Eric E. Mast

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.

Hepatitis C Virus Infection as an Opportunistic Disease in Persons Infected with Human Immunodeficiency Virus

Hepatitis C virus (HCV) is an RNA virus of the Flaviviridae family and is a major cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Owing to shared routes of transmission, HCV and human immunodeficiency virus (HIV) coinfection are common, affecting approximately one-third of all HIV-infected persons in the United States. In addition, HIV coinfection is associated with higher HCV RNA level and a more rapid progression of HCV-related liver disease, which leads to an increased risk of cirrhosis. HCV infection may also impact the course and management of HIV disease, particularly by increasing the risk of antiretroviral drug-induced hepatotoxicity. Thus, chronic HCV infection acts as an opportunistic disease in HIV-infected persons, because the incidence of infection is increased and the natural history of HCV infection is accelerated in coinfected persons. Strategies to prevent primary HCV infection and to modify the progression of HCV-related liver disease are urgently needed for HIV-HCV-coinfected individuals.

Strategies to prevent and control hepatitis B and C virus infections: a global perspective

Hepatitis B virus (HBV) and hepatitis C virus (HCV) are major causes of acute and chronic liver disease worldwide. Chronic infection with these viruses often leads to chronic liver disease, including cirrhosis or primary hepatocellular carcinoma. Both HBV and HCV are bloodborne viruses; however, HBV is transmitted efficiently by both percutaneous and mucosal exposures, and HCV is transmitted predominantly by percutaneous exposures. Because the relative importance of various modes of transmission of these viruses differs by country, the choice of specific prevention and control strategies depends primarily on the epidemiology of infection in a particular country. Comprehensive hepatitis B prevention strategies should include (1) prevention of perinatal HBV transmission, (2) hepatitis B vaccination at critical ages to interrupt transmission and (3) prevention of nosocomial HBV transmission. The prevention of hepatitis C is problematic because a vaccine to prevent HCV infection is not expected to be developed in the foreseeable future. From a global perspective, the greatest impact on the disease burden associated with HCV infection will most likely be achieved by focusing efforts on primary prevention strategies to reduce or eliminate the risk for transmission from nosocomial exposures (e.g. blood transfusion, unsafe injection practices) and high-risk practices (e.g. injecting drug use).

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.

Acute Hepatitis E by a New Isolate Acquired in the United States

OBJECTIVE To report the first case of acute hepatitis E by a novel isolate acquired in the United States and confirmed by nucleotide sequencing. MATERIAL AND METHODS We describe the clinical manifestations and the results of associated laboratory studies in a man who was found to have acute hepatitis E infection. RESULTS A 62-year-old man was hospitalized because of fever, abdominal pain, and jaundice. After an initial evaluation did not provide a cause, his serum was found to be positive for IgG anti-hepatitis E virus (HEV) by three antibody assays. Serum was also positive for HEV RNA by reverse transcriptase polymerase chain reaction (PCR). Sequencing results from the PCR products demonstrated substantial differences at the nucleotide level between this strain and the known Mexican and Burmese strains. CONCLUSION On the basis of this initial report, HEV should be considered an etiologic agent in patients with acute non-ABC hepatitis in the United States.

Recommendations for Identification and Public Health Management of Persons with Chronic Hepatitis B Virus Infection

Early identification of persons with chronic HBV infection enables infected persons to receive necessary care to prevent or delay onset of liver disease, and enables the identification and vaccination of susceptible household contacts and sex partners, interrupting ongoing transmission. Testing has been recommended previously to enable primary prevention of HBV infection among close contacts for pregnant women, household contacts and sex partners of HBV‐infected persons, persons born in countries with hepatitis B surface antigen (HBsAg) prevalence of more than 8%, persons who are the source of blood or body fluid exposures that might warrant postexposure prophylaxis (e.g., needlestick injury to a healthcare worker or sexual assault), and to enable appropriate treatment for infants born to HBsAg‐positive mothers and persons infected with human immunodeficiency virus. Recently, with the increasing availability of efficacious hepatitis B treatment, the Centers for Disease Control and Prevention published new recommendations for public health evaluation and management for chronically infected persons and their contacts and extended testing recommendations to include persons born in geographic regions with HBsAg prevalence of greater than 2%, men who have sex with men, and injection drug users. Patient and provider education, developing partnerships between health departments and community organizations, and other resources will be needed to assure appropriate populations are tested and care provided for persons newly identified as HBsAg‐positive. (HEPATOLOGY 2009;49:S35–S44.)

Prevalence of and Risk Factors for Antibody to Hepatitis E Virus Seroreactivity among Blood Donors in Northern California

To evaluate antibody to hepatitis E virus (anti-HEV) seroreactivity, 5000 US blood donors were tested for anti-HEV by two EIAs: a mosaic protein assay (MPr-EIA) and a recombinant protein assay (RPr-EIA). Overall, 59 (1.2%) were seroreactive by MPr-EIA and 70 (1.4%) were seroreactive by RPr-EIA. The overall concordance between tests was 98.5% (4925/5000); the concordance among reactive sera by either test was only 27% (27/102). In a case-control study, seroreactive persons were more likely than seronegative persons to have traveled to countries in which HEV is endemic (odds ratio [OR] for MPr-EIA = 4.3, P < .001; OR for RPr-EIA = 2.5, P = .005), but 31% of MPr-EIA anti-HEV-reactive persons and 38% of RPr-EIA anti-HEV-reactive persons had no history of international travel. These findings suggest that travelers to regions in which HEV is endemic can acquire subclinical HEV infection. The significance of anti-HEV seroreactivity among persons without an international travel history needs to be determined.

Empty virus‐like particle‐based enzyme‐linked immunosorbent assay for antibodies to hepatitis E virus

Hepatitis E, an enterically transmitted non‐A, non‐B hepatitis, is a serious viral infection that occasionally causes large epidemics in developing countries. In developed countries, the disease only appears sporadically due to the transmission routes, and it is considered to be less important. The hepatitis E virus (HEV) cannot grow in cultured cells and no reliable assay system has ever been developed. In addition, the present diagnostic are not perfect, and actual rates of HEV infection may be underestimated. Highly purified empty virus‐like particles (VLPs) of HEV have been produced by the use of a recombinant baculovirus vector in insect cells. Using these VLPs as an antigen, an enzyme‐linked immunosorbent assay (ELISA) for antibodies to HEV was developed. A panel of 164 sera that were randomized and coded, and sera collected periodically from three patients with hepatitis E were used for the evaluation. The sensitivity of the assay was shown to be equal to or better than that obtained in previous research that used the same serum panel. The ELISA demonstrated that the serum IgM level of the patients was highest at the onset of the clinical illness and then rapidly decreased. In contrast, a high level of circulating IgG antibody titers lasted for more than 4 years. In Japan, a non‐endemic country, the prevalence of the IgG class antibody to HEV in healthy individuals was found to range from 1.9% to 14.1%, depending on the geographical area. Only one out of 900 (0.1%) serum samples was IgM‐positive. The IgM class antibody to HEV was detected in 10.8% of non‐A, non‐B, and non‐C acute hepatitis patients in northeast China, whereas none of the patients in Korea had the IgM antibody. The ELISA utilizing the VLPs is sensitive and specific in its detection of the IgM and IgG antibodies to HEV. The ELISA is therefore useful for diagnosing HEV infection and for seroepidemiological study of hepatitis E. J. Med. Virol. 62:327–333, 2000.

IgM and IgG antibodies to hepatitis E virus (HEV) detected by an enzyme immunoassay based on an HEV-specific artificial recombinant mosaic protein.

To develop an enzyme immunoassay (EIA) for IgM antibody to hepatitis E virus (HEV) (IgM anti‐HEV) and IgG antibody to HEV (IgG anti‐HEV), a synthetic gene encoding several liner immuno‐dominant antigenic epitopes from HEV structural proteins was assembled as a chimeric recombinant mosaic protein (Mpr) with glutathione S‐transferase and used as an immunodiagnostic target. In addition, a neutralization confirmation test was developed using individual synthetic peptides. Among 614 patients with acute hepatitis from 10 geographically distinct outbreaks, IgG anti‐HEV was found in 546 (88.9%), with a range of 77–100% depending on the outbreak. Of 130 patients tested for IgM anti‐HEV, 126 (96.9%) were positive. Among patients tested within 4 months of onset of jaundice, 37/37 (100%) were IgG anti‐HEV positive. For patients from whom sera were collected 1–16 days after onset of jaundice, the geometric mean IgG titer (GMT) was 1:47,000; the GMT increased to 1:70,710 30–40 days after onset of jaundice and decreased to 1:1,778 3–4 months after the onset of jaundice. For patients tested 6–8 months after onset of jaundice, 11/12 (92%) were IgG anti‐HEV positive, and the GMT was 1:2,908. IgM anti‐HEV was detected in 43/43 (100%) sera collected 1–40 days after onset of jaundice, and the GMT for IgM anti‐HEV was 1:10,000 at that time. For sera collected 3–4 and 6–12 months after onset of jaundice, 7/14 (50%) and 5/12 (40%) respectively, were IgM anti‐HEV positive. In conclusion, an artificial mosaic protein composed of linear antigenic epitopes from open reading frame 2 (ORF2) and ORF3 of HEV has been successfully applied to the development of a sensitive and specific EIA for the detection of IgG and IgM anti‐HEV activity. These assays were used for the verification of HEV infection in outbreak settings and for the diagnosis of HEV infection in sporadic cases.

Progress toward elimination of hepatitis B virus transmission in the United States

The strategy to eliminate hepatitis B virus (HBV) transmission in the United States is comprised of the following components: (1) preventing perinatal transmission, (2) routine infant vaccination, (3) catch-up vaccination of children in high-risk groups at any age, (4) catch-up vaccination of all children at 11-12 years of age and (5) vaccination of adolescents and adults in high-risk groups. According to recent surveys, > 85% of pregnant women are screened for hepatitis B surface antigen (HBsAg). Of infants born to HBsAg-positive women identified in 1995, 93% received appropriate immunoprophylaxis at birth; however, only 69% were fully vaccinated by 6-8 months of age. From 1991 (when routine infant hepatitis B vaccination was first recommended) to 1996, the proportion of 19-35-month-old children who have received three doses of hepatitis B vaccine has increased from < 10 to 83%. During this time, rates of acute hepatitis B in children 7-10 years of age have declined by 27% and rates among children 3-6 years of age have declined by 62%. Implementation of programmes for catch-up vaccination of all adolescents at 11-12 years of age and for vaccination of adolescents and adults in high-risk groups have only recently begun and no data are available to assess the progress of these programmes. However, 26% (13/50) of states now have laws requiring adolescents to be vaccinated in order to enter school. Current data indicate that substantial progress has been made in implementing a strategy to eliminate HBV transmission in the United States. Future efforts need to be focused on improving complete immunoprophylaxis of infants of HBsAg-positive mothers, increasing vaccine coverage among 11-12 year old children and implementing programmes to vaccine adolescents and adults in high-risk groups.