HIV pre-exposure prophylaxis and its implementation in the PrEP Impact Trial in England: a pragmatic health technology assessment.

BACKGROUND: HIV pre-exposure prophylaxis (PrEP) is highly effective in preventing HIV acquisition. To enable routine commissioning of PrEP in England, we aimed to establish population need, duration of need, PrEP uptake, and duration of use in attendees of sexual health services (SHS) in England. METHODS: The Impact Trial was a prospective, open-label, single-arm, multicentre trial conducted at 157 SHS across England between Oct 13, 2017, and July 12, 2020. Clinicians assessed HIV-negative attendees for their risk of HIV acquisition to identify those who were eligible to participate and receive either daily or event-based oral PrEP (tenofovir disoproxil maleate with emtricitabine), as appropriate. Eligible participants were aged 16 years or older, considered HIV-negative on the day of enrolment, and willing to adhere to the trial procedures. Non-trial attendees are mutually exclusive of trial participants and included SHS attendees who were not recruited to the Impact Trial at any point. They include HIV-negative individuals aged 16 years or older who attended a participating SHS at least once after recruitment at that SHS had begun and before Feb 29, 2020. The main outcomes assessed were PrEP need, uptake, and use, and HIV and sexually transmitted infection (STI) incidence. Data are presented up to Feb 29, 2020, before the introduction of COVID-19 control measures. The study is registered with ClinicalTrials.gov, NCT03253757. FINDINGS: In this analysis, we include 21 356 of 24 268 participants enrolled before Feb 29, 2020. 20 403 participants (95·5%) were men who have sex with men (MSM). Uptake of PrEP among SHS attendees clinically assessed and coded as eligible was 21 292 (57·1%) of 37 289. 18 400 trial participants had at least one post-enrolment visit and a median of 361 days of follow-up (IQR 143-638); 14 039 (75·9%) of these had enough PrEP prescribed to provide protection for 75% of their follow-up time. Among MSM, HIV incidence was 0·13 (95% CI 0·08-0·19) per 100 person-years in trial participants (27 seroconversions) and 0·95 (95% CI 0·88-1·03) per 100 person-years in non-trial attendees (587 seroconversions; proportionate reduction of 86·8%, 95% CI 80·2-91·6). 18 607 bacterial STIs were recorded (incidence 68·1 per 100 person-years in trial participants who were MSM). 4343 (24·4%) MSM participants were diagnosed with two or more STIs, accounting for 14 800 (79·5%) of all 18 607 diagnoses. INTERPRETATION: PrEP need was higher than initially estimated by an expert stakeholder group. The high proportion of follow-up time protected by PrEP suggests that the need for protection persisted throughout trial participation for most participants. HIV incidence among MSM trial participants was low. The large unmet need for PrEP suggests that greater provision is required to maximise the potential of a national programme. The high incidence of bacterial STIs among participants, concentrated within a subgroup of PrEP users, presents an opportunity for tailored STI control measures. FUNDING: NHS England.

Personal risk or societal benefit? Investigating adults' support for COVID-19 childhood vaccination.

Parental hesitancy poses a serious threat to the success of the COVID-19 childhood vaccination campaign. We investigate whether adults' opinions on childhood vaccination can be influenced via two survey experiments in Italy (n = 3,633 participants) and the UK (n = 3,314 participants). Respondents were randomly assigned to: a "risk treatment" that highlighted the potential risks of COVID-19 to a child, a "herd immunity treatment" that emphasized the community benefits of pediatric vaccination, or a control message. Participants' probability of supporting COVID-19 childhood vaccination was then assessed on a 0-100 scale. We find that the "risk treatment" reduced the proportion of Italian parents strongly against vaccination by up to 29.6 %, while increasing the proportion of neutral parents by up to 45.0 %. The "herd immunity treatment", instead, was only effective among non-parents, resulting in a lower proportion of individuals against pediatric vaccination and a higher proportion of individuals in favor (both shifted by around 20 %).

Methods for modelling excess mortality across England during the COVID-19 pandemic.

Excess mortality is an important measure of the scale of the coronavirus-2019 pandemic. It includes both deaths caused directly by the pandemic, and deaths caused by the unintended consequences of containment such as delays to accessing care or postponements of healthcare provision in the population. In 2020 and 2021, in England, multiple groups have produced measures of excess mortality during the pandemic. This paper describes the data and methods used in five different approaches to estimating excess mortality and compares their estimates.The fundamental principles of estimating excess mortality are described, as well as the key commonalities and differences between five approaches. Two of these are based on the date of registration: a quasi-Poisson model with offset and a 5-year average; and three are based on date of occurrence: a Poisson model without offset, the European monitoring of excess mortality model and a synthetic controls model. Comparisons between estimates of excess mortality are made for the period March 2020 through March 2021 and for the two waves of the pandemic that occur within that time-period.Model estimates are strikingly similar during the first wave of the pandemic though larger differences are observed during the second wave. Models that adjusted for reduced circulation of winter infection produced higher estimates of excess compared with those that did not. Models that do not adjust for reduced circulation of winter infection captured the effect of reduced winter illness as a result of mobility restrictions during the period. None of the estimates captured mortality displacement and therefore may underestimate excess at the current time, though the extent to which this has occurred is not yet identified. Models use different approaches to address variation in data availability and stakeholder requirements of the measure. Variation between estimates reflects differences in the date of interest, population denominators and parameters in the model relating to seasonality and trend.

Estimating age-stratified influenza-associated invasive pneumococcal disease in England: A time-series model based on population surveillance data.

BACKGROUND: Measures of the contribution of influenza to Streptococcus pneumoniae infections, both in the seasonal and pandemic setting, are needed to predict the burden of secondary bacterial infections in future pandemics to inform stockpiling. The magnitude of the interaction between these two pathogens has been difficult to quantify because both infections are mainly clinically diagnosed based on signs and symptoms; a combined viral-bacterial testing is rarely performed in routine clinical practice; and surveillance data suffer from confounding problems common to all ecological studies. We proposed a novel multivariate model for age-stratified disease incidence, incorporating contact patterns and estimating disease transmission within and across groups. METHODS AND FINDINGS: We used surveillance data from England over the years 2009 to 2017. Influenza infections were identified through the virological testing of samples taken from patients diagnosed with influenza-like illness (ILI) within the sentinel scheme run by the Royal College of General Practitioners (RCGP). Invasive pneumococcal disease (IPD) cases were routinely reported to Public Health England (PHE) by all the microbiology laboratories included in the national surveillance system. IPD counts at week t, conditional on the previous time point t-1, were assumed to be negative binomially distributed. Influenza counts were linearly included in the model for the mean IPD counts along with an endemic component describing some seasonal background and an autoregressive component mimicking pneumococcal transmission. Using age-specific counts, Akaike information criterion (AIC)-based model selection suggested that the best fit was obtained when the endemic component was expressed as a function of observed temperature and rainfall. Pneumococcal transmission within the same age group was estimated to explain 33.0% (confidence interval [CI] 24.9%-39.9%) of new cases in the elderly, whereas 50.7% (CI 38.8%-63.2%) of incidence in adults aged 15-44 years was attributed to transmission from another age group. The contribution of influenza on IPD during the 2009 pandemic also appeared to vary greatly across subgroups, being highest in school-age children and adults (18.3%, CI 9.4%-28.2%, and 6.07%, CI 2.83%-9.76%, respectively). Other viral infections, such as respiratory syncytial virus (RSV) and rhinovirus, also seemed to have an impact on IPD: RSV contributed 1.87% (CI 0.89%-3.08%) to pneumococcal infections in the 65+ group, whereas 2.14% (CI 0.87%-3.57%) of cases in the group of 45- to 64-year-olds were attributed to rhinovirus. The validity of this modelling strategy relies on the assumption that viral surveillance adequately represents the true incidence of influenza in the population, whereas the small numbers of IPD cases observed in the younger age groups led to significant uncertainty around some parameter estimates. CONCLUSIONS: Our estimates suggested that a pandemic wave of influenza A/H1N1 with comparable severity to the 2009 pandemic could have a modest impact on school-age children and adults in terms of IPD and a small to negligible impact on infants and the elderly. The seasonal impact of other viruses such as RSV and rhinovirus was instead more important in the older population groups.

Predictors of first ischemic lower limb ulcer in dialysis patients: an observational cohort study.

BACKGROUND: Lower limb ischemia affects the quality of life, physical activity and life expectancy of dialysis patients. The aim of this study was to investigate the risk factors associated with ischemic foot ulcers considering clinical, laboratory and therapeutic domains. METHODS: This observational cohort study was based on data from the Nephrology and Dialysis Department database of Alessandro Manzoni Hospital, Lecco (Italy). All of the incident patients who started dialysis between 1 January 1999 and 29 February 2012 were enrolled, excluding temporary guests, patients with acute renal failure and patients with previous limb ischemia or amputation. Multivariate Cox regression analysis identified the predictors in each domain, which were matched in the final model. A time-dependent approach was used to take into account the evolution of some of the prognostic covariates. RESULTS: Of the 526 incident dialysis patients, 120 developed a lower limb ischemic lesion after a median of 13 months. The incidence of new ulcers was constant during the study period (6 per 100 person-years), but higher in the diabetics with a relative rate of 4.5. The variables significantly related to an increased risk of lower limb ulcers were age, male gender, diabetes, ischemic heart disease, treatment with proton pump inhibitors, iron, anticoagulants and calcium-based binders, and blood levels of phosphorus, triglycerides and C-reactive protein. CONCLUSION: The incidence of lower limb ulcers was highest during the early dialysis follow-up and was associated with, in addition to diabetes, modifiable laboratory and therapeutic predictors such as anticoagulants, proton pump inhibitors, calcium-containing binders, calcimimetics and iron.

Postmenopausal hormone therapy and risk of stroke: A pooled analysis of data from population-based cohort studies.

BACKGROUND: Recent research indicates a favourable influence of postmenopausal hormone therapy (HT) if initiated early, but not late, on subclinical atherosclerosis. However, the clinical relevance of timing of HT initiation for hard end points such as stroke remains to be determined. Further, no previous research has considered the timing of initiation of HT in relation to haemorrhagic stroke risk. The importance of the route of administration, type, active ingredient, and duration of HT for stroke risk is also unclear. We aimed to assess the association between HT and risk of stroke, considering the timing of initiation, route of administration, type, active ingredient, and duration of HT. METHODS AND FINDINGS: Data on HT use reported by the participants in 5 population-based Swedish cohort studies, with baseline investigations performed during the period 1987-2002, were combined in this observational study. In total, 88,914 postmenopausal women who reported data on HT use and had no previous cardiovascular disease diagnosis were included. Incident events of stroke (ischaemic, haemorrhagic, or unspecified) and haemorrhagic stroke were identified from national population registers. Laplace regression was employed to assess crude and multivariable-adjusted associations between HT and stroke risk by estimating percentile differences (PDs) with 95% confidence intervals (CIs). The fifth and first PDs were calculated for stroke and haemorrhagic stroke, respectively. Crude models were adjusted for age at baseline only. The final adjusted models included age at baseline, level of education, smoking status, body mass index, level of physical activity, and age at menopause onset. Additional variables evaluated for potential confounding were type of menopause, parity, use of oral contraceptives, alcohol consumption, hypertension, dyslipidaemia, diabetes, family history of cardiovascular disease, and cohort. During a median follow-up of 14.3 years, 6,371 first-time stroke events were recorded; of these, 1,080 were haemorrhagic. Following multivariable adjustment, early initiation (<5 years since menopause onset) of HT was associated with a longer stroke-free period than never use (fifth PD, 1.00 years; 95% CI 0.42 to 1.57), but there was no significant extension to the time period free of haemorrhagic stroke (first PD, 1.52 years; 95% CI -0.32 to 3.37). When considering timing as a continuous variable, the stroke-free and the haemorrhagic stroke-free periods were maximal if HT was initiated approximately 0-5 years from the onset of menopause. If single conjugated equine oestrogen HT was used, late initiation of HT was associated with a shorter stroke-free (fifth PD, -4.41 years; 95% CI -7.14 to -1.68) and haemorrhagic stroke-free (first PD, -9.51 years; 95% CI -12.77 to -6.24) period than never use. Combined HT when initiated late was significantly associated with a shorter haemorrhagic stroke-free period (first PD, -1.97 years; 95% CI -3.81 to -0.13), but not with a shorter stroke-free period (fifth PD, -1.21 years; 95% CI -3.11 to 0.68) than never use. Given the observational nature of this study, the possibility of uncontrolled confounding cannot be excluded. Further, immortal time bias, also related to the observational design, cannot be ruled out. CONCLUSIONS: When initiated early in relation to menopause onset, HT was not associated with increased risk of incident stroke, regardless of the route of administration, type of HT, active ingredient, and duration. Generally, these findings held also for haemorrhagic stroke. Our results suggest that the initiation of HT 0-5 years after menopause onset, as compared to never use, is associated with a decreased risk of stroke and haemorrhagic stroke. Late initiation was associated with elevated risks of stroke and haemorrhagic stroke when conjugated equine oestrogen was used as single therapy. Late initiation of combined HT was associated with haemorrhagic stroke risk.