Bryce D. Smith, PhD; Rebecca L. Morgan, MPH; Geoff A. Beckett, PA-C, MPH; Yngve Falck-Ytter, MD; Deborah Holtzman, PhD; John W. Ward, MD
This article was published at www.annals.org on 16 August 2012.
Acknowledgment: The authors thank David Meyers, MD, Agency for Healthcare Research and Quality, for his editorial assistance.
Financial Support: Division of Viral Hepatitis at the CDC.
Potential Conflicts of Interest: None disclosed. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=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.
Smith B., Morgan R., Beckett G., Falck-Ytter Y., Holtzman D., Ward J.; 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
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Published: Ann Intern Med. 2012;157(11):817-822.
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 Centers for Disease Control and Prevention (CDC) estimates that 3.4 to 4.9 million persons have ever been infected with hepatitis C virus (HCV) in the United States (1). All of these persons develop HCV antibodies (anti-HCV), and approximately 75% develop a chronic infection. This results in an estimated 2.7 to 3.9 million persons living with HCV infection in the United States (1). Incidence of HCV increased markedly during the 1970s and 1980s, reaching an average of 230 000 new infections each year throughout the 1980s (2). Incidence declined rapidly in the 1990s because of effective screening of blood donors starting in 1992 and reduced numbers of new infections among persons who inject drugs. Incidence declined until 2006 and has since remained stable, with an estimated 17 000 new infections in 2010 (2). Those who were infected in the remote past have been living with HCV infection for 20 to 40 years and are at increased risk for HCV-related morbidity and mortality.
Hepatitis C virus infection is the leading indication for liver transplantation (3–6) and accounts for more than 50% of incident hepatocellular carcinoma (HCC), (7) the fastest-growing cause of cancer-related death in the United States (8). Annual HCV-associated mortality in the United States increased over 50% from 1999 to 2007. Data from death certificates show that HCV-associated deaths are now more frequent than deaths caused by HIV (9). Modeling studies forecast substantial increases in morbidity and mortality among HCV-infected persons as they enter into their third, fourth, and fifth decades of living with infection (10, 11). The CDC estimates that without diagnosis and treatment 1.76 million persons with HCV infection will develop cirrhosis during their lifetimes, over 400 000 will develop HCC, and over 1 million will die from HCV-associated disease (10).
In 1998, the CDC issued recommendations for identifying HCV-infected persons (12). Testing for HCV was recommended for persons most likely to be infected, including those who had ever injected drugs, received clotting factor concentrates produced before 1987, ever received long-term hemodialysis, had laboratory evidence of liver disease (persistently elevated alanine aminotransferase levels), or received transfusions of blood or blood components or organ transplants before July 1992. Screening also was recommended for persons who had a recognized blood exposure (health care, emergency medical, and public safety workers after sticks from needles or sharps or mucosal exposure, and children born to HCV-infected mothers). In 1999, HCV testing was recommended for persons infected with HIV (13).
The success of risk-based testing strategies has been limited. Depending on the level of risk in the population and site-specific testing practices, an estimated 45% to 85% of U.S. adults are chronically infected with HCV yet unaware of their condition (14–17). Testing for HCV seromarkers is suboptimal even among high-risk populations for whom routine testing is recommended (18, 19). A sizeable percentage of these persons remain unaware of their infection status (20).
Hepatitis C virus infection is typically asymptomatic until significant liver disease occurs, so a primary care clinician would have few reasons to order diagnostic tests on the basis of patient presentation. If all persons with a single elevated alanine aminotransferase level were tested for HCV, approximately 50% of chronic cases would remain unidentified (21) and 20% to 30% of infected persons with persistently normal alanine aminotransferase levels develop serious liver disease (22). In addition, many health care providers lack knowledge about the prevalence, natural history, diagnostic tests, testing algorithms, and management of HCV infection (18, 19, 23), and accuracy of patient recall of risk behaviors, including drug use, decreases over time (24).
Because of the limited effectiveness of the current HCV testing recommendations alone in identifying undiagnosed infections, the CDC considered a birth year–based HCV testing strategy to increase the proportion of infected persons who know their HCV infection status: 1-time HCV testing of persons born during 1945–1965. These persons account for 76.5% of all prevalence of those with HCV antibodies (25). Because alcohol accelerates progression of liver disease in HCV-infected persons (26), the CDC also addressed brief alcohol screening for those with HCV infection (27).
The target population was adults born or living in the United States. Efforts were focused on identifying testing strategies that would increase the proportion of HCV-infected persons who know their status. In particular, the CDC examined whether a testing strategy based on year of birth would identify persons living with HCV infection who have not been identified by risk-based testing. The CDC also considered 1) associations between achieving a sustained virologic response (SVR) with treatment and clinical outcomes and 2) potential effectiveness and benefits of offering brief alcohol interventions to HCV-infected persons.
A 35-member workgroup comprising persons within the CDC's Division of Viral Hepatitis; members of other federal agencies; representatives from local and state health departments and from advocacy, community, and professional groups; clinicians; and methodologists guided the development of the recommendations. Table 1 shows the questions that were asked.
Questions to Guide the Development of Recommendations
Two independent reviewers searched multiple databases to identify English-language studies pertinent to the questions. For prevalence data, we selected cross-sectional and cohort studies with data relevant to the United States that had been identified through searches of the following databases between 1995 and May 2011: MEDLINE, EMBASE, CINAHL, the Cochrane Central Register of Controlled Trials, Sociological Abstracts, and the Database of Abstracts of Reviews of Effects. We searched the same databases through February 2012 to identify studies that examined the association of HCC with HCV treatment among persons who achieved an SVR compared with those who did not. To identify observational studies and controlled trials with data related to mortality, serious adverse events, and quality of life (QOL) among treated HCV-infected persons, we conducted a series of MEDLINE searches from database inception through July 2011. For evidence related to effective alcohol screening and counseling interventions, we selected systematic reviews or meta-analyses of trials that were identified in MEDLINE searches through July 2011.
The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework was used to develop these recommendations (28). Two investigators with experience using this framework independently produced evidence tables and profiles for each question. The criteria considered when determining the quality of the evidence were risk of bias, imprecision, indirectness (for example, addressing a different population than the one under consideration), inconsistency of results, publication bias, dose–response effect, magnitude of the effect, and plausible confounders. The final quality of evidence for the outcomes was categorized into 1 of 4 levels: very low, low, moderate, and high.
To determine the strength of the recommendations, the 9 workgroup members from the Division of Viral Hepatitis and the external workgroup assessed the quality of evidence, benefits and harms, values and preferences (of persons being targeted for testing), and resource implications before arriving at a consensus on the recommendations. These workgroup members have expertise in hepatitis C prevention, epidemiology, education and training, and research and evaluation, as well as in the GRADE framework. Recommendations can be categorized into strongly for or against the recommendation or conditionally for or against the recommendation.
The draft recommendations went through a peer-review and public-comment process. For peer review, 3 experts in the field of viral hepatitis, who had not been involved with the recommendation development process, commented on the draft recommendation. The draft recommendations were externally posted on the Federal Register Management System (www.regulations.gov) for public comment from 22 May to 8 June 2012. Modifications were made to the document on the basis of the comments received. Most comments requested additional information on the mode of transmission and methodological framework used to grade the evidence.
Recommendation 1: The CDC recommends that adults born during 1945–1965 should receive 1-time testing for HCV without prior ascertainment of HCV risk. (Grade: strong recommendation; moderate-quality evidence).
Of 31 studies that addressed the prevalence of HCV infection in the United States, 3 involved nationally representative samples and provided evidence directly related to the populations of comparison: persons born during 1945–1965 living in the United States and the general population (1, 29, 30). These studies, as well as a recent CDC analysis of 1999 to 2008 NHANES (National Health and Nutrition Examination Survey) data, found that the proportion of persons born during 1945–1965 with HCV antibody was higher than that of the general population. The NHANES analysis specifically found that that the anti-HCV prevalence in the 1945–1965 birth cohort was 3.25%, which was substantially higher than that among adults aged 20 years or older who were born outside of the birth cohort (0.80%) (26).
Several studies examined treatment effectiveness and the relationship between achieving an SVR with treatment and clinical outcomes. Of note, among persons with chronic HCV infection, spontaneous viral clearance is highly unlikely and SVR can currently be achieved only by an interferon-based treatment regimen. Newer direct-acting antiviral agents increase the chance of SVR from an average of 41.3% for pegylated interferon and ribavirin therapy to nearly 70% with triple therapy (pooled risk difference, 28% [95% CI, 24% to 32%] [data not shown]) (30–35).
One observational study (36) providing the highest-quality evidence available relevant to HCV infection–related mortality among persons born during 1945–1965 found that achieving SVR with treatment was associated with lower risk for all-cause mortality (pooled unadjusted relative risk, 0.46 [CI, 0.41 to 0.51]). The study compared persons who responded to therapy with those who did not. It did not address a screened population or an untreated population. Differences in stage of liver disease between the groups had the potential to bias findings. However, adjusted analysis for baseline prognostic factors, including the presence of cirrhosis, showed a significant association between lower risk for mortality and SVR in patients with genotype 1 (relative risk, 0.70 [CI, 0.59 to 0.83]); lower risk for mortality associated with SVR also was observed among patients with genotypes 2 and 3.
We found 30 observational studies that examined the relationship between achieving SVR with treatment and developing HCC. Our meta-analysis of these data found that achieving a treatment-related SVR was associated with a reduction in the risk for HCC among persons at all stages of liver disease (adjusted hazard ratio, 0.24 [CI, 0.18 to 0.31]), as well as among those with advanced liver disease (adjusted hazard ratio, 0.23 [CI, 0.16 to 0.35]) (36). We rated the certainty of these findings as moderate-quality evidence because of the large magnitude of effect.
Studies report that many adverse events associated with HCV treatment can lead to treatment discontinuation or other illnesses. Typical adverse events include infections, anemia, rash, pruritus, disabling fatigue, fever, nausea, diarrhea, muscle aches, and mood disorders that can rarely lead to suicides. More than 98% of patients undergoing treatment have at least 1 adverse event; however, almost all adverse events resolve when therapy is discontinued (35). Adding new direct-acting antiviral agents increases the risk for adverse events which can lead to discontinuation of treatment (relative risk, 1.34 [CI, 0.95 to 1.87] [data not shown]) (30–35).
One previously published systematic review examined the effect of HCV testing and treatment on patients' QOL (37). Based on the Short Form-36 vitality subscore, patients receiving testing and treatment had a mean QOL score that was 6.6 points higher than that of patients in the control group, suggesting that those who received testing and treatment had a higher QOL (Table 2).
GRADE Evidence Profile for HCV Testing Followed by Antiviral Treatment Versus No Antiviral Treatment
A 1-time HCV test of persons born during 1945–1965 was found to be cost-effective at $35 700 per quality-adjusted life-year gained, similar to screening for colorectal cancer, breast cancer, and cervical cancer (38). Average testing costs (including antibody testing, nucleic acid testing for persons who are antibody-positive, and posttest counseling) were estimated to be $54 per person, and treatment costs averaged $60 292 for genotype 1 and $12 080 for genotypes 2 and 3 (38).
Recommendation 2: The CDC recommends that all persons identified with 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).
A meta-analysis of 22 randomized, controlled trials published in 2010 examined the effects of a brief alcohol intervention versus no intervention on reduction of alcohol use (39). Patients who had a brief intervention to reduce alcohol consumption had a mean reduction of alcohol consumed per week of 38.42 g (CI, 30.91 to 65.44 g) compared with those in the control group. We rated this evidence moderate quality due to indirectness because the studies did not specifically examine patients with HCV infection (Table 3).
GRADE Evidence Profile for Brief Alcohol Screening and Intervention
The CDC now recommends 1-time HCV testing for all persons born during 1945–1965 (27). These recommendations augment the CDC's 1998 and 1999 recommendations based on risk and medical indications and are not meant to replace them. We judged that the benefits of testing and treating persons with HCV infection are greater than the harms. Although certain harms (that is, worry or anxiety while waiting for test results, insurability, liver biopsy complications, and severe adverse events during treatment) can be detrimental to patients, the benefits associated with diagnosis and effective treatment include SVR, which is associated with significant reductions in HCC and all-cause mortality.
The CDC also recommends that all infected persons receive alcohol screening and counseling as indicated. Brief alcohol screenings are effective in reducing alcohol use and maintaining that reduction for 1 year or more. Because alcohol is known to accelerate progression of HCV-associated liver disease (27), screening to evaluate the level of alcohol consumption followed by counseling to reduce or cease alcohol use can avoid this acceleration. Screening tools shown to be effective in eliciting history of alcohol use from patients include the Alcohol Use Disorders Identification Test and are available from the National Institute on Alcohol Abuse and Alcoholism (http://pubs.niaaa.nih.gov/publications/Practitioner/CliniciansGuide2005/clinicians_guide.htm). The World Health Organization has published intervention tools to help patients reduce alcohol use (www.who.int/substance_abuse/activities/sbi/en/index.html). Although the screening and intervention may be uncomfortable or cause anxiety, the benefits of alcohol reduction for persons with HCV infection outweigh those harms. Finally, the CDC recommends that all infected persons receive medical care (for example, hepatitis A and B virus vaccinations as needed and medical monitoring of disease progression), but detailed care and treatment recommendations are beyond the scope of these guidelines. The patient and provider should make treatment decisions considering such factors as disease stage, genotype, comorbid conditions, and adverse events of therapy.
The U.S. Preventive Services Task Force (USPSTF) and the CDC both issue preventive recommendations using evidence-based methods that include evaluating available data on a topic and drawing conclusions on the basis of the strength of the evidence. However, several differences exist between the organizations, including their affiliation, target audience, and scope. Congress created the USPSTF in 1984 as an independent panel of clinical experts to evaluate and make recommendations for preventive services to be delivered in the context of primary care. The USPSTF is not a government agency—it makes recommendations that are independent of the Department of Health and Human Services. The CDC is an operating division of the Department of Health and Human Services and clears all preventive recommendations with other Department of Health and Human Services agencies as appropriate. The USPSTF focuses on the primary care setting and provider–patient interactions and considers the harms and benefits (generally, reduced morbidity and mortality) to the patient directly resulting from a given intervention. The CDC has a broader public health focus that includes diverse settings outside of primary care and considers not only the benefits and harms of an intervention but also the potential harms of an absence of public health action and of future transmission of disease.
The USPSTF's 2004 HCV screening recommendations and the CDC's birth cohort recommendation are not directly comparable; updated USPSTF recommendations are expected within a year. In 2004, the USPSTF found insufficient evidence to recommend for or against HCV screening among high-risk persons (for example, persons who have ever injected drugs) and against routine testing for all asymptomatic adults (40). The CDC's recommendation for 1-time HCV testing is only for persons born during 1945–1965, not for all adults. The CDC's recommendation is, to a large degree, built on an intermediate measure (SVR) and its strong association with reductions in HCC and all-cause mortality.
The USPSTF prefers data from randomized, controlled trials that begin with randomization into screened and nonscreened groups and follow participants through to morbidity and mortality, but these data are not available. Although these types of studies provide the most conclusive evidence about the benefits and harms of a screening intervention, they also are resource-intensive and require long periods of follow-up. The CDC based its HCV testing recommendations on the prevalence in the target population, the many persons who are unaware of their infection status, potential benefits of care and treatment, and projections of increasing morbidity and mortality in the absence of an intervention.
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Ephraim Back, MD,MPH
December 31, 2012
CDC Hepatitis C screening guideline does not address high percentage of patients who will test false positive
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.
1. 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.
2. Centers for Disease Control and Prevention. Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945-1965. MMWR Recomm Rep. 2012;61 (RR-4):1-32.
3. Centers for Disease Control and Prevention. Guidelines for laboratory testing and result reporting of antibody to hepatitis C virus. MMWR Recomm Rep. 2003;52(RR–3):1-16.
Ephraim Back, MD,MPHChairmanDepartment of Family MedicineEllis MedicineSchenectady, NYbacke@ellismedicine.org
Richard B. Lynn, MD
American College of Physicians
January 2, 2013
Should patients at low risk of HCV infection be screened?
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.
1. Smith BD, Morgan RL, Beckett GA, Falck-Ytter Y, Holtzman D, Ward JW. Hepatitis C virus testing of persons born during 1945 to 1965: Recommendations from the Centers for Disease Control and Prevention. Ann Intern Med. 2012;157:817-822. [PMID:22910836]
2. Rein DB, Smith BD, Wittenborn JS, Lesesne SB, Wagner LD, Robin DW, Patel N, Ward JW, Weinbaum CM. The cost-effectiveness of birth-cohort screening for hepatitis C antibody in U.S. primary care settings. Ann Intern Med. 2012;156:263-270. [PMID: 22056542]
3. Armstrong GL, Wasley A, Simard EP, McQuillan GM, Kuhmert WL, Alter MJ. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med. 2006;144:705-714. [PMID: 16702586]
4. Napper LE, Fisher DG, Reynolds GL, Johnson ME. HIV risk behavior self-report reliability at different recall periods. AIDS Behav. 2010;14:152-61. [PMID: 19475504]
Bryce Smith, MD
March 13, 2013
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.
1. CDC. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. MMWR Recomm Rep. 1998;47(No. RR-19):1-39.
2. CDC. Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945-1965. MMWR Recomm Rep. 2012;61(RR-4):1-32.
3. Spradling PR, Rupp L, Moorman AC, Lu M, Teshale EH, Gordon SC, et al. Hepatitis B and C Virus Infection Among 1.2 Million Persons With Access to Care: Factors Associated With Testing and Infection Prevalence. Clin Infect Dis. 2012;55(8):1047-55
4. Rein DB, Wagner D, Brown K, Fallon M, Federman A, Massoud, Smith BD. Hepatitis C Antibody Testing and Follow-up in Primary Care Settings: A Retrospective Study of Four Large, Primary Care Service Centers Infection among Persons Born during 1945-1965 in the United States. National Summit on HIV and Viral Hepatitis Diagnosis, Prevention and Access to Care, Washington, DC, 2012.
5. Smith BD, Patel, N., Beckett, G., Ward, J.W. (2011). Comparison of Hepatitis C Virus Infection Screening Strategies: Elevated Alanine Aminotransferase Levels versus Birth Cohort. Presented at the American Association for the Study of Liver Disease Liver Meeting, San Francisco, CA.
6. Rein DB, Smith BD, Wittenborn JS, Lesesne SB, Wagner LD, Roblin DW, Patel N and Weinbaum CM. The cost-effectiveness of birth year-based and universal hepatitis C screening and indicated treatment in the United States. Annals of Internal Medicine 2012;156(4):263-70. Epub 2011 Nov 4.
7. CDC. Guidelines for laboratory testing and result reporting of antibody to hepatitis C virus. MMWR 2003;52(No. RR-3):1-24.
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