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Background: Characteristics of US blood donors with recent (RBI) or occult (OBI) hepatitis B virus (HBV) infection are not well defined., Methods: Donors with RBI and OBI were identified by nucleic acid and serologic testing among 34.4 million donations during 2009-2015. Consenting donors were interviewed and their HBV S-gene sequenced., Results: The overall rate of HBV-infected donors was 7.95 per 100,000; of these, 0.35 per 100,000 and 1.70 per 100,000 were RBI and OBI, respectively. RBI (n = 120) and OBI (n = 583) donors constituted 26% of all HBV-infected (n = 2735) donors. Detection of HBV DNA in 92% of OBI donors required individual donation nucleic acid testing. Donors with OBI compared to RBI were older (mean age, 48 vs 39 years; p < 0.0001) with lower median viral loads (9 vs. 529 IU/mL; p < 0.0001). A higher proportion of OBI than RBI donors were born or resided in an endemic country (39% vs. 5%; p = 0.0078). Seventy-seven percent of all RBI and OBI donors had multiple sex partners, an HBV-risk factor. Of 40 RBI and 10 OBI donors whose S gene was sequenced, 33 (83%) and 6 (60%), respectively, carried HBV subgenotype A2; 18 (55%) and 2 (33%), respectively, shared an identical sequence. Infection with 1 or more putative HBV-immune-escape mutants was identified in 5 (50%) of OBI but no RBI donors., Conclusion: RBI and OBI continue to be identified at low rates, confirming the importance of comprehensive HBV DNA screening of US blood donations. HBV-infected donors require referral for care and evaluation and contact tracing; their HBV strains may provide important information on emergent genotypes., (© 2018 AABB.)

Historical enquiry into diseases with morbidity or mortality predilections for particular demographic groups can permit clarification of their emergence, endemicity, and epidemicity. During community-wide outbreaks of hepatitis A in the pre-vaccine era, clinical attack rates were higher among juveniles rather than adults. In community-wide hepatitis E outbreaks, past and present, mortality rates have been most pronounced among pregnant women. Examination for these characteristic predilections in reports of jaundice outbreaks in the USA traces the emergence of hepatitis A and also of hepatitis E to the closing three decades of the 19th century. Thereafter, outbreaks of hepatitis A burgeoned, whereas those of hepatitis E abated. There were, in addition, community-wide outbreaks that bore features of neither hepatitis A nor E; they occurred before the 1870s. The American Civil War antedated that period. If hepatitis A had yet to establish endemicity, then it would not underlie the jaundice epidemic that was widespread during the war. Such an assessment may be revised, however, with the discovery of more extant outbreak reports.

Fecal contamination of drinking water is associated with large hepatitis E virus (HEV) outbreaks of genotypes 1 and 2 in endemic areas. Sporadic transmission of HEV genotypes 3 and 4 in high-income countries has been associated with exposure to blood and animal contact. The objective of the study was to identify the risk factors for hepatitis E and the genotype(s) causing sporadic hepatitis E in Dhaka, Bangladesh. We selected, from a diagnostic center in Dhaka between November 2008 and November 2009, cases presenting with jaundice and anti-HEV IgM antibodies and age-matched controls were defined as those with no history of jaundice and normal blood test results. Serum samples were tested for HEV RNA using real-time reverse transcriptase polymerase chain reaction followed by a sequencing and phylogenetic analysis. A total of 109 cases and 109 controls were enrolled. The cases were more likely to be male (adjusted matched odds ratios [mOR] 2.2, 95% CI: 1.2-3.9; P = 0.01), or have reported contact with another person's blood or blood product, or contact with blood-contaminated sharp instruments (adjusted mOR 2.1, 95% CI: 1.1-4.1; P = 0.03) than controls. There were no significant differences between the cases and the controls in terms of reported high-risk sexual intercourse, consumption of undercooked meat, or contact or drinking fecally-contaminated water. The sera from three cases carried HEV RNA, all belonging to genotype 1. Findings from this study suggest that contact with human blood and sharing sharp instruments may transmit sporadic hepatitis E in Dhaka, Bangladesh. Efforts to prevent the transmission of blood-borne pathogens may also prevent sporadic HEV transmission in this endemic setting.

A cloned stable cell line, HepG2-HBVE6, was established following transfection of HepG2 cells with a retroviral plasmid into which a 1.1-fold genomic construct of hepatitis B virus (HBV) belonging to genotype E (HBV/E) was inserted. The cell line retains the entire HBV/E insert, and produces episomal HBV DNA. It expresses HBV pregenomic, preS1 and preS2/S transcripts, and sheds hepatitis B surface and e antigens as well as structures resembling HBV-subviral and Dane particles. The HepG2-HBVE6 cell line, in permitting recapitulation of the HBV life cycle, may be used for studying viral characteristics, therapeutic and preventative outcomes and for preparing reagents specific to HBV genotype E., (Published by Elsevier B.V.)

AbstractThe incidence of hepatitis E in Singapore appears to be increasing. A retrospective case-series study of patients diagnosed with hepatitis E in a tertiary hospital from 2009 to 2013 was conducted. Of 16 cases, eight (50%) were solid-organ transplant recipients (SOTRs), and 14 (88%) were found infected by genotype 3 hepatitis E virus (HEV-3). Bayesian inferences based on HEV subgenomic sequences from seven cases suggest that HEV-3 strains were introduced to Singapore as two principal lineages. Within limitations of the study, it can be inferred that one lineage, in the 3efg clade, emerged about 83 years ago, probably originating from Japan, whereas the other, in the 3abchij clade, emerged about 40 years ago, from the United States. Establishment and subsequent transmissions of strains from these two lineages likely contribute to the current endemicity of hepatitis E in Singapore.

Although large outbreaks of hepatitis E are regularly identified in south Asia, the majority of south Asian countries lack surveillance systems for this disease, which has hindered burden of disease estimates and prioritization of resources for prevention. Our study aimed to identify small hepatitis E outbreaks through a sentinel private laboratory in Dhaka, Bangladesh. We identified patients with detectable IgM antibody against hepatitis E virus. We defined a small outbreak as at least two laboratory-confirmed cases or ≥ 2 acute jaundice cases from the sentinel cases' family, neighborhood, or workplace. From November 2008 to November 2009, we identified 29 small outbreaks of hepatitis E from one private laboratory. The median number of cases in each outbreak was three. Cases were identified every month. Eighteen outbreaks occurred among families or neighbors, and 11 in the workplace. Among 103 cases identified as part of outbreaks, 31 (30%) sought care for diagnosis. In Bangladesh, collaboration between government public health surveillance and private laboratories can strengthen capacity for outbreak detection and improve estimates of disease burden., (© The American Society of Tropical Medicine and Hygiene.)

There have been increasing reports of food-borne zoonotic transmission of hepatitis E virus (HEV) genotype 3, which causes chronic infections in immunosuppressed patients. We performed phylogenetic analyses of the HEV sequence (partial and full-length) from 1 patient from the Middle East who underwent liver transplantation, and compared it with other orthohepevirus A sequences. We found the patient to be infected by camelid HEV. This patient regularly consumed camel meat and milk, therefore camelid HEV, which is genotype 7, might infect human beings. Our finding links consumption of camel-derived food products to post-transplantation hepatitis E, which, if detected at early stages, can be cured with antiviral therapy and reduced administration of immunosuppressive agents., (Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Unlabelled: Six strategies for identifying hepatitis C virus (HCV) viremia, involving testing for HCV antibody (HCVAb) followed by a nucleic acid test (NAT) for HCV RNA when the antibody test is positive, are compared. Decision analysis was used to determine mean relative cost per person tested and outcomes of HCV viremia detection. Parameters included proportions of test population with HCVAb and viremia plus specificity, sensitivity, and cost of individual tests. For testing a population with an HCVAb seroprevalence of 3.25%, all strategies when adopting quantitative NAT vary little in cost (range, $29.50-$30.70) and are highly viremia specific (≥0.9997). Four of the strategies using venipuncture blood for HCVAb testing (whether laboratory conducted or employing a rapid, point-of-care assay) and for NAT (whether done by reflex or using separately drawn blood) achieve the highest viremia sensitivities (range, 0.9950-0.9954). Point-of-care HCVAb testing in fingerstick blood followed by NAT in venipuncture blood yields relatively lower viremia sensitivity (0.9301). The strategy that requires returning for NAT is even less viremia sensitive (<0.9000) because of follow-up loss. Strategies adopting qualitative rather than quantitative NAT are slightly cheaper (range, $28.90-$29.99), similarly viremia specific (≥0.9997), but less viremia sensitive (≤0.9456). Viremia sensitivity and specificity remain the same regardless of the proportion of HCVAb-seropositive persons in the cohort being tested., Conclusions: Strategies involving HCVAb testing in venipuncture blood, whether laboratory conducted or using a point-of-care assay, when followed by quantitative NAT done reflexively or in separately drawn blood, are comparably economical and suitably viremia sensitive. Less cost-effective is point-of-care HCVAb testing in fingerstick blood followed by NAT in venipuncture blood. Least cost-effective is the strategy requiring the tested person to return for NAT., (© 2015 by the American Association for the Study of Liver Diseases.)

Unlabelled: Hepatitis E viral (HEV) infection imposes a heavy health burden worldwide and is common in the United States. Previous investigations of risks addressed environmental and host behavioral/lifestyle factors, but host genetic factors have not been examined. We assessed strength of associations between antibody to HEV (anti-HEV) immunoglobulin G seropositivity indicating past or recent HEV infection and human genetic variants among three major racial/ethnic populations in the United States, involving 2434 non-Hispanic whites, 1919 non-Hispanic blacks, and 1919 Mexican Americans from the Third National Health and Nutrition Examination Survey, 1991-1994. We studied 497 single-nucleotide polymorphisms across 190 genes (particularly those associated with lipid metabolism). The genomic control method was used to adjust for potential population stratification. Non-Hispanic blacks had the lowest seroprevalence of anti-HEV immunoglobulin G (15.3%, 95% confidence interval [CI] 12.3%-19.0%) compared with non-Hispanic whites (22.3%, 95% CI 19.1%-25.7%) and Mexican Americans (21.8%, 95% CI 19.0%-25.3%; P<0.01). Non-Hispanic blacks were the only population that showed association between anti-HEV seropositivity and functional ε3 and ε4 alleles of the apolipoprotein E (APOE) gene, encoding the apolipoprotein E protein that mediates lipoprotein metabolism. Seropositivity was significantly lower in participants carrying APOE ε4 (odds ratio=0.5, 95% CI 0.4-0.7; P=0.00004) and ε3 (odds ratio=0.6, 95% CI 0.4-0.8; P=0.001) compared to those carrying APOE ε2. No significant associations were observed between other single-nucleotide polymorphisms and anti-HEV seropositivity in non-Hispanic blacks or between any single-nucleotide polymorphisms and anti-HEV seropositivity in non-Hispanic whites or Mexican Americans., Conclusion: Both APOE ε3 and ε4 are significantly associated with protection against HEV infection in non-Hispanic blacks; additional studies are needed to understand the basis of protection so that preventive services can be targeted to at-risk persons., (Published 2015. This article is a U.S. Government work and is in the public domain in the USA.)

Unlabelled: The extent of provider-to-patient hepatitis C virus (HCV) transmission from diversion, self-injection, and substitution ("tampering") of anesthetic opioids is unknown. To quantify the contribution of opioid tampering to nosocomial HCV outbreaks, data from health care-related HCV outbreaks occurring in developed countries from 1990 to 2012 were collated, grouped, and compared. Tampering was associated with 17% (8 of 46) of outbreaks, but 53% (438 of 833) of cases. Of the tampering outbreaks, six (75%) involved fentanyl, five (63%) occurred in the United States, and one each in Australia, Israel, and Spain. Case counts ranged from 5 to 275 in the tampering outbreaks (mean, 54.8; median, 25), and 1-99 in the nontampering outbreaks (mean, 10.4; median, 5); between them, the difference in mean ranks of counts was significant (P < 0.01). To estimate HCV transmission risks from tampering, risk-assessment models were constructed, and these risks compared with those from surgery. HCV transmission risk from exposure to an opioid preparation tampered by a provider of unknown HCV infection status who is a person who injects drugs (PWID; 0.62%; standard error [SE] = 0.38%) exceeds 16,757 times the risk from surgery by a surgeon of unknown HCV infection status (0.000037%; SE = 0.000029%) and 135 times by an HCV-infected surgeon (0.0046%; SE = 0.0033%). To pose a 50% patient transmission risk, an infected surgeon may take 30 years, compared to <1 year for a PWID tamperer, and weeks or days for a PWID tamperer who intensifies access to opioids., Conclusion: Disproportionately, many cases of HCV infection from nosocomial outbreaks were attributable to provider tampering of anesthetic opioids. Transmission risk from tampering is substantially higher than from surgery., (© 2015 by the American Association for the Study of Liver Diseases. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

HCV strains belonging to genotype 4 may be gaining endemicity across Continental Europe but the extent of their spread in the United Kingdom is unknown. Sera referred from patients attending hospitals in England between 2004 through 2008 were characterised. A total of 243 sera carried HCV genotype 4. The most common subtypes were 4a (33%) and 4d (35%). Compared to patients infected by 4d, those infected by 4a were 20 times more likely to be Middle Eastern than English, and those infected by non-4a/4d were older, tended to be female, and 50 or 12 times more likely to be Middle Eastern or South Asian, respectively, than English. Persons infected by 4d tended to be English rather than Middle Eastern or South Asian. One group of 4d strains clustered with strains reported from persons in Europe engaged in male homosexual activity. Surveillance of trends in the importation and subsequent spread of HCV genotype 4 and its subtypes is advocated., (© 2014 Wiley Periodicals, Inc.)

Background: Previous population-based estimates in the United States have shown a relatively high prevalence of hepatitis E virus (HEV) antibody. We sought to determine whether changes in the prevalence of HEV antibody have occurred over time., Methods: We analyzed data from the 2009-2010 National Health and Nutrition Examination Survey (NHANES) and NHANES III (1988-1994). Using the same serologic assay, we compared the estimated anti-HEV immunoglobulin G (IgG) prevalence and risk factors for antibody positivity for the 2 periods., Results: The prevalence of HEV antibody among those aged ≥6 years declined from 10.2% (95% confidence interval [CI], 9.1%-11.4%) during 1988-1994 to 6.0% (5.2%-6.8%) during 2009-2010, and the prevalence for those of US birth ranged from 9.6% (8.4%-10.9%) to 5.2% (4.4%-6.2%). Among US-born persons, the estimated HEV antibody prevalence declined significantly for all subgroups of age, sex, region of residence, and number of persons per room in the household; significant declines also were observed for persons at or above poverty level and for persons of non-Hispanic white, non-Hispanic black, and Mexican American race/ethnicity. No clear associations with food consumption were found., Conclusions: The anti-HEV prevalence is declining in the United States. Although the decline suggests a decrease in exposure to HEV over time, the risks associated with exposure remain unknown., (Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Unlabelled: The recent epidemic history of hepatitis B virus (HBV) infections in the United States is complex, as indicated by current disparity in HBV genotype distribution between acute and chronic hepatitis B cases and the rapid decline in hepatitis B incidence since the 1990s. We report temporal changes in the genetic composition of the HBV population using whole-genome sequences (n = 179) from acute hepatitis B cases (n = 1,206) identified through the Sentinel County Surveillance for Acute Hepatitis (1998 to 2006). HBV belonged mainly to subtypes A2 (75%) and D3 (18%), with times of their most recent common ancestors being 1979 and 1987, respectively. A2 underwent rapid population expansions in ca. 1995 and ca. 2002, coinciding with transient rises in acute hepatitis B notification rates among adults; D3 underwent expansion in ca. 1998. A2 strains from cases identified after 2002, compared to those before 2002, tended to cluster phylogenetically, indicating selective expansion of specific strains, and were significantly reduced in genetic diversity (P = 0.001) and frequency of drug resistance mutations (P = 0.001). The expansion of genetically close HBV A2 strains was associated with risk of infection among male homosexuals (P = 0.03). Incident HBV strains circulating in the United States were recent in origin and restricted in genetic diversity. Disparate transmission dynamics among phylogenetic lineages affected the genetic composition of HBV populations and their capacity to maintain drug resistance mutations. The tendency of selectively expanding HBV strains to be transmitted among male homosexuals highlights the need to improve hepatitis B vaccination coverage among at-risk adults., Importance: Hepatitis B virus (HBV) remains an important cause of acute and chronic liver disease globally and in the United States. Genetic analysis of HBV whole genomes from cases of acute hepatitis B identified from 1998 to 2006 in the United States showed dominance of genotype A2 (75%), followed by D3 (18%). Strains of both subtypes were recent in origin and underwent rapid population expansions from 1995 to 2000, indicating increase in transmission rate for certain HBV strains during a period of decline in the reported incidence of acute hepatitis B in the United States. HBV A2 strains from a particular cluster that experienced the most recent population expansion were more commonly detected among men who have sex with men. Vaccination needs to be stepped up to protect persons who remain at risk of HBV infection., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)

Objective: To resolve discrepant hepatitis B surface antigen (HBsAg) results for pregnant women screened for hepatitis B virus (HBV) infection., Study Design: A case was defined as discrepant HBsAg (reactive followed by non-reactive) result during the same pregnancy. The Centers for Disease Control and Prevention examined a convenience sample of cases passively reported by US Perinatal Hepatitis B Prevention Programs. Using a standard form, available results were obtained for hepatitis B tests and vaccination histories. Results were independently reviewed by 3 viral hepatitis experts and a clinical virologist to resolve discrepancies. The initial HBsAg result was classified as probable true positive, probable false positive, or unresolved., Results: From April 2009-December 2011, 142 (75.9%) of 187 reported discrepant cases met the case definition. Of the 142 initial reactive HBsAg results, 113 (79.5%) were laboratory-confirmed, and 89 (62.7%) were resolved. Among these 89 cases, the initial test was a probable true positive in 14 (15.7%), and a false positive in 75 (84.3%). Total antibody to hepatitis B core antigen was positive for 11 (78.6%) of the true positive cases and negative for 67 (89.3%) of the false positive cases. True positives included 2 cases of resolving acute HBV infection and one case recently given hepatitis B vaccination., Conclusions: In this retrospective analysis of discrepant HBsAg-reactive screening results from pregnant women, the majority were false positives, but true positives occurred. Testing for total hepatitis B core antibody, an indicator of past or current HBV infection, was useful for resolving discrepancies., (Published by Elsevier Inc.)

In the United States, of the 1.1 million persons infected with human immunodeficiency virus (HIV) and the 2.7 million infected with hepatitis C virus (HCV), approximately 16% and 50%, respectively, are unaware of their infection. Highly effective treatments have turned both diseases into manageable conditions, and in the case of hepatitis C, a disease that can be cured. Early diagnosis is imperative so that infected persons can take measures to stay healthy, get into care, benefit from therapy, and reduce the risk of transmission. In this report, we review current recommendations provided by the Centers for Disease Control and Prevention (CDC) and the United States Preventive Services Task Force on whom to screen for HIV and HCV infections, and recommendations from the CDC, the Association of Public Health Laboratories, and the Clinical and Laboratory Standards Institute on how to test for these infections., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Using hepatitis C virus (HCV) and interferon (IFN) resistance as a proof of concept, we have devised a new method for calculating the effect of a drug on a viral population, as well as the resistance of the population's individual intrahost variants. By means of next-generation sequencing, HCV variants were obtained from sera collected at nine time points from 16 patients during the first 48 h after injection of IFN-α. IFN-resistance coefficients were calculated for individual variants using changes in their relative frequencies, and for the entire intrahost viral population using changes in viral titer. Population-wide resistance and presence of IFN-resistant variants were highly associated with pegylated IFN-α2a/ribavirin treatment outcome at week 12 (P = 3.78 × 10(-5) and 0.0114, respectively). This new method allows an accurate measurement of resistance based solely on changes in viral titer or the relative frequency of intrahost viral variants during a short observation time.

Background & Aims: The extent of HBV infection to infants of HBV/HIV-coinfected pregnant women in sub-Saharan Africa is unknown. The aim of this study was to assess prevalence of HBV infection among antiretroviral-naïve, HIV-infected pregnant women in Malawi and examine HBV transmission to their infants., Methods: Plasma from 2048 HIV-infected, Malawian women and their infants were tested for markers of HBV infection. Study participants were provided standard-of-care health services, which included administration of pentavalent vaccine to infants at 6, 10, and 14 weeks of age., Results: One-hundred and three women (5%) were HBsAg-positive; 70 of these HBsAg-positive women were also HBV-DNA-positive. Sixteen women (0.8%) were HBV-DNA-positive but HBsAg-negative. Five of 51 infants (9.8%) born to HBsAg-positive and/or HBV-DNA-positive women were HBV-DNA-positive by 48 weeks of age.HBV DNA concentrations of two infants of mothers who received extended lamivudine-containing anti-HIV prophylaxis were <4 log10 IU/ml compared to ⩾ 8 log10 IU/ml in three infants of mothers who did not., Conclusions: HBV DNA was detected in nearly 10% of infants born to HBV/HIV-coinfected women. Antenatal testing for HIV and HBV, if instituted, can facilitate implementation of prophylactic measures against infant infection by both viruses., (Published by Elsevier B.V.)

Background: Next-generation sequencing (NGS) allows for sampling numerous viral variants from infected patients. This provides a novel opportunity to represent and study the mutational landscape of Hepatitis C Virus (HCV) within a single host., Results: Intra-host variants of the HCV E1/E2 region were extensively sampled from 58 chronically infected patients. After NGS error correction, the average number of reads and variants obtained from each sample were 3202 and 464, respectively. The distance between each pair of variants was calculated and networks were created for each patient, where each node is a variant and two nodes are connected by a link if the nucleotide distance between them is 1. The work focused on large components having > 5% of all reads, which in average account for 93.7% of all reads found in a patient., Conclusions: Most intra-host variants are organized into distinct single-mutation components that are: well separated from each other, represent genetic distances between viral variants, robust to sampling, reproducible and likely seeded during transmission events. Facilitated by NGS, large components offer a novel evolutionary framework for genetic analysis of intra-host viral populations and understanding transmission, immune escape and drug resistance.

Coinfection with HIV and hepatitis B virus (HBV) is common in resource-limited settings but is frequently not diagnosed. The authors retrospectively tested specimens for HBV in HIV-infected Thai women who had participated in an antiretroviral therapy (ART) clinical study. A substantial proportion (27 of 211; 13%) of HIV-infected women were HBV coinfected. Among HIV/HBV-coinfected women, the authors observed similar rates of antiretroviral-associated liver toxicity (despite nevirapine [NVP] use) and CD4 count reconstitution as observed in HIV-monoinfected women. Hepatitis B surface antigen (HBsAg) screening detected the majority (81%) of HBV coinfections, including all 5 HBV-coinfected women who did not suppress HBV despite 48 weeks of lamivudine (3TC)-containing ART and could be used to tailor ART for patients diagnosed with HBV coinfection in accordance with World Health Organization guidelines. Although HBsAg screening did not diagnose 5 occult HBV coinfections, these women achieved HBV suppression on 3TC-containing ART, suggesting that not detecting occult HBV coinfection would have limited clinical impact.

The aim of this study was to estimate the amount of childhood hepatitis B virus transmission in children born in the UK, a very low-prevalence country, that is preventable only by universal hepatitis B immunization of infants. Oral fluid specimens were collected from schoolchildren aged 7-11 years in four inner city multi-ethnic areas and tested for the presence of antibody to hepatitis B core antigen (anti-HBc). Those found positive or indeterminate were followed up with testing on serum to confirm their hepatitis B status. The overall prevalence of anti-HBc in children was low [0.26%, 95% confidence interval (CI) 0.14-0.44]. The estimated average annual incidence of hepatitis B was estimated to be 29.26/100 000 children (95% CI 16.00-49.08). The total incidence that is preventable only by a universal infant immunization programme in the UK was estimated to be between 5.00 and 12.49/100 000. The study demonstrates that the extent of horizontal childhood hepatitis B virus transmission is low in children born in the UK and suggests that schools in the UK are an uncommon setting for the transmission of the virus. Targeted hepatitis B testing and immunization of migrants from intermediate- and high-prevalence countries is likely to be a more effective measure to reduce childhood transmission than a universal infant immunization programme.

To investigate characteristics of hepatitis E cases in the United States, we tested samples from persons seronegative for acute hepatitis A and B whose clinical specimens were referred to the Centers for Disease Control and Prevention during June 2005-March 2012 for hepatitis E virus (HEV) testing. We found that 26 (17%) of 154 persons tested had hepatitis E. Of these, 15 had not recently traveled abroad (nontravelers), and 11 had (travelers). Compared with travelers, nontravelers were older (median 61 vs. 32 years of age) and more likely to be anicteric (53% vs. 8%); the nontraveler group also had fewer persons of South Asian ethnicity (7% vs. 73%) and more solid-organ transplant recipients (47% vs. 0). HEV genotype 3 was characterized from 8 nontravelers and genotypes 1 or 4 from 4 travelers. Clinicians should consider HEV infection in the differential diagnosis of hepatitis, regardless of patient travel history.

Hepatitis C virus (HCV) is an increasing cause of morbidity and mortality in the United States. Many of the 2.7-3.9 million persons living with HCV infection are unaware they are infected and do not receive care (e.g., education, counseling, and medical monitoring) and treatment. CDC estimates that although persons born during 1945-1965 comprise an estimated 27% of the population, they account for approximately three fourths of all HCV infections in the United States, 73% of HCV-associated mortality, and are at greatest risk for hepatocellular carcinoma and other HCV-related liver disease. With the advent of new therapies that can halt disease progression and provide a virologic cure (i.e., sustained viral clearance following completion of treatment) in most persons, targeted testing and linkage to care for infected persons in this birth cohort is expected to reduce HCV-related morbidity and mortality. CDC is augmenting previous recommendations for HCV testing (CDC. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. MMWR 1998;47[No. RR-19]) to recommend one-time testing without prior ascertainment of HCV risk for persons born during 1945-1965, a population with a disproportionately high prevalence of HCV infection and related disease. Persons identified as having HCV infection should receive a brief screening for alcohol use and intervention as clinically indicated, followed by referral to appropriate care for HCV infection and related conditions. These recommendations do not replace previous guidelines for HCV testing that are based on known risk factors and clinical indications. Rather, they define an additional target population for testing: persons born during 1945-1965. CDC developed these recommendations with the assistance of a work group representing diverse expertise and perspectives. The recommendations are informed by the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework, an approach that provides guidance and tools to define the research questions, conduct the systematic review, assess the overall quality of the evidence, and determine strength of the recommendations. This report is intended to serve as a resource for health-care professionals, public health officials, and organizations involved in the development, implementation, and evaluation of prevention and clinical services. These recommendations will be reviewed every 5 years and updated to include advances in the published evidence.

Space-time clustering of people who fall acutely ill with jaundice, then slip into coma and death, is an alarming phenomenon, more markedly so when the victims are mostly or exclusively pregnant. Documentation of the peculiar, fatal predisposition of pregnant women during outbreaks of jaundice identifies hepatitis E and enables construction of its epidemic history. Between the last decade of the 18th century and the early decades of the 20th century, hepatitis E-like outbreaks were reported mainly from Western Europe and several of its colonies. During the latter half of the 20th century, reports of these epidemics, including those that became serologically confirmed as hepatitis E, emanated from, first, the eastern and southern Mediterranean littoral and, thereafter, Southern and Central Asia, Eastern Europe, and the rest of Africa. The dispersal has been accompanied by a trend towards more frequent and larger-scale occurrences. Epidemic and endemic hepatitis E still beset people inhabiting Asia and Africa, especially pregnant women and their fetuses and infants. Their relief necessitates not only accelerated access to potable water and sanitation but also vaccination against hepatitis E.

In Saudi Arabia, the prevalence of transplantation-associated Kaposi's sarcoma (KS) is high, and there is disparity in the prevalence rates of human herpesvirus 8 (HHV-8) infection between patients with renal disease and the general population. It was hypothesized that oral HHV-8 transmission among patients undergoing hemodialysis treatment contributes to the high prevalence of infection in renal disease patients. The detection rates of anti-HHV8-IgG in plasma and HHV-8-DNA in CD45(+)-peripheral blood cells of 72 hemodialysis patients were compared first with those of 178 blood donors and 60 pregnant women. Between the hemodialysis patients and the apparently healthy people sampled, the detection rate of anti-HHV-8-IgG was 16.7% versus 0.4% (P < 0.001) and that of HHV-8-DNA was 4.2% versus 0.4%, (P < 0.05). HHV-8 DNA was determined in oral samples and the HHV-8 viral load measured in saliva of patients undergoing hemodialysis. The amount of virus shed into saliva ranged between 8,600 and 119,562,500 (mean: 24,009,360) genome-equivalents/ml among the five patients in whom oral HHV-8 DNA was detected. Finally, HHV-8-subgenomic sequencing was conducted which showed that orally shed HHV-8 in four patients belonged to genotype C2, and in one patient to genotypes A1 and C2. HHV-8 shed in the mouth of hemodialysis patients may be extensive and diverse. Oral fluid in addition to blood is thus a likely vehicle for transmission of HHV-8, possibly contributing to the high risk of HHV-8 infection in patients undergoing hemodialysis and to KS following immunosuppression after renal transplantation., (Copyright © 2012 Wiley Periodicals, Inc.)

Treatment with lamivudine of patients infected with hepatitis B virus (HBV) results in a high rate of drug resistance, which is primarily associated with the rtM204I/V substitution in the HBV reverse transcriptase domain. Here we show that the rtM204I/V substitution, although essential, is insufficient for establishing resistance against lamivudine. The analysis of 639 HBV whole-genome sequences obtained from 11 patients shows that rtM204I/V is independently acquired by more than one intra-host HBV variant, indicating the convergent nature of lamivudine resistance. The differential capacity of HBV variants to develop drug resistance suggests that fitness effects of drug-resistance mutations depend on the genetic structure of the HBV genome. An analysis of Bayesian networks that connect rtM204I/V to many sites of HBV proteins confirms that lamivudine resistance is a complex trait encoded by the entire HBV genome rather than by a single mutation. These findings have implications for public health and offer a more general framework for understanding drug resistance.

Background: A large outbreak of hepatitis B virus (HBV) infection in the U.K. occurred between 2001 and 2005 in Bristol, U.K., Objectives: To identify HBV strains circulating amongst risk groups in the HBV outbreak cohort., Study Design: Cross-sectional study of acute HBV outbreak cases in Bristol., Results: HBV sequences from sera of 95 of the 237 cases (40%) were characterised. The majority of cases (77%) were found to carry an HBV variant belonging to genotype D, designated HBV(BV). Eighty-eight percent (36/41) of sequences from injection drug users were HBV(BV) as were 70% (19/27) from those with heterosexual intercourse as the primary identified risk factor. Of 15 sequences characterised from cases of pre-outbreak acute or chronic hepatitis B residing in Bristol, 40% also carried HBV(BV); the earliest was from a case identified in 1994., Conclusion: The findings from this study link the spread of HBV(BV) from injecting drug users to the general population through heterosexual intercourse during the outbreak. The molecular sequencing of specimens from this outbreak reports the emergence of HBV(BV), a HBV strain circulating in Bristol and South West England, as the cause of one of the largest outbreaks of acute hepatitis B in the U.K., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Recent approvals of direct-acting, orally delivered pharmaceuticals for the treatment of patients with infection by HCV and of a point-of-care assay for community screening of HCV infection have generated impetus to widen the identification of HCV-infected individuals. Diagnosis of HCV infection is, however, still based on the detection of anti-HCV immunoglobulin G. As treatment is intended for individuals with current infection, testing for evidence of infection would need to centre on the detection of HCV viraemia. Minimizing the complexity and costs associated with HCV nucleic acid testing and speeding the development and validation of HCV antigen assays expedite the identification of HCV-viraemic individuals. Establishing means to diagnose recent HCV infection and to engage in surveillance of drug-resistant HCV are also apposite. Successful implementation of these various measures brightens prospects for the eventual elimination of HCV.

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.

Background: Knowledge of the genotypic distribution of hepatitis B virus (HBV) facilitates epidemiologic tracking and surveillance of HBV infection as well as prediction of its disease burden. In the United States, HBV genotyping studies have been conducted for chronic but not acute hepatitis B., Methods: Serum samples were collected from patients with acute hepatitis B cases reported from the 6 counties that participated in the Sentinel Counties Study of Acute Viral Hepatitis from 1999 through 2005. Polymerase chain reaction followed by nucleotide sequencing of a 435-base pair segment of the HBV S gene was performed, and the sequences were phylogenetically analyzed., Results: Of 614 patients identified with available serum samples, 75% were infected with genotype A HBV and 18% were infected with genotype D HBV. Thirty-two percent of genotype A sequences constituted a single subgenotype A2 cluster. The odds of infection with genotype A (vs with genotype D) were 5 times greater among black individuals than among Hispanic individuals (odds ratio [OR], 5; 95% confidence interval [CI], 2.3-10.7). The odds of infection with genotype A were 49, 8, and 4 times greater among patients from Jefferson County (Alabama), Pinellas County (Florida), and San Francisco (California), respectively, than among those living in Denver County (Colorado). Genotype A was less common among recent injection drug users than it was among non-injection drug users (OR, 0.2; 95% CI, 0.1-0.4)., Conclusions: HBV genotype distribution was significantly associated with ethnicity, place of residence, and risk behavior.

In 2007, a previously uninfected kidney transplant recipient tested positive for human immunodeficiency virus type 1 (HIV) and hepatitis C virus (HCV) infection. Clinical information of the organ donor and the recipients was collected by medical record review. Sera from recipients and donor were tested for serologic and nucleic acid-based markers of HIV and HCV infection, and isolates were compared for genetic relatedness. Routine donor serologic screening for HIV and HCV infection was negative; the donor's only known risk factor for HIV was having sex with another man. Four organs (two kidneys, liver and heart) were transplanted to four recipients. Nucleic acid testing (NAT) of donor sera and posttransplant sera from all recipients were positive for HIV and HCV. HIV nucleotide sequences were indistinguishable between the donor and four recipients, and HCV subgenomic sequences clustered closely together. Two patients subsequently died and the transplanted organs failed in the other two patients. This is the first recognized cotransmission of HIV and HCV from an organ donor to transplant recipients. Routine posttransplant HIV and HCV serological testing and NAT of recipients of organs from donors with suspected risk factors should be considered as routine practice., (©2011 The Authors Journal compilation©2011 The American Society of Transplantation and the American Society of Transplant Surgeons.)

The detection of compensatory mutations that abrogate negative fitness effects of drug-resistance and vaccine-escape mutations indicates the important role of epistatic connectivity in evolution of viruses, especially under the strong selection pressures. Mapping of epistatic connectivity in the form of coordinated substitutions should help to characterize molecular mechanisms shaping viral evolution and provides a tool for the development of novel anti-viral drugs and vaccines. We analyzed coordinated variation among amino acid sites in 370 the hepatitis B virus (HBV) polymerase sequences using Bayesian networks. Among the HBV polymerase domains the spacer domain separating terminal protein from the reverse-transcriptase domain, showed the highest network centrality. Coordinated substitutions preserve the hydrophobicity and charge of Spacer. Maximum likelihood estimates of codon selection showed that Spacer contains the highest number of positively selected sites. Identification of 67% of the domain lacking an ordered structure suggests that Spacer belongs to the class of intrinsically disordered domains and proteins whose crucial functional role in the regulation of transcription, translation and cellular signal transduction has only recently been recognized. Spacer plays a central role in the epistatic network associating substitutions across the HBV genome, including those conferring viral virulence, drug resistance and vaccine escape. The data suggest that Spacer is extensively involved in coordination of HBV evolution.

Distinguishing between acute and chronic HCV infections is clinically important given that early treatment of infected patients leads to high rates of sustained virological response. Analysis of 2179 clonal sequences derived from hypervariable region 1 (HVR1) of the HCV genome in samples obtained from patients with acute (n = 49) and chronic (n = 102) HCV infection showed that intra-host HVR1 diversity was 1.8 times higher in patients with chronic than acute infection. Significant differences in frequencies of 5 amino acids (positions 5, 7, 12, 16 and 18) and the average genetic distances among intra-host HVR1 variants were found using analysis of molecular variance. Differences were also observed in the polarity, volume and hydrophobicity of 10 amino acids (at positions 1, 4, 5, 12, 14, 15, 16, 21, 22 and 29). Based on these properties, a classification model could be constructed, which permitted HVR1 variants from acute and chronic cases to be discriminated with an accuracy of 88%. Progression from acute to chronic stage of HCV infection is accompanied by characteristic changes in amino acid composition of HVR1. Identifying these changes may permit diagnosis of recent HCV infection.

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.

Hepatitis E, which is caused by hepatitis E virus (HEV), may now be considered a zoonosis as well as an anthroponosis. Pigs, boars and deer have been identified as reservoirs, and their flesh and entrails--as meat and offal--as vehicles of HEV transmission. Shellfish also act as vehicles. Dietary, gastronomic and culinary preferences influence how extensively HEV conveyed by these vehicles can be inactivated before their ingestion by the host. Another route of infection is paved by HEV that is enterically shed by humans and by live animals into the environment. Although anthroponotic transmission of HEV is primarily environmental, zoonotic transmission may proceed along both foodborne and environmental routes.

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.