Guidelines for Laboratory Testing and Result Reporting for Antibody to

Hepatitis C Virus

Miriam J. Alter, Ph.D.

Division of Viral Hepatitis

Centers for Disease Control and Prevention

BPAC September 18, 2003

2

Guidelines Development

Working group– Federal agencies• CDC, FDA (CDRH, CBER)

– Professional associations• APHL• ASCP• CAP• NACB• AACC• ACLA

– Other experts• University and VA hospital laboratories

Other collaborators– Blood collection

establishments– Manufacturers

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These Guidelines Are NOT Intended

For screening or notification of blood, plasma or other donors, as provided for under FDA guidance or regulations

To change manufacturers labeling for performing a specific test

To dictate medical practice, i.e., what tests physicians are able to order

4

Testing for Anti-HCV

Recommended for initially identifying persons with HCV infection

Antibody screening assay followed by more specific assay for screening-test-positives– As is done for HBsAg and anti-HIV

Verifying presence of anti-HCV– Minimizes unnecessary medical visits and psychological harm for

persons who test falsely positive

– Ensures counseling, medical referral and evaluation targeted for persons serologically confirmed as having been HCV infected

5

Performance of Screening Tests

Positive Predictive Value (PPV)– Probability that a person with a positive test is a

true positive– Varies depending on prevalence of infection in

population being screened

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How Anti-HCV Test Results Are Used

Clinical diagnosis of etiology of liver disease Postexposure management Screening asymptomatic persons– Most being tested for the first time

– Risk for infection highly variable• High-risk (e.g., injection drug users)

• Low-risk (e.g., health-care workers)

• Lower-risk (e.g., worried well)

Public health surveillance– Monitor incidence and prevalence to target and evaluate prevention

efforts

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Testing Practices

In 1998, CDC published recommendations that all screening-test positives undergo more specific testing– Broad educational programs targeted to physicians and other

health care providers Little impact on test ordering practices Substantial variation among laboratories in routine testing

algorithms– Many report screening test positive results only– Those that confirm use different methods (RIBA, NAT)

Without additional information, may not be able to determine true antibody or HCV infection status

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Anti-HCV Testing Practices of State and Territorial Public Health and VA Medical Center Laboratories, 2002

Tests offered n=43 n=67

Screening test 65% 100%

RIBA 38% 21%

Qualitative NAT 29% 75%

Quantitative NAT 13% 98%

Supplemental testing performed n=29 n=67

All screening-test-positive results 35% 22%

Low-positive screening-test results* 10% 3%

Only by physician request 17% 75%

None offered 38% 0%

* Signal to cut-off ratio below a specified value

Source: Werner B, APHL, 2002; Dufour R, VA, 2002

Testing Practices Public health VAMC

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Purpose of Laboratory Guidelines

Adoption of standard algorithm by all laboratories that perform in vitro diagnostic testing*– Ensure results reflect true antibody status– Independent of clinical information or origin of sample

Educate– Importance of more specific testing– Accurate interpretation of screening and supplemental results– When more specific testing should be performed– Which tests to use

Eliminate cost as barrier to more specific testing

* Not intended for screening or notification of donors

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Options for More Specific Testing When Anti-HCV Test Requested

Perform more specific testing on all screening-test positives; or

Use screening test positive signal to cutoff ratios to determine need for more specific testing – Cutoff performs the same regardless of the

population being tested

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Evaluation of Anti-HCV S/CO Ratios

Screening tests– Ortho 3.0 enzyme immunoassay (EIA) (n=25,532)– Abbott 2.0 EIA (N=8,754)– Ortho VITROS enhanced chemiluminescent assay

(CIA) (n=1326) More specific testing of screening-test positives– RIBA 3.0– NAT (Amplicor, Procleix, Nested RT-PCR)

Study Groups for Evaluating EIA and CIA S/Co Ratios by Prevalence of HCV Infection

0 5 10 15 20 25

Percentage Anti-HCV Positive

College students

Prison HCWs

Gen Population

STD patients

Hemodialysis

Selected for Risk 1187*

2066

6606

388

6340

* Number tested

>9000

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Proportion of Anti-HCV RR EIA Results Testing RIBA Positive by S/CO Ratio

0

20

40

60

80

100

1.0-<3.0 3.0-<3.5 3.5-<3.8 >3.8

Per

cent

RIB

A P

osit

ive

Students HCWs NHANES IV STD Dialysis Hi-risk

Source: MMWR 2003;52(No. RR-3):1-15.

(N=231) (N=18) (N=21) (N=765)

EIA S/CO Ratio

_

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Proportion of Anti-HCV EIA* Screening-Test Positives Testing RIBA or NAT Positive by Average S/Co Ratio

0

20

40

60

80

100

Per

cent

RIB

A o

r N

AT

P

osit

ive

<3.8 >3.8

Screening-test-positive average s/co ratio

Source: MMWR 2003;52(No. RR-3):1-15.

* EIA 2.0 or EIA 3.0

_

Group prevalence 2% 10% 25%

RIBA positive

NAT positive

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Proportion of Anti-HCV CIA* Screening Test Positives Testing RIBA Positive by S/Co Ratio

0

20

40

60

80

100

Per

cent

RIB

A P

osit

ive

1.0-7.9 8.0

Screening-test-positive s/co ratio

2% 10% >20%

Source: MMWR 2003;52(No. RR-3):1-15

* VITROS Anti-HCV assay

Prevalence

>

15

Proportion of Anti-HCV Screening Test Positives Requiring RIBA Based on Low S/Co

Ratiosby HCV Prevalence

0

5

10

15

20

25

30

35

Per

cent

Low

S/C

o R

atio

s

1-5% 10% >20%

HCV Prevalence

EIA <3.8 CIA <8.0

Source: MMWR 2003;52(No. RR-3):1-15

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Using Screening Test Positive S/Co Ratio to Determine Need For Additional Testing*

Positives with high s/co ratios can be reported based on screening test results alone– >95% will be RIBA positive

Only positives with low s/co ratios require additional testing (most falsely positive)– <20% will confirm positive

Limits cost while improving accuracy of reported results– <5% of high risk persons require additional testing

*Applies only to HCV EIA 2.0, HCV version 3.0 ELISA, and VITROS Anti-HCV

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Implementation

Determine reflex testing option to be used Revise SOP– Algorithm chosen– Procedure for reporting results– Provide interpretation of results with report

Educate staff and customers Modify requisition form

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Implications

Patients and physicians can reliably interpret results– Further clinical evaluation limited to true positives– Limit unnecessary medical visits and psychological

stress on patients who test falsely positive Substantially improve ability to establish

public health surveillance systems to monitor effect of prevention and intervention activities

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Interpretation of HCV Test Results

Screening RIBA for NAT for Anti-HCV HCV InfectionTest Anti-HCV HCV RNA Status Status

- NA* NA - None

* Not applicable

+ - NA - None

+ + Not done + Past/current

+ +/not done + + Current

+ Not done - Unknown Unknown†

† Single negative HCV RNA result cannot determine infection status

+ + - + Past/current§

§ HCV RNA can be intermittent; repeat HCV RNA

+ Not done Not done Unknown Unknown