Financial Support: Division of Viral Hepatitis at the CDC.
Potential Conflicts of Interest: None disclosed. Forms can be viewed at =M12-1787.
Requests for Single Reprints: Bryce D. Smith, PhD, 1600 Clifton Road, MS G-37, Atlanta, GA 30333; e-mail, BSmith6@cdc.gov.
Current Author Addresses: Drs. Smith, Holtzman, and Ward; Ms. Morgan; and Mr. Beckett: 1600 Clifton Road, MS G-37, Atlanta, GA 30333.
Dr. Falck-Ytter: 10701 East Boulevard, Cleveland, OH 44106.
Author Contributions: Conception and design: B.D. Smith, R.L. Morgan, G.A. Beckett, Y. Falck-Ytter, J.W. Ward.
Analysis and interpretation of the data: B.D. Smith, R.L. Morgan, G.A. Beckett, Y. Falck-Ytter, D. Holtzman.
Drafting of the article: B.D. Smith, R.L. Morgan, G.A. Beckett.
Critical revision of the article for important intellectual content: B.D. Smith, R.L. Morgan, G.A. Beckett, Y. Falck-Ytter, D. Holtzman, J.W. Ward.
Final approval of the article: B.D. Smith, R.L. Morgan, D. Holtzman, J.W. Ward.
Statistical expertise: R.L. Morgan, Y. Falck-Ytter.
Obtaining of funding: J.W. Ward.
Administrative, technical, or logistic support: R.L. Morgan.
Collection and assembly of data: R.L. Morgan, Y. Falck-Ytter.
The Centers for Disease Control and Prevention (CDC) and a group of governmental and private sector partners developed these evidence-based recommendations to increase the proportion of hepatitis C virus (HCV)–infected persons who know their status and are linked to appropriate care and treatment. The recommendations also address brief alcohol screening, as alcohol accelerates progression of liver disease among HCV-infected individuals. These recommendations augment CDC's 1998 and 1999 recommendations based on risk and medical indications and are not meant to replace those recommendations.
These recommendations are based on systematic reviews of evidence published from 1995 through February 2012 in MEDLINE, EMBASE, CINAHL, the Cochrane Central Register of Controlled Trials, Sociological Abstracts, and Database of Abstracts of Reviews of Effects. Selected studies included cross-sectional and cohort studies that addressed either prevalence of hepatitis C in the United States or clinical outcomes (for example, hepatocellular carcinoma and serious adverse events) among treated patients and systematic reviews of trials that assessed effectiveness of brief screening interventions for alcohol consumption. The Grading of Recommendations Assessment, Development, and Evaluation framework was used to assess quality of the evidence.
Adults born during 1945–1965 should receive 1-time testing for HCV without prior ascertainment of HCV risk. (Grade: strong recommendation; moderate-quality evidence).
All persons with identified HCV infection should receive a brief alcohol screening and intervention as clinically indicated, followed by referral to appropriate care and treatment services for HCV infection and related conditions (Grade: strong recommendation; moderate-quality evidence).
The Hepatitis C virus (HCV) screening guideline recently released by the Centers for Disease Control and Prevention (CDC) promotes universal screening of all persons born during 1945-1965. (1,2) While this strategy will lead to the identification of the many previously undiagnosed persons who are chronically infected with HCV, it will also lead to many persons being falsely diagnosed with past Hepatitis C infection. Per a 2003 CDC HCV testing guideline, the proportion of false-positive HCV antibody test results among immunocompetent populations with anti-HCV prevalences <10% averages approximately 35% (range: 15%--60%). This testing guideline warns that “not relying exclusively on anti-HCV screening-test--positive results to determine whether a person has been infected with HCV is critical” and recommends that all screening positive results be verified with a “supplemental test with high specificity”. (3) While the HCV nucleic acid test (NAT) test, which is currently recommended for confirmation, can distinguish between active and past infection, it cannot distinguish between true and false positives. The HCV recombinant immunoblot assay (RIBA) test, which can verify true infection, is unfortunately unavailable in the United States.Although the CDC guideline acknowledges that certain harms (“worry or anxiety while waiting for test results, insurability”) can result from universal screening, it does not address the very real harm of false diagnosis (with implications regarding past or present risk behaviors), which can occur in 1/3 of persons who test positive. Furthermore, the current guideline published in the MMWR does not even consider the possibility of false positives, stating that “a person whose anti-HCV test is reactive should be considered to either 1) have current HCV infection or 2) have had HCV infection in the past that has subsequently resolved (i.e., cleared)”. (2) At the very least, prior to adopting universal screening by utilizing a highly sensitive HCV antibody test with no highly specific confirmatory test, physicians need to be provided with accurate information regarding the interpretation of HCV antibody tests, so as to be able to appropriately counsel patients who test HCV antibody positive.
The recent recommendations by the CDC (1) expanded screening for hepatitis C virus from those with increased risk for the infection to include the entire age cohort born during 1945 to 1965. This recommendation was based on the relatively high risk of the infection in this age cohort. Consideration was given to benefit vs risk for the individual patient as well as a cost analysis for screening the age cohort population (2). However, the cost analysis should have been performed for a different population. The cost analysis should have been performed for the group that was added to the screening recommendations, which is those in the age cohort who are not at increased risk of infection.In this age cohort there is a relatively high incidence of HCV, however, a large portion of the infected group is derived from the relatively small group of those who are at high risk. Although a number of risk factors are listed, an earlier study (3) reported that for persons between the ages of 20 and 59, half of the risk for HCV infection comes from the 1.1% who had ever injected illicit drugs. Adding the 3.4% who received a transfusion before 1992 and the 6.1% with 20 or more lifetime sex partners, accounts for three-quarters of the risk of HCV infection. With the addition of testing those with an elevated ALT level, 93.5% of the HCV infected population would be identified.In justifying the new guidelines, the CDC states that the accuracy of patient recall of risk behaviors decreases over time, but this assumption is based on a meta-analysis about HIV infected patients which compared 1, 3 and 6 month recall (4). Interestingly, for ‘heroin use’ and ‘number of sex partners’ the 6 month recall was the best. This assumption of poor recall for healthy patients being considered for HCV screening is not adequately evidence based. I for one, born in 1956, am confident that I would remember if I ever injected drugs, received a blood transfusion or had 20 or more sex partners. If the high risk group is excluded from the age cohort, the result is a large population with a low risk of infection. I suspect that a cost analysis of screening for HCV of this low risk population would find that it would not be cost effective. In addition, the benefit vs risk of screening this low risk population would need to be considered.The key point is that the CDC has added this large population, those in that age cohort born during 1945 to 1965 who are not at increased risk, to their recommendations for HCV screening. This recommendation would result in the screening of millions of additional persons and cost billions of dollars. Before this step is taken cost-effectiveness studies and benefit vs risk analyses should be performed for this low risk population. At this point it is not clear what screening recommendation should be given to an individual patient who reliably claims not to be at increased risk of HCV.
We agree with Dr. Lynn’s assertion that effective screening for history of injection drug use, receipt of blood products before 1992, and testing for elevated alanine aminotransferase (ALT) levels would identify the majority of chronic hepatitis C virus (HCV) infections among persons born during 1945-1965. Indeed, CDC has recommended risk-based screening since 1998.(1) Unfortunately, risk-based screening alone has had limited success as 45%-85% of infected persons are unaware of their infection.(2) Not only are persons unaware of having had a risk that led to infection, studies also have shown that physicians often do not ask their patients about risk behaviors, especially those considered sensitive. Furthermore, even when ALT levels are persistently elevated, only a minority of patients are tested for HCV.(3, 4) Risk-based testing alone is insufficient to reduce HCV-associated morbidity and mortality, currently on the rise in the United States. Augmenting risk-based testing with testing of the 1945-1965 birth cohort, a population accounting for 76% of persons who have been infected with HCV, is thus a reasonable strategy to overcome the problems of patient disclosure and physician reluctance to solicit risk information.(5) Dr. Lynn also asserts that the cost effectiveness analysis (CEA) should have been based on a birth-cohort population that excluded persons at high risk of infection. Because birth-cohort testing applies to persons at all levels of risk born during those years, exclusion of persons at high risk from the CEA model would be inappropriate. The model that CDC developed is most sensitive to the high costs of treatment. In our sensitivity analysis, the costs of testing account for only about 10% of the total cost of the intervention and therefore have a relatively small effect on the cost effectiveness of the intervention.(6) While there would be an incremental decrease in the cost effectiveness if fewer persons were tested, the difference would not be sufficient to change the conclusion that the overall intervention is cost effective. Another challenge is the lack of data on the proportion of high-risk persons who have not yet been tested, limiting our ability to estimate the number of persons who would be tested.
Dr. Back expresses concern that implementation of the recommendation would result in many persons receiving false-positive diagnoses of HCV infection. However, 2003 guidelines for laboratory testing and result reporting of antibody to HCV have recommended following a weak reactive HCV antibody test with a recombinant immunoblot assay (RIBA) to confirm antibody status, thus minimizing the occurrence of false antibody positives (7). Because, as Dr. Back notes, RIBA is not currently available, CDC is recommending the use of a HCV RNA test, thus focusing on identification of HCV viremia rather than antibody positivity. In this way, the presence of current HCV infection can be determined. Testing to detect current HCV infection is a two-step process: 1) HCV antibody tests identify persons exposed to HCV (but does not determine active infection status), and 2) HCV RNA testing (using Nucleic Acid Tests) determines if someone is currently infected. Therefore, an anti-HCV positive result that is HCV RNA negative cannot be a false-positive diagnosis of infection since the interpretation of those results is that the patient is not infected. CDC’s recent birth cohort recommendation shifts the focus away from HCV antibody to identification of infection as this provides clinically actionable data. Identification of current infection is the first step required to provide counseling messages that can reduce the risk of transmission to others, slow fibrosis progression and evaluate clinical markers to make decisions regarding the provision of treatment to reduce HCV-related morbidity and mortality.
7. CDC. Guidelines for laboratory testing and result reporting of antibody to hepatitis C virus. MMWR 2003;52(No. RR-3):1-24.
Smith BD, Morgan RL, Beckett GA, Falck-Ytter Y, Holtzman D, Ward JW. Hepatitis C Virus Testing of Persons Born During 1945–1965: Recommendations From the Centers for Disease Control and Prevention. Ann Intern Med. 2012;157:817–822. doi: 10.7326/0003-4819-157-9-201211060-00529