Anna McNaughton

Hepatitis B virus infection as a neglected tropical disease

CITATION: OHara, G. A., et al. 2017. Hepatitis B virus infection as a neglected tropical disease. PLOS Neglected Tropical Diseases, 11(10): e0005842, doi:10.1371/journal.pntd.0005842.

Human Herpes Virus 6 (HHV-6) - Pathogen or Passenger? A pilot study of clinical laboratory data and next generation sequencing

ABSTRACT Background Human herpes virus 6 (HHV-6) is a ubiquitous organism that can cause a variety of clinical syndromes ranging from short-lived rash and fever through to life-threatening encephalitis. Objectives We set out to generate observational data regarding the epidemiology of HHV-6 infection in clinical samples from a UK teaching hospital and to compare different diagnostic approaches. Study design First, we scrutinized HHV-6 detection in samples submitted to our hospital laboratory through routine diagnostic pathways. Second, we undertook a pilot study using Illumina next generation sequencing (NGS) to determine the frequency of HHV-6 in CSF and respiratory samples that were initially submitted to the laboratory for other diagnostic tests. Results Of 72 samples tested for HHV-6 by PCR at the request of a clinician, 24 (33%) were positive for HHV-6. The majority of these patients were under the care of the haematology team (30/41, 73%), and there was a borderline association between HHV-6 detection and both Graft versus Host Disease (GvHD) and Central nervous system (CNS) disease (p=0.05 in each case). We confirmed detection of HHV-6 DNA using NGS in 4/20 (20%) CSF and respiratory samples. Conclusions HHV-6 is common in clinical samples submitted from a high-risk haematology population, and enhanced screening of this group should be considered. NGS can be used to identify HHV-6 from a complex microbiomee, but further controls are required to define the sensitivity and specificity, and to correlate these results with clinical disease. Our results underpin ongoing efforts to develop NGS technology for viral diagnostics.

Can we meet global challenges for elimination of Hepatitis B Virus infection by 2030? Vaccine-mediated immunity in a South African cohort and a model of transmission and prevention

Background: Sustainable Development Goals and the World Health Organisation (WHO) Global health sector strategy on viral hepatitis have set a challenge for the elimination of hepatitis B virus (HBV) infection as a public health concern by the year 2030. Based on current estimates of 250 million individuals with chronic infection, an intensive scale-up of preventive interventions will be required to achieve this goal, alongside enhanced diagnosis and treatment. Although a safe, effective HBV vaccine has been part of the Expanded Programme on Immunisation since the mid-1990s, the extent to which enhanced immunization can contribute to these elimination targets is currently uncertain. We set out to characterise the epidemiology of HBV infection and the prevalence of vaccine-mediated protection in a cohort of South African children in order to inform a model of HBV transmission and prevention. This has allowed us to develop robust, evidence-based insights into the extent to which scaling up vaccination and prevention of mother-to-child transmission (PMTCT) might ultimately contribute to HBV elimination, and to assess the extent to which the targets for 2030 are realistic. Methods and findings: We studied a cohort of 310 children (136 HIV-positive; 174 HIV-negative) aged 6-60 months in Kimberley, South Africa. We screened for HBV infection (HBsAg) and exposure (anti-HBc); these were each present in 3 children ( 60 months), we demonstrated significantly higher antibody titres in the younger group (pSustainable Development Goals set a challenge for the elimination of hepatitis B virus (HBV) as a public health concern by 2030. We evaluate the current and future role of HBV vaccination and prevention of mother to child transmission (PMTCT) as tools for elimination, through the combined scrutiny of a paediatric cohort in South Africa and a model to simulate transmission and prevention. Existing efforts have been successful in reducing prevalence of infection (HBsAg) in children to <1%. Our model anticipates that current combination efforts of vaccination and PMTCT can significantly reduce population prevalence (HBsAg) by 2030, but will reduce the prevalence of HBV e-antigen positive carriers more slowly, with potential implications for public health control. With strategies and resources already available, significant, positive public health impact is possible, although time to HBV elimination as a public health concern is likely to be longer than that proposed by current goals. ABBREVIATIONS 3TC Lamivudine Anti-HBc Antibody to hepatitis B core antigen (antibody mediated by exposure to infection) Anti-HBe Antibody to hepatitis B envelope antigen Anti-HBs Antibody to hepatitis B surface antigen (vaccine-mediated antibody) ART Anti-retroviral therapy COSAC Coinfection in South African children EPI Expanded Programme on Immunisation FTC Entecavir HBV Hepatitis B virus HBcAg Hepatitis B core antigen HBeAg Hepatitis B envelope antigen HBsAg Hepatitis B surface antigen HBIg Hepatitis B immunoglobulin HIV Human immunodeficiency virus (type 1) KReC Kimberley Respiratory Cohort PMTCT Prevention of mother to child transmission RTHB Road to Health Book TDF Tenofovir UN United Nations WHO World Health OrganisationBackground: Sustainable Development Goals and the World Health Organisation (WHO) Global health sector strategy on viral hepatitis have set a challenge for the elimination of hepatitis B virus (HBV) infection as a public health concern by the year 2030. Based on current estimates of 250 million individuals with chronic infection, an intensive scale-up of interventions will be required. We set out to characterise the epidemiology of HBV infection and the prevalence of vaccine-mediated protection in a cohort of South African children, and used these data, alongside parameters from the published literature, to inform a model of HBV transmission and prevention. This has allowed us to develop evidence-based insights into the extent to which scaling up vaccination and prevention of mother-to-child transmission (PMTCT) might ultimately contribute to HBV elimination, and to assess the extent to which the targets for 2030 are realistic. nnMethods and findings: We studied a cohort of 310 children (136 HIV-positive; 174 HIV-negative) aged 6-60 months in Kimberley, South Africa. Less than 1% of children in this setting were HBV infected (HBsAg positive). A vaccine-mediated antibody (anti-HBs) titre ≥10 mIU/ml was present in 238/310 children (77%). Anti-HBs titres were higher in HIV-negative children and in younger children (p<0.0001 in each case). Using these data, together with estimates of HBV transmission and epidemiology derived from the wider literature, we developed a model of HBV infection dynamics. We used this model to investigate the influence of prevention strategies, focusing on vaccination and PMTCT. Current vaccination efforts can be predicted to reduce population prevalence by ~20% in the first 25 years, but can bring the prevalence of HBV e-antigen (HBeAg)-positive chronic carriers down by ~40% in the same time period. We show likely additional benefit in providing catch-up vaccination in the short-term, but little long-term difference. Combining neonatal vaccination with robust PMTCT is the most effective population-level strategy to secure short-term impact, but coverage of both interventions needs to be high. Thus with strategies and resources already available, significant, positive public health impact is possible, although time to HBV elimination is likely to be substantially longer than that proposed by current goals.nnConclusions: At the level of an individual cohort, these data reflect the substantial overall success of HBV immunisation, with

Utilising a Cohort Study of Hepatitis B Virus (HBV) Vaccine-Mediated Immunity in South African Children to Model Infection Dynamics: Can We Meet Global Targets for Elimination by 2030?

Background: Sustainable Development Goals and the World Health Organisation (WHO) Global health sector strategy on viral hepatitis have set a challenge for the elimination of hepatitis B virus (HBV) infection as a public health concern by the year 2030. Based on current estimates of 250 million individuals with chronic infection, an intensive scale-up of preventive interventions will be required to achieve this goal, alongside enhanced diagnosis and treatment. Although a safe, effective HBV vaccine has been part of the Expanded Programme on Immunisation since the mid-1990s, the extent to which enhanced immunization can contribute to these elimination targets is currently uncertain. We set out to characterise the epidemiology of HBV infection and the prevalence of vaccine-mediated protection in a cohort of South African children in order to inform a model of HBV transmission and prevention. This has allowed us to develop robust, evidence-based insights into the extent to which scaling up vaccination and prevention of mother-to-child transmission (PMTCT) might ultimately contribute to HBV elimination, and to assess the extent to which the targets for 2030 are realistic. Methods and findings: We studied a cohort of 310 children (136 HIV-positive; 174 HIV-negative) aged 6-60 months in Kimberley, South Africa. We screened for HBV infection (HBsAg) and exposure (anti-HBc); these were each present in 3 children ( 60 months), we demonstrated significantly higher antibody titres in the younger group (pSustainable Development Goals set a challenge for the elimination of hepatitis B virus (HBV) as a public health concern by 2030. We evaluate the current and future role of HBV vaccination and prevention of mother to child transmission (PMTCT) as tools for elimination, through the combined scrutiny of a paediatric cohort in South Africa and a model to simulate transmission and prevention. Existing efforts have been successful in reducing prevalence of infection (HBsAg) in children to <1%. Our model anticipates that current combination efforts of vaccination and PMTCT can significantly reduce population prevalence (HBsAg) by 2030, but will reduce the prevalence of HBV e-antigen positive carriers more slowly, with potential implications for public health control. With strategies and resources already available, significant, positive public health impact is possible, although time to HBV elimination as a public health concern is likely to be longer than that proposed by current goals. ABBREVIATIONS 3TC Lamivudine Anti-HBc Antibody to hepatitis B core antigen (antibody mediated by exposure to infection) Anti-HBe Antibody to hepatitis B envelope antigen Anti-HBs Antibody to hepatitis B surface antigen (vaccine-mediated antibody) ART Anti-retroviral therapy COSAC Coinfection in South African children EPI Expanded Programme on Immunisation FTC Entecavir HBV Hepatitis B virus HBcAg Hepatitis B core antigen HBeAg Hepatitis B envelope antigen HBsAg Hepatitis B surface antigen HBIg Hepatitis B immunoglobulin HIV Human immunodeficiency virus (type 1) KReC Kimberley Respiratory Cohort PMTCT Prevention of mother to child transmission RTHB Road to Health Book TDF Tenofovir UN United Nations WHO World Health OrganisationBackground: Sustainable Development Goals and the World Health Organisation (WHO) Global health sector strategy on viral hepatitis have set a challenge for the elimination of hepatitis B virus (HBV) infection as a public health concern by the year 2030. Based on current estimates of 250 million individuals with chronic infection, an intensive scale-up of interventions will be required. We set out to characterise the epidemiology of HBV infection and the prevalence of vaccine-mediated protection in a cohort of South African children, and used these data, alongside parameters from the published literature, to inform a model of HBV transmission and prevention. This has allowed us to develop evidence-based insights into the extent to which scaling up vaccination and prevention of mother-to-child transmission (PMTCT) might ultimately contribute to HBV elimination, and to assess the extent to which the targets for 2030 are realistic. nnMethods and findings: We studied a cohort of 310 children (136 HIV-positive; 174 HIV-negative) aged 6-60 months in Kimberley, South Africa. Less than 1% of children in this setting were HBV infected (HBsAg positive). A vaccine-mediated antibody (anti-HBs) titre ≥10 mIU/ml was present in 238/310 children (77%). Anti-HBs titres were higher in HIV-negative children and in younger children (p<0.0001 in each case). Using these data, together with estimates of HBV transmission and epidemiology derived from the wider literature, we developed a model of HBV infection dynamics. We used this model to investigate the influence of prevention strategies, focusing on vaccination and PMTCT. Current vaccination efforts can be predicted to reduce population prevalence by ~20% in the first 25 years, but can bring the prevalence of HBV e-antigen (HBeAg)-positive chronic carriers down by ~40% in the same time period. We show likely additional benefit in providing catch-up vaccination in the short-term, but little long-term difference. Combining neonatal vaccination with robust PMTCT is the most effective population-level strategy to secure short-term impact, but coverage of both interventions needs to be high. Thus with strategies and resources already available, significant, positive public health impact is possible, although time to HBV elimination is likely to be substantially longer than that proposed by current goals.nnConclusions: At the level of an individual cohort, these data reflect the substantial overall success of HBV immunisation, with

Hepatitis B vaccination as an elimination tool assessed in a paediatric cohort and simulated in a model.

Background: Sustainable Development Goals and the World Health Organisation (WHO) Global health sector strategy on viral hepatitis have set a challenge for the elimination of hepatitis B virus (HBV) infection as a public health concern by the year 2030. Based on current estimates of 250 million individuals with chronic infection, an intensive scale-up of preventive interventions will be required to achieve this goal, alongside enhanced diagnosis and treatment. Although a safe, effective HBV vaccine has been part of the Expanded Programme on Immunisation since the mid-1990s, the extent to which enhanced immunization can contribute to these elimination targets is currently uncertain. We set out to characterise the epidemiology of HBV infection and the prevalence of vaccine-mediated protection in a cohort of South African children in order to inform a model of HBV transmission and prevention. This has allowed us to develop robust, evidence-based insights into the extent to which scaling up vaccination and prevention of mother-to-child transmission (PMTCT) might ultimately contribute to HBV elimination, and to assess the extent to which the targets for 2030 are realistic. Methods and findings: We studied a cohort of 310 children (136 HIV-positive; 174 HIV-negative) aged 6-60 months in Kimberley, South Africa. We screened for HBV infection (HBsAg) and exposure (anti-HBc); these were each present in 3 children ( 60 months), we demonstrated significantly higher antibody titres in the younger group (pSustainable Development Goals set a challenge for the elimination of hepatitis B virus (HBV) as a public health concern by 2030. We evaluate the current and future role of HBV vaccination and prevention of mother to child transmission (PMTCT) as tools for elimination, through the combined scrutiny of a paediatric cohort in South Africa and a model to simulate transmission and prevention. Existing efforts have been successful in reducing prevalence of infection (HBsAg) in children to <1%. Our model anticipates that current combination efforts of vaccination and PMTCT can significantly reduce population prevalence (HBsAg) by 2030, but will reduce the prevalence of HBV e-antigen positive carriers more slowly, with potential implications for public health control. With strategies and resources already available, significant, positive public health impact is possible, although time to HBV elimination as a public health concern is likely to be longer than that proposed by current goals. ABBREVIATIONS 3TC Lamivudine Anti-HBc Antibody to hepatitis B core antigen (antibody mediated by exposure to infection) Anti-HBe Antibody to hepatitis B envelope antigen Anti-HBs Antibody to hepatitis B surface antigen (vaccine-mediated antibody) ART Anti-retroviral therapy COSAC Coinfection in South African children EPI Expanded Programme on Immunisation FTC Entecavir HBV Hepatitis B virus HBcAg Hepatitis B core antigen HBeAg Hepatitis B envelope antigen HBsAg Hepatitis B surface antigen HBIg Hepatitis B immunoglobulin HIV Human immunodeficiency virus (type 1) KReC Kimberley Respiratory Cohort PMTCT Prevention of mother to child transmission RTHB Road to Health Book TDF Tenofovir UN United Nations WHO World Health OrganisationBackground: Sustainable Development Goals and the World Health Organisation (WHO) Global health sector strategy on viral hepatitis have set a challenge for the elimination of hepatitis B virus (HBV) infection as a public health concern by the year 2030. Based on current estimates of 250 million individuals with chronic infection, an intensive scale-up of interventions will be required. We set out to characterise the epidemiology of HBV infection and the prevalence of vaccine-mediated protection in a cohort of South African children, and used these data, alongside parameters from the published literature, to inform a model of HBV transmission and prevention. This has allowed us to develop evidence-based insights into the extent to which scaling up vaccination and prevention of mother-to-child transmission (PMTCT) might ultimately contribute to HBV elimination, and to assess the extent to which the targets for 2030 are realistic. nnMethods and findings: We studied a cohort of 310 children (136 HIV-positive; 174 HIV-negative) aged 6-60 months in Kimberley, South Africa. Less than 1% of children in this setting were HBV infected (HBsAg positive). A vaccine-mediated antibody (anti-HBs) titre ≥10 mIU/ml was present in 238/310 children (77%). Anti-HBs titres were higher in HIV-negative children and in younger children (p<0.0001 in each case). Using these data, together with estimates of HBV transmission and epidemiology derived from the wider literature, we developed a model of HBV infection dynamics. We used this model to investigate the influence of prevention strategies, focusing on vaccination and PMTCT. Current vaccination efforts can be predicted to reduce population prevalence by ~20% in the first 25 years, but can bring the prevalence of HBV e-antigen (HBeAg)-positive chronic carriers down by ~40% in the same time period. We show likely additional benefit in providing catch-up vaccination in the short-term, but little long-term difference. Combining neonatal vaccination with robust PMTCT is the most effective population-level strategy to secure short-term impact, but coverage of both interventions needs to be high. Thus with strategies and resources already available, significant, positive public health impact is possible, although time to HBV elimination is likely to be substantially longer than that proposed by current goals.nnConclusions: At the level of an individual cohort, these data reflect the substantial overall success of HBV immunisation, with

HBV vaccination and PMTCT as elimination tools in the presence of HIV: insights from a clinical cohort and dynamic model

Background: Sustainable Development Goals and the World Health Organisation (WHO) Global health sector strategy on viral hepatitis have set a challenge for the elimination of hepatitis B virus (HBV) infection as a public health concern by the year 2030. Based on current estimates of 250 million individuals with chronic infection, an intensive scale-up of preventive interventions will be required to achieve this goal, alongside enhanced diagnosis and treatment. Although a safe, effective HBV vaccine has been part of the Expanded Programme on Immunisation since the mid-1990s, the extent to which enhanced immunization can contribute to these elimination targets is currently uncertain. We set out to characterise the epidemiology of HBV infection and the prevalence of vaccine-mediated protection in a cohort of South African children in order to inform a model of HBV transmission and prevention. This has allowed us to develop robust, evidence-based insights into the extent to which scaling up vaccination and prevention of mother-to-child transmission (PMTCT) might ultimately contribute to HBV elimination, and to assess the extent to which the targets for 2030 are realistic. Methods and findings: We studied a cohort of 310 children (136 HIV-positive; 174 HIV-negative) aged 6-60 months in Kimberley, South Africa. We screened for HBV infection (HBsAg) and exposure (anti-HBc); these were each present in 3 children ( 60 months), we demonstrated significantly higher antibody titres in the younger group (pSustainable Development Goals set a challenge for the elimination of hepatitis B virus (HBV) as a public health concern by 2030. We evaluate the current and future role of HBV vaccination and prevention of mother to child transmission (PMTCT) as tools for elimination, through the combined scrutiny of a paediatric cohort in South Africa and a model to simulate transmission and prevention. Existing efforts have been successful in reducing prevalence of infection (HBsAg) in children to <1%. Our model anticipates that current combination efforts of vaccination and PMTCT can significantly reduce population prevalence (HBsAg) by 2030, but will reduce the prevalence of HBV e-antigen positive carriers more slowly, with potential implications for public health control. With strategies and resources already available, significant, positive public health impact is possible, although time to HBV elimination as a public health concern is likely to be longer than that proposed by current goals. ABBREVIATIONS 3TC Lamivudine Anti-HBc Antibody to hepatitis B core antigen (antibody mediated by exposure to infection) Anti-HBe Antibody to hepatitis B envelope antigen Anti-HBs Antibody to hepatitis B surface antigen (vaccine-mediated antibody) ART Anti-retroviral therapy COSAC Coinfection in South African children EPI Expanded Programme on Immunisation FTC Entecavir HBV Hepatitis B virus HBcAg Hepatitis B core antigen HBeAg Hepatitis B envelope antigen HBsAg Hepatitis B surface antigen HBIg Hepatitis B immunoglobulin HIV Human immunodeficiency virus (type 1) KReC Kimberley Respiratory Cohort PMTCT Prevention of mother to child transmission RTHB Road to Health Book TDF Tenofovir UN United Nations WHO World Health OrganisationBackground: Sustainable Development Goals and the World Health Organisation (WHO) Global health sector strategy on viral hepatitis have set a challenge for the elimination of hepatitis B virus (HBV) infection as a public health concern by the year 2030. Based on current estimates of 250 million individuals with chronic infection, an intensive scale-up of interventions will be required. We set out to characterise the epidemiology of HBV infection and the prevalence of vaccine-mediated protection in a cohort of South African children, and used these data, alongside parameters from the published literature, to inform a model of HBV transmission and prevention. This has allowed us to develop evidence-based insights into the extent to which scaling up vaccination and prevention of mother-to-child transmission (PMTCT) might ultimately contribute to HBV elimination, and to assess the extent to which the targets for 2030 are realistic. nnMethods and findings: We studied a cohort of 310 children (136 HIV-positive; 174 HIV-negative) aged 6-60 months in Kimberley, South Africa. Less than 1% of children in this setting were HBV infected (HBsAg positive). A vaccine-mediated antibody (anti-HBs) titre ≥10 mIU/ml was present in 238/310 children (77%). Anti-HBs titres were higher in HIV-negative children and in younger children (p<0.0001 in each case). Using these data, together with estimates of HBV transmission and epidemiology derived from the wider literature, we developed a model of HBV infection dynamics. We used this model to investigate the influence of prevention strategies, focusing on vaccination and PMTCT. Current vaccination efforts can be predicted to reduce population prevalence by ~20% in the first 25 years, but can bring the prevalence of HBV e-antigen (HBeAg)-positive chronic carriers down by ~40% in the same time period. We show likely additional benefit in providing catch-up vaccination in the short-term, but little long-term difference. Combining neonatal vaccination with robust PMTCT is the most effective population-level strategy to secure short-term impact, but coverage of both interventions needs to be high. Thus with strategies and resources already available, significant, positive public health impact is possible, although time to HBV elimination is likely to be substantially longer than that proposed by current goals.nnConclusions: At the level of an individual cohort, these data reflect the substantial overall success of HBV immunisation, with

A blind spot? Confronting the stigma of hepatitis B virus (HBV) infection - A systematic review

Background: Stigma, poverty, and lack of knowledge present barriers to the diagnosis and treatment of chronic infection, especially in resource-limited settings. Chronic Hepatitis B virus (HBV) infection is frequently asymptomatic, but accounts for a substantial long-term burden of morbidity and mortality. In order to improve the success of diagnostic, treatment and preventive strategies, it is important to recognise, investigate and tackle stigma. We set out to assimilate evidence for the nature and impact of stigma associated with HBV infection, and to suggest ways to tackle this challenge. Methods: We carried out a literature search in PubMed using the search terms ‘hepatitis B’, ‘stigma’ to identify relevant papers published between 2007 and 2017 (inclusive), with a particular focus on Africa. Results: We identified a total of 32 articles, of which only two studies were conducted in Africa. Lack of knowledge of HBV was consistently identified, and in some settings there was no local word to describe HBV infection. There were misconceptions about HBV infection, transmission and treatment. Healthcare workers provided inaccurate information to individuals diagnosed with HBV, and poor understanding resulted in lack of preventive measures. Stigma negatively impacted on help-seeking, screening, disclosure, prevention of transmission, and adherence to treatment, and had potential negative impacts on mental health, wellbeing, employment and relationships. Conclusion: Stigma is a potentially major barrier to the successful implementation of preventive, diagnostic and treatment strategies for HBV infection, and yet we highlight a ‘blind spot’, representing a lack of data and limited recognition of this challenge. There is a need for more research in this area, to identify and evaluate interventions that can be used effectively to tackle stigma, and to inform collaborative efforts between patients, clinical services, policy makers, traditional healers, religious leaders, charity organisations and support groups.

A systematic review of hepatitis B virus (HBV) drug and vaccine escape mutations in Africa: A call for urgent action

International sustainable development goals for the elimination of viral hepatitis as a public health problem by 2030 highlight the pressing need to optimize strategies for prevention, diagnosis and treatment. Selected or transmitted resistance associated mutations (RAMs) and vaccine escape mutations (VEMs) in hepatitis B virus (HBV) may reduce the success of existing treatment and prevention strategies. These issues are particularly pertinent for many settings in Africa where there is high HBV prevalence and co-endemic HIV infection, but lack of robust epidemiological data and limited education, diagnostics and clinical care. The prevalence, distribution and impact of RAMs and VEMs in these populations are neglected in the current literature. We therefore set out to assimilate data for sub-Saharan Africa through a systematic literature review and analysis of published sequence data, and present these in an on-line database (https://livedataoxford.shinyapps.io/1510659619-3Xkoe2NKkKJ7Drg/). The majority of the data were from HIV/HBV coinfected cohorts. The commonest RAM was rtM204I/V, either alone or in combination with associated mutations, and identified in both reportedly treatment-naïve and treatment-experienced adults. We also identified the suite of mutations rtM204V/I + rtL180M + rtV173L, that has been associated with vaccine escape, in over 1/3 of cohorts. Although tenofovir has a high genetic barrier to resistance, it is of concern that emerging data suggest polymorphisms that may be associated with resistance, although the precise clinical impact of these is unknown. Overall, there is an urgent need for improved diagnostic screening, enhanced laboratory assessment of HBV before and during therapy, and sustained roll out of tenofovir in preference to lamivudine alone. Further data are needed in order to inform population and individual approaches to HBV diagnosis, monitoring and therapy in these highly vulnerable settings.

Insights From Deep Sequencing of the HBV Genome—Unique, Tiny, and Misunderstood

n n Hepatitis B virus (HBV) is a unique, tiny, partially double-stranded, reverse-transcribing DNA virus with proteins encoded by multiple overlapping reading frames. The substitution rate is surprisingly high for a DNA virus, but lower than that of other reverse transcribing organisms. More than 260 million people worldwide have chronic HBV infection, which causes 0.8 million deaths a year. Because of the high burden of disease, international health agencies have set the goal of eliminating HBV infection by 2030. Nonetheless, the intriguing HBV genome has not been well characterized. We summarize data on the HBV genome structure and replication cycle, explain and quantify diversity within and among infected individuals, and discuss advances that can be offered by application of next-generation sequencing technology. In-depth HBV genome analyses could increase our understanding of disease pathogenesis and allow us to better predict patient outcomes, optimize treatment, and develop new therapeutics.n n

Hepatitis B Virus Adaptation to the CD8+ T Cell Response: Consequences for Host and Pathogen

Chronic viral hepatitis infections are a major public health concern, with an estimated 290 million individuals infected with hepatitis B virus (HBV) globally. This virus has been a passenger in human populations for >30,000u2009years, and remains highly prevalent in some settings. In order for this endemic pathogen to persist, viral adaptation to host immune responses is pre-requisite. Here, we focus on the interplay between HBV infection and the CD8+ T cell response. We present the evidence that CD8+ T cells play an important role in control of chronic HBV infection and that the selective pressure imposed on HBV through evasion of these immune responses can potentially influence viral diversity, chronicity, and the outcome of infection, and highlight where there are gaps in current knowledge. Understanding the nature and mechanisms of HBV evolution and persistence could shed light on differential disease outcomes, including cirrhosis and hepatocellular carcinoma, and help reach the goal of global HBV elimination by guiding the design of new strategies, including vaccines and therapeutics.