Virology, serology, and demography of hepatitis E viremic blood donors in South East England.

BACKGROUND: Hepatitis E virus (HEV) Genotype 3 (G3) in England comprises two principal phylogenetic groups (Group 1 and Group 2) and can be transmitted by transfusion. Unselected screening identified 79 viremic donors; 76 participated in a follow-up study. STUDY DESIGN AND METHODS: Viral RNA dynamics, phylogenetics, and seroconversion were characterized in the donors. Detailed demographic, travel, clinical, and lifestyle questionnaires were undertaken. RESULTS: The majority of viremic individuals (57/79) were seronegative at time of donation but all seroconverted. Viremia was short-lived, with a median of 6.5 weeks to confirmed viral clearance. All infections were acquired in the United Kingdom and were G3, with Group 2 viruses predominating (43/54; 80%). Infection was associated with some clinical symptoms both at and after donation (8/77; 10%). Viral loads and symptoms were more pronounced in Group 1 infections. There was no serologic evidence of reinfection. Donors were more commonly male (p = 0.002); both male and female donors were older than comparator donors. Animal contact was unlikely to be the source of infection. Consumption of chicken and pig meat was common to all infected donors; processed pig meat was most commonly purchased from one particular retail chain. CONCLUSION: Viremic donors represent primary infection in older members of the community and reflect a widespread zoonotic in the United Kingdom. The two phylogenetic groups of HEV G3 display different pathogenicity and the more common Group 2 appears less adapted to humans. There are no objective demographic criteria that can identify donors at enhanced HEV risk.

Clinical Care Pathways for Patients With Hepatitis C: Reducing Critical Barriers to Effective Treatment.

Background. Engagement of individuals infected with hepatitis C virus (HCV) with care pathways remains a major barrier to realizing the benefits of new and more effective antiviral therapies. After an exploratory study, we have undertaken an evidence-based redesign of care pathways for HCV, including the following: (1) reflex testing of anti-HCV-positive samples for HCV RNA; (2) annotation of laboratory results to recommend referral of actively infected patients to specialist clinics; (3) educational programs for primary care physicians and nurses; and (4) the establishment of needs-driven community clinics in substance misuse services. Methods. In this study, we conducted a retrospective cohort study of progression through care pathways of individuals with a new diagnosis of HCV infection made between January 2010 and January 2012. We also analyzed patient flow through new care pathways and compared this with our baseline study of identical design. Results. A total of 28 980 samples were tested for anti-HCV antibody during the study period and yielded 273 unique patients with a new diagnosis of HCV infection. Of these, 38% were tested in general practice, 21% were tested in substance misuse services, 23% were tested in secondary care, and 18% were tested in local prisons. Overall, 80% of patients were referred to specialist clinics, 70% attended for assessment, and 38% commenced treatment, in comparison to 49%, 27%, and 10%, respectively, in the baseline study. Referral rates from all testing sources improved. Conclusions. This study provides timely evidence that progression through care pathways can be enhanced, and it demonstrates reduction of key barriers to eradication of HCV.

The Impact of HCV Infection Duration on HIV Disease Progression and Response to cART amongst HIV Seroconverters in the UK.

INTRODUCTION: The effect of HCV infection on HIV disease progression remains unclear; the effect of HCV infection duration on HIV disease progression is unknown. METHODS: We used data from a cohort of HIV seroconverters to investigate the effect of HCV infection duration on time from HIV seroconversion to CD4 <350 cells/mm3, AIDS or death, censoring at the earlier of cART initiation or last clinic visit, adjusting for confounders and splitting data into follow up periods from HIV seroconversion (<2, 2-4 and >4 years). We additionally compared CD4 cell decline following HCV infection to that of mono-infected individuals with similar HIV infection duration by fitting a random effects model. In a separate analysis, we used linear mixed models to we examine the effect of HCV infection and its duration on CD4 increase over 48 weeks following cART. RESULTS: Of 1655 individuals, 97 (5.9%) were HCV co-infected. HCV<1 year was associated with a higher risk of endpoint in each follow-up period from HIV seroconversion (HR [95% CI] 2.58 [1.51, 4.41], p = 0.001; 3.80 [1.20, 12.03], p = 0.023; 2.03 [0.88, 4.71], p = 0.098 for <2, 2-4 and >4 years respectively), compared to mono-infected individuals. However, we found no evidence of an association for those with HCV>2 years (all p>0.89). Individuals experienced a somewhat greater decrease in CD4 count following HCV infection lasting 13 months, relative to individuals with HIV alone, (estimate = -3.33, 95% CI [-7.29, 0.63] cells/mm3 per month, p = 0.099). Of 1502 initiating cART, 106 (7.1%) were HCV co-infected, with no evidence of HCV duration at cART being associated with immunological response (p = 0.45). CONCLUSIONS: The impact of HCV co-infection on HIV disease progression appears to be restricted to the first year after HCV infection.

Molecular epidemiology of newly acquired hepatitis C infections in England 2008-2011: genotype, phylogeny and mutation analysis.

BACKGROUND: Analysis of laboratory testing data collected through the Sentinel Surveillance programme has provided a method for identifying individuals who have recently acquired their hepatitis C virus (HCV) infection. Access to samples from these individuals provided a rare opportunity to undertake molecular characterization studies. OBJECTIVES: To describe the epidemiology and genetic diversity of hepatitis C in recent seroconverter infections and to predict how this will impact on HCV treatment and control. STUDY DESIGN: One hundred and forty seven samples were available from individuals, identified to have recently acquired their HCV infection. Genotype determination with additional phylogenetic analysis was carried out on NS5B sequences. Analysis across the NS3 region investigated the presence of antiviral resistance mutations. Where possible, molecular data was linked to demographic and risk/behavioural factor information. RESULTS: The majority of new infections occurred in males with a mean age of 37 years. The most commonly observed genotypes were 1a (49%) and 3a (42%) and injecting drug use (58%) was the most common risk factor. Genotype distribution differed between persons who inject drugs and those with other risk factors suggesting two possible epidemics. Phylogenetic analysis indicated possible transmission networks within specific risk groups. Amino acid changes associated with antiviral resistance were noted in the NS3 region in some samples. CONCLUSIONS: Continued surveillance of linked molecular, virological, demographic and epidemiological information on recently acquired infections will contribute to understanding the on-going HCV epidemic in England.

Acute hepatitis B in blood donors over a 5-year period in England and North Wales: who is getting infected?

BACKGROUND: Hepatitis B virus (HBV) remains the infection most frequently recognized by donation testing in blood donors. It is usually a persistent infection and mostly reflects the country of origin of the donor or the donor's family. There are, however, a minority of acute infections and this study undertook their phylogenetic analysis to determine the likely source of infection. STUDY DESIGN AND METHODS: Plasma samples from 11 donors donating between July 2005 and June 2010, whose test results revealed recent infection with hepatitis B, were available for further analysis. Plasma DNA was extracted, amplified, sequenced, and analyzed phylogenetically. Donor and virus characteristics were compared with the overall demography of all hepatitis B-infected donors attending over the same period. RESULTS: Three of the 11 individuals were first-time donors. Nine were male, of whom eight were white British. All had serum markers of very recent infection. Only two indicated known HBV exclusion risk factors at postdonation discussion not declared previously. Genotype A was present in seven, Genotype B in two, and Genotype C in two, contrasting with the pattern in persistently infected persons in the United Kingdom. A single A2 strain was identified in six of the white British male donors, suggesting epidemiologic linkage. CONCLUSION: Phylogenetic analysis of HBV-infected donors performed in real time can potentially lead to identification of undeclared risk factors that donor health questionnaires may fail to identify.

Using surveillance data to determine treatment rates and outcomes for patients with chronic hepatitis C virus infection.

UNLABELLED: The aim of this work was to develop and validate an algorithm to monitor rates of, and response to, treatment of patients infected with hepatitis C virus (HCV) across England using routine laboratory HCV RNA testing data. HCV testing activity between January 2002 and December 2011 was extracted from the local laboratory information systems of a sentinel network of 23 laboratories across England. An algorithm based on frequency of HCV RNA testing within a defined time period was designed to identify treated patients. Validation of the algorithm was undertaken for one center by comparison with treatment data recorded in a clinical database managed by the Trent HCV Study Group. In total, 267,887 HCV RNA test results from 100,640 individuals were extracted. Of these, 78.9% (79,360) tested positive for viral RNA, indicating an active infection, 20.8% (16,538) of whom had a repeat pattern of HCV RNA testing suggestive of treatment monitoring. Annual numbers of individuals treated increased rapidly from 468 in 2002 to 3,295 in 2009, but decreased to 3,110 in 2010. Approximately two thirds (63.3%; 10,468) of those treated had results consistent with a sustained virological response, including 55.3% and 67.1% of those with a genotype 1 and non-1 virus, respectively. Validation against the Trent clinical database demonstrated that the algorithm was 95% sensitive and 93% specific in detecting treatment and 100% sensitive and 93% specific for detecting treatment outcome. CONCLUSIONS: Laboratory testing activity, collected through a sentinel surveillance program, has enabled the first country-wide analysis of treatment and response among HCV-infected individuals. Our approach provides a sensitive, robust, and sustainable method for monitoring service provision across England.

Molecular analysis of precursor lesions in familial pancreatic cancer.

BACKGROUND: With less than a 5% survival rate pancreatic adenocarcinoma (PDAC) is almost uniformly lethal. In order to make a significant impact on survival of patients with this malignancy, it is necessary to diagnose the disease early, when curative surgery is still possible. Detailed knowledge of the natural history of the disease and molecular events leading to its progression is therefore critical. METHODS AND FINDINGS: We have analysed the precursor lesions, PanINs, from prophylactic pancreatectomy specimens of patients from four different kindreds with high risk of familial pancreatic cancer who were treated for histologically proven PanIN-2/3. Thus, the material was procured before pancreatic cancer has developed, rather than from PanINs in a tissue field that already contains cancer. Genome-wide transcriptional profiling using such unique specimens was performed. Bulk frozen sections displaying the most extensive but not microdissected PanIN-2/3 lesions were used in order to obtain the holistic view of both the precursor lesions and their microenvironment. A panel of 76 commonly dysregulated genes that underlie neoplastic progression from normal pancreas to PanINs and PDAC were identified. In addition to shared genes some differences between the PanINs of individual families as well as between the PanINs and PDACs were also seen. This was particularly pronounced in the stromal and immune responses. CONCLUSIONS: Our comprehensive analysis of precursor lesions without the invasive component provides the definitive molecular proof that PanIN lesions beget cancer from a molecular standpoint. We demonstrate the need for accumulation of transcriptomic changes during the progression of PanIN to PDAC, both in the epithelium and in the surrounding stroma. An identified 76-gene signature of PDAC progression presents a rich candidate pool for the development of early diagnostic and/or surveillance markers as well as potential novel preventive/therapeutic targets for both familial and sporadic pancreatic adenocarcinoma.

The diversity of chronic hepatitis B virus infections within blood donors in England and North Wales 2005 through 2010.

BACKGROUND: In 2010 hepatitis B virus (HBV) was the most frequently detected infection in UK blood donation screening, typically found in first-time, male, chronically infected donors born abroad. To date there has been no comprehensive characterization of the virologic profile of these infections. STUDY DESIGN AND METHODS: Epidemiologic and serologic data were collected retrospectively for 344 chronically HBV-infected blood donors identified from July 2005 to June 2010. Additional laboratory testing was carried out to determine the HBV genotype, viral load, and prevalence of clinically significant mutations and to detect hepatitis delta virus (HDV) coinfection. RESULTS: Five HBV genotypes (A-E) were found, Genotypes D (45%), A (20%), and E (20%) were the most prevalent. A strong association was seen between genotype and donor ethnicity (p < 0.001) and between genotype and place of residence (p = 0.006). Clinically significant mutations were observed across hepatitis B surface antigen (17%), basal core promoter (25%) and precore (78%) regions. An antiviral resistance profile was identified in one donor. Evidence of HDV coinfection was found in 2% of donors. CONCLUSION: The data show the diversity of HBV in asymptomatic chronic infections detected in blood donors in England and North Wales and demonstrates the presence of mutations which may impact on disease. The global nature of these infections and the inability to identify chronically infected donors before donation highlights the importance of using screening assays capable of detecting a broad range of genotypes and mutations. Furthermore, the integration of the virologic and demographic data allows us to more accurately construct a profile of our chronically HBV-infected blood donors.

Changing patterns of sexual risk behavior among London gay men: 1998-2008.

OBJECTIVES: To examine changes in the sexual behavior of London gay men between 1998 and 2008. METHODS: Gay men using London gyms were surveyed annually between 1998 and 2005, and again in 2008 (n=6064; range, 482-834 per year). Information was collected on human immunodeficiency virus (HIV) status of the respondent, unprotected anal intercourse (UAI) in the previous 3 months, type (main or casual) and HIV status of partner for UAI. Nonconcordant UAI (ncUAI) was defined as UAI with a partner of unknown or discordant HIV status. Concordant UAI (cUAI) was defined as UAI with a partner of the same HIV status ("serosorting"). RESULTS: Between 1998 and 2008, the percentage of men reporting UAI increased from 24.3% to 36.6% (P=0.07). This overall increase concealed important differences between nonconcordant and concordant UAI. While the percentage of men engaging in cUAI increased steadily between 1998 and 2008 (9.8%, 20.8%; P=0.01), the percentage reporting ncUAI increased between 1998 and 2001 (14.5%, 23.7%; P<0.001), decreased between 2001 and 2005 (23.7%, 15.6%; P<0.001), and then leveled off between 2005 and 2008 (15.6%, 15.7%; P=0.2). However, the percentage of men reporting ncUAI with a main partner increased between 2005 and 2008 for HIV-positive men (2.5%, 8.1%; P<0.05) and HIV negative men (2.1%, 5.5%; P=0.06). While the percentage of HIV negative men who reported cUAI with a main partner (i.e., serosorting) increased between 1998 and 2008 (12.4%, 21.1%; P<0.05), less than half established seroconcordance by testing together. CONCLUSIONS: The patterns of sexual behavior among London's gay men between 1998 and 2008 were dynamic and complex. Our data suggest that HIV risk with a main partner and HIV testing among couples should be given greater priority by health promotion programmes.

HIV type-1 drug resistance in antiretroviral treatment-naive adults infected with non-B subtype virus in the United Kingdom.

BACKGROUND: There is an increasing prevalence of non-B subtype HIV type-1 (HIV-1) infections in Europe, reflecting patterns of migration. We examined the characteristics of HIV-1 drug resistance in antiretroviral treatment (ART)-naive individuals migrating to the UK. METHODS: Resistance tests reported to the UK HIV Drug Resistance Database between 2001 and 2006 were included. Demographic data were obtained via linkage to national databases. Resistance was defined as ≥ 1 drug resistance mutation. Non-B HIV-1 subtype was used as a surrogate marker of infection acquired outside the UK. Logistic regression was used to examine the association between demographics and the prevalence of resistance. RESULTS: Overall, 196/4,291 (4.6%) samples with non-B subtype showed resistance compared with 745/6,435 (11.6%) samples for subtype B. Among non-B subtypes, the prevalence of resistance decreased over time (6.0% in 2001-2003 to 3.2% in 2006) and was independently associated with later calendar year of sampling (P=0.001). Resistance was confined mainly to one ART class (85%); non-nucleoside reverse transcriptase inhibitor resistance was more common in subtype C (47%) compared with non-B non-C subtypes (29%; P=0.02). M184V was more common in non-B subtypes (non-B 30% versus B 5%; P<0.001) and T215 variants were more common in subtype B (non-B 10% versus B 49%; P<0.001). CONCLUSIONS: In ART-naive individuals living in the UK, but who are likely to have acquired HIV-1 abroad, we observed a downward trend in resistance over time, which is surprising in light of ART roll-out in resource-limited settings. Reassuringly, resistance was mainly confined to one drug class; however, patterns of resistance differed by subtype, with some evidence of possible undisclosed prior therapy in non-B subtypes.