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BackgroundCurrent clinical guidelines recommend treating chronic hepatitis B virus (HBV) infection in a minority of cases, but there are relatively scarce data on evolution or progression of liver inflammation and fibrosis in cases of chronic HBV (CHB) that do not meet treatment criteria. We aimed to assess the impact of TDF on liver disease, and the risk of renal impairment in treated CHB patients in comparison to untreated patients.MethodsWe studied a longitudinal ethnically diverse CHB cohort in the UK attending out-patient clinics between 2005 and 2018. We examined TDF treatment (vs. untreated) as the main exposure, with HBV DNA viral load (VL), ALT, elastography scores and eGFR as the main outcomes, using paired tests and mixed effects model for longitudinal measurements. Additionally, decline of eGFR during follow-up was quantified within individuals by thresholds based on clinical guidelines. Baseline was defined as treatment initiation for TDF group and the beginning of clinical follow-up for untreated group respectively.ResultsWe included 206 adults (60 on TDF, 146 untreated), with a median ± IQR follow-up duration of 3.3 ± 2.8 years. The TDF group was significantly older (median age 39 vs. 35 years,p = 0.004) and more likely to be male (63% vs. 47%,p = 0.04) compared to the untreated group. Baseline difference between TDF and untreated groups reflected treatment eligibility criteria. As expected, VL and ALT declined significantly over time in TDF-treated patients. Elastography scores normalised during treatment in the TDF group reflecting regression of inflammation and/or fibrosis. However, 6/81 (7.4%) of untreated patients had a progression of fibrosis stage from F0-F1 to F2 or F3. There was no evidence of difference in rates or incidence of renal impairment during follow-up in the TDF vs. untreated group.ConclusionsRisk of liver inflammation and fibrosis may be raised in untreated patients compared to those receiving TDF, and TDF may benefit a larger percentage of the CHB population.

IntroductionVaccination and anti-viral therapy with nucleos(t)ide analogues (NAs) are key approaches to reducing the morbidity, mortality and transmission of hepatitis B virus (HBV) infection. However, the efficacy of these interventions may be reduced by the emergence of drug resistance-associated mutations (RAMs) and/or vaccine escape mutations (VEMs). We have assimilated data on the global prevalence and distribution of HBV RAMs/VEMs from publicly available data and explored the evolution of these mutations.MethodsWe analysed sequences downloaded from the Hepatitis B Virus Database, and calculated prevalence of 41 RAMs and 38 VEMs catalogued from published studies. We generated maximum likelihood phylogenetic trees and used treeBreaker to investigate the distribution of selected mutations across tree branches. We performed phylogenetic molecular clock analyses using BEAST to estimate the age of mutations.ResultsRAM M204I/V had the highest prevalence, occurring in 3.8% (109/2838) of all HBV sequences in our dataset, and a significantly higher rate in genotype C sequence at 5.4% (60/1102, p=0.0007). VEMs had an overall prevalence of 1.3% (37/2837) and had the highest prevalence in genotype C and in Asia at 2.2% (24/1102; p=0.002) and 1.6% (34/2109; p=0.009) respectively. Phylogenetic analysis suggested that most RAM/VEMs arose independently, however RAMs including A194T, M204V and L180M formed clusters in genotype B. We show evidence that polymorphisms associated with drug and vaccine resistance may have been present in the mid 20th century suggesting that they can arise independently of treatment/ vaccine exposure.DiscussionHBV RAMs/VEMs have been found globally and across genotypes, with the highest prevalence observed in genotype C variants. Screening for the genotype and for resistant mutations may help to improve stratified patient treatment. As NAs and HBV vaccines are increasingly being deployed for HBV prevention and treatment, monitoring for resistance and advocating for better treatment regimens for HBV remains essential.

Contains fulltext : 282658.pdf (Publisher’s version ) (Open Access) IMPORTANCE: The Global Burden of Disease study conducted between 1990 and 2016, based on a global study of 195 countries and territories, identified Parkinson disease (PD) as the fastest growing neurological disorder when measured using death and disability. Most people affected by PD live in low- and middle-income countries (LMICs) and experience large inequalities in access to neurological care and essential medicines. This Special Communication describes 6 actions steps that are urgently needed to address global disparities in PD. OBSERVATIONS: The adoption by the 73rd World Health Assembly (WHA) of resolution 73.10 to develop an intersectoral global action plan on epilepsy and other neurological disorders in consultation with member states was the stimulus to coordinate efforts and leverage momentum to advance the agenda of neurological conditions, such as PD. In April 2021, the Brain Health Unit at the World Health Organization convened a multidisciplinary, sex-balanced, international consultation workshop, which identified 6 workable avenues for action within the domains of disease burden; advocacy and awareness; prevention and risk reduction; diagnosis, treatment, and care; caregiver support; and research. CONCLUSIONS AND RELEVANCE: The dramatic increase of PD cases in many world regions and the potential costs of PD-associated treatment will need to be addressed to prevent possible health service strain. Across the board, governments, multilateral agencies, donors, public health organizations, and health care professionals constitute potential stakeholders who are urged to make this a priority.

Bangladesh is one of the top-ten most heavily burdened countries for viral hepatitis, with hepatitis B (HBV) infections responsible for the majority of cases. Recombinant and occult HBV infections (OBI) have been reported previously in the region. We investigated an adult fever cohort (n=201) recruited in Dhaka, to determine the prevalence of HBV and OBI. A target-enrichment deep sequencing pipeline was applied to samples with HBV DNA >3.0 log10 IU ml−1. HBV infection was present in 16/201 (8 %), among whom 3/16 (19 %) were defined as OBI (HBsAg-negative but detectable HBV DNA). Whole genome deep sequences (WGS) were obtained for four cases, identifying genotypes A, C and D. One OBI case had sufficient DNA for sequencing, revealing multiple polymorphisms in the surface gene that may contribute to the occult phenotype. We identified mutations associated with nucleos(t)ide analogue resistance in 3/4 samples sequenced, although the clinical significance in this cohort is unknown. The high prevalence of HBV in this setting illustrates the importance of opportunistic clinical screening and DNA testing of transfusion products to minimise OBI transmission. WGS can inform understanding of diverse disease phenotypes, supporting progress towards international targets for HBV elimination.

Background COVID-19 vaccine supply shortages are causing concerns about compromised immunity in some countries as the interval between the first and second dose becomes longer. Conversely, countries with no supply constraints are considering administering a third dose. We assessed the persistence of immunogenicity after a single dose of ChAdOx1 nCoV-19 (AZD1222), immunity after an extended interval (44–45 weeks) between the first and second dose, and response to a third dose as a booster given 28–38 weeks after the second dose. Methods In this substudy, volunteers aged 18–55 years who were enrolled in the phase 1/2 (COV001) controlled trial in the UK and had received either a single dose or two doses of 5 × 1010 viral particles were invited back for vaccination. Here we report the reactogenicity and immunogenicity of a delayed second dose (44–45 weeks after first dose) or a third dose of the vaccine (28–38 weeks after second dose). Data from volunteers aged 18–55 years who were enrolled in either the phase 1/2 (COV001) or phase 2/3 (COV002), single-blinded, randomised controlled trials of ChAdOx1 nCoV-19 and who had previously received a single dose or two doses of 5 × 1010 viral particles are used for comparison purposes. COV001 is registered with ClinicalTrials.gov, NCT04324606, and ISRCTN, 15281137, and COV002 is registered with ClinicalTrials.gov, NCT04400838, and ISRCTN, 15281137, and both are continuing but not recruiting. Findings Between March 11 and 21, 2021, 90 participants were enrolled in the third-dose boost substudy, of whom 80 (89%) were assessable for reactogenicity, 75 (83%) were assessable for evaluation of antibodies, and 15 (17%) were assessable for T-cells responses. The two-dose cohort comprised 321 participants who had reactogenicity data (with prime-boost interval of 8–12 weeks: 267 [83%] of 321; 15–25 weeks: 24 [7%]; or 44–45 weeks: 30 [9%]) and 261 who had immunogenicity data (interval of 8–12 weeks: 115 [44%] of 261; 15–25 weeks: 116 [44%]; and 44–45 weeks: 30 [11%]). 480 participants from the single-dose cohort were assessable for immunogenicity up to 44–45 weeks after vaccination. Antibody titres after a single dose measured approximately 320 days after vaccination remained higher than the titres measured at baseline (geometric mean titre of 66·00 ELISA units [EUs; 95% CI 47·83–91·08] vs 1·75 EUs [1·60–1·93]). 32 participants received a late second dose of vaccine 44–45 weeks after the first dose, of whom 30 were included in immunogenicity and reactogenicity analyses. Antibody titres were higher 28 days after vaccination in those with a longer interval between first and second dose than for those with a short interval (median total IgG titre: 923 EUs [IQR 525–1764] with an 8–12 week interval; 1860 EUs [917–4934] with a 15–25 week interval; and 3738 EUs [1824–6625] with a 44–45 week interval). Among participants who received a third dose of vaccine, antibody titres (measured in 73 [81%] participants for whom samples were available) were significantly higher 28 days after a third dose (median total IgG titre: 3746 EUs [IQR 2047–6420]) than 28 days after a second dose (median 1792 EUs [IQR 899–4634]; Wilcoxon signed rank test p=0·0043). T-cell responses were also boosted after a third dose (median response increased from 200 spot forming units [SFUs] per million peripheral blood mononuclear cells [PBMCs; IQR 127–389] immediately before the third dose to 399 SFUs per milion PBMCs [314–662] by day 28 after the third dose; Wilcoxon signed rank test p=0·012). Reactogenicity after a late second dose or a third dose was lower than reactogenicity after a first dose. Interpretation An extended interval before the second dose of ChAdOx1 nCoV-19 leads to increased antibody titres. A third dose of ChAdOx1 nCoV-19 induces antibodies to a level that correlates with high efficacy after second dose and boosts T-cell responses. Funding UK Research and Innovation, Engineering and Physical Sciences Research Council, National Institute for Health Research, Coalition for Epidemic Preparedness Innovations, National Institute for Health Research Oxford Biomedical Research Centre, Chinese Academy of Medical Sciences Innovation Fund for Medical Science, Thames Valley and South Midlands NIHR Clinical Research Network, AstraZeneca, and Wellcome.

AimCurrent clinical recommendations suggest treating chronic hepatitis B virus (HBV) infection in a minority of cases, but more data are needed to determine the benefits and risks of Tenofovir disoproxil fumarate (TDF) therapy. We aimed to assess the impact of TDF on liver disease, and the risk of nephrotoxicity.MethodWe studied a longitudinal UK chronic HBV (CHB) cohort attending out-patient clinics between 2005 and 2018, analysing data for 206 ethnically diverse adults (60 on TDF, 146 untreated), with median follow-up 3.3±2.8 years.ResultsPatients prescribed TDF were older (39 vs. 35 years, p=0.004) with a male excess (63% vs. 47%, p=0.04) compared to untreated patients. Reflecting treatment eligibility criteria, at baseline, treated patients were more likely to have elevated ALT (pConclusionTDF may have long-term benefits for a wider pool of the CHB population.

Background:Tenofovir (TFV) is a widely used treatment for chronic hepatitis B virus (HBV) infection. There is a high genetic barrier to the selection of TFV resistance-associated mutations (RAMs), but the distribution and clinical significance of TFV RAMs are not well understood. We here present assimilated evidence for putative TFV RAMs with the aims of cataloguing and characterising mutations that have been reported, and starting to develop insights into mechanisms of resistance.Methods:We carried out a systematic literature search in PubMed and Scopus to identify clinical,in vitroandin silicoevidence of TFV resistance. We included peer-reviewed studies presenting original data regarding virological TFV breakthrough, using published methods to assess the quality of each study. We generated a list of RAMs that have been reported in association with TFV resistance, developing a ‘long-list’ (all reported RAMs) and a ‘short-list’ (a refined list supported by the most robust evidence). We assessed the potential functional and structural consequences by mapping onto the crystal structure for HIV reverse transcriptase (RT), as the structure of HBV RT has not been solved.Results:We identified a ‘long-list’ of 37 putative TFV RAMs in HBV RT, occurring within and outside sites of enzyme activity, some of which can be mapped onto a homologous HIV RT structure. A ‘short-list’ of nine sites are supported by the most robust evidence. If clinically significant resistance arises, it is most likely to be in the context of suites of multiple RAMs. Other factors including adherence, viral load, HBeAg status, HIV coinfection and NA dosage may also influence viraemic suppression.Conclusion:There is emerging evidence for polymorphisms that may reduce susceptibility to TVF. However, good correlation between viral sequence and treatment outcomes is currently lacking; further studies are essential to optimise individual treatment and public health approaches.

Background International Sustainable Development Goals (SDGs) for elimination of hepatitis B virus (HBV) infection set ambitious targets for 2030. In African populations, infant immunisation has been fundamental to reducing incident infections in children, but overall population prevalence of chronic hepatitis B (CHB) infection remains high. In high-prevalence populations, adult catch-up vaccination has sometimes been deployed, but an alternative Test and Treat (T&T) approach could be used as an intervention to interrupt transmission. Universal T&T has not been previously evaluated as a population intervention for HBV infection, despite high-profile data supporting its success with human immunodeficiency virus (HIV). Methods and findings We set out to investigate the relationship between prevalence of HBV infection and exposure in Africa, undertaking a systematic literature review in November 2019. We identified published seroepidemiology data representing the period 1995–2019 from PubMed and Web of Science, including studies of adults that reported prevalence of both hepatitis B surface antigen (HBsAg; prevalence of HBV infection) and antibody to hepatitis B core antigen (anti-HBc; prevalence of HBV exposure). We identified 96 studies representing 39 African countries, with a median cohort size of 370 participants and a median participant age of 34 years. Using weighted linear regression analysis, we found a strong relationship between the prevalence of infection (HBsAg) and exposure (anti-HBc) (R2 = 0.45, p < 0.001). Region-specific differences were present, with estimated CHB prevalence in Northern Africa typically 30% to 40% lower (p = 0.007) than in Southern Africa for statistically similar exposure rates, demonstrating the need for intervention strategies to be tailored to individual settings. We applied a previously published mathematical model to investigate the effect of interventions in a high-prevalence setting. The most marked and sustained impact was projected with a T&T strategy, with a predicted reduction of 33% prevalence by 20 years (95% CI 30%–37%) and 62% at 50 years (95% CI 57%–68%), followed by routine neonatal vaccination and prevention of mother to child transmission (PMTCT; at 100% coverage). In contrast, the impact of catch-up vaccination in adults had a negligible and transient effect on population prevalence. The study is constrained by gaps in the published data, such that we could not model the impact of antiviral therapy based on stratification by specific clinical criteria and our model framework does not include explicit age-specific or risk-group assumptions regarding force of transmission. Conclusions The unique data set collected in this study highlights how regional epidemiology data for HBV can provide insights into patterns of transmission, and it provides an evidence base for future quantitative research into the most effective local interventions. In combination with robust neonatal immunisation programmes, ongoing PMTCT efforts, and the vaccination of high-risk groups, diagnosing and treating HBV infection is likely to be of most impact in driving advances towards elimination targets at a population level., Anna McNaughton and colleagues study the epidemiology of hepatitis B virus in African countries, and assess strategies to reduce disease burden., Author summary Why was this study done? Hepatitis B virus (HBV) infection is a major global health problem, with an estimated 290 million infections worldwide; international targets set the challenge for this public health threat to be eliminated by 2030. Administering HBV vaccine to babies is a very successful way to prevent new infections, but previous studies have shown that this strategy will take many decades to bring about elimination targets. We set out to investigate other approaches that can be used in combination with the infant vaccination schedule, using data from a meta-analysis and modelling the impact of vaccinating older children and adults, or enhancing testing and treatment (T&T) of existing HBV infections. What did the researchers do and find? We undertook a review and meta-analysis of all the published data describing the frequency of HBV infection, as well as the frequency of exposure to HBV infection in African populations, working with data from 96 studies published between 1995 and 2019. Using these data, we demonstrated a significant relationship between exposure and infection (overall p < 0.001) and identified differences between geographic regions. Using an existing mathematical model, our findings suggest that vaccinating older age groups has negligible sustained effect on HBV rates in a population, but universal T&T of HBV is predicted to have a substantial impact. What do these findings mean? Our results show different patterns of HBV infection and transmission in different regions of Africa, illustrating that interventions may need to be tailored according to the specific setting. We have demonstrated that vaccination campaigns targeting older children and adults are unlikely to be an effective use of resources in most African populations, and that resources are better diverted to improving diagnosis and treatment of existing infections. The study is limited by gaps in existing data, such that many populations in Africa are poorly represented. Our conclusions are drawn from the output of a model and will need to be validated in clinical practice.

Bangladesh is one of the world’s top ten burdened countries for viral hepatitis. We investigated an adult fever cohort (n=201) recruited in Dhaka, to determine the prevalence of hepatitis B virus (HBV) infection and to identify cases of occult hepatitis B infection (OBI). HBV exposure (anti-HBc) was documented in 72/201 (36%), and active HBV infection in 16/201 (8%), among whom 3 were defined as OBI (defined as detectable HBV DNA but negative HBsAg). Applying a target-enrichment sequencing pipeline to samples with HBV DNA >3.0log10 IU/ml, we obtained deep whole genome sequences for four cases, identifying genotypes A, C and D. Polymorphisms in the surface gene of the OBI case may account for the negative HBsAg status. We identified mutations associated with nucleos(t)ide analogue resistance, although the clinical significance in this cohort is not known. The high prevalence of HBV in this setting highlights the benefits of offering screening in hospital patients and the importance of HBV DNA testing of transfusion products to reduce the risk of transmission. In order to work towards international Sustainable Development Goal targets for HBV elimination, increased investment is required for diagnosis, treatment and prevention in Bangladesh.

ObjectivesLiver disease is a major cause of morbidity and mortality in sub-Saharan Africa, but its prevalence, distribution and aetiology have not been well characterised. We therefore set out to examine liver function tests (LFTs) and liver fibrosis scores in a rural African population.DesignWe undertook a cross-sectional survey of LFTs. We classified abnormal LFTs based on reference ranges set in America and in Africa. We derived fibrosis scores (aspartate aminotransferase (AST) to Platelet Ratio Index (APRI), fibrosis-4, gamma-glutamyl transferase (GGT) to platelet ratio (GPR), red cell distribution width to platelet ratio and S-index). We collected information about alcohol intake, and infection with HIV, hepatitis B virus (HBV) and hepatitis C virus (HCV).SettingWe studied a population cohort in South-Western Uganda.ParticipantsData were available for 8099 adults (median age 30 years; 56% female).ResultsThe prevalence of HBV, HCV and HIV infection was 3%, 0.2% and 8%, respectively. The prevalence of abnormal LFTs was higher based on the American reference range compared with the African reference range (eg, for AST 13% vs 3%, respectively). Elevated AST/ALT ratio was significantly associated with self-reported alcohol consumption (p2 was 11% (suggesting alcoholic hepatitis). The highest prevalence of fibrosis was predicted by the GPR score, with 24% of the population falling above the threshold for fibrosis. There was an association between the presence of HIV or HBV and raised GPR (p=0.005) and S-index (pConclusionsFurther work is required to determine normal reference ranges for LFTs in this setting, to evaluate the specificity and sensitivity of fibrosis scores and to determine the aetiology of liver disease.

Introduction Many patients with Parkinson's disease (PD) in sub-Saharan Africa (SSA) are thought to be undiagnosed and untreated, leading to poor health outcomes. Increasing rates of diagnosis and treatment, with consequent improvements in the quality of life of people with PD in SSA requires an understanding of how PD is perceived and conceptualized within communities. Methods A cross-sectional survey was conducted among a group of Xhosa speaking black South Africans. The survey involved the administration of questionnaires on beliefs, knowledge and attitudes about PD to the public, people with PD (PwPD) and traditional healers (THs). Results 18% of the participants could identify PD through its symptoms. Mental illness, other diseases, stress, expressing strong emotions, consumption of certain foods or drinks and witchcraft were identified as possible causes of PD. PwPD and THs had a greater knowledge of PD than the public and greater age was a significant predictor of greater knowledge. The public and THs had a greater degree of concern about a range of symptoms of PD compared to PwPD. Conclusion There is a striking lack of knowledge about PD amongst black South Africans. Almost half the members of the general public interviewed felt that PwPD should not live amongst their community, and a third considered that witchcraft could be a cause of PD. Finding ways to effectively educate members of a community about PD would make it easier for PwPD to adapt to their condition within their communities.

Highlights • We compared HBV monoinfection with HBV/coinfection in a cross-sectional cohort from South Africa. • HBV/HIV coinfected individuals were more likely to undergo assessment by fibroscan. • HBV monoinfection was less likely to be treated than HBV/HIV coinfection. • Indications of severe liver disease were more common in HBV monoinfection. • Cases of hepatocellular carcinoma all arose in HBV monoinfection., Objectives Prompted by international targets for elimination of hepatitis B virus (HBV), we set out to characterise individuals with HBV monoinfection vs. those coinfected with HBV/HIV, to evaluate the impact of therapy and to guide improvements in clinical care. Methods We report observational data from a real world cross-sectional cohort of 115 adults with chronic hepatitis B infection (CHB), at a university hospital in Cape Town, South Africa. HIV coinfection was present in 39 (34%) subjects. We recorded cross-sectional demographic, clinical and laboratory data. Results Compared to those with HIV coinfection, HBV monoinfected adults were less likely to be HBeAg-positive (p=0.01), less likely to have had assessment with elastography (p

BackgroundTenofovir (TFV) is a widely used antiviral treatment for chronic hepatitis B virus (HBV) infection. There is a high genetic barrier to the selection of TFV resistance-associated mutations (RAMs), but the distribution and clinical significance of TFV RAMs are not well understood, and the topic remains contentious. We here present assimilated evidence for putative TFV RAMs with the aims of cataloguing and characterising mutations that have been reported, and starting to develop insights into the mechanisms of resistance and potential clinical significance.MethodsWe carried out a systematic literature search in PubMed to identify clinical,in vitroandin silicoevidence of TFV resistance. The structure of HBV reverse transcriptase (RT) has not been solved; we therefore compared HBV RT to the crystal structure for HIV RT to map the likely sites of RAMs.ResultsWe identified a ‘long-list’ of 37 putative TFV RAMs in HBV RT, occurring within and outside sites of enzyme activity, some of which can be mapped onto a homologous HIV RT structure. Based on quality and quantity of supporting data, we generated a ‘short-list’ of nine sites that are supported by the most robust evidence. Most resistance arises as a result of suites of multiple RAMs. Other factors including adherence, viral load, HBeAg status, HIV coinfection and NA dosage may also influence viraemic suppression.ConclusionThere is emerging evidence for polymorphisms that may reduce susceptibility to TVF. A better understanding of HBV drug resistance is imperative to optimise approaches to public health elimination targets.

IntroductionLiver disease is a major cause of morbidity and mortality in sub-Saharan Africa. However, its prevalence, distribution and aetiology have not been well characterised. We examined liver function tests (LFTs) and calculated liver fibrosis scores in a rural population in Uganda.MethodologyA cross-sectional survey of LFTs was undertaken in 2011 in a rural population cohort in South-Western Uganda. We classified abnormal LFTs based on reference ranges set in America and in Africa. We derived fibrosis scores (AST to Platelet Ratio Index, fibrosis-4, GGT to platelet ratio, red cell distribution width to platelet ratio, and S-index) to evaluate the potential prevalence of liver disease. We collected information about alcohol intake, and infection with HIV, HBV and HCV, to determine the contribution made by these factors to liver inflammation or fibrosis.ResultsData were available for 8,099 participants (median age 30 years; 56% female). The prevalence of HBV, HCV and HIV infection were 3%, 0.2% and 8%, respectively. The prevalence of abnormal LFTs was higher based on the American reference range compared to the African reference range (e.g. for AST 13% vs 3%, respectively). The prevalence of AST/ALT ratio >2 was 11%, suggestive of alcoholic hepatitis. The highest prevalence of fibrosis was suggested by the GPR score, with 24% of the population falling above the threshold for fibrosis. By multivariate analysis, elevated LFTs and fibrosis scores were most consistently associated with older age, male sex, being under-weight, infection with HIV or HBV, and alcohol consumption. Based on population attributable risk, the highest proportion of elevated fibrosis scores was associated with alcohol use (e.g. 64% of elevated S-index scores).ConclusionFurther work is required to determine normal reference ranges for LFTs in this setting, to evaluate the specificity and sensitivity of fibrosis scores, and to determine aetiology of liver disease.KEY FINDINGSWhat is already known?Liver disease is not well characterised in many parts of sSA despite the high prevalence of chronic viral infections (HIV, HBV and HCV), and potential exposure to hepatotoxins including alcohol, aflatoxins and traditional herbal medicine.Non-invasive blood tests for markers of fibrosis are relatively simple and offer a safe route to assess for liver fibrosis, however, their diagnostic accuracy is not well established in sSA.Appropriate reference ranges for LFTs are crucial for optimising the sensitivity and specificity of the detection of underlying liver disease.What are the new findings?There is a disparity in the prevalence of abnormal LFTs in our study cohort when comparing two references ranges (American vs. local reference ranges).Based on GPR score, there is a high prevalence of liver fibrosis (almost 1 in 4 of this population) and elevated GPR score is associated with older age, male sex, being under-weight, infection with HIV or HBV, and alcohol consumption.Alcohol consumption accounted for 64% of abnormal S-index scores, 32% of elevated FIB-4 scores, and 19% of GPR abnormalities.What do the new findings imply?Appropriate reference ranges for LFTs are necessary to contribute to an understanding of the burden and aetiology of liver disease.Alcohol, HIV and HBV are risk factors for deranged LFTs and liver fibrosis, with alcohol making the most significant and striking contribution.Further investigation is needed to determine other factors that contribute to liver disease in this setting.

Advances in the diagnosis, monitoring, and treatment of hepatitis B virus (HBV) infection are urgently required if we are to meet international targets for elimination by the year 2030. Here we demonstrate how routine clinical data can be harnessed through an unbiased electronic pipeline, showcasing the significant potential for amassing large clinical data sets that can help to inform advances in patient care and provide insights that may help to inform new cure strategies. Our cohort from a large UK hospital includes adults from diverse ethnic groups that have previously been underrepresented in the literature. By tracking two protein biomarkers that are used to monitor chronic HBV infection, we provide new insights into the timelines of HBV clearance, both on and off treatment. These results contribute to improvements in individualized clinical care and may provide important clues into the immune events that underpin disease control., HBsAg and HBeAg have gained traction as biomarkers of control and clearance during chronic hepatitis B virus infection (CHB). Improved understanding of the clearance correlates of these proteins could help inform improvements in patient-stratified care and advance insights into the underlying mechanisms of disease control, thus underpinning new cure strategies. We collected electronic clinical data via an electronic pipeline supported by the National Institute for Health Research Health Informatics Collaborative (NIHR HIC), adopting an unbiased approach to the generation of a robust longitudinal data set for adults testing HBsAg positive from a large UK teaching hospital over a 6-year period (2011 to 2016 inclusive). Of 553 individuals with CHB, longitudinal data were available for 319, representing >107,000 weeks of clinical follow-up. Among these 319 individuals, 13 (4%) cleared HBsAg completely. Among these 13, the HBsAg clearance rate in individuals on nucleos(t)ide analogue (NA) therapy (n = 4 [31%]; median clearance time,150 weeks) was similar to that in individuals not on NA therapy (n = 9 [69%]; median clearance time, 157 weeks). Those who cleared HBsAg were significantly older and less likely to be on NA therapy than nonclearers (P = 0.003 and P = 0.001, respectively). Chinese ethnicity was associated with HBeAg positivity (P = 0.025). HBeAg clearance occurred in individuals both on NA therapy (n = 24; median time, 49 weeks) and off NA therapy (n = 19; median time, 52 weeks). Improved insights into the dynamics of these biomarkers can underpin better prognostication and patient-stratified care. Our systematized approach to data collection paves the way for scaling up efforts to harness clinical data to address research questions and support improvements in clinical care.

BACKGROUND: People from low- and middle-income countries are disproportionately affected by the global burden of adverse health effects caused by ambient air pollution (AAP). However, data from Sub-Saharan Africa (SSA) are still scarce. We systematically reviewed the literature to describe the existing knowledge on AAP and health outcomes in SSA. METHODS: We searched PubMed, Medline-OVID, EMBASE and Scopus databases to identify studies of AAP and health outcomes published up to November 15, 2017. We used a systematic review approach to critically analyze and summarize levels of outdoor air pollutants, and data on health effects associated with AAP. We excluded occupational and indoor exposure studies. RESULTS: We identified 60 articles, with 37 only describing levels of AAP and 23 assessing the association between air pollution and health outcomes. Most studies (75%) addressing the relation between AAP and disease were cross-sectional. In general, exposure data were only obtained for selected cities in the framework of temporary international collaborative research initiatives without structural long-term continuation. Measurements of AAP revealed 10-20 fold higher levels than WHO standards. Of the 23 studies reporting health effects, 14 originated from South Africa, and most countries within SSA contributed no data at all. No studies, except from South Africa, were based on reliable morbidity or mortality statistics at regional or country level. The majority of studies investigated self-reported respiratory symptoms. Children and the elderly were found to be more susceptible to AAP. CONCLUSION: AAP and its negative health effects have been understudied in SSA compared with other continents. The limited direct measurements of air pollutants indicate that AAP in SAA cities is high compared with international standards. Efforts are needed to monitor AAP in African cities, to identify its main sources, and to reduce adverse health effects by enforcing legislation. ispartof: ENVIRONMENTAL RESEARCH vol:173 pages:174-188 ispartof: location:Netherlands status: published

International goals for elimination of hepatitis B virus (HBV) infection set ambitious targets for 2030. In many African populations, HBV prevalence remains high (≥8%) despite the roll-out of infant HBV immunisation from the mid-1990’s onwards. Enhanced efforts are now urgently required to improve an understanding of population epidemiology, in order to determine which interventions are most likely to be effective in advancing populations towards elimination goals. In populations with a high prevalence of infection, catch-up HBV vaccination of adults has sometimes been deployed as a preventive strategy. An alternative approach of ‘test and treat’ could be applied as a tool to interrupt transmission. We used a systematic approach to investigate the relationship between prevalence of HBV infection (HBsAg) and exposure (anti-HBc) in Africa, and then applied a mathematical model to investigate the impact of catch-up vaccination and a ‘test and treat’ strategy in Uganda, representing a high prevalence setting. We demonstrate a strong relationship between the prevalence of HBsAg and anti-HBc (p

Advancing interventions to tackle the huge global burden of hepatitis B virus (HBV) infection depends on improved insights into virus epidemiology, transmission, within-host diversity, drug resistance and pathogenesis, all of which can be advanced through the large-scale generation of full-length virus genome data. Here we describe advances to a protocol that exploits the circular HBV genome structure, using isothermal rolling-circle amplification to enrich HBV DNA, generating concatemeric amplicons containing multiple successive copies of the same genome. We show that this product is suitable for Nanopore sequencing as single reads, as well as for generating short-read Illumina sequences. Nanopore reads can be used to implement a straightforward method for error correction that reduces the per-read error rate, by comparing multiple genome copies combined into a single concatemer and by analysing reads generated from plus and minus strands. With this approach, we can achieve an improved consensus sequencing accuracy of 99.7% and resolve intra-sample sequence variants to form whole-genome haplotypes. Thus while Illumina sequencing may still be the most accurate way to capture within-sample diversity, Nanopore data can contribute to an understanding of linkage between polymorphisms within individual virions. The combination of isothermal amplification and Nanopore sequencing also offers appealing potential to develop point-of-care tests for HBV, and for other viruses.

Yellow fever (YF) remains a threat to global health, with an increasing number of major outbreaks in the tropical areas of the world over the recent past. In light of this, the Eliminate Yellow Fever Epidemics Strategy was established with the aim of protecting one billion people at risk of YF through vaccination by the year 2026. The current YF vaccine gives excellent protection, but its use is limited by shortages in supply due to the difficulties in producing the vaccine. There are good grounds for believing that alternative fractional dosing regimens can produce strong protection and overcome the problem of supply shortages as less vaccine is required per person. However, immune responses to these vaccination approaches are yet to be fully understood. In addition, published data on immune responses following YF vaccination have mostly quantified neutralising antibody titers. However, vaccine-induced antibodies can confer immunity through other antibody effector functions beyond neutralisation, and an effective vaccine is also likely to induce strong and persistent memory T cell responses. This review highlights the gaps in knowledge in the characterisation of YF vaccine-induced protective immunity in the absence or presence of neutralising antibodies. The assessment of biophysical antibody characteristics and cell-mediated immunity following YF vaccination could help provide a comprehensive landscape of YF vaccine-induced immunity and a better understanding of correlates of protective immunity.

Higher academic institutions in the UK need to drive improvements in equity, diversity, and inclusion (EDI) through sustainable practical interventions. A broad view of inclusivity is based on an intersectional approach that considers race, geographical location, caring responsibilities, disability, neurodiversity, religion, and LGBTQIA+ identities. We describe the establishment of a diverse stakeholder group to develop practical grass-roots recommendations through which improvements can be advanced. We have developed a manifesto for change, comprising six domains through which academic institutions can drive progress through setting short, medium, and long-term priorities. Interventions will yield rewards in recruitment and retention of a diverse talent pool, leading to enhanced impact and output.

IntroductionTenofovir disoproxil fumarate (TDF) is widely recommended for treatment of chronic hepatitis B virus (HBV) infection because it is safe, affordable and has a high genetic barrier to resistance. TDF resistance associated mutations (RAMs) have been reported, but data are limited, particularly for Africa. We set out to identify RAMs in individuals with detectable HBV viraemia on TDF treatment.MethodsWe recruited adults with chronic HBV infection from Cape Town, South Africa, identifying individuals with a TDF resistance phenotype, defined as persistent HBV vireamia despite >12 months of TDF treatment. We sequenced HBV DNA using MiSeq Illumina with whole genome target enrichment, and analysed to determine the genotype and identify potential TDF RAMs, based on a pre-defined list of polymorphisms.ResultsAmong 66 individuals with chronic HBV, we identified three meeting our phenotypic definition for TDF resistance, of whom two were coinfected with HIV. The sequences grouped as genotypes A1 and D3. In one participant, the consensus HBV sequence had ten polymorphisms that have been described in association with TDF resistance. Significant treatment non-adherence in this individual was unlikely, as HIV RNA was suppressed. TDF RAMs were also present in HBV sequences from the other two participants, but other factors including treatment non-adherence may also have had a role in failure of HBV DNA suppression in these cases.DiscussionOur findings add to the evidence that RAMs in HBV RT can underpin a TDF resistant phenotype. This is the first time these RAMs have been reported from Africa in association with clinical evidence of TDF resistance.Contribution to the Field StatementTreatment of chronic hepatitis B virus (HBV) infection with nucleos(t)ide analogues (NAs) is one of the key strategies that needs to be upscaled in order to achieve the 2030 United Nations elimination target for viral hepatitis. Tenofovir disoproxil fumarate (TDF) is widely recommended for the treatment of chronic HBV infection because it has a high genetic barrier to resistance. However, TDF resistance associated mutations (RAMs) have been reported, but data are limited, with a need for further investigation. Within a cross-sectional cohort of adults with chronic HBV infection recruited in Cape Town, South Africa, we describe combinations of HBV polymorphisms in three adults with detectable HBV viraemia whilst on TDF treatment. This is the first evidence of potential TDF resistance in adults being treated for chronic HBV in Africa and it adds to the growing evidence of TDF resistance globally. It remains necessary to advocate for the development of new antiviral treatments for chronic HBV infection if we are to attain elimination targets.

HBsAg and HBeAg have gained traction as biomarkers of control and clearance during monitoring of chronic hepatitis B virus infection (CHB). An improved understanding of the correlates of clearance of these proteins could help inform improvements in patient-stratified care and advance insights into the underlying mechanisms of disease control, thus underpinning new cure strategies. We collected electronic clinical data via an electronic pipeline supported by the National Institute for Health Research Health Informatics Collaborative (NIHR-HIC), adopting an unbiased approach to generating a robust longitudinal dataset for adults testing HBsAg-positive from a large UK teaching hospital over a six year period (2011-2016 inclusive). From 553 individuals with CHB, longitudinal data were available for 319, representing >107,000 weeks of clinical follow-up. Among these 319 individuals, 13 (4%) cleared HBsAg completely. HBsAg clearance rate was similar in individuals on NA therapy (n=4, median clearance time 150 weeks) vs those not on NA therapy (n=9, median clearance time 157 weeks). Those who cleared HBsAg were significantly older, and less likely to be on NA therapy compared to non-clearers (p=0.003 and p=0.001, respectively). Chinese ethnicity was associated with HBeAg positivity (p=0.025). HBeAg clearance occurred both on NA therapy (n=24, median time 49 weeks) and off NA therapy (n=19, median time 52 weeks). Improved insights into the dynamics of these biomarkers can underpin better prognostication and patient-stratified care. Our systematised approach to data collection paves the way for scaling up efforts to harness clinical data to address research questions and underpin improvements in clinical care provision.IMPORTANCEAdvances in the diagnosis, monitoring and treatment of hepatitis B virus (HBV) infection are urgently required if we are to meet international targets for elimination by the year 2030. Here we demonstrate how routine clinical data can be harnessed through an unbiased electronic pipeline, showcasing the significant potential for amassing large clinical datasets that can help to inform advances in patient care, and provide clues that inform new cure strategies. Our cohort from a large UK hospital includes adults from diverse ethnic groups that have previously been under-represented in the literature. Tracking two protein biomarkers that are used to monitor chronic HBV infection, we provide new insights into the timelines of HBV clearance, both on and off treatment. These results contribute to improvements in individualised clinical care and may provide important clues into the immune events that underpin disease control.

In light of sustainable development goals for 2030, an important priority for Africa is to have affordable, accessible and sustainable hepatitis B virus (HBV) prevention of mother to child transmission (PMTCT) programmes, delivering screening and treatment for antenatal women and implementing timely administration of HBV vaccine for their babies. We developed a decision-analytic model simulating 10,000 singleton pregnancies to assess the cost-effectiveness of three possible strategies for deployment of tenofovir in pregnancy, in combination with routine infant vaccination: S1: no screening nor antiviral therapy; S2: screening and antiviral prophylaxis for all women who test HBsAg-positive; S3: screening for HBsAg, followed by HBeAg testing and antiviral prophylaxis for women who are HBsAg-positive and HBeAg-positive. Our outcome was cost per infant HBV infection avoided and the analysis followed a healthcare perspective. S1 predicts 45 infants would be HBV-infected at six months of age, compared to 21 and 28 infants in S2 and S3, respectively. Relative to S1, S2 had an incremental cost of $3,940 per infection avoided. S3 led to more infections and higher costs. Given the long-term health burden for individuals and economic burden for society associated with chronic HBV infection, screening pregnant women and providing tenofovir for all who test HBsAg+ may be a cost-effective strategy for South Africa.

We developed a decision-analytic model that assessed the cost-effectiveness of three possible HBV PMTCT approaches in pregnancy; S1: no PMTCT intervention; S2:screening and antiviral prophylaxis for all women who test HBsAg-positive; S3: screening of all women for HBsAg, followed by HBeAg testing and antiviral prophylaxis for women who are HBsAg-positive and HBeAg-positive. We compared use of standard laboratory assays with a point of care test for HBsAg. Our outcome was cost per HBV infection avoided and the analysis followed a healthcare perspective.We populated our model with data from South Africa.

Background: International goals for hepatitis B virus (HBV) infection set ambitious targets for elimination by 2030. In populations with a high prevalence of infection, catch-up HBV vaccination of adults is sometimes deployed. An alternative approach of 'test and treat' could be applied as a population intervention for HBV. Methods: We used a systematic approach to determine the relationship between prevalence of HBV infection (HBsAg) and exposure (anti-HBc) in Africa. We applied a mathematical model to compare the impact of catch-up vaccination with a 'test and treat' strategy in a high prevalence setting. Findings: There is a strong relationship between the prevalence of HBsAg and anti-HBc (p

Background There is a dearth of knowledge about the availability and affordability of the different drug treatments for Parkinson's disease (PD) across sub-Saharan Africa (SSA). We aimed to determine the availability and affordability of drugs for treating PD in Kenya. Methods A facility-based survey was conducted in selected medicine outlets (pharmacies) in what were formerly the headquarter towns of the eight provinces of Kenya. We used the World Health Organization/Health Action International methodology to obtain data for drugs used to treat PD. Unit price for each drug was obtained. Results Forty-eight outlets were visited in total, six in each of Kenya's eight provinces. Levodopa (L-dopa) was available in only 24 (50.0%) outlets. Only one public pharmacy sold l-dopa (14 were private and nine were other types of outlet). Ergot-derived dopamine agonists (DAs) and anticholinergics were available in 37 and 35 outlets, respectively. Monoamine-oxidase inhibitors, non-ergot-derived DAs, and catechol-O-methyl transferase inhibitors were available in four, two and zero outlets, respectively. Mean cost of 100 l-dopa tablets was $48.2, though costs varied widely (range, $28.2–$82.4). Only five outlets considered l-dopa affordable, all of which sold 100 tablets for less than $31. Conclusion There is a lack of availability of PD drugs in Kenya, particularly in public pharmacies, where costs are generally lower. Few pharmacists consider the drugs available to be affordable. If PD is to be effectively managed in Kenya, then strategies are needed to increase the availability and affordability of medication.

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.

The World Health Organization (WHO) estimates that acute lower respiratory infections account for 4 million deaths per year. The rates are even higher in developing countries. Influenza, a virus causing respiratory infections, has widely been studied in developed countries. However, there is paucity of data on its epidemiology, seasonality and burden in most developing countries. In the contrary, Kenya (a developing country) has an elaborate national epidemio-surveillance network for influenza, where a lot of data is generated on the epidemiology and seasonality of influenza in Kenya and the East African region. Several steps have been taken to control influenza in Kenya, including vaccination and surveillance programs. However, some challenges still exist. This article explores the pattern of influenza and existing interventions in Kenya, and highlights suggestions on what can be done to adequately control this virus in future.

Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist - Modelling cost-effectiveness of alternative strategies for prevention of mother to child transmission of hepatitis B virus infection in South Africa. Available on-line at https://doi.org/10.6084/m9.figshare.7265582.v2 . (DOC 68 kb)

Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist - Modelling cost-effectiveness of alternative strategies for prevention of mother to child transmission of hepatitis B virus infection in South Africa. Available on-line at https://doi.org/10.6084/m9.figshare.7265582.v2 . (DOC 68 kb)

In this article we set out to represent hepatitis B virus (HBV) infection within the framework proposed by the World Health Organisation (WHO) for neglected tropical diseases. This highlights substantial challenges to the international community, demonstrating that a large burden of HBV morbidity falls upon low and middle-income countries in the tropics, that disease is strongly associated with both poverty and stigma, and that it is under-resourced compared to other comparable public health concerns. We have collated experiences of healthcare workers, researchers and patients from a variety of settings in sub-Saharan Africa to illustrate the real, practical, day-to-day challenges posed by HBV infection. The NTD paradigm can be applied to consider how best the international community directs funding, advocacy, education, manpower and research to tackle these issues. The existing armamentarium of strategies to tackle HBV prevention, diagnosis and treatment could be implemented within existing infrastructure, most notably building HBV resources into the systems that have been developed for HIV. This discussion is crucial to working towards WHO Sustainable Development Goals that aim for elimination of viral hepatitis as a public health problem by 2030.