Wendi L. Kuhnert

The Prevalence of Hepatitis C Virus Infection in the United States, 1999 through 2002

Context The Third National Health and Nutrition Examination Survey (NHANES III), conducted between 1988 and 1994, indicated that 1.8% of people in the United States had been infected with hepatitis C virus (HCV), 70% of whom had chronic infection. Most anti-HCVpositive individuals were between 30 and 49 years of age. Contribution Data from the recent NHANES (19992002) show little change in anti-HCV prevalence, but peak prevalence has shifted to individuals between 40 and 49 years of age. More than 85% of HCV RNApositive individuals may be identified through targeted testing of 18% of adults between 20 and 59 years of age: persons with abnormal serum alanine aminotransferase levels, those who have used injection drugs, and those who received blood transfusions before 1992. Cautions Incarcerated and homeless people were not included in the survey. Implications Despite a decrease in new HCV infections, aging of chronically infected individuals may presage an imminent increase in complications. The Editors A decade ago, the Third National Health and Nutrition Examination Survey (NHANES III, 19881994) showed hepatitis C virus (HCV) to be the most common chronic bloodborne infection in the United States (1). An estimated 3.9 million people (1.8% of the population) tested positive for antibody to HCV (anti-HCV), and 2.7 million had chronic infection. Most (65%) anti-HCVpositive persons were 30 to 49 years of age and had been infected for fewer than 20 years. The genetic diversity of HCV circulating in the United States (2) and the pattern of age-specific prevalence (3, 4) both suggest that the incidence of infection increased substantially in the 1960s and 1970s and peaked in the 1980s. Identification of HCV-positive persons for appropriate counseling and management is the major focus of a national prevention program, and routine testing is recommended for persons most likely to have HCV infection (5). To determine the characteristics of HCV-infected persons in the general United States population today and to monitor trends in prevalence, we analyzed data on HCV infection from the most recent NHANES. Methods The National Center for Health Statistics has conducted NHANES periodically to compile nationally representative statistics on the health of the U.S. population (6). The most recent series was begun in 1999 and is designed to run continuously; data are released every 2 years. Our analysis includes data collected from 1999 through 2002. Participants were chosen according to a stratified, multistage algorithm to produce a representative sample of the civilian, noninstitutionalized population of all 50 states and the District of Columbia. Extensive efforts were made to ensure high participation rates, and all respondents were reimbursed for time and travel expenses (6). Initially, a questionnaire covering only nonsensitive topics was used to interview participants in person at home. Information on potentially sensitive subjects, such as sexual practices and illicit drug use, was obtained later at a mobile examination center by means of computer-assisted interviewing technology. The ethnicity of each participant was categorized as non-Hispanic white, non-Hispanic black, and Mexican American. Persons not fitting these categories were classified as other and were included in the total population. Blood samples were obtained at the mobile examination center (7). Only participants who were 6 years of age or older were eligible for HCV testing because of low sample volume in younger children. Laboratory Methods Serum specimens were sent to the Centers for Disease Control and Prevention, where they were tested for anti-HCV by using Ortho HCV enzyme-linked immunosorbent assay (ELISA), version 3.0 (Ortho-Clinical Diagnostics, Raritan, New Jersey). Supplemental recombinant immunoblot assays (RIBA) (Chiron RIBA HCV Strip Immunoblot Assay, version 3.0, Chiron Corp., Emeryville, California) were performed on all specimens that were repeatedly reactive by ELISA testing. For those specimens classified as positive or indeterminate by RIBA, separate, archived aliquots stored at 70C and suitable for nucleic acid amplification testing were submitted for quantitative HCV RNA testing using Cobas Amplicor HCV Monitor Test, version 2.0 (Roche Molecular Diagnostics, Pleasanton, California). If that result was below the level of detection, a qualitative assay (Amplicor HCV Test, version 2.0, Roche Molecular Diagnostics) was performed. Samples found to be reactive by enzyme immunoassay and confirmed by RIBA or Amplicor were considered to be anti-HCVpositive. Alanine aminotransferase (ALT) levels (reference range, 0 to 39 U/L) were measured in specimens that had been stored and shipped under appropriate refrigeration conditions (4C to 8C). Statistical Analysis All statistical analyses were performed with SUDAAN software (RTI International, Research Triangle Park, North Carolina) according to National Center for Health Statistics guidelines. We used appropriate study design variables and published weights that were further adjusted to compensate for missing anti-HCV values (8). These weights accounted for oversampling of certain demographic groups (6) and for nonparticipation such that the sum of the weights for persons with anti-HCV results equaled the U.S. civilian, noninstitutionalized population 6 years of age and older. To estimate the number of HCV RNApositive persons, these weights were further adjusted to compensate for the RIBA-positive and RIBA-indeterminate specimens that were unavailable for RNA testing because of inadequate specimen volumes. Proportions from univariable analyses were compared by using chi-square tests (as implemented in SUDAAN). The P values presented were not corrected for multiple comparisons; P values less than 0.05 were considered statistically significant. Two logistic regression models were used for multivariable analysis; 1 model was used for persons 20 to 59 years of age whose drug use and sexual practices data were available, and the other model was used for persons 60 years of age or older. Two variables, history of blood transfusion (both models) and injection drug use (persons 20 to 59 years of age), were forced into the models on the basis of substantial published data that has established them as risk factors for HCV infection. We sought the most parsimonious model by using these and all other variables that were significant at a P value less than 0.20 on univariable analysis. With the resulting model, we then examined the effect of adding other variables of interest, including those variables that had been excluded at earlier steps in the modeling process. In the final models, all first-order interactions were examined for statistical significance, epidemiologic plausibility, and the impact of their inclusion on the other model parameters. Role of the Funding Source No external funding was received for this study. Results Of 21509 participants 6 years of age or older, 17548 were interviewed and 15079 gave a blood sample suitable for anti-HCV testing (final response rate for testing, 70.1%). Among those who completed home interviews, participation rates did not differ significantly between those with and without risk factors for HCV infection. The weighted prevalence of anti-HCV in the United States was 1.6% (95% CI, 1.3% to 1.9%), corresponding to 4.1 million (CI, 3.4 million to 4.9 million) anti-HCVpositive persons (Table 1). Of anti-HCVpositive participants, 78.8% had specimens suitable for HCV RNA testing; 79.7% (CI, 70.4% to 86.6%) of these tested positive for HCV RNA. After we accounted for untested specimens, the nationwide prevalence of HCV RNA among all participants was 1.3% (CI, 1.0% to 1.5%), equating to 3.2 million (CI, 2.7 million to 3.9 million) HCV RNApositive persons. Table 1. Prevalence of Antibody to Hepatitis C Virus by Demographic Characteristics and Potential Risk Factors Demographic Characteristics Associated with HCV Infection Anti-HCV prevalence was significantly higher in men than in women (Table 1). Prevalence was also higher in non-Hispanic black participants than in either of the other 2 ethnic groups. Among persons younger than 50 years of age, prevalence of anti-HCV increased with age from 1.0% in those 20 to 29 years of age to a peak of 4.3% in those 40 to 49 years of age (Figure 1). Among older persons, anti-HCV prevalence decreased to 1.6% in persons 50 to 59 years of age and to 0.9% in persons 60 years of age and older. Prevalence was higher in men than in women in most age groups (Figure 1). The higher overall prevalence among non-Hispanic black persons compared with non-Hispanic white persons was almost entirely attributable to differences among older participants. Among participants 40 to 49 years of age, 9.4% of non-Hispanic black persons had positive results for anti-HCV compared with 3.8% of non-Hispanic white persons (P< 0.001); of participants 50 years of age or older, 3.3% of non-Hispanic black persons had positive results compared with 0.9% of non-Hispanic white persons (P= 0.002). The demographic group with the highest prevalence was non-Hispanic black men between 40 and 49 years of age (13.6% [CI, 10.0% to 18.2%]). Prevalence was not significantly different between non-Hispanic black and non-Hispanic white persons who were younger than 40 years of age (1.2% vs. 1.1%; P= 0.73). Participants who were born in the United States had a higher prevalence of anti-HCV than those who were not, and prevalence increased with decreasing family income and level of education (Table 1). Among men, prevalence did not vary according to service in the military (Table 1). The sample of women who had served in the military was too small to analyze. Figure 1. Prevalence of antibodies to hepatitis C virus ( HCV ) by ethnicity, age, and sex. The overall prevalence of anti-HCV in the current survey was similar to that observed in NHANES III, but the peak in age-specific prevale

Incidence and Transmission Patterns of Acute Hepatitis C in the United States, 1982-2006

BACKGROUND Monitoring disease incidence and transmission patterns is important to characterize groups at risk for hepatitis C virus (HCV) infection. Clinical cases generally represent about 20% to 30% of all newly acquired infections. METHODS We used sentinel surveillance to determine incidence and transmission patterns for acute hepatitis C in the United States using data from 25 years of population-based surveillance in the general community. Acute cases of hepatitis C were identified from 1982 through 2006 by a stimulated passive surveillance system in 4 to 6 US counties. Cases were defined by a discrete onset of symptoms, alanine aminotransferase (ALT) levels greater than 2.5 times the upper limit of normal (×ULN), negative findings for serologic markers for acute hepatitis A and B, and positive findings for antibody to HCV or HCV RNA. Incidence and frequency of reported risk factors were the main outcome measures. RESULTS Of 2075 patients identified, the median age was 31 years, 91.5% had ALT values greater than 7×ULN, 77.3% were jaundiced, 22.5% were hospitalized, and 1.2% died. Incidence averaged 7.4 per 100,000 individuals (95% confidence interval [CI], 6.4-8.5 per 100,000) during 1982 to 1989 then declined averaging 0.7 per 100,000 (95% CI, 0.5-1.0 per 100,000) during 1994 to 2006. Among 1748 patients interviewed (84.2%), injection drug use (IDU) was the most commonly reported risk factor. The average number of IDU-related cases declined paralleling the decline in incidence, but the proportion of IDU-related cases rose from 31.8% (402 of 1266) during 1982 to 1989 to 45.6% (103 of 226) during 1994 to 2006. Among IDU-related cases reported during 1994 to 2006, 56 of 61 individuals (91.8%) had been in a drug treatment program and/or incarcerated. CONCLUSIONS The incidence of acute HCV declined substantially over the 25 years of population-based surveillance. Despite declines, IDU is the most common risk factor for new HCV infection.

Differences in Response to a Hepatitis B Vaccine Booster Dose Among Alaskan Children and Adolescents Vaccinated During Infancy

BACKGROUND. The duration of protection provided by hepatitis B vaccination is unknown, but the presence of immune memory can be evaluated indirectly by measuring the immune response to a booster dose of vaccine. METHODS. Participants included 74 adolescents (aged 11.7–14.9 years) who had received a plasma-derived 3-dose primary vaccine series and 138 adolescents (aged 10.0–14.7 years) and 166 children (aged 5.0–7.0 years) who received a recombinant 3-dose primary vaccine series. All were born to hepatitis B surface antigen–negative mothers and had received the first dose of hepatitis B vaccine within 7 days of birth. The proportion of participants with serologic evidence of protective immunity (antibody to hepatitis B surface antigen ≥10 mIU/mL) at baseline (prebooster), the proportion who developed an anamnestic response (increase to ≥10 mIU/mL or at or more than fourfold increase in antibody to hepatitis B surface antigen to >10 mIU/mL), and the geometric mean concentration by 1, 2, and 4 weeks after a 5-μg recombinant vaccine booster dose were determined. RESULTS. No participant had evidence of chronic hepatitis B virus infection. Overall, 99% of the group of children who received recombinant hepatitis B vaccine, 83% of the group of adolescents who received recombinant hepatitis B vaccine, and 69% of the group of adolescents who received the plasma-derived vaccine had an anamnestic response to a booster dose; among responders, the geometric mean concentration at 2 weeks postbooster was 3360 and 128 mIU/mL among adolescents who received plasma-derived vaccine with antibodies to hepatitis B surface antigen ≥10 and <10 mIU/mL at baseline, respectively, compared with 1283 and 369 mIU/mL among adolescents who received recombinant hepatitis B vaccine and 5091 and 696 mIU/mL for children who received recombinant hepatitis B vaccine. The anamnestic response rate at 2 weeks postbooster among participants with antibodies to hepatitis B surface antigen <10 mIU/mL at baseline was inversely associated with age; 97% of 5-year-olds responded compared with 60% of 14-year-olds. CONCLUSIONS. Although most participants responded to a booster dose of hepatitis B vaccine, the significance of the increased proportion of nonresponses among older adolescents might indicate waning immune memory.

Molecular Epidemiology of Foodborne Hepatitis A Outbreaks in the United States, 2003

BACKGROUND Molecular epidemiologic investigations can link geographically separate foodborne hepatitis A outbreaks but have not been used while field investigations are in progress. In 2003, outbreaks of foodborne hepatitis A were reported in multiple states. METHODS Case-control studies were conducted in 3 states. Hepatitis A virus was sequenced from serologic specimens from individuals associated with outbreaks and from individuals concurrently ill with hepatitis A in non-outbreak settings in the United States and Mexico. RESULTS Case-control studies in Tennessee (TN), North Carolina (NC), and Georgia (GA) found green onions to be associated with illness among restaurant patrons (TN: odds ratio [OR], 65.5 [95% confidence interval {CI}, 8.9-482.5; NC: OR, 2.4 [95% CI, 0.3-21.9]; GA: OR, 20.9 [95% CI, 3.9-110.3]). Viral sequences from TN case patients differed by 2 nt, compared with those from case patients in NC and GA. A third sequence, differing from the TN and GA/NC sequences by 1 nt, was identified among case patients in a subsequent outbreak in Pennsylvania. Each outbreak sequence was identical to > or =1 sequence isolated from northern Mexican resident(s) with hepatitis A. The sources of green onions served in restaurants in TN and GA were 3 farms in northern Mexico. CONCLUSIONS Ongoing viral strain surveillance facilitated the rapid implementation of control measures. Incorporation of molecular epidemiologic methods into routine hepatitis A surveillance would improve the detection of hepatitis A outbreaks and increase our understanding of hepatitis A epidemiology in the United States.

Near Elimination of Hepatitis B Virus Infections Among Hawaii Elementary School Children After Universal Infant Hepatitis B Vaccination

OBJECTIVES. Hawaii implemented routine infant hepatitis B vaccination in 1992 and required it for school entry in 1997. Previously, in 1989, a serologic survey among Hawaii school children in grades 1 to 3 indicated that 1.6% had chronic hepatitis B virus infection, and 2.1% had resolved infection. We conducted a follow-up survey to examine changes in hepatitis B virus infection rates. PATIENTS AND METHODS. This study was performed in Oahu, Hawaii, during the 2001–2002 school year among children in grades 2 and 3. Consenting parents/guardians provided demographic information including place of birth. Participants were tested for serologic evidence of hepatitis B virus infection and their vaccination status was determined by reviewing school records. Rates of symptomatic acute hepatitis B among persons aged ≤19 years were calculated from cases reported from Hawaii to the Centers for Disease Control and Prevention between 1990 and 2004. RESULTS. Completed hepatitis B vaccination series were documented for 83% of the 2469 participants by age 18 months and for 97% by age 5 years. Past or present hepatitis B virus infection was detected among 6 participants (0.24%), including 1 (0.04%) with chronic infection and 5 (0.20%) with resolved infections. Compared with the 1989 survey, these prevalences represent declines of 97% and 90% in chronic and resolved hepatitis B virus infections, respectively. The incidence of symptomatic acute hepatitis B in Hawaii children and adolescents aged ≤19 years decreased from 4.5 cases per 100000 in 1990 to 0.0 during 2002–2004. To date, the last reported case in a child aged <15 years in Hawaii occurred in 1996. CONCLUSIONS.. Hepatitis B virus infection has nearly been eliminated in Hawaii children born after universal infant hepatitis B vaccination was implemented. These findings suggest that hepatitis B prevention goals are being met through routine immunization and related prevention programs among US children.

Seroprevalence of hepatitis A virus antibodies in the U.S.: results from the National Health and Nutrition Examination Survey.

Objectives. We described seroprevalence of antibody to hepatitis A virus (anti-HAV) in the United States during 1999–2006 and compared it with seroprevalence before the availability of vaccine. Methods. We analyzed data from the 1988–1994 and 1999–2006 National Health and Nutrition Examination Survey (NHANES) to obtain estimates of anti-HAV seroprevalence for the U.S. household population. We grouped region of residence based on the 1999 Advisory Committee on Immunization Practices recommendations into 17 states with any recommendation (vaccinating) and 33 states without any recommendation (non-vaccinating). Results. During 1999–2006, the overall seroprevalence of anti-HAV was 34.9% (95% confidence interval [CI] 33.1, 36.7). During 1999–2006, U.S.-born children living in vaccinating states (33.8%, 95% CI 26.2, 42.2) had a higher seroprevalence than children in non-vaccinating states (11.0%, 95% CI 9.4, 12.8; p<0.001). Seroprevalence among children increased from 8.0% (95% CI 6.3, 10.1) during 1988–1994 to 20.2% (95% CI 16.0, 24.8) during 1999–2006 (p<0.001). For U.S.-born children aged 6–19 years, the strongest factor associated with seroprevalence was residence in vaccinating states. Among U.S.-born adults aged >19 years, the overall age-adjusted seroprevalence of anti-HAV was 29.9% (95% CI 28.3, 31.5) during 1999–2006, which was not significantly different from the seroprevalence during 1988–1994 (32.2%, 95% CI 30.1, 34.4). Conclusions. Increases in seroprevalence among children in vaccinating states suggest a positive effect of the 1999 vaccination recommendations.

Reduction in hepatitis B virus seroprevalence among U.S.-born children of foreign-born Asian parents—Benefit of universal infant hepatitis B vaccination☆

We demonstrate that after implementation of recommendations for universal infant hepatitis B vaccination, HBV infection prevalence among children of foreign-born Asian parents in Georgia declined dramatically; horizontal transmission of infection within households has occurred infrequently; and the vast majority of infants and children have received the recommended hepatitis B vaccinations. These results provide evidence of the success of the hepatitis B infant vaccination program and highlight its potential impact on reducing chronic HBV infection morbidity and mortality among U.S. populations at high risk.

Changes in hepatitis C virus (HCV) viral load and interferon-alpha levels in HIV/HCV-coinfected patients treated with highly active antiretroviral therapy.

Background: Reports are mixed as to whether highly active antiretroviral therapy (HAART) increases liver transaminase levels or hepatitis C virus (HCV) titers in HIV/HCV-coinfected individuals. It is hypothesized that increases in HCV RNA titers may result from changes in endogenous interferon-&agr; (IFN-&agr;) production. Methods: HIV/HCV-coinfected patients receiving HAART were tested at baseline, 1, 2, 3, 6, and 9 months for liver transaminase levels, HIV and HCV viral loads, and IFN-&agr;. Linear regression analysis was used to determine the effect of HAART on liver transaminase levels, HCV viral load, and IFN-&agr;. Results: Initiating HAART did not increase liver transaminase levels in majority of cases. In patients (n = 30) with baseline HIV titer >10,000 copies/mL, HCV titers increased 0.69 log10 and IFN-&agr; decreased −0.96 log10 during HAART, in association with a ≥0.5 log10 decrease in HIV titer. As HIV titers reached their nadir approximately 4 months after initiation of HAART, HCV titers remained 0.54 log10 and IFN-&agr; −0.71 log10 above and below baseline levels, respectively. HCV titers and IFN-&agr; levels did not change from baseline in patients with baseline HIV titer ≤10,000 copies/mL. Conclusions: Coinfected patients did not have evidence of hepatoxicity HAART. In patients with baseline HIV titer >10,000 copies/mL, suppression of HIV replication by HAART was associated with an increase in HCV titer and a decrease in endogenous IFN-&agr; levels.

Infection with Hepatitis C Virus among HIV-Infected Pregnant Women in Thailand

Objective. The purpose of this study was to describe the epidemiology of coinfection with hepatitis C virus (HCV) and HIV among a cohort of pregnant Thai women. Methods. Samples from 1771 pregnant women enrolled in three vertical transmission of HIV studies in Bangkok, Thailand, were tested for HCV. Results. Among HIV-infected pregnant women, HCV seroprevelance was 3.8% and the active HCV infection rate was 3.0%. Among HIV-uninfected pregnant women, 0.3% were HCV-infected. Intravenous drug use by the woman was the factor most strongly associated with HCV seropositivity. Among 48 infants tested for HCV who were born to HIV/HCV coinfected women, two infants were HCV infected for an HCV transmission rate of 4.2% (95% 0.51–14.25%). Conclusions. HCV seroprevalence and perinatal transmission rates were low among this Thai cohort of HIV-infected pregnant women.

Hepatitis Viruses—Prevention and Control in the Laboratory Setting

At least five human hepatitis viruses have been identified worldwide. Within the United States, hepatitis A, B, and C are endemic and account for over 97% of acute viral hepatitis infections. Infection with hepatitis E virus (HEV) is rarely reported in the United States but causes large waterborne outbreaks in developing countries. Mounting evidence indicates that HEV is a zoonotic agent that may result in asymptomatic infections. Both hepatitis A and E are transmitted by the fecal-oral route, while hepatitis B, C, and D are bloodborne diseases. This review summarizes the physical properties of these viruses and describes the timing and location of virus during an infection as background information for intelligent handing of these agents in the laboratory. The approaches and methods that should be used for control and prevention are summarized based upon the mode of transmission and the availability of vaccine prevention.