Research ArticleComparison of Hepatitis C Virus Testing Strategies: Birth Cohort Versus Elevated Alanine Aminotransferase Levels
Introduction
An estimated 4 million people have previously been infected with hepatitis C virus (HCV) in the U.S.1 All individuals infected with HCV develop antibodies (anti-HCV) and about 75%–85% have evidence of HCV-RNA, indicating chronic (current) infection.1, 2 Most people living with HCV infection are adults in their late forties to late sixties and thought to have been infected 25–45 years ago.3, 4 Without testing and treatment over their lifetimes, the CDC estimates that 60% of people with HCV infection will develop cirrhosis.5
In 2007, HCV infection surpassed HIV as an underlying or contributing cause of mortality and accounted for more than 15,000 deaths in the U.S.6 It is projected that among adults with untreated HCV infection, 37% (1,071,000) will die from complications of hepatitis C in their lifetimes.5 Recent advances in direct-acting antiviral medications for HCV infection have increased cure rates to 90% in clinical trials.7, 8 However, any benefit from these new treatments requires identification of people with current infection.
Previous studies have estimated that 40%–85% of infected individuals may be undiagnosed and are not aware of their infection, methods to reduce the progression of their liver disease, or behavioral steps to avoid transmission.9, 10, 11, 12, 13, 14 Although risk-based testing can in principle identify approximately 79%–99% of HCV-infected people,1, 15, 16 it has been limited in its effectiveness in routine clinical practice.15, 17, 18, 19, 20, 21 For example, only 58%–63% of primary care providers inquire about patients’ history of risk factors for HCV infection.19, 20, 21 When probed, patients may not fully disclose past or current exposures.22, 23, 24, 25, 26
Additionally, an estimated 20%–30% of HCV-infected individuals do not report any risk factors and would not be identified by risk-based screening strategies.13, 14, 27 It has been suggested that provider motivation and the amount of clinical staff resources (e.g., time) required for adequate and sustainable evaluation of patients for risk factors may represent further limitations to risk-based testing.13, 28, 29
Alanine aminotransferase (ALT) is an enzyme produced by the liver that is a moderately sensitive indicator of liver injury when elevated; therefore, the CDC and the American Association for the Study of Liver Disease both recommend HCV testing for persons with elevated ALT levels.30, 31 Studies suggest that providers are more likely to test patients for HCV based on elevated ALT than on assessment of exposure risk factors.17, 32
The prevalence of HCV infection among individuals with elevated ALT levels may be several-fold higher compared with those with normal ALT levels.1, 10, 11, 33 Thus, it has been suggested that HCV testing based on abnormal ALT levels alone could be used to identify 56%–69% of asymptomatic anti-HCV-positive (anti-HCV+) people.30, 34 However, three recent studies9, 15, 35 in eight unique primary care settings found that of all people with elevated ALT, 43%–86% were not tested for anti-HCV.
Testing all individuals with elevated ALT would require that these levels be measured as part of routine care and providers have ready access to results; however, current literature35, 36, 37, 38 suggests that only an estimated 46% of patients are evaluated for liver function. The ALT strategy also has other limitations, including lack of a standard definition for the upper limit of normal (ULN)39, 40; sensitivity to demographic subgroups (i.e., gender, race/ethnicity)41, 42, 43, 44, 45, 46; alcohol consumption; fatty liver45; and the requirement for multiple tests over time to establish persistence.45, 47
In 2012, the CDC recommended a one-time HCV test48 for people born during 1945–1965, a high-prevalence cohort that is estimated to account for 67%–76% of adult HCV infections.1, 16, 49 The purpose of this analysis is to compare the sensitivity, number of identified cases, and size of the population that would be tested using either the birth cohort or elevated ALT testing strategy.
Section snippets
Study Population
The National Health and Nutrition Examination Survey (NHANES) is a cross-sectional, nationally representative, multistage, stratified probability cluster survey of the U.S civilian, non-institutionalized population. Each participant is interviewed and medically examined, during which biological specimens are collected for laboratory testing. Information on informed consent procedures, the survey design, and implementation is discussed in the survey documentation.50 Data collected from 1999 to
Participant Characteristics
The estimated interview response rate for adults aged 20–70 years from 1999 to 2008 was 76.4% (n=21,313/27,897) (Figure 1). Of the 21,313 participants who were interviewed, 20,341 (95.4%) were medically examined and 19,130 provided specimens for anti-HCV testing. The final analytic sample consisted of 19,055 participants (93.7% of those examined) following exclusion of participants with indeterminate anti-HCV results (n=75).
Characteristics of the study population are reported in Table 1. The
Discussion
Our findings indicate that targeting the high-prevalence birth cohort for HCV testing has the potential to identify about 1 million more anti-HCV+ people compared to a strategy based on a single elevated ALT result. The prevalence of anti-HCV within the birth cohort is about four times that in the adult population born before 1945 or after 1965, and using the birth cohort as the basis of anti-HCV testing would identify nearly 77% of anti-HCV cases in the U.S. adult population compared to 50%
Acknowledgments
The 50% sensitivity finding for the ALT strategy was previously published in support of the CDC’s recommendation to test people born during 1945–1965 for hepatitis C infection.
(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 CDC. Ann Intern Med 2012;157[11]:817–22.). Support for this paper was provided entirely by the CDC.
The findings and conclusions in this report are those of the authors
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