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Hepatitis C virus (HCV) infection is unidentified in an estimated 40%–85% of infected adults. Surveillance and modeling data have found significant increases in HCV-associated morbidity and mortality.
Purpose
To compare two HCV antibody (anti-HCV) testing strategies based on (1) elevated alanine aminotransferase levels (ALT) and (2) a birth cohort approach for people born during 1945–1965.
Methods
Data from 19,055 adults aged 20–70 years who completed the National Health and Nutrition Examination Survey in 1999–2008 were analyzed in 2013. Two independent models were evaluated, based on membership in the 1945–1965 birth cohort or elevated ALT, to compare the number of identified anti-HCV-positive (anti-HCV+) individuals; proportion of total identified cases; and the number of people that would be tested using either strategy.
Results
The prevalence of anti-HCV among adults aged 20–70 years was estimated at 2.0% (95% CI=1.8%, 2.3%), representing about 3.6 million people. The birth cohort strategy would result in testing about 85.4 million people and identifying nearly 2.8 million anti-HCV+ people with a sensitivity of 76.6%. The ALT strategy would test about 21.5 million adults and identify approximately 1.8 million anti-HCV+ people with a sensitivity of 50.0%. Implementing both strategies concurrently would identify 87.3% of anti-HCV+ adults.
Conclusions
The birth cohort strategy, which is recommended by both the CDC and the U.S. Preventive Services Task Force, would identify 1 million more anti-HCV+ people than the elevated ALT approach. Concurrent implementation would identify an even larger number of individuals ever infected.
Introduction
An estimated 4 million people have previously been infected with hepatitis C virus (HCV) in the U.S.
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.
Galbraith JW, Franco R, Rodgers J, et al. Screening in emergency department identifies a large cohort of unrecognized chronic hepatitis C virus. Paper presented at the 64th Annual Meeting of the American Association for the Study of Liver Diseases; 2013 Nov 1–5; Washington DC.
Barriers to and facilitators of hepatitis C testing, management, and treatment among current and former injecting drug users: a qualitative exploration.
Batki S, Sorensen J. Care of injection drug users with HIV. In: Cohen PT, Sande MA, Volberding P, eds. The AIDS knowledge base: a textbook on HIV disease from the University of California, San Francisco and San Francisco General Hospital. 3rd ed. Philadelphia PA. Lippincott, Williams, & Wilkins, 1999.
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.
Galbraith JW, Franco R, Rodgers J, et al. Screening in emergency department identifies a large cohort of unrecognized chronic hepatitis C virus. Paper presented at the 64th Annual Meeting of the American Association for the Study of Liver Diseases; 2013 Nov 1–5; Washington DC.
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.
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.
Public Policy Committee of the American Association for the Study of Liver Disease. Serum activity of alanine aminotransferase (ALT) as an indicator of health and disease.
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.
Public Policy Committee of the American Association for the Study of Liver Disease. Serum activity of alanine aminotransferase (ALT) as an indicator of health and disease.
Rein DB, Wagner D, Brown K, et al. 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 U.S. National Summit on HIV and Viral Hepatitis Diagnosis, Prevention and Access to Care; 2012 Nov 26–28; Washington DC.
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 literature
Rein DB, Wagner D, Brown K, et al. 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 U.S. National Summit on HIV and Viral Hepatitis Diagnosis, Prevention and Access to Care; 2012 Nov 26–28; Washington DC.
Should patients with abnormal liver function tests in primary care be tested for chronic viral hepatitis: cost minimisation analysis based on a comprehensively tested cohort. BMC.
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)
Nonalcoholic Steatohepatitis Clinical Research Network. Influence of local reference populations on upper limits of normal for serum alanine aminotransferase levels.
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.
Methods
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.
Data collected from 1999 to 2008 were analyzed. Analysis was restricted to participants aged 20–70 years at the time of survey who were interviewed, medically examined, and provided samples for anti-HCV testing. Participants without specimens for testing and those with indeterminate anti-HCV test results were excluded from the final analytic sample.
Outcome Variable
The outcome measure was anti-HCV prevalence as determined by serologic testing. Specimens were tested for HCV antibodies by repeated enzyme-linked immunosorbent assay (ELISA version 3.0; Ortho Diagnostic Systems, Inc., Raritan NJ). All anti-HCV+ specimens were confirmed by recombinant immunoblot assay (RIBA version 3.0; Chiron Corporation, Emeryville CA). Participants who tested positive by both ELISA and RIBA were considered anti-HCV+. Further, HCV-RNA testing results were not available for all cycles of NHANES and were not included in this study.
Anti-HCV Testing Variables
Participants’ birth year and ALT levels were selected as the variables for evaluation of anti-HCV testing strategies. Birth year was estimated by subtracting participant age at time of survey from the estimated year in which the participant was surveyed.
Persons with birth year 1945–1965 were classified as being within the birth cohort. Elevated ALT was defined as ≥40 IU/L based on a one-time measurement of serum ALT activity (Hitachi 917, Roche Diagnostics, Indianapolis IN [1999–2001]; Beckman Synchron LX20 and DxC800, Beckman Coulter, Inc., Fullerton CA [2002–2008]). The analytic sensitivity and range of the different analyzers were similar and the distributions of ALT activity did not differ significantly.
CDC National Center for Heaalth Statistics. NHANES public release data file: laboratory 40—standard biochemistry profile, follicle stimulating hormone, and luteinizing hormone.
and public health significance: race/ethnicity; gender; veteran status; family income; health insurance status; daily alcohol consumption within the past 12 months; lifetime injection drug use (IDU; cocaine, heroin, and methamphetamine); and history of blood transfusion before 1992. NHANES questions related to history of injection drug use are restricted to adult participants aged 20–59 years. All analyses involving IDU were similarly restricted.
Statistical Analysis
Weighted means, proportions, SEs, and 95% CIs were estimated to describe participant characteristics. Weighted estimates of anti-HCV prevalence were derived for all adults aged 20–70 years and by subgroups. Differences in prevalence between subgroups were determined by specifying linear contrasts. Statistical significance was defined as a two-sided p-value <0.05.
Two models were evaluated using the birth cohort and ALT testing strategies applied to the target population of persons aged 20–70 years. For the birth cohort strategy, it was assumed that all persons born during 1945–1965 would receive a one-time anti-HCV test. Sensitivity was defined as the number of anti-HCV+ people within the birth cohort divided by the total number of anti-HCV+ individuals aged 20–70 years.
Similarly, for the ALT strategy, it was assumed that all participants would have ALT test results available and those with elevated ALT levels would be tested for anti-HCV. For this strategy, sensitivity was calculated as the number of anti-HCV+ people with elevated ALT divided by the total number of anti-HCV+ people aged 20–70 years. Sensitivity analyses were subsequently performed to examine the impact of (1) using alternate cut-off levels for the ALT ULN (i.e., 31 U/L for men and 20 U/L for women, in comparison to the standard 40 U/L for both genders)
or (2) testing everyone in the 1945–1965 birth cohort in addition to testing adults outside the birth cohort who have elevated (≥40 U/L) ALT levels.
Data were analyzed using SAS-callable SUDAAN, version 10.0.1 (RTI International, Research Triangle Park NC) to account for the complex survey design. Sampling and design variables published by NHANES were used to account for the probability of being medically examined and tested for anti-HCV.
Variance and SEs were estimated using the Taylor linearization method. Data analyses were completed in 2013.
Results
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).
Figure 1Participant flow and response rates, adults aged 20–70 years, NHANES 1999–2008
aNHANES publishes screen samples for adults aged 20–29, 30–39, 40–49, 50–59, 60–69, 70–79, and ≥80 years. The screen sample for adults aged 70 years is not published by the single-year age group. Thus, we estimated the screen sample for persons aged 20–70 years based on the interview response rate for persons aged 20–69 years (76.4%; cdc.gov/nchs/nhanes/response_rates_cps.htm).
bThe denominator used to calculate the response rate was estimated as described above
HCV, hepatitis C virus; NHANES, National Health and Nutrition Examination Survey
Characteristics of the study population are reported in Table 1. The average age of the participants was 42.7 years (SE=0.2 years). Approximately 10.9% (95% CI=9.4%, 12.6%) of participants were non-Hispanic black; 46.8% (45.8%, 47.9%) were in the birth cohort; 2.1% (1.8%, 2.5%) reported past or current injection drug use; 6.3% (5.9%, 6.8%) received blood transfusion before 1992; and 11.8% (11.2%, 12.4%) had elevated ALT levels (Table 1).
Table 1Characteristics of adults aged 20–70 years, National Health and Nutrition Examination Survey 1999–2008
Characteristic
All participants
Anti-HCV-positive
Unweighted,n
Weighted, % (95% CI)
Unweighted,n
Weighted, % (95% CI)
Overall
19,055
429
Age (years; M [SE])
19,055
42.7 (0.2)
429
45.7 (0.5)
Born from 1945 to 1965
No
11,332
53.2 (52.1, 54.2)
121
23.4 (18.8, 28.9)
Yes
7,723
46.8 (45.8, 47.9)
308
76.6 (71.1, 81.2)
Serum alanine aminotransferase level (U/L)
<40
16,635
88.2 (87.6, 88.8)
204
50.0 (43.8, 56.2)
≥40
2,264
11.8 (11.2, 12.4)
217
50.0 (43.8, 56.2)
Gender
Female
9,981
51.0 (50.4, 51.6)
153
37.2 (31.0, 43.7)
Male
9,074
49.0 (48.4, 49.6)
276
62.8 (56.3, 69.0)
Race/ethnicity
Non-Hispanic white
8,726
70.0 (67.2, 72.7)
178
66.5 (60.9, 71.7)
Non-Hispanic black
3,961
10.9 (9.4, 12.6)
147
20.0 (16.2, 24.5)
Mexican American
4,391
8.3 (7.1, 9.7)
73
6.5 (4.4, 9.5)
Other
1,977
10.8 (9.2, 12.6)
31
7.0 (4.3, 11.1)
Family income to poverty threshold
>2 times
9,920
67.6 (65.7, 69.4)
138
41.6 (36.1, 47.4)
1–2 times
4,334
19.1 (17.9, 20.4)
128
28.8 (23.6, 34.6)
Below
3,403
13.3 (12.3, 14.3)
137
29.6 (24.4, 35.3)
Health insurance coverage
Yes
14,179
79.8 (78.5, 81.0)
285
65.3 (59.5, 70.8)
No
4,746
20.2 (19.0, 21.5)
136
34.7 (29.2, 40.5)
Served in the U.S. armed forces
No
16,977
88.3 (87.6, 89.1)
350
83.2 (77.6, 87.6)
Yes
2,074
11.7 (10.9, 12.4)
78
16.8 (12.4, 22.4)
Average number of alcoholic drinks per day, last year
Among anti-HCV+ participants, 43.4% (95% CI=37.6%, 49.5%) reported a history of IDU; 15.2% (11.3%, 20.1%) received blood transfusion prior to 1992; 57.6% (51.4%, 63.5%) reported drinking two or more alcoholic beverages per day; and 34.7% (29.2%, 40.5%) were uninsured (Table 1). Cumulatively, people with a documented history of IDU or blood transfusion accounted for 53.8% (48.4%, 59.2%) of anti-HCV+ participants.
Prevalence of Anti-HCV
Anti-HCV prevalence estimates are reported in Table 2. The overall prevalence of anti-HCV among adults aged 20–70 years was estimated at 2.0% (95% CI=1.8%, 2.3%). Based on population estimates from the 1999–2008 Current Population Surveys,
this corresponds to about 3.6 million non-institutionalized civilian adults with HCV antibodies. Anti-HCV prevalence was higher among participants born during 1945–1965 (3.2% [2.8%, 3.8%]) compared to those outside the birth cohort (0.9% [0.7%, 1.1%]), as well as among participants with elevated ALT levels (8.4% [7.0%, 9.9%]) compared to those with normal ALT levels (1.1% [0.9%, 1.3%]).
Table 2Prevalence of hepatitis C virus antibody by participant characteristics, adults aged 20–70 years, National Health and Nutrition Examination Survey 1999–2008
Characteristic
Participants,n
Weighted anti-HCV prevalence, % (95% CI)
p-value
Overall
19,055
2.0 (1.8, 2.3)
Born from 1945 to 1965
No
11,332
0.9 (0.7, 1.1)
ref
Yes
7,723
3.2 (2.8, 3.8)
<0.001
Serum alanine aminotransferase level (U/L)
<40
16,635
1.1 (0.9, 1.3)
ref
≥40
2,264
8.4 (7.0, 9.9)
<0.001
Gender
Female
9,981
1.4 (1.2, 1.8)
ref
Male
9,074
2.5 (2.2, 3.0)
<0.001
Race/ethnicity
Non-Hispanic white
8,726
1.9 (1.6, 2.2)
ref
Non-Hispanic black
3,961
3.6 (3.1, 4.3)
<0.001
Mexican American
4,391
1.6 (1.1, 2.2)
0.26
Other
1,977
1.3 (0.8, 2.1)
0.10
Family income to poverty threshold
>2 times
9,920
1.2 (1.0, 1.5)
ref
1–2 times
4,334
3.0 (2.4, 3.7)
<0.001
Below
3,403
4.4 (3.7, 5.3)
<0.001
Health insurance coverage
Yes
14,179
1.6 (1.4, 1.9)
ref
No
4,746
3.4 (2.7, 4.1)
<0.001
Served in the U.S. armed forces
No
16,977
1.9 (1.6, 2.2)
ref
Yes
2,074
2.9 (2.1, 3.9)
<0.05
Average number of alcoholic drinks per day, last year
Using the birth cohort strategy as the testing criterion, about 85.4 million people would be tested for anti-HCV and about 2.8 million individuals with anti-HCV would be identified, yielding a sensitivity of 76.6% (Table 3). In contrast, the ALT strategy would result in testing 21.5 million adults and identifying 1.8 million anti-HCV+ people with a sensitivity of 50.0%. In addition, assuming that 75%–85% of anti-HCV+ persons are currently infected, testing everyone within the birth cohort would identify an estimated 2.1–2.4 million current HCV infections compared to 1.4–1.5 million for the ALT strategy (Table 3).
Table 3Hepatitis C virus testing strategy, 1945–1965 birth cohort versus elevated alanine aminotransferase levels
it was estimated that 72.8 million adults would be tested and 75.7% of anti-HCV+ people (men=75.1%, women=76.8%) would be identified. If the birth cohort strategy was implemented, and, at the same time, the ALT strategy was implemented among people outside the birth cohort, 87.3% of anti-HCV+ adults aged 20–70 years would be identified.
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% identified using the ALT strategy.
Most adults currently living with HCV were likely infected 25–45 years ago
and may not admit to or recall past behaviors that put them at risk for HCV infection. The high prevalence of HCV infection in the 1945–1965 birth cohort is most often the consequence of receipt of a blood transfusion prior to 1992 or of IDU
Although our analysis confirmed IDU and blood transfusion as important transmission risk factors responsible for more than 54% of anti-HCV+ cases, another 46% did not report either of these exposure risk factors. The birth cohort testing strategy does not rely on solicitation of risk factors and would test all members of the birth cohort even if they do not disclose historic exposures to HCV risk factors.
In contrast, the ALT strategy would mean testing 60 million fewer people but would fail to identify approximately 700,000–900,000 with current HCV infection (Table 3). By various estimates, approximately 30%–50% of individuals with current HCV infection demonstrate persistently normal ALT levels (PNALT)
and would not be identified by an ALT test. More concerning, one third of HCV-infected people with PNALT have significant fibrosis progression and could be treated if diagnosed.
These findings are supported by previous studies: A recent study found that a testing strategy based on the 1946–1964 birth cohort would identify 76% of anti-HCV+ people
and adoption of this approach has the potential to lead to the diagnosis of substantially more HCV infections compared to the ALT strategy.
There are several limitations to this study. First, NHANES samples include only the U.S. civilian, non-institutionalized population; the exclusion of high-prevalence populations (e.g., incarcerated and homeless persons) likely underestimates anti-HCV prevalence. Second, the sensitivity of the ALT strategy varies with the choice of ULN, which varies by the laboratory conducting the test. In this study, it was found that using a ULN of 31 U/L for men and 20 U/L for women
can lead to the identification of nearly 76% of anti-HCV+ people. This would make the ALT strategy comparable to the birth cohort strategy on the basis of sensitivity. However, based on our review of the limitations of risk-based screening and the ALT strategy, we believe that an ALT strategy that recommends gender or other demographic-specific cut-off levels would be no less difficult to implement than the current screening guidelines. Historically, a ULN of 40 U/L has been generally adopted,
Third, elevated ALT level was defined based on a one-time measurement of serum ALT activity. It is reasonable to think that if NHANES captured longitudinal data from which persistence of ALT elevation could be examined, the sensitivity of the ALT approach in identifying anti-HCV+ individuals could be diminished,
as fewer have PNALT than those with a single elevated ALT, and consequently the advantage of the birth cohort strategy could be more pronounced.
Finally, key implementation assumptions were made about both strategies, which may not hold in practice and inflate the reported effectiveness of both strategies. The birth cohort strategy assumes that all people born during 1945–1965 would be tested. The ALT strategy implies that providers would have unrestricted access to patient medical records, that ALT levels are regularly evaluated, and all individuals with elevated ALT levels would be tested for HCV infection. Results from this study indicate that substantial proportions of anti-HCV+ adults do not have health insurance coverage. Accordingly, not all adults would have access to health care under either strategy. Of those with some access to health services, not all would be tested. For example, under the birth cohort strategy, cohort members may refuse testing because of perceived absence of historic risk factors or fear of stigma. Similarly, under the ALT strategy, ALT levels may not be measured for all patients seeking primary care and a substantial proportion of patients with elevated ALT levels may not be tested for HCV.
Rein DB, Wagner D, Brown K, et al. 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 U.S. National Summit on HIV and Viral Hepatitis Diagnosis, Prevention and Access to Care; 2012 Nov 26–28; Washington DC.
The CDC and the U.S. Preventive Services Task Force recommend a one-time HCV test for all people born during 1945–1965 without the need for solicitation of behavioral or clinical risk factors.
The current study provides important evidence for the effectiveness of the birth cohort strategy in identifying HCV cases that would go unidentified using an ALT-only strategy. However, we expect the implementation of the birth cohort screening strategy to happen concurrently with the continued use of ALT-based screening, resulting in averting more HCV-related illnesses and deaths. The results of this study indicate that combining the birth cohort and ALT strategies would identify more than 87% of anti-HCV cases.
The CDC is actively working to support implementation through development of best practices for integrating testing into medical settings (e.g., use of electronic health systems) and development of quality indicators and performance measures. The CDC has augmented testing capacity using Prevention for Public Health Funds and is educating the public about HCV and the need for testing while simultaneously providing clinicians training to improve testing and care through the Know More Hepatitis campaign (cdc.gov/knowmorehepatitis).
The CDC has also conducted panels with stakeholder groups (providers, public health professionals, health plans and payers, laboratories, and federal partners)
and is implementing strategies with these partners. The birth cohort HCV testing recommendation has been adopted by the American Medical Association, American College of Physicians, American Association for the Study of Liver Disease, and Infectious Diseases Society of America.
American Association for the Study of Liver Diseases, Infectious Disease Society of America Recommendations for testing, managing,and treating hepatitis C.
American Association for the Study of Liver Diseases,
Alexandria VA2014
It is expected that increasing the proportion of people who have knowledge of their HCV infection will result in increases in linkage to care and treatment as well as provision of prevention services. Among those for whom treatment is contraindicated, prevention strategies to avoid disease transmission (e.g., risk reduction interventions for persons who inject drugs) and attenuate progression of liver disease (e.g., reducing use of alcohol) are available. In conclusion, the CDC recommends that healthcare providers prioritize the implementation of the birth cohort testing strategy to achieve the public health goals of reducing morbidity and mortality associated with HCV infection.
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 and do not necessarily represent the official position of the Centers for Disease Control and Prevention.
No financial disclosures were reported by the authors of this paper.
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Public Policy Committee of the American Association for the Study of Liver Disease. Serum activity of alanine aminotransferase (ALT) as an indicator of health and disease.
Rein DB, Wagner D, Brown K, et al. 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 U.S. National Summit on HIV and Viral Hepatitis Diagnosis, Prevention and Access to Care; 2012 Nov 26–28; Washington DC.
Should patients with abnormal liver function tests in primary care be tested for chronic viral hepatitis: cost minimisation analysis based on a comprehensively tested cohort. BMC.
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