Hepatitis C Virus Infection Among U.S. Military Personnel: An Assessment Of Risks and Screening Strategies

Hepatitis C Virus Infection Among U.S. Military Personnel: An Assessment Of Risks and Screening Strategies

Office of the Assistant Secretary of Defense -- Health Affairs, the Pentagon; Washington, DC

http://www.bloodbook.com/hep-vet.html

April 5, 1999

Executive Summary

The Fiscal Year (FY) 1999 Senate Armed Services Committee Report directed the Department of Defense (DoD) to study the extent of service-connected hepatitis C infection, to include the advisability and feasibility of testing for hepatitis C virus (HCV) during separation and retirement physicals (enclosure 1). The Department previously had initiated a comprehensive research strategy to study hepatitis C virus infection among military members. Investigations begun in 1998 included: 1) the first large-scale, randomized sero-epidemiological investigation of over 20,000 military personnel; 2) analysis of DoD hospital records of inpatient admissions for acute and chronic viral hepatitis during the last 20 years; and, 3) cost analysis of testing for HCV infection.

In this report to Congress, the Office of the Assistant Secretary of Defense (Health Affairs) provides the initial results of these studies.

In the sero-epidemiologic investigation, the overall prevalence of hepatitis C infection among 10,000 active duty personnel serving in 1997 was 0.48% (about 5 per 1000 troops). Troops less than 35 years of age had the lowest risk of HCV infection (0.1%), which is 1 infected person per 1000 personnel. The highest risk was found among individuals 35 years of age and older (1.7% prevalence), nonwhite racial/ethnic groups, and enlisted personnel; women generally had a lower risk of infection.

For recruits enlisting in 1997, the prevalence of infection was just 0.1% (1 per 1000 recruits). The risk of infection for Reservists was similar to active duty personnel after adjusting for age. The prevalence of infection in active duty personnel who had been on duty since the Vietnam era was actually lower (1%) than the prevalence (3%) among other military personnel of similar age (greater than 40 years old). Individuals retiring from the military in 1997 were on average 45 years old and had a prevalence of infection of 1.7%.

As expected in any mass screening of a low risk population, questionable test results were common, which required extensive re-testing to determine who actually was infected. For example, in the testing of recruits the number of inconclusive results was actually higher than positive test results, which required additional analysis by polymerase chain reaction assays that have yet to be approved by the FDA.

The hospitalization records study indicated a steadily decreasing risk of acute viral hepatitis in the U.S. military during the last 20 years. A similar trend has been observed in the civilian community where a greater than 80% reduction in acute hepatitis C infection has occurred. In the general population, hepatitis C infection has primarily been associated with illicit drug use.

Today's military personnel are at substantially less risk of hepatitis C infection than civilians because of very low levels of drug abuse. The 0.48% prevalence of infection found in active duty troops is more than three times lower than the 1.8% prevalence found in the CDC study of the general U.S. population. The low risk of viral hepatitis in the U.S. military can be attributed to existing DoD programs, including:

High induction standards, which include testing for illicit drug use and human immunodeficiency virus (HIV) infection

Routine, randomized drug screening throughout military service

Routine medical screening and examinations of active duty and Reserve personnel

Routine physical performance testing that identifies chronic health problems

Hepatitis C testing of blood donors and the donor/recipient "lookback" program

Universal precautions to prevent transmission of bloodborne infections

Total force hepatitis A immunization and risk-based hepatitis B immunization

The Department's extensive investigations indicate no requirement at this time to deviate from national screening policy on HCV as established by the Centers for Disease Control and Prevention (CDC), Recommendations for Prevention and Control of Hepatitis C Virus (HCV) Infection and HCV-Related Chronic Disease, Morbidity and Mortality Weekly Report, October 16, 1998 / Vol. 47 / No. RR-19 (enclosure 2). Also, expanded HCV screening would not enhance military force readiness because of the very low levels of HCV infection among active duty personnel and because HCV infection seldom leads to clinical disease during military service.

Because older service members have a higher prevalence of infection, individuals 35 years of age and older who separate or retire from service will be specifically screened for risk factors of HCV infection and tested when indicated based on CDC guidelines (enclosure 3). The results of this targeted screening, and subsequent evaluation, counseling, and treatment, will be annotated in the service members’ medical record, which will provide continuity of care within the Department of Veterans Affairs (VA) health care system. By basing testing on CDC national consensus guidelines, the military population most at risk of HCV infection will be screened, ensuring appropriate use of health care dollars.

The Department also has initiated a concerted provider and patient education program (enclosure 4). This effort emphasizes increased awareness of the risk factors for hepatitis C infection so that potentially exposed individuals and their health care providers understand the need for testing and counseling. Additionally, every physician within DoD is being contacted and provided a brochure prepared by the CDC with important information about the risk, diagnosis, and treatment of hepatitis C.

Background

Hepatitis C virus (HCV) is a positive-stranded RNA virus in the family Flaviviridae.^1,2 This very heterogeneous virus can be divided into at least six distinct genotypes and over 90 subtypes. HCV was not identified until 1988, although for several decades an unidentified virus had been suspected to be a major cause of hepatitis following blood transfusions.³Since its discovery, HCV infection has been detected worldwide. In developed countries, HCV infection has been found in 0.5 to 2% of the general population and in less than 1% of volunteer blood donors.^1,2

In the largest U.S. study conducted to date by the Centers for Disease Control (CDC), HCV infection was found in 1.8% of 21,241 persons greater than six years old.⁴ The highest prevalence of infection was observed in males (2.5% prevalence) and persons aged 30 to 49 years (4.2% prevalence). Groups at increased risk included African-Americans (3.2% prevalence), Hispanics (2.1% prevalence), and individuals at lower socioeconomic status. A history of drug abuse was strongly associated with infection. Notably, military veterans had a lower prevalence of infection (1.2%) compared to other age-matched subjects (1.7%).⁴

In the United States, the annual incidence of new HCV infections has declined more than 80% during the last 10 years from an estimated 230,000 infections to 36,000 in 1996.^4-6 Despite a rapidly decreasing incidence of transmission, an estimated 3.9 million Americans have been infected with HCV.⁴

Transmission

Hepatitis C virus is transmitted predominantly by the blood-borne route through large or repeated direct percutaneous exposures.⁶ In addition, perinatal infection occurs in about 5-6% of infants born to HCV infected mothers.^7,8 Whether HCV is commonly transmitted by heterosexual or homosexual contact is not well understood, but this mode of infection is less efficient than parenteral exposure.^9-12 For persons in long term sexual relations with one person, the risk of HCV infection is very low. Snorting drugs like cocaine may be another mode of transmission.^4,6,13 Prior studies in the USA have not demonstrated an association between HCV infection and medical and dental procedures, tattooing, acupuncture, ear piercing, or foreign travel.⁶

Since the development in 1990 of a commercial serological assay for HCV infection, blood donors have been screened for this infectious disease.¹ Consequently, blood transfusions rarely account for recently acquired HCV infections.¹⁴ The current risk for transfusion-associated HCV infection is estimated to be 0.001% per unit transfused.^6,15

The reasons why HCV transmission has decreased in the general population are not well known but may be related to changes in risk behaviors (drug use and sexual activity) due to the AIDS epidemic.^1,2 "Injecting drug use currently accounts for most HCV transmission in the United States, and has accounted for a substantial proportion of HCV infections during past decades."⁶ Hemophiliacs and dialysis patients are also at higher risk of HCV infection.^1,2Health care and emergency personnel are at increased risk of infection from accidental needle-sticks.^16,17"HCV is not spread by sneezing, hugging, coughing, food or water, sharing eating utensils or drinking glasses, or casual contact."⁶

Because blood-borne transmission predominates, the most effective method for reducing HCV transmission is to avoid illicit drugs and the use of contaminated needles.

Clinical Course

The majority of individuals infected with HCV do not develop acute jaundice but remain asymptomatic.^2,5 However, 75-85% of acute infections become chronic.¹⁸ Chronic HCV infection is again asymptomatic in most cases and usually does not lead to clinically apparent liver disease or premature mortality.^1,2 Most individuals with chronic HCV infection therefore are not ill, and infection is only found because of blood tests conducted as part of a routine physical examination or because of standard testing of blood donations.

Although usually asymptomatic, nearly all patients with chronic HCV infection have indications of chronic hepatitis on liver biopsy.² After one or more decades, possibly 10-20% of chronic infections progress to cirrhosis, which is associated with the development of hepatocellular carcinoma in 1% to 5% of chronic HCV infections.^5,19 Factors linked to progressive liver fibrosis include:²⁰

age greater than 40 years at the time of HCV infection

male sex

alcohol consumption

Currently, HCV is the major infectious cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma.^1,2 HCV infection also is the leading cause of liver disease requiring organ transplantation among adults.¹ Possibly 8-10 thousand deaths each year in the USA result from hepatitis C virus infection.^4,5

The lack of long-term clinical data is a major shortcoming when trying to predict the future health care burden of chronic liver disease due to prior HCV transmission. Most studies have been relatively small and involved unique populations. In one study of 568 cases of blood transfusion-associated non-A, non-B hepatitis (mostly hepatitis C), there was no difference in all-cause mortality between cases and transfused controls without hepatitis after more than 20 years of follow-up.^21,22

In a study of 8,568 U.S. military recruits who had a blood sample collected and stored between 1948 and 1954, 0.4% had antibody to hepatitis C virus (anti-HCV).²³As in recent military populations, HCV infection was more frequent in nonwhite race/ethnic groups. Among 26 recruits with HCV infection, there was no increase in mortality or liver cancer during over forty years of follow-up. Other studies have provided mixed results, indicating both favorable and poor long term prognosis from chronic hepatitis C virus infection.^24-27

Treatment

At present, there is no specific means of preventing hepatitis C virus infection, and the only therapy of proven benefit is expensive, often poorly tolerated, and results in a favorable long-term response in a minority of patients. Parenteral alpha interferon has been the most effective treatment for chronic HCV infection but is associated with numerous side-effects, including anemia, flu-like symptoms, and psychiatric manifestations.^5,28 Also, treatment may be too demanding when patients have serious medical conditions. Consequently, treatment often is contraindicated, and patients frequently do not complete a full course of interferon therapy.⁶

Sustained biochemical response to interferon has been observed in 15-20% of patients treated for six months and in 25-30% of patients treated for 12 to 18 months.²⁹ Research studies have shown that the concurrent use of the oral drug ribavirin increases the rate of sustained response with alpha interferon to 28% for infection with genotype 1 and to over 50% with other genotypes.^30-32 In addition to biochemical response, treatment with alpha interferon may lower the risk of hepatocellular carcinoma among HCV infected patients with cirrhosis.^33,34

In June 1998, the U.S. Food and Drug Administration (FDA) approved the used of combination therapy with oral ribavirin and parenteral interferon alfa-2b for the treatment of chronic hepatitis C. At present, treatment is recommended for patients with persistently elevated alanine aminotransferase (ALT) levels, positive HCV RNA, and a liver biopsy with either portal or bridging fibrosis, or at least moderate degrees of inflammation and necrosis.⁵ Treatment is not recommended for HCV infected individuals who have persistently normal ALT levels, which occurs in about 30-40% of chronic HCV infections.Treatment of individuals with normal ALT levels has not been shown to be beneficial.³⁵ Because of substantial ongoing research, these treatment guidelines could change over the next few years.³⁶

Although treatment often is not effective, the risk of serious liver disease can be reduced by abstinence from alcohol consumption and by the prevention of other viral infections of the liver with the hepatitis A and B vaccines. A vaccine to prevent HCV infection directly will be difficult to develop because of the rapid mutation rate of this virus and the lack of protective immunity following natural infection.³⁷

Diagnosis and Screening

Commercial tests for hepatitis C infection first became available in May 1990. More sensitive and specific (multi-antigen) tests were developed in 1992. Infection with HCV is diagnosed by finding antibody to HCV (anti-HCV) in serum samples.^1,2 Testing for anti-HCV requires two different types of assays because screening tests are prone to false positive results. Sera are tested initially with a sensitive enzyme-immunoassay (EIA) based on recombinant viral proteins. Samples found to be reactive in two separate EIA assays then are evaluated by a more specific and costly, supplemental test -- generally an immunoblot assay that uses a nitrocellulose strip (RIBA).

This multi-step procedure detects anti-HCV in > 97% of infected patients.^2,6 However, anti-HCV may not be detected by this approach for several weeks or months after initial infection and among immunocompromised patients. Diagnosis in these cases can be made by the identification of HCV RNA using a gene amplification technique, reverse transcription polymerase chain reaction (RT-PCR), which is a more difficult and expensive test.²Also, there has been substantial variability between laboratories in the performance of PCR tests for HCV, and no PCR test kit has been approved by the FDA.³⁸

In a report released in October 1998,⁶ the CDC issued the following recommendations on HCV screening:

Screening was recommended for:

1. Persons who should be tested routinely for HCV infection based on their risk for infection --

Persons who ever injected illegal drugs, even once

Persons with selected medical conditions, including those:

1) who received clotting factor concentrates produced before 1987

2) who were ever on chronic (long-term) hemodialysis

3) who have persistently abnormal alanine aminotransferase levels

Prior recipients of transfusions or organ transplants, including those:

1) who were notified that they received blood from a donor who later tested positive for HCV infection

2) who received a transfusion of blood or blood components before July 1992

3) who received an organ transplant before July 1992

2. Persons who should be tested routinely for HCV-infection based on a recognized exposure --

Healthcare, emergency medical, and public safety workers after needle sticks, sharps, or mucosal exposures to HCV-positive blood

Children born to HCV-positive women

HCV testing was of uncertain need for:

Recipients of transplanted tissue

Intranasal cocaine and other non-injecting illegal drug users

Persons with a history of tattooing or body piercing

Persons with a history of multiple sex partners or sexually transmitted diseases (STDs)

Long-term steady sex partners of HCV-positive persons .

Implementation of screening recommendations have uncovered asymptomatic HCV carriers. However, there are questions about the benefits of screening, especially in low risk populations, because the long-term consequences of infection are not well understood and because sexual and household transmission appear to be rare. Another consideration in developing screening policies is the possible adverse consequences of testing.⁶ These problems include disclosure of test results to others, which could result in disrupted personal relationships. Discriminatory action is also possible from loss of employment, insurance, and educational opportunities.⁶

Hepatitis C in the U.S. Military

HCV infection has been found to be relatively uncommon among active duty military personnel^39-44 and an infrequent cause of chronic liver disease.⁴⁵ In published studies of general active duty personnel,^41,42 the prevalence of HCV infection was found to be less than one-half percent, as shown in table 1.

Table 1. Prevalence of anti-HCV among military populations in studies published in peer-reviewed journals

Population

Date of Study

Number Tested

Prevalence

Blood donors³⁹

1990-91

5,719

0.2%

Military recruits⁴⁰

1989

1,538

0.3%

Deployed personnel^41,42

1988-90

3,082

0.4%

STD clinic patients⁴³

1990-91

470

1.1%

HIV infected military members⁴⁴

1986-90

235

3.4%

In addition to a low prevalence of HCV infection, the rate of viral hepatitis has declined substantially among U.S. military populations because of 1) frequent, random drug screening, which identifies individuals at increased risk of HCV infection;⁴⁶ and, 2) high induction standards, including drug screening and testing for human immunodeficiency virus (HIV) infection, which tend to exclude high risk groups from military service. Foreign deployments, tattooing, and the type of intramuscular immune serum globulin (gamma globulin) used in the past for hepatitis A prophylaxis prior to duty in developing countries have not been associated with HCV transmission.^6,41,47

The major risk factor for HCV infection -- parenteral drug abuse -- is very uncommon in the U.S. military. Results from periodic surveys of military personnel (1998 Department of Defense Survey of Health Related Behaviors Among Military Personnel),⁴⁸ indicate that the use of heroin or other opiates during the past 30 days occurs in only 0.2% of the force, and the prevalence of any illicit drug use among military members is less than one-third the rate reported in age-matched civilian populations. Current low levels of drug abuse contrast with data from previous behavioral risk factor surveys first conducted in 1980, which found self-reported use of any illicit drug during the past 30 days in 28% of surveyed military members compared to 2.7% today, which represents a decrease of over 90% during the last 18 years.

High standards of induction, including the requirement to be free of HIV infection and to have a negative drug test, tend to exclude applicants who have used illicit drugs. In addition, accession standards identify applicants with active liver disease. A history of hepatitis infection (including hepatitis C) within the preceding six months and persistent symptoms is a disqualifying condition for accession, as is objective evidence of impairment of liver function and chronic hepatitis. However, recruits found to be infected with HCV are not routinely separated from military service if they have no signs or symptoms of liver disease.

After induction, multiple screening points exist in a military member's career for the diagnosis of liver disease and the identification of occupational and personal risk factors for viral hepatitis infection and liver damage. Military members are randomly screened for drug use throughout military service. Additionally, military personnel have to undergo routine health examinations, which screen for liver diseases like hepatitis, and the periodic Health Enrollment Assessment Review (HEAR) assists clinicians in identifying persons at risk for liver disease. Throughout military service, members have to pass a physical fitness test every 6 to 12 months, which also identifies individuals with chronic health problems. At the end of active military duty, the retirement and separation physical for military members includes a clinical assessment of liver disease and follow-on blood tests as needed to diagnose viral hepatitis.

Targeted testing and treatment for HCV infection also occurs during military service when clinically indicated. Examples include follow-up for needle-stick injuries in the medical care setting. Similarly, military members found to be infected with HCV during testing of donated blood are evaluated and treated. A large proportion of the military force -- approximately 100,000 active duty personnel -- donate blood each year. Lastly, military personnel who have alcohol use problems and a higher risk of hepatitis C related morbidity are clinically evaluated for liver disease, including viral hepatitis.

In addition to these screening and intervention strategies, DoD has implemented a HCV blood donor and recipient lookback program (enclosure 5). On June 29, 1998, Dr. Sue Bailey, Assistant Secretary of Defense (Health Affairs), issued a memorandum to all military Services requiring blood donor lookback and recipient notification. The revised policy also included testing and care of former beneficiaries who may have been exposed to hepatitis C virus through transfusion in the military health care system. This policy letter also required the Services to be more inclusive than required by the FDA: the DoD lookback includes donors who test repeatedly reactive for anti-HCV with either the first or second generation tests, and not just the more accurate multi-antigen tests for anti-HCV. On July 2, 1998, Health Affair's Blood Program Office issued Blood Program Letter 98-03 that implemented and outlined DoD's HCV donor lookback, and recipient and consignee notification procedures. The Military Services had implemented their lookback policies by October 5, 1998.

The Department of Defense's multiple and overlapping surveillance programs identify military members who could be infected with the hepatitis C virus. Preventive health intervention, clinical evaluation, and treatment are available for all active duty personnel at risk of liver disease from infectious and non-infectious causes. Hepatitis C infection by itself does not render military personnel unfit for continued military service. As is true for other chronic health problems, individuals are medically evaluated and separated from the military when HCV infection interferes with the performance of routine military duties and the ability to meet fitness and retention standards.

In order to provide needed information about this infectious disease problem, the Department of Defense has initiated an extensive outreach effort, which is directed at both health care providers and beneficiaries. Every physician within DoD is being contacted and provided a brochure prepared by the CDC with important information about hepatitis C. The TRICARE communications office has initiated several programs to reach DoD beneficiaries who may need to be evaluated and tested for HCV infection. These efforts include a news release for Service public affairs officers to distribute to base newspapers and other media sources (like TRICARE contractor and regional newsletters). The TRICARE web page has a health update message on hepatitis C, which includes links to the CDC and National Institutes of Health (NIH) Internet sites on hepatitis C information (enclosure 4).

Military Veterans

In contrast to a relatively low level of HCV infection among active duty military personnel, the number of patients detected as having HCV infection has steadily increased over a several year period in VA health care facilities.⁴⁹An electronic survey of 125 VA Medical Centers conducted from February through December of 1997 identified nearly 15 thousand VA patients who tested positive for hepatitis C antibody.⁵⁰ VA transplant program data also indicate that 52% of liver transplant patients have hepatitis C virus infection.

Of greater concern are two recent studies of the prevalence of HCV infection in VA's patient population. A six-week inpatient survey at the VA Medical Center, Washington, DC, found anti-HCV in 20% of participants.⁵¹ A similar investigation at the VA Medical Center in San Francisco found 10-19% of patients to be antibody positive.^50,52The high levels of infection observed in these two studies may have been due to inner city drug abuse.⁵³ Whether VA patients living in areas with less illicit drug use are as frequently infected with HCV has yet to be determined.

High levels of liver disease and HCV infection among VA patients may be due to unique characteristics that distinguish this population from active duty and reserve military personnel and from the general community. The VA health care system primarily serves men, and about one-third of users are over age 65 and two-thirds have annual incomes below $20,000.⁵³ Substance abuse is a problem among some VA patient populations.

On June 11, 1998, the VA announced that it would begin screening veterans for hepatitis C virus infection based on the presence of risk factors for infection.⁵⁰ And on January 27, 1999, the VA announced that it would offer FDA approved combination drug treatment for HCV infection, when clinically indicated.⁵⁴

Coordinated Federal Response

Dr. Sue Bailey, Assistant Secretary of Defense (Health Affairs), initiated formation of an "Interagency Working Group on Hepatitis C Virus" on August 10, 1998. The intent of the working group is "to serve as a catalyst for bringing separate agencies closer together and for working toward development of appropriate strategies to both prevent new infections and minimize the impact of current hepatitis C virus infections on our civilian and military populations." The Working Group represents a forum to discuss issues related to HCV of common interest to the various Agencies and promote cooperation and collaboration regarding clinical and research initiatives. This working group is composed of public health officials from the CDC, NIH, VA, and DoD. Its first meeting was held on October 6, 1998.

Each Military Service has a representative on this interagency working group:

Army: Dr. Shailesh Kadakia for the Army (210-916-4578)

COL_Shailesh_Kadakia @bamc.smtplink.amedd.army.mil

Navy: Dr. W. Z. .McBride for the Navy (202-762-3495)

WZMcBride@us.med.navy.mil

Air Force: Dr. Dana Bradshaw for the Air Force (202-767-4286)

Dana.bradshaw@usafsg.bolling.af.mil

These representatives provide DoD health care professionals with the most recent guidance on screening and treatment of HCV infection. In addition, the NIH maintains an Internet site, which contains substantial amounts of information on hepatitis C: www.hepnet.com/nih/contents.html.

Assessment of Risks and Potential Intervention Strategies in DoD

The 1999 Senate Armed Services Committee Report No. 105-189 on S. 2060 directed the Department of Defense (DoD) to study the extent of service-connected hepatitis C infection, to include the advisability and feasibility of testing for hepatitis C virus during separation and retirement physicals. Such tests could increase the cost of separation and retirement physicals. However, early detection of hepatitis C may reduce costs to the Department of Defense and the Department of Veterans Affairs by reducing the rate of serious liver disease. Additionally, an individual identified as infected with hepatitis C would understand that he or she should not donate blood, thus assisting in maintaining a safe blood supply. The committee directed the Secretary of Defense to report the results of the study to the Committee on Armed Services of the Senate and the National Security Committee of the House of Representatives not later than March 31, 1999.

The Department had previously initiated a comprehensive hepatitis C research plan in 1998, which included: 1) the first large-scale, sero-epidemiological investigation of over 20,000 randomly selected military personnel; 2) analysis of DoD hospital records of inpatient admissions for acute and chronic viral hepatitis during the last 20 years; and, 3) cost analysis of testing for HCV infection. The goals of these investigations were to:

1. Determine the prevalence of hepatitis C virus infection among current U.S. military personnel and evaluate the risk of acquiring HCV infection during military service; and,

2. Provide information to assess various surveillance strategies for their effectiveness in identifying HCV infected military members, including the following possible approaches for anti-HCV testing --

Assessment at the time of routine blood donations and when clinically indicated during standard health screening and medical care within the Military Health Services System;

Assessment of potential military recruits at induction health screening, which would identify individuals who could not provide blood during military service, should refrain from alcohol consumption, and would need to be followed medically during a military career;

Assessment of military personnel at the same time as routine, periodic testing for HIV infection every 1 to 5 years; and,

Assessment of military personnel just prior to separation or retirement from the military, which would identify veterans who may need clinical follow-up in the VA health care system.

Investigation Methods

Serological Survey

In order to assess the prevalence and incidence of HCV infection, serum samples from varied populations were obtained from the DoD Serum Repository, which is used for surveillance of HIV infection and storage of serum samples collected before and after overseas deployments. Active duty personnel and selected Reservists routinely provide a venous blood sample for the serum repository every 1 to 5 years. For this investigation, all subjects were drawn at random from military personnel serving in 1997 who provided a serum sample. Subjects were chosen in proportion to the size of each major Service within the U.S. military: Army (34% of entire military force), Navy (26%), Air Force (27%), and Marine Corps (12%). No other selection criterion was used.

Because military personnel provide serial serum samples, the computerized database was scanned for prior samples of the selected subjects, and if any were available, the first serum sample obtained for the repository also was chosen. About 70% of military personnel in 1997 had more than two sequentially obtained serum samples in the repository. Analysis of sequential samples provided incidence data of infection during military service.

Serum samples and associated demographic data were given a unique investigation number. All personal identifiers were then removed from both single and matched samples and from computerized demographic data. Testing therefore was done anonymously, without the possibility of linking subsequent serological test results to individuals. Analyzable data included: serological test results, age, gender, race/ethnicity, marital status, home of record, service branch, rank, length of military service, and military job classification. The following population groups were evaluated initially:

A random selection of 10,000 active duty military personnel providing routine serum samples during the calendar year 1997. A random selection of service personnel was essential in order to determine the overall prevalence of HCV infection in the U.S. military.

A random selection of 2000 sera from selected Reservists providing a routine serum sample during the calendar year 1997.

A random selection of 2000 military recruits inducted during 1997.

Additional, random over-sampling of various groups that provided serum in 1997 is being conducted to obtain more precise estimates of the risk in these military populations --

Vietnam era personnel: 1000 personnel currently on active duty who had been serving in the military since January 1, 1974.

Active duty retirees with at least 20 years of military service: 2000 individuals.

Women: testing of 2000 active duty personnel is in progress.

Minority racial/ethnic groups: testing of 1000 active duty personnel is planned.

Over-sampling is being considered for the following groups --

Health care personnel: 1000 individuals

Officers: 1000 active duty members

Sample size calculations were based on the prevalence of HCV infection in prior studies of U.S. military personnel and estimates of HCV infection in the civilian community. To detect a two-fold increase in prevalence among military personnel as compared to the general population, a sample size of 5000 has power of 99% (i.e., beta error of less than 0.01) to detect this difference at the alpha = 0.05 level (one-sided). Moreover, a sample size of 5000 allows for a 95% confidence interval to estimate the difference in prevalence in the military and the general civilian population to within +/- 0.6%. The statistical methods employed were standard methods for comparing the differences in binomial proportions, which use the binomial and Chi-square distributions for hypothesis testing and confidence interval estimation. A Type I error of alpha = 0.05 was assumed.

The most recently collected serum samples initially were screened for anti-HCV using commercial, second generation EIA test kits (Abbott HCV EIA 2.0; Abbott Laboratories, Abbott Park, IL). Sera that were reactive were re-tested in duplicate by EIA. Repeatedly reactive samples by EIA were then tested by immunoblot assay (Chiron RIBA HCV 2.0; Chiron Corporation, Emeryville, CA). Only samples that were reactive by both EIA and immunoblot assay were considered positive. For samples found positive or indeterminate by RIBA, any previously collected, matching serum sample was tested by EIA and RIBA.

A selection of samples that were indeterminate by RIBA were further tested by RT-PCR at the CDC to evaluate positivity.⁵⁵

Hospitalization Study

DoD hospitalization databases were evaluated to determine how frequently the Military Health System cares for active duty personnel who either develop acute viral hepatitis or require medical care for chronic hepatitis. This part of the DoD effort was a continuation of a prior investigation of medical records for hospital admissions due to viral hepatitis.⁴⁶

In DoD hospitals, a summary of discharge information is maintained in a computerized database. Diagnoses at discharge are coded using the International Classification of Diseases (ICD). Data are available for hospitalizations within Navy medical centers since 1975 and for all hospitalizations within the military health care system since 1989. A military member's first hospital admission per year for viral hepatitis was used for this analysis.

Cost Analysis

The purpose of this analysis was to estimate the one time costs of detecting HCV infection using three potential HCV testing strategies: 1) screening of recruits at the Military Entrance Processing Station (MEPS); 2) all force testing of active duty and selected Reserve personnel; and, 3) testing of retiring/separating active duty and selected Reserve service members.

Decision analyses using a cost and outcome analytic model were conducted from a military perspective using DATA 3.0, TreeAge Software, Inc., Williamstown, MA (enclosure 6). Estimated costs were approximated in 1998 dollars. No future costs were considered; consequently, discounting was not performed. The medical outcome was defined as an identified case of HCV infection. The case finding potential of each strategy was based on initial data obtained from the current sero-prevalence investigation using serum repository samples. Observed prevalence estimates were age adjusted and assumed to estimate the true population prevalence.

Assay sensitivities were derived from the available literature and expert opinion. Economic outcomes were defined as all screening-related program costs, as well as the costs of lost recruiting and processing associated with a recruit applicant disqualified because of HCV infection. Program costs included cost of serum collection (materials, personnel, and overhead), cost of initial and confirmatory assays, and cost of preliminary clinical work-up based on confirmed HCV infection. Testing for anti-HCV was modeled independently from the HIV screening program.

All screening costs assumed initial testing of sera by EIA according to manufacturer guidelines, confirmation of repeatedly reactive EIA results using RIBA, and testing of RIBA indeterminate samples by RT-PCR. Additionally, all HCV infected individuals received an initial work-up, including an internal medicine outpatient visit and PCR (if not done as part of diagnosis) and viral genotyping. Lost productivity for time of tests and work-up was not considered. For recruit applicants processing through the MEPS, HCV infection was presumed to be a disqualifying condition. Initial clinical work-ups and RT-PCR were not conducted for individuals not inducted into the military.

Results were extrapolated to a recruit entry applicant pool of 300,000 persons receiving entry physicals per year for active duty (Office of Assistant Secretary of Defense - Force Management Policy [OASD-FMP], Washington, DC, 1999) and 141,000 for Reserves/National Guard (OASD - Reserve Affairs [RA], 1998). For total military force screening, active duty and selected Reserve personnel were considered for testing. Results were extrapolated to 1,480,000 active duty and 934,000 Reserve population totals (Defense Manpower Data Center, Monterey, CA, 1999). Individuals retiring or separating from the active duty military or the selected Reserves were analyzed in aggregate (totals from DMDC, 1996, and OASD-RA, 1998, respectively; enclosure 6).

Results of DoD Investigations

Serological Survey

To date, testing has been completed on a random sample of greater than 17,000 military personnel, including: 1) 10,000 active duty troops; 2) 2000 recruits; 3) 2000 selected Reservists; 4) 1000 Vietnam era troops; and, 5) 2000 retirees. The demographic characteristics of the initial population of 10,000 active duty personnel were very similar to the overall military population. Also, the sample of Reservists had comparable demographic characteristics to the overall Reserve population, which is older than active duty troops. The mean age of the sample of active duty personnel was 28.2 years, and the mean age of surveyed Reservists was 34.7 years.

The overall prevalence of anti-HCV among active duty troops was 0.48% (95% CI, 0.3 to 0.6%) (table 2). The prevalence of infection among recruits was just 0.1% (95% CI, 0 to 0.36%).

Table 2. Prevalence of anti-HCV by RIBA among evaluated military personnel

% Positive (number positive/number tested)*

Category

Recruits

Active Duty

Reservists

(n = 2000)

(n = 10,000)

(n = 2000)

Sex

Male

0.1 (2/1649)

0.5 (43/8428)

0.6 (9/1593)

Female

0 (0/351)

0.3 (5/1572)

1.2 (5/407)

Age groups (in year)

<19

0.2 (2/1305)

0 (0/1127)

0 (0/173)

20 - 24

0 (0/537)

0.1 (2/3189)

0 (0/240)

25 - 29

0 (0/87)

0.1 (2/2091)

0.8 (2/255)

30 - 34

0 (0/16)

0.3 (5/1551)

0.4 (1/256)

35 - 39

0 (0)

1.1 (14/1219)

1.7 (4/240)

> 40

0 (0/1)

3.0 (25/823)

1.2 (7/587)

Race/ethnicity

White

0.08 (1/1294)

0.4 (26/6951)

0.5 (7/1415)

Nonwhite

0.14 (1/706)

0.7 (22/3043)

1.3 (7/527)

Rank

Enlisted

0.1 (2/1956)

0.5 (42/8492)

0.9 (14/1557)

Officer

0 (0/44)

0.4 (6/1508)

0 (0/440)

*Denominator totals vary slightly because of missing demographic information.

For Reservists, who tend to be older than active duty personnel, the overall prevalence of infection (0.54% after adjusting for the younger age of the active duty sample) was comparable to other troops. Enlisted personnel and nonwhite racial/ethnic groups had a higher prevalence of HCV infection; female troops generally had a lower level of infection. A higher risk of HCV infection was found in older military personnel. Among 12,810 active duty personnel, the prevalence of infection was:

0.1% in 7958 troops < 35 years of age (1 per 1000 troops)

1.5% in 1305 troops 35-39 years of age

1.8% in 3547 troops > 39 years of age

Active duty troops who had been on duty during the Vietnam era had a lower prevalence of infection than general military personnel of similar age (tables 2 and 3). The level of infection in 1997 among retirees with a mean age of 45 years was 1.7% (95% CI, 1.2 to 2.4%).

Table 3. Prevalence of anti-HCV by RIBA among evaluated military personnel

% Positive (no positive/no tested)

Category

Vietnam Era

Retirees

(n = 1000)

(n = 2000)

Sex

Male

1.0 (10/960)

1.7 (31/1869)

Female

0 (0/40)

2.3 (3/131)

Age groups (in years)

< 19

0 (0)

0 (0)

20 - 24

0 (0)

0 (0)

25 - 29

0 (0)

0 (0)

30 - 34

0 (0)

0 (0)

35 - 39

0 (0)

5.8 (5/86)

> 40

1.0 (10/1000)

1.7 (29/1724)

Race/ethnicity

White

0.4 (3/788)

1.0 (15/1434)

Nonwhite

3.3 (7/211)

3.4 (19/565)

Rank

Enlisted

1.7 (7/412)

2.2 (27/1228)

Officer

0.5 (3/587)

0.9 (7/751)

Incidence data were available for the random selection of 10,000 active duty personnel. In this group, a previous serum repository sample had been obtained from 7,368 troops (74%). There was a mean interval of 4.6 years between sequential serum samples, which provided 34,020 person-years of exposure. In this cohort, 6 individuals seroconverted to anti-HCV for an annual incidence of 18 new infections per 100,000 troops (0.018% per year). This risk translates into 1 new HCV infection each year among every 5,670 troops, or approximately 252 new HCV infections per year in 1.4 million active duty troops.

As expected in mass screening of a low risk population, false positive serologic test results were common. In the initial testing of 5000 randomly-selected, active duty personnel, there were 44 samples that were repeatedly reactive by EIA and required immunoblot confirmation. Among these 44 EIA reactive samples, just one-half (22) were RIBA positive and 7 were indeterminate. For the 2000 tested recruits, a greater number of serum samples were indeterminate by RIBA (3 samples ) than positive (2 samples). Importantly, none of these indeterminate samples was positive by RT-PCR when tested at the CDC.

Hospitalization Study

Analysis of hospitalizations within military hospitals for acute hepatitis shows a steady decline in admissions during the last 20 years (figure 1). All types of viral hepatitis have declined in the U.S. military (figure 2). Drug abuse was associated with hospitalizations for viral hepatitis in this military population,⁴⁶ and the decline in admissions for viral hepatitis have paralleled the decrease in illicit drug use within DoD.⁴⁸

In 1997, there were 300 hospitalizations for acute hepatitis within DoD hospitals in a population of over 1.4 million active duty personnel (figure 3). Among these admissions for viral hepatitis, just 62 (21%) patients were diagnosed with acute hepatitis C. As in prior studies, the risk of viral hepatitis was higher among men and nonwhite racial/ethnic groups.^4,56

Hospitalization of active duty personnel for chronic hepatitis and cirrhosis has been very infrequent in recent years. In the U.S. Navy, there were just 5 admissions for chronic hepatitis in 1996 and 13 in 1995. For all of DoD in 1997, there were 39 admissions for chronic hepatitis and 131 for cirrhosis among active duty personnel.

Cost Analysis

Testing all incoming recruits at MEPS for a year would cost approximately $4,300,000 in screening and lost recruiting efforts for active duty recruitment and approximately $2,000,000 for Reserve/National Guard recruitment (tables 4 and 5). An estimated 148 cases of HCV infection among active duty recruits and 70 cases among Reserve/National Guard recruits would be identified at a cost of $29,000 per case. Because so few military applicants have chronic viral hepatitis, any policy on HCV infection would have negligible impact on current retention standards.

One time total force screening for all active duty military would cost about $20,000,000 in screening program costs and initial work-up costs. An estimated 4,419 cases of HCV infection would be identified at a cost of $4,500 per case. Force testing of all selected Reserve military personnel would cost $13,000,000 in screening program and initial work-up costs. An estimated 4,394 cases of HCV infection would be identified at a cost of $2,900 per case.

Testing all active duty members at separation or retirement would cost $3,200,000 in screening program costs and initial clinical evaluation costs. An estimated 723 cases of HCV infection would be found at a cost of $4,400 per case. Testing active duty individuals at separation or retirement older than 34 years would cost $900,000, which would identify 632 cases of HCV infection at a cost of $1,400 per case. Screening individuals 35 years of age and older would thus target more than 87% of potentially infected individuals leaving active military duty.

Table 4. One time estimated costs of HCV screening of active duty members

Number

Total Costs

Number cases

Costs per case

Category

Tested

identified

identified

Recruits

300,000

$4,300,000

148

$29,000

Total Force

1,48,000

$20,000,000

4419

$4,500

Retirement/Separation

All

234,000

$3,200,000

723

$4,400

35 years of age and older

43,100

$900,000

632

$1,400

Testing all selected Reserve members at separation or retirement would cost about $2,000,000 in screening program costs and initial clinical evaluation costs. An estimated 818 cases of HCV infection would be identified at a cost of $2,400 per case of HCV infection. Testing Reserve personnel older than 34 years at separation would cost $600,000 and identify approximately 351 infections at a cost of $1,700 per case.

Table 5. One time estimated costs of HCV screening of Selected Reserves

Number

Total Costs

Number cases

Costs per case

Category

Tested

identified

identified

Recruits

141,000

$2,000,000

70

$29,000

Total Force

875,000

$13,000,000

4394

$2,900

Retirement/Separation

All

126,000

$2,000,000

818

$2,400

35 years of age and older

32,500

$600,000

351

$1,700

The results of this one-time cost analysis should be used as a tool in conjunction with other considerations to determine the best HCV screening policy for the military. It is important to note that after initiating screening of military personnel using any one of these three strategies, the cost per case identified could greatly increase for the other strategies because many cases already would have been identified. Therefore, implementation of all strategies would greatly increase the costs of identifying each HCV infection. Also, a screening program will require more than testing of individuals for hepatitis C infection. Provision also has to be made for clinical evaluation, counseling on prognosis, treatment, reducing transmission risks, and finally long-term medical follow-up. Any screening policy will have to consider potential adverse social and personal consequences of being identified as infected with HCV or potentially infected when testing is inconclusive.

The large number of false positive tests by EIA and indeterminate confirmatory test results highlights a problem found when screening is conducted in a population with a low prevalence of disease: test results have a low positive predictive value. Therefore, a screening program will have to provide for the confirmation of indeterminate results, which will add to the difficulties of counseling tested individuals and to the complexity and cost of the program.

Conclusion

The risk of hepatitis C infection among U.S. military personnel was found to be substantially less than in the civilian community. The 0.48% prevalence of infection in active duty troops was more than three times lower than the 1.8% prevalence found in the CDC study of the general U.S. population. Although military personnel are at lower risk, the demographic characteristics of infected individuals were similar in both populations. As true for many other infectious diseases, military personnel reflect the problem in the civilian community but at reduced overall levels of disease burden.

These data are consistent with the previous CDC study of the general civilian population, which identified a lower risk of hepatitis C infection among military veterans. These results are also consistent with previously published studies of hepatitis C infection among active duty troops. In this investigation of active duty troops serving in 1997, the prevalence of infection was 0.48%, which is almost the same prevalence found among 3000 active duty Navy and Marine Corps personnel serving in 1988-1990^41,42 and also among U.S. military recruits surveyed more than 40 years ago.²³Although there may have been an increase in HCV infection during the 1960's, current military personnel have a very low risk of infection that may be similar to the levels seen among troops of the WWII and Korean War generation.

Importantly, the incidence of hospital admissions for acute viral hepatitis has been steadily declining during the last 20 years in the U.S. military, and there has been a steep decrease in the rate of new hepatitis C virus infections in the civilian population. At present, hepatitis C is primarily a problem among individuals who have ever injected illegal drugs. Because of low levels of drug use in the military, hepatitis C infection is much less a problem in this population. The decreased risk of viral hepatitis infection among active duty forces can be attributed to existing DoD programs, including:

High induction standards, which include testing for illicit drug use and the human immunodeficiency virus (HIV) virus infection

Routine, randomized drug screening throughout military service

Routine medical screening and examinations of active duty and Reserve personnel

Routine physical performance testing that identifies chronic health problems

Hepatitis C testing of blood donors and the donor/recipient "lookback" program

Universal precautions to prevent transmission of bloodborne infections

Total force hepatitis A immunization and risk-based hepatitis B immunization

The low prevalence of hepatitis C infection among active duty troops and randomly surveyed veterans in the general population have to be contrasted with reports of a 10-20% prevalence of infection in two populations of VA patients.⁵² The reason for this difference may be explained by the unique nature of VA patients and particular risk factors among the two study groups living in inner cities.^51,53

The data from current DoD investigations clearly demonstrate that military personnel are at low risk for HCV infection and do not support a requirement to deviate from national screening policy on HCV infection as established by the Centers for Disease Control and Prevention (enclosure 2). Based on the findings of a higher prevalence in older service members, the Department will implement a targeted risk-based testing program using CDC screening guidelines for individuals who are 35 years of age or older and are separating or retiring from military service (enclosure 3). This risk-based testing program has been reviewed by the members in the "Interagency Working Group on Hepatitis C Virus." The results of screening and subsequent evaluation, counseling, and treatment will be annotated in the service member's permanent medical record, which will provide continuity of care within the Department of Veterans Affairs health care system.

The DoD also has initiated an aggressive provider and patient education program (enclosure 4). This effort emphasizes increased awareness of the risk factors for hepatitis C infection so that potentially exposed individuals and their health care providers understand the need for testing and counseling. Additionally, every physician within DoD is being contacted and provided a brochure prepared by the CDC with important information about the risk, diagnosis, and treatment of hepatitis C.

The future health care burden of higher rates of HCV transmission during past decades is difficult to predict but could be substantial in the civilian community.⁵⁷ Also, current treatment for chronic hepatitis C is only partially effective and there is little prospect for developing a vaccine in the near-term. Further clinical research therefore is critical in order to develop improved treatment regimens.

References

__________________________________________________________________

Alter MJ. Epidemiology of hepatitis C in the West. Semin Liver Dis 1995;15:5-14.

Di Bisceglie AM. Hepatitis C. Lancet 1998;351:351-355.

Choo Q-L, Kuo G, Weiner AJ, et al. Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 1989;244:359-362.

McQuillan GM, Alter MJ, Moyer ILA, Lambert SB, Margolis HS. A population based serologic study of hepatitis C virus infection in the United States. In: Rizzetto M, Purcell RH, Gerin JL, Verme G. Viral Hepatitis and Liver Disease. Turin, Italy: Edizioni Minerva Medica, 1997.

NIH Consensus Program. National Institutes of Health Consensus Development Conference Panel Statement: Management of hepatitis C. Hepatology 1997;26(Suppl 1):2S-10S.

Centers for Disease Control. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV–related chronic disease. MMWR, Recommendations and Reports 1998;47:1-39.

Thomas SL, Newell M-L, Peckham CS, Ades AE, Hall AJ. A review of hepatitis C virus (HCV) vertical transmission: risks of transmission to infants born to mothers with and without HCV viraemia or human immunodeficiency virus infection. Int J Epidemiol 1998;27:108-117.

Thomas DL, Villano SA, Riester KA, et al. Perinatal transmission of hepatitis C virus from human immunodeficiency virus type 1 - infected mothers. J Infect Dis 1998;177:1480-1488.

Donahue JG, Nelson KE, Munoz A, et al. Antibody to hepatitis C virus among cardiac surgery patients, homosexual mean, and intravenous drug users in Baltimore, Maryland. Am J Epidemiol 1991;134:1206-1211.

van Doornum GJJ, Hooykaas C, Cuypers MT, et al. Prevalence of hepatitis C virus infections among heterosexuals with multiple partners. J Med Virol 1991;35:22-27.

Brettler DB, Mannucci PM, Gringeri A, et al. The low risk of hepatitis C virus transmission among sexual partners of hepatitis C-infected males: An international, multicenter study. Blood 1992;80:540-543.

Thomas DL, Zenilman JM, Alter HJ, et al. Sexual transmission of hepatitis C virus among patients attending Baltimore sexually transmitted diseases clinics -- An analysis of 309 sexual partnerships. J Infect Dis 1995;171:768-775.

Conry-Cantilena C, VanRaden M, Bibble J, et al. Routes of infection, viremia, and liver disease in blood donors found to have hepatitis C virus infection. N Engl J Med 1996;334:1691-1696.

Donahue JG, Munoz A, Ness PM, et al. The declining risk of post-transfusion hepatitis C virus infection. N Engl J Med 1992;327:369-373.

Schreiber, GB, Busch, MP, Leeinman SH, Korelitz JJ. The risk of transfusion-transmitted viral infections. N Engl J Med 1996;334:1685-1690.

Mitsui T, Iwano K, Masuko K, et al. Hepatitis C virus infection in medical personnel after needlestick accident. Hepatology 1992;16:1109-1114.

Lanphear BP, Linnemann CC, Cannon CG, DeRonde MM, Pendy L, Kerley LM. Hepatitis C virus infection in healthcare workers: Risk of exposure and infection. Infect Control Hosp Epidemiol 1994;15;745-750.

Alter MJ, Margolis HS, Krawczynski K, et al. The natural history of community-acquired hepatitis C in the United States. N Engl J Med 1992;327:1899-1905

Di Bisceglie AM. Hepatitis C and hepatocellular carcinoma. Hepatology 1997;26:34s-38s.

Poynard T, Bedossa P, Opolon P, for the OBSVIRC, METAVIR, CLINIVIR, DOSVIRC groups. Natural history of liver fibrosis progression in patients with chronic hepatitis C. Lancet 1997;349:825-32.

Seeff LB, Bisle;;-Bales Z, Wright EC, et al. Long-term mortality after transfusion- associated non-A, non-B hepatitis. N Engl J Med 1992;327:1906-11.

Seeff LB, Hollinger FB, Alter HJ, et al. Updated long-term mortality of transfusion-associated hepatitis. American Association for the Study of Liver Diseases, Chicago, IL, November 1998, Abstract

Seeff LB, Miller RN, Rabkin CS, et al. 45-50 year follow-up of hepatitis C virus (HCV) infection among young military recruits. American Association for the Study of Liver Diseases, Chicago, IL, November 1998, Abstract

Crowe J, Doyle C, Fielding JF, et al. Presentation of hepatitis C in a unique uniform cohort 17 years from inoculation. Gastroenterology 1995;108:A1054, Abstract.

Tong MJ, El-Farra NS, Reikes AR, Co RL. Clinical outcomes after transfusion-associated hepatitis C. N Engl J Med 1995;332:1463-1466.

Tong MJ, El-Farra NS. Clinical sequelae of hepatitis C acquired from injection drug use. West J Med 1996;164:399-404.

Niederau C, Lange S, Heintges T, et al. Prognosis of chronic hepatitis C: Results of a large, prospective cohort study. Hepatology 1998;28:1687-1695.

Manesis EK, Moschos M, Brouzas D, et al. Neurovisual impairment: A frequent complication of alpha-interferon treatment in chronic viral hepatitis. Hepatology 1998;27:1421-1427.

Poynard T, Leroy V, Cohard M, et al. Meta-analysis of interferon randomized trials in the treatment of viral hepatitis C: effects of dose and duration. Hepatology 1996;24:778-89.

Reichard O, Norkrans G, Fryden A, et al. Randomised, double-blind, placebo-controlled trial of interferon alpha-2b with and without ribavirin for chronic hepatitis C. Lancet 1998;351:83-87.

McHutchison JG, Gordon SC, Schiff ER, et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N Engl J Med 1998;339:1485-1492.

Davis GL, Esteban-Mur R, Rustgi V, et al. Interferon alfa-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C. N Engl J Med 1998;339:1493-1499.

International Interferon-alpha Hepatocellular Carcinoma Study Group. Effect of interferon-alpha on progression of cirrhosis to hepatocellular carcinoma: a retrospective cohort study. Lancet 1998;351:1535-1539.

Imai Y, Kawata S, Tamura S, et al. Relation of interferon therapy and hepatocellular carcinoma in patients with chronic hepatitis C. Ann Intern Med 1998;129:94-99.

Serfaty L, Chazouilleres O, Pawlotsky JM, Andreani T, Pellet C, Poupon R. Interferon alfa therapy in patients with chronic hepatitis C and persistently normal aminotransferase activity. Gastroenterology 1996;110:291-295.

McConnell J. Hepatitis treatment moves on. Lancet 1998;352:964.

Farci P, Alter HJ, Wong DC, et al. Prevention of hepatitis C virus infection in chimpanzees after antibody-mediated in vitro neutralization. Proc Natl Acad Sci USA 1994;91:7792-7796.

Zaaijer HL, Cuypers HTM, Reesink HW, et al. Reliability of polymerase chain reaction for detection of hepatitis C virus. Lancet 1993;341:722-724.

Hyams KC, Cross ER, Bianco MA, Soyk-Sarty DR, Roper CM, Dahut WL, Holmberg JA. Geographic risk factors for viral hepatitis and cytomegalovirus infection among United States Armed Forces blood donors. Transfusion 1992;32:644-647.

Hyams KC, Struewing JP, Gray GC. Seroprevalence of hepatitis A, B, and C in a United States military recruit population. Mil Med 1992;157:579-582.

Hawkins R, Malone JD, Cloninger LA, Rozmajzl PJ, Lewis D, Butler J, Cross E, Gray S, Hyams KC. Risk of viral hepatitis among military personnel assigned to US Navy ships. J Infect Dis 1992;165:716-719.

Brodine S, Hyams KC, Molgaard CA, Ito SI, Thomas RJ, Roberts CR, Golbeck AL, Oldfield EC, Blattner WA. The risk of human T-cell leukemia virus and viral hepatitis infection among US Marines stationed in Okinawa, Japan. J Infect Dis 1995;171:693-696.

Hyams KC, Krogwold RA, Brock S, Cross E, Wignall SF, Hayes C. Heterosexual transmission of viral hepatitis and cytomegalovirus among U.S. military personnel stationed in the western Pacific. J STD 1993;20:36-40.

Malone JD, Hyams KC. Hepatitis C infection in a HIV-1 positive military population. J AIDS 1992;5:427-428.

McCarthy M, Kim JP, Le TP, Cross E, Hyams KC. Chronic liver disease among military patients: The role of hepatitis C and G virus infection. Manuscript in review.

Hyams KC, Palinkas LA, Burr RG. Viral hepatitis in the US Navy, 1975-1984. Am J Epidemiol 1989;130:319-326.

Schneider L, Geha R, Magnuson WG. Outbreak of hepatitis C associated with intravenous immunoglobulin administration -- United States, October 1993-June 1994. MMWR 1994;43:505-509.

Bray RM, Project Director. 1998 Department of Defense Survey of Health Related Behaviors Among Military Personnel. Research Triangle Institute; Research Triangle Park, North Carolina, February 1999.

Roselle GA, Mendenhall CL, Danko LH. A four-year review of patients with hepatitis C antibody in Department of Veterans Affairs facilities. Mil Med 1997;162:711-714.

Kizer, KW. Under Secretary for Health's Information Letter -- Hepatitis C: Standards for Provider Evaluation and Testing, Department of Veterans Affairs, Veterans Health Administration, Washington DC. IL 10-98-013, June 11, 1998.

Pham DQ, Walse D, Montgomery J, Buskell-Bales Z, Collier K, Lokken G, Claggett J, Wilson L, Biswas R, Gibert C, Seeff LB. Seroepidemiology of hepatitis C and B in an urban VA medical center. Hepatology 1994;326A.

Late M. Action urged to stem hepatitis C. U.S. Medicine 1998;April:3,4243.

Ashton CM, Petersen NJ, Souchek J, et al. Geographic variations in utilization rates in veterans affairs hospitals and clinics. N Engl J Med 1999;340:32-39.

Health Agencies Update. Hepatitis C drugs for veterans. JAMA 1999;281:600.

Wolfe L, Tamatsukuri S, Sayada C, et al. Detection of HCV RNA in serum using a single-tube, single enzyme PCR in combination with a colorimeteric microwell assay. In: "Hepatitis C Virus: New Diagnostic Tools, ed. Group Francais d'Estudes Moleculaires des Hepatites, GEMHEP. John Libbey, London, 1994; pp 83-94.

McQuillan GM, Coleman PJ, Kruszon-Moran D, Moyer LA, Lambert SB, Margolis HS. Prevalence of hepatitis B virus infection in the United States: The National Health and Nutrition examination Surveys, 1976 through 1994. Am J Public Health 1999;89:14-18.

El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med 1999;340:745-750.

Enclosures

_______________________________________________________________

Enclosure 1: Defense Authorization Bill, Fiscal Year 1999; Report Language (1999 Senate Armed Services Committee Report No. 105-189 on S. 2060)

Enclosure 2: CDC MMWR, Recommendations and Reports: October 16, 1998 / 47(RR19);1-39

Enclosure 3: Proposed Hepatitis C Virus (HCV) Antibody Screening Policy

Enclosure 4: Hepatitis C Health Watch on Tricare web page

Enclosure 5: DoD blood donor lookback and recipient notification

Enclosure 6: Model Parameter Values -- probability and costs

Enclosure 1

Defense Authorization Bill, Fiscal Year 1999

Report Language (1999 Senate Armed Services Committee Report No. 105-189 on S. 2060)

HEPATITIS C TESTING: The committee understands that the incidence of service-connected hepatitis C infection may be increasing. The committee directs the Secretary of Defense to study the extent of service-connected hepatitis C infection, to include the advisability and feasibility of including an antibody or antigen test sufficient to detect hepatitis C virus during separation and retirement physicals. Such tests could increase the cost of separation and retirement physicals. However, early detection of hepatitis C may reduce costs to the Department of Defense and the Department of Veterans Affairs by reducing the rate of serious liver disease. Additionally, an individual identified as infected with hepatitis C would understand that he or she should not donate blood, thus assisting in maintaining a safe blood supply. The committee directs the Secretary of Defense to report the results of the study to the Committee on Armed Services of the Senate and the National Security Committee of the House of Representatives not later than March 31, 1999.

Enclosure 2

CDC MMWR, Recommendations and Reports: October 16, 1998 / 47(RR19);1-39

Enclosure 3

Proposed Hepatitis C Virus (HCV) Antibody Screening Policy

According to the Centers for Disease Control and Prevention (CDC), testing should be offered routinely to persons most likely to be infected with HCV who might require medical management, and testing should be accompanied by appropriate counseling and medical follow-up (Recommendations for Prevention and Control of Hepatitis C Virus (HCV) Infection and HCV-Related Chronic Disease, Morbidity and Mortality Weekly Reports, October 16, 1998 / Vol. 47 / No. RR-19). In addition, anyone who wishes to know or is concerned regarding their HCV-infection status should be provided the opportunity for counseling, testing, and appropriate follow-up. The determination of which persons are at risk and who to recommend for routine testing is based on various considerations, including a known epidemiologic relationship between a risk factor and acquiring HCV infection, prevalence of risk behavior or characteristic in the population, prevalence of infection among those with a risk behavior or characteristic, and the need for persons with a recognized exposure to be evaluated for infection.

ACTION:

To determine the need for hepatitis C screening, the following statement will be administered and placed in the medical record for all Service personnel 35 years of age or older who separate or retire from military service.

Individuals who answer "yes" and want to be screened for HCV will receive testing for HCV antibody, including appropriate confirmatory testing. An individual does not have to specify a particular risk factor to justify screening.

If positive for HCV infection, the individual will receive appropriate clinical evaluation and treatment and receive counseling on lifestyle modifications and measures to protect others from infection.

H