1 Epidemiology Department, Naval Medical Research Center, Silver Spring, MD.
2 Office of the Assistant Secretary of DefenseHealth Affairs, the Pentagon, Washington, DC.
3 Army Medical Surveillance Activity, US Army Center for Health Promotion and Preventive Medicine, Washington, DC.
4 Hepatitis Branch, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA.
5 Department of Preventive Medicine and Biometrics, Uniformed Services University of the Health Sciences, Bethesda, MD.
6 Department of Gastroenterology, Veterans Affairs Medical Center, Washington, DC.
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ABSTRACT |
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hepatitis; hepatitis C; hepatitis C antibodies; hepatitis C, chronic; hepatitis, viral, human; hepatitis viruses; military medicine; substance abuse, intravenous
Abbreviations: anti-HCV, antibody to hepatitis C virus; CI, confidence interval; DoD, US Department of Defense; EIA, enzyme immunoassay; HIV, human immunodeficiency virus; RIBA, recombinant immunoblot assay; RT-PCR, reverse transcriptase-polymerase chain reaction.
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INTRODUCTION |
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In a sample of the general US population, the overall prevalence of antibody to HCV (anti-HCV) was found to be 2.6 percent among adults aged 2059 years (3.7 percent in males and 1.6 percent in females) (3). In contrast, studies conducted in two populations of Department of Veterans Affairs patients found much higher rates of infection, ranging from 10 to 20 percent (4
6
). Additionally, 810 percent of 26,000 patients in Department of Veterans Affairs medical centers who volunteered to be tested during a national screening day on March 17, 1999, were positive for anti-HCV (7
).
High rates of HCV infection among Department of Veterans Affairs patients have raised questions about whether certain aspects of military service and foreign travel, such as exposure to blood during combat, sexual contacts, tattoos, and receipt of immune globulin for hepatitis A prophylaxis, increase the risk of HCV infection (6, 8
). To determine the prevalence and incidence of HCV infection among troops currently serving in the US military, we conducted the following seroepidemiologic investigation.
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MATERIALS AND METHODS |
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Repository samples are stored in a central location at 25°C. A computerized database links stored serum samples with the service member's demographic data: age, gender, race/ethnicity, educational level, marital status, service branch, rank, length of military service, and military job classification.
For this investigation, subjects were drawn at random from all military personnel serving in 1997 who provided a serum sample. According to the US Army Medical Surveillance Activity in Washington, DC, approximately 60 percent of active-duty personnel and 27 percent of Reservists supplied a sample for the repository in 1997. Because military personnel provide serial serum samples, the computerized database was scanned for prior samples from selected subjects. If any sera were available 1 year or more previously, the first (oldest) sample obtained for the repository also was chosen. About 70 percent of military personnel tested in 1997 had at least two sequentially obtained serum samples in the repository.
The following population groups that provided serum samples during calendar year 1997 were evaluated first: 1) a random selection of 10,000 active-duty military personnel, 2) a random sample of 2,000 selected Reservists, and 3) a random sample of 2,000 active-duty personnel inducted during 1997 ("recruits"). In addition to these three general populations, random oversampling of less numerous populations providing samples in 1997 were selected to obtain more precise estimates of risk, including 1) 1,000 troops currently on active duty who had served in the military before January 1, 1974 ("Vietnam era" personnel), 2) 2,000 active-duty personnel who retired in 1997 after completing 20 or more years of military service, 3) 2,000 women active-duty personnel, 4) 1,000 non-White/non-African-American active-duty troops, and 5) 1,000 active-duty personnel who had a health care job classification.
Of all 21,000 survey participants selected, no person was chosen for analysis more than once. Subjects were selected in proportion to the size of each major Service within the US military: Army (34 percent of the entire force), Navy (28 percent), Air Force (26 percent), and Marine Corps (12 percent). No other selection criterion was used.
Sample size calculations were based on the prevalence of HCV infection in prior studies of US military personnel and estimates of HCV infection in the civilian community (3). To detect a twofold increase in prevalence among military personnel as compared with the general population, a sample size of 10,000 has power of 99 percent (i.e., beta error of <0.01) to detect this difference at the alpha = 0.05 level (one-sided). A sample size of 10,000 allows for a 95 percent confidence interval to estimate the difference in prevalence in the military and the general civilian population to within ±0.4 percent.
This investigation was conducted under DoD surveillance directives (10). Serum samples and associated demographic data were given a unique investigation number. All personal identifiers then were removed from both single and matched samples and from computerized demographic information. Therefore, testing was conducted anonymously, without the possibility of connecting subsequent serologic test results to persons.
The most recently collected serum samples were tested for anti-HCV by using a second-generation enzyme immunoassay (EIA) (Abbott HCV EIA 2.0; Abbott Laboratories, Abbott Park, Illinois). Repeatedly reactive samples were tested by a supplemental recombinant immunoblot assay (RIBA) (Chiron RIBA HCV 2.0; Chiron Corporation, Emeryville, California). Only those samples that were positive by RIBA were considered anti-HCV positive and indicative of current or past HCV infection (1).
For samples found positive by RIBA, any previously collected, matching serum sample was tested for anti-HCV. New infection was defined as seroconversion from anti-HCV negative to anti-HCV positive in a paired sample collected at a later date.
RIBA-indeterminate samples from 10,000 randomly selected active-duty personnel and 2,000 recruits were further tested for HCV RNA at the Centers for Disease Control and Prevention in Atlanta, Georgia, by using reverse transcriptase-polymerase chain reaction (RT-PCR) (Amplicor HCV) (11). In addition, all of the most recently collected anti-HCV-positive specimens from four population groups (active-duty personnel, recruits, retirees, and troops who had served during the Vietnam War era) were tested for HCV RNA by nested RT-PCR amplification of the 5' noncoding region, as described previously (12
). Samples found to be HCV RNA negative were extracted a second time with the same procedure and were incubated for an additional 45 minutes at 50°C with 25 units of reverse transcriptase (Boehringer Mannheim Corporation, Indianapolis, Indiana) and 10 units of RNAsin (Boehringer Mannheim Corporation). To determine HCV genotypes, nested RT-PCR was used to amplify nonstructural coding region 5b (NS-5b) using methods and primers described previously (12
, 13
), except that the following internal primers were used for nested PCR: R1 (5'-GCTCTCAGGCTCGCCGCGTCCTC-3') and R2 (5'-GCTCTCAGGTTCCGCTGCTCCTC-3'). HCV genotypes were determined from the 300 nucleotide sequence of the NS-5b region (14
, 15
). Each specimen's sequence was compared with published sequences by using a multiple sequence alignment program (Pileup, Wisconsin Genetic Computer Group) (15
).
PCR products were separated by electrophoresis on a 2 percent agarose gel, and positive specimens were identified by ethidium bromide staining (12). PCR products were purified and were sequenced by using internal primers with an ABI PRISM Dye or dRhodamine Terminator Cycle Sequencing Kit (Applied Biosystems, Inc., Foster City, California). Electrophoresis and nucleotide identification were performed with an automated DNA sequencer (ABI 377; Applied Biosystems, Inc.).
Data were analyzed by using the chi-square test with Yates' correction or Student's t test for univariate analysis. Multivariate analysis was conducted by using logistic regression, with anti-HCV serologic results as the dependent variable (SPSS, Inc., Chicago, Illinois). The variables race/ethnicity, rank, marital status, years of formal education, job description, and branch of military service were evaluated initially in separate logistic regression models while controlling for age and gender. All variables found to be associated with HCV infection then were evaluated in a final model, again controlling for age and gender.
Prevalence estimates were reported with 95 percent confidence intervals by using the Poisson distribution approximation (16). A type I error of alpha = 0.05 was assumed.
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RESULTS |
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African Americans tended to have a higher prevalence of HCV infection than other racial/ethnic groups (tables 2 and 3). Among 11,000 active-duty personnel (10,000 randomly selected troops plus 1,000 oversampled non-White/non-African-American personnel), the prevalence of infection was 0.8 percent among African Americans, 0.6 percent among Hispanics, and 0.4 percent among Whites (table 4). Enlisted personnel also tended to have a higher prevalence of infection than officers did (tables 2 and 3).
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Among 1,000 oversampled health care personnel (mean age, 30.6 years), the prevalence of HCV infection was 0.7 percent (95 percent CI: 0.3, 1.45), which was comparable to other active-duty troops of similar age (tables 2 and 3). In specific medical job categories, the highest prevalence of infection was found among 220 evaluated nurses (mean age, 36 years); four (1.8 percent) were positive for anti-HCV.
Among 10,000 randomly selected active-duty troops, two variables were associated with anti-HCV positivity in separate logistic regression models that controlled for age and gender: race/ethnicity (African Americans compared with other personnel; odds ratio = 2.2, 95 percent CI: 1.2, 4.1) and rank (enlisted personnel compared with officers; odds ratio = 6.3, 95 percent CI: 2.3, 17.2). However, when age, gender, race/ethnicity, and rank were evaluated together in a single logistic regression model, only age (odds ratio for each 10 years = 5.9, 95 percent CI: 3.9, 8.8) and enlisted rank (odds ratio = 5.5, 95 percent CI: 2.0, 15.6) were independently associated with HCV antibody; gender and race/ethnicity were not significantly associated with infection.
For the random sample of 10,000 active-duty personnel, a previous serum repository sample was available for 7,368 of them (74 percent). The mean interval between serial serum samples was 4.6 years (range, 111 years), which provided 34,020 person-years of observation. In this cohort, six persons seroconverted to anti-HCV, for an annual incidence of 1.8 new infections per 10,000 troops (0.018 percent per year, 95 percent CI: 0.007, 0.04). This risk translates into one new HCV infection each year for every 5,670 troops or approximately 252 new HCV infections per year in a total active-duty force of 1.4 million. Of the six persons who seroconverted, their ages ranged from 22 to 40 years, five were male, four were of non-White race/ethnicity, all were of enlisted rank, and none had a medical job classification.
As expected in mass screening of a low-risk population, false-positive serologic test results were common. In the initial testing of 10,000 active-duty personnel, 90 serum samples were repeatedly reactive by EIA, but only 48 (53 percent) were RIBA positive and 16 were indeterminate. For the 2,000 recruits tested, the numbers of serum samples that were indeterminate (3 samples) or positive (2 samples) by RIBA were similar. Importantly, none of these 19 indeterminate samples was positive by RT-PCR, which indicates that among active-duty military forces and recruits, RIBA-indeterminate results are usually false positive.
HCV RNA was found in 81 (86 percent) of 94 anti-HCV-positive samples tested. Among these 81 samples, 51 (63 percent) were genotype 1a, 18 (22 percent) genotype 1b, 1 (1 percent) genotype 2a, 6 (7 percent) genotype 2b, and 5 (6 percent) genotype 3a. Analysis of the prevalence of HCV RNA positivity and of specific genotypes demonstrated no association with age, gender, race/ethnicity, rank, or Vietnam era service; however, the sample size was small. Among the six persons who seroconverted during military service, HCV RNA was found in four: three type 1a and one type 2b.
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DISCUSSION |
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In addition to low levels of infection overall, potentially high-risk groups, such as health care personnel and Vietnam era veterans (17), did not have an increased risk of infection. However, the relatively low prevalence of anti-HCV among troops who had served in the Vietnam War era is not representative of all populations of Vietnam veterans; this group was very healthy, as demonstrated by their ability to serve on active military duty for a prolonged periodat least 23 years.
A low prevalence of HCV infection among active-duty military personnel is consistent with the largest study of the general civilian population in the United States, which found that persons who had served in the military were not at increased risk for HCV infection (a 1.7 percent prevalence compared with a 2.2 percent prevalence among those who had not served in the military) (3). In addition, the HCV-infection-associated demographic characteristics of currently infected troops were similar to those of the civilian population, with a higher prevalence among older age groups and African Americans (3
). But, as found in the general US population, race/ethnicity was not independently associated with HCV infection when a measure of socioeconomic statusrank in this study of military personnelwas considered (3
).
The results of this study also are consistent with previously published studies of US military populations (1820
). Similar to the 0.5 percent prevalence of infection found among troops serving in 1997, 0.4 percent of 3,000 active-duty Navy and Marine Corps personnel surveyed in 19881990 were anti-HCV positive (18
, 19
). For the recruit population, the 0.1 percent prevalence of infection observed in this study is lower than the 0.3 percent prevalence found among recruits in 1991 (20
) and the 0.4 percent prevalence found in a study of 8,568 recruits whose blood samples were taken and stored 50 years ago during the Korean War (21
).
In addition to low levels of HCV infection found in serologic studies of contemporary military forces, the incidence of hospital admissions for all types of acute viral hepatitis has been steadily declining in the US military (22). Taken together, these data suggest that military personnel are following the national trend, with a decreasing risk of acquiring HCV infection but at lower overall levels of HCV transmission compared with the general population.
The reduced risk of HCV infection among today's troops is probably due to the very low level of injection drug use in the military, the major mode of HCV transmission in the United States (23, 24
). For the same reason, HIV infection, another parenterally transmitted virus, is found less frequently among US military populations (9
). A decreased risk of injection drug use and blood-borne infections can be attributed to multiple and overlapping DoD programs that began in the late 1970s to counter high rates of illicit drug use and to promote health and fitness. These programs include 1) rigorous induction standards, which encompass testing for illicit drugs and HIV infection before recruits are trained; 2) routine, randomized drug screening throughout military service; 3) regular medical screening, clinical examinations, and HIV testing of active-duty and Reserve personnel; and 4) physical performance testing every 612 months that helps identify chronic health problems.
Of consequence for military personnel and veterans who have served overseas, HCV transmission has not been associated with military deployments, intramuscular immune globulin, and contact between intact skin and infected blood (1, 18
, 19
, 25
). In addition, prior US studies have not found medical and dental procedures, tattooing, acupuncture, or body piercing to be associated with transmission of HCV (1
). Importantly, HCV is not spread by casual contact (1
), and HCV is now very rarely transmitted by blood transfusions (26
28
). Sexual contact, however, could be a source of infection because 1520 percent of HCV infections in the general population may be due to high-risk sexual activity (e.g., multiple partners) (1
, 3
, 29
31
). Our finding that current military personnel and the civilian population are infected with similar HCV genotypes (a predominance of genotype 1) is consistent with patterns of transmission within the United States.
The low prevalence of HCV infection among active-duty troops and randomly surveyed veterans in the general population has to be contrasted with the 1020 percent prevalence of infection found in studies of Department of Veterans Affairs patients (46
). The reason for this difference may be explained by the unique nature of these patients (4
). The primary recipients of health care in the Department of Veterans Affairs are lower income, older men who may have a history of substance abuse (32
). As a result, the majority of HCV infections have been found in male Vietnam era veterans who lived through a time of both increased drug use and unscreened blood transfusions before HCV testing was possible; few Department of Veterans Affairs patients younger than 35 years of age have been infected with HCV (7
, 8
). Selection bias may also contribute to higher rates in these studies, because veterans who have risk factors for infection may be more concerned and likely to volunteer for testing.
On the basis of the findings from our study, which showed a consistently higher prevalence of HCV infection in older service members, DoD has implemented a targeted risk-based HCV screening program using Centers for Disease Control and Prevention screening guidelines for persons who are 35 years of age or older and are separating or retiring from military service (1). Because this group in the present study included 87 percent of all active-duty personnel with HCV infection, the program will provide screening for the primary population at risk. In addition to increased screening, DoD has implemented an HCV blood donor and recipient lookback program, as in the civilian sector, and has initiated an extensive outreach effort (33
).
Even though the risk of HCV infection is low in the military, the future health care burden of prior HCV infections could be substantial in the general and veteran community (1, 3
). The potential extent of the problem has been difficult to evaluate because gaps exist in our knowledge about this chronic infection. Identification of HCV and development of tests to detect HCV infection occurred only in the last decade (34
). Consequently, there has been insufficient time to conduct the long-term studies needed to determine the prognosis of chronic hepatitis C virus in different populations (21
, 35
38
).
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ACKNOWLEDGMENTS |
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The authors thank Stephanie Gray (Naval Medical Research Center, Washington, DC) for laboratory assistance, Kimmie F. Kohlhase (Army Medical Surveillance Activity, Washington, DC) for data management, and Dr. Michael Purdy (Centers for Disease Control and Prevention, Atlanta, Georgia), for technical assistance.
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NOTES |
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REFERENCES |
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