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IntroductionOur objective was to describe and compare self-reported side effects of COVID-19 vaccines in the USA.MethodsA web-based registry enrolled volunteers who received a COVID-19 vaccine between March 19 –July 15, 2021. We collected self-reported short-term side effects, medical consultation, hospitalization, and quality of life impact following completed vaccination regimens (Pfizer, Moderna, J&J).ResultsWe recruited 6,966 volunteers who completed their full course of vaccination (median age 48 years, IQR 35.0-62.0; 83.6% female): Pfizer 3,486; Moderna 2,857; J&J 623. Few (3.1%) sought medical care for post-vaccination side effects. Hospitalization (n=17; 0.3%) and severe allergic reactions (n=39; 0.6%) also were rare. Those with autoimmune disease or lung disease were approximately twice as likely to seek medical care (adjusted odds ratio (aOR) 2.01 [95% CI: 1.39;2.92] and 1.70 [95% CI: 1.12;2.58] respectively). 92.4% of participants reported ≥1 side effect (median 3), with injection site reactions (78.9%), fatigue (70.3%), headache (49.0%) reported most frequently. More side effects were reported after the second dose of two-dose vaccines (medians: 1 vs. 2 for Pfizer and 1 vs. 3 for Moderna for first and second doses respectively) versus 3 for J&J’s single-dose vaccine. For the employed, the median number of workdays missed was one. Diabetics and those vaccinated against influenza were substantially less likely to report ≥3 symptoms (aOR 0.68, 95% CI 0.56,0.82 and aOR 0.82, 95% CI 0.73,0.93, respectively.)DiscussionThe total side effect burden was, not unexpectedly, greater with two-dose regimens but all three vaccines appear relatively safe. Very few subjects reported side effects serious enough to warrant medical care or reported post-vaccination hospitalization. While these findings do not address possible long-term effects, they do inform on their short-term safety and tolerability and will hopefully provide some reassurance and positively inform the benefit-risk and pharmacoeconomic assessment for all three vaccines.Clinicaltrials.govNCT04368065

Background. Respiratory syncytial virus (RSV) infection is a cause of substantial morbidity and mortality in young children. There is currently no effective therapy available. Methods. This was a phase 2 study of the oral RSV fusion protein inhibitor AK0529 in infants aged 1-24 months, hospitalized with RSV infection. In part 1 patients (n=24) were randomized 2:1 to receive a single dose of AK0529 up to 4 mg/kg or placebo. In part 2 patients (n=48) were randomized 2:1 to receive AK0529 at 0.5, 1 or 2 mg/kg bid or placebo for five days. Sparse pharmacokinetic samples were assessed using population pharmacokinetics modelling. Safety, tolerability, viral load, signs and symptoms were assessed daily during treatment. Results. No safety or tolerability signals were detected for AK0529: grade ≥3 treatment-emergent adverse events occurred in 4.1% of patients in AK0529 and 4.2% in placebo groups, respectively, and none led to death or withdrawal from the study. In part 2, targeted drug exposure was reached with 2 mg/kg bid. A numerically greater reduction in median viral load with 2 mg/kg bid AK0529 than with placebo at 96 hours was observed. A -4.0 (95% CI: -4.51, -2.03) median reduction in RSV signs and symptom score from baseline to 96 hours was observed in the 2 mg/kg group, compared with -2.0 (95% CI: -3.42, -1.82) in the placebo group. Conclusions. AK0529 was well tolerated in hospitalized RSV-infected infants. Treatment with AK0529 2 mg/kg bid was observed to reduce viral load and clinical signs and symptoms.

Reynolds MW, Xie Y, Knuth KB, et al. Infect Drug Resist. 2022;1:5167–5182. Page 5172, Figure 2, the text “7,352 completed vaccine regimen” should read “7,532completed vaccine regimen” and “1,014 never reported infection” should read “1,414 never reported infection”. The correct Figure 2 is as follows. Figure 2 Flowchart of study sample and participant counts with COVID-19 infection. Page 5172, COVID-19 Infected Study Participants section, 2nd line, the text “(31.8% and 20.3%, were college-educated versus 40.5% among fully vaccinated)” should read “(31.8% and 20.3%, were above-college-educated versus 40.5% among fully vaccinated)”. Page 5172, COVID-19 Symptoms and Impact Among Vaccinated vs Unvaccinated section, 2nd paragraph, line 6, the text “1.6% among the 198 infected after partial vaccination, and 2.0% among the 3018 infected while unvaccinated” should read “2.0% among the 198 infected after partial vaccination, and 1.6% among the 3018 infected while unvaccinated”. The authors apologize for any confusion this may have caused.

Objective The objective of this study was to describe the acute side effects experienced by pregnant women who received a coronavirus disease 2019 (COVID-19) vaccine in the United States and to compare their experience to nonpregnant women of similar age. Study Design Adults who received a COVID-19 vaccine in the United States were invited via social media to enroll in an online, longitudinal, community-based registry ( www.helpstopCOVID19.com ). Participants self-reported pregnancy status, vaccination dates, manufacturer, acute side effects, impact on work and self-care, medical consultation, and hospitalization. This analysis was restricted to women aged 20 to 39 at the time of vaccination. Side effects reported by pregnant women were compared to those reported by nonpregnant women. Results This analysis included 946 pregnant women, with 572 (60%) receiving at least one dose of Pfizer, 321 (34%) Moderna, and 53 (6%) J&J, and 1,178 nonpregnant women. Demographic and medical history were similar across manufacturers for both cohorts.Overall, pregnant women reported similar side effects as nonpregnant women, with the most common being injection site reactions (83 vs. 87%), fatigue (72 vs.78%), and headache (45 vs. 59%). Pregnant women reported fewer side effects (median: 3 vs. 4, respectively). In both cohorts, very few reported seeking medical care ( Conclusion Pregnant women reported similar COVID-19 vaccine side effects as nonpregnant women, although fewer total side effects; pregnant women judged these side effects to have less impact on work and self-care. While these results do not address pregnancy outcomes or long-term effects, findings about acute side effects and impact offer reassurance for all three vaccines in terms of tolerability. Key Points

It is important to assess the extent to which the real-world effectiveness of marketed vaccines is consistent with that observed in the clinical trials, and to characterize how well vaccines prevent COVID-19 symptoms. We conducted a modified test-negative design (TND) to evaluate the RW effectiveness of three COVID-19 vaccines by leveraging data from an on-going, US community-based registry. Vaccine effectiveness was examined in two ways: considering cases who (1) tested positive for COVID-19 (695 cases, 1,786 controls) and who (2) tested positive with at least one moderate/severe COVID-19 symptom (165 cases, 2,316 controls). Any vaccination (full or partial) was associated with a 95% reduction in the odds of having a positive COVID-19 test [adjusted odds ratio (aOR) = 0.05 (95% confidence interval (CI): 0.04, 0.06)]. Full vaccination was associated with an aOR of 0.03 (95% CI: 0.03, 0.05) while partial vaccination had an aOR of 0.08 (95% CI: 0.06, 0.12). Any vaccination was associated with a 71% reduction in the odds of testing positive and having at least one moderate/severe symptom (aOR=0.29 (95% CI: 0.20, 0.40)). High effectiveness was observed across all three vaccine manufacturers both for prevention of positive COVID-19 test results and prevention of moderate/severe COVID-19 symptoms.Clinicaltrials.govNCT04368065

Background Symptomatic COVID-19 is prevalent in the community. We identify factors indicating COVID-19 positivity in non-hospitalized patients and prognosticators of moderate-to-severe disease. Methods Appeals conducted in April-June 2020 in social media, collaborating medical societies and patient advocacy groups recruited 20,476 participants ≥18 years who believed they had COVID-19 exposure. Volunteers consented on-line and reported height, weight, concomitant illnesses, medication and supplement use, residential, occupational or community COVID-19 exposure, symptoms and symptom severity on a 4-point scale. Of the 12,117 curated analytic population 2,279 reported a COVID-19 viral test result: 865 positive (COVID+) and 1,414 negative (COVID-). Results The triad of anosmia, ageusia and fever best distinguished COVID+ from COVID-participants (OR 6.07, 95% CI: 4.39 to 8.47). COVID+ subjects with BMI≥30, concomitant respiratory disorders or an organ transplant had increased risk of moderate-to- severe dyspnoea. Race and anti-autoimmunity medication did not affect moderate-to-severe dyspnea risk. Conclusions The triad of anosmia, ageusia and fever differentiates COVID-19. Elevated risks of severe symptoms outside the hospital were most evident among the obese and those with pulmonary comorbidity. Race and use of medication for autoimmune disease did not predict severe disease. These findings should facilitate rapid COVID-19 diagnosis and triage in settings without testing. Trial registration Clinicaltrials.gov NCT04368065, EU PAS register EUPAS36240., Highlights • The triad of anosmia, ageusia and fever differentiates COVID-19. The triad of anosmia, ageusia and fever best distinguished those who tested positive from those who tested negative. • Amongst those reporting a positive COVID-19 result, there were no significant differences by race or use of medication for autoimmune disease with respect to the risk of experiencing moderate or severe dyspnea. • Moderate-to-severe dyspnea in the community, a highly concerning symptom with potential long-term consequences, appears to be concentrated in the obese and those with underlying respiratory disorders.

Background Tafenoquine is an 8-aminoquinoline anti-malarial drug recently approved as a single-dose (300 mg) therapy for Plasmodium vivax relapse prevention, when co-administered with 3-days of chloroquine or other blood schizonticide. Tafenoquine 200 mg weekly after a loading dose is also approved as travellers’ prophylaxis. The development of tafenoquine has been conducted over many years, using various dosing regimens in diverse populations. Methods This review brings together all the preclinical and clinical data concerning tafenoquine central nervous system safety. Data were assembled from published sources. The risk of neuropsychiatric adverse events (NPAEs) with single-dose tafenoquine (300 mg) in combination with chloroquine to achieve P. vivax relapse prevention is particularly examined. Results There was no evidence of neurotoxicity with tafenoquine in preclinical animal models. In clinical studies in P. vivax relapse prevention, nervous system adverse events, mainly headache and dizziness, occurred in 11.4% (36/317) of patients with tafenoquine (300 mg)/chloroquine versus 10.2% (19/187) with placebo/chloroquine; and in 15.5% (75/483) of patients with tafenoquine/chloroquine versus 13.3% (35/264) with primaquine (15 mg/day for 14 days)/chloroquine. Psychiatric adverse events, mainly insomnia, occurred in 3.8% (12/317) of patients with tafenoquine/chloroquine versus 2.7% (5/187) with placebo/chloroquine; and in 2.9% (14/483) of patients with tafenoquine/chloroquine versus 3.4% (9/264) for primaquine/chloroquine. There were no serious or severe NPAEs observed with tafenoquine (300 mg)/chloroquine in these studies. Conclusions The risk:benefit of single-dose tafenoquine/chloroquine in P. vivax relapse prevention is favourable in the presence of malaria, with a low risk of NPAEs, similar to that seen with chloroquine alone or primaquine/chloroquine.

Background Tafenoquine is a new drug for malaria prevention. The goal of the present work was to conduct a specific neurobehavioral study in rats with histopathological assessment of the brain. Methods The clinical, hematological, behavioral, motor activity, and neurohistopathologic changes induced by different dose levels of tafenoquine were evaluated following single super-therapeutic dose administration. Toxicokinetic data were generated to allow extrapolation to clinical exposures. Results At the highest dose (500 mg/kg), two animals (of 12) died. Surviving animals showed clinical signs of toxicity and had reduced body weight 7–8 days after dosing. Decreases in motor activity were observed on more than one occasion at doses > 9-fold higher than the clinical exposure. No statistically significant changes were observed for other behavioral endpoints. No neurohistopathological changes were noted. Changes in hematological and clinical pathology endpoints were observed at the lowest dose level (125 mg/kg). For context, the human dosing regimen is a 10 mg/kg load followed by 3.3 mg/kg weekly (in a 60 kg person). Conclusions As in humans, adverse events other than neurotoxicity were dose-limiting for tafenoquine in rats. This raises the prospect that a new weekly prophylactic, without neurologic liability, may become available in the near future.

Aims A modular interdisciplinary platform was developed to investigate the economic impact of oseltamivir treatment by dosage regimen under simulated influenza pandemic scenarios. Methods The pharmacology module consisted of a pharmacokinetic distribution of oseltamivir carboxylate daily area under the concentration–time curve at steady state (simulated for 75 mg and 150 mg twice daily regimens for 5 days) and a pharmacodynamic distribution of viral shedding duration obtained from phase II influenza inoculation data. The epidemiological module comprised a susceptible, exposed, infected, recovered (SEIR) model to which drug effect on the basic reproductive number (R0), a measure of transmissibility, was linked by reduction of viral shedding duration. The number of infected patients per population of 100 000 susceptible individuals was simulated for a series of pandemic scenarios, varying oseltamivir dose, R0 (1.9 vs. 2.7), and drug uptake (25%, 50%, and 80%). The number of infected patients for each scenario was entered into the health economics module, a decision analytic model populated with branch probabilities, disease utility, costs of hospitalized patients developing complications, and case-fatality rates. Change in quality-adjusted life years was determined relative to base case. Results Oseltamivir 75 mg relative to no treatment reduced the median number of infected patients, increased change in quality-adjusted life years by deaths averted, and was cost-saving under all scenarios; 150 mg relative to 75 mg was not cost effective in low transmissibility scenarios but was cost saving in high transmissibility scenarios. Conclusion This methodological study demonstrates proof of concept that the disciplines of pharmacology, disease epidemiology and health economics can be linked in a single quantitative framework.

Background Tafenoquine was recently approved for Plasmodium vivax radical cure (KRINTAFEL™) and malaria prevention (ARAKODA™). Methods A review of the non-clinical and clinical literature was conducted to assess whether tafenoquine (and primaquine) exhibit the same neurologic lesions and associated clinical signs as earlier 8-aminoquinolines, as has been alleged in recent opinion pieces. Results Plasmocid, pamaquine and pentaquine damage specific neuro-anatomical structures in Rhesus monkeys and humans leading to corresponding deficits in neurologic function. Neurologic therapeutic indices for these 3 drugs calculated based on monkey data were well correlated with human data. Despite 60 years of use, there is no evidence that primaquine exhibits similar neurotoxicity in humans. Discussion/conclusions Extrapolation of data from Rhesus monkeys to humans, and the available clinical data, suggest that tafenoquine also does not exhibit pamaquine, pentaquine or plasmocid-like clinical neurologic signs in humans.

Aims To predict the optimal chemoprophylactic dose of mefloquine in infants of 5-10 kg using physiologically based pharmacokinetic (PBPK) and clinical effectiveness models. Methods The PBPK model was developed in Simcyp version 14.1 and verified against clinical pharmacokinetic data in adults; the final model, accounting for developmental physiology and enzyme ontogeny was then applied in the paediatric population. The clinical effectiveness model utilized real-world chemoprophylaxis data with stratification of output by age and including infant data from the UK population. Results PBPK simulations in infant populations depend on the assumed fraction of mefloquine metabolized by CYP3A4 (0.47, 0.95) and on the associated CYP3A4 ontogeny (Salem, Upreti). However, all scenarios suggest that a dose of 62.5 mg weekly achieves or exceeds the exposure in adults following a 250 mg weekly dose and results in a minimum plasma concentration of 620 ng ml-1 , which is considered necessary to achieve 95% prophylactic efficacy. The clinical effectiveness model predicts a 96% protective efficacy from mefloquine chemoprophylaxis at 62.5 mg weekly. Conclusions The PBPK and clinical effectiveness models are mutually supportive and suggest a prophylactic dose of 62.5 mg weekly in the Caucasian 5-10 kg infant population travelling to endemic countries. This dual approach offers a novel route to dose selection in a vulnerable population, where clinical trials would be difficult to conduct.

Simulation models are used widely in pharmacology, epidemiology and health economics (HEs). However, there have been no attempts to incorporate models from these disciplines into a single integrated model. Accordingly, we explored this linkage to evaluate the epidemiological and economic impact of oseltamivir dose optimisation in supporting pandemic influenza planning in the USA. An HE decision analytic model was linked to a pharmacokinetic/pharmacodynamics (PK/PD) – dynamic transmission model simulating the impact of pandemic influenza with low virulence and low transmissibility and, high virulence and high transmissibility. The cost-utility analysis was from the payer and societal perspectives, comparing oseltamivir 75 and 150 mg twice daily (BID) to no treatment over a 1-year time horizon. Model parameters were derived from published studies. Outcomes were measured as cost per quality-adjusted life year (QALY) gained. Sensitivity analyses were performed to examine the integrated model's robustness. Under both pandemic scenarios, compared to no treatment, the use of oseltamivir 75 or 150 mg BID led to a significant reduction of influenza episodes and influenza-related deaths, translating to substantial savings of QALYs. Overall drug costs were offset by the reduction of both direct and indirect costs, making these two interventions cost-saving from both perspectives. The results were sensitive to the proportion of inpatient presentation at the emergency visit and patients’ quality of life. Integrating PK/PD–EPI/HE models is achievable. Whilst further refinement of this novel linkage model to more closely mimic the reality is needed, the current study has generated useful insights to support influenza pandemic planning.

Aims The aim was to investigate the QT effect of a single dose combination regimen of piperaquine phosphate (PQP) and a novel aromatic trioxolane, OZ439, for malaria treatment. Methods Exposure–response (ER) analysis was performed on data from a placebo-controlled, single dose, study with OZ439 and PQP. Fifty-nine healthy subjects aged 18 to 55 years received OZ439 alone or placebo in a first period, followed by OZ439 plus PQP or matching placebos in period 2. OZ439 and PQP doses ranged from 100–800 mg and 160–1440 mg, respectively. Twelve-lead ECG tracings and PK samples were collected serially pre- and post-dosing. Results A significant relation between plasma concentrations and placebo-corrected change from baseline QTcF (ΔΔQTcF) was demonstrated for piperaquine, but not for OZ439, with a mean slope of 0.047 ms per ng ml−1 (90% CI 0.038, 0.057). Using an ER model that accounts for plasma concentrations of both piperaquine and OZ439, a largest mean QTcF effect of 14 ms (90% CI 10, 18 ms) and 18 ms (90% CI 14, 22 ms) was predicted at expected plasma concentrations of a single dose 800 mg OZ439 combined with PQP 960 mg (188 ng ml−1) and 1440 mg (281 ng ml−1), respectively, administered in the fasted state. Conclusions Piperaquine prolongs the QTc interval in a concentration-dependent way. A single dose regimen combining 800 mg OZ439 with 960 mg or 1440 mg PQP is expected to result in lower peak piperaquine plasma concentrations compared with available 3 day PQP-artemisinin combinations and can therefore be predicted to cause less QTc prolongation.

Tafenoquine is a new prophylactic antimalarial drug. The current analysis presents an integrated safety assessment of the Tafenoquine Anticipated Clinical Regimen (Tafenoquine ACR) from 5 clinical trials, including 1 conducted in deployed military personnel and 4 in non-deployed residents, which also incorporated placebo and mefloquine comparator groups.Adverse events (AEs) were coded according to the Medical Dictionary for Regulatory Activities (MedDRAThe incidence of at least one AE was 80.6%, 64.1%, 67.6% and 94.9% in the mefloquine, placebo, tafenoquine Resident Non-ADF and tafenoquine Deployed ADF groups, respectively. The latter group had a higher incidence of AEs related to military deployment. AEs that occurred at ≥ 1% incidence in both tafenoquine sub-groups and at a higher frequency than placebo included diarrhea, nausea, vomiting, gastroenteritis, nasopharyngeal tract infections, and back/neck pain.Weekly administration of tafenoquine for up to six months increased the incidence of gastrointestinal AEs, certain infections, and back/neck pain, but not the overall incidence of AEs versus placebo. CLINICAL TRIAL REGISTRATION NUMBERS/CLINICALTRIALS.NCT02491606; NCT02488980; NCT02488902.

Summary Background Chemoprophylaxis against falciparum malaria is recommended for travellers from non-endemic countries to malarious destinations, but debate continues on benefit, especially with regard to mefloquine. Quantification of benefit for travellers from the United Kingdom (UK) was modelled to assist clinical and public health decision making. Methods The model was constructed utilising: World Tourism Organization data showing total number of arrivals from the UK in countries with moderate or high malaria risk; data from a retrospective UK Clinical Practice Research Datalink (CPRD) drug utilisation study; additional information on chemoprophylaxis, case fatality and tolerability were derived from the travel medicine literature. Chemoprophylaxis with the following agents was considered: atovaquone-proguanil (AP), chloroquine with and without proguanil (C ± P), doxycycline (Dx), mefloquine (Mq). The model was validated for the most recent year with temporally matched datasets for UK travel destinations and imported malaria (2007) against UK Health Protection Agency data on imported malaria. Results The median (mean) duration of chemoprophylaxis for each agent in weeks (CPRD) was: AP 3.3 (3.5), C ± P 9 (12.1), Dx 8 (10.3), Mq 9 (12.3): the maximum duration of use of all regimens was 52 weeks. The model correctly predicted falciparum malaria deaths and gave a robust estimate of total cases – model: 5 deaths from 1118 cases; UK Health Protection Agency: 5 deaths from 1153 cases. The number needed to take chemoprophylaxis (NNP) to prevent a case of malaria considered against the ‘background’ reported incidence in non-users of chemoprophylaxis deemed in need of chemoprophylaxis was: C ± P 272, Dx 269, Mq 260, AP 252; the NNP to prevent a UK traveller malaria death was: C ± P 62613, Dx 61923, Mq 59973, AP 58059; increasing the ‘background’ rate by 50% yielded NNPs of: C ± P 176, Dx 175, Mq 171, AP 168. The impact of substituting atovaquone-proguanil for all mefloquine usage resulted in a 2.3% decrease in estimated infections. The number of travellers experiencing moderate adverse events (AE) or those requiring medical attention or drug withdrawal per case prevented is as follows: C ± P 170, Mq 146, Dx 114, AP 103. Conclusions The model correctly predicted the number of malaria deaths, providing a robust and reliable estimate of the number of imported malaria cases in the UK, and giving a measure of benefit derived from chemoprophylaxis use against the likely adverse events generated. Overall numbers needed to prevent a malaria infection are comparable among the four options and are sensitive to changes in the background infection rates. Only a limited impact on the number of infections can be expected if Mq is substituted by AP.

Introduction: The goal of this study was to evaluate whether any characteristics that are evident at presentation for urgent medical attention could be used to differentiate cases of H5N1 in the absence of viral testing. Methodology: Information about exposure to poultry, clinical signs and symptoms, treatments, and outcomes was abstracted from existing data in the global avian influenza registry (www.avianfluregistry.org) using standardized data collection tools for documented and possible cases of H5N1 infection who presented for medical attention between 2005-2011 during known H5N1 outbreaks in Azerbaijan, Indonesia, Pakistan and Turkey. Results: Demography, exposure to poultry, and presenting symptoms were compared, with only the common symptoms of fever and headache presenting significantly more frequently in confirmed H5N1 cases than in possible cases. Reported exposure to infected humans was also more common in confirmed cases. In contrast, unexplained respiratory illness, sore throat, excess sputum production, and rhinorrhea were more frequent in possible cases. Overall, oseltamivir treatment showed a survival benefit, with the greatest benefit shown in H5N1 cases who were treated within two days of symptom onset (51% reduction in case fatality). Conclusion: Since prompt treatment with antivirals conferred a strong survival benefit for H5N1 cases, presumptive antiviral treatment should be considered for all possible cases presenting during an outbreak of H5N1 as a potentially life-saving measure.

International audience; no abstract

A modular interdisciplinary platform was developed to investigate the economic impact of oseltamivir treatment by dosage regimen under simulated influenza pandemic scenarios.The pharmacology module consisted of a pharmacokinetic distribution of oseltamivir carboxylate daily area under the concentration-time curve at steady state (simulated for 75 mg and 150 mg twice daily regimens for 5 days) and a pharmacodynamic distribution of viral shedding duration obtained from phase II influenza inoculation data. The epidemiological module comprised a susceptible, exposed, infected, recovered (SEIR) model to which drug effect on the basic reproductive number (ROseltamivir 75 mg relative to no treatment reduced the median number of infected patients, increased change in quality-adjusted life years by deaths averted, and was cost-saving under all scenarios; 150 mg relative to 75 mg was not cost effective in low transmissibility scenarios but was cost saving in high transmissibility scenarios.This methodological study demonstrates proof of concept that the disciplines of pharmacology, disease epidemiology and health economics can be linked in a single quantitative framework.

A 2008 review by our group concluded that the risk of neuropsychiatric adverse events (NPAEs) in influenza patients was not increased by oseltamivir exposure, and did not identify any mechanism by which oseltamivir or its metabolites could cause or worsen such events. The current article reviews new information on this topic. Between September 16, 2007 and May 15, 2010, 1,805 spontaneously-reported NPAEs were identified in 1,330 patients receiving oseltamivir: 767 (42.5%) from Japan, 296 (16.4%) from the USA, and 742 (41.1%) from other countries. NPAEs were more common in children: 1,072 (59.4%) events were in those aged ≤16 years. NPAEs often occurred within 48 h of treatment initiation (953 events; 52.8%). Nearly half of the events were serious in nature (838; 46.4%). The three largest categories of events were abnormal behavior (457 events, 25.3%), miscellaneous psychiatric events (370; 20.5%), and delusions/perceptual disturbances (316 events, 17.5%). A total of 1,545 events (85.6%) in eight different categories were considered to be delirium or delirium-like. Twenty-eight suicide-related events were reported. A US healthcare claims database analysis showed that the risk of NPAEs in 7,798 oseltamivir-treated patients was no higher than that in 10,411 patients not on antivirals, but a study on oseltamivir and abnormal behavior in Japan was less conclusive. NPAE frequency in oseltamivir-exposed Japanese and Taiwanese children with influenza was the same as in unexposed children. New analysis of the UK General Practice Research Database showed that the relative adjusted risk of NPAEs in influenza patients was 2.18-times higher than in the general population. Other epidemiology studies report frequent occurrence of encephalitis and similar disorders in influenza patients independently of oseltamivir exposure. The new data support the findings of the original assessment. Evidence suggests that influenza-related encephalopathies are caused by influenza-induced inflammatory responses, but more work is needed to confirm the underlying mechanisms.

Please cite this paper as: Masuet-Aumatell et al. (2012) Prevention of influenza among travellers attending at a UK travel clinic: beliefs and perceptions. A cross-sectional study. Influenza and Other Respiratory Viruses 7(4), 574–583. Background Travellers’ compliance with measures to prevent influenza through the use of antivirals and influenza vaccine remains very poor despite influenza being one of the commonest travel and vaccine-preventable diseases. A study was undertaken to assess travellers’ beliefs, perceptions and intentions to take antivirals for the treatment and prevention of influenza during the H1N1 pandemic. Methods A cross-sectional survey (n = 96) of travellers who attended the Royal Free Travel Health Centre, London, UK was undertaken in September 2009. A self-administered questionnaire was completed by a traveller in advance of their pre-travel health consultation. Logistic regression identified variables independently associated with compliance. Results Influenza vaccination uptake for the 5 years preceding the study was found to be 20·8%. This was statistically significantly higher for older travellers and those with underlying health conditions (P

Background. Oseltamivir is widely used as treatment for influenza virus A subtype H5N1 (hereafter, “H5N1”) infection but, like any intervention, is not always effective. Methods. We used Avian Influenza Registry data from 10 countries to examine the risk of death in 215 patients with confirmed H5N1 infection who were treated with oseltamivir, according to viral clade, age, respiratory failure, and adjunctive treatment with corticosteroids or antibiotics. Results. The median age of infected individuals was 18 years, and 50% were male. The highest fatality rate occurred in a country with clade 2.1 virus circulation, and the lowest occurred in countries with clade 2.2 virus circulation (P< .001). In univariate analyses, age of ≤5 years and treatment ≤2 days after symptom onset were protective against fatality. When accounting for all risk factors, early initiation of oseltamivir was found to be particularly effective in individuals without respiratory failure (odds ratio, 0.17; P= .04). Patients who had advanced respiratory failure requiring ventilatory support at the time of oseltamivir initiation were more likely to die from the episode of H5N1 infection than patients who did not (P< .001). Adjunctive therapy did not improve the likelihood of surviving the episode. Conclusions. Oseltamivir is especially effective for treating H5N1 infection when given early and before onset of respiratory failure. The effect of viral clade on fatality and treatment response deserves further investigation.

Background. Avian influenza continues to pose a threat to humans and maintains the potential for greater transmissibility. Understanding the clinical presentation and prognosis in children will help guide effective diagnosis and treatment. Methods. A global patient registry was created to enable systematic collection of clinical, exposure, treatment, and outcomes data on confirmed cases of H5N1. Bivariate and multivariate statistical tools were used to describe clinical presentation and evaluate factors prognostic of survival. Results. Data were available from 13 countries on 193 children

Influenza may cause neuropsychiatric disorders, including confusion, delirium, convulsions, and encephalopathy. We conducted a case-control study to evaluate the association between diagnosed influenza and the risk of developing Alzheimer's disease (AD) using the UK-based Clinical Practice Research Datalink (CPRD). We identified 19,463 patients who developed an incident AD diagnosis between 1998 and 2013 and matched them 1:1 to dementia-free controls on age, sex, general practice, calendar time and number of years of recorded history. We calculated adjusted odds ratios (aORs) with 95% confidence intervals (CIs) of developing AD in association with previous influenza infections and stratified by number of infections prior to the AD diagnosis date. Patients with a previous influenza infection were not at an increased risk of developing AD as compared to those with no previous infection (aOR, 95% CI 0.94, 0.87-1.02) overall. Nor was increasing number of infections related to an increased risk of developing AD; the aOR (95% CI) for those with 1, 2, or ⩾3 episodes was 0.98 (0.90-1.07), 0.70 (0.56-0.88), and 0.92 (0.63-1.34), respectively. Presence of an underlying chronic inflammatory disease in those with an influenza infection did not increase the risk of developing AD (aOR, 95% CI 0.83, 0.71-0.96), either, and there was no association between the severity of influenza infections (based on recorded neurological or bacterial complications) and the risk of AD. In conclusion, considering the limitations of this large observational study, we found no association between influenza infections and the risk of developing AD.

Please cite this paper as: Blumentals WA. et al. (2012) Body mass index and the incidence of influenza-associated pneumonia in a UK primary care cohort. Influenza and Other Respiratory Viruses 6(1), 28–36. Background Accumulating data suggest an association between increased BMI/obesity and morbidity in patients with pandemic (H1N1) 2009 influenza. Information on metabolic status and prognosis in seasonal influenza is lacking, however. Methods A retrospective cohort study was carried out using the UK General Practice Research Database. Patients aged ≥18 with ≥1 recorded BMI in the 12–58 kg/m2 range between January 1, 2000, and December 31, 2007, were observed for an influenza-associated pneumonia diagnosis after the date of baseline BMI, including ‘influenza with pneumonia’ or a diagnosis of ‘pneumonia’ up to 30 days after a diagnosis of ‘influenza’. Results A total of 1 074 315 patients were included, of whom 73·2% were within the reference BMI range or overweight and 2·2% were underweight (

The clinical course of pandemic H1N1 2009 influenza can be severe, particularly in the very young and patients with comorbidities. Pandemic H1N1 2009 is sensitive to the antiviral agents oseltamivir and zanamivir but is resistant to the M2 inhibitors. Although few clinical data are yet available, treatment of pandemic H1N1 2009 influenza in hospital settings with oseltamivir or zanamivir appears to be beneficial. In hospitalized patients with severe influenza treated with oseltamivir, mortality and length of stay are significantly reduced, and viral load is reduced more quickly than in untreated patients. In patients at high risk treated with oseltamivir or zanamivir, reductions in the risk of complications and mortality after treatment have been demonstrated with oseltamivir and zanamivir, although there are fewer data on the latter. There is no evidence yet that other antiviral agents are effective in severe or pandemic H1N1 2009 influenza. Current World Health Organization guidance strongly recommends the use of oseltamivir for severe or progressive infection with pandemic H1N1 2009, with zanamivir as an alternative if the infecting virus is oseltamivir-resistant. Very little resistance to oseltamivir has been found to date.

Current guidelines for Japanese encephalitis (JE) vaccine relate to an older mouse brain derived vaccine with an uncertain history of adverse events including delayed anaphylaxis. JE is widely distributed, including in urban areas. Underreporting is likely in many endemic countries, and atypical clinical forms exist. A new JE vaccine produced in Vero cells has become available, which appears equi-efficacious to the mouse brain derived vaccine. In development trials the new JE vaccine was as well tolerated as placebo. A review of existing guidelines for JE vaccine use in travelers should be considered.

A literature review revealed that mefloquine neurotoxicity has been demonstrated at both the preclinical and clinical levels, with nausea, dizziness, sleep disturbances, anxiety and psychosis, amongst other adverse neuropsychiatric events, reported in users. Females and individuals of low body mass index (BMI) are at apparent greater risk. Mechanisms of possible neurotoxicity may include binding to neuroreceptors and cholinesterases, inhibition of sarcoendoplasmic reticulum ATPase (SERCA) and interference with cellular Ca(2+) homeostasis, accumulation in the CNS, and reductions in CNS efflux in individuals possessing certain MDR1 polymorphisms. It may be prudent to avoid mefloquine in females and low BMI individuals, and in combination with other potentially neurotoxic agents such as the artemisinin antimalarials.

The aim of this study was to assess the ability of currently deployed antimalarials to inhibit mammalian sarcoendoplasmic reticulum calcium adenosine triphosphatase (SERCA). Artemisinins exert their antiplasmodial action by inhibiting parasite PfATP6, a SERCA enzyme, and possess neurotoxic potential; mefloquine is neurotoxic and inhibits mammalian SERCA, an orthologue of PfATP6. SERCA in rabbit muscle was tested in vitro for inhibition by artemisinin and amino alcohol antimalarials. Significant inhibition of mammalian SERCA, as mean difference from uninhibited, control values was seen with both enantiomers of mefloquine: (+)-mefloquine (10 microM: -35.83, 95% CI -59.63 to -12.03; 50 microM: -54.06, 95% CI -77.86 to -30.26); (-)-mefloquine (10 microM: -24.35, 95% CI -41.56 to -7.15; 50 microM: -58.42, 95% CI -75.62 to -41.22); lumefantrine (1 microM: -25.46, 95% CI -45.82 to -5.10; 5 microM -34.83, 95% CI -60.08 to -9.58; 10 microM: -25.80, 95% CI -51.05 to -0.55); desbutyl-lumefantrine (5 microM: -50.16, 95% CI -84.24 to -16.08); dihydroartemisinin (1 microM: -39.25, 95% CI -63.74 to -14.76; 5 microM: -39.30, 95% CI -64.88 to -13.72). Dihydroartemisinin in higher concentrations (10 microM) stimulated SERCA activity: (+40.90, 95% CI 11.37 to 70.44). No statistically significant inhibition was seen with artemether at 1, 5 and 10 microM. Equimolar combinations of artemether and lumefantrine or of dihydroartemisinin and lumefantrine, when studied at concentrations that inhibit SERCA individually, failed to show any inhibition. Dihydroartemisinin, mefloquine, lumefantrine and desbutyl lumefantrine inhibit mammalian SERCA at periphysiological concentrations, although the neurotoxicity of mefloquine is not wholly attributable to this property. Candidate antimalarials should be screened pre-clinically for SERCA inhibition.

Therapeutic effects of racemic mefloquine were assessed in Schistosoma mansoni-infected mice, and evaluated by recording worm burden, the status of egg maturation and viability, and intestinal mast cell recruitment. Age-matched mice were divided into four groups, of which two were infected. At 8 weeks postinfection, one group of infected and one group of uninfected mice were treated with a single dose of mefloquine (150 mg/kg). Ten days after treatment, all animals were killed. Mefloquine at 150 mg/kg had no effect on worm burden, but significantly reduced the number of eggs in the first three developmental egg stages. Analysis of intestinal mast cell numbers showed that mefloquine induced mastocytosis both in infected and control animals. In conclusion, mefloquine significantly reduces egg production in S. mansoni-infected mice, suggesting a therapeutic potency in schistosomiasis therapy. Mefloquine also exerts a significant proinflammatory effect on the intestine. Through its effect on egg production, mefloquine may be a cause of silent schistosomiasis in travelers using mefloquine for malaria chemoprophylaxis. Further study of the anti-schistosomal activity of mefloquine is warranted, as its activity against other helminths.

This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original DOI. On 3 October 2007, 40 participants with diverse expertise attended the workshop Tamiflu and the Environment: Implications of Use under Pandemic Conditions to assess the potential human health impact and environmental hazards associated with use of Tamiflu during an influenza pandemic. Based on the identification and risk-ranking of knowledge gaps, the consensus was that oseltamivir ethylester-phosphate (OE-P) and oseltamivir carboxylate (OC) were unlikely to pose an ecotoxicologic hazard to freshwater organisms. OC in river water might hasten the generation of OC-resistance in wildfowl, but this possibility seems less likely than the potential disruption that could be posed by OC and other pharmaceuticals to the operation of sewage treatment plants. The work-group members agreed on the following research priorities: a) available data on the ecotoxicology of OE-P and OC should be published; b) risk should be assessed for OC-contaminated river water generating OC-resistant viruses in wildfowl; c) sewage treatment plant functioning due to microbial inhibition by neuraminidase inhibitors and other antimicrobials used during a pandemic should be investigated; and d) realistic worst-case exposure scenarios should be developed. Additional modeling would be useful to identify localized areas within river catchments that might be prone to high pharmaceutical concentrations in sewage treatment plant effluent. Ongoing seasonal use of Tamiflu in Japan offers opportunities for researchers to assess how much OC enters and persists in the aquatic environment. Environmental Knowledge Transfer Network, the Worshipful Company of Water Conservators, and the Chartered Institution of Water & Environmental Management.

Summary Context Influenza is a viral pathogen that imposes an under-recognized burden of central nervous system (CNS) disease. Objective To describe the epidemiology, clinical features and etiology of the CNS disease entities associated with influenza. Data sources English-language publications from MEDLINE. Data extraction Articles were identified using “influenza, human”[Mesh] AND “nervous system diseases”[Mesh] and screened for inclusion based on relevance and scientific rigor. Results Febrile seizure is the most frequently encountered influenza-associated CNS complication, with one in five children hospitalized with influenza experiencing one or more events. In most instances, symptoms resolve without neurological sequelae, although the risk for subsequent afebrile seizure may be increased. Influenza-associated encephalitis/encephalopathy is a less common but potentially more serious complication that is widely reported in Japanese populations, although cases from other East Asian countries, North America, and Europe have been described. Clinical manifestations are diverse, and typically involve febrile seizures and abnormal behaviors in mild cases, with rapid evolution through decreased consciousness to coma in severe forms. In cases of serious disease, the prognosis is often poor, with outcomes including death or severe neurological sequelae. Influenza is also a known trigger for a number of rarely encountered, yet often serious, CNS diseases, including the encephalopathic condition of Reye's syndrome, the peripheral neuropathy known as Guillain–Barre syndrome, and the lesser known complaints of Kleine–Levin syndrome and post-encephalitic Parkinson's disease. Conclusions Influenza imposes a sizeable burden of CNS disease. Increased awareness and monitoring of CNS function is indicated, especially in infants and young children.

Purified rabies vaccine cultured on Vero cells (Verorab, sanofi pasteur) is WHO-approved for pre- and post-exposure prophylaxis by intradermal and intramuscular routes. During 20 years of use, over 40 million doses of Verorab have been administered in more than 100 countries. No serious adverse event due to Verorab has been reported in clinical trials involving 3937 persons, and Verorab is better tolerated than human diploid cell vaccine (HDCV). Pre-exposure prophylaxis is confirmed immunogenic in 1437 subjects by all routes, with prompt responses following boosting; Verorab boosts effectively subjects pre-immunized with HDCV. Unlike HDCV, Verorab is not associated with post-boosting serum sickness. In the absence of data in immunodeficient/HIV-positive individuals, pre-exposure immunization is urged as early as possible. Essen, Zagreb, Thai Red Cross Intradermal (TRC-ID) and other post-exposure intramuscular and intradermal regimens are documented. Two thousand one hundred and eighty-three subjects received post-exposure prophylaxis, including 874 high risk, severe or confirmed rabid attacks. Co-administration of rabies immune globulin (RIG) does not affect neutralizing antibody levels when Essen or TRC-ID regimens are employed; levels are lower with the Zagreb regimen. Verorab has been administered safely and effectively post-exposure to 251 pregnant women, without any increase in congenital malformations or spontaneous abortions. From a pediatric perspective, safety and efficacy have been demonstrated in 759 children (0-15 years). Intradermal post-exposure Verorab is an effective and inexpensive option for developing countries. Inadvertent subcutaneous administration does not reduce immunogenicity. WHO already strongly recommends the replacement of nerve tissue vaccines with modern vaccines. Extensive clinical experience supports the use of Verorab for intramuscular and intradermal pre- and post-exposure prophylaxis, including in special situations.

A wide range of viral, bacterial, and protozoal diseases pose risk to long-term tropical travelers. Risk varies geographically and with lifestyle. For some infections, risk increases with duration of stay, coming to resemble that of the local population. Risk management strategies include vaccination, chemoprophylaxis, avoidance measures, and screening, where appropriate. Vaccination against hepatitis A and B, typhoid, and rabies is recommended for all long-term travelers to (sub-)tropical areas. Lowering of the vaccination threshold for Japanese encephalitis is suggested. Meningococcal disease is rare in travelers, but vaccination is safe and acceptable. The efficacy of Bacillus Calmette-Guérin (BCG) is uncertain; immunological testing avoids BCG's confounding of tuberculin testing. Diarrhea is common, and self-treatment may be recommended. Sexually transmitted infections including human immunodeficiency virus (HIV) are serious risks; education, screening, and HIV postexposure prophylaxis following involuntary exposure are recommended. Many infections are chronic or asymptomatic, and appropriate screening is recommended on return or after prolonged exposure.

Importance Case-reports provided evidence that influenza infections, particularly severe episodes, may exert neuronal damage in the CNS and thereby increase the risk of depression. Objective It was the aim of this study to analyse the association between influenza infections and the risk of developing incident depression. Design We conducted a case-control analysis between 2000 and 2013 using the large UK-based primary care database Clinical Practice Research Datalink (CPRD). Setting This database contains anonymous longitudinal data from primary care. At present, it contains over 100 million person-years of data from some 10 million active patients. Participants We encompassed 103 307 patients below the age of 80 years with an incident major depression diagnosis between 2000 and 2013, and matched each case to one control patient on age, sex, general practice, number of medical encounters, and years of history in the CPRD prior to the index date. Exposure Major depression diagnosis was identified by READ-codes based on ICD-10 codes (F32), with a minimum of three prescriptions for antidepressant drugs recorded after the diagnosis. Main outcome We calculated relative risk estimates of developing depression in association with previous influenza infections, stratified by the number, timing and severity of such events, and we adjusted for a variety of comorbidities, smoking status, alcohol intake, body mass index, use of oral corticosteroids, and benzodiazepines. Results Patients with a previous influenza infection had an increased risk of developing depression (OR 1.30, 95%CI 1.25–1.34) compared to patients with no history of influenza infections. A recent influenza infection recorded within 30–180 days prior to the index date yielded an adjusted 1.57 (95%CI 1.36–1.81), and an increasing number of previous influenza infections was associated with increasing odds ratios (⩾3 recorded influenza infections, adjusted OR 1.48, 95%CI 1.22–1.81). Conclusion This study suggests that influenza infections are associated with a moderately increased risk of developing depression.

SUMMARYSeveral epidemiological studies suggest a possible involvement of viral infection in the development of epilepsy. While recent research from in vitro studies increasingly supports the role of herpes simplex virus type 1 (HSV-1) in the pathogenesis of epilepsy, little is known about the role of other viral infections such as influenza. Using data from the Clinical Practice Research Datalink (CPRD), we conducted a matched case-control analysis to assess the association between GP-diagnosed influenza infections and the risk of developing an incident diagnosis of epilepsy. During the study period 11 244 incident epilepsy cases and 44 976 matched control patients were identified. Prior exposure to influenza was reported in 7·5% of epilepsy cases and 6·7% of controls [adjusted odds ratio (aOR) 1·12, 95% confidence interval (CI) 1·03–1·22]. Prior history of ‘complicated influenza’, i.e. influenza associated with a possible super-infection, was associated with a slightly increased epilepsy risk (aOR 1·64, 95% CI 1·10–2·46), particularly if recorded within the 2 months preceding the epilepsy diagnosis (aOR 6·03, 95% CI 1·10–33·2). Our findings suggest that prior influenza exposure does not appear to materially alter the risk of developing epilepsy. By contrast, influenza episodes accompanied by complications were associated with a slightly increased epilepsy risk.

Background Although Johannesburg International Airport (JIA) acts as a hub for travel into Africa, little was known of the knowledge, attitudes, and practices (KAP) with respect to infectious disease prevention of departing travelers. Methods The study was conducted among departing passengers at JIA from August to October 2003. Travelers aged at least 18 years, resident in non-malarious developed countries and departing from JIA for risk destinations, were given either a malaria (Q-mal, n = 219) or vaccine-preventable disease (Q-vac, n = 200) questionnaire. European Travel Health Advisory Board traveler KAP questionnaires were used. Results African destinations accounted for 99% of the total. Traveler mean age was 42 years, with 30% aged 50 years or above. Leisure (42%) and business (37%) were the commonest travel reasons; 8% of subjects were visiting friends or relatives. Forty-six per cent of travelers prepared for their trip at least 1 month in advance; 86% had sought pre-travel health advice, with travel clinics and the Iinternet being rated highest by travelers for quality of advice. World Health Organization immunization guidelines were followed poorly: only 37% and 27%, respectively, of travelers had demonstrable proof of protection against hepatitis A and B, with 40% of all Q-vac travelers unable to produce a vaccination certificate. Of travelers to yellow fever- endemic countries, 76% were able to produce a valid vaccination certificate; 22% of travelers to countries not endemic for yellow fever had nevertheless been specifically immunized against yellow fever for their journeys. Forty-nine per cent of Q-mal travelers carried either no or inappropriate antimalarials. Conclusions Considerable deficiencies in KAP were documented with regard to travel vaccinations and malaria protection in travelers departing JIA. Improved vaccine uptake and antimalarial prescribing are required for travelers to Africa.

Epidemiological studies have shown a clear association between maternal infection and schizophrenia or autism in the progeny. Animal models have revealed maternal immune activation (mIA) to be a profound risk factor for neurochemical and behavioural abnormalities in the offspring. Microglial priming has been proposed as a major consequence of mIA, and represents a critical link in a causal chain that leads to the wide spectrum of neuronal dysfunctions and behavioural phenotypes observed in the juvenile, adult or aged offspring. Such diversity of phenotypic outcomes in the mIA model are mirrored by recent clinical evidence suggesting that infectious exposure during pregnancy is also associated with epilepsy and, to a lesser extent, cerebral palsy in children. Preclinical research also suggests that mIA might precipitate the development of Alzheimer and Parkinson diseases. Here, we summarize and critically review the emerging evidence that mIA is a shared environmental risk factor across CNS disorders that varies as a function of interactions between genetic and additional environmental factors. We also review ongoing clinical trials targeting immune pathways affected by mIA that may play a part in disease manifestation. In addition, future directions and outstanding questions are discussed, including potential symptomatic, disease-modifying and preventive treatment strategies.

Concerns about the tolerability of mefloquine highlight the need for new drugs to prevent malaria. Atovaquone-proguanil (Malarone; GlaxoSmithKline) was safe and effective for prevention of falciparum malaria in lifelong residents of malaria-endemic countries, but experience in nonimmune people is limited. In a randomized, double-blind study, nonimmune travelers received malaria prophylaxis with atovaquone-proguanil (493 subjects) or mefloquine (483 subjects). Information about adverse events (AEs) and potential episodes of malaria was obtained 7, 28, and 60 days after travel. AEs were reported by an equivalent proportion of subjects who had received atovaquone-proguanil or mefloquine (71.4% versus 67.3%; difference, 4.1%; 95% confidence interval, -1.71 to 9.9). Subjects who received atovaquone-proguanil had fewer treatment-related neuropsychiatric AEs (14% versus 29%; P=.001), fewer AEs of moderate or severe intensity (10% versus 19%; P=.001), and fewer AEs that caused prophylaxis to be discontinued (1.2% versus 5.0%; P=.001), compared with subjects who received melfoquine. No confirmed diagnoses of malaria occurred in either group. Atovaquone-proguanil was better tolerated than was mefloquine, and it was similarly effective for malaria prophylaxis in nonimmune travelers.

Summary Background Mefloquine belongs to the priority chemoprophylaxis drugs for travelers to malaria endemic regions. We aimed to assess the prescribing patterns for mefloquine and other antimalarials. Methods We conducted a descriptive drug utilization study using the U.K. Clinical Practice Research Datalink (CPRD). We assessed characteristics of individuals with a first-time antimalarial prescription for mefloquine, atovaquone/proguanil, chloroquine and/or proguanil, or doxycycline between 2001 and 2012. Results Of 165,218 individuals with a first-time antimalarial prescription, 108,344 (65.6%), 25,294 (15.3%), 23,195 (14.0%), and 8385 (5.1%) were prescribed atovaquone/proguanil, mefloquine, doxycycline, and chloroquine and/or proguanil, respectively. Among mefloquine users, 7.5% had a history of a neuropsychiatric disorder (versus 12.6%–13.7% among other antimalarial users) and 0.04% had a history of severe liver disease (versus 0.04%–0.1% among other antimalarial users). A total of 19.4% mefloquine users were children younger than 12 years (versus 0.4%–15.8% among other antimalarials), and 1.3% pregnant or postpartum women (versus 0.4%–1.4% among users of other antimalarials). Conclusions The most frequently prescribed antimalarial chemoprophylaxis was atovaquone/proguanil. Mefloquine was occasionally prescribed for patients with comorbidities listed as contraindications, but most practitioners observed contraindications. Mefloquine was often prescribed for children and pregnant women.

AIMS The effectiveness of oseltamivir to improve seasonal influenza symptoms in clinical practice was analyzed using pooled data from patients who were also taking analgesics and other over-the-counter (OTC) medications. METHODS Data were pooled from 1,709 patients aged 13 - 64 years with confirmed seasonal influenza who enrolled in six randomized, placebo-controlled trials of oseltamivir (75 mg b.i.d. for 5 days) and took OTC analgesics (+/- other medications). Rates of improvement of seven symptoms, two functional measures (sleep quality and ability to undertake usual activities) and fever (body temperature) were calculated between Days 1 and 6 of illness. Time to reach defined tolerability thresholds was compared using Kaplan-Meier analysis. Two subgroup analyses were performed in patients taking cough and cold remedies (n = 635) and antibiotics (n = 175) in addition to analgesics. RESULTS Six symptoms and both functional measures improved faster with oseltamivir than placebo, including nasal congestion (difference in rate, 19.3%), cough (34.1%), sleep quality (13.7%) and ability to perform usual activities (12.0%). Results in the Analgesics + cough/cold subgroup analysis were similar. In the Analgesics + antibiotics subgroup, three symptoms and both functional measures improved faster with oseltamivir. In all three analyses, median time to reach tolerability thresholds for all measures was faster in oseltamivir patients than placebo patients. CONCLUSIONS Oseltamivir treatment of patients with seasonal influenza already receiving OTC medications produced a faster reduction in severity of most symptoms and a quicker return to ability to perform normal activities compared with patients who took OTC medications and placebo.

Given the limited understanding about pharmacokinetic-pharmacodynamic (PK-PD) determinants of oseltamivir efficacy, data from two phase 2 influenza virus inoculation studies were evaluated. Healthy volunteers in studies 1 and 2 were experimentally infected with influenza A/Texas (the concentration of neuraminidase inhibitor which reduced neuraminidase activity by 50% [IC 50 ] = 0.18 nM) or B/Yamagata (IC 50 = 16.76 nM), respectively. In study 1, 80 subjects received 20, 100, or 200 mg of oral oseltamivir twice daily (BID), 200 mg oseltamivir once daily, or placebo for 5 days. In study 2, 60 subjects received 75 or 150 mg of oral oseltamivir BID or placebo for 5 days. Oseltamivir carboxylate (OC) (active metabolite) PK was evaluated using individual PK data and a population PK model to derive individual values for area under the concentration-time curve from 0 to 24 h (AUC 0–24 ), minimum concentration of OC in plasma ( C min ), and maximum concentration of OC in plasma ( C max ). Exposure-response relationships were evaluated for continuous (area under composite symptom score curve [AUCSC], area under the viral titer curve, and peak viral titer) and time-to-event (alleviation of composite symptom scores and cessation of viral shedding) efficacy endpoints. Univariable analyses suggested the existence of intuitive and highly statistically significant relationships between OC AUC 0–24 evaluated as a 3-group variable and AUCSC, time to alleviation of composite symptom scores, and time to cessation of viral shedding. The upper OC AUC 0–24 threshold (∼14,000 ng · h/ml) was similar among these endpoints. Multivariable analyses failed to demonstrate the influence of study/strain on efficacy endpoints. These results provide the first demonstration of exposure-response relationships for efficacy for oseltamivir against influenza and suggest that OC exposures beyond those achieved with the approved oseltamivir dosing regimen will provide enhanced efficacy. The clinical applicability of these observations requires further investigation.