Friday, April 18, 2014

Previous Exposure to HCV Among Persons Born During 1945–1965

Previous Exposure to HCV Among Persons Born During 1945–1965

Prevalence and Predictors, United States, 1999-2008

Bryce D. Smith, PhD, Geoff A. Beckett, PA-C, MPH, Anthony Yartel, MPH, Deborah Holtzman, PhD, Nita Patel, DrPH, John W. Ward, MD
Am J Public Health. 2014;104(3):474-481.

Abstract and Introduction

Objectives. We examined HCV exposure prevalence and predictors among persons in the United States born during 1945–1965.

Methods. With data from the 1999–2008 National Health and Nutrition Examination Survey, we calculated the proportion of persons born during 1945–1965 who tested positive for HCV antibody (anti-HCV) and analyzed the prevalence by sociodemographic and behavioral risk factors.

Results. Anti-HCV prevalence in the 1945–1965 birth cohort was 3.2% (95% confidence interval [CI] = 2.8%, 3.8%), substantially higher than among other adults (0.9%). Within the cohort, anti-HCV prevalence was higher among non-Hispanic Blacks (6.4%; 95% CI = 5.3%, 7.7%), persons with injection drug use histories (56.8%; 95% CI = 48.4%, 64.8%), and persons with elevated alanine aminotransferase levels (12.7%; 95% CI = 10.7%, 15.1%). Injection drug use (adjusted odds ratio = 98.4; 95% CI = 58.8, 164.5) was the strongest anti-HCV prevalence predictor. Among anti-HCV–positive persons, 57.8% reported having 2 or more alcoholic drinks daily.

Conclusions. With the high prevalence of HCV among persons born during 1945–1965, the increasing morbidity and mortality associated with HCV, and reductions in liver cancer and HCV-related mortality when HCV is eradicated, it is critically important to identify persons with HCV and link them to appropriate care.

In the United States, the incidence of HCV infection rose dramatically through the 1970s and 1980s reaching more than 200 000 new infections per year through the mid- to late-1980s.[1] This high incidence resulted in a disproportionately high burden of HCV infection among Americans who were born between the mid-1940s and the mid-1960s, a birth cohort popularly referred to as the baby boom generation.[2] Alter et al. first documented the relatively high prevalence of HCV infection among this cohort in their analysis of1988–1994 National Health and Nutrition Examination Survey (NHANES) data, reporting that 65% of persons with HCV infection were aged 30 to 49 years during the survey period.[3] In an analysis of NHANES data from 1999 to 2002, a similarly high proportion of all persons with HCV antibody had been born from 1945 through 1964.[1] This cohort effect on the high prevalence of HCV infection in the baby boom generation has been attributed largely to exposures (principally injection drug use [IDU] and blood transfusion before 1992) that occurred many years before the survey periods.[1,3] However, a significant proportion of HCV-infected persons do not report any risk factors,[4–6] perhaps because of fear of being stigmatized,[7] or simply lack of recall or knowledge of exposures such as those that may occur in health care settings.[8,9]

A validated Markov model forecasting lifetime morbidity and mortality attributable to HCV infection projected that of 2.9 million persons with untreated HCV infection who did not have cirrhosis of the liver in 2005, 1 071 000 (36.8%) will die from complications of HCV.[10] In the United States, HCV-associated disease is the leading indication for liver transplantation and HCV infection is a leading cause of hepatocellular carcinoma.[11–14] Approximately 73.9% of HCV-associated mortality occurs among persons born from1945 to 1965.[15]

In 1998, the Centers for Disease Control and Prevention recommended[16] that persons with certain risk factors (e.g., any history of IDU) or medical conditions (e.g., persistently elevated alanine aminotransferase [ALT] levels) be tested for HCV infection. Despite these recommendations, testing practices over the past decade have had limited success in identification of HCV infection in the United States as estimates of the proportion of persons who are unaware of their infection range from 40% to 85%.[17–20] Contributing to the limited success of the recommendations is the difficulty in obtaining risk behavior history that occurred in the distant past, the primarily asymptomatic nature of the infection, and a less than optimal level of physician knowledge regarding the natural history and prevalence of infection, the current recommendations for testing, and interpretation of test results.[21–24]

In 2011, the prospects for successful medical treatment of HCV infection were significantly improved with the US Food and Drug Administration licensure of 2 direct-acting antiviral medications, both in the protease inhibitor class. In clinical trials, the rates of sustained viral response—equivalent to a "virological cure"—increased from 44% with use of the current standard regimen, to 75% when a direct-acting antiviral medication was added to that regimen in treatment of persons infected with HCV genotype 1, the genotype that is most common in the United States.[25] Since this article was accepted for publication, the US Food and Drug Administration has approved new HCV medications[26,27] that have further increased cure rates to as high as 90% in clinical trials.

Persons who achieve a sustained viral response after treatment experience significantly less liver-related morbidity (including hepatocellular carcinoma),[28] less liver-related mortality,[29] and reductions in all-cause mortality.[30] However, the potential population benefits from these improvements in treatment effectiveness will be limited unless there are concurrent increases in the rate of identification and treatment of HCV-infected persons.[31]

Because of the limited effectiveness of risk based testing strategies to date and the high prevalence of HCV infection and projected disease burden, the Centers for Disease Control and Prevention recently issued the Recommendations for the Identification and Initial Care of Chronic Hepatitis C Virus Infection Among Persons Born During 1945–1965[32] with the goal of identifying persons with HCV infection who are undiagnosed. The recommendation was subsequently made by the US Preventive Services Task Force.[33] The purpose of the current study was to determine the proportion of persons in the birth cohort who were positive for antibody to HCV (anti-HCV), and to examine the sociodemographic and behavioral risk factors associated with anti-HCV prevalence.

We analyzed NHANES data collected from 1999 to 2008. NHANES is an annual nationally representative multistage, stratified probability cluster survey of the US civilian, noninstitutionalized population. Information on the survey design and implementation, including institutional review board approval and consent, is detailed in the survey documentation.[34,35]
Anti-HCV testing is administered to NHANES participants aged 6 years or older. We restricted our analysis to adult participants born from 1945 to 1965 who were interviewed and provided serum samples for anti-HCV testing. Birth year was estimated by subtracting participant age at time of survey from estimated year in which participant was surveyed. Because NHANES does not release data on participant birth year or the actual year in which a participant was interviewed or examined, we estimated the earliest survey year for each participant according to the variable, "six month time period when the examination was performed: November 1 through April 30, May 1 through October 31." As an example, for the 1999–2000 survey cycle, participants examined from November 1 to April 30 were assigned an earliest survey year of 1999 and those examined from May 1 through October 30 were assigned to the 2000 survey year. We excluded participants without specimens for testing and those with indeterminate anti-HCV results from the final analytic sample.

Outcome Variable
The outcome measure was anti-HCV prevalence as determined by serologic testing. We chose anti-HCV status as an endpoint because HCV RNA testing was not performed for the 2003–2004 NHANES cycle, and we determined that combining data from all 10 years (1999–2008) was necessary to achieve sufficient subdomain sample sizes for improved precision and reliability of point estimates.

Specimens were tested for antibodies to HCV by repeated enzyme-linked immunosorbent assay (ELISA version 3.0, Ortho Diagnostic Systems Inc, Raritan, NJ). Reactive specimens were confirmed by recombinant immunoblot assay (RIBA version 3.0, Chiron Corporation, Emeryville, CA). Participants who tested positive by both ELISA and RIBA were categorized as anti-HCV–positive.

Independent Variables
We examined the following independent variables as potential predictors or confounders of anti-HCV prevalence within the birth cohort: race/ethnicity, gender, country of birth, veteran status, marital status, educational attainment, family income, health insurance status, daily alcohol consumption within the past 12 months, age at first sexual intercourse, number of lifetime sexual partners, lifetime IDU (cocaine, heroin, and methamphetamine), history of blood transfusion before 1992, and ALT level.[1,3] We categorized race/ethnicity as non-Hispanic White, non-Hispanic Black, Mexican American, and other. We categorized educational attainment as completed less than high school and completed high school or more; marital status as married or living with partner, divorced or separated or widowed, and never married; and family income as greater than 2 times federal poverty threshold, 1 to 2 times federal poverty threshold, and less than the federal poverty threshold. We defined elevated ALT as 40 or more international units per liter. For independent variables with 10% or more of observations with missing values, we created an "unknown" category to include those missing values as valid for analysis. Accordingly, we categorized alcohol consumption as 0 or 1, 2 or more, and unknown number of drinks per day within the past year; age at first sexual intercourse as 17 years or younger, 18 years or older, and unknown; number of lifetime sexual partners as 0 to 9, 10 to 19, 20 or more, and unknown; lifetime drug use as never, non–injection drug use, IDU, and unknown.
NHANES questions related to sexual behavior and history of IDU are restricted to adult participants younger than 60 years. Thus, all analyses involving these variables in the current study were similarly restricted.

Statistical Analysis
We generated proportions and 95% confidence intervals (CIs) to describe the characteristics of the 1945–1965 birth cohort. We also produced estimates of anti-HCV prevalence in the birth cohort and by subgroups. We specified linear contrasts of estimates to test for statistical differences in characteristics between anti-HCV–positive participants and all participants, and to test for differences in anti-HCV prevalence between subgroups. We assessed statistical reliability of estimated proportions by evaluating relative standard errors (< 30%) and by ensuring that subdomains met NHANES minimum sample size requirements. We generated unadjusted odds ratios from univariate logistic regression models. We defined statistical significance as P value less than .05.

We developed a multivariate logistic regression model to identify independent risk factors associated with anti-HCV positivity within the birth cohort after we controlled for covariates. We specified an estimated full model by including all independent variables with a P value of less than .1 from the univariate analyses. Using a backward elimination procedure, we removed variables with the lowest observed partial F-statistic at a predetermined P value of less than .1. We simultaneously tested for 2-way interaction effects between race and IDU or gender and IDU, by using multiple partial F-tests. We assessed multicollinearity among covariates by review of diagnostic statistics including variance inflation factors (> 2.5), condition indices (> 15), and variance proportions (> 0.5; SAS version 9.3, SAS Institute, Cary, NC). In deciding whether to exclude a covariate because of collinearity, we also considered the relative importance of the covariate, its relationship with key variables such as IDU, and its contribution to the overall model fit.

We used the Hosmer–Lemeshow goodness-of-fit test to evaluate the overall fit of the final model. Except as otherwise specified, we analyzed all data with SAS-callable SUDAAN to account for the complex survey design (version 10.0.1, Research Triangle Institute, Research Triangle Park, NC). We rescaled sample weights after combining data across multiple survey years. We estimated variance and standard errors by using the Taylor series (linearization) method

We identified a total of 8167 participants estimated to be born from 1945 to 1965 who were both interviewed and examined. After we excluded participants without specimens (n = 411) and those with indeterminate anti-HCV results (n = 33), the final analytic sample for the birth cohort was 7723 (95% of those examined). Table 1 shows the demographic, behavioral, and clinical characteristics of the birth cohort population and those in the cohort who were anti-HCV–positive. Relative to the total birth cohort population, a greater proportion of anti-HCV–positive participants were male, non-Hispanic Black, had a family income below the poverty threshold, and had no health insurance coverage. Among anti-HCV–positive participants, 41.9% reported a history of IDU, 16.2% received a blood transfusion before 1992, 57.8% consumed 2 or more alcoholic drinks per day, and 51.3% had elevated ALT levels. Combined, persons with a history of IDU or blood transfusion accounted for 51.7% of anti-HCV–positive participants; 48.3% reported no known exposure risks.

Prevalence of Anti-HCV in the Birth Cohort
Prevalence estimates for the birth cohort and subgroups are presented in Table 2. The overall prevalence of anti-HCV in the birth cohort was estimated at 3.2% (95% CI = 2.8%, 3.8%) or approximately 2.8 million (2.4 million to 3.2 million) persons with anti-HCV. Anti-HCV prevalence was higher among men (4.3%; 95% CI = 3.6%, 5.2%), non-Hispanic Blacks (6.4%; 95% CI = 5.3%, 7.7%), and persons with a family income below the poverty threshold (7.8%; 95% CI = 6.3%, 10.0%), respectively, compared with women, non-Hispanic Whites, and persons with a family income of more than 2 times the poverty threshold.

Table 2.  Characteristics and Risk Factors Associated With HCV Antibody Prevalence Among Adults Born From 1945 to 1965: National Health and Nutrition Examination Survey, 1999–2008
CharacteristicParticipants Tested, No.Prevalence of Anti-HCVUnadjusted Odds Ratios
% (95% CI)P a Unadjusted OR (95% CI)P
Overall77233.2 (2.8, 3.8)
   Female (Ref)39112.2 (1.7, 2.9)1.0
   Male38124.3 (3.6, 5.2)< .0012.0 (1.4, 2.8)< .001
   Non-Hispanic White (Ref)36482.9 (2.3, 3.6)1.0
   Non-Hispanic Black17006.4 (5.3, 7.7)< .0012.3 (1.7, 3.0)< .001
   Mexican American15643.3 (2.4, 4.4).511.1 (0.8, 1.6).5
Marital status
   Married or living with partner (Ref)51702.7 (2.2, 3.4)1.0
   Divorced, separated, or widowed16404.3 (3.3, 5.5).241.6 (1.1, 2.3).02
   Never married7475.7 (4.0 8.0).0042.2 (1.4, 3.3)< .001
Country of birth
   United States58363.6 (3.1, 4.2)< .0013.3 (1.9, 5.6)< .001
   Other (Ref)18841.1 (0.7, 1.8)1.0
Education level
   £ high school38384.8 (4.0, 5.9)< .0012.3 (1.7, 3.1)< .001
   > high school (Ref)38792.2 (1.8, 2.7)1.0
Family income to poverty threshold
   > 2 times (Ref)44642.1 (1.7, 2.7)1.0
   1–2 times15245.6 (4.2, 7.5)< .0012.8 (1.9, 4.1)< .001
   Below11837.8 (6.3, 9.6)< .0013.9 (2.9, 5.3)< .001
Health insurance coverage
   Yes (Ref)59192.7 (2.3, 3.1)1.0
   No17576.2 (4.8, 8.0)< .0012.4 (1.8, 3.3)< .001
Served in the US armed forces
   No (Ref)67653.0 (2.5, 3.5)1.0
   Yes9555.1 (3.7, 6.9).011.7 (1.2, 2.5).004
Average no. of alcoholic drinks/d, last y
   0–1 (Ref)24921.2 (0.8, 1.8)1.0
   ‡ 232724.3 (3.6, 5.3)< .0013.7 (2.3, 5.9)< .001
   Unknown19594.2 (3.3, 5.2)< .0013.6 (2.3, 5.6)< .001
Age at first sexual intercourse (up to 59b y; n = 7210), y
   £ 1732585.0 (4.3, 5.9)< .0013.7 (2.5, 5.5)< .001
   ‡ 18 (Ref)28711.4 (1.0, 2.1)1.0
   Unknown10813.5 (2.5, 5.0).0042.5 (1.5, 4.4)< .001
No. of lifetime sexual partners (up to 59b y; n = 7210)
   0–9 (Ref)45071.4 (1.0, 2.0)1.0
   10–199163.9 (2.6, 5.7).0012.9 (1.8, 4.6)< .001
   ‡ 2011339.9 (8.2, 11.9)< .0017.8 (5.2, 11.8)< .001
   Unknown6544.5 (3.1, 6.5).0013.3 (1.9, 5.7)< .001
Lifetime drug use (up to 59b y; n = 7210)
   Never (Ref)51011.2 (0.9, 1.6)1.0
   Non-IDU12803.7 (2.8, 4.8)< .0013.1 (2.1, 4.5)< .001
   IDU18756.8 (48.4, 64.8)< .001107.0 (69.3, 165.1)< .001
   Unknown6424.7 (3.3, 6.8)< .0014.0 (2.5, 6.6)< .001
Blood transfusion before 1992
   No (Ref)70302.9 (2.5, 3.5)1.0
   Yes5816.7 (4.8, 9.4).0022.4 (1.6, 3.5)< .001
Serum alanine aminotransferase level, U/L
   < 40 (Ref)65991.8 (1.5, 2.2)1.0
   ‡ 40105612.7 (10.7, 15.1)< .0018.0 (6.0, 10.5)< .001
Note. Anti-HCV = HCV antibody; CI = confidence interval; IDU = injection drug use; OR = odds ratio.

aObtained by specifying linear contrasts of proportions among the levels of the subgroups.

bNational Health and Nutrition Examination Survey data collection on certain risk factors was limited to participants aged 20–59 years at time of survey; accordingly the 2005–2006 and 2007–2008 National Health and Nutrition Examination Survey cycles do not contain data risk factor for participants born in 1945–1946 and 1945–1948, respectively.

Among participants reporting a history of IDU, 56.8% (95% CI = 48.4%, 64.8%) were anti-HCV–positive compared with 1.2% (95% CI = 0.9%, 1.6%) for those who had never used any illicit drugs. Persons who received a blood transfusion before 1992 had a higher prevalence of anti-HCV (6.7%; 95%CI = 4.8%, 9.4%) than did those without this history (2.9%; 95% CI = 2.5%, 3.5%). Among persons with elevated ALT levels, 12.7% (95% CI = 10.7%, 15.1%) were anti-HCV–positive relative to 1.8% (95% CI = 1.5%, 2.2%) for those with normal ALT levels.

Factors Associated With Anti-HCV Prevalence Within the Birth Cohort
Unadjusted odds ratios (ORs) and 95% CIs for characteristics associated with anti-HCV prevalence are displayed in Table 2. Men, non-Hispanic Blacks, and persons with a family income below the poverty threshold, respectively, were more likely to be anti-HCV–positive compared with women, non-Hispanic Whites, and persons with family income of more than 2 times the poverty level. Injection drug use was the strongest predictor of anti-HCV prevalence among the birth cohort. Other characteristics significantly associated with anti-HCV prevalence were elevated ALT level, consumption of 2 or more alcoholic drinks per day, sexual intercourse before age 18 years, 20 or more lifetime sexual partners, and blood transfusion before 1992.

After we controlled for covariates in a multivariate logistic regression model (Table 3), IDU (adjusted OR = 98.4; 95% CI = 58.8, 164.5) remained the strongest predictor of anti-HCV prevalence. We also identified the following variables as significant risk factors for anti-HCV prevalence in the multivariate model: elevated ALT level (9.0; 95% CI = 6.0, 13.7), a family income below the poverty threshold (4.7; 95% CI = 3.0, 7.4), US-born (3.2; 95% CI = 1.7, 6.1), non-Hispanic Black race (2.3; 95% CI = 1.7, 3.2), and blood transfusion before 1992 (2.3; 95% CI = 1.3, 4.0). We removed number of sexual partners and age at first sexual intercourse from the multivariate model because of collinear relationships with IDU. No interaction terms were significant.

These findings highlight the relatively high prevalence of anti-HCV (3.2%) among persons in the 1945–1965 birth cohort compared with the prevalence among adults aged 20 to 70 years during the 1999–2008 survey period, but born before 1945 or after 1965 (0.9%; unpublished Centers for Disease Control and Prevention data); persons in the birth cohort were 4 times more likely to be anti-HCV–positive than adults outside the cohort. Our finding that history of IDU, blood transfusion, elevated ALT, Black race, and poverty were associated with HCV infection within the birth cohort is consistent with previous findings based on the general US adult population.[1,3] However, IDU and blood transfusions before 1992, the most common exposure risks reported by persons infected with HCV, account for only 52% of infections and the remaining 48% report no known exposure risk and may not be identified through risk-based testing approaches. Testing for HCV infection on the basis of the birth cohort presents an opportunity to identify a significant proportion of cases that may otherwise go undetected in a subpopulation that accounts for approximately 75% of the burden of HCV infection in the adult US population.[5] The 1945–1965 birth cohort has the highest incidence of HCV-related liver disease and death, which is projected to increase sharply over the next 2 decades.[10,36,37]

Most persons in the birth cohort are likely to have been infected for 20 to 40 years or more, and multiple models have indicated that there will be dramatic increases in the numbers of HCV-infected persons with significant liver disease over the next 10 to 20 years[31,38] without effective public health interventions. Even with declining prevalence in the overall US population, HCV disease burden is expected to increase significantly because of the aging of the infected population.[10,36] Identification of HCV-infected persons and planning for care and therapy now, however, will improve efforts for long-term care and management of the infected population.[39] Although treatment response is better among persons younger than 40 years than those aged 40 years or older, persons older than 65 years have been shown to respond as well to therapy as those between the ages of 40 and 65 years, a fact that will become increasingly important as the birth cohort ages into retirement.[40]

For HCV-infected persons for whom antiviral treatment is indicated,[41] there have been recent medical advances that significantly improve the efficacy of therapy. Unfortunately, HCV treatment rates are low.[42] We found that almost one third of anti-HCV–positive persons in this cohort report being uninsured, a problem that certainly contributes to low treatment rates and difficulty accessing care. Expansion of coverage for medical care could increase access to care and treatment.
Even for those infected persons who do not receive antiviral medication, because of treatment contraindications or for other reasons, interventions are available that may limit disease progression and decrease HCV transmission to other persons. Reducing alcohol use can prevent exacerbation of liver disease. In our analysis, however, we found that nearly 58% of anti-HCV–positive persons in the birth cohort reported drinking 2 or more alcoholic drinks per day on average. Alcohol use is associated with development and progression of fibrosis and significant increase in liver-related and overallmortality.[41,43,44] Among HCV-infected persons, history of and current moderate alcohol use (approximately 2 drinks/day or less) have been found to be associated with a 2-fold increase in all-cause mortality and 7-fold increase for those who report drinking 2 or 3 drinks per day.[43] The prevalence of alcohol use among anti-HCV–positive birth cohort members suggests that use of Screening and Brief Interventions for Referral for Treatment of the Reduction of Alcohol Use as recommended by the US Preventive Services Task Force may be beneficial.[45] It has furthermore been suggested that, among heavy drinkers, knowledge of HCV-positive status and brief counseling received from health care providers upon diagnosis may be important factors in the reduction of alcohol use.[46,47]

There are limitations in this study. First, NHANES samples include only the US civilian, noninstitutionalized population. A large number of high-risk persons who are incarcerated, institutionalized, or homeless are excluded; thus, these analyses are likely to result in an underestimate of anti-HCV prevalence. Second, behavioral risk-factor data were limited to participants aged 60 years or younger. As a consequence, for the 2005–2006 NHANES cycle, no risk-factor information was available for participants born during 1945–1946 (who would have been aged 60–61 years during the 2005–2006 cycle). Likewise, there were no risk factor data for participants born during 1945– 1948 in the 2007–2008 cycle. Third, nearly all risk-factor data used in this analysis were self-reported. Participants may overreport or underreport behaviors in response to questions such as IDU or number of lifetime sexual partners, which might bias our results. Fourth, participant birth year was approximated from estimated year of interview and age at survey.
Finally, we did not examine differences by sociodemographic and risk characteristics between persons who knew and those who did not know their HCV-infection status (positive or negative) before testing because prior knowledge of HCV-infection status is not assessed for NHANES participants. However, among participants who test positive for anti-HCV or those with an indeterminate test result for anti-HCV plus a positive HCV-RNA, NHANES conducts a separate follow-up survey to ascertain knowledge of HCV infection status before receiving notification of results from NHANES. Although analyses[31,48] of the follow-up survey data have suggested differences— by age, access to health care, knowledge of risk factors—between HCV-positive persons who were aware of their status versus those who were unaware, those findings are by themselves limited by small sample sizes, low survey response rates, and their lack of generalizability to all persons, HCV-positive or -negative.

This study provides additional evidence of the high prevalence of anti-HCV among persons in the 1945–1965 birth cohort consistent with earlier studies of infection prevalence. Considerable racial and socioeconomic disparities by anti-HCV positivity status also are apparent within the cohort. High rates of alcohol use reported by anti-HCV–positive respondents suggest the importance of diagnosing infection and providing effective interventions to decrease alcohol consumption and slow the progression of liver disease. In light of the high prevalence of HCV infection among persons born during 1945–1965, the increasing morbidity and mortality associated with HCV infection, and reductions in liver cancer and HCV-related mortality when HCV infection is eliminated, it is critically important to identify those persons living with hepatitis C and link them to appropriate care and treatment.


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