Population-Based Hepatitis C Surveillance and Treatment in a National Managed Care Organization

, , ,
The American Journal of Managed Care, April 2004, Volume 10, Issue 4

Objectives: To use a national population-based automatedclaims database to study the testing rate, prevalence, and prescribingpatterns for chronic hepatitis C.

Study Design: A retrospective descriptive study that analyzesmedical and pharmacy automated claims from affiliated healthplans in 4 regions of the United States.

Methods: Data were collected from 11 UnitedHealth Group–affiliated health plans (3.9 million members) from January 1, 1997,to December 31, 1999. Medical claims were used to identify personstested for hepatitis C virus (HCV). Persons with chronic HCVwere identified through medical and pharmacy claims. Patterns ofdrug use and treatment were analyzed, including prescribingphysician specialty and proportion of patients receiving baselineand follow-up testing.

Results: Of 27 871 members tested for HCV (0.7%), 1869(6.7%) were diagnosed as having chronic HCV. Tested patientswere more likely to be female (odds ratio [OR], 1.1) and older (≥25years; OR, 4.1). Of 3259 patients with HCV, most were male (OR,1.8) and older (≥25 years; OR, 32.0). Of these patients, 33.6% (n =670) of men and 25.2% (n = 319) of women received treatment.Combination therapy users were more likely to undergo baseline(OR, 4.8) and follow-up (OR, 6.2) testing compared with interferonalfa monotherapy users.

Conclusions: Of the total population, 0.7% were tested forHCV, of whom 6.7% were diagnosed as having chronic HCV.Although women were more likely to undergo testing, prevalenceand therapy rates for chronic HCV were higher in men. Mostpatients did not receive recommended baseline and follow-up testing,and the approximate 30% therapy rate suggested that manypatients with HCV remain untreated.

(Am J Manag Care. 2004;10:250-256)

During the past 2 decades, hepatitis C virus (HCV)has been recognized as a silent epidemic and anemerging public health threat.1,2 Estimates bythe Centers for Disease Control and Prevention suggestthat approximately 4 million persons in the UnitedStates are infected with HCV.2 Many have not beendiagnosed, because fewer than 20% are symptomatic3and the condition may be latent.4 Chronic HCV infectionis the leading cause of liver transplantation in theUnited States and Europe.5 Hepatitis C virus also mayaccount for a 2-fold increase in the incidence of hepatocellularcarcinoma between 1975 and 1998.6 The totalsocietal cost estimates may be as high as $600 millionper year in the United States.2

Healthy People 2000

Most of the prevalence data on hepatitis C in theUnited States are derived from the National Health andNutrition Examination Study (NHANES) study, whichwas a survey of noninstitutionalized civilians carriedout between 1988 and 1994. The prevalence of anti-HCV was 1.8%, indicating that there were 3.9 millionpersons infected with HCV, of whom 2.7 million hadchronic infection.7 Prevalence rates vary according tothe population studied. A San Francisco VeteransAdministration medical center study8 of more than1000 patients indicated an anti-HCV prevalence of 18%,while another study9 of homeless veterans suggested anHCV prevalence of 42%. The global prevalence of anti-HCV is estimated at 2.9%, with lower prevalence ratesnoted in Western Europe, Australia, and SoutheastAsia.10 11 set a goal of decreasingthe prevalence of this virus from 18.3 per 100 000 personsin 1987 to 13.7 per 100 000 persons in 2000.Healthy People 201012 specifies the additional goal ofreducing new cases of HCV from 2.4 per 100 000 personsin 1996 to 1 per 100 000 persons in 2010.

Managed care organizations (MCOs) are key sites forsurveillance of the prevalence and treatment of HCV forseveral reasons. First, healthcare delivery has increasinglyshifted from the public sector to private healthcaresystems through MCOs. Second, the age group most frequentlydiagnosed as having HCV, ages 30 to 49 years, islikely to be employed and covered by employer-insuredhealthcare. Approximately 93% of privately insured personsreceiving coverage from their employer are enrolledin managed care.13 Third, a national MCO setting provides population-based automated data to determine theprevalence and treatment pattern of HCV in the generalmedical community. Previous studies have focused onselect regional practices, rather than a broader comparisonacross several geographic areas.14 In addition, mostof the published literature on the treatment of HCV summarizesclinical trials that may not reflect treatment patternsin the general medical community.15

The objectives of this retrospective population-basedadministrative claims study were to determine theprevalence of chronic HCV infection in a national MCOby age, sex, geographic region, and insurance type; toquantify the rate of testing for HCV in a national MCOby these same factors; and to characterize the prescribingof medications for HCV, including patterns of druguse and treatment.

METHODS

Data Source and Study Population

Employer-insured and Medicaid-covered populationsof 11 geographically diverse health plans affiliated withUnitedHealth Group were included in this study. These11 plans, with 3.9 million persons enrolled fromJanuary 1, 1997 to December 31, 1999, were located inthe following geographic regions: Midwest (6 plans, 2.1million enrollees), Southeast (3 plans, 1.1 millionenrollees), Northeast (1 plan, 450 000 enrollees), andWest (1 plan, 326 000 enrollees). The plans were mostlyindependent practice association models, contractingwith large networks of physicians typically reimbursedon a discounted fee-for-service basis.

UnitedHealth Group maintains longitudinally linkedcomputerized claims research databases.16,17 The dataused in this study include enrollment files with demographics,outpatient pharmacy claims, and physicianand facility claims. The prescription claims databasecontains information on prescription drugs dispensed tohealth plan members in the ambulatory care settingfrom retail pharmacies. Employer-insured members paida higher copayment for brand drugs compared withgeneric equivalents. Medications not on the PreferredDrug List were available to enrollees for a higher copayment.Physician claims include services provided byphysicians and other health care providers on an outpatientbasis (including laboratory tests), whereas hospitaland other facility claims include emergency care andinpatient services provided to health plan members.

Analyses were conducted in the aggregate and bygeographic region. Patient confidentiality was preservedbecause the files used for the study analyses did notcontain patient-specific identifiers. An independentinstitutional review board approved this study.

Testing for HCV

Current ProceduralTerminology-4 (CPT-4)

During the 3-year study, outpatient physician andfacility claims were used to identify members whounderwent testing for HCV, using HCV antibody andHCV RNA tests. Hepatitis C testing was defined as atleast 1 outpatient claim with a procedure code for 1 or more ofthe following: (1) hepatitis C antibody test (86803); (2)hepatitis panel (80059) that includes hepatitis A, B, andC antibody tests; (3) hepatitis C confirmatory test(86804); or (4) HCV RNA test (87520, 87521, or 87522)used to confirm active infection and monitor diseaseprogression during drug therapy. Laboratory tests frominpatient facility claims were not included in the studybecause they could not reliably identify tests for HCV,as they are bundled under hospital billing codes. Therate of HCV testing by age, sex, geographic region, andinsurance type (employer-insured vs Medicaid) was calculated,using each health plan's enrollee population asa denominator.

Patients With Chronic HCV

InternationalClassification of Diseases, Ninth Revision (ICD-9)

A combination of physician, facility, and pharmacyclaims files was screened during the study to identifyhealth plan members with chronic HCV, defined as havingat least 1 primary or secondary diagnosiscode for chronic HCV (070.44 or 070.54) or at least 1prescription for interferon in combination with ribavirin.The prevalence rate of chronic hepatitis C by age group,sex, geographic region, and insurance type was calculatedusing enrollee population as a denominator.

Patterns of Drug Use and Treatment

The automated outpatient pharmacy claims ofpatients with chronic HCV were screened to determinethe proportion of patients receiving interferon monotherapy,combination interferon alfa-2b and ribavirintherapy, or no treatment. The following types of interferonwere included: interferon alfa-2a, interferon alfa-2b, interferon alfacon-1, and interferon alfa-n3.Interferons commonly used for the treatment of conditionsother than hepatitis C, such as multiple sclerosis,were excluded from this study (eg, interferon beta-1a,interferon beta-1b, and interferon gamma-1b). The percentagesof patients with interferon claims alone(monotherapy users), combination therapy claimsalone (combination therapy), or both interferon andcombination therapy claims (both) were calculated.The specialty type of the prescribing physician was alsodetermined based on the pharmacy claims.

Further analyses of drug treatment patterns, includingduration of treatment and baseline and follow-uptesting, were completed on a subset of patients meetingcertain criteria. First, patients had to be "new users" ofthese medications. A patient was considered a new userif he or she had no prescriptions for interferon or combinationtherapy during the 3 months before the firstprescription (index date). For some patients, a break intherapy of at least 3 months' duration may signify thestart of a new course of therapy. Second, new users hadto be continuously enrolled in the health plan, with nogap in enrollment greater than 32 days from at least 3months before the index date through 6 months afterthe index date (a minimum of 9 months' continuousenrollment). These additional criteria allowed forappropriate standardized comparisons across treatmentgroups because patients had to be enrolled at least 9months and were new users (of these medications).Duration of therapy was determined by calculating thenumber of months between the patient's first and lastprescriptions and then adding the days' supply amountof the final prescription.

Treatment Monitoring

Pharmacy claims were analyzed to determinewhether recommended guidelines for monitoring theresponse to drug therapy were followed. We determinedif a patient received a baseline HCV RNA (CPT codes,87520, 87521, or 87522) or alanine aminotransferase(CPT codes, 84460, 80058, or 80012-80019) test beforeinitiating treatment with interferon alone or combinationtherapy. In addition, we identified whether apatient received follow-up testing within the first 6months following treatment initiation.

Statistical Analysis

Data were analyzed using the Statistical AnalysisSystem program (SAS Institute Inc, Cary, NC). Rates ofchronic HCV and testing for HCV were calculated.Logistic regression analyses were conducted to evaluatethe effects of sex, age, geographic region, and insurancetype on the prevalence of chronic HCV and testing forthe disease. For the subset of patients receiving drugtherapy for chronic HCV, differences in the rates ofbaseline and follow-up testing also were examined.

RESULTS

Testing for HCV

Of 3.9 million members, 27 871 (0.7%) were tested forHCV (Table). More than half of those tested (53.3%)were female (n = 14 849). Women had a higher overalltesting rate (74.8%) than men (66.6%), 1.08; 95% confidenceinterval [CI], 1.05-1.10) (Figure 1). Testing ratesincreased with age from 119 per 100 000 for childrenyounger than 18 years of age, to 1461 per 100 000 forthe group aged 55 to 64 years. As expected, patients 25years or older were more likely than younger patients toundergo testing for HCV(OR, 4.1; 95% CI, 4.0-4.3).The Northeast region hadthe highest testing rate(1582/100 000), and theWest had the lowest(497/100 000). Comparedwith the Midwest region,patients in the Northeastwere significantly morelikely to undergo testing(OR, 2.5; 95% CI, 2.4-2.6).Medicaid beneficiaries hada higher rate of testing(917/100 000) comparedwith employer-insuredmembers (696/100 000)(OR, 1.6; 95% CI, 1.5-1.7).Of the patients who underwenttesting for HCV, 6.7%(n = 1869) had a claimsdiagnosis for chronic HCV.Whereas the testing ratewas higher for women,patients who were testedand diagnosed with chronic HCV were more likely to bemale (61.7% of those tested and diagnosed).

Disease Prevalence

Across the 11 health plans, 3259 members (0.08% ofthe total population) were identified as having chronicHCV based on the diagnosis codes in claims data(Table). Of these, 38.8% (n = 1265) were female. Asshown in Figure 2, the rate of chronic HCV was 64 per100 000 for women and 102 for 100 000 for men. Menwere significantly more likely to have a diagnosis codefor chronic HCV compared with women (OR, 1.76; 95%CI, 1.64-1.89). The group aged 45 to 54 years had thehighest observed prevalence rate of chronic HCV infection(277 per 100 000), followed by the group aged 35 to44 years (190/100 000). Persons younger than 25 yearshad the lowest disease prevalence (13/100 000). Thosediagnosed with chronic HCV tended to be 25 years orolder (OR, 32.0; 95% CI, 26.3-39.0). Compared with theMidwest, the Northeast region had the highest rate ofchronic HCV based on claims diagnosis codes(127/100 000) (OR, 1.6; 95% CI, 1.4-1.7). Overall,Medicaid beneficiaries had a higher rate of chronic HCVthan employer-insured members (OR, 4.3; 95% CI, 3.8-4.9), based on claims data.

Patterns of Drug Use and Treatment

Of 3259 patients with chronic HCV, 989 (30.3%)received treatment during the 3-year study. Approximately33.6% (n = 670) of men and 25.2% (n = 319) ofwomen underwent drug therapy for HCV. Most treatedpatients (67.7%) were men. The highest rate of treatedpatients was in the Northeast region (35/100 000) andthe lowest in the West (13/100 000). Of those whoreceived treatment, 22.3% were prescribed interferonmonotherapy, 58.0% were prescribed combination therapy,and 19.6% both therapies. Approximately 62.5% ofprescriptions for these medications were written by gastroenterologists,15.3% by primary care physicians, and12.7% by other specialists, including oncologists (5.2%),infectious disease specialists (3.6%), and hematologists(1.3%). A further 9.4% of prescriptions were obtained atfacilities such as hospitals, emergency departments, andurgent care centers.

Of the 989 patients with chronic HCV who underwenttreatment, 704 (71.2%) met the new user criteria(no treatment in the 3 months before the index date)and had continuous enrollment of at least 9 months.Subsequent analyses were conducted on this subset ofpatients, including duration of drug therapy and baselineand follow-up testing.

Of the 704 new users, 57.0% (n = 401) were combinationtherapy users, 22.9% (n = 161) were interferonmonotherapy users, and 20.2% (n = 142) received both.Of the 142 users of both, 78.9% (n = 112) were initiallyprescribed interferon monotherapy, and 21.1% (n = 30)initially received combination therapy. This suggeststhat many patients who received combination therapywere likely to have failed interferon monotherapy first.

As expected, duration of treatment was shorter forpatients who received combination therapy only (median,5 months; range, <1 to 24 months) than for those whoreceived interferon monotherapy (median, 7 months;range, <1 to 32 months). Patients filling prescriptions forboth interferon and combination therapy had the longestduration of treatment (median, 14 months; range, 2-37months), with 53.5% (76/142) taking more than 1 year tocomplete the course of treatment for both therapies.

Of combination therapy users, 64.8% (260/401) completedthe standard 6-month therapy regimen within 6months, while 75.8% (122/161) of interferon monotherapyusers completed the standard 12-month therapy regimenwithin 12 months. These criteria are based on therecommended course of therapy. The proportion of treatedpatients who discontinued therapy within the first3 months was 28.2% (113/401) for combination therapyusers and 19.9% (32/161) for interferon monotherapyusers. Although it is likely that these patientsdiscontinued therapy because of nonresponse, we cannotbe certain of this based on the claims data alone.

Treatment Monitoring

Of the 704 persons who received treatment forchronic HCV, 454 (64.5%) had a claim for baseline RNAor alanine aminotransferase testing before beginningdrug therapy. Figure 3 shows the percentage of patientsundergoing baseline testing by type of drug treatment(interferon monotherapy, combination therapy, orboth). Of 161 interferon-only users, 44.1% (n = 71)received baseline testing, compared with 78.3%(314/401) of combination therapy—only users. Only6.2% (10/161) of interferon-only users received an RNAtest and an alanine aminotransferase test, comparedwith 34.7% (139/401) of combination therapy users.The likelihood of receiving a baseline test was associatedwith the type of drug a patient was prescribed. Combinationtherapy users were significantly more likelythan interferon monotherapy users to receive a baselinetest (OR, 4.8; 95% CI, 3.2-7.2). Approximately 87% of allbaseline testing occurred between the ages of 35 and 54years, with the group aged 45 to 54 years having thehighest rate of baseline testing (44/100 000), followedby the group aged 35 to 44 years (27/100 000). Patients25 years or older also were more likely to get a baselinetest than younger patients (OR, 13.3; 95% CI, 2.7-65.0).No differences were found with respect to sex, geographicregion, or insurance type.

Overall, 32.5% (229/704) of patients receivedan RNA test within the first 6 months of treatment.For combination therapy—only users, thispercentage was higher at 41.6% (167/401),compared with 10.6% (17/161) for interferononlyusers. Combination therapy users alsowere significantly more likely to receive followuptesting compared with interferon monotherapyusers (OR, 6.2; 95% CI, 3.6-10.7). Nodifferences were found with respect to age, sex,geographic region, or insurance type.

DISCUSSION

Despite a significant decline in the incidenceof HCV infection during the pastdecade, morbidity and mortality amongpatients with chronic HCV will continue torise during the next 10 to 20 years, resulting ina substantial societal health and economic burden.18The cost of treating chronic liver disease from HCV willfall, in large part, on MCOs.19 Although research suggeststhat standard interferon and ribavirin combinationtherapies are cost effective,20-22 we found thatapproximately 70% of patients infected with HCV didnot receive antiviral therapy. This may have significantimplications for the economic burden during the next10 to 20 years. Many of these patients are likely to haveasymptomatic disease, which may also explain theirlow referral rate for treatment. Assuming a 20% referralfor treatment, a previous analysis of HCV screening inaverage-risk, asymptomatic patients was found not tobe cost effective.23 An increased referral pattern fortreatment and a higher disease progression mayimprove the cost-effectiveness ratio of screening.However, the approximate 30% treatment rate in ourstudy may still not be enough to show a cost benefit forscreening. In our study, men had a greater overallincidence of chronic HCV infection and were morelikely to receive drug therapy. Women, however, had ahigher rate of diagnostic testing. This suggests the needto promote awareness of risk factors to increasescreening for high-risk men in MCOs. In general, treatmentis cost effective, and although screening shouldbe reserved for patients at high risk, there is a need toincrease rates of referral for treatment.

The rate of treatment monitoring varied by the typeof drug therapy at baseline and during follow-up. Abouttwo thirds of patients treated for HCV had a claim forbaseline RNA or alanine aminotransferase testing, witha higher rate of testing for combination therapy (78.3%)than for interferon monotherapy (44.1%). The recommendationfor HCV RNA monitoring within 6 monthsof initiating therapy was followed only one third of thetime, again with a higher rate for combination therapy(41.6%) than for interferon monotherapy (10.6%).These findings suggest that increases in the rate of baselinetesting are needed and an even greater need existsto improve the rate of follow-up testing. This was especiallyevident for interferon monotherapy, althoughhigher rates of monitoring for the newer combinationtherapy suggest a trend toward increased rates of testing.

It is difficult to gauge how different our results wouldbe if our study included the current standard of carewith the combination of pegylated interferon and ribavirintherapy. The pegylated interferons were notavailable outside the clinical trial setting during ourstudy. There may have been an increased referral fortreatment due to the incremental benefits in terms ofsustained virologic response for the pegylated interferonand ribavirin therapy. If our study had been moved forwardby 18 months, the proportion of patients receivinginterferon monotherapy would have been expected todecline. Furthermore, we would have expected a higherproportion of patients to receive baseline HCV RNAtesting before initiation of combination therapy, as thisis an important predictor of response.

Several interesting patterns emerged regarding HCVsurveillance and treatment. With respect to geographiccomparisons, the health plan with the greatest testingrate also had the highest rate of HCV (Northeast),defined by claims for diagnosis or drug therapy. Thisunderscores the importance of testing to identify HCVand the need to provide subsequent treatment. In general,we found a greater prevalence of HCV in theMedicaid-covered population than among employerinsuredenrollees. Possible reasons may include a higherrate of injection drug use among the unemployed andpoor, as well as comorbid associations such as humanimmunodeficiency virus and alcohol use, which mayworsen liver injury and prompt earlier testing in thispopulation. However, many cases of HCV infection aredetected incidentally during routine health screening,when minor abnormalities of liver enzyme test resultsmay prompt further investigations.24

There are few studies of healthcare delivery topatients with HCV, and most of the interest appears tolie with optimizing current treatment regimens andresponse outcomes.25-27 A multidisciplinary approach isrequired to ensure adequate healthcare delivery andadherence to therapy. This requires the combinedefforts of healthcare providers such as the treatingphysician and assistants, psychiatrists, social workers,nurses, pharmacists, and other support care staff. Ourstudy indicated that many of the prescriptions werewritten by nongastroenterologists, and better educationamong primary care physicians regarding risk factorsmay lead to more appropriate HCV testing practices andsubsequent referral for treatment. However, there is discordanceregarding appropriateness of therapy for HCVinfection even among hepatologists.28 There is anonuniform practice of HCV testing and educationamong drug treatment programs. A significant proportionof these programs did not test for HCV, and residentialdrug-free programs were more likely to providebetter education and testing for HCV compared withoutpatient-based services.25 This may relate to differencesin available resources and more favorable patient-staffratios. There is a need to enhance healthcaredelivery systems to create a better link with screeningand referral patterns in the community setting.

Because our study is large and US population—based,covering different geographic locations, it summarizesinformation on HCV surveillance through testing andtreatment using an extensive automated claims database.Denominators are available through enrollmentfiles, allowing calculation of rates of testing and prevalenceof HCV infection using claims data. In addition,we are able to link patient characteristics and healthservices use across sites of care to provide a longitudinalperspective and use patterns of therapies. Mostimportant, we can estimate treatment patterns of HCVin the general medical community, in contrast to clinicaltrials conducted with a subset of the patient populationin tertiary and specialty centers. Analyzing testingpatterns, we also can compare actual clinical practicewith recommended guidelines.

As with any study based on administrative claimsdata, there are certain inherent limitations. We mayhave underestimated testing and prevalence becauseeach was claims-based and required the submission of abill for payment. Because providers were paid only aftersubmission of a bill, it is likely that this information iscomplete. Claims for nonparticipating providers also areincluded in the automated database. However, if a testwas conducted or a drug prescribed outside the managedcare system and not submitted, this informationwould not be available. For patients who may have beentested or received a diagnosis of HCV before enrollmentin this setting, such information also would not be partof the claims files. Therefore, although the rates of testingand treatment may be underestimated, comparativerates across subgroups should be accurate (such ascomparisons by sex or age group). Our method of classifyingpatients as having chronic HCV may overestimatethe number of patients with chronic disease(defined as having HCV RNA or polymerase chain reactiontesting) because we do not have access to the testresults for positive confirmation. Therefore, we alsostudied rates of treatment with HCV therapies. Due tocosts, we did not review medical records to validateclaims for HCV testing, diagnosis, or treatment. Finally,for those patients who discontinued treatment, thisstudy did not attempt to identify the reasons for discontinuationfrom submitted claims because these reasonsmay be multifactorial or not apparent.

In summary, this study allowed us to analyze someof the epidemiologic and treatment-related issues inchronic HCV infection from a larger, national frame ofreference outside the scope of the randomized clinicaltrial setting. The study also demonstrates the value ofstudying chronic HCV surveillance and treatment usingpopulation-based claims data in a national, employer-insuredmanaged care setting. Based on nearly 4 millionmembers in 11 geographically diverse health plans,the overall rate of HCV testing was 0.7%, of which 6.7%of patients were diagnosed based on claims for chronicHCV. Whereas the incidence and use of drug therapywere greater for men, women were more likely to betested for HCV. The low overall therapy rate of approximately30% suggests the need for development of drugtherapies with fewer adverse effects that may be suitablefor a larger number of patients infected with HCVand a greater awareness of appropriate therapies.

In addition, a greater understanding of recommendationsfor baseline and follow-up testing during thecourse of drug therapy is needed. This may beachieved by the implementation of guidelines for prevention,HCV testing, and treatment, along with theeducation of healthcare providers, as well as qualityassurance measures to ensure that recommendedpractices are followed. Simple algorithms and regularupdates through education meetings for primary careproviders may improve initial testing rates and ensurebetter counseling for infected patients. Collaborativetreatment and support networks among practices alsomay enhance testing rates and encourage attendanceat clinics. The provision of improved healthcare deliverysystems needs to be extended to special populationsthat do not have access to services or areineligible for current therapies. Healthcare providersinvolved in the care of these patients or other high-riskpopulations also need to be encouraged to regularlyattend educational programs regarding HCVinfection. Lessons learned from this population-basedstudy provide greater insight into community practiceas it relates to HCV infection and may help identifyimportant areas for further public health research andeducation.

Acknowledgments

We thank Paula Rheault for programming expertise andBharati Manda, MS, for statistical expertise.

From the UnitedHealth Group, Center for Health Care Policy and Evaluation, Minneapolis, Minn (DS, SDS), and the Duke Clinical Research Institute and Division of Gastroenterology, Duke University Medical Center, Durham, NC (KP, JGM).

No financial support was provided for this study, directly or through a third party.

The results of this study were presented in part at the 52nd Annual Meeting of the American Association for the Study of Liver Disease, November 9-11, 2001, Dallas, Tex.

Address correspondence to: Deborah Shatin, PhD, UnitedHealth Group, Center for Health Care Policy and Evaluation, 12125 Technology Drive, MN002-0260, Minneapolis, MN 55344. E-mail deborah_shatin@uhc.com.

N Engl J Med.

1. Alter MJ, Sampliner RE. Hepatitis C: and miles to go before we sleep. 1989;321:1538-1540.

Hepatitis C: SilentEpidemic, Mute Public Health Response, 105th Congress, 2nd Sess, HouseReport 105-820.

2. Committee on Government Reform and Oversight. Washington, DC: US Government Printing Office; October 1998.

Hepatology.

3. Hoofnagle JH. Hepatitis C: the clinical spectrum of disease. 1997;26:15S-20S.

MMWR Morb Mortal Wkly Rep.

4. Centers for Disease Control and Prevention. Recommendations for preventionand control of hepatitis C virus (HCV) infection and HCV-related chronic disease. 1998;47(RR-19):1-39.

Hepatology.

5. National Institutes of Health Consensus Development Conference Panel.National Institutes of Health Consensus Development Conference Panel statement:management of hepatitis C. 1997;26(suppl 1):2S-10S.

AnnIntern Med.

6. El-Serag HB, Davila JA, Petersen NJ, McGlynn KA. The continuing increase inthe incidence of hepatocellular carcinoma in the United States: an update. 2003;139:817-823.

N Engl J Med.

7. Alter MJ, Kruszon-Moran D, Nainan OV, et al. The prevalence of hepatitis Cvirus infection in the United States, 1988 through 1994. 1999;341:556-562.

Hepatology.

8. Briggs ME, Baker C, Hall R, Gaziano JM, et al. Prevalence and risk factors forhepatitis C virus infection at an urban Veterans Administration medical center. 2001;34:1200-1205.

J Clin Gastroenterol.

9. Cheung RC, Hanson AK, Maganti K, Keeffe EB, Matsui SM. Viral hepatitis andother infectious diseases in a homeless population. 2002;34:476-480.

Microbes Infect.

10. Ray Kim W. Global epidemiology and burden of hepatitis C. 2002;4:1219-1225.

Healthy People 2000:National Health Promotion and Disease Prevention Objectives for the Nation.

11. US Department of Health and Human Services. Washington, DC: Public Health Service; 1991.

Healthy People 2010:Understanding and Improving Health.

12. US Department of Health and Human Services. 2nd ed. Washington, DC: US Dept ofHealth and Human Services; 2000.

Source Book of Health InsuranceData, 1999-2000.

13. Health Insurance Association of America. Washington, DC: Health Insurance Association of America;1999.

J Viral Hepat.

14. Rosenberg DM, Cook SF, Lanza LL. Health care, treatment patterns and costof services for patients infected with chronic hepatitis C virus in a large insuredNew England population. 2000;7(5):361-367.

Med Care.

15. Brook RH, Lohr KN. Efficacy, effectiveness, variations, and quality: boundary-crossingresearch. 1985;23:710-722.

Pharmacoepidemiology.

16. Shatin D, Drinkard C, Stergachis A. UnitedHealth Group. In: Strom BL, ed. 3rd ed. New York, NY: John Wiley & Sons Ltd; 2000:295-305.

Med Care.

17. Quam L, Ellis LBM, Venus P, Clouse J, Taylor CG, Leatherman S. Usingclaims data for epidemiologic research: the concordance of claims-based criteriawith the medical record and patient survey for identifying a hypertensive population. 1993;131:498-507.

Am J PublicHealth.

18. Wong JB, McQuillan GM, McHutchison JG, Poynard T. Estimating futurehepatitis C morbidity, mortality, and costs in the United States. 2000;90:1562-1569.

Am J Manag Care.

19. Williams I. New epidemiologic data on hepatitis B and C. 1998;4(suppl):S667-S670.

Hepatology.

20. Younossi ZM, Singer ME, McHutchison JG, Shermock KM. Cost effectivenessof interferon alpha-2b combined with ribavirin for the treatment of chronic hepatitisC. 1999;30:1318-1324.

J Hepatol.

21. Buti M, Casado MA, Fosbrook L, Wong JB, Esteban R. Cost effectiveness ofcombination therapy for naive patients with chronic hepatitis C. 2000;33:651-658.

Gut.

22. Siebert U, Sroczynski G, Rossol S, et al, German Hepatitis C Model(GEHMO) Group, International Hepatitis Interventional Therapy (IHIT) Group.Cost effectiveness of peginterferon alpha-2b plus ribavirin versus interferon alpha-2b plus ribavirin for initial treatment of chronic hepatitis C. 2003;52:425-432.

Am J Med.

23. Singer ME, Younossi ZM. Cost effectiveness of screening for hepatitis C virusin asymptomatic, average-risk adults. 2001;111:614-621.

J ClinGastroenterol.

24. Sarbah SA, Younossi ZM. Hepatitis C: an update on the silent epidemic. 2000;30:125-143.

J Subst AbuseTreat.

25. Strauss SM, Falkin GP, Vassilev Z, Des Jarlais DC, Astone J. A nationwidesurvey of hepatitis C services provided by drug treatment programs. 2002;22:55-62.

J Clin Gastroenterol.

26. Navarro VJ, St Louis TE, Bell BP. Identification of patients with hepatitis Cvirus infection in New Haven County primary care practices. 2003;36(5):431-435.

Am J Gastroenterol.

27. Shehab TM, Orrego M, Chunduri R, Lok AS. Identification and managementof hepatitis C patients in primary care clinics. 2003;98(3)22:639-644.

Can J Gastroenterol.

28. Wang P, Yi Q, Scully L, Heathcote J, Krahn M. Indications for interferon/ribavirintherapy in hepatitis C patients: findings from a survey of Canadian hepatologists. 2003;17:183-186.