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Despite widespread use, questions remain about the efficacy of oseltamivir in the treatment of influenza. We aimed to do an individual patient data meta-analysis for all clinical trials comparing oseltamivir with placebo for treatment of seasonal influenza in adults regarding symptom alleviation, complications, and safety. We included all published and unpublished Roche-sponsored randomised placebo-controlled, double-blind trials of 75 mg twice a day oseltamivir in adults. Trials of oseltamivir for treatment of naturally occurring influenza-like illness in adults reporting at least one of the study outcomes were eligible. We also searched Medline, PubMed, Embase, the Cochrane Central Register of Controlled Trials, and the ClinicalTrials.gov trials register for other relevant trials published before Jan 1, 2014 (search last updated on Nov 27, 2014). We analysed intention-to-treat infected, intention-to-treat, and safety populations. The primary outcome was time to alleviation of all symptoms analysed with accelerated failure time methods. We used risk ratios and Mantel-Haenszel methods to work out complications, admittances to hospital, and safety outcomes. We included data from nine trials including 4328 patients. In the intention-to-treat infected population, we noted a 21% shorter time to alleviation of all symptoms for oseltamivir versus placebo recipients (time ratio 0·79, 95% CI 0·74–0·85; p<0·0001). The median times to alleviation were 97·5 h for oseltamivir and 122·7 h for placebo groups (difference −25·2 h, 95% CI −36·2 to −16·0). For the intention-to-treat population, the estimated treatment effect was attenuated (time ratio 0·85) but remained highly significant (median difference −17·8 h). In the intention-to-treat infected population, we noted fewer lower respiratory tract complications requiring antibiotics more than 48 h after randomisation (risk ratio [RR] 0·56, 95% CI 0·42–0·75; p=0·0001; 4·9% oseltamivir vs 8·7% placebo, risk difference −3·8%, 95% CI −5·0 to −2·2) and also fewer admittances to hospital for any cause (RR 0·37, 95% CI 0·17–0·81; p=0·013; 0·6% oseltamivir, 1·7% placebo, risk difference −1·1%, 95% CI −1·4 to −0·3). Regarding safety, oseltamivir increased the risk of nausea (RR 1·60, 95% CI 1·29–1·99; p<0·0001; 9·9% oseltamivir vs 6·2% placebo, risk difference 3·7%, 95% CI 1·8–6·1) and vomiting (RR 2·43, 95% CI 1·83–3·23; p<0·0001; 8·0% oseltamivir vs 3·3% placebo, risk difference 4·7%, 95% CI 2·7–7·3). We recorded no effect on neurological or psychiatric disorders or serious adverse events. Our findings show that oseltamivir in adults with influenza accelerates time to clinical symptom alleviation, reduces risk of lower respiratory tract complications, and admittance to hospital, but increases the occurrence of nausea and vomiting. Multiparty Group for Advice on Science (MUGAS) foundation.

Oseltamivir has been used to treat children with influenza for nearly two decades, with treatment currently approved for infants 2 weeks of age or older, but efficacy and safety remain controversial. Newer randomized placebo controlled trials (RCT), not included in previous meta-analyses, can add to the evidence base. We conducted a systematic review to identify RCTs of oseltamivir therapy in children. We obtained individual patient data and examined protocol-defined outcomes. We then conducted a two-stage, random effects meta-analysis to determine the efficacy of treatment in reducing the duration of illness, estimated using differences in restricted mean survival time (RSMT) by treatment group. We also examined complications and safety. We identified 5 trials including 2561 patients in the intent to treat (ITT) and 1598 in the intent to treat infected (ITTI) population. Overall, oseltamivir treatment significantly reduced the duration of illness in the ITTI population (RMST difference -17.6 hours 95% CI: -34.7 to -0.62 hours). In trials that enrolled patients without asthma, the difference was larger (-29.9 hours 95% CI -53.9 to -5.8 hours). Risk of otitis media was 34% lower in the ITTI population. Vomiting was the only adverse event with a significantly higher risk in the treatment group. Despite substantial heterogeneity in pediatric trials, we found that treatment with oseltamivir significantly reduced the duration of illness in those with influenza and lowered the risk of developing otitis media. Alternative endpoints may be required to evaluate the efficacy of oseltamivir in pediatric patients with asthma.

Respiratory syncytial virus is a common cause of illness and hospitalization, especially among infants and immunocompromised persons, but there are no accepted antiviral therapies. In this RSV challenge study, GS-5806, a new compound, showed activity against RSV. Respiratory syncytial virus (RSV) infection accounts for substantial morbidity and mortality among infants 1 – 7 and is the most common reason for hospitalization of infants in the United States, 8 with an even greater outpatient burden of disease. Estimates indicate that among children younger than 2 years of age, the annual rate of RSV-related hospitalization is 5.2 per 1000, the rate of emergency department encounters is 32 to 57 per 1000, and the rate of outpatient visits is 66 to 177 per 1000. 2 Among infants younger than 1 year of age, the risk of death from respiratory causes is increased by a . . .

Guidelines for the diagnosis and treatment of patients with encephalitis were prepared by an Expert Panel of the Infectious Diseases Society of America. The guidelines are intended for use by health care providers who care for patients with encephalitis. The guideline includes data on the epidemiology, clinical features, diagnosis, and treatment of many viral, bacterial, fungal, protozoal, and helminthic etiologies of encephalitis and provides information on when specific etiologic agents should be considered in individual patients with encephalitis.

BackgroundIntravenous ganciclovir administered for 6 weeks improves hearing outcomes in infants with symptomatic congenital cytomegalovirus (CMV) disease involving the central nervous system MethodsTwenty-four subjects received antiviral therapy for 6 weeks. Serial pharmacokinetic assessments were performed after administration of valganciclovir oral solution and of intravenous ganciclovir ResultsOn the basis of a previous pharmacokinetic study of the use of intravenous ganciclovir in this population, a target AUC12(area under the concentration-time curve over a 12-h period) of 27 mg × h/L was defined. The median dose of oral valganciclovir administered in the present trial was 16 mg/kg, which produced a geometric mean AUC12 of 27.4 mg × h/L. The bioavailability of valganciclovir was 41.1%. Of the 18 subjects who had detectable CMV in whole blood at baseline or during therapy, 11 had <4 log viral DNA copies/mL at baseline, and 7 had ⩾4 log viral DNA copies/mL at baseline; subjects who started the study with the higher viral burden experienced greater decreases in viral load but did not clear virus during the 42-day course of therapy. Neutropenia of grade 3 or 4 developed in 38% of subjects ConclusionsIn neonates with symptomatic congenital CMV disease, valganciclovir oral solution provides plasma concentrations of ganciclovir comparable to those achieved with administration of intravenous ganciclovir. The results of the present study cannot be extrapolated to extemporaneously compounded liquid formulations of valganciclovir

Malignant tumors of the central nervous system (CNS) continue to be a leading cause of cancer-related mortality in both children and adults. Traditional therapies for malignant brain tumors consist of surgical resection and adjuvant chemoradiation; such approaches are often associated with extreme morbidity. Accordingly, novel, targeted therapeutics for neoplasms of the CNS, such as immunotherapy with oncolytic engineered herpes simplex virus (HSV) therapy, are urgently warranted. Herein, we discuss treatment challenges related to HSV virotherapy delivery, entry, replication, and spread, and in so doing focus on host anti-viral immune responses and the immune microenvironment. Strategies to overcome such challenges including viral re-engineering, modulation of the immunoregulatory microenvironment and combinatorial therapies with virotherapy, such as checkpoint inhibitors, radiation, and vaccination, are also examined in detail.

Abstract Background Viral loads (VLs) frequently are followed during treatment of symptomatic congenital cytomegalovirus disease, but their predictive value is unclear. Methods Post hoc analysis of 2 antiviral studies was performed. Seventy-three subjects were treated for 6 weeks and 47 subjects were treated for 6 months. Whole blood VL was determined by real-time polymerase chain reaction before and during therapy. Results Higher baseline VL was associated with central nervous system involvement (3.82 log, range 1–5.65 vs 3.32 log, range 1–5.36; P = .001), thrombocytopenia (3.68 log, range 1–5.65 vs 3.43 log, range 1–5.36; P = .03), and transaminitis at presentation (3.73 log, range 1–5.60 vs 3.39 log, range 1–5.65; P = .009), but with overlap in the amount of virus detected between groups. In subjects treated for 6 months, lower VL at presentation correlated with better hearing outcomes at 12 months, but VL breakpoints predictive of hearing loss were not identified. Sustained viral suppression during 6 months of therapy correlated with better hearing outcomes at 6, 12, and 24 months (P = .01, P = .0007, P = .04), but a majority without viral suppression still had improved hearing. Conclusions In infants with symptomatic congenital cytomegalovirus disease, higher whole blood VL before initiation of antiviral therapy has no clinically meaningful predictive value for long-term outcomes. In symptomatic congenital CMV infection, higher blood viral load before therapy correlates with thrombocytopenia, transaminitis, and CNS involvement but has little predictive value for long-term outcome. Early and sustained viral suppression during therapy may correlate with a better hearing outcome.

We have previously demonstrated safety of G207, a doubly mutated (deletion of both γ134.5 loci, insertional inactivation of UL39) herpes simplex virus (HSV) for patients stereotactically inoculated in enhancing portions of recurrent malignant gliomas. We have now determined safety of two inoculations of G207, before and after tumor resection. Inclusion criteria were histologically proven recurrent malignant glioma, Karnofsky score ≥70, and ability to resect the tumor without ventricular system breach. Patients received two doses of G207 totaling 1.15 × 109 plaque-forming units with 13% of this total injected via a catheter placed stereotactically in the tumor. Two or five days later, tumor was resected en bloc with catheter in place. The balance of G207 dose was injected into brain surrounding the resection cavity. Six patients with recurrent glioblastoma multiforme were enrolled. Two days after the second G207 inoculation, one patient experienced transient fever, delirium, and hemiparesis, which entirely resolved on high-dose dexamethasone. No patient developed HSV encephalitis or required treatment with acyclovir. Radiographic and neuropathologic evidence suggestive of antitumor activity is reported. Evidence of viral replication was demonstrated. G207 appears safe for multiple dose delivery, including direct inoculation into the brain surrounding tumor resection cavity.

penta [cl11.4]>The pediatric population experiences preventable hospitalizations and serves as a reservoir for influenza and its transmission to other children as well as adults. As a consequence, the Advisory Committee on Immunization Practices has recommended initiating influenza immunization of children as young as 6 months of age through 23 months of age and, recently, up to 5 years of age. However, immunization of older children has not yet become a priority of the US Public Health Service. As a consequence, the importance of antiviral agents, particularly neuraminidase (NA) inhibitors, cannot be overemphasized. From an epidemiological perspective, influenza resulted in higher childhood mortality than did Bordetella pertussis infection in 2003–2004. During that season, 153 children died of influenza, and two‐thirds were <5 years of age. Importantly, nearly 50% of these children were previously healthy, with no underlying illness. Currently, 2 NA inhibitors are approved for the treatment of influenza in children. Zanamivir is approved for children >7 years of age, and oseltamivir is approved for children >1 year of age. Arguably, the younger children are at particular risk for influenza complications and hospitalization. In placebo‐controlled studies in children >1 year of age, oseltamivir therapy accelerated resolution of clinical illness and defervescence and decreased both the incidence of otitis media and the concomitant use of antibiotics. However, oseltamivir is not currently approved for children <1 year of age. Three clinical toxicology studies identified neurotoxicity in newborn rats administered this medication. In these preclinical toxicology studies, the dose of oseltamivir exceeded that which would be used in humans. In addition, the metabolism of oseltamivir is different in rats than in humans. A key component of influenza therapy is the possibility for development of resistance. Although in studies performed in North America, resistance was not a frequent event, it has been documented in Japanese children treated with this medication; the adequacy of the dose used has been questioned. Children represent only one unique study population among others. Individuals who are at increased risk for influenza infection include the elderly, the immunocompromised, and pregnant women. Collectively, antiviral medications must be evaluated in populations in which they have not yet been assessed. The development of additional antiviral drugs is an important recommendation for the future, so that antiviral resistance can be circumvented. Similarly, availability of drugs for children <1 year of age is mandatory.