing options.
a The CPT codes provided are based on AMA guidelines and are for informational purposes only. CPT coding is the sole responsibility of the billing party. Please direct any questions regarding coding to the payer being billed.
b Reflex tests are performed at an additional charge and are associated with additional CPT codes.

Table 5. Clinical Application of Molecular Laboratory Tests for Hepatitis

Test

Codes

CPT

Codesa

Test Clinical Application
Hepatitis B Virus (HBV)  
8369 87517 Hepatitis B Virus DNA, Quantitative Real-time PCR Determine need to treat chronic HBV infection

Indicator of chronic hepatitis when still positive 6 months after diagnosis of acute HBV infection

Monitor response to therapy

Demonstrate viral replication in patients with mutant HBV (eg, HBeAg- and HBeAb+ individuals)

Predict likelihood of response to therapy

Indicate emergence of resistant variants during antiviral therapy

Linear range: 20-170,000,000 IU/mL

16694b 87517 Hepatitis B Virus DNA, Quantitative PCR with Reflex to HBV Genotype Determine need to treat chronic HBV infection

Predict likelihood of response to therapy

Detect HBV mutations associated with resistance to antiviral agents

Identify HBV genotype (A–H) for epidemiologic and prognostic purposes

Detect mutations in precore and basal core promoter regions, which may influence immune response and outcome

10529c 87912 Hepatitis B Virus Drug Resistance, Genotype,
and BCP/Precore Mutations
Detect hepatitis B virus (HBV) mutations associated with resistance to antiviral agents

Identify HBV genotype (A–H) for epidemiologic and prognostic purposes

Detect mutations in precore and basal core promoter regions, which may influence immune response and outcome

Hepatitis C Virus (HCV)  
37811d 87902 Hepatitis C Viral RNA Genotype, LiPA® Predict likelihood of therapeutic response

Determine the duration of treatment

37273c 87521 Hepatitis C Viral RNA, Qualitative TMA

Diagnose acute infection

Confirm EIA diagnosis of acute or chronic infection

Differentiate between resolved and active infection

Demonstrate resolution of infection

Test for recurrence or reinfection

LOD = 5.3 IU/mL

11348b,c 87522 Hepatitis C Viral RNA, Quantitative Real-time PCR with Reflex to Genotype, LiPA® Confirm active infection and establish baseline viral load. Genotype used to guide treatment selection and duration

Linear range: 15-100,000,000 IU/mL

Perform only for baseline evaluation. If baseline RNA already measured, order genotype LiPA only.

10051b,c 87522 Hepatitis C Viral RNA, Quantitative Real-Time PCR with Reflex to Qualitative TMA All indications listed for qualitative HCV RNA assay (test code 37237) above

Establish baseline viral load

Predict response to antiviral therapy

Differentiate lack of therapeutic response from partial therapeutic response

Linear range: 15-100,000,000 IU/mL (if <15 IU/mL, reflex to TMA Qualitative assay)

35645 87522
 
Hepatitis C Viral RNA, Quantitative Real-Time PCR

Confirm active HCV infection and establish baseline viral load

Assess prognosis (prior to the initiation of therapy)

Monitor response to therapy

Test for recurrence or reinfection

Linear range: 15-100,000,000 IU/mL

LOD: 10-13 IU/mL

90251c,e 81400 AccuType® IL28B Predict response to therapy in patients with genotype 1 hepatitis C virus infection
91416c,e 87902 AccuType® Ribavirin (ITPA) Assess risk for ribavirin-induced anemia in patients treated for HCV infection

Help establish frequency of monitoring in patients being treated with ribavirin

90924c 87902 Hepatitis C Viral RNA NS3 Genotype

Detect NS3 mutations associated with resistance to NS3 protease inhibitors, including boceprevir, telaprevir and simeprevir

Detect the NS3 Q80K polymorphism associated with a lower SVR rate for pegylated interferon, ribavirin and simeprevir treatment regimens for HCV genotype 1a

92447c 87902 Hepatitis C Viral RNA NS5A Drug Resistance Detect mutations or polymorphisms in the NS5A gene associated with NS5A inhibitor treatment failure
92204c 87902 Hepatitis C Viral RNA NS5B Drug Resistance Detect mutations or polymorphisms in the NS5B gene associated with NS5B inhibitor treatment failure
Hepatitis D Virus (HDV)  
34469c 87798 Hepatitis D Virus RNA, Qualitative Real-Time PCR

Confirm HDV infection in individuals with reactive HDV antibody results13

Diagnose HDV infection in symptomatic, HBsAg-positive, HDV antibody-negative individuals with suggestive clinical features

LOD, limit of detection.
a The CPT codes provided are based on AMA guidelines and are for informational purposes only. CPT coding is the sole responsibility of the billing party. Please direct any questions regarding coding to the payer being billed.
b Reflex tests are performed at an additional charge and are associated with additional CPT codes.
c This test was developed and its performance characteristics have been determined by Quest Diagnostics. Performance characteristics refer to the analytical performance of the test.
d This test was developed and its performance characteristics have been determined by Quest Diagnostics. It has not been cleared or approved by the U.S. Food and Drug Administration. The FDA has determined that such clearance or approval is not necessary. Performance characteristics refer to the analytical performance of the test.
e
Additional assistance in interpretation of results is available from our Genetic Counselors by calling 1-866-GENE-INFO (866-436-3463).

Acute Viral Hepatitis Infection: Diagnosis and Follow Up [return to contents]

Test Selection

Clinical indications for testing for acute viral hepatitis include flu-like symptoms and either jaundice or ALT >400 IU/L. Four initial serologic tests are generally used to diagnose acute viral hepatitis in symptomatic patients: HAV immunoglobulin M (IgM) antibody, HBV surface antigen (HBsAg), HBV core IgM antibody (HBcAb, IgM), and HCV antibody (Figure 1). HDV antibody or RNA testing may be considered for acute HBV patients with fulminant hepatitis (Figure 1).

Figure 1. Diagnosis of Acute Hepatitis

HAV: HAV IgM antibody is the preferred test for diagnosis of acute HAV infection because it rises early (5 to 10 days after onset of symptoms) and persists only 3 to 12 months.

HBV: HBsAg and HBcAb are the preferred tests for diagnosis of both acute and chronic HBV infection. HBcAb IgM, however, is detectable during acute but not chronic HBV infection. Simultaneous use of HBsAg and HBcAb IgM tests therefore not only detects both acute and chronic HBV infection but also helps to differentiate between them.

HDV: HDV antibody testing is used to detect coinfection with HDV in patients with HBV infection.

HCV: HCV antibody immunoassays are used as the initial test for diagnosing HCV infection, because such assays have high sensitivity, wide availability, and low cost. However, antibody is not detectable until 4-10 weeks after exposure. Negative antibody tests should therefore be followed up with a repeat antibody test or an HCV RNA test if the patient has a history of exposure within the previous 6 months. Since HCV RNA is detectable 2 to 3 weeks after exposure, RNA tests can detect virus prior to seroconversion. RNA tests also serve to confirm active infection in patients with reactive antibody results, differentiate between active and resolved infection, and diagnose infection in immunocompromised individuals. The RNA test is the test of choice for detecting recurrence or reinfection, since antibody tests cannot differentiate past and current infection.

Follow-up testing in patients with acute viral hepatitis focuses on evaluation of liver function and monitoring infection for resolution or progression to chronic infection (Figure 2).

Figure 2. Laboratory Management of Patients with Hepatitis

Test Interpretation

Interpretations of individual tests are summarized in Table 6. However, results of an individual test cannot be interpreted in isolation; Table 7 provides an overview of how these tests can be used in concert to evaluate the presence of acute viral hepatitis.

Reactive (positive) screening antibody test results indicate that the patient has generated an immune response to that type of hepatitis virus and should be evaluated further with type-specific supplemental testing (eg, antigen, DNA, or RNA testing). Positive antigen, DNA, or RNA test results indicate active infection. In an infant less than 18 months of age, a positive antibody test result may indicate passive transfer of maternal antibody. Testing with a type-specific antigen or nucleic acid-based assay may reveal active infection.

Negative screening antibody results most likely indicate absence of infection. False-negative antibody results may occur in acute disease prior to seroconversion and in patients with a suppressed or nonfunctioning immune system. Thus, a negative result does not exclude the possibility of infection. If clinical suspicion is high, negative results may be followed up with testing for type-specific antigen, DNA, or RNA as appropriate, or by retesting at a subsequent date. Negative nucleic acid testing indicates absence of active infection. In rare cases, a negative nucleic acid-based test result could reflect a viral load below the assay's limit of detection.

Table 6. Interpretation of Individual Test Results in the Diagnosis of Acute and Chronic Viral Hepatitis
Marker Interpretation
HAV  
   HAV IgM A reactive result indicates current or recent infection. A negative result indicates absence of infection.
   HAV total Ab The presence of total HAV antibody in the absence of HAV IgM antibody indicates immunity against HAV infection.
HBV  
   HBsAg A reactive result indicates that a person has HBV infection and is infectious.
   HBcAb, total Presence indicates past or present HBV infection.
   HBc IgM Presence usually indicates HBV infection within the preceding 4 to 6 months (ie, acute infection).
   HBeAb Presence indicates resolving infection or response to therapy.
   HBsAb Presence indicates recovery and immunity against HBV infection or successful vaccination.
   HBV DNA Presence indicates active infection.
HDV  
   HDV Ab, total Reactive results, coincident with the presence of HBsAg, indicate past or current HBV/HDV coinfection or superinfection.
   HDV IgM Reactive results, coincident with the presence of HBsAg, indicate past or current HBV/HDV coinfection or superinfection. Negative results in the presence of positive HDV total antibody indicates resolved infection.
HCV  
   HCV Ab Reactive antibody results (with confirmatory HCV RNA results) indicate active infection. A positive result, in conjunction with a negative HCV RNA test, may indicate a resolved infection or a false-positive. False-positive HCV antibody results are more likely in people at low risk of HCV infection
   HCV RNA Positive results indicate current infection. A negative result indicates absence of current infection.
Table 7. Interpretation of Serologic and Nucleic Acid Testing for Acute Viral Hepatitis
Hepatitis Virus HAV
IgM
HBs
Ag
HBV
DNA
HBc
IgM
HBc
Total
HCV
Ab
HCV
RNA
HDV
Ab
HDV
RNA
A + - - - - - - - -
B - + + + - - - - -
B with D coinfection - + + + - - - + +
B with D superinfection - + + - - - - + +
C - - - - - ± + - -

Chronic Viral Hepatitis: Diagnosis [return to contents]

Test Selection

In patients with acute hepatitis B or C, markers of active HBV infection or HCV infection should be tested 6 months after initial diagnosis to document resolution or chronic infection (Figure 2). Table 3 summarizes at-risk groups that should be screened for chronic HBV and HCV infection. Serologic tests used to screen for chronic hepatitis in patients without previous hepatitis test results include assays for HCV antibody and HBsAg (Figure 3).16,17

Figure 3. Diagnosis of Chronic Hepatitis

HDV superinfection should be considered in chronic HBV carriers who experience a further acute attack and/or rapidly progressive liver disease. The HDV antibody assay is generally the initial test.13 Positive antibody results may be followed by HDV RNA testing for confirmation.13 HDV RNA testing may also be useful in HBsAg-positive/HDVAb-negative individuals if coinfection or superinfection is strongly suspected. HBc IgM testing can help distinguish between HDV coinfection and superinfection, since HBc IgM is a marker of acute infection. Thus, if positive, coinfection is more likely than superinfection.

Test Interpretation

HBV

Table 8 summarizes the correlation of HBV marker patterns with infection status. In patients with previously documented HBV infection, the presence of HBsAg and/or HBV DNA >6 months after the initial diagnosis indicates chronic HBV infection.17,20 In patients without previously documented HBV infection, absence of HBsAg is consistent with lack of or resolved infection; vaccination is generally recommended for patients with negative results for both HBsAg and HBsAb, whereas those with negative HBsAg and reactive HBsAb have immunity due to past (resolved) infection or vaccination.17 Chronic infection in patients without previously documented HBV can be identified on the basis of negative HBc IgM results in the presence of positive results on one of the following tests: HBsAg, HBeAg, or HBV DNA.20

Most chronic HBV infections are characterized by high HBV DNA levels (>20,000 IU/mL). Lower HBV DNA values (2000-20,000 IU/mL) are common in HBeAg-negative chronic infection, which is associated with a low likelihood of spontaneous disease remission. Patients with chronic infection generally have persistent or intermittent ALT elevation.17

Table 8. Interpretation of Hepatitis B Markers14,17
Marker HBV Infection Status
Susceptible Successful Vaccination Resolved (Immune) Acute
(Early)
Acute (Resolving) Chronic (Low Infectivity)a Chronic (High Infectivity)
HBsAg - - - + + + +
HBc total Ab - - + + + + +
HBV DNA - - -b + -b ±c +
HBc IgM Ab - - - + ± - -
HBeAgd - - - + ± - ±
HBeAbd - - + - ± ± -
HBsAb - + + - - - -

a Includes inactive HBsAg carrier state.
b Very low levels may be detected with highly sensitive assays.
c HBV DNA levels are below 2000 IU/mL in the inactive carrier state.
d In mutant HBV infection, HBeAg is absent and HBeAb may test positive even when HBV DNA is positive.

HDV

Nonreactive HDV antibody results are consistent with absence of HDV infection. In acute infection (usually coinfection) both HDV IgM and IgG can be positive, but IgM predominates. In chronic infection (typically superinfection), both IgM and IgG levels are typically high and long-lasting. HDV IgM tends to disappear with resolution of infection while HDV IgG persists. Thus, negative HDV IgM in a patient with positive total antibody results indicates resolved HDV infection. Positive HDV RNA results in patients with HDV antibodies indicates active infection, whereas negative results indicate resolved infection.

HCV

Nonreactive HCV antibody results indicate absence of infection. However, individuals with suspected recent exposure (<6 months previously) should either receive HCV RNA testing or undergo follow-up antibody testing to rule out infection. HCV RNA testing might also be considered for immunocompromised individuals.16 Reactive HCV antibody results need to be confirmed with HCV RNA testing. Positive HCV RNA results are consistent with current infection and negative results indicate absence of current infection. In patients with reactive antibody results who are negative for HCV RNA, repeat HCV RNA testing can be considered if the patient has suspected recent (<6 months) exposure or clinically suspected hepatitis. Retesting of a new sample might be considered if sample mishandling is suspected.

Chronic Viral Hepatitis: Treatment Decisions and Monitoring [return to contents]

Laboratory markers play a central role in monitoring disease activity, evaluating patients for treatment of chronic HBV and HCV infection, and monitoring treatment response.

HBV

Therapy for chronic HBV infection is geared toward limiting progressive liver disease and adverse outcomes such as liver failure, HCC, and death.21 Treatments include alpha interferon or pegylated alpha-interferon and nucleoside analogs (lamivudine, adefovir dipivoxil, entecavir, telbivudine, and tenofovir disoproxil fumarate). All may improve laboratory markers, including ALT, HBV DNA, HBsAg, and even liver pathology. Improvements in long-term clinical outcomes such as mortality, however, are less well established. Current treatments typically do not clear HBV infection or provide long-term virologic suppression (due to emergence of drug-resistant variants).21 Tenofovir, however, may be promising; a clinical trial has shown response without resistance for 6.5 years.22 Thus, treatment is generally limited to patients with a strong risk of liver damage in the near-term who are likely to benefit from treatment. Laboratory surveillance is important for guiding the decision to treat.

Decision to Treat

Current guidelines recommend treatment for HBV patients with severe complications of infection, including acute liver failure, cirrhosis with clinical complications, or HBV DNA and cirrhosis or advanced fibrosis.21 Treatment is also recommended for patients with HBV reactivation after immunosuppressive therapy.

For patients not receiving immediate therapy, laboratory testing is useful to guide monitoring and therapeutic decisions (Figure 4).17,21 ALT measurement is important for assessing liver function and need for treatment. In chronic HBV infection, the baseline ALT level is positively associated with mortality from liver disease17 and inversely related to the likelihood of treatment response. HBV DNA measurement is also useful for assessing disease activity, the need for treatment,21 and the likelihood of treatment response: as with ALT, HBV DNA levels correlate positively with disease activity and negatively with treatment response. The HBV e antigen (HBeAg) test helps to classify HBV-infected individuals into HBeAg-positive and HBeAg-negative groups to aid in treatment selection: in HBeAg-positive patients, persistently elevated ALT is an indication for treatment17; in HBeAg-negative patients, serial HBV DNA measurement is also used to inform monitoring and treatment decisions (Figure 4). Additional prognostic factors, including age, gender, family history of HCC, alcohol abuse, and coinfection with HIV, HCV, or HDV, also play a role in treatment decisions.21

Figure 4. Monitoring of Chronic Hepatitis B Virus Infection in Patients Not Initially Treated

During Treatment

Monitoring of ALT levels during treatment helps to assess treatment response: falling levels are consistent with response to treatment. Quantitative HBV DNA assays can help monitor response to therapy and predict the emergence of resistance to antiviral agents. Results are used to guide changes in drug selection after therapy initiation: a change in regimen may be appropriate for patients receiving a nucleoside analog who do not achieve a primary response (<2-log decrease in HBV DNA within 6 months).17 In HBeAg-positive patients, the loss of HBeAg is an indicator of treatment response.

The HBV genotyping assay is used to determine the HBV genotype, which is important for epidemiologic studies and may be associated with the clinical course and response to therapy.23-27 HBV drug resistance testing can detect the emergence of mutations associated with resistance to antiviral drugs. Although increasing levels of HBV DNA in patients receiving antiviral therapy is a strong indicator of drug resistance, confirmatory testing for resistance-associated mutations (Table 9) can help differentiate primary nonresponse from breakthrough infection.17 The presence of resistance-associated mutations in patients with virologic breakthrough or rebound suggests the need to add or replace a drug in the regimen.1

Table 9. HBV DNA Polymerase Gene Mutations Associated with Resistance to
Nucleos(t)ide Analogs
 

Lamivudine
(3TC)

Famciclovir

Adefovir
(ADV)

Entecavir
(ETV)

Telbivudine
(LdT)

Mutation(s)

L180M+M204V/I;

A181T

V207I

N236T;

A181V

M250V; T184G;

S202Ia

M204I; L180M+M204V

a Associated with reduced susceptibility to ETV when combined with lamivudine-associated mutations. A resistance profile for tenofovir has not yet been established.

HCV

Decision to Treat and Treatment Selection

Therapy for chronic HCV infection is geared toward eradicating viral infection and preventing complications such as HCC and liver failure. Treatment is generally recommended for adults with active HCV infection who have a life-expectancy ≥12 months. Previously, treatment primarily consisted of pegylated interferon-alpha/ribavirin combination therapy. This is no longer recommended with the advent of direct-acting agents (DAAs). Though costly, DAAs are much better tolerated and have significantly higher SVRs than older regimens. DAAs are likely to help almost all patients with chronic infection (all stages). Initiation of treatment is more urgent in patients with certain conditions (eg, advanced fibrosis or compensated cirrhosis).16

Baseline testing for HCV-infected patients includes HCV RNA measurement to verify active infection and establish baseline viral load, as well as routine laboratory markers used to guide the decision to treat (hemoglobin, complete blood count, bilirubin, serum creatinine, ALT)  (Table 10; Figure 5).

Table 10. HCV Monitoring Panels Consistent with Current Guidelines11,19
Test Codes CPT Codesa Test Clinical Application
91704b,c

80076

85025

82565

86708

87340

86704

86703

87902

86706

Hepatitis C-Infected Patient, Baseline Panel 1

Includes hepatic function panel; CBC
(includes differential and platelet counts); creatinine; HBsAb (qualitative); HAV, total
Ab; HBsAg w/ rfl confirmation; HBcAb, total; HIV-1/2 Ab w/ rfl, HCV RNA genotype, LiPA
.

Assess risk from underlying medical conditions and comorbid infections prior to initiation of HCV therapy

Establish baseline laboratory parameters in order to define changes during therapy

Determine HCV genotype to guide treatment selection and duration of therapy

91707b,c

80076

85025

82565

86703

87902

Hepatitis C-Infected Patient, Baseline Panel 2

Includes hepatic function panel; CBC
(includes differential and platelet counts); creatinine; HIV-1/2 Ab w/ rfl; HCV genotype, LiPA
.

Assess risk from underlying medical conditions and comorbid infections prior to, during, and after initiation of HCV therapy
91705c

86038

86255

83516

86376

83520

Hepatitis C-Infected Patient, Autoimmune Panel

Includes ANA IFA screen w/ rfl titer/pattern, mitochondrial Ab w/ rfl titer, actin (smooth muscle) Ab (IgG), LKM-1 Ab (IgG), SLA autoantibody.

Identify contraindications for hepatitis C therapies that could increase risk for exacerbations of symptoms from peginterferon and ribavirin
91706

85025

82565

84460 

87522

Hepatitis C-Infected Patient, Treatment Panel

Includes CBC (with differential/ platelet
counts); creatinine; ALT; quantitative HCV RNA, real-time PCR
.

Assess response to therapy and adverse effects
92688c,e

82172

83883

82247

84460

83010

82977

Liver Fibrosis, FibroTest-ActiTest Panel

Assist with non-invasive evaluation of liver fibrosis in patients with HCV infection

a The CPT codes provided are based on AMA guidelines and are for informational purposes only. CPT coding is the sole responsibility of the billing party. Please direct any questions regarding coding to the payer being billed.
b Reflex tests are performed at an additional charge and are associated with additional CPT codes.
c This test was developed and its performance characteristics have been determined by Quest Diagnostics. It has not been cleared or approved by the U.S. Food and Drug Administration. The FDA has determined that such clearance or approval is not necessary. Performance characteristics refer to the analytical performance of the test.
d This test was developed and its performance characteristics have been determined by Quest Diagnostics. Performance characteristics refer to the analytical performance of the test.
e Biopsy to assess liver fibrosis has been recommended if needed to assist with prognosis or treatment decisions.18,19 Although noninvasive assessment of fibrosis can be used, it is not considered a replacement for biopsy in routine practice.

Figure 5. Laboratory Testing in the Management of Chronic Hepatitis C Virus (HCV) Infection

Biopsy, the historic "gold standard" for assessing fibrosis, may be useful when the results will assist in prognosis or be used to guide treatment decisions (Figure 5).18,19 However, the procedure carries a moderate risk of complications and is subject to sampling error. Imaging and predictive models that incorporate serum markers may be useful to assess the likelihood of advanced fibrosis. One such model, the FibroTest-ActiTest, is based on serum levels of α2-macroglobulin, haptoglobin, apolipoprotein A1, total bilirubin, gamma glutamyl transferase (GGT), and ALT, along with age and sex. This test is meant as a screening tool to avoid unnecessary biopsies. A fibrosis score is calculated and equated to a Metavir stage (ie, F0 to F4), reflecting the level of fibrosis. Additionally, a necroinflammation activity score is calculated and equated to a Metavir grade (ie, A0 to A3), reflecting liver inflammation. The lowest and highest scores may obviate the need for a biopsy, while intermediary scores should be interpreted in the overall clinical context of the individual patient.

Once the decision to treat has been made, HCV genotype is the primary virologic consideration in treatment selection and duration (Figure 5, Table 11). Since peginterferon alpha/ribavirin/simeprevir therapy is no longer recommended, testing for the NS3 Q80K polymorphism is no longer needed for treatment selection in patients with genotype 1a infection. Presence of Q80K does not preclude sofosbuvir plus simeprevir therapy.16

Table 11. Recommended Treatment Regimens Based on HCV Genotype16,a

Genotype

Drug Regimen

Duration, Weeks

1a

Ledipasvir/sofosbuvir
Paritaprevir/ritonavir/ombitasvir plus dasabuvir with RBV
Sofosbuvir plus simeprevir with or without RBV

12 (24 if cirrhosis)
12 (24 if cirrhosis)
12 (24 if cirrhosis)

1b

Ledipasvir/sofosbuvir
Paritaprevir/ritonavir/ombitasvir plus dasabuvir
(with RBV if cirrhosis)
Sofosbuvir plus simeprevir with or without RBV

12 (24 if cirrhosis)
12 (24 if cirrhosis)

12 (24 if cirrhosis)

2

Sofosbuvir and RBV

12 (16 if cirrhosis)

3

Sofosbuvir with RBV

24

4

Ledipasvir/sofosbuvir
Paritaprevir/ritonavir/ombitasvir with RBV
Sofosbuvir and RBV

12
12
24

5

Sofosbuvir and RBV plus PEG-IFN

12

6

Ledipasvir/sofosbuvir

12

RBV, ribavirin; PEG-IFN, peginterferon alpha-interferon alpha.
a Alternative regimens are also available for genotypes 3 to 6.

Host factors influencing treatment response include age, gender, ethnicity, and genetic polymorphisms. For example, individuals of European descent have higher rates of sustained virologic response (SVR; absence of detectable HCV RNA ≥24 weeks after end of treatment) than do African Americans when interferon/ribavirin therapies are used.28,29 Half of this difference is caused by the single nucleotide polymorphism (SNP) IL28B rs12979860.29 This SNP has 3 possible genotypes: CC, CT, and TT. The CC genotype is associated with better rates of rapid virologic response (RVR; undetectable serum HCV RNA at treatment week 4) and SVR than are the CT or TT genotypes.28-30 Thus, testing for IL28B genotype has been recommended in cases in which the result would influence the decision to initiate therapy with interferon and ribavirin.18

In addition to IL28B genotype, another genetic host factor that may play a role in HCV treatment selection or dosing is a pair of polymorphisms (rs1127354 and rs7270101) in the inosine triphosphatase gene (ITPA). Patients whose ITPA variants are associated with the lowest ITPA activity have the lowest likelihood of having ribavirin-induced anemia31; those with genotype 1 infection,32 but not those with type 2 or 3 infection,33 are also less likely to require a ribavirin dose reduction. Assessment of anemia risk in combination with clinical evaluation may help determine the frequency of monitoring for anemia in patients receiving ribavirin. Although ribavirin-associated anemia may lead to dose reduction, ITPA variants have not been associated with the likelihood of SVR.32,33

During Treatment

After treatment is initiated, measurement of HCV viral load at specified times helps predict the likelihood of SVR and guide treatment decisions (Figure 5).11,19 The same quantitative test should be used each time to avoid technology-related variability.

Measurement at week 4 can help assess treatment response and adherence to therapy. Patients without cirrhosis typically have an undetectable level at this time. If HCV RNA is still detectable, the measurement may be repeated 2 weeks later, at week 6. If the viral load increases by more than 1 log10 IU/mL, treatment should be discontinued.16

Absence of detectable HCV RNA at the end of treatment indicates treatment response. Since DAAs are effective in most patients, viral load measurement at end of treatment is optional; however, viral load testing should be done 12 weeks after completion of therapy to ensure SVR. Testing again at ≥24 weeks after end of treatment may be desirable in selected patients.16

NS3 sequence analysis may be used to detect mutations associated with resistance to NS3 protease inhibitors, including boceprevir, telaprevir, and simeprevir. The emergence of resistance-associated mutations in patients with genotype 1a or 1b HCV infection may result in DAA resistance and failure of the therapeutic regimen.

Sequence analysis of the NS5A and NS5B genes can be used to detect mutations or polymorphisms associated with resistance to NS5A inhibitors (eg, ledipasvir) and NS5B inhibitors (eg, sofosbuvir), respectively.34-37

Chronic Viral Hepatitis: Demonstrate Recovery [return to contents]

Recovery in patients with a known history of chronic HBV or the presence of HBcAb and/or HBsAb is signaled by the disappearance of HBsAg and HBV DNA along with persistently normal ALT levels. Some individuals have detectable DNA after disappearance of HBsAg. While this may not be associated with active disease in immunocompetent individuals, it may represent treatment failure or failure of natural immunity when HBs antibody is absent. HBV DNA-positive individuals may be at risk for recurrent HBV disease, cirrhosis, and HCC. Additionally, HBV DNA-positive organ donors could potentially transmit the infection to organ transplant recipients. HCV recovery is indicated by repeatedly negative HCV RNA test results. HCV antibody almost always persists, but does not protect against reinfection. HDV Ab and HDV RNA disappear within months after recovery.

References [return to contents]

  1. Centers for Disease Control and Prevention. Surveillance for viral hepatitis–United States, 2012. http://www.cdc.gov/hepatitis/Statistics/2012Surveillance/Commentary.htm. Updated August 26, 2014. Accessed January 16, 2015.

  2. Centers for Disease Control and Prevention. Hepatitis E information for health professionals. http://www.cdc.gov/hepatitis/ChooseE.htm. Updated September 17, 2012. Accessed January 22, 2015.

  3. Kucirka LM, Farzadegan H, Feld JJ, et al. Prevalence, correlates, and viral dynamics of hepatitis delta among injection drug users. J Infect Dis. 2010;202:845-852.

  4. Gish RG, Yi DH, Kane S, et al. Coinfection with hepatitis B and D: epidemiology, prevalence and disease in patients in Northern California. J Gastroenterol Hepatol. 2013;28:1521-1525.

  5. Teshale EH, Hu DJ, Holmberg SD. The two faces of hepatitis E virus. Clin Infect Dis. 2010;51:328-334.

  6. Caredda F, Rossi E, d'Arminio MA, et al. Hepatitis B virus-associated coinfection and superinfection with delta agent: indistinguishable disease with different outcome. J Infect Dis. 1985;151:925-928.

  7. Craxi A, Raimondo G, Longo G, et al. Delta agent infection in acute hepatitis and chronic HBsAg carriers with and without liver disease. Gut. 1984;25:1288-1290.

  8. Weinbaum CM, Williams I, Mast EE, et al. Recommendations for identification and public health management of persons with chronic hepatitis B virus infection. MMWR Recomm Rep. 2008;57:1-20.

  9. Smith BD, Morgan RL, Beckett GA, et al. Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945-1965. MMWR Recomm Rep. 2012;61:1-32.

  10. Moyer VA. Screening for hepatitis C virus infection in adults: US Preventive Services Task Force recommendation statement. Ann Intern Med. 2013;159:349-357.

  11. Ghany MG, Strader DB, Thomas DL, et al. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology. 2009;49:1335-1374.

  12. Hughes SA, Wedemeyer H, Harrison PM. Hepatitis delta virus. Lancet. 2011;378:73-85.

  13. Bernabe-Ortiz A, Carcamo CP, Scott JD, et al. HBV infection in relation to consistent condom use: a population-based study in Peru. PLoS One. 2011;6:e24721.

  14. Centers for Disease Control and Prevention. Hepatitis B FAQs for health professionals. http://www.cdc.gov/hepatitis/HBV/HBVfaq.htm#general. Updated March 21, 2014. Accessed January 23, 2015.

  15. Centers for Disease Control and Prevention. Hepatitis C FAQs for health professionals. http://www.cdc.gov/hepatitis/HCV/HCVfaq.htm. Updated December 9, 2014. Accessed January 22, 2015.

  16. American Association for the Study of Liver Diseases (AASLD) and Infectious Diseases Society of America (IDSA). Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org/full-report-view. Updated December 19, 2014. Accessed January 20, 2015.

  17. Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology. 2009;50:661-662.

  18. Yee HS, Chang MF, Pocha C, et al. Update on the management and treatment of hepatitis C virus infection: recommendations from the Department of Veterans Affairs Hepatitis C Resource Center Program and the National Hepatitis C Program Office. Am J Gastroenterol. 2012;107:669-689.

  19. Ghany MG, Nelson DR, Strader DB, et al. An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology. 2011;54:1433-1444.

  20. Centers for Disease Control and Prevention. Hepatitis B, chronic: 2012 case definition. http://wwwn.cdc.gov/NNDSS/script/casedef.aspx?CondYrID=715&DatePub=1/1/2012%2012:00:00%20AM. Updated December 23, 2014. Accessed January 26, 2015.

  21. Belongia EA, Costa J, Gareen IF, et al. NIH consensus development statement on management of hepatitis B. NIH Consens State Sci Statements. 2008;25:1-29.

  22. Buti M, Tsai N, Petersen J, et al. Seven-year efficacy and safety of treatment with tenofovir disoproxil fumarate for chronic hepatitis B virus infection [published online ahead of print December 23, 2014]. Dig Dis Sci. doi:10.1007/s10620-014-3486-7.

  23. Kao JH, Chen PJ, Lai MY, et al. Genotypes and clinical phenotypes of hepatitis B virus in patients with chronic hepatitis B virus infection. J Clin Microbiol. 2002;40:1207-1209.

  24. Lindh M, Hannoun C, Dhillon AP, et al. Core promoter mutations and genotypes in relation to viral replication and liver damage in East Asian hepatitis B virus carriers. J Infect Dis. 1999;179:775-782.

  25. Bonino F, Marcellin P, Lau GK, et al. Predicting response to peginterferon alfa-2a, lamivudine and the two combined for HBeAg-negative chronic hepatitis B. Gut. 2007;56:699-705.

  26. Janssen HL, van Zonneveld M, Senturk H, et al. Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial. Lancet. 2005;365:123-129.

  27. Kao JH, Wu NH, Chen PJ, et al. Hepatitis B genotypes and the response to interferon therapy. J Hepatol. 2000;33:998-1002.

  28. Stattermayer AF, Stauber R, Hofer H, et al. Impact of IL28B genotype on the early and sustained virologic response in treatment-naive patients with chronic hepatitis C. Clin Gastroenterol Hepatol. 2011;9:344-350.

  29. Ge D, Fellay J, Thompson AJ, et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature. 2009;461:399-401.

  30. Sarrazin C, Susser S, Doehring A, et al. Importance of IL28B gene polymorphisms in hepatitis C virus genotype 2 and 3 infected patients. J Hepatol. 2011;54:415-421.

  31. Fellay J, Thompson AJ, Ge D, et al. ITPA gene variants protect against anaemia in patients treated for chronic hepatitis C. Nature. 2010;464:405-408.

  32. Thompson AJ, Fellay J, Patel K, et al. Variants in the ITPA gene protect against ribavirin-induced hemolytic anemia and decrease the need for ribavirin dose reduction. Gastroenterology. 2010;139:1181-1189.

  33. Thompson AJ, Santoro R, Piazzolla V, et al. Inosine triphosphatase genetic variants are protective against anemia during antiviral therapy for HCV2/3 but do not decrease dose reductions of RBV or increase SVR. Hepatology. 2011;53:389-395.

  34. Sun JH, O'Boyle DR II, Zhang Y, et al. Impact of a baseline polymorphism on the emergence of resistance to the hepatitis C virus nonstructural protein 5A replication complex inhibitor, BMS-790052. Hepatology. 2012;55:1692-1699.

  35. Wong KA, Worth A, Martin R, et al. Characterization of hepatitis C virus resistance from a multiple-dose clinical trial of the novel NS5A inhibitor GS-5885. Antimicrob Agents Chemother. 2013;57:6333-6340.

  36. Wyles D. Antiviral resistance and the future landscape of hepatitis C virus infection therapy. J Infect Dis. 2013;207(suppl 1):S33-S39.

  37. Paolucci S, Fiorina L, Mariani B, et al. Naturally occurring resistance mutations to inhibitors of HCV NS5A region and NS5B polymerase in DAA treatment-naïve patients. Virol J. 2013;10:1-7.
     

Content reviewed 3/2015

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* The tests listed by specialist are a select group of tests offered. For a complete list of Quest Diagnostics tests, please refer to our Directory of Services.