The potential public health impact of adolescent 4CMenB vaccination on Neisseria gonorrhoeae infection in England: a modelling study.

INTRODUCTION: Diagnoses of gonorrhoea in England rose by 26% between 2018 and 2019. Recent evidence that a vaccine against meningococcal B disease currently offered to infants in the UK (4CMenB) could additionally protect (with 31% efficacy) against gonorrhoea has led to renewed hope for a vaccine. A Phase 2 proof-of-concept trial of 4CMenB vaccination against gonorrhoea in adults is currently underway. OBJECTIVES: To investigate the potential public health impact of adolescent gonorrhoea vaccination in England, considering different implementation strategies. METHODS: We developed a deterministic transmission-dynamic model of gonorrhoea infection among heterosexual 13-64-year-olds stratified by age, sex and sexual activity. We explored the impact of a National Immunisation Programme (NIP) among 14-year-olds for a vaccine with 31% efficacy, 6 years' duration of protection, and 85% uptake. We also explored how impact might change for varying efficacy (20-50%) and uptake (75-95%), the addition of a catch-up programme, the use of boosters, and varying duration of protection. RESULTS: An NIP against gonorrhoea could lead to 50,000 (95% credible interval, CrI 31,000-80,000) and 849,000 (95%CrI 476,000-1,568,000) gonorrhoea infections being averted over 10 and 70 years, respectively, in England, for a vaccine with 31% efficacy and 85% uptake. This is equivalent to 25% (95%CrI 17-33%) of heterosexual infections being averted over 70 years. Vaccine impact is predicted to increase over time and be greatest among 13-18-year-olds (39% of infections 95%CrI 31-49% averted) over 70 years. Varying vaccine efficacy and duration of protection had a noticeable effect on impact. Catch-up and booster vaccination increased the short- and long-term impact, respectively. CONCLUSIONS: A partially-effective vaccine against gonorrhoea infection, delivered to 14-year-olds alongside the MenACWY vaccine, could have an important population impact on gonorrhoea. Catch-up and booster vaccination could be considered alongside cohort vaccination to increase impact.

Competition, coinfection and strain replacement in models of Bordetella pertussis.

Pertussis, or whooping cough, is an important respiratory infection causing considerable infant mortality worldwide. Recently, incidence has risen in countries with strong vaccine programmes and there are concerns about antigenic shift resulting in vaccine evasion. Interactions between pertussis and non-vaccine-preventable strains will play an important role in the evolution and population dynamics of pertussis. In particular, if we are to understand the role strain replacement plays in vaccinated settings, it will be essential to understand how strains or variants of pertussis interact. Here we explore under what conditions we would expect strain replacement to be of concern in pertussis. We develop a dynamic transmission model that allows for coinfection between Bordetella pertussis (the main causative agent of pertussis) and a strain or variant unaffected by the vaccine. We incorporate both neutrality (in the sense of ecological/population genetic neutrality) and immunity into the model, leaving the specificity of the immune response flexible. We find that strain replacement may be considerable when immunity is non-specific. This is in contrast to previous findings where neutrality was not considered. We conclude that the extent to which models reflect ecological neutrality can have a large impact on conclusions regarding strain replacement. This will likely have onward consequences for estimates of vaccine efficacy and cost-effectiveness.

Impact and cost-effectiveness of chlamydia testing in Scotland: a mathematical modelling study.

BACKGROUND: Chlamydia is the most common sexually transmitted bacterial infection in Scotland, and is associated with potentially serious reproductive outcomes, including pelvic inflammatory disease (PID) and tubal factor infertility (TFI) in women. Chlamydia testing in Scotland is currently targeted towards symptomatic individuals, individuals at high risk of existing undetected infection, and young people. The cost-effectiveness of testing and treatment to prevent PID and TFI in Scotland is uncertain. METHODS: A compartmental deterministic dynamic model of chlamydia infection in 15-24 year olds in Scotland was developed. The model was used to estimate the impact of a change in testing strategy from baseline (16.8% overall testing coverage; 0.4 partners notified and tested/treated per treated positive index) on PID and TFI cases. Cost-effectiveness calculations informed by best-available estimates of the quality-adjusted life years (QALYs) lost due to PID and TFI were also performed. RESULTS: Increasing overall testing coverage by 50% from baseline to 25.2% is estimated to result in 21% fewer cases in young women each year (PID: 703 fewer; TFI: 88 fewer). A 50% decrease to 8.4% would result in 20% more PID (669 additional) and TFI (84 additional) cases occurring annually. The cost per QALY gained of current testing activities compared to no testing is £40,034, which is above the £20,000-£30,000 cost-effectiveness threshold. However, calculations are hampered by lack of reliable data. Any increase in partner notification from baseline would be cost-effective (incremental cost per QALY gained for a partner notification efficacy of 1 compared to baseline: £5,119), and would increase the cost-effectiveness of current testing strategy compared to no testing, with threshold cost-effectiveness reached at a partner notification efficacy of 1.5. However, there is uncertainty in the extent to which partner notification is currently done, and hence the amount by which it could potentially be increased. CONCLUSIONS: Current chlamydia testing strategy in Scotland is not cost-effective under the conservative model assumptions applied. However, with better data enabling some of these assumptions to be relaxed, current coverage could be cost-effective. Meanwhile, increasing partner notification efficacy on its own would be a cost-effective way of preventing PID and TFI from current strategy.

An early evaluation of clinical and economic costs and benefits of implementing point of care NAAT tests for Chlamydia trachomatis and Neisseria gonorrhoea in genitourinary medicine clinics in England.

OBJECTIVES: To estimate the costs and benefits of clinical pathways incorporating a point of care (POC) nucleic acid amplification test (NAAT) for chlamydia and gonorrhoea in genitourinary medicine (GUM) clinics compared with standard off-site laboratory testing. METHOD: We simulated 1.2 million GUM clinic attendees in England. A simulation in Microsoft Excel was developed to compare existing standard pathways of management for chlamydia and gonorrhoea with a POC NAAT. We conducted scenario analyses to evaluate the robustness of the model findings. The primary outcome was the incremental cost-effectiveness ratio. Secondary outcomes included the number of inappropriate treatments, complications and transmissions averted. RESULTS: The baseline cost of using the point of POC NAAT was £103.9 million compared with £115.6 million for standard care. The POC NAAT was also associated with a small increase of 46 quality adjusted life years, making the new test both more effective and cheaper. Over 95 000 inappropriate treatments might be avoided by using a POC NAAT. Patients receive diagnosis and treatment on the same day as testing, which may also prevent 189 cases of pelvic inflammatory disease and 17 561 onward transmissions annually. DISCUSSION: Replacing standard laboratory tests for chlamydia and gonorrhoea with a POC test could be cost saving and patients would benefit from more accurate diagnosis and less unnecessary treatment. Overtreatment currently accounts for about a tenth of the reported treatments for chlamydia and gonorrhoea and POC NAATs would effectively eliminate the need for presumptive treatment.

INCIDENCE OF HERPES SIMPLEX VIRUS KERATITIS AND OTHER OCULAR DISEASE: GLOBAL REVIEW AND ESTIMATES.

PURPOSE: We aimed to review available data on the incidence of herpes simplex virus (HSV) keratitis and other HSV ocular disease and to estimate the global burden of HSV ocular disease. METHODS: We searched Medline and Embase databases to October 2020 for studies reporting on the incidence of HSV ocular disease. Study quality was evaluated using a four-point checklist. Pooled estimates were applied to 2016 population data to estimate global HSV ocular disease burden. Numbers with uniocular vision impairment (any visual acuity <6/12) were estimated by applying published risks to case numbers. RESULTS: Fourteen studies had incidence data; seven met our quality criteria. In 2016, an estimated 1.7 (95% confidence interval, 95% CI 1.0-3.0) million people had HSV keratitis, based on a pooled incidence of 24.0 (95% CI 14.0-41.0; N = 2; I2 = 97.7%) per 100,000 person-years. The majority had epithelial keratitis (pooled incidence 16.1 per 100,000; 95% CI 11.6-22.3; N = 3; I2 = 92.6%). Available studies were few and limited to the USA and Europe. Data were even more limited for HSV uveitis and retinitis, although these conditions may collectively contribute a further >0.1 million cases. Based on global incidence, some 230,000 people may have newly acquired uniocular vision impairment associated with HSV keratitis in 2016. CONCLUSION: Over 1.8 million people may have herpetic eye disease annually. Preventing HSV infection could therefore have an important impact on eye health. Herpetic eye disease burden is likely to have been underestimated, as many settings outside of the USA and Europe have higher HSV-1 prevalence and poorer access to treatment.

A scoping review of antibiotic use practices and drivers of inappropriate antibiotic use in animal farms in WHO Southeast Asia region.

Antibiotic use (ABU) plays an important role in the proliferation of antimicrobial resistance (AMR). Global antimicrobial consumption in food production is projected to rise by 67% from 2010 to 2030, but available estimates are limited by the scarcity of ABU data and absence of global surveillance systems. The WHO South-East Asia (WHO SEA) region is at high risk of emergence of AMR, likely driven by intensifying farm operations and worsening ABU hotspots. However, little is known about farm-level ABU practices in the region. To summarize emerging evidence and research gaps, we conducted a scoping review of ABU practices following the Arksey and O'Malley methodological framework. We included studies published between 2010 and 2021 on farm-level ABU/AMR in the 11 WHO SEA member states, and databases were last searched on 31 October 2021. Our search strategy identified 184 unique articles, and 25 publications underwent full-text eligibility assessment. Seventeen studies, reported in 18 publications, were included in the scoping review. We found heterogeneity in the categorizations, definitions, and ABU characterization methods used across studies and farm types. Most studies involved poultry, pig, and cattle farms, and only one study examined aquaculture. Most studies evaluated ABU prevalence by asking respondents about the presence or absence of ABU in the farm. Only two studies quantified antibiotic consumption, and sampling bias and lack of standardized data collection methods were identified as key limitations. Emerging evidence that farm workers had difficulty differentiating antibiotics from other substances contributed to the uncertainty about the reliability of self-reported data without other validation techniques. ABU for growth promotion and treatment were prevalent. We found a large overlap in the critically important antibiotics used in farm animals and humans. The ease of access to antibiotics compounded by the difficulties in accessing quality veterinary care and preventive services likely drive inappropriate ABU in complex ways.

What Is the Burden of Heterosexually Acquired HIV Due to HSV-2? Global and Regional Model-Based Estimates of the Proportion and Number of HIV Infections Attributable to HSV-2 Infection.

BACKGROUND: Biological and epidemiological evidence suggest that herpes simplex virus type 2 (HSV-2) elevates HIV acquisition and transmission risks. We improved previous estimates of the contribution of HSV-2 to HIV infections by using a dynamic transmission model. SETTING: World Health Organization regions. METHODS: We developed a mathematical model of HSV-2/HIV transmission among 15- to 49-year-old heterosexual, non-drug-injecting populations, calibrated using region-specific demographic and HSV-2/HIV epidemiological data. We derived global and regional estimates of the contribution of HSV-2 to HIV infection over 10 years [the transmission population-attributable fraction (tPAF)] under 3 additive scenarios, assuming: (1) HSV-2 increases only HIV acquisition risk (conservative); (2) HSV-2 also increases HIV transmission risk (liberal); and (3) HIV or antiretroviral therapy (ART) also modifies HSV-2 transmission risk, and HSV-2 decreases ART effect on HIV transmission risk (fully liberal). RESULTS: Under the conservative scenario, the predicted tPAF was 37.3% (95% uncertainty interval: 33.4%-43.2%), and an estimated 5.6 (4.5-7.0) million incident heterosexual HIV infections were due to HSV-2 globally over 2009-2018. The contribution of HSV-2 to HIV infections was largest for the African region [tPAF = 42.6% (38.0%-51.2%)] and lowest for the European region [tPAF = 11.2% (7.9%-13.8%)]. The tPAF was higher among female sex workers, their clients, and older populations, reflecting their higher HSV-2 prevalence. The tPAF was approximately 50% and 1.3- to 2.4-fold higher for the liberal or fully liberal scenario than the conservative scenario across regions. CONCLUSION: HSV-2 may have contributed to at least 37% of incident HIV infections in the past decade worldwide, and even more in Africa, and may continue to do so despite increased ART access unless future improved HSV-2 control measures, such as vaccines, become available.

One Health drivers of antibacterial resistance: Quantifying the relative impacts of human, animal and environmental use and transmission.

OBJECTIVES: Antibacterial resistance (ABR) is a major global health security threat, with a disproportionate burden on lower-and middle-income countries (LMICs). It is not understood how 'One Health', where human health is co-dependent on animal health and the environment, might impact the burden of ABR in LMICs. Thailand's 2017 "National Strategic Plan on Antimicrobial Resistance" (NSP-AMR) aims to reduce AMR morbidity by 50% through 20% reductions in human and 30% in animal antibacterial use (ABU). There is a need to understand the implications of such a plan within a One Health perspective. METHODS: A model of ABU, gut colonisation with extended-spectrum beta-lactamase (ESBL)-producing bacteria and transmission was calibrated using estimates of the prevalence of ESBL-producing bacteria in Thailand. This model was used to project the reduction in human ABR over 20 years (2020-2040) for each One Health driver, including individual transmission rates between humans, animals and the environment, and to estimate the long-term impact of the NSP-AMR intervention. RESULTS: The model predicts that human ABU was the most important factor in reducing the colonisation of humans with resistant bacteria (maximum 65.7-99.7% reduction). The NSP-AMR is projected to reduce human colonisation by 6.0-18.8%, with more ambitious targets (30% reductions in human ABU) increasing this to 8.5-24.9%. CONCLUSIONS: Our model provides a simple framework to explain the mechanisms underpinning ABR, suggesting that future interventions targeting the simultaneous reduction of transmission and ABU would help to control ABR more effectively in Thailand.

Estimating the COVID-19 epidemic trajectory and hospital capacity requirements in South West England: a mathematical modelling framework.

OBJECTIVES: To develop a regional model of COVID-19 dynamics for use in estimating the number of infections, deaths and required acute and intensive care (IC) beds using the South West England (SW) as an example case. DESIGN: Open-source age-structured variant of a susceptible-exposed-infectious-recovered compartmental mathematical model. Latin hypercube sampling and maximum likelihood estimation were used to calibrate to cumulative cases and cumulative deaths. SETTING: SW at a time considered early in the pandemic, where National Health Service authorities required evidence to guide localised planning and support decision-making. PARTICIPANTS: Publicly available data on patients with COVID-19. PRIMARY AND SECONDARY OUTCOME MEASURES: The expected numbers of infected cases, deaths due to COVID-19 infection, patient occupancy of acute and IC beds and the reproduction ('R') number over time. RESULTS: SW model projections indicate that, as of 11 May 2020 (when 'lockdown' measures were eased), 5793 (95% credible interval (CrI) 2003 to 12 051) individuals were still infectious (0.10% of the total SW population, 95% CrI 0.04% to 0.22%), and a total of 189 048 (95% CrI 141 580 to 277 955) had been infected with the virus (either asymptomatically or symptomatically), but recovered, which is 3.4% (95% CrI 2.5% to 5.0%) of the SW population. The total number of patients in acute and IC beds in the SW on 11 May 2020 was predicted to be 701 (95% CrI 169 to 1543) and 110 (95% CrI 8 to 464), respectively. The R value in SW was predicted to be 2.6 (95% CrI 2.0 to 3.2) prior to any interventions, with social distancing reducing this to 2.3 (95% CrI 1.8 to 2.9) and lockdown/school closures further reducing the R value to 0.6 (95% CrI 0.5 to 0.7). CONCLUSIONS: The developed model has proved a valuable asset for regional healthcare services. The model will be used further in the SW as the pandemic evolves, and-as open-source software-is portable to healthcare systems in other geographies.

The global and regional burden of genital ulcer disease due to herpes simplex virus: a natural history modelling study.

Introduction: Herpes simplex virus (HSV) infection can cause painful, recurrent genital ulcer disease (GUD), which can have a substantial impact on sexual and reproductive health. HSV-related GUD is most often due to HSV type 2 (HSV-2), but may also be due to genital HSV type 1 (HSV-1), which has less frequent recurrent episodes than HSV-2. The global burden of GUD has never been quantified. Here we present the first global and regional estimates of GUD due to HSV-1 and HSV-2 among women and men aged 15-49 years old. Methods: We developed a natural history model reflecting the clinical course of GUD following HSV-2 and genital HSV-1 infection, informed by a literature search for data on model parameters. We considered both diagnosed and undiagnosed symptomatic infection. This model was then applied to existing infection estimates and population sizes for 2016. A sensitivity analysis was carried out varying the assumptions made. Results: We estimated that 187 million people aged 15-49 years had at least one episode of HSV-related GUD globally in 2016: 5.0% of the world's population. Of these, 178 million (95% of those with HSV-related GUD) had HSV-2 compared with 9 million (5%) with HSV-1. GUD burden was highest in Africa, and approximately double in women compared with men. Altogether there were an estimated 8 billion person-days spent with HSV-related GUD globally in 2016, with 99% of days due to HSV-2. Taking into account parameter uncertainty, the percentage with at least one episode of HSV-related GUD ranged from 3.2% to 7.9% (120-296 million). However, the estimates were sensitive to the model assumptions. Conclusion: Our study represents a first attempt to quantify the global burden of HSV-related GUD, which is large. New interventions such as HSV vaccines, antivirals or microbicides have the potential to improve the quality of life of millions of people worldwide.

Global and regional estimates of the contribution of herpes simplex virus type 2 infection to HIV incidence: a population attributable fraction analysis using published epidemiological data.

BACKGROUND: A 2017 systematic review and meta-analysis of 55 prospective studies found the adjusted risk of HIV acquisition to be at least tripled in individuals with herpes simplex virus type 2 (HSV-2) infection. We aimed to assess the potential contribution of HSV-2 infection to HIV incidence, given an effect of HSV-2 on HIV acquisition. METHODS: We used a classic epidemiological formula to estimate the global and regional (WHO regional) population attributable fraction (PAF) and number of incident HIV infections attributable to HSV-2 infection by age (15-24 years, 25-49 years, and 15-49 years), sex, and timing of HSV-2 infection (established vs recently acquired). Estimates were calculated by incorporating HSV-2 and HIV infection data with pooled relative risk (RR) estimates for the effect of HSV-2 infection on HIV acquisition from a systematic review and meta-analysis. Because HSV-2 and HIV have shared sexual and other risk factors, in addition to HSV-related biological factors that increase HIV risk, we only used RR estimates that were adjusted for potential confounders. FINDINGS: An estimated 420 000 (95% uncertainty interval 317 000-546 000; PAF 29·6% [22·9-37·1]) of 1·4 million sexually acquired incident HIV infections in individuals aged 15-49 years in 2016 were attributable to HSV-2 infection. The contribution of HSV-2 to HIV was largest for the WHO African region (PAF 37·1% [28·7-46·3]), women (34·8% [23·5-45·0]), individuals aged 25-49 years (32·4% [25·4-40·2]), and established HSV-2 infection (26·8% [19·7-34·5]). INTERPRETATION: A large burden of HIV is likely to be attributable to HSV-2 infection, even if the effect of HSV-2 infection on HIV had been imperfectly measured in studies providing adjusted RR estimates, potentially because of residual confounding. The contribution is likely to be greatest in areas where HSV-2 is highly prevalent, particularly Africa. New preventive interventions against HSV-2 infection could not only improve the quality of life of millions of people by reducing the prevalence of herpetic genital ulcer disease, but could also have an additional, indirect effect on HIV transmission. FUNDING: WHO.

Economic evaluation of the cost of different methods of retesting chlamydia positive individuals in England.

OBJECTIVES: The National Chlamydia Screening Programme (NCSP) in England opportunistically screens eligible individuals for chlamydia infection. Retesting is recommended three3 months after treatment following a positive test result, but no guidance is given on how local areas should recall individuals for retesting. Here , we compare cost estimates for different recall methods to inform the optimal delivery of retesting programmes. DESIGN: Economic evaluation. SETTING: England. METHODS: We estimated the cost of chlamydia retesting for each of the six most commonly used recall methods in 2014 based on existing cost estimates of a chlamydia screen. Proportions accepting retesting, opting for retesting by post, returning postal testing kits and retesting positive were informed by 2014 NCSP audit data. Health professionals 'sense-checked' the costs. PRIMARY AND SECONDARY OUTCOMES: Cost and adjusted cost per chlamydia retest; cost and adjusted cost per chlamydia retest positive. RESULTS: We estimated the cost of the chlamydia retest pathway, including treatment/follow-up call, to be between £45 and £70 per completed test. At the lower end, this compared favourably to the cost of a clinic-based screen. Cost per retest positive was £389-£607. After adjusting for incomplete uptake, and non-return of postal kits, the cost rose to £109-£289 per completed test (cost per retest positive: £946-£2,506). The most economical method in terms of adjusted cost per retest was no active recall as gains in retest rates with active recall did not outweigh the higher cost. Nurse-led client contact by phone was particularly uneconomical, as was sending out postal testing kits automatically. CONCLUSIONS: Retesting without active recall is more economical than more intensive methods such as recalling by phone and automatically sending out postal kits. If sending a short message service (SMS) could be automated, this could be the most economical way of delivering retesting. However, patient choice and local accessibility of services should be taken into consideration in planning.

Assessing the reliability of eBURST using simulated populations with known ancestry.

BACKGROUND: The program eBURST uses multilocus sequence typing data to divide bacterial populations into groups of closely related strains (clonal complexes), predicts the founding genotype of each group, and displays the patterns of recent evolutionary descent of all other strains in the group from the founder. The reliability of eBURST was evaluated using populations simulated with different levels of recombination in which the ancestry of all strains was known. RESULTS: For strictly clonal simulations, where all allelic change is due to point mutation, the groups of related strains identified by eBURST were very similar to those expected from the true ancestry and most of the true ancestor-descendant relationships (90-98%) were identified by eBURST. Populations simulated with low or moderate levels of recombination showed similarly high performance but the reliability of eBURST declined with increasing recombination to mutation ratio. Populations simulated under a high recombination to mutation ratio were dominated by a single large straggly eBURST group, which resulted from the incorrect linking of unrelated groups of strains into the same eBURST group. The reliability of the ancestor-descendant links in eBURST diagrams was related to the proportion of strains in the largest eBURST group, which provides a useful guide to when eBURST is likely to be unreliable. CONCLUSION: Examination of eBURST groups within populations of a range of bacterial species showed that most were within the range in which eBURST is reliable, and only a small number (e.g. Burkholderia pseudomallei and Enterococcus faecium) appeared to have such high rates of recombination that eBURST is likely to be unreliable. The study also demonstrates how three simple tests in eBURST v3 can be used to detect unreliable eBURST performance and recognise populations in which there appears to be a high rate of recombination relative to mutation.

The secret life of the multilocus sequence type.

Such are the challenges, and the potential, presented by complete genome sequences that the eventual erosion of the boundaries between biochemistry, ecology, bioinformatics, population biology, epidemiology and medical microbiology will perhaps be the most profound legacy of the genomics revolution. The development of nucleotide sequence-based typing schemes (multilocus sequence typing (MLST)) represents a similar synthesis, for this technique both matches the practical requirements for a highly portable standard for strain characterisation whilst also being firmly grounded in the population biology principles of multilocus enzyme electrophoresis (MLEE). Contrary to recent claims that population biology analyses of public health-oriented MLST data 'obscures its utility in applied microbiology' [Maiden MC. Multilocus sequence typing of bacteria. Annu Rev Microbiol 2006;60:561-88.], we argue that such an emphasis is essential for full interpretation of the data. Here we note a pertinent case in point; how a consideration of the rates of genetic recombination can help to explain why MLST data tend to correlate with virulence properties in some species (Neisseria meningitidis) but not in others (Staphylococcus aureus). We also discuss how the argument applies to the identification of recently emerged methicillin-resistant S. aureus (MRSA) clones using MLST. We conclude with a speculative rationale for promoting the 'clonal complexes' of S. aureus to species status.

Effect of HSV-2 infection on subsequent HIV acquisition: an updated systematic review and meta-analysis.

BACKGROUND: HIV and herpes simplex virus type 2 (HSV-2) infections cause a substantial global disease burden and are epidemiologically correlated. Two previous systematic reviews of the association between HSV-2 and HIV found evidence that HSV-2 infection increases the risk of HIV acquisition, but these reviews are now more than a decade old. METHODS: For this systematic review and meta-analysis, we searched PubMed, MEDLINE, and Embase (from Jan 1, 2003, to May 25, 2017) to identify studies investigating the risk of HIV acquisition after exposure to HSV-2 infection, either at baseline (prevalent HSV-2 infection) or during follow-up (incident HSV-2 infection). Studies were included if they were a cohort study, controlled trial, or case-control study (including case-control studies nested within a cohort study or clinical trial); if they assessed the effect of pre-existing HSV-2 infection on HIV acquisition; and if they determined the HSV-2 infection status of study participants with a type-specific assay. We calculated pooled random-effect estimates of the association between prevalent or incident HSV-2 infection and HIV seroconversion. We also extended previous investigations through detailed meta-regression and subgroup analyses. In particular, we investigated the effect of sex and risk group (general population vs higher-risk populations) on the relative risk (RR) of HIV acquisition after prevalent or incident HSV-2 infection. Higher-risk populations included female sex workers and their clients, men who have sex with men, serodiscordant couples, and attendees of sexually transmitted infection clinics. FINDINGS: We identified 57 longitudinal studies exploring the association between HSV-2 and HIV. HIV acquisition was almost tripled in the presence of prevalent HSV-2 infection among general populations (adjusted RR 2·7, 95% CI 2·2-3·4; number of estimates [Ne]=22) and was roughly doubled among higher-risk populations (1·7, 1·4-2·1; Ne=25). Incident HSV-2 infection in general populations was associated with the highest risk of acquisition of HIV (4·7, 2·2-10·1; Ne=6). Adjustment for confounders at the study level was often incomplete but did not significantly affect the results. We found moderate heterogeneity across study estimates, which was explained by risk group, world region, and HSV-2 exposure type (prevalent vs incident). INTERPRETATION: We found evidence that HSV-2 infection increases the risk of HIV acquisition. This finding has important implications for management of individuals diagnosed with HSV-2 infection, particularly for those who are newly infected. Interventions targeting HSV-2, such as new HSV vaccines, have the potential for additional benefit against HIV, which could be particularly powerful in regions with a high incidence of co-infection. FUNDING: World Health Organization.

First estimates of the global and regional incidence of neonatal herpes infection.

BACKGROUND: Neonatal herpes is a rare but potentially devastating condition with an estimated 60% fatality rate without treatment. Transmission usually occurs during delivery from mothers with herpes simplex virus type 1 (HSV-1) or type 2 (HSV-2) genital infection. However, the global burden has never been quantified to our knowledge. We developed a novel methodology for burden estimation and present first WHO global and regional estimates of the annual number of neonatal herpes cases during 2010-15. METHODS: We applied previous estimates of HSV-1 and HSV-2 prevalence and incidence in women aged 15-49 years to 2010-15 birth rates to estimate infections during pregnancy. We then applied published risks of neonatal HSV transmission according to whether maternal infection was incident or prevalent with HSV-1 or HSV-2 to generate annual numbers of incident neonatal infections. We estimated the number of incident neonatal infections by maternal age, and we generated separate estimates for each WHO region, which were then summed to obtain global estimates of the number of neonatal herpes infections. FINDINGS: Globally the overall rate of neonatal herpes was estimated to be about ten cases per 100 000 livebirths, equivalent to a best-estimate of 14 000 cases annually roughly (4000 for HSV-1; 10 000 for HSV-2). We estimated that the most neonatal herpes cases occurred in Africa, due to high maternal HSV-2 infection and high birth rates. HSV-1 contributed more cases than HSV-2 in the Americas, Europe, and Western Pacific. High rates of genital HSV-1 infection and moderate HSV-2 prevalence meant the Americas had the highest overall rate. However, our estimates are highly sensitive to the core assumptions, and considerable uncertainty exists for many settings given sparse underlying data. INTERPRETATION: These neonatal herpes estimates mark the first attempt to quantify the global burden of this rare but serious condition. Better collection of primary data for neonatal herpes is crucially needed to reduce uncertainty and refine future estimates. These data are particularly important in resource-poor settings where we may have underestimated cases. Nevertheless, these first estimates suggest development of new HSV prevention measures such as vaccines could have additional benefits beyond reducing genital ulcer disease and HSV-associated HIV transmission, through prevention of neonatal herpes. FUNDING: World Health Organization.

Developing a realistic sexual network model of chlamydia transmission in Britain.

BACKGROUND: A national chlamydia screening programme is currently being rolled out in the UK and other countries. However, much of the epidemiology remains poorly understood. In this paper we present a stochastic, individual based, dynamic sexual network model of chlamydia transmission and its parameterisation. Mathematical models provide a theoretical framework for understanding the key epidemiological features of chlamydia: sexual behaviour, health care seeking and transmission dynamics. RESULTS: The model parameters were estimated either directly or by systematic fitting to a variety of appropriate data sources. The fitted model was representative of sexual behaviour, chlamydia epidemiology and health care use in England. We were able to recapture the observed age distribution of chlamydia prevalence. CONCLUSION: Estimating parameters for models of sexual behaviour and transmission of chlamydia is complex. Most of the parameter values are highly correlated, highly variable and there is little empirical evidence to inform estimates. We used a novel approach to estimate the rate of active treatment seeking, by combining data sources, which improved the credibility of the model results. The model structure is flexible and is broadly applicable to other developed world settings and provides a practical tool for public health decision makers.

Global estimates of prevalent and incident herpes simplex virus type 2 infections in 2012.

BACKGROUND: Herpes simplex virus type 2 (HSV-2) infection causes significant disease globally. Adolescent and adult infection may present as painful genital ulcers. Neonatal infection has high morbidity and mortality. Additionally, HSV-2 likely contributes substantially to the spread of HIV infection. The global burden of HSV-2 infection was last estimated for 2003. Here we present new global estimates for 2012 of the burden of prevalent (existing) and incident (new) HSV-2 infection among females and males aged 15-49 years, using updated methodology to adjust for test performance and estimate by World Health Organization (WHO) region. METHODS AND FINDINGS: We conducted a literature review of HSV-2 prevalence studies world-wide since 2000. We then fitted a model with constant HSV-2 incidence by age to pooled HSV-2 prevalence values by age and sex. Prevalence values were adjusted for test sensitivity and specificity. The model estimated prevalence and incidence by sex for each WHO region to obtain global burden estimates. Uncertainty bounds were computed by refitting the model to reflect the variation in the underlying prevalence data. In 2012, we estimate that there were 417 million people aged 15-49 years (range: 274-678 million) living with HSV-2 infection world-wide (11.3% global prevalence), of whom 267 million were women. We also estimate that in 2012, 19.2 million (range: 13.0-28.6 million) individuals aged 15-49 years were newly-infected (0.5% of all individuals globally). The highest burden was in Africa. However, despite lower prevalence, South-East Asia and Western Pacific regions also contributed large numbers to the global totals because of large population sizes. CONCLUSIONS: The global burden of HSV-2 infection is large, leaving over 400 million people at increased risk of genital ulcer disease, HIV acquisition, and transmission of HSV-2 to partners or neonates. These estimates highlight the critical need for development of vaccines, microbicides, and other new HSV prevention strategies.

Global and Regional Estimates of Prevalent and Incident Herpes Simplex Virus Type 1 Infections in 2012.

BACKGROUND: Herpes simplex virus type 1 (HSV-1) commonly causes orolabial ulcers, while HSV-2 commonly causes genital ulcers. However, HSV-1 is an increasing cause of genital infection. Previously, the World Health Organization estimated the global burden of HSV-2 for 2003 and for 2012. The global burden of HSV-1 has not been estimated. METHODS: We fitted a constant-incidence model to pooled HSV-1 prevalence data from literature searches for 6 World Health Organization regions and used 2012 population data to derive global numbers of 0-49-year-olds with prevalent and incident HSV-1 infection. To estimate genital HSV-1, we applied values for the proportion of incident infections that are genital. FINDINGS: We estimated that 3709 million people (range: 3440-3878 million) aged 0-49 years had prevalent HSV-1 infection in 2012 (67%), with highest prevalence in Africa, South-East Asia and Western Pacific. Assuming 50% of incident infections among 15-49-year-olds are genital, an estimated 140 million (range: 67-212 million) people had prevalent genital HSV-1 infection, most of which occurred in the Americas, Europe and Western Pacific. CONCLUSIONS: The global burden of HSV-1 infection is huge. Genital HSV-1 burden can be substantial but varies widely by region. Future control efforts, including development of HSV vaccines, should consider the epidemiology of HSV-1 in addition to HSV-2, and especially the relative contribution of HSV-1 to genital infection.