Weekly: May 10, 2013 / 62(18);362-365
On May 7, 2013, this report was posted as an MMWR Early Release on the MMWR website (http://www.cdc.gov/mmwr).
In the United States, an estimated 4.1 million persons have been
infected with hepatitis C virus (HCV), of whom an estimated 3.2 (95%
confidence interval [CI] = 2.7–3.9) million are living with the
New infections continue to be reported particularly among persons who
inject drugs and persons exposed to HCV-contaminated blood in
health-care settings with inadequate infection control (2).
Since 1998, CDC has recommended HCV testing for persons with risks for HCV infection (3). In 2003, CDC published guidelines for the laboratory testing and result reporting of antibody to HCV (4).
In 2012, CDC amended testing recommendations to include one-time HCV
testing for all persons born during 1945–1965 regardless of other risk
CDC is issuing this update in guidance because of 1) changes in
the availability of certain commercial HCV antibody tests, 2) evidence
that many persons who are identified as reactive by an HCV antibody test
might not subsequently be evaluated to determine if they have current
HCV infection (5), and 3) significant advances in the development of antiviral agents with improved efficacy against HCV (6). Although previous guidance has focused on strategies to detect and confirm HCV antibody (3,4),
reactive results from HCV antibody testing cannot distinguish between
persons whose past HCV infection has resolved and those who are
currently HCV infected. Persons with current infection who are not
identified as currently infected will not receive appropriate preventive
services, clinical evaluation, and medical treatment. Testing
strategies must ensure the identification of those persons with current
This guidance was written by a workgroup convened by CDC and the
Association of Public Health Laboratories (APHL), comprising experts
from CDC, APHL, state and local public health departments, and academic
and independent diagnostic testing laboratories, in consultation with
experts from the Veterans Health Administration and the Food and Drug
Administration (FDA). The workgroup reviewed laboratory capacities and
practices relating to HCV testing, data presented at the CDC 2011
symposium on identification, screening and surveillance of HCV infection
(7), and data from published scientific literature on HCV
testing. Unpublished data from the American Red Cross on validation of
HCV antibody testing also were reviewed.
Changes in HCV Testing Technologies
Since the 2003 guidance was published (4), there have been two developments with important implications for HCV testing:
- Availability of a rapid test for HCV antibody. The
OraQuick HCV Rapid Antibody Test (OraSure Technologies) is a rapid assay
for the presumptive detection of HCV antibody in fingerstick capillary
blood and venipuncture whole blood. Its sensitivity and specificity are
similar to those of FDA–approved, laboratory-conducted HCV antibody
assays (8). In 2011, a Clinical Laboratory Improvements
Amendments waiver was granted to the test by FDA. The waiver provides
wider testing access to persons at risk for HCV infection, permitting
use of the assay in nontraditional settings such as physician offices,
hospital emergency departments, health department clinics, and other
freestanding counseling and testing sites.
- Discontinuation of RIBA HCV. The Chiron RIBA HCV 3.0 Strip
Immunoblot Assay (Novartis Vaccines and Diagnostics) that was
for supplemental testing of blood samples after initial HCV antibody
testing is no longer available. As a result, the only other FDA-approved
supplemental tests for HCV infection are those that detect HCV viremia.
Identifying Current HCV Infections
In 2011, FDA approved boceprevir (Victrelis, Merck & Co.) and
telaprevir (Incivek, Vertex Pharmaceuticals) for treatment of chronic
hepatitis C genotype 1 infection, in combination with pegylated
interferon and ribavirin, in adult patients with compensated liver
disease. Boceprevir and telaprevir interfere directly with HCV
replication. Persons who complete treatment using either of these drugs
combined with pegylated interferon and ribavirin are more likely to
clear virus (i.e., have virologic cure), compared to those given
standard therapy based on pegylated interferon and ribavirin (9).
Viral clearance, when sustained, stops further spread of HCV and is
associated with reduced risk for hepatocellular carcinoma (10) and all-cause mortality (11). Other compounds under study in clinical trials hold promise for even more effective therapies (6).
Because antiviral treatment is intended for persons with current
HCV infection, these persons need to be distinguished from persons whose
infection has resolved. HCV RNA in blood, by nucleic acid testing
(NAT), is a marker for HCV viremia and is detected only in persons who
are currently infected. Persons with reactive results after HCV antibody
testing should be evaluated for the presence of HCV RNA in their blood.
Benefits of Testing for Current HCV Infection
Accurate testing to identify current infection is important to 1)
help clinicians and other providers correctly identify persons infected
with HCV, so that preventive services, care and treatment can be
offered; 2) notify tested persons of their infection status, enabling
them to make informed decisions about medical care and options for HCV
treatment, take measures to limit HCV-associated disease progression
(e.g., avoidance or reduction of alcohol intake, and vaccination against
hepatitis A and B), and minimize risk for transmitting HCV to others;
and 3) inform persons who are not currently infected of their status and
the fact that they are not infectious.
Recommended Testing Sequence
The testing sequence in this guidance is intended for use by
primary care and public health providers seeking to implement CDC
recommendations for HCV testing (1,3,4).
In most cases, persons identified with HCV viremia have chronic HCV
infection. This testing sequence is not intended for diagnosis of acute
hepatitis C or clinical evaluation of persons receiving specialist
medical care, for which specific guidance is available (12).
Testing for HCV infection begins with either a rapid or a laboratory-conducted assay for HCV antibody in blood (Figure).
A nonreactive HCV antibody result indicates no HCV antibody detected. A
reactive result indicates one of the following: 1) current HCV
infection, 2) past HCV infection that has resolved, or 3) false
positivity. A reactive result should be followed by NAT for HCV RNA. If
HCV RNA is detected, that indicates current HCV infection. If HCV RNA is
not detected, that indicates either past, resolved HCV infection, or
false HCV antibody positivity.
Initial Testing for HCV Antibody. An FDA-approved test for
HCV antibody should be used. If the OraQuick HCV Rapid Antibody Test is
used, the outcome is reported as reactive or nonreactive. If a
laboratory-based assay is used, the outcome is reported as reactive or
nonreactive without necessarily specifying signal-to-cutoff ratios.
Testing for HCV RNA. An FDA-approved NAT assay intended
for detection of HCV RNA in serum or plasma from blood of at-risk
patients who test reactive for HCV antibody should be used. There are
several possible operational steps toward NAT after initial testing for
- Blood from a subsequent venipuncture is submitted
for HCV NAT if the blood sample collected is reactive for HCV antibody
during initial testing.
- From a single venipuncture, two specimens are collected in
separate tubes: one tube for initial HCV antibody testing; and a second
tube for HCV NAT if the HCV antibody test is reactive.
- The same sample of venipuncture blood used for initial HCV
antibody testing, if reactive, is reflexed to HCV NAT without another
blood draw for NAT (13).
- A separate venipuncture blood sample is submitted for HCV NAT
if the OraQuick HCV Rapid Antibody Test for initial testing of HCV
antibody has used fingerstick blood.
Supplemental Testing for HCV Antibody
If testing is desired to distinguish between true positivity and
biologic false positivity for HCV antibody, then, testing may be done
with a second HCV antibody assay approved by FDA for diagnosis of HCV
infection that is different from the assay used for initial antibody
testing. HCV antibody assays vary according to their antigens, test
platforms, and performance characteristics, so biologic false positivity
is unlikely to be exhibited by more than one test when multiple tests
are used on a single specimen (14).
Test Interpretation and Further Action
“Acute hepatitis C” and “hepatitis C (past or present)” are
nationally notifiable conditions, and are subject to mandated reporting
to health departments by clinicians and laboratorians, as determined by
local, state or territorial law and regulation. Surveillance case
definitions are developed by the Council of State and Territorial
Epidemiologists in collaboration with CDC (15). In all but a few
jurisdictions, positive results from HCV antibody and HCV RNA testing
that are indicative of acute, or past or present HCV infection, are
reportable. Specific policies for laboratory reporting are found at
health department websites (16).
Research, development, validation, and cost-effectiveness studies
are ongoing to inform the best practices for detecting HCV viremia and
for distinguishing between resolved HCV infection and biologic false
positivity for HCV antibody in persons in whom HCV RNA is not detected.
Outcomes of these studies will provide comprehensive guidance on
testing, reporting, and clinical management, and will improve case
definitions for disease notification and surveillance.
Jane P. Getchell, DrPH, Kelly E. Wroblewski, MPH, Assn of
Public Health Laboratories. Alfred DeMaria Jr, MD, Massachusetts Dept of
Public Health. Christine L. Bean, PhD, New Hampshire Dept of Health.
Monica M. Parker, PhD, New York State Dept of Health. Mark Pandori, PhD,
San Francisco Dept of Public Health. D. Robert Dufour, MD, VA Medical
Center, Washington, DC. Michael P. Busch, MD, PhD, Blood Systems Inc.
Mark E. Brecher, MD, LabCorp. William A. Meyer, PhD, Rick L. Pesano, MD,
PhD, Quest Diagnostics. Chong-Gee Teo, MD, PhD, Geoffrey A. Beckett,
MPH, Aufra C. Araujo, PhD, Bernard M. Branson, MD, Jan Drobeniuc, MD,
PhD, Rikita Hatia, MPH, Scott D. Holmberg, MD, MPH, Saleem Kamili, PhD,
John W. Ward, MD, National Center for HIV/AIDS, Viral Hepatitis, STD,
and TB Prevention, CDC. Corresponding contributor: Chong-Gee Teo, email@example.com, 404-639-2378.
Recommendations for the identification of chronic hepatitis C virus
infection among persons born during 1945–1965. MMWR 2012;61(No. RR-4).
- CDC. Viral hepatitis surveillance, United States, 2009–2011.
Atlanta, GA: US Department of Health and Human Services, CDC; 2012.
Available at http://www.cdc.gov/hepatitis/statistics/2010surveillance/index.htm.
Recommendations for prevention and control of hepatitis C virus (HCV)
infection and HCV-related chronic disease. MMWR 1998;47(No. RR–19).
- CDC. Guidelines for laboratory testing and result reporting of antibody to hepatitis C virus. MMWR 2003;52(No. RR–3).
- CDC. Vital signs: evaluation of hepatitis C virus infection testing and reporting—eight U.S. sites, 2005–2011. MMWR 2013;62(18).
- Poordad F, Dieterich D. Treating hepatitis C: current standard
of care and emerging direct-acting antiviral agents. J Viral Hepat
- CDC. Viral Hepatitis Resource Center: 2011 HCV Symposium.
Atlanta, GA: US Department of Health and Human Services, CDC; 2011.
Available at http://www.cdc.gov/hepatitis/resources/mtgsconf/hcvsymposium2011.htm.
- Shivkumar S, Peeling R, Jafari Y, Joseph L, Pant Pai N.
Accuracy of rapid and point-of-care screening tests for hepatitis C: a
systematic review and meta-analysis. Ann Intern Med 2012;157:558–66.
- Cooper C, Lester R, Thorlund K, et al. Direct-acting antiviral
therapies for hepatitis C genotype 1 infection: a multiple treatment
comparison meta-analysis. QJM 2013;106:153–63.
- Morgan RL, Baack B, Smith BD, Yartel A, Pitasi M, Falck-Ytter
Y. Eradication of hepatitis C virus infection and the development of
hepatocellular carcinoma. A meta-analysis of observational studies. Ann
Intern Med 2013;158:329–37.
- Backus LI, Boothroyd DB, Phillips BR, Belperio P, Halloran J,
Mole LA. A sustained virologic response reduces risk of all-cause
mortality in patients with hepatitis C. Clin Gastroenterol Hepatol
- Ghany MG, Strader DB, Thomas DL, Seeff LB; American Association
for the Study of Liver Diseases. Diagnosis, management, and treatment
of hepatitis C: an update. Hepatology 2009;49:1335–74.
- Gale HB, Dufour DR, Qazi NN, Kan VL. Comparison of serial
hepatitis C virus detection in samples submitted through serology for
reflex confirmation versus samples directly submitted for quantitation. J
Clin Microbiol 2011;49:3036–9.
- Vermeersch P, Van Ranst M, Lagrou K. Validation of a strategy
for HCV antibody testing with two enzyme immunoassays in a routine
clinical laboratory. J Clin Virol 2008;42:394–8.
- CDC. MMWR: Public health resources—state health departments.
Atlanta, GA: US Department of Health and Human Services, CDC; 2011.
Available at: http://www.cdc.gov/mmwr/international/relres.html.
- CDC. 2013 National notifiable infectious conditions. Atlanta,
GA: US Department of Health and Human Services, CDC; 2012. Available at http://wwwn.cdc.gov/nndss/script/conditionlist.aspx?type=0&yr=2013.
FIGURE. Recommended testing sequence for identifying current hepatitis C virus (HCV) infection
Alternate Text: The figure above shows
recommended testing sequence for identifying current hepatitis C virus
(HCV) infection. Testing for HCV infection begins with either a rapid or
a laboratory-conducted assay for HCV antibody in blood. A nonre¬active
HCV antibody result indicates no HCV antibody detected. A reactive
result indicates one of the following: 1) current HCV infec¬tion, 2)
past HCV infection that has resolved, or 3) false positivity. A reactive
result should be followed by NAT for HCV RNA. If HCV RNA is detected,
that indicates current HCV infection. If HCV RNA is not detected, that
indicates either past, resolved HCV infection, or false HCV antibody
HCV antibody nonreactive
No HCV antibody detected
Sample can be reported as nonreactive for HCV antibody. No further action required.
If recent HCV exposure in person tested is suspected, test for HCV RNA.*
HCV antibody reactive
Presumptive HCV infection
A repeatedly reactive result is
consistent with current HCV infection, or past HCV infection that has
resolved, or biologic false positivity for HCV antibody. Test for HCV
RNA to identify current infection.
HCV antibody reactive,
HCV RNA detected
Current HCV infection
Provide person tested with appropriate counseling and link person tested to medical care and treatment.†
HCV antibody reactive,
HCV RNA not detected
No current HCV infection
No further action required in most cases.
If distinction between true
positivity and biologic false positivity for HCV antibody is desired,
and if sample is repeatedly reactive in the initial test, test with
another HCV antibody assay.
In certain situations§ follow up with HCV RNA testing and appropriate counseling.