Jan Drobeniuc

Chronic Hepatitis C Virus Infection in the United States, National Health and Nutrition Examination Survey 2003 to 2010

Context Chronic hepatitis C virus (HCV) infection is an important public health issue. Using data from a U.S. household survey conducted between 2003 and 2010, the authors compared the estimated prevalence of chronic HCV infection and risk factors for infection with those from earlier periods. Contribution The estimated prevalence of chronic HCV infection in the United States has decreased. Risk factors are essentially unchanged from previous periods and were reported by only about one half of infected persons. Caution Homeless and incarcerated persons were not surveyed. Implication The burden of chronic HCV infection in the United States is substantial. National data on prevalence are useful for the design of programs for HCV screening, linkage to care, and treatment. The Editors Hepatitis C virus (HCV) infection is a treatable but underrecognized and underdiagnosed disease. An estimated 130 to 170 million persons, 2% to 3% of the worlds population, are living with HCV infection, and almost 500000 persons die of HCV-related conditions each year (primarily decompensated cirrhosis and liver cancer) (1). In the United States, previous estimates have consistently indicated that approximately 3 million or more persons have chronic HCV infection. An analysis of 21241 serum specimens from participants in NHANES (National Health and Nutrition Examination Survey), which provides nationally representative statistics on the health of the U.S. noninstitutionalized civilian population, indicated that 2.7 million persons (95% CI, 2.4 to 3.0 million persons) had chronic HCV infection between 1988 and 1994 (2). A similar analysis of 15079 NHANES specimens between 1999 and 2002 estimated that 3.2 million persons (95% CI, 2.7 to 3.9 million persons) had chronic HCV infection (3). These estimates do not include cases of chronic HCV not captured by NHANES, notably among homeless persons and persons who were incarcerated during the survey (4). The Institute of Medicine recently concluded that it is essential to know the dimensions and direction of this epidemic, which has major implications for health burden and costs for the United States (5). Current treatment can cure HCV in a substantial proportion of persons who complete therapy, thereby decreasing the risk for hepatocellular carcinoma and all-cause mortality. However, many persons infected with HCV remain untested and unaware of their infection, are unknown to the health care system, and are not captured in case-based surveillance because they are typically asymptomatic (6). Deaths among persons with HCV infection have superseded deaths in those with HIV infection (7). Surveillance for antibody to HCV (anti-HCV) and HCV RNA has been part of NHANES since the 1980s, although RNA testing for NHANES III was done retrospectively. Surveillance through such a large national survey presents the best measurement of the prevalence of anti-HCV and chronic HCV infection in the general U.S. population. Accordingly, using methods similar to analyses from 20 and 10 years ago (2, 3), we analyzed data from participants in NHANES between 2003 and 2010 to estimate the prevalence of HCV infection and to determine risk factors and exposures associated with chronic infection. Methods Survey Design The National Health and Nutrition Examination Survey, conducted by the Centers for Disease Control and Preventions National Center for Health Statistics, collects nationally representative data on the health and nutritional status of the U.S. noninstitutionalized civilian population. This survey uses a complex, stratified, multistage probability sampling design and collects information from approximately 5000 persons annually using standardized interviews, physical examinations, and tests of biological samples. Participants were interviewed in their homes using the interviewer-administered Computer-Assisted Personal Interviewing system to ascertain demographic characteristics and in the Mobile Examination Center to ascertain possible risks and exposures for HCV infection. Persons aged 16 years or older and emancipated minors were interviewed directly; an adult proxy provided information for participants younger than 16 years and for persons unable to answer the questions themselves. All participants provided written informed consent. More detailed information on survey design for NHANES, including approval from the National Center for Health Statistics Institutional Review Board (Hyattsville, Maryland), is available from the survey documentation at www.cdc.gov/nchs/nhanes/nhanes_questionnaires.htm. Laboratory Testing Qualitative determination of anti-HCV in blood serum or plasma was measured using direct solid-phase enzyme immunoassay with an anti-HCV screening chemiluminescence immunoassay (VITROS Anti-HCV Immunodiagnostic System, Ortho Clinical Diagnostics, Rochester, New York). Screening reactive specimens were then tested using a confirmatory recombinant immunoblot assay (RIBA) (RIBA HCV 3.0 Strip Immunoblot Assay, Chiron, Emeryville, California), an in vitro qualitative immunoassay for the detection of anti-HCV in human serum or plasma. Samples with positive results on RIBA testing were reported as confirmed positive for anti-HCV, those with results that were negative were reported as negative for anti-HCV, and those with indeterminate results were reported as indeterminate. In clinical practice, it is most important to identify persons who are currently infected; however, for surveillance purposes, we are interested in having a reliable measure of both those who are currently infected and those who were ever infected. Although the sensitivity and specificity of anti-HCV tests have improved over time for at-risk populations, estimating the true prevalence in a low-risk, low-prevalence population, such as that sampled in NHANES, requires a confirmatory test, such as RIBA, to eliminate false-positive results from our estimates of persons ever infected. Serum samples that were confirmed positive or indeterminate for anti-HCV were further tested for HCV RNA using an in vitro nucleic acid amplification test for the quantitation of HCV RNA in human serum or plasma. We used the COBAS AMPLICOR HCV Test, version 2.0 (Roche Diagnostics, Indianapolis, Indiana), on the COBAS AMPLICOR Analyzer (Roche Diagnostics) for samples from 2005 to 2010 and the COBAS AmpliPrep/TaqMan HCV Test, version 2 (Roche Diagnostics), on the COBAS TaqMan 48 Analyzer (Roche Diagnostics) for samples from 2003 to 2004. We considered persons to have chronic HCV infection if results of their test for anti-HCV were confirmed positive or indeterminate and results of their test for HCV RNA were positive. Our comparison group comprised persons who tested negative for anti-HCV; these participants were considered to be never infected with HCV. Those who tested positive for anti-HCV but negative for HCV RNA (resolved infections; n= 90) and those who had no serum available for RNA testing (n= 51) were not included in our analyses, except for estimation of overall anti-HCV prevalence, because we wanted to focus on chronic HCV infection. Statistical Analysis SAS-Callable SUDAAN, Release 10.0 (Research Triangle Institute, Research Triangle Park, North Carolina) (8), a statistical package designed to analyze complex survey data, was used for analysis. Estimates were weighted to represent the total U.S. noninstitutionalized civilian population and to account for oversampling and nonresponse to the household interview and physical examination. Two-year sample weights (WTMEC2yr) were further adjusted to account for the fact that not all examination participants were tested for anti-HCV, not all participants who tested positive or indeterminate for anti-HCV had samples available for HCV RNA testing, and multiple years of data were used. A P value less than 0.05 was considered statistically significant. We analyzed demographic characteristics (age at interview, sex, race/ethnicity, birthplace, education, and income), potential risk factors or exposures (receipt of blood or a blood product before 1992, any past injection drug use, and number of lifetime sexual partners), and a proxy for sexual risk (antibodies to herpes simplex virus type 2) (9, 10). Although sex is not a usual method of transmission of HCV infection (11), number of sexual partners and presence of herpes simplex virus type 2 antibodies are included because these are indices of increased likelihood of being infected with HCV and have been used in previous analyses. We restricted most analyses to persons aged 20 years or older because only 2 persons aged 6 to 19 years had evidence of chronic HCV infection (that is, tested positive for HCV RNA) and because data on drug use and sexual behaviors among those younger than 20 years are not available from NHANES public-use data files. Ages included in our reporting of risks and exposures reflect age eligibility for a particular question or laboratory test rather than a focus on particular age groups. We used bivariate analyses to estimate demographic characteristics of persons with chronic HCV infection and those who were never infected and to estimate the prevalence of potential risk factors or exposures among population subgroups. Chi-square tests were used for statistical comparisons between subgroups. Simple (unadjusted) and multivariate logistic regression analyses were used to identify factors associated with chronic HCV infection. We performed separate logistic analyses for persons aged 20 to 59 years and those aged 60 years or older because NHANES does not query those older than 59 years about sexual behaviors or drug use. We retained 3 potential confoundersage at interview, sex, and race/ethnicityin all multivariate models. Variables that were associated with HCV infection in previous NHANES analyses (2, 3) were included in multivariate models to identify factors independently associated with chronic HCV infection. Variables not inclu

Hepatitis E Virus Antibody Prevalence among Persons Who Work with Swine

Prevalence of antibody and risk factors to hepatitis E virus (HEV) infection were determined in a cross-sectional study of 2 group-matched populations: swine farmers (n=264) and persons without occupational exposure to swine (n=255) in Moldova, a country without reported cases of hepatitis E. The prevalence of HEV infection was higher among swine farmers than among the comparison group (51.1% vs. 24.7%; prevalence ratio, 2.07; 95% confidence interval [CI], 1.62-2.64). In multivariate analysis, HEV infection was associated with an occupational history of cleaning barns or assisting sows at birth (odds ratio [OR], 2.46; 95% CI, 1.52-4.01), years of occupational exposure (OR, 1.04 per year; 95% CI, 1.01-1.07), and a history of drinking raw milk (OR, 1.61; 95% CI, 1.08-2.40). HEV infection was not associated with civilian travel abroad or having piped water in the household. The increased prevalence of HEV infection among persons with occupational exposure to swine suggests animal-to-human transmission of this infection.

Serologic Assays Specific to Immunoglobulin M Antibodies against Hepatitis E Virus: Pangenotypic Evaluation of Performances

Six immunoassays for detecting immunoglobulin M antibodies to hepatitis E virus were evaluated. Serum samples representing acute infection by each of the 4 viral genotypes as well as nonacute hepatitis E virus infection constituted the test panels. Diagnostic sensitivities and specificities as well as interassay agreement varied widely. Analytical sensitivity limits also were determined and were found to be particularly disparate.

Evidence of Person-to-Person Transmission of Hepatitis E Virus during a Large Outbreak in Northern Uganda

BACKGROUND Outbreaks of infection with hepatitis E virus (HEV) are frequently attributed to contaminated drinking water, even if direct evidence for this is lacking. METHODS We conducted several epidemiologic investigations during a large HEV infection outbreak in Uganda. RESULTS Of 10,535 residents, 3218 had HEV infection; of these, 2531 lived in households with >1 case. HEV was not detected in drinking water or zoonotic sources. Twenty-five percent of cases occurred > or = 8 weeks after onset of hepatitis in an index case in the household. Households with > or = 2 cases were more likely to have a member(s) who attended a funeral, had close contact with a jaundiced person, or washed hands in a common basin with others (P < .05 for all). CONCLUSIONS A high attack rate in households, lack of a common source of infection, and poor hygienic practices in households with > or = 2 cases suggest person-to-person transmission of HEV during this outbreak.

Hepatitis E Epidemic, Uganda

In October 2007, an epidemic of hepatitis E was suspected in Kitgum District of northern Uganda where no previous epidemics had been documented. This outbreak has progressed to become one of the largest hepatitis E outbreaks in the world. By June 2009, the epidemic had caused illness in >10,196 persons and 160 deaths.

Laboratory Diagnostics for Hepatitis C Virus Infection

Identification of prevalent infection by hepatitis C virus (HCV) is based serologically on detecting anti-HCV immunoglobulin G, using immunoassays, immunoblot assays, and, more recently, immunochromatography-based rapid tests. None discriminate between active and resolved HCV infection. Tests for detecting HCV RNA identify active HCV infection but are costly. Serologic assays for HCV antigens have been developed and show potential for diagnosis of active HCV infection, and their performance characteristics are undergoing evaluation. The diagnosis of acute HCV infection without the demonstration of seroconversion remains elusive.

Restricted Enzooticity of Hepatitis E Virus Genotypes 1 to 4 in the United States

ABSTRACT Hepatitis E is recognized as a zoonosis, and swine are known reservoirs, but how broadly enzootic its causative agent, hepatitis E virus (HEV), is remains controversial. To determine the prevalence of HEV infection in animals, a serological assay with capability to detect anti-HEV-antibody across a wide variety of animal species was devised. Recombinant antigens comprising truncated capsid proteins generated from HEV-subgenomic constructs that represent all four viral genotypes were used to capture anti-HEV in the test sample and as an analyte reporter. To facilitate development and validation of the assay, serum samples were assembled from blood donors (n = 372), acute hepatitis E patients (n = 94), five laboratory animals (rhesus monkey, pig, New Zealand rabbit, Wistar rat, and BALB/c mouse) immunized with HEV antigens, and four pigs experimentally infected with HEV. The assay was then applied to 4,936 sera collected from 35 genera of animals that were wild, feral, domesticated, or otherwise held captive in the United States. Test positivity was determined in 457 samples (9.3%). These originated from: bison (3/65, 4.6%), cattle (174/1,156, 15%), dogs (2/212, 0.9%), Norway rats (2/318, 0.6%), farmed swine (267/648, 41.2%), and feral swine (9/306, 2.9%). Only the porcine samples yielded the highest reactivities. HEV RNA was amplified from one farmed pig and two feral pigs and characterized by nucleotide sequencing to belong to genotype 3. HEV infected farmed swine primarily, and the role of other animals as reservoirs of its zoonotic spread appears to be limited.

Laboratory-based Surveillance for Hepatitis E Virus Infection, United States, 2005–2012

Clinicians should consider this virus in the differential diagnosis of hepatitis, regardless of patient travel history.

Hepatitis E virus infection in HIV-infected persons.

To determine whether hepatitis E virus (HEV) is a cause of hepatitis among HIV-infected persons, we evaluated 1985–2009 data for US military beneficiaries. Evidence of acute or prior HEV infection was detected for 7 (4%) and 5 (3%) of 194 HIV-infected persons, respectively. HEV might be a cause of acute hepatitis among HIV-infected persons.

Persistence of long-term immunity to hepatitis B among adolescents immunized at birth.

The long-term duration of recombinant hepatitis B vaccine-induced immunity among persons vaccinated starting at birth is still not well understood. Waning of vaccine-induced immunity could leave young adults at risk of hepatitis B virus infection due to behavioral or occupational exposures. We followed a cohort of children immunized starting at birth with a 3-dose regimen of recombinant hepatitis B vaccine (5 mcg, 2.5 mcg, 2.5 mcg). They were challenged with a booster dose of the hepatitis B vaccine 10 and 15 years after vaccination to assess anamnestic response as a measure of persistence of protection. Among 108 participants who had lost protective antibody levels against hepatitis B, the majority (>70%) had an anamnestic response to the booster dose; response rates did not decline significantly between 10 and 15 years follow-up periods. A high antibody concentration following primary vaccination was independently associated with an anamnestic response later on in life. Nonetheless, ~20-30% of participants were unable to mount an immune response after boosting. Hepatitis B revaccination might be required for persons vaccinated starting at birth if opportunities for hepatitis B virus exposure exist. Future vaccine recommendations should be based on studies ascertaining protection against clinically significant disease.