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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

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), and human immunodeficiency virus (HIV). Hepatitis may also be due to other diseases or medications.

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

New Infections in US,

20101 Estimate

Chronically Infected People in US,

2010 Estimate1

HAV 17,000 NA
HBV 38,000 0.8–1.4 million
HCV 17,000 2.7–3.9 million
HDV Unknown

Rare in United Statesa

HEV2 Unknownb NA
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%.4

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 tends to resolve spontaneously, whereas 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% (3,000/y) 10% (adults) 90% (infants) 1%-10% Yes
HCV Parenteral, perinatal, possibly sexual 2-23 wk 1-5% (12,000/y) 50%-80%
 
80%-90% Yes
HDV Parenteral, sexual, perinatal 6-26 wk 2-20%

Variablea
 

80% in

superinfectiona

Yesa

HEV2 Fecal-oral 2-9 wk 1%b Rarec Rarec No
a 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).
b 10%-30% in pregnant women.
c Chronic carriage may be more common in HIV-infected individuals. There have also been anecdotal reports of reactivation of resolved infection.8

Treatment for HAV is supportive, whereas specific antiviral therapies are available for HBV and HCV infection. Prompt and accurate diagnosis of HBV and HCV is needed to avoid complications of chronic disease. Timely diagnosis of all forms of viral hepatitis is useful for preventing transmission and (especially in the case of orally transmitted viruses) 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 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 Testing2,9-12
Risk Group HAV HBV HCV HDV
Individuals with clinical symptoms or elevated liver enzyme levels X X X  
Individuals born in highly or moderately endemic areas  X    
Children of immigrants from highly endemic areas (if the children were not vaccinated as infants)   X    
Individuals with HIV or HCV infection   X    
Household and sexual contacts of infected persons   X    

Pregnant womena

  X    
Children born to infected women   X X  
Intravenous drug users (current or past)   X X  
Men who have sex with men   X X  
Health care workers after percutaneous exposure   X X  
Individuals receiving immunosuppressive therapy, including recipients of organ transplants, multiple blood transfusions, or cancer chemotherapy   X X  
Hemodialysis patients   X X  
Updated: Individuals born 1945 through 1965 (baby boomer population, which accounts for up to 75% of adult HCV cases in the United States)b     X  
Individuals who received a transfusion before 1992 or clotting factor concentrates produced before 1987     X  
Individuals who have received an unregulated tattoo or used drugs intranasally     X  
Individuals who have a history of sexually transmitted infections or participate in high-risk sexual activities     X  
Inmates of correctional facilities     X  
Individuals with HBV infection      

Xc

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 HCV testing is also indicated for pregnant women at high risk for HCV infection.
b The Centers for Disease Control and Prevention (CDC) recommends one-time HCV antibody testing for all individuals born 1945 through 1965.10 Those with positive antibody results should be tested using an HCV nucleic acid test to determine whether there is active infection. The US Preventive Services Task Force also recommends that one-time HCV screening be offered for this age group.11
c If HDV coinfection or superinfection is clinically suspected.

Test Availability [return to contents]

  • Chemistry tests (eg, ALT, bilirubin) are used to assess disease progression and liver damage.

  • Serologic tests include immunoassays for antibodies and antigens. Targets are available to assess

   Presence and severity 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 subtype (for epidemiological 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

87340

86705

86709

86803

Hepatitis Panel, Acute with Reflex to Confirmation

Includes HAV IgM; HBsAg w/rfl confirmation;

HBcAb; HCV Ab

Detect 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 acute hepatitis caused by hepatitis A, B, or C
Hepatitis A Virus (HAV)  
512 86709 HAV Antibody (IgM) First-line diagnostic test for acute hepatitis A
508 86709 HAV Total Antibody 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 resolution of HBV infection (disappearance of HBeAg and appearance of HBeAb)

499 86706 HBV Surface Antibody, Qualitative Indicate prior exposure to antigen or vaccine
8475   Hepatitis B Surface Antibody Quantitation

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 in pre- and post-infusion specimens
498   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

17375 87340 Donor, Hepatitis B Surface Antigen Refl
to Confirm
Screen for HBV infection in donors of human cells, tissues and tissue-based products
Hepatitis C Virus (HCV)  
91438 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
91408 86803 Donor, HCV Antibody Screen with Reflex
to 2nd HCV Screen
Screen for HCV infection in donors of human cells, tissues and tissue-based products
Hepatitis D Virus (HDV)  
4990(X)   Hepatitis D 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 results13
HBIG, hepatitis B immune globulin.
Refer to the Quest Diagnostics Test Center (http://www.questdiagnostics.com/testcenter/TestCenterHome.action) 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 payor 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(X) 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

10529(X)c 87912 HBV 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

37273 87521 HCV RNA, Qualitative TMA Confirm EIA diagnosis of acute or chronic infection (LOD = 5.3 IU/mL)

Differentiate between resolved and active infection

Demonstrate resolution of infection

11348b 87522 Hepatitis C Viral RNA, Quantitative
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.

10051(X)a,b 87522 Hepatitis C Viral RNA, Quantitative Real-Time PCR with Reflex to Qualitative TMA All indications listed for qualitative HCV RNA assay 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)

35645e 86692
 
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

Linear range: 15 - 100,000,000 IU/mL
LOD: 10-13 IU/mL

90251c,f 83891 83898 83896(x2) 83912 AccuType® IL28B Predict response to therapy in patients with genotype 1 hepatitis C virus infection
91416c 87902 AccuType® Ribavirin (ITPA)f 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 boceprevir and telaprevir in patients who have received or are receiving NS3 protease inhibitor therapy
Hepatitis Delta Virus (HDV)  
34469c 87798 Hepatitis D Virus, RNA, Qualitative Real-Time PCR Confirm HDV infection in individuals with reactive HDV antibody results14

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 Nichols Institute. 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 Nichols Institute. 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 The performance characteristics of this assay have been determined by Quest Diagnostics Nichols Institute. Performance characteristics refer to the analytical performance of the test.

f Additional assistance in interpretation of results is available from our Genetic Counselors by calling 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 rapid onset of jaundice and viral illness. 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 fulmininant 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 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: An HCV antibody immunoassay is used as the initial assay for diagnosing HCV infection, because such tests have high sensitivity, wide availability, and low cost. However, antibody is not detected for many months after infection. RNA tests serve to confirm active infection in patients with reactive antibody results, detect virus prior to seroconversion, and differentiate between active and resolved 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 non-functioning 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
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 Ab indicates resolved infection.
HCV  
HVC Ab Reactive antibody results (with confirmatory HCV RNA results) indicate active infection. False-positive HCV antibody results may occur in cases of alcoholic liver disease, autoimmune chronic active hepatitis, or improper sample storage and testing conditions.
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 HBsAg 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 2 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, HBsAg, and HBsAb (Figure 3).5,9,15,16

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.14 Positive antibody results may be followed by HDV RNA testing for confirmation.14 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.

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.15,17 In patients without previously documented HBV infection, absence of HBsAg is consistent with lack of 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.15 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.17

Most chronic HBV infections are characterized by high HBV DNA levels (>20,000 IU/mL). Lower HBV DNA values (2,000-20,000 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.15

Table 8. Interpretation of Hepatitis B Markers15, 16
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 2,000 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. Presence of HDV IgG and IgM is consistent with current or past HDV coinfection or superinfection. HDV IgG and IgM levels are typically high and long-lasting in chronic HDV infection. 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. HCV RNA testing might also be considered for immunocompromised individuals.5 Reactive HCV antibody results need to be confirmed with HCV RNA testing (or an alternate method). 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 Infection: Demonstrate Recovery

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. HDV Ab and HDV RNA disappear within months after recovery.

Chronic Viral Hepatitis Infection: Treatment Decisions and Monitoring

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.18 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).18 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 serum HBV and cirrhosis or advanced fibrosis.18 Treatment is also recommended for patients with HBV reactivation after immunosuppressive therapy. Because of the high risk of vertical transmission, presence of HBsAg in a pregnant woman is an indication for hepatitis B immune globulin (HBIG) therapy and hepatitis B vaccination of the newborn immediately after birth.

For patients not receiving immediate therapy, laboratory testing is useful to guide monitoring and therapeutic decisions (Figure 4).15,18 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 disease15 and inversely related to the likelihood of treatment response. HBV DNA measurement is also useful for assessing disease activity, the need for treatment,18 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 treatment15; 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.18

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.15 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. The HBV genotype assay can also 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.15 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. Treatments include combination therapy with pegylated interferon-alpha and ribavirin, with the addition of direct-acting agents (DAAs) for patients with HCV genotype 1 infection. These drugs can be costly, are often poorly tolerated, and are not always effective.19 Treatment is generally recommended for adult HCV patients with active infection who 1) have compensated liver disease with acceptable hematologic and biochemical indices; 2) are willing to adhere to treatment; and 3) have no contraindications (see references 19 and 20 for detailed guidance on treatment eligibility). Thus, baseline and treatment monitoring panels for HCV-infected patients include 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, blood count, bilirubin, serum creatinine, ALT) (Table 10; Figure 5).

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

Biopsy, the “gold standard” for assessing fibrosis, may be useful when the results will assist in prognosis or be used to guide for treatment decisions (Figure 5).19,20 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 HepaScore®, is based on serum levels of α2-macroglobulin, hyaluronic acid, gamma glutamyl transferase (GGT), and total bilirubin, along with age and sex. This test is meant as a screening tool to avoid unnecessary biopsies. Patients with scores below the threshold value (0.55) generally have mild or no fibrosis, whereas scores above the threshold are consistent with more advanced fibrosis. 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.

Table 10. HCV Monitoring Panels Consistent with Current Guidelines12,19
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 or 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
91705b

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
91706d

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
19647c,e

82977

82247

83520

83883

Liver Fibrosis Panel (HepaScore®)

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 Nichols Institute. 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 Nichols Institute. 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.19,20 Although noninvasive assessment of fibrosis can be used, it is not considered a replacement for biopsy in routine practice.

Host factors influencing treatment response and, potentially, the decision to treat 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.21,22 Half of this difference is caused by the single nucleotide polymorphism (SNP) IL28B rs12979860.5 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.21-23 A favorable IL28B genotype improves the treatment response considerably in individuals infected with HCV genotype 1.21 Thus, testing for IL28B genotype has been recommended in cases in which the result would influence the decision to initiate therapy.20

Once the decision to treat has been made, HCV genotype is the primary virologic consideration in treatment selection and duration (Figure 5). Patients with genotype 2 or 3 infection typically respond well to 24 weeks of standard treatment with pegylated interferon plus ribavirin. Patients with type 1 or 4 infection have lower SVR rates to standard interferon/ribavirin regimens than do those infected with type 2 or 3.23 The addition of a DAA such as boceprevir and telaprevir is recommended for patients with genotype 1 infection.12,19,20

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).12,19 The same quantitative test should be used each time to avoid technology-related variability.

For non-cirrhotic patients with genotype 1 HCV, response-guided therapy has been recommended to optimize the duration of triple therapy (a DAA in addition to ribavirin and pegylated interferon alpha). With this approach, HCV viral load is measured periodically to guide treatment decisions.12,19 Results below a predetermined threshold suggest that a shortened regimen may be effective. Conversely, failure to achieve milestone reductions in viral load indicate that further treatment will likely not be effective and could lead to emergence of HCV variants that are resistant to the DAA being used. Specific time points for measurement, and target viral load reductions, vary with the DAA used.19,20

For patients with genotype 2 or 3 infection, HCV RNA is generally measured during therapy at weeks 4, 12, and 24. Patients who achieve a rapid virologic response (RVR; undetectable HCV RNA 4 weeks after treatment initiation) may be candidates for shortened therapy.12 Patients who do not achieve a partial (≥2 log reduction in HCV RNA) or complete (HCV RNA-negative) early virologic response are unlikely to have an SVR. The timing of monitoring for all genotypes will likely change as new drugs become available.

Regardless of genotype, absence of detectable HCV RNA at the end of treatment indicates treatment response. Absence of HCV RNA 24 weeks after the end of therapy indicates SVR, whereas detection of RNA at this time point indicates relapse.

In patients receiving a DAA, analysis of specific sequences in the NS3 gene of HCV may be used to detect mutations associated with resistance to boceprevir and telaprevir. Although the role of these mutations in clinical decisions has not been established, 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.

In addition to IL28B genotype, another genetic host factor that may play a role in HCV disease management 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 anemia24; those with genotype 1 infection,25 but not those with type 2 or 3 infection,26 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.25,26

References [return to contents]

  1. Centers for Disease Control and Prevention. Viral Hepatitis Surveillance – United States, 2010. May 24, 2013. http://www.cdc.gov/hepatitis/statistics/2010surveillance/Commentary.htm. Accessed August 14, 2013.

  2. Centers for Disease Control and Prevention. Hepatitis E information. April 1, 2013. http://www.cdc.gov/hepatitis/ChooseE.htm. Accessed August 19, 2013.

  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.

  5. Centers for Disease Control and Prevention. Testing for HCV infection: an update of guidance for clinicians and laboratorians. MMWR Morb Mortal Wkly Rep. 2013;62:362-365.

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

  9. 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.

  10. 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.

  11. Moyer VA. Screening for hepatitis C virus infection in adults: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2013;159:349-357.

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

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

  14. 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.

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

  16. Centers for Disease Control and Prevention. Hepatitis B Information for Health Professionals. April 1, 2013. http://www.cdc.gov/hepatitis/HBV/HBVfaq.htm#general. Accessed September 8, 2013.

  17. Centers for Disease Control and Prevention. Hepatitis B, chronic: 2012 case definition. April 1, 2013. http://wwwn.cdc.gov/NNDSS/script/casedef.aspx?CondYrID=715&DatePub=1/1/2012 12:00:00 AM. Accessed September 8, 2013.

  18. 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.

  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. 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.

  21. 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.

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

  23. 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.

  24. 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.

  25. 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.

  26. 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.
     

Content reviewed 11/2013

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