COVID-19 vaccination and Guillain-Barré syndrome: analyses using the National Immunoglobulin Database.

Vaccination against viruses has rarely been associated with Guillain-Barré syndrome (GBS), and an association with the COVID-19 vaccine is unknown. We performed a population-based study of National Health Service data in England and a multicentre surveillance study from UK hospitals to investigate the relationship between COVID-19 vaccination and GBS. Firstly, case dates of GBS identified retrospectively in the National Immunoglobulin Database from 8 December 2021 to 8 July 2021 were linked to receipt dates of COVID-19 vaccines using data from the National Immunisation Management System in England. For the linked dataset, GBS cases temporally associated with vaccination within a 6-week risk window of any COVID-19 vaccine were identified. Secondly, we prospectively collected incident UK-wide (four nations) GBS cases from 1 January 2021 to 7 November 2021 in a separate UK multicentre surveillance database. For this multicentre UK-wide surveillance dataset, we explored phenotypes of reported GBS cases to identify features of COVID-19 vaccine-associated GBS. Nine hundred and ninety-six GBS cases were recorded in the National Immunoglobulin Database from January to October 2021. A spike of GBS cases above the 2016-2020 average occurred in March-April 2021. One hundred and ninety-eight GBS cases occurred within 6 weeks of the first-dose COVID-19 vaccination in England [0.618 cases per 100,000 vaccinations; 176 ChAdOx1 nCoV-19 (AstraZeneca), 21 tozinameran (Pfizer) and one mRNA-1273 (Moderna)]. The 6-week excess of GBS (compared to the baseline rate of GBS cases 6-12 weeks after vaccination) occurred with a peak at 24 days post-vaccination; first-doses of ChAdOx1 nCoV-19 accounted for the excess. No excess was seen for second-dose vaccination. The absolute number of excess GBS cases from January-July 2021 was between 98-140 cases for first-dose ChAdOx1 nCoV-19 vaccination. First-dose tozinameran and second-dose of any vaccination showed no excess GBS risk. Detailed clinical data from 121 GBS patients were reported in the separate multicentre surveillance dataset during this timeframe. No phenotypic or demographic differences identified between vaccine-associated and non-vaccinated GBS cases occurring in the same timeframe. Analysis of the linked NID/NIMS dataset suggested that first-dose ChAdOx1 nCoV-19 vaccination is associated with an excess GBS risk of 0.576 (95% confidence interval 0.481-0.691) cases per 100 000 doses. However, examination of a multicentre surveillance dataset suggested that no specific clinical features, including facial weakness, are associated with vaccination-related GBS compared to non-vaccinated cases. The pathogenic cause of the ChAdOx1 nCoV-19 specific first dose link warrants further study.

Safety of COVID-19 vaccination and acute neurological events: A self-controlled case series in England using the OpenSAFELY platform.

INTRODUCTION: We investigated the potential association of COVID-19 vaccination with three acute neurological events: Guillain-Barré syndrome (GBS), transverse myelitis and Bell's palsy. METHODS: With the approval of NHS England we analysed primary care data from >17 million patients in England linked to emergency care, hospital admission and mortality records in the OpenSAFELY platform. Separately for each vaccine brand, we used a self-controlled case series design to estimate the incidence rate ratio for each outcome in the period following vaccination (4-42 days for GBS, 4-28 days for transverse myelitis and Bell's palsy) compared to a within-person baseline, using conditional Poisson regression. RESULTS: Among 7,783,441 ChAdOx1 vaccinees, there was an increased rate of GBS (N = 517; incidence rate ratio 2·85; 95% CI2·33-3·47) and Bell's palsy (N = 5,350; 1·39; 1·27-1·53) following a first dose of ChAdOx1 vaccine, corresponding to 11.0 additional cases of GBS and 17.9 cases of Bell's palsy per 1 million vaccinees if causal. For GBS this applied to the first, but not the second, dose. There was no clear evidence of an association of ChAdOx1 vaccination with transverse myelitis (N = 199; 1·51; 0·96-2·37). Among 5,729,152 BNT162b2 vaccinees, there was no evidence of any association with GBS (N = 283; 1·09; 0·75-1·57), transverse myelitis (N = 109; 1·62; 0·86-3·03) or Bell's palsy (N = 3,609; 0·89; 0·76-1·03). Among 255,446 mRNA-1273 vaccine recipients there was no evidence of an association with Bell's palsy (N = 78; 0·88, 0·32-2·42). CONCLUSIONS: COVID-19 vaccines save lives, but it is important to understand rare adverse events. We observed a short-term increased rate of Guillain-Barré syndrome and Bell's palsy after first dose of ChAdOx1 vaccine. The absolute risk, assuming a causal effect attributable to vaccination, was low.

A European multicentre drug utilisation study of the impact of regulatory measures on prescribing of codeine for pain in children.

PURPOSE: In June 2013, following recommendations from the World Health Organization (WHO) and Food and Drug Administration (FDA), the European Medicines Agency agreed updates to the codeine product information regarding use for pain in children younger than 12 years and children undergoing tonsillectomy or adenoidectomy (TA) for obstructive sleep apnoea. This study was conducted to (a) assess effectiveness of these measures on codeine prescribing in the "real-world" setting and (b) test feasibility of a study using a common protocol by regulators with access to databases. METHODS: The study was performed using BIFAP (Spain), CPRD (UK), and IMS® Disease Analyzer (France and Germany) databases. Prescribers included general practitioners (GPs) (France and UK), GPs and paediatricians together (Spain), and GPs, paediatricians, and ear, nose, and throat (ENT) specialists separately (Germany). Between January 2010 and June 2015, prevalence of codeine prescribing was obtained every 6 months, and a time series analysis (joinpoint) was performed. Codeine prescribing within ±30 days of TA was also identified. Furthermore, doses, durations, and prior prescribing of other analgesics were investigated. RESULTS: Over the 5-year period, codeine prescribing decreased in children younger than 12 years (by 84% in France and Spain, 44% in GP practices in Germany, and 33% in the United Kingdom). The temporal pattern was compatible with the regulatory intervention in France and the United Kingdom, whereas a decrease throughout the study period was seen in Germany and Spain. Decreased prescribing associated with TA was suggested in ENT practices in Germany. CONCLUSIONS: Codeine prescribing for children decreased in line with introduced regulatory measures. Multidatabase studies assessing impact of measures by EU regulators are feasible.

How Clinical Practice Research Datalink data are used to support pharmacovigilance.

Pharmacovigilance can be defined as the science of monitoring medicines and vaccines after license for use, the purpose of which is to quantify and characterise the safety profile of a medicine, identify previously unknown adverse reactions, inform risk-benefit assessment, and support the development of actions that can be taken to reduce risks, optimise benefits and monitor their effectiveness. This review discusses the Clinical Practice Research Datalink (CPRD), which is the source of the largest research database in the UK with longitudinal, representative primary care data linked to data from other healthcare settings. CPRD supports international pharmacovigilance by providing a large, anonymised representative general population database with comprehensive capture of patient risk factors and outcomes to researchers within academic, regulatory and pharmaceutical organisations. The specific advantages of CPRD data are discussed in the context of the 'six Vs of big data' including volume, velocity, variety, veracity, validity and value. Examples of where CPRD data have been used for pharmacovigilance research and how these have fed into guidelines and policy are discussed.

Safety of multicomponent meningococcal group B vaccine (4CMenB) in routine infant immunisation in the UK: a prospective surveillance study.

BACKGROUND: Safety data for the multicomponent meningococcal group B vaccine (4CMenB) has so far been limited to experience from clinical trials and isolated local outbreaks. Since the UK is the first country to implement a nationwide routine immunisation programme with 4CMenB (at age 8 weeks, 16 weeks, and then 1 year), we aimed to assess the safety of 4CMenB in this setting. METHODS: In this prospective surveillance study, we assessed suspected adverse reactions of 4CMenB in children up to age 18 months reported in the UK Yellow Card Scheme and primary care records extracted from the Clinical Practice Research Datalink (CPRD). We proactively assessed reports of fever, local reactions, Kawasaki disease, seizures, and sudden death, and compared the number of spontaneous reports with the expected number of events based on background incidence and the number of children vaccinated. We also identified any unexpected adverse reactions and estimated compliance with subsequent doses of routine vaccinations. FINDINGS: From Sept 1, 2015, to May 31, 2017, approximately 1·29 million children aged 2-18 months received about a combined 3 million doses of 4CMenB. 902 reports of suspected adverse reactions were received through the UK Yellow Card Scheme, of which 366 (41%) were related to local reactions and 364 (40%) related to fever. The only unexpected finding was that 160 reports of local reactions described a persistent nodule at the site of injection, usually without other local symptoms. There were 55 (6%) reports of seizures, with an age-adjusted observed-to-expected ratio of 0·13 (95% CI 0·10-0·17). Ecological analyses found similar rates of seizures within 7 days of routine immunisation in the periods before and after 4CMenB introduction, with incidence rate ratios of 1·30 (95% CI 0·56-3·00) at age 2 months, 1·53 (0·49-4·74) at age 4 months, and 1·26 (0·69-2·32) at age 12 months. Of the 902 reports, three (<1%) were of Kawasaki disease (observed-to-expected ratio 1·40, 95% CI 0·29-4·08) and three (<1%) of sudden infant death syndrome within 3 days of vaccination in children aged 2-4 months (0·44, 0·12-1·14). Analysis of routine immunisations recorded in CPRD found that 11 602 (95·1%) of 12 199 children had received the second dose of 4CMenB by 26 weeks of age, 1793 (84·7%) of 2117 had received the third dose by 62 weeks of age, and 4CMenB introduction had not reduced compliance with doses of other routine vaccinations. INTERPRETATION: We found no significant safety concerns after widespread use of 4CMenB in UK infants, and the vaccine appears to have been well accepted by parents. However, it is important to continue monitoring the safety and long-term effect of the immunisation programme in the UK to further characterise the reported suspected adverse reactions. FUNDING: None.

Exploring the Potential Routine Use of Electronic Healthcare Record Data to Strengthen Early Signal Assessment in UK Medicines Regulation: Proof-of-Concept Study.

INTRODUCTION: Electronic healthcare record (EHR) databases are used within pharmacoepidemiology studies to confirm or refute safety signals arising from spontaneous adverse event reports. However, there has been limited routine use of such data earlier in the signal management process, to help rapidly contextualise signals and strengthen preliminary assessment or to inform decisions regarding action including the need for further studies. This study explores the value of EHR used in this way within a regulatory environment via an automated analysis platform. METHODS: Safety signals raised at the UK Medicines and Healthcare products Regulatory Agency (MHRA) between July 2014 and June 2015 were individually reviewed by a multi-disciplinary team. They assessed the feasibility of identifying the exposure and event of interest using primary care data from the Clinical Practice Research Datalink (CPRD) within the Commonwealth Vigilance Workbench (CVW) Longitudinal Module platform, which was designed to facilitate routine descriptive analysis of signals using EHR. Three signals, where exposure and event could be well identified, were retrospectively analysed using the platform. RESULTS: Of 69 unique new signals, 20 were for drugs prescribed predominately in secondary care or available without prescription, which would not be identified in primary care. A further 17 were brand, formulation, or dose-specific issues, were related to mortality, were relevant only to a subgroup of patients, or were drug interactions, and hence could not be reviewed using the platform given its limitations. Analyses of exposure and incidence of the adverse event could be produced using CPRD within the CMV Longitudinal Module for 32 (46%) signals. The case studies demonstrated that the data provided supporting evidence for confirming initial assessment of the signal and deciding upon the need for further action. CONCLUSIONS: CPRD can routinely provide useful early insights into clinical context when assessing a large proportion of safety signals within a regulatory environment provided that a flexible approach is adopted within the analysis platform.

Benefit-Risk Monitoring of Vaccines Using an Interactive Dashboard: A Methodological Proposal from the ADVANCE Project.

INTRODUCTION: New vaccines are launched based on their benefit-risk (B/R) profile anticipated from clinical development. Proactive post-marketing surveillance is necessary to assess whether the vaccination uptake and the B/R profile are as expected and, ultimately, whether further public health or regulatory actions are needed. There are several, typically not integrated, facets of post-marketing vaccine surveillance: the surveillance of vaccination coverage, vaccine safety, effectiveness and impact. OBJECTIVE: With this work, we aim to assess the feasibility and added value of using an interactive dashboard as a potential methodology for near real-time monitoring of vaccine coverage and pre-specified health benefits and risks of vaccines. METHODS: We developed a web application with an interactive dashboard for B/R monitoring. The dashboard is demonstrated using simulated electronic healthcare record data mimicking the introduction of rotavirus vaccination in the UK. The interactive dashboard allows end users to select certain parameters, including expected vaccine effectiveness, age groups, and time periods and allows calculation of the incremental net health benefit (INHB) as well as the incremental benefit-risk ratio (IBRR) for different sets of preference weights. We assessed the potential added value of the dashboard by user testing amongst a range of stakeholders experienced in the post-marketing monitoring of vaccines. RESULTS: The dashboard was successfully implemented and demonstrated. The feedback from the potential end users was generally positive, although reluctance to using composite B/R measures was expressed. CONCLUSION: The use of interactive dashboards for B/R monitoring is promising and received support from various stakeholders. In future research, the use of such an interactive dashboard will be further tested with real-life data as opposed to simulated data.

Trends in diagnosis and treatment for people with dementia in the UK from 2005 to 2015: a longitudinal retrospective cohort study.

BACKGROUND: The objectives of this study were to describe changes in the proportion of people diagnosed with dementia and the pharmacological treatments prescribed to them over a 10 year period from 2005 to 2015 at a time of UK policy strategies and prioritisation of dementia. We aimed to explore the potential impact of policy on dementia care. METHODS: In this longitudinal retrospective cohort study, we included all patients registered at a Clinical Practice Research Datalink (CPRD) practice between July 1, 2005, and June 30, 2015, with a diagnosis of dementia defined using Read codes. The main outcomes were the number and proportion of acceptable patients, who met the CPRD threshold for data quality, in a GP practice defined by the CPRD as contributing up-to-standard data with a diagnosis of dementia and the number and proportion of these with a prescription for an antidementia or antipsychotic medication. We examined the prevalence of dementia diagnosis and prescribing by calendar quarter, and stratified by age, sex, and UK country (England, Scotland, Wales, or Northern Ireland). We investigated the use of antidementia drugs, alone and in combination, antipsychotics, antidepressants, anxiolytics, and hypnotics. The trend in the proportion of patients with a diagnosis of dementia, before and after the introduction of the UK National Dementia Strategy, was estimated using an interrupted time-series analysis. FINDINGS: 8 966 224 patients were identified in the CPRD whose most recent registration period overlapped the study period. Of these, 128 249 (1·4%) had a diagnosis of dementia before the end of the study period. The proportion of people diagnosed with dementia in the UK doubled from 0·42% (19 635 of 4 640 290 participants) in 2005 to 0·82% (25 925 of 3 159 754 participants) in 2015 (χ2 test for trend, p<0·0001), and the proportion of those who received antidementia medication increased from 15·0% (2942 of 19 635) to 36·3% (9406 of 25 925). The interrupted time-series analysis showed a significant acceleration in the rate of diagnosis of dementia after the introduction of the UK National Dementia Strategy (p<0·0001). There was a large reduction in antipsychotic drug prescription in dementia from 22·1% (4347 of 19 635) in 2005 to 11·4% (2943 of 25 925) by 2015. INTERPRETATION: Over the 10 years studied, there is evidence of a sustained positive change in diagnosis rates of dementia and in the quality of drug treatment provided to those diagnosed. The prescription of antidementia drugs more than doubled and the prescription of potentially hazardous antipsychotics halved after the introduction of national dementia strategies. These data support the formulation and delivery of national policy to improve the quality of care for people with dementia. FUNDING: None.

The impact of regulatory action on the co-prescribing of renin-angiotensin system blockers in UK primary care.

PURPOSE: The aim of this study was to assess the impact of regulatory action taken in June 2014 on the co-prescribing of renin-angiotensin system (RAS) blockers in UK primary care. METHODS: RAS blocker prescriptions, issued between 01/01/2009-30/06/2015, were extracted from the Clinical Practice Research Datalink to estimate the quarterly prevalence (number of patients with at least one co-prescription) and incidence (number of patients first receiving a RAS blocker co-prescription) of co-prescribing. Two different RAS blockers prescribed on the same day constituted a co-prescription. RESULTS: A total of 880 364 patients were prescribed a single RAS blocker during the study period. Prevalence of co-prescribing increased from 4812 patients per million person-years in Q1 2009 to 4865 in Q1 2010. A reduction then occurred decreasing to 2901 patients per million person-years in Q2 2014 when the EU review concluded and continued to decrease thereafter despite a continued increase in the prevalence of prescribing of a single RAS blocker. Incidence of new co-prescribing decreased from 454 patients per million person-years in Q1 2009 to 159 in Q2 2014, but remained relatively constant at ~119 patients per million person-years on average after the EU review concluded. A total of 96% of co-prescriptions were for an ACE inhibitor + ARB, and 4% accounted for an ACE inhibitor or ARB + renin inhibitor. CONCLUSIONS: Recently, there has been a decrease in the prevalence and incidence of RAS blocker co-prescribing. Reassuringly, overall co-prescribing reduced in line with recommendations, although there was a decreasing trend prior to this likely due in part to prior publication of the data used in the EU review. © 2017 Crown copyright. Pharmacoepidemiology and Drug Safety © 2017 John Wiley & Sons, Ltd.

Patterns of anti-diabetic medication use in patients with type 2 diabetes mellitus in England and Wales.

PURPOSE: The purpose of this study is to characterise how Type 2 Diabetes Mellitus (T2DM) is treated in England and Wales and whether this adheres to 2009 National Institute for Health and Care Excellence (NICE) guidance on management of T2DM. METHODS: Data for T2DM patients aged 18+ years prescribed at least one anti-diabetic drug between 01/01/2000-30/06/2012 were extracted from the Clinical Practice Research Datalink. We examined the sequences in which anti-diabetic drugs were prescribed and, for patients on the most common anti-diabetic drug pathways, evaluated average HbA1c values at treatment initiation and at progression to a second or third-line anti-diabetic drug class, including insulin. RESULTS: The cohort included 123 671 patients, 56% males, 95% aged 40+ and 79% with at least one recorded HbA1c level. Metformin was the first prescription for 98 957 (80%) patients, with mean HbA1c of 8.68% prior to initiation (95% confidence interval [CI] 8.67, 8.69). A total of 19 890 (16%) patients received sulphonylureas first-line (mean HbA1c = 9.31%, 95%CI 9.27, 9.35). 1402 (12%) insulin users were prescribed insulin first-line (mean HbA1c = 9.89%, 95%CI 9.59, 10.19). A total of 96 895 (78%) patients were managed in line with one of the treatment pathways recommended by NICE. Patients prescribed insulin second-line after metformin had a mean HbA1c of 10.11% (95%CI 9.83, 10.38) prior to first prescription of insulin and 9.98% (95%CI 9.73, 10.23) at baseline. Both values were significantly higher than other groups initiating new treatment. CONCLUSIONS: In over three-quarters of patients, anti-diabetic drugs are being prescribed per NICE guidance. When insulin is being used earlier than recommended, there appears to be a need for urgent and rapid glycaemic control. © 2016 Crown Copyright. Pharmacoepidemiology and Drug Safety © 2016 John Wiley & Sons, Ltd.

Risk of Narcolepsy after AS03 Adjuvanted Pandemic A/H1N1 2009 Influenza Vaccine in Adults: A Case-Coverage Study in England.

STUDY OBJECTIVES: An increased risk of narcolepsy has been observed in children following ASO3-adjuvanted pandemic A/H1N1 2009 (Pandemrix) vaccine. We investigated whether this risk extends to adults in England. METHODS: Six adult sleep centers in England were visited between November 2012 and February 2014 and vaccination/clinical histories obtained from general practitioners. Suspected narcolepsy cases aged older than 17 y were selected. The risk of narcolepsy following Pandemrix was calculated using cases diagnosed by the time of the center visits and those with a diagnosis by November 30, 2011 after which there was increased awareness of the risk in children. The odds of vaccination in cases and in matched population data were compared using a case-coverage design. RESULTS: Of 1,446 possible cases identified, most had onset before 2009 or were clearly not narcolepsy. Of the 60 remaining cases, 20 were excluded after expert review, leaving 40 cases with narcolepsy; 5 had received Pandemrix between 3 and 18 mo before onset. All the vaccinated cases had cataplexy, two received a diagnosis by November 2011 and two were aged 40 y or older. The odds ratio for vaccination in cases compared to the population was 4.24 (95% confidence interval 1.45-12.38) using all cases and 9.06 (1.90-43.17) using cases with a diagnosis by November 2011, giving an attributable risk of 0.59 cases per 100,000 doses. CONCLUSIONS: We found a significantly increased risk of narcolepsy in adults following Pandemrix vaccination in England. The risk was lower than that seen in children using a similar study design.

Incidence of pneumococcal and varicella disease in HIV-infected children and adolescents in the United Kingdom and Ireland, 1996-2011.

BACKGROUND: To define the burden of hospitalization due to 2 vaccine-preventable infections, invasive pneumococcal disease (IPD) and varicella zoster (VZ), among HIV-infected children in the UK and Ireland. METHODS: Analysis of hospitalizations of HIV-infected children <18 years receiving pediatric care and reported to the Collaborative HIV Paediatric Study (CHIPS) between 1996 and 2011. RESULTS: Admissions for IPD and VZ combined accounted for ~5% of all hospital admissions for HIV-infected children each year. When compared with background rates for healthy children, the admission rate ratio for HIV-infected children on combination antiretroviral therapy (cART) was 16.7, 14.8 and 126.7 for IPD, varicella and herpes zoster, respectively, and 156.7, 86.1 and 470, respectively, for HIV-infected children not on cART. Those admitted with IPD or VZ were more likely to have Centers for Disease Control stage B/C at presentation with HIV than those without such admissions (36.8% for IPD, 29.7% for VZ and 22.1% for no IPD or VZ, P = 0.006), and were more likely to subsequently commence cART (94.7%, 91.3% and 80.2% respectively, P = 0.004). CONCLUSIONS: There is a clear increased risk of admission with IPD or VZ in HIV-infected compared with uninfected children, magnified in those who have not yet commenced cART. It is anticipated that the introduction of new guidelines will result in improved vaccine uptake and thereby reduce the burden of IPD and VZ disease. Subsequent evaluation will assess the impact of these guidelines.

Effectiveness of maternal pertussis vaccination in England: an observational study.

BACKGROUND: In October, 2012, a pertussis vaccination programme for pregnant women was introduced in response to an outbreak across England. We aimed to assess the vaccine effectiveness and the overall effect of the vaccine programme in preventing pertussis in infants. METHODS: We undertook an analysis of laboratory-confirmed cases and hospital admissions for pertussis in infants between Jan 1, 2008, and Sept 30, 2013, using data submitted to Public Health England as part of its enhanced surveillance of pertussis in England, to investigate the effect of the vaccination programme. We calculated vaccine effectiveness by comparing vaccination status for mothers in confirmed cases with estimates of vaccine coverage for the national population of pregnant women, based on data from the Clinical Practice Research Datalink. FINDINGS: The monthly total of confirmed cases peaked in October, 2012 (1565 cases), and subsequently fell across all age groups. For the first 9 months of 2013 compared with the same period in 2012, the greatest proportionate fall in confirmed cases (328 cases in 2012 vs 72 cases in 2013, -78%, 95% CI -72 to -83) and in hospitalisation admissions (440 admissions in 2012 vs 140 admissions in 2013, -68%, -61 to -74) occurred in infants younger than 3 months, although the incidence remained highest in this age group. Infants younger than 3 months were also the only age group in which there were fewer cases in 2013 than in 2011 (118 cases in 2011 vs 72 cases in 2013), before the resurgence. 26?684 women included in the Clinical Practice Research Datalink had a livebirth between Oct 1, 2012 and Sept 3, 2013; the average vaccine coverage before delivery based on this cohort was 64%. Vaccine effectiveness based on 82 confirmed cases in infants born from Oct 1, 2012, and younger than 3 months at onset was 91% (95% CI 84 to 95). Vaccine effectiveness was 90% (95% CI 82 to 95) when the analysis was restricted to cases in children younger than 2 months. INTERPRETATION: Our assessment of the programme of pertussis vaccination in pregnancy in England is consistent with high vaccine effectiveness. This effectiveness probably results from protection of infants by both passive antibodies and reduced maternal exposure, and will provide valuable information to international policy makers. FUNDING: Public Health England.

Safety of pertussis vaccination in pregnant women in UK: observational study.

OBJECTIVE: To examine the safety of pertussis vaccination in pregnancy. DESIGN: Observational cohort study. SETTING: The UK Clinical Practice Research Datalink. PARTICIPANTS: 20,074 pregnant women with a median age of 30 who received the pertussis vaccine and a matched historical unvaccinated control group. MAIN OUTCOME MEASURE: Adverse events identified from clinical diagnoses during pregnancy, with additional data from the matched child record identified through mother-child linkage. The primary event of interest was stillbirth (intrauterine death after 24 weeks' gestation). RESULTS: There was no evidence of an increased risk of stillbirth in the 14 days immediately after vaccination (incidence rate ratio 0.69, 95% confidence interval 0.23 to 1.62) or later in pregnancy (0.85, 0.44 to 1.61) compared with historical national rates. Compared with a matched historical cohort of unvaccinated pregnant women, there was no evidence that vaccination accelerated the time to delivery (hazard ratio 1.00, 0.97 to 1.02). Furthermore, there was no evidence of an increased risk of stillbirth, maternal or neonatal death, pre-eclampsia or eclampsia, haemorrhage, fetal distress, uterine rupture, placenta or vasa praevia, caesarean delivery, low birth weight, or neonatal renal failure, all serious events that can occur naturally in pregnancy. CONCLUSION: In women given pertussis vaccination in the third trimester, there is no evidence of an increased risk of any of an extensive predefined list of adverse events related to pregnancy. In particular, there was no evidence of an increased risk of stillbirth. Given the recent increases in the rate of pertussis infection and morbidity and mortality in neonates, these early data provide initial evidence for evaluating the safety of the vaccine in pregnancy for health professionals and the public and can help to inform vaccination policy making.

Bivalent human papillomavirus vaccine and the risk of fatigue syndromes in girls in the UK.

INTRODUCTION: Over 70% of cervical cancers are related to human papillomavirus types 16 and 18. In 2008, the vaccine Cervarix, protecting against these two strains, was introduced into the routine UK immunisation programme for girls aged 12-13 years, with a catch-up in girls aged up to 18 years. As part of the risk management planning for this new campaign, the Medicines and Healthcare products Regulatory Agency (MHRA) anticipated a range of conditions, including chronic fatigue syndrome, which might be reported as adverse events in temporal association with the vaccine. METHODS: Near-real time 'observed vs. expected' analyses were conducted comparing the number of reports of fatigue syndromes submitted via the MHRA's Yellow Card passive surveillance scheme to the expected number, using background rates calculated from the Clinical Practice Research Datalink (CPRD) and estimates of vaccination coverage. Subsequently, an ecological analysis and a self-controlled case series (SCCS), both using CPRD, compared the incidence rate of fatigue syndromes in girls before and after the start of the vaccination campaign and the risk in the year post-vaccination compared to other periods. RESULTS: The number of spontaneous reports of chronic fatigue following Cervarix vaccination was consistent with estimated background rates even assuming low reporting. Ecological analyses suggested that there had been no change in the incidence of fatigue syndromes in girls aged 12-20 years after the introduction of the vaccination despite high uptake (IRR: 0.94, 95% CI: 0.78-1.14). The SCCS, including 187 girls, also showed no evidence of an increased risk of fatigue syndromes in the year post first vaccination (IRR: 1.07, 95% CI: 0.57-2.00, p=0.84). DISCUSSION: The successful implementation of an enhanced pharmacovigilance plan provided immediate reassuring evidence that there was no association between vaccination with Cervarix and an increased risk of chronic fatigue syndromes. This has now also been further demonstrated in more comprehensive epidemiological studies.

Lopinavir dosing in HIV-infected children in the United Kingdom and Ireland.

BACKGROUND: Uncertainty surrounds the correct dosing of lopinavir/r (LPV/r) in HIV-infected children not receiving non-nucleoside reverse transcriptase inhibitors. The licensed total daily dose is 460 mg/m², whereas the original study, reporting excellent viral load (VL) suppression, used a higher 600 mg/m² dose. METHODS: We calculated LPV/r daily doses prescribed from 2000 to 2009 within the UK/Irish national Collaborative HIV Paediatric Study (CHIPS) cohort. Logistic and binomial mixed models were used to explore whether higher LPV/r doses affected VL suppression. RESULTS: Four hundred forty-four of 1201 (37%) children on antiretroviral therapy in CHIPS had taken lopinavir/r without non-nucleoside reverse transcriptase inhibitors. Of 1065 recorded doses, 48% were syrup, 27% capsules and 25% tablets. Ten percent of doses were >10% below 460 mg/m² per day, and 12% were >10% above 600 mg/m². In multivariable models, predictors of lower doses were: once versus twice daily dosing (32 mg/m² lower); syrup versus tablets/capsules (33 mg/m² lower); higher weight-for-age and height-for-age (24 mg/m² and 13 mg/m² lower per unit higher, respectively); and older age (13 mg/m lower per year older for those aged >10 years, P < 0.05). Dosing varied widely by hospital (P = 0.0004), with some targeting higher and others lower doses. For those receiving lopinavir/r for ≥6 months, there was a greater chance of VL <400 copies/mL with higher doses (odds ratio = 1.15 [95% confidence interval: 1.06-1.25 per 50 mg/m² higher], P = 0.001). CONCLUSIONS: Findings suggest substantial variation and large hospital-level effects in the LPV/r dose prescribed to HIV-infected children in the United Kingdom/Ireland. Higher doses appeared to improve long-term VL suppression, which may be critical in children who need life-long therapy. Results highlight the importance of optimizing dosing in HIV-infected children of all ages.

Mean Corpuscular Volume as a Marker for Adherence to Zidovudine-Containing Therapy in HIV-Infected Adults.

OBJECTIVES: To assess whether mean corpuscular volume (MCV) is useful in detecting non-adherence to AZTcontaining therapy. DESIGN: Observational study within randomised controlled trial. METHODS: We combined data from two treatment arms in SPARTAC, an RCT of short-course cART in primary HIV infection, classifying participants as responders (HIV-RNA decrease ≥1 log(10) or reaching <400copies/ml) or nonresponders following cART initiation. We assessed the sensitivity and specificity of using different percentage increases in MCV for accurately differentiating between responders and non-responders. We further examined changes in MCV levels up to 24 weeks after protocol-indicated cART cessation. RESULTS: Of 119 participants included in this analysis, 73 (61%) were women, 71 of whom were randomised in Africa. Ninety-eight (88%) and 84 (85%) were classified as responders at 4 and 12 weeks respectively following cART initiation. MCV increased by a mean 3% and 1% at week 4, and 14% and <1% at 12 weeks for responders and non-responders. A 2% MCV increase at 4 weeks had 62% sensitivity and specificity for identifying virological response. At 12 weeks, an 8% increase had 89% sensitivity and specificity. In responders, MCV remained lower for individuals in African compared to non-African sites throughout and rose from 85 vs 90 fL at cART start to 96 vs 103 fL at 12 weeks post-initiation then fell to 88 vs 93 fL and 86 vs 89 fL at 12 and 48 weeks post-cessation. CONCLUSION: In low-income countries, where HIV RNA may be unavailable, 12-weekly MCV measurements may be useful in monitoring adherence to AZT-containing regimens.

The prevalence of darunavir-associated mutations in HIV-1-infected children in the UK.

BACKGROUND: We examined the prevalence of ritonavir-boosted darunavir (DRV) resistance-associated mutations (RAMs) in HIV-infected children in the UK to determine the drug's potential clinical utility as a first-line or second-line protease inhibitor (PI). METHODS: The prevalence of DRV RAMs, identified from IAS 2010 and Stanford, and the Stanford susceptibility score, were estimated in PI-naive and PI-experienced children in the Collaborative HIV Paediatric Study and the UK HIV Drug Resistance Database 1998-2008. Associations between type/duration of PI exposure and area under the viraemia curve on PI with the number of RAMs were investigated using multivariate Poisson regression. RESULTS: A total of 17/417 (4%) children with a resistance test when PI-naive had one IAS DRV RAM, and 1 had a Stanford mutation; none had multiple DRV RAMs. A total of 177 PI-experienced children had a test after a median 2.7 years (IQR 1.1-5.2) on PIs; 19 (11%) had one IAS DRV RAM, 7 (4%) had two RAMs, 1 (0.6%) had three RAMs and 1 (0.6%) had four RAMs. DRV RAMs were independently associated with increased years on a PI, a larger area under the viraemia curve since starting PIs, and any exposure to PIs other than lopinavir (all P≤0.05). Only 6 (3%) PI-experienced children had intermediate-level DRV/ritonavir resistance; none had high-level resistance. CONCLUSIONS: DRV resistance was negligible in PI-naive children and those with lopinavir PI exposure alone. However resistance increased with increasing time, and with higher levels of viraemia, on PIs. Once-daily DRV/ritonavir would be valuable as a second PI or an alternative first PI, particularly if coformulated with a booster in an appropriate formulation for children.