Miriam J. Alter

The Prevalence of Hepatitis C Virus Infection in the United States, 1988 through 1994

BACKGROUND Because many persons with chronic hepatitis C virus (HCV) infection are asymptomatic, population-based serologic studies are needed to estimate the prevalence of the infection and to develop and evaluate prevention efforts. METHODS We performed tests for antibody to HCV (anti-HCV) on serum samples from 21,241 persons six years old or older who participated in the third National Health and Nutrition Examination Survey, conducted during 1988 through 1994. We determined the prevalence of HCV RNA by means of nucleic acid amplification and the genotype by means of sequencing. RESULTS The overall prevalence of anti-HCV was 1.8 percent, corresponding to an estimated 3.9 million persons nationwide (95 percent confidence interval, 3.1 million to 4.8 million) with HCV infection. Sixty-five percent of the persons with HCV infection were 30 to 49 years old. Seventy-four percent were positive for HCV RNA, indicating that an estimated 2.7 million persons in the United States (95 percent confidence interval, 2.4 million to 3.0 million) were chronically infected, of whom 73.7 percent were infected with genotype 1 (56.7 percent with genotype 1a, and 17.0 percent with genotype 1b). Among subjects 17 to 59 years of age, the strongest factors independently associated with HCV infection were illegal drug use and high-risk sexual behavior. Other factors independently associated with infection included poverty, having had 12 or fewer years of education, and having been divorced or separated. Neither sex nor racial-ethnic group was independently associated with HCV infection. CONCLUSIONS In the United States, about 2.7 million persons are chronically infected with HCV. People who use illegal drugs or engage in high-risk sexual behavior account for most persons with HCV infection.

Global epidemiology of hepatitis C virus infection

Hepatitis C virus (HCV) is a major cause of liver disease worldwide and a potential cause of substantial morbidity and mortality in the future. The complexity and uncertainty related to the geographic distribution of HCV infection and chronic hepatitis C, determination of its associated risk factors, and evaluation of cofactors that accelerate its progression, underscore the difficulties in global prevention and control of HCV. Because there is no vaccine and no post-exposure prophylaxis for HCV, the focus of primary prevention efforts should be safer blood supply in the developing world, safe injection practices in health care and other settings, and decreasing the number of people who initiate injection drug use.

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

The Natural History of Community-Acquired Hepatitis C in the United States

BACKGROUND Chronic liver disease develops in more than half of patients with post-transfusion hepatitis C, but little is known about the natural history of community-acquired hepatitis C. METHODS In 1985 and 1986 we identified adults with acute non-A, non-B hepatitis in four counties in the United States and followed them prospectively. We used three markers to detect hepatitis C virus (HCV) infection in stored samples of serum: antibody to HCV (anti-HCV) detected by second-generation serologic assays; HCV RNA detected by polymerase-chain-reaction assay; and antibody to HCV antigen (anti-HCVAg) detected by fluorescent-antibody-blocking assay. RESULTS Of 130 patients with non-A, non-B hepatitis, 106 (82 percent) had HCV infection, 93 were positive for anti-HCV, and 13 were positive only for HCV RNA or anti-HCVAg. Chronic hepatitis developed in 60 (62 percent) of 97 HCV-infected patients followed for 9 to 48 months, with no relation to the risk factors for infection. Ten of the 30 patients who had liver biopsies had chronic active hepatitis. In samples collected 42 to 48 months after the onset of hepatitis, HCV RNA was detected in 12 of 13 tested patients with chronic hepatitis and in all 15 tested patients with hepatitis that had resolved. Anti-HCV persisted in all but two of the initially positive patients, for a rate of antibody loss of 0.6 per 100 person-years. CONCLUSIONS Patients with community-acquired hepatitis C have a high rate of chronic hepatitis. HCV may be a major cause of chronic liver disease in the United States, and in most patients HCV infection seems to persist for at least several years, even in the absence of active liver disease.

Molecular Cloning and Disease Association of Hepatitis G Virus: A Transfusion-Transmissible Agent

An RNA virus, designated hepatitis G virus (HGV), was identified from the plasma of a patient with chronic hepatitis. Extension from an immunoreactive complementary DNA clone yielded the entire genome (9392 nucleotides) encoding a polyprotein of 2873 amino acids. The virus is closely related to GB virus C (GBV-C) and distantly related to hepatitis C virus, GBV-A, and GBV-B. HGV was associated with acute and chronic hepatitis. Persistent viremia was detected for up to 9 years in patients with hepatitis. The virus is transfusion-transmissible. It has a global distribution and is present within the volunteer blood donor population in the United States.

National surveillance of dialysis-associated diseases in the United States, 2002.

In December 2002, all U.S. chronic hemodialysis centers were surveyed regarding selected patient care practices and dialysis‐associated diseases. The results were compared with similar surveys conducted in previous years. In 2002, 85% of hemodialysis centers were free‐standing and 81% operated for profit; the proportion of centers operating for profit has increased each year since 1985. During 1995–2002, the percentage of patients who received dialysis through central catheters increased from 13% to 26%; this trend is worrisome, as infections and antimicrobial use are higher among patients receiving dialysis through catheters. However, during the same period, the percentage of patients receiving dialysis through fistulas increased from 22% to 33%. The percentage of centers reporting one or more patients infected or colonized with vancomycin‐resistant enterococci (VRE) increased from 12% in 1995 to 30% in 2002. During 1997–2002, the percentage of patients vaccinated against hepatitis B virus (HBV) infection increased from 47% to 56% and the percentage of staff vaccinated increased from 87% to 90%. In 2002, routine testing for antibody to hepatitis C virus (anti‐HCV) was performed on patients at 64% of centers; anti‐HCV was found in 7.8% of patients. In 2001, the Centers for Disease Control (CDC) published Recommendations for Preventing Transmission of Infections among Chronic Hemodialysis Patients. Centers were surveyed regarding their awareness of the recommendations and about a variety of infection control practices. In general, the incidence of HBV and HCV was not substantially different for the infection control practices evaluated, including where staff obtain clean supplies for patient treatment, reuse of unused and unopened supplies, and practices for changing external transducer filters/protectors. However, in 2002, the incidence of HBV infection was higher among patients in centers where injectable medications were prepared on a medication cart or medication area located in the treatment area compared to a dedicated medication room. Also, those centers that used a disposable container versus a nondisposable container for priming the dialyzer had a significantly lower incidence of HCV.

Acute non-A-E hepatitis in the United States and the role of hepatitis G virus infection

BACKGROUND Little is known about the relation of the newly discovered hepatitis G virus (HGV) to the cause and clinical course of acute and chronic viral hepatitis. METHODS We selected patients from a surveillance study of acute viral hepatitis in four U.S. counties who had acute disease during 1985 to 1986 or 1991 to 1995. Serum samples were tested for HGV RNA by the polymerase chain reaction. RESULTS HGV RNA was detected in 4 of 45 patients with a diagnosis of non-A-E hepatitis (9 percent), 23 of 116 patients with hepatitis C (20 percent), 25 of 100 patients with hepatitis A (25 percent), and 32 of 100 patients with hepatitis B (32 percent) (P<0.05 for the comparison of hepatitis B with hepatitis non-A-E or C). The clinical characteristics of the acute illness were similar for patients with HGV alone and those with hepatitis A, B, or C with or without HGV infection. During a follow-up period of one to nine years, chronic hepatitis did not develop in any of the patients with HGV alone, but 75 percent were persistently positive for HGV RNA, as were 87 percent of those with both hepatitis C and HGV infection. The rates of chronic hepatitis were similar in patients with hepatitis C alone (60 percent) and those with both hepatitis C and HGV infection (61 percent). CONCLUSIONS The evidence from this surveillance study does not implicate HGV as an etiologic agent of non-A-E hepatitis. Persistent infection with HGV was common, but it did not lead to chronic disease and did not affect the clinical course in patients with hepatitis A, B, or C.

A Multistate, Foodborne Outbreak of Hepatitis A

BACKGROUND We investigated a large, foodborne outbreak of hepatitis A that occurred in February and March 1997 in Michigan and then extended the investigation to determine whether it was related to sporadic cases reported in other states among persons who had consumed frozen strawberries, the food suspected of causing the outbreak. METHODS The cases of hepatitis A were serologically confirmed. Epidemiologic studies were conducted in the two states with sufficient numbers of cases, Michigan and Maine. Hepatitis A virus RNA detected in clinical specimens was sequenced to determine the relatedness of the virus from outbreak-related cases and other cases. RESULTS A total of 213 cases of hepatitis A were reported from 23 schools in Michigan and 29 cases from 13 schools in Maine, with the median rate of attack ranging from 0.2 to 14 percent. Hepatitis A was associated with the consumption of frozen strawberries in a case-control study (odds ratio for the disease, 8.3; 95 percent confidence interval, 2.1 to 33) and a cohort study (relative risk of infection, 7.5; 95 percent confidence interval, 1.1 to 53) in Michigan and in a case-control study in Maine (odds ratio for infection, 3.4; 95 percent confidence interval, 1.0 to 14). The genetic sequences of viruses from 126 patients in Michigan and Maine were identical to one another and to those from 5 patients in Wisconsin and 7 patients in Arizona, all of whom attended schools where frozen strawberries from the same processor had been served, and to those in 2 patients from Louisiana, both of whom had consumed commercially prepared products containing frozen strawberries from the same processor. CONCLUSIONS We describe a large outbreak of hepatitis A in Michigan that was associated with the consumption of frozen strawberries. We found apparently sporadic cases in other states that could be linked to the same source by viral genetic analysis.

Hepatitis C virus infection in the United States

Hepatitis C virus (HCV) infection is the most common chronic bloodborne infection in the United States, and most infected persons are younger than 50 years old. The relative importance of the two most common exposures associated with transmission of HCV, blood transfusion and intravenous drug use (IVDU), has changed over time. Blood transfusion, which accounted for a substantial proportion of HCV infections acquired >10 years ago, rarely accounts for recently acquired infections. In contrast, IVDU has consistently accounted for a substantial proportion of HCV infections and currently accounts for 60% of HCV transmission while sexual exposures account for up to 20%. Other known exposures (occupational, hemodialysis, household, perinatal) together account for about 10% of infections. In the remaining 10%, no recognized source of infection can be identified, although most persons in this category are associated with low socioeconomic level. Case-control studies have found no association with military service or exposures resulting from medical, surgical or dental procedures, tattooing, acupuncture, ear piercing or foreign travel. Reducing the burden of HCV infection and disease in the United States requires implementation of primary prevention activities that reduce or eliminate HCV transmission and secondary prevention activities that reduce liver and other chronic diseases in HCV-infected persons by identifying them and providing appropriate medical management and antiviral therapy. Surveillance and evaluation activities also are important to determine the effectiveness of these programs in reducing the incidence of disease, identifying persons infected with HCV, and promoting healthy lifestyles and behaviors.

Risk Factors for Perinatal Transmission of Hepatitis C Virus (HCV) and the Natural History of HCV Infection Acquired in Infancy

BACKGROUND The goal of the present study was to assess risk factors for perinatal hepatitis C virus (HCV) transmission and the natural history of infection among HCV-infected infants. METHODS In a cohort study, 244 infants born to HCV-positive mothers were followed from birth until age > or =12 months. Maternal serum was collected at enrollment and delivery; infant serum was collected at birth and at 8 well-child visits. Testing included detection of antibody to HCV, detection of HCV RNA (qualitative and quantitative), and genotyping. HCV-infected infants were followed annually until age 5 years. RESULTS Overall, 9 of 190 (4.7% [95% confidence interval (CI), 2.3%-9.1%]) infants born to mothers who were HCV RNA positive at delivery became infected, compared with 0 of 54 infants born to HCV RNA-negative mothers (P=.10). Among HCV RNA-positive mothers, the rate of transmission was 3.8% (95% CI, 1.7%-8.1%) from the 182 who were human immunodeficiency virus (HIV) negative, compared with 25.0% (95% CI, 4.5%-64.4%) from the 8 who were HIV positive (P<.05). Three infected infants resolved their infection (i.e., became HCV RNA negative). In multivariate analysis restricted to HCV RNA-positive mothers, membrane rupture > or =6 h (odds ratio [OR], 9.3 [95% CI, 1.5-179.7]) and internal fetal monitoring (OR, 6.7 [95% CI, 1.1-35.9]) were associated with transmission of HCV to infants. CONCLUSION If duration of membrane rupture and internal fetal monitoring are confirmed to be associated with transmission, interventions may be possible to decrease the risk of transmission.