Richard S. Tedder

Indigenous hepatitis E virus infection in England: More common than it seems

BACKGROUND Indigenous hepatitis E virus (HEV) is increasingly diagnosed in England due to a better awareness and understanding of the virus. However, the true burden of infection and therefore its implication to public health remains undefined. OBJECTIVES To estimate the HEV seroprevalence in the general population and to investigate how the risk of HEV infection had fluctuated over time. STUDY DESIGN Two sample collections stratified by age ranging from 1 to 80 years, were screened for HEV IgG antibody. The two collections were separated by 13 years enabling the average incidence between 1991 and 2004 to be estimated. Additional force of infection calculations were also undertaken. RESULTS An overall HEV antibody prevalence of 13% was determined, increasing with age and peaking at 25% in those aged over 50 years. Analysis of the two sample collections demonstrated a temporal shift in seroprevalence indicating that the risk of acquiring HEV infection was not solely age dependant. Data showed that the force of infection had been particularly high in the middle of the 20th century but had subsequently decreased. Current HEV incidence estimates revealed that the incidence did not vary in different age groups. CONCLUSIONS This study indicated a high anti-HEV seroprevalence in England and that there was a period of increased risk of acquiring HEV infection which has now decreased. Incidence estimates show that shared risk factors still exist for acquiring HEV infection across all age groups in England.

HIV-2-induced immunosuppression among asymptomatic West African prostitutes: evidence that HIV-2 is pathogenic, but less so than HIV-1.

Two hundred and forty-one prostitutes working in The Gambia were tested for retroviral infections and their immune system evaluated. Sixty-three were seropositive for HIV-2 only, five for HIV-1 only and six for both HIV-1 and HIV-2 (26.1, 2.1 and 2.5%, respectively). When compared to seronegative individuals, the 63 women infected with HIV-2 clearly had an abnormal immune system, with significantly lower CD4+ and higher CD8+ lymphocyte counts and percentages, lower CD4+:CD8+ ratios, lower CD25+ (activated) lymphocyte counts, and lower lymphocyte proliferation responses after stimulation with phytohaemagglutinin, purified protein derivative (PPD), Candida or pokeweed mitogen, and higher levels of neopterin and beta 2-microglobulin. However, when the HIV-2-seropositive prostitutes were compared with the five women infected with HIV-1, the former were less abnormal, with significantly higher CD4+ percentages and CD4+:CD8+ ratios and lower CD8+ percentages and counts. Immunological anomalies were seen in five women known to have been infected with HIV-2 for less than 17 months. Coinfection with HTLV-1 resulted in more severe immunological alterations than infection with HIV-2 alone.

Is there evidence of recent hepatitis E virus infection in English and North Welsh blood donors

Background and Objective  The risk of hepatitis E virus (HEV) to blood safety remains unknown in England. Reports of persistent HEV infection with serious disease sequelae indicate that transfusion transmitted HEV is not a trivial disease in immunosuppressed patients.

Detection of hepatitis E virus RNA in plasma mini-pools from blood donors in England.

Dear Editor, We read with interest the letter from Baylis et al., [1] reporting on the detection of hepatitis E virus (HEV) RNA and antibody in plasma fractionation pools, which originated from several regions across the globe. The authors report that 10% of the pools were HEV RNA positive and discuss the transmission risk through the use of plasmaderived medicinal products. We recently reported evidence of current HEV infection in English and Welsh blood donors indicating a turnover of the virus in the donor panel and the potential for transfusion-associated transmission [2]. To ascertain further the risk of HEV to the English blood supply, serological and molecular investigations were undertaken in plasma minipools collected in 2007. Each mini-pool was made up of 48 individual donors and had originally been prepared for hepatitis C RNA screening. Extraction and detection of HEV RNA was carried out on 880 mini-pools (equivalent to approximately 42 000 individual donors) as previously described [2]. Six of the 880 pools (0Æ7%) had detectable HEV RNA. As expected, viral loads in the HEV RNApositive pools were low (£ 2000 GEq ⁄ ml). Additional HEV antibody (anti-HEV) testing found all 6 (100%) and 1 ⁄ 6 (17%) of the HEV RNA-positive pools to be anti-HEV IgG and IgM reactive respectively. Of the 100 HEV RNA-negative pools tested, 73% and 0% were HEV IgG and IgM reactive respectively. The high incidence of asymptomatic infection with HEV gives ample opportunity for blood donors to infect recipients. Studies undertaken in the general English population indicate an anti-HEV seroprevalence of 13% and estimate that 60 000 cases occur per year [3]. It is therefore perhaps unsurprising that our study demonstrates a high antiHEV IgG prevalence in the mini-pools tested. The detection of HEV RNA and anti-HEV IgM demonstrates current HEV infections. In contrast, Baylis et al. [1] found HEV IgG only in the pools from Asia, which is very surprising given the UK seroprevalence. They also report eightfold higher rates of HEV RNA in tested pools from Europe but do not disclose the pool size. Some of these differences may be explained by variations in the make up of the pools and in the detection assays used. Collectively, these reports provide evidence of the potential to transmit HEV from blood ⁄ blood components and products. However, the extent of HEV transmission posttransfusion and the outcome of receiving HEV-containing transfusion products remain poorly explored. The risks of transfusion-associated HEV deserves due consideration in light of emerging data on the significant harm of persistent HEV in the immunosuppressed [4, 5]. It is estimated that 75% of UK blood ⁄ blood components are given as haematological support to this population. The issue of HEV and blood safety therefore warrants further studies and debate.

Chronic Hepatitis E as a cause for cryptogenic cirrhosis in HIV

Chronic Hepatitis E infection (HEV) is reported in immunocompromised patients. A 45-year-old HIV-infected man had no cause found for a persistent transaminitis which predated commencement of antiretroviral therapy. Hepatic elastography and liver biopsy revealed cirrhosis. In 2010, he tested positive for HEV IgM/IgG antibodies. Plasma HEV RNA was detected. Archived samples revealed HEV viraemia since 2000. A 24-week course of pegylated interferon was commenced and HEV RNA became undetectable at week 4 until week 27 post treatment cessation. Chronic HEV infection should be considered in HIV patients as a cause for unexplained transaminitis and cryptogenic liver cirrhosis.

Seroprevalence of hepatitis B and C virus in HIV-1 and HIV-2 infected Gambians

BackgroundThe prevalence of HIV/hepatitis co-infection in sub-Saharan Africa is not well documented, while both HIV and HBV are endemic in this area.ObjectiveThe aim of this study is to determine the seroprevalence of HBV and HCV virus in HIV-infected subjects in the Gambia.MethodsPlasma samples from HIV infected patients (190 individuals with clinically defined AIDS and 382 individuals without AIDS) were tested retrospectively for the presence of HBV sero-markers and for serum HBV DNA, screened for HCV infection by testing for anti-HCV antibody and HCV RNA.ResultsHBsAg prevalence in HIV-positive individuals is 12.2%. HIV/HBV co-infected individuals with CD4 count of <200 cells uL-1 have a higher HBV DNA viral load than patients with higher CD4 count (log 4.0 vs. log 2.0 DNA copies/ml, p < 0.05). Males (OR = 1.8, 95% CI: 1.0, 3.2) were more likely to be HBsAg positive than female. HCV seroprevalence was 0.9% in HIV-positive individuals.ConclusionThe prevalence of HBsAg carriage in HIV- infected Gambians is similar to that obtained in the general population. However co-infected individuals with reduced CD4 levels, indicative of AIDS had higher prevalence of HBeAg retention and elevated HBV DNA levels compared to non-AIDS patients with higher CD4 count.

Dynamics of lamivudine-resistant hepatitis B virus during adefovir monotherapy versus lamivudine plus adefovir combination therapy.

Adefovir dipivoxil has been used alone or together with lamivudine to suppress lamivudine‐resistant hepatitis B virus (HBV). However, the dynamics of HBV populations under different selection pressures and their impact on treatment outcome are poorly understood. Pyrosequencing® was applied to quantify longitudinally the evolution of wild type and lamivudine/ adefovir‐resistant HBV. Eight patients, with lamivudine‐resistant HBV, were randomized to receive adefovir monotherapy or adefovir/lamivudine combination therapy for a median of 79 and 71 weeks, respectively. Pyrosequencing® proved highly sensitive with a lower limit of quantitation of minor HBV populations of 2% irrespective of viraemia levels. Adefovir/lamivudine treatment resulted in greater viraemia reduction than adefovir monotherapy. During combination therapy, lamivudine‐resistant HBV populations (codons 180 and 204) remained dominant (>90%) and no adefovir‐resistance developed. During adefovir monotherapy, reversion to wild‐type HBV was detected in two patients with one patient accumulating rapidly adefovir‐resistant HBV along with increased viraemia. In conclusion, the dynamics of drug‐resistant HBV strains vary under different selection pressures which have a significant impact on the success of rescue therapy, as well as for the selection of new mutations. The use of techniques such as Pyrosequencing provides an evidence‐based approach for successful management of drug‐resistant HBV. J. Med. Virol. 80: 1160–1170, 2008.

Global control of hepatitis B virus: does treatment-induced antigenic change affect immunization?

Since its widespread introduction, the hepatitis B vaccine has become an essential part of infant immunization programmes globally. The vaccine has been particularly important for countries where the incidence of hepatitis B virus-related hepatocellular carcinoma is high. Effective treatment options for individuals with chronic hepatitis B infection were limited until 1998 when lamivudine, the first nucleoside analogue drug, was introduced. As a single treatment agent, however, lamivudine has a significant drawback: it induces lamivudine-resistant hepatitis B virus strains that may pose a risk to the global hepatitis B immunization programme. Mutations associated with drug treatment can cause changes to the surface antigen protein, the precise part of the virus that the hepatitis B vaccine mimics. However, the emergence of antiviral drug-associated potential vaccine escape mutants (ADAP-VEMs) in treated patients does not necessarily pose a significant, imminent threat to the global hepatitis B immunization programme. Nonetheless, there is already evidence that current treatment regimens have resulted in the selection of stable ADAP-VEMs. Treatment is currently intended to prevent the long-term complications of hepatitis B virus infection, with little consideration given to potential adverse public health impacts. To address individual and public health concerns, trials are urgently needed to find the optimal combination of existing drugs that are effective but do not induce the emergence of ADAP-VEMs. This paper examines the mechanism of antiviral drug-selected changes in the portion of the viral genome that also affects the surface antigen, and explores their potential impact on current hepatitis B immunization programmes.

The Diversity and Management of Chronic Hepatitis B Virus Infections in the United Kingdom: A Wake-up Call

BACKGROUND Through migration, diversity of chronic hepatitis B virus (HBV) infection has changed, affecting disease burden and control. We describe clinical and viral characteristics of chronic HBV in the United Kingdom. METHODS A total of 698 individuals with chronic HBV infection were recruited from referral liver centers. Demographic, clinical, and laboratory data were collected. RESULTS Sixty-one percent of patients were male, 80% were not born in the United Kingdom, and the largest ethnicity was East/Southeast Asian (36%). Twenty-two percent were hepatitis B e antigen (HBeAg) seropositive; 20.4% (59/289) had cirrhosis and 10 (1.7%) had hepatocellular carcinoma. Genotype D was most common (31%) followed by A, C, B, and E (20%, 20%, 19%, and 9%, respectively). Genotype was significantly associated with country of birth, length of time in the United Kingdom, HBeAg status, and precore and basal core promoter mutations. One-third were on treatment, with men independently more likely to be treated. Only 18% of those on treatment were on recommended first-line therapies, and 30% were on lamivudine monotherapy. Among treated individuals, 27% had antiviral drug resistance. Testing rates for human immunodeficiency virus, hepatitis C virus, and delta coinfections were low. CONCLUSIONS We demonstrated diversity of chronic HBV infections in UK patients, suggesting that optimal management requires awareness of the variable patterns of chronic HBV in countries of origin. We also found less-than-optimal clinical management practices, possible gender-based treatment bias, and the need to improve testing for coinfections.

First case of genotype 4 human hepatitis E virus infection acquired in India

This report describes a case of severe hepatitis in an individual returning from India which was found to be the result of infection with HEV genotype 4. HEV was diagnosed using a novel RT-PCR assay (with internal control) for HEV RNA detection/quantitation, described herein. This is the first documented report of zoonotic transmission of HEV genotype 4 infection acquired in India.