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1.  Prescription of antiviral drugs during the 2009 influenza pandemic: an observational study using electronic medical files of general practitioners in the Netherlands 
Background
After the clinical impact of the A(H1N1) pdm09 virus was considered to be mild, treatment with antiviral drugs was recommended only to patients who were at risk for severe disease or who had a complicated course of influenza. We investigated to what extent antiviral prescriptions in primary care practices were in accordance with the recommendations, what proportion of patients diagnosed with influenza had been prescribed antiviral drugs, and to what extent prescriptions related to the stated indications for antiviral treatment.
Methods
We used data from routine electronic medical records of practices participating in the Netherlands Information Network of General Practice LINH in the period August - December 2009. We considered patient and practice characteristics, clinical diagnoses and drug prescriptions of all patients who contacted their general practitioner in the given period and who had been prescribed antiviral medication (n = 351) or were diagnosed with influenza (n = 3293).
Results
Of all antiviral prescriptions, 69% were in accordance with the recommendations. Only 5% of patients diagnosed with influenza were prescribed antiviral drugs. This percentage increased to 12% among influenza patients belonging to the designated high risk groups. On the other hand, 2.5% of influenza patients not at high risk of complications received antiviral treatment. In addition to the established high risk factors, the total number of drug prescriptions for a patient in this year was a determinant of antiviral prescriptions. Information on time since onset of symptoms and the clinical presentation of patients was not available.
Conclusions
General practitioners in the Netherlands have been restrictive in prescribing antiviral drugs during the influenza pandemic, even when patients met the criteria for antiviral treatment.
doi:10.1186/2050-6511-14-55
PMCID: PMC3854647  PMID: 24143932
Drug prescriptions; General practice; Influenza; Human; Antivirals; Pandemics; Practice guidelines as topic
2.  Triple-Combination Antiviral Drug for Pandemic H1N1 Influenza Virus Infection in Critically Ill Patients on Mechanical Ventilation ▿ § 
Antimicrobial Agents and Chemotherapy  2011;55(12):5703-5709.
A recent in vitro study showed that the three compounds of antiviral drugs with different mechanisms of action (amantadine, ribavirin, and oseltamivir) could result in synergistic antiviral activity against influenza virus. However, no clinical studies have evaluated the efficacy and safety of combination antiviral therapy in patients with severe influenza illness. A total of 245 adult patients who were critically ill with confirmed pandemic influenza A/H1N1 2009 (pH1N1) virus infection and were admitted to one of the intensive care units of 28 hospitals in Korea were reviewed. Patients who required ventilator support and received either triple-combination antiviral drug (TCAD) therapy or oseltamivir monotherapy were analyzed. A total of 127 patients were included in our analysis. Among them, 24 patients received TCAD therapy, and 103 patients received oseltamivir monotherapy. The 14-day mortality was 17% in the TCAD group and 35% in the oseltamivir group (P = 0.08), and the 90-day mortality was 46% in the TCAD group and 59% in the oseltamivir group (P = 0.23). None of the toxicities attributable to antiviral drugs occurred in either group of our study, including hemolytic anemia and hepatic toxicities related to the use of ribavirin. Logistic regression analysis indicated that the odds ratio for the association of TCAD with 90-day mortality was 0.58 (95% confidence interval, 0.24 to 1.42; P = 0.24). Although this study was retrospective and did not provide virologic outcomes, our results suggest that the treatment outcome of the triple combination of amantadine, ribavirin, and oseltamivir was comparable to that of oseltamivir monotherapy.
doi:10.1128/AAC.05529-11
PMCID: PMC3232815  PMID: 21968371
3.  Using decision support for population tracking of adherence to recommended asthma guidelines 
BMJ Open  2014;4(3):e003759.
Objective
Decision support systems linked to administrative databases provide a unique opportunity to monitor adherence to guidelines and target disease management strategies towards patients not receiving guideline-based therapy. The objective of this study was to evaluate the discrepancy between actual asthma treatments prescribed by primary care physicians compared to those recommended by evidence-based guidelines using a decision support tool linked to a provincial health administrative database.
Design
The drug and medical services information of individuals with asthma was identified from the provincial health database and was pushed through an asthma decision support system (ADSS). Recommendations aimed at optimising asthma treatment were generated on two index dates, 15 September 2007 (index date 1) and 15 March 2008 (index date 2).
Setting
Primary care settings in a large Canadian metropolitan area.
Participants
Individuals with asthma and provincial health insurance primary and secondary outcome measures: well controlled asthma.
Results
16 803 eligible individuals were identified on index date 1, and 18 103 on index date 2. The distribution of recommendation categories was similar on both index dates. 94% were classified as well controlled and 7% as not well controlled. Among well-controlled individuals, the largest proportion was in the maintain treatment category (63.8%), followed by the maintain/decrease treatment category (28.2%) and the decrease treatment category (2.7%). Almost all individuals who were not well controlled had the recommendation to increase treatment (88%) with a small proportion in the refer category (1%).
Conclusions
The ADSS was able to identify subgroups of patients from an administrative database that could benefit from a medication review and possible change. Decision support systems linked to an administrative database can be used to identify individuals with uncontrolled asthma or prescriptions that deviate from recommended treatment. When connected to the point of care, this can provide an opportunity for physicians to intervene early.
doi:10.1136/bmjopen-2013-003759
PMCID: PMC3948455  PMID: 24595132
Epidemiology
4.  The Clinical Usefulness of the SD Bioline Influenza Antigen Test® for Detecting the 2009 Influenza A (H1N1) Virus 
Yonsei Medical Journal  2011;52(4):683-685.
Though the 2009 worldwide influenza A (H1N1) pandemic has been declared to have ended, the influenza virus is expected to continue to circulate from some years as a seasonal influenza. A rapid antigen test (RAT) can aid in rapid diagnosis and allow for early antiviral treatment. We evaluated the clinical usefulness of RAT using SD Bioline Influenza Antigen Test® kit to detect the influenza virus, considering various factors. From August 1, 2009 to October 10, 2009, a total of 938 patients who visited the outpatient clinic at Korea University Guro Hospital with influenza-like illnesses were enrolled in the study. Throat or nasopharyngeal swab specimens were obtained from each of the patients. Using these specimens, we evaluated the influenza detection rate by rapid antigen test based on the real-time reverse-transcriptase polymerase chain reaction (rRT-PCR) method. In comparison with rRT-PCR, the sensitivity and specificity of the RAT were 44.0% and 99.9%, respectively. The cyclic threshold values of RAT negative specimens were higher than RAT positive specimens (30.1±3.1 vs. 28.3±3.9, p=0.031). The sensitivity of the RAT kit was higher in patients who visited clinics within two days of symptom onset (60.4% vs. 11.1%, p=0.026). The results of this study show that the RAT cannot be recommended for general use in all patients with influenza-like illness because of its low sensitivity. The RAT may be used, only in the settings with limited diagnostic resources, for patients who visit a clinic within two days of symptom onset.
doi:10.3349/ymj.2011.52.4.683
PMCID: PMC3104440  PMID: 21623614
Influenza; diagnosis; sensitivity; specificity
5.  The Emergence of Oseltamivir-Resistant Seasonal Influenza A (H1N1) Virus in Korea During the 2008-2009 Season 
Objectives
To monitor antiviral drug resistance among seasonal influenza viruses isolated in Korea during the 2008-2009 influenza season, we examined influenza isolates collected through Korea Influenza Surveillance Scheme for antiviral drug susceptibility.
Methods
For genetic analysis of antiviral drug resistance, the matrix (M2) and neuraminidase (NA) genes of each isolate were amplified by reverse transcription-polymerase chain reaction and followed by nucleotide sequencing. For phylogenetic analyses, the sequences of hemagglutinin (HA) and NA genes of each isolate were aligned using multiple alignment program. For phenotypic analysis of antiviral drug resistance, drug susceptibilities against M2 inhibitor (amantadine) and NA inhibitors (oseltavimir and zanamivir) were determined by virus yield reduction assay and fluorometric NA inhibition assay, respectively.
Results
In Korea, the resistant influenza viruses against oseltamivir were first detected in sealsonal influenza A(H1N1) viruses on Week 48 of 2008. Since then, the number of oseltamivir-resistant A(H1N1) viruses was continuously increased and had reached the highest peak on Week 52 of 2008. 533 (99.8%) of 534 A(H1N1) viruses were resistant to oseltamivir and all of them harbored the H275Y mutation in the NA gene during the 2008-2009 season. The oseltamivir resistance identified by sequencing was confirmed by NA inhibition assay. Genetic analysis based on HA gene of the resistant A(H1N1) viruses revealed that the viruses were identified as A/Brisbane/10/2007-like strain which was vaccine strain for the 2008-2009 season.
Conclusions
The oseltamivir-resistant A(H1N1) viruses were first emerged in Europe in November 2007 and then circulated globally. One year later, the oseltamivir-resistant A(H1N1) viruses were first detected in Korea in November 2008 and continued circulating until the Week 7 of 2009 during the 2008-2009 season. Considering the pandemic preparedness, it should be continued to monitor the emergence and the characterization of antiviral drug resistant influenza viruses.
doi:10.1016/j.phrp.2011.11.042
PMCID: PMC3767087  PMID: 24159470
antiviral drug resistance; Korea; oseltamivir resistance; seasonal influenza A(H1N1) virus
6.  Triple Combination of Amantadine, Ribavirin, and Oseltamivir Is Highly Active and Synergistic against Drug Resistant Influenza Virus Strains In Vitro 
PLoS ONE  2010;5(2):e9332.
The rapid emergence and subsequent spread of the novel 2009 Influenza A/H1N1 virus (2009 H1N1) has prompted the World Health Organization to declare the first pandemic of the 21st century, highlighting the threat of influenza to public health and healthcare systems. Widespread resistance to both classes of influenza antivirals (adamantanes and neuraminidase inhibitors) occurs in both pandemic and seasonal viruses, rendering these drugs to be of marginal utility in the treatment modality. Worldwide, virtually all 2009 H1N1 and seasonal H3N2 strains are resistant to the adamantanes (rimantadine and amantadine), and the majority of seasonal H1N1 strains are resistant to oseltamivir, the most widely prescribed neuraminidase inhibitor (NAI). To address the need for more effective therapy, we evaluated the in vitro activity of a triple combination antiviral drug (TCAD) regimen composed of drugs with different mechanisms of action against drug-resistant seasonal and 2009 H1N1 influenza viruses. Amantadine, ribavirin, and oseltamivir, alone and in combination, were tested against amantadine- and oseltamivir-resistant influenza A viruses using an in vitro infection model in MDCK cells. Our data show that the triple combination was highly synergistic against drug-resistant viruses, and the synergy of the triple combination was significantly greater than the synergy of any double combination tested (P<0.05), including the combination of two NAIs. Surprisingly, amantadine and oseltamivir contributed to the antiviral activity of the TCAD regimen against amantadine- and oseltamivir-resistant viruses, respectively, at concentrations where they had no activity as single agents, and at concentrations that were clinically achievable. Our data demonstrate that the TCAD regimen composed of amantadine, ribavirin, and oseltamivir is highly synergistic against resistant viruses, including 2009 H1N1. The TCAD regimen overcomes baseline drug resistance to both classes of approved influenza antivirals, and thus may represent a highly active antiviral therapy for seasonal and pandemic influenza.
doi:10.1371/journal.pone.0009332
PMCID: PMC2825274  PMID: 20179772
7.  Trends in antiviral therapy of adults hospitalized with influenza in Canada since the end of the 2009 pandemic 
Background
Multiple observational studies have associated antiviral treatment of patients hospitalized with influenza with improved outcome, including reduced mortality. During the 2009–2010 H1N1 pandemic increased use of antiviral treatment of hospital patients was reported. We have carried out prospective surveillance for influenza in patients in a large network of Canadian hospitals since 2006. We wished to assess trends in antiviral use in the two seasons (2010–2011 and 2011–2012) since the end of the pandemic.
Findings
Adults (>16 years) testing positive for influenza at the time of or during admission to participating Canadian hospitals were prospectively reviewed. In 2009–2010 there were 1132 confirmed cases, 1107 in 2010–2011 and 631 in 2011–2012. Information on antiviral therapy was available in >95% in each year. Rising to 89.6% in 2009, the proportion of adult patients treated with antiviral therapy fell to 79.9% and 65.7% in the two subsequent seasons (p < 0.001). Oseltamivir was the antiviral agent used in >98% of cases in each year. The median time from onset of symptoms to initiation of antiviral therapy was three days. The treatment proportion fell across all age groups, co-morbid conditions and disease severity.
Conclusion
Despite evidence for benefit of antiviral therapy, and clinical practice guidelines recommending treatment of this population, antiviral therapy of Canadian adults hospitalized with influenza has progressively fallen in the two seasons since the end of the 2009–2010 influenza pandemic.
doi:10.1186/2047-2994-3-2
PMCID: PMC3895698  PMID: 24405855
8.  Prone Positioning and Intravenous Zanamivir may Represent Effective Alternatives for Patients with Severe ARDS Virus A (H1N1) Related Pneumonia in Hospitals with no Access to ECMO 
The first patient with influenza A/H1N1-related pneumonia was admitted to an Italian ICU at the end of August 2009. Until then, despite the international alarm, the level of awareness was low and very few Italian hospitals were equipped with ECMOs. Moreover the PCR test for A H1N1 virus was sporadically available and the emergency departments of even the largest institutions could rely only on the rapid test for the urgent screening of patients with pneumonia and respiratory failure. On September 5th, a young and “apparently” previously healthy man, was admitted to our ICU because of a severe ARDS caused by influenza A H1N1 virus. As there was no ECMO available, he was treated with prolonged cycles of prone positioning ventilation. Antiviral treatment was started with Oseltamivir, but as enteral absorption was impaired by paralytic ileus and tube feeding intolerance, Oseltamivir had to be discontinued. Intravenous Zanamivir 1200 mg/day for ten days was therefore prescribed as “off label” antiviral therapy. A bone marrow biopsy allowed the diagnosis of an initial stage of “hairy cells leukaemia.” ARDS related to A/H1N1 influenza was the first sign of the disease in our patient. He did well with complete clearance of the infection from the BAL after 10 days of Zanamivir, although the nasopharyngeal swabs remained positive for ten more days. Prone positioning ventilation may be a life-saver strategy in patients with severe ARDS when ECMO is not immediately available. However, prone positioning ventilation is often associated with severe impairment of the absorption of drugs that require enteral administration via the nasogastric tube. In these cases, intravenous Zanamivir may be an effective alternative strategy.
doi:10.1155/2010/146456
PMCID: PMC3010614  PMID: 21197475
9.  Correlates of severe disease in patients with 2009 pandemic influenza (H1N1) virus infection 
Background
In the context of 2009 pandemic influenza (H1N1) virus infection (pandemic H1N1 influenza), identifying correlates of the severity of disease is critical to guiding the implementation of antiviral strategies, prioritization of vaccination efforts and planning of health infrastructure. The objective of this study was to identify factors correlated with severity of disease in confirmed cases of pandemic H1N1 influenza.
Methods
This cumulative case–control study included all laboratory-confirmed cases of pandemic H1N1 influenza among residents of the province of Manitoba, Canada, for whom the final location of treatment was known. Severe cases were defined by admission to a provincial intensive care unit (ICU). Factors associated with severe disease necessitating admission to the ICU were determined by comparing ICU cases with two control groups: patients who were admitted to hospital but not to an ICU and those who remained in the community.
Results
As of Sept. 5, 2009, there had been 795 confirmed cases of pandemic H1N1 influenza in Manitoba for which the final treatment location could be determined. The mean age of individuals with laboratory-confirmed infection was 25.3 (standard deviation 18.8) years. More than half of the patients (417 or 52%) were female, and 215 (37%) of 588 confirmed infections for which ethnicity was known occurred in First Nations residents. The proportion of First Nations residents increased with increasing severity of disease (116 [28%] of 410 community cases, 74 [54%] of 136 admitted to hospital and 25 [60%] of 42 admitted to an ICU; p < 0.001), as did the presence of an underlying comorbidity (201 [35%] of 569 community cases, 103 [57%] of 181 admitted to hospital and 34 [76%] of 45 admitted to an ICU; p < 0.001). The median interval from onset of symptoms to initiation of antiviral therapy was 2 days (interquartile range, IQR 1–3) for community cases, 4 days (IQR 2–6) for patients admitted to hospital and 6 days (IQR 4–9) for those admitted to an ICU (p < 0.001). In a multivariable logistic model, the interval from onset of symptoms to initiation of antiviral therapy (odds ratio [OR] 8.24, 95% confidence interval [CI] 2.82–24.1), First Nations ethnicity (OR 6.52, 95% CI 2.04–20.8) and presence of an underlying comorbidity (OR 3.19, 95% CI 1.07–9.52) were associated with increased odds of admission to the ICU (i.e., severe disease) relative to community cases. In an analysis of ICU cases compared with patients admitted to hospital, First Nations ethnicity (OR 3.23, 95% CI 1.04–10.1) was associated with increased severity of disease.
Interpretation
Severe pandemic H1N1 influenza necessitating admission to the ICU was associated with a longer interval from onset of symptoms to treatment with antiviral therapy and with the presence of an underlying comorbidity. First Nations ethnicity appeared to be an independent determinant of severe infection. Despite these associations, the cause and outcomes of pandemic HINI influenza may involve many complex and interrelated factors, all of which require further research and analysis.
doi:10.1503/cmaj.091884
PMCID: PMC2826467  PMID: 20093297
10.  Epidemiological and clinical characteristics of patients who died from Influenza A(H1N1)pdm09 in Viet Nam 
We describe the epidemiological and clinical characteristics of patients who died from influenza A(H1N1)pdm09 in hospitals in Viet Nam between August 2009 and March 2010.
Of 58 fatal cases, 32 (55%) were below 30 years of age and 14 (24%) were pregnant females. Forty-five (78%) patients had at least one underlying medical condition including chronic heart, kidney or lung diseases or pregnancy. Twelve (21%) cases sought medical attention on the day of symptom onset. Only 13 (36%) of 36 cases for whom treatment data were available had been given antiviral drugs within the recommended two days of symptom onset.
The clinical and epidemiologic characteristics of the patients who died from influenza A(H1N1)pdm09 are similar to those reported from other countries. To improve preparedness and response to future pandemics, Viet Nam needs to strengthen the surveillance of influenza; increase laboratory capacity to test for influenza viruses; and develop strategies for promoting the timely attendance of at-risk individuals at health facilities and the early administration of antiviral drugs, particularly for persons with underlying medical conditions and pregnant females.
doi:10.5365/WPSAR.2011.2.3.003
PMCID: PMC3729071  PMID: 23908901
11.  Antiviral and Antibiotic Prescribing for Influenza in Primary Care 
BACKGROUND
Anti-influenza antiviral medications reduce influenza-related morbidity, but may often be used inappropriately.
OBJECTIVE
To measure the rate of antiviral and antibiotic prescribing, the appropriateness of antiviral prescribing, and evaluate independent predictors of antiviral and antibiotic prescribing for influenza in primary care.
DESIGN AND PATIENTS
Retrospective analysis of 958 visits of clinician-diagnosed influenza in 21 primary care clinics in eastern Massachusetts from 1999 to 2007. We considered antiviral prescribing appropriate if patients had symptoms for 2 or fewer days, had fever, and any 2 of headache, sore throat, cough, or myalgias.
MEASUREMEMTS AND MAIN RESULTS
Clinicians prescribed antivirals in 557 (58%) visits and antibiotics in 104 visits (11%). Of antiviral prescriptions, 38% were not appropriate, most commonly because of symptoms for more than 2 days (24% of antiviral prescriptions). In multivariate modeling, selected independent predictors of antiviral prescribing were symptom duration of 2 or fewer days (odds ratio [OR], 12.4; 95% confidence interval [CI], 8.3 to 18.6), year (OR, 1.4 for each successive influenza season; 95% CI, 1.3 to 1.7), patient age (OR, 1.3 per decade; 95% CI, 1.2 to 1.5), and, compared to having no influenza testing, having a negative influenza test (OR, 5.5; 95% CI, 3.4 to 9.1) or a positive influenza test (OR, 11.4; 95% CI, 6.7 to 19.3). Independent predictors of antibiotic prescribing included otoscopic abnormalities (OR, 3.3; 95% CI, 1.8 to 6.0), abnormal lung examination (OR, 4.0; 95% CI, 2.1 to 6.2), and having a chest x-ray performed (OR, 2.2; 95% CI, 1.3 to 3.8).
CONCLUSIONS
Primary care clinicians are much more likely to prescribe antivirals to patients with symptoms for 2 or fewer days, but also commonly prescribe antivirals inappropriately.
doi:10.1007/s11606-009-0933-9
PMCID: PMC2659164  PMID: 19225847
influenza, human; antiviral agents; antibacterial agents; drug utilization
12.  Decision Making with Regard to Antiviral Intervention during an Influenza Pandemic 
Medical Decision Making  2010;30(4):E64-E81.
Background
Antiviral coverage is defined by the proportion of the population that takes antiviral prophylaxis or treatment. High coverage of an antiviral drug has epidemiological and evolutionary repercussions. Antivirals select for drug resistance within the population, and individuals may experience adverse effects. To determine optimal antiviral coverage in the context of an influenza outbreak, we compared 2 perspectives: 1) the individual level (the Nash perspective), and 2) the population level (utilitarian perspective).
Methods
We developed an epidemiological game-theoretic model of an influenza pandemic. The data sources were published literature and a national survey. The target population was the US population. The time horizon was 6 months. The perspective was individuals and the population overall. The interventions were antiviral prophylaxis and treatment. The outcome measures were the optimal coverage of antivirals in an influenza pandemic.
Results
At current antiviral pricing, the optimal Nash strategy is 0% coverage for prophylaxis and 30% coverage for treatment, whereas the optimal utilitarian strategy is 19% coverage for prophylaxis and 100% coverage for treatment. Subsidizing prophylaxis by $440 and treatment by $85 would bring the Nash and utilitarian strategies into alignment. For both prophylaxis and treatment, the optimal antiviral coverage decreases as pricing of antivirals increases. Our study does not incorporate the possibility of an effective vaccine and lacks probabilistic sensitivity analysis. Our survey also does not completely represent the US population. Because our model assumes a homogeneous population and homogeneous antiviral pricing, it does not incorporate heterogeneity of preference.
Conclusions
The optimal antiviral coverage from the population perspective and individual perspectives differs widely for both prophylaxis and treatment strategies. Optimal population and individual strategies for prophylaxis and treatment might be aligned through subsidization.
doi:10.1177/0272989X10374112
PMCID: PMC3319452  PMID: 20634545
mathematical models; economic evaluation; decision analysis
13.  A Phase II Study of DAS181, a Novel Host Directed Antiviral for the Treatment of Influenza Infection 
The Journal of Infectious Diseases  2012;206(12):1844-1851.
Background. DAS181, a novel host-directed antiviral in development for influenza treatment, was assessed in this phase II clinical trial.
Methods. This study was a double-blind, placebo-controlled phase II clinical trial assessing influenza viral load and patient safety in otherwise healthy influenza-infected participants. Participants were randomized to a single-dose, multiple-dose, or placebo group and were followed for safety and virologic outcomes.
Results. A total of 177 laboratory-confirmed influenza-infected participants were enrolled in the trial, which encompassed 3 influenza seasons from 2009–2011 in both the Northern and Southern Hemispheres. Thirty-seven percent of participants had confirmed infection with influenza B, 33% with seasonal H3N2, 29% with pandemic 2009 H1N1, and 1 participant was positive for both influenza B and pandemic 2009 H1N1. Significant effects were observed in regard to decreased change from baseline viral load and viral shedding in the multiple-dose group compared with placebo as measured by quantitative polymerase chain reaction (P < .05). No instances of H274Y were observed among viral isolates from this trial. Overall, the drug was generally well tolerated.
Conclusions. DAS181 significantly reduced viral load in participants infected with influenza, thus warranting future clinical development of this novel host-directed therapy.
Clinical Trials.gov Identifier. NCT01037205
doi:10.1093/infdis/jis622
PMCID: PMC3570175  PMID: 23045618
14.  Can Antiviral Drugs Contain Pandemic Influenza Transmission? 
PLoS ONE  2011;6(3):e17764.
Antiviral drugs dispensed during the 2009 influenza pandemic generally failed to contain transmission. This poses the question of whether preparedness for a future pandemic should include plans to use antiviral drugs to mitigate transmission.
Simulations using a standard transmission model that allows for infected arrivals and delayed vaccination show that attempts to contain transmission require relatively few antiviral doses. In contrast, persistent use of antiviral drugs when the reproduction number remains above 1 use very many doses and are unlikely to reduce the eventual attack rate appreciably unless the stockpile is very large. A second model, in which the community has a household structure, shows that the effectiveness of a strategy of dispensing antiviral drugs to infected households decreases rapidly with time delays in dispensing the antivirals. Using characteristics of past pandemics it is estimated that at least 80% of primary household cases must present upon show of symptoms to have a chance of containing transmission by dispensing antiviral drugs to households. To determine data needs, household outbreaks were simulated with 50% receiving antiviral drugs early and 50% receiving antiviral drugs late. A test to compare the size of household outbreaks indicates that at least 100–200 household outbreaks need to be monitored to find evidence that antiviral drugs can mitigate transmission of the newly emerged virus.
Use of antiviral drugs in an early attempt to contain transmission should be part of preparedness plans for a future influenza pandemic. Data on the incidence of the first 350 cases and the eventual attack rates of the first 200 hundred household outbreaks should be used to estimate the initial reproduction number R and the effectiveness of antiviral drugs to mitigate transmission. Use of antiviral drugs to mitigate general transmission should cease if these estimates indicate that containment of transmission is unlikely.
doi:10.1371/journal.pone.0017764
PMCID: PMC3065466  PMID: 21464934
15.  Antiviral Strategies for Emerging Influenza Viruses in Remote Communities 
PLoS ONE  2014;9(2):e89651.
Background
Due to the lack of timely access to resources for critical care, strategic use of antiviral drugs is crucial for mitigating the impact of novel influenza viruses with pandemic potential in remote and isolated communities. We sought to evaluate the effect of antiviral treatment and prophylaxis of close contacts in a Canadian remote northern community.
Methods
We used an agent-based, discrete-time simulation model for disease spread in a remote community, which was developed as an in-silico population using population census data. Relative and cumulative age-specific attack rates, and the total number of infections in simulated model scenarios were obtained.
Results
We found that early initiation of antiviral treatment is more critical for lowering attack rates in a remote setting with a low population-average age compared to an urban population. Our results show that a significant reduction in the relative, age-specific attack rates due to increasing treatment coverage does not necessarily translate to a significant reduction in the overall arrack rate. When treatment coverage varies from low to moderate, targeted prophylaxis has a very limited impact in reducing attack rates and should be offered at a low level (below 10%) to avoid excessive waste of drugs.
Conclusions
In contrast to previous work, for conservative treatment coverages, our results do not provide any convincing evidence for the implementation of targeted prophylaxis. The findings suggest that public health strategies in remote communities should focus on the wider availability (higher coverage) and timely distribution of antiviral drugs for treatment of clinically ill individuals.
doi:10.1371/journal.pone.0089651
PMCID: PMC3931825  PMID: 24586937
16.  Economic Model for Emergency Use Authorization of Intravenous Peramivir 
Objectives
To develop 3 computer simulation models to determine the potential economic effect of using intravenous (IV) antiviral agents to treat hospitalized patients with influenza-like illness, as well as different testing and treatment strategies.
Study Design
Stochastic decision analytic computer simulation model.
Methods
During the 2009 influenza A(H1N1) pandemic, the Food and Drug Administration granted emergency use authorization of IV neuraminidase inhibitors for hospitalized patients with influenza, creating a need for rapid decision analyses to help guide use. We compared the economic value from the societal and third-party payer perspectives of the following 4 strategies for a patient hospitalized with influenza-like illness and unable to take oral antiviral agents: Strategy 1: Administration of IV antiviral agents without polymerase chain reaction influenza testing. Strategy 2: Initiation of IV antiviral treatment, followed by polymerase chain reaction testing to determine whether the treatment should be continued. Strategy 3: Performance of polymerase chain reaction testing, followed by initiation of IV antiviral treatment if the test results are positive. Strategy 4: Administration of no IV antiviral agents. Sensitivity analyses varied the probability of having influenza (baseline, 10%; range, 10%–30%), IV antiviral efficacy (baseline, oral oseltamivir phosphate; range, 25%–75%), IV antiviral daily cost (range, $20–$1000), IV antiviral reduction of illness duration (baseline, 1 day; range, 1–2 days), and ventilated vs nonventilated status of the patient.
Results
When the cost of IV antiviral agents was no more than $500 per day, the incremental cost-effectiveness ratio for most of the IV antiviral treatment strategies was less than $10,000 per quality-adjusted life-year compared with no treatment. When the cost was no more than $100 per day, all 3 IV antiviral strategies were even more cost-effective. The order of cost-effectiveness from most to least was strategies 3, 1, and 2. The findings were robust to changing risk of influenza, influenza mortality, IV antiviral efficacy, IV antiviral daily cost, IV antiviral reduction of illness duration, and ventilated vs nonventilated status of the patient for both societal and third-party payer perspectives.
Conclusion
Our study supports the use of IV antiviral treatment for hospitalized patients with influenza-like illness.
PMCID: PMC3763185  PMID: 21485418
17.  Supply of Neuraminidase Inhibitors Related to Reduced Influenza A (H1N1) Mortality during the 2009–2010 H1N1 Pandemic: An Ecological Study 
PLoS ONE  2012;7(9):e43491.
Background
The influenza A (H1N1) pandemic swept across the globe from April 2009 to August 2010 affecting millions. Many WHO Member States relied on antiviral drugs, specifically neuraminidase inhibitors (NAIs) oseltamivir and zanamivir, to treat influenza patients in critical condition. Such drugs have been found to be effective in reducing severity and duration of influenza illness, and likely reduced morbidity during the pandemic. However, it is less clear whether NAIs used during the pandemic reduced H1N1 mortality.
Methods
Country-level data on supply of oseltamivir and zanamivir were used to predict H1N1 mortality (per 100,000 people) from July 2009 to August 2010 in forty-two WHO Member States. Poisson regression was used to model the association between NAI supply and H1N1 mortality, with adjustment for economic, demographic, and health-related confounders.
Results
After adjustment for potential confounders, each 10% increase in kilograms of oseltamivir, per 100,000 people, was associated with a 1.6% reduction in H1N1 mortality over the pandemic period (relative rate (RR) = 0.84 per log increase in oseltamivir supply). While the supply of zanamivir was considerably less than that of oseltamivir in each Member State, each 10% increase in kilogram of active zanamivir, per 100,000, was associated with a 0.3% reduction in H1N1 mortality (RR = 0.97 per log increase).
Conclusion
While there are limitations to the ecologic nature of these data, this analysis offers evidence of a protective relationship between antiviral drug supply and influenza mortality and supports a role for influenza antiviral use in future pandemics.
doi:10.1371/journal.pone.0043491
PMCID: PMC3439456  PMID: 22984431
18.  Influenza vaccines and influenza antiviral drugs in Africa: are they available and do guidelines for their use exist? 
BMC Public Health  2014;14:41.
Background
Influenza viruses cause significant morbidity and mortality in Africa, particularly among high-risk groups, but influenza vaccines and antiviral drugs may not be commonly available and used. The main aim of this study was to determine the availability and use of influenza vaccines and antiviral drugs as well as to describe existing related guidelines and policies in Africa.
Methods
A self-administered survey was distributed among key influenza experts in 40 African countries.
Results
Of the 40 countries surveyed, 31 (78%) responded; 14/31 (45%) reported availability of seasonal influenza vaccine, and 19/31 (65%) reported availability of antiviral drugs for the treatment of influenza. Vaccine coverage data were only available for 4/14 (29%) countries that reported availability of seasonal influenza vaccine and ranged from <0.5% to 2% of the population.
Conclusions
Influenza vaccines and antiviral drugs are available in many countries in Africa but coverage estimates are low and remain largely unknown. Describing the local burden of disease and identifying funding are essential to encourage countries to use influenza vaccine more widely.
doi:10.1186/1471-2458-14-41
PMCID: PMC3898391  PMID: 24433304
Influenza; Vaccine; Antiviral; Drugs; Policy; Recommendations; Africa
19.  Mass Spectrometry-Based Comparative Sequence Analysis for the Genetic Monitoring of Influenza A(H1N1)pdm09 Virus 
PLoS ONE  2014;9(4):e92970.
The pandemic influenza A (H1N1) 2009 virus (pH1N1) contains novel gene segments of zoonotic origin that lack virulence and antiviral resistance markers. We aimed to evaluate the applicability and accuracy of mass spectrometry-based comparative sequence analysis (MSCSA) to detect genetic mutations associated with increased virulence or antiviral resistance in pH1N1. During the 2009 H1N1 pandemic, routine surveillance specimens and clinical antiviral resistance monitoring specimens were analyzed. Routine surveillance specimens obtained from 70 patients with pH1N1 infection were evaluated for mutations associated with increased virulence (PB1-F2, PB2 and NS1 genes) or antiviral resistance (neuraminidase gene, NA) using MSCSA and Sanger sequencing. MSCSA and Sanger sequencing results revealed a high concordance (nucleotides >99%, SNPs ∼94%). Virulence or resistance markers were not detected in routine surveillance specimens: all identified SNPs encoded for silent mutations or non-relevant amino acid substitutions. In a second study population, the presence of H275Y oseltamivir resistant virus was identified by real-time PCR in 19 of 35 clinical antiviral resistance monitoring specimens obtained from 4 immunocompromised patients with ≥14 days prolonged pH1N1 excretion. MSCSA detected H275Y in 24% (4/19) of positive specimens and Sanger sequencing in 89% (17/19). MSCSA only detected H275Y when the mutation was dominant in the analyzed specimens. In conclusion, MSCSA may be used as a rapid screening tool during molecular surveillance of pH1N1. The low sensitivity for the detection of H275Y mutation in mixed viral populations suggests that MSCSA is not suitable for antiviral resistance monitoring in the clinical setting.
doi:10.1371/journal.pone.0092970
PMCID: PMC3974683  PMID: 24699508
20.  Surveillance of hospitalizations with pandemic A(H1N1) 2009 influenza infection in Queensland, Australia 
Objective
To describe the demographic and clinical characteristics of patients hospitalized with pandemic A(H1N1) 2009 infection in Queensland, Australia between 25 May and 3 October 2009 and to examine the relationship between timing of antiviral treatment and severity of illness.
Method
Using data from the Queensland Health EpiLog information system, descriptive analysis and logistic regression modelling were used to describe and model factors which influence patient outcomes (death, admission to intensive care unit and/or special care unit). Data on patients admitted to hospital in Queensland with confirmed pandemic A(H1N1) 2009 infection were included in this analysis.
Results
1236 patients with pandemic A(H1N1) 2009 infection were admitted to hospitals in Queensland during the study period. Of the total group: 15% were admitted to an intensive care unit or special care unit; 3% died; 34% were under the age of 18 years and 8% were 65 years of age or older; and 55% had at least one underlying medical condition. Among the 842 patients for whom data were available regarding the use of antiviral drugs, antiviral treatment was initiated in 737 (87.5%) patients, treatment commenced at a median of one day (range 1–33 days) after onset of illness. Admission to an intensive care unit or special care unit (ICU/SCU) or death was significantly associated with increased age, lack of timeliness of antiviral treatment, chronic renal disease and morbid obesity.
Discussion
Early antiviral treatment was significantly associated with lower likelihood of ICU/SCU admission or death. Early antiviral treatment for influenza cases may therefore have important public health implications.
doi:10.5365/WPSAR.2010.1.1.013
PMCID: PMC3730959  PMID: 23908886
21.  Characteristics of Hospitalized Children with 2009 Pandemic Influenza A (H1N1): A Multicenter Study in Korea 
Journal of Korean Medical Science  2012;27(4):408-415.
The majority of Korean patients with pandemic influenza A (H1N1) during the 2009 epidemic were under 20 yr of age. The limited data on the clinical characteristics of these children led us to conduct a case note-based investigation of children admitted to 6 university hospitals with 2009 H1N1 influenza. A total of 804 children was enrolled. The median age was 5 yr; 63.8% were males; and 22.4% had at least one chronic underlying disease. Ninety-five of the patients (11.8%) were critically ill and they suffered more from shortness of breath, dyspnea and lymphopenia than the other patients. Among all the patients, 98.8% were treated with antivirals and 73% received treatment within 48 hr of illness onset. All the enrolled patients are alive and appear to have had good outcomes, probably due to the early intervention and antiviral treatment. This study deals with hospitalized children whose diagnoses of influenza A (H1N1) were confirmed, and therefore provides important new information about the clinical patterns of children with influenza A (H1N1) in Korea.
doi:10.3346/jkms.2012.27.4.408
PMCID: PMC3314854  PMID: 22468105
Pandemic Influenza A (H1N1); Children; Korea; Epidemiology; Clinical Characteristics
22.  Clinical Outcome of Novel H1N1 (Swine Flu)-Infected Patients During 2009 Pandemic at Tertiary Referral Hospital in Western India 
Background:
The first case of 2009 pandemic influenza A (H1N1) virus in Gujarat, India, was reported in August 2009. Oseltamivir was used for treatment of pandemic influenza in India. We discuss the clinical characteristics and outcome of the hospitalized patients with H1N1 infection during 2009 pandemic influenza season.
Materials and Methods:
Hospitalized patient with laboratory-confirmed H1N1 flu during August 2009 to February 2010 were included in this retrospective study. Data were collected from hospital ICU charts. Patients discharged from hospital were considered cured from swine flu. Data analysis was performed using CDC software EPI Info v3.5.3. Both univariate and multivariate analyses were conducted.
Results:
A total of 63 patients were included in the study, of them 41 (65%) males and 22 (35%) females. Median age was 34 (3-69) years and median duration of symptoms before hospitalization was 5 (2-20) days. Common presenting symptoms include fever 58 (92.06%), cough 58 (92.06%), breathlessness 38 (60.31%), common cold 14 (22.22%), vomiting 12 (19.04%), weakness 9 (14.28%), throat pain 7 (11.11%), body ache 5 (7.93%), and chest pain 4 (6.34%). Co-morbidities were seen in 13 (20.63%) patients. Steroids were used in 39 (61.90%) patients, and ventilatory support was required in 17 (26.98%) patients. On presentation chest x-ray was normal in 20 (31.74%) patients, while pulmonary opacities were seen in 43 (68.26%) patients. Forty-seven (74.60%) patients were cured and discharged from hospital, 14 (22.22%) patients died, and 2 (3.17%) patients were shifted to other hospital. Ventilatory requirement, pneumonia, and co-morbidities were the independent predictors of mortality, while age, sex, and steroid use were not associated with increased mortality.
Conclusion:
2009 pandemic influenza A had the same clinical features as seasonal influenza except vomiting. Mortality rate was high in 2009 H1N1-infected patients with pneumonia, co-morbid conditions, and patients who required ventilatory support.
doi:10.4103/0974-777X.116868
PMCID: PMC3766340  PMID: 24049362
2009 H1N1; Pandemic flu; Swine flu; Viral pneumonia
23.  Paediatric acquired demyelinating syndromes: incidence, clinical and magnetic resonance imaging features 
Objective
Changing trends in multiple sclerosis (MS) epidemiology may first be apparent in the childhood population affected with first onset acquired demyelinating syndromes (ADSs). We aimed to determine the incidence, clinical, investigative and magnetic resonance imaging (MRI) features of childhood central nervous system ADSs in the British Isles for the first time.
Methods
We conducted a population active surveillance study. All paediatricians, and ophthalmologists (n = 4095) were sent monthly reporting cards (September 2009–September 2010). International Paediatric MS Study Group 2007 definitions and McDonald 2010 MS imaging criteria were used for acute disseminated encephalomyelitis (ADEM), clinically isolated syndrome (CIS) and neuromyelitis optica (NMO). Clinicians completed a standard questionnaire and provided an MRI copy for review.
Results
Card return rates were 90%, with information available for 200/222 positive notifications (90%). After exclusion of cases, 125 remained (age range 1.3–15.9), with CIS in 66.4%, ADEM in 32.0% and NMO in 1.6%. The female-to-male ratio in children older than 10 years (n = 63) was 1.52:1 (p = 0.045). The incidence of first onset ADS in children aged 1–15 years old was 9.83 per million children per year (95% confidence interval [CI] 8.18–11.71). A trend towards higher incidence rates of ADS in children of South Asian and Black ethnicity was observed compared with White children. Importantly, a number of MRI characteristics distinguished ADEM from CIS cases. Of CIS cases with contrast imaging, 26% fulfilled McDonald 2010 MS diagnostic criteria.
Conclusions
We report the highest surveillance incidence rates of childhood ADS. Paediatric MS diagnosis at first ADS presentation has implications for clinical practice and clinical trial design.
doi:10.1177/1352458512445944
PMCID: PMC3409874  PMID: 22516794
pediatric multiple sclerosis; paediatric multiple sclerosis; acute disseminated encephalomyelitis; demyelination; demyelinating; pediatric; paediatric; childhood; adolescent; epidemiology; incidence; magnetic resonance imaging
24.  Paediatric acquired demyelinating syndromes: incidence, clinical and magnetic resonance imaging features 
Objective:
Changing trends in multiple sclerosis (MS) epidemiology may first be apparent in the childhood population affected with first onset acquired demyelinating syndromes (ADSs). We aimed to determine the incidence, clinical, investigative and magnetic resonance imaging (MRI) features of childhood central nervous system ADSs in the British Isles for the first time.
Methods:
We conducted a population active surveillance study. All paediatricians, and ophthalmologists (n = 4095) were sent monthly reporting cards (September 2009–September 2010). International Paediatric MS Study Group 2007 definitions and McDonald 2010 MS imaging criteria were used for acute disseminated encephalomyelitis (ADEM), clinically isolated syndrome (CIS) and neuromyelitis optica (NMO). Clinicians completed a standard questionnaire and provided an MRI copy for review.
Results:
Card return rates were 90%, with information available for 200/222 positive notifications (90%). After exclusion of cases, 125 remained (age range 1.3–15.9), with CIS in 66.4%, ADEM in 32.0% and NMO in 1.6%. The female-to-male ratio in children older than 10 years (n = 63) was 1.52:1 (p = 0.045). The incidence of first onset ADS in children aged 1–15 years old was 9.83 per million children per year (95% confidence interval [CI] 8.18–11.71). A trend towards higher incidence rates of ADS in children of South Asian and Black ethnicity was observed compared with White children. Importantly, a number of MRI characteristics distinguished ADEM from CIS cases. Of CIS cases with contrast imaging, 26% fulfilled McDonald 2010 MS diagnostic criteria.
Conclusions:
We report the highest surveillance incidence rates of childhood ADS. Paediatric MS diagnosis at first ADS presentation has implications for clinical practice and clinical trial design.
doi:10.1177/1352458512445944
PMCID: PMC3409874  PMID: 22516794
pediatric multiple sclerosis; paediatric multiple sclerosis; acute disseminated encephalomyelitis; demyelination; demyelinating; pediatric; paediatric; childhood; adolescent; epidemiology; incidence; magnetic resonance imaging
25.  Intrahousehold Transmission of Pandemic (H1N1) 2009 Virus, Victoria, Australia 
Emerging Infectious Diseases  2011;17(9):1599-1607.
TOC Summary: Antiviral prophylaxis for quarantined contacts reduces secondary transmission.
To examine intrahousehold secondary transmission of pandemic (H1N1) 2009 virus in households in Victoria, Australia, we conducted a retrospective cross-sectional study in late 2009. We randomly selected case-patients reported during May–June 2009 and their household contacts. Information collected included household characteristics, use of prevention and control measures, and signs and symptoms. Secondary cases were defined as influenza-like illness in household contacts within the specified period. Secondary transmission was identified for 18 of 122 susceptible household contacts. To identify independent predictors of secondary transmission, we developed a model. Risk factors were concurrent quarantine with the household index case-patient, and a protective factor was antiviral prophylaxis. These findings show that timely provision of antiviral prophylaxis to household contacts, particularly when household members are concurrently quarantined during implementation of pandemic management strategies, delays or contains community transmission of pandemic (H1N1) 2009 virus.
doi:10.3201/eid1709.101948
PMCID: PMC3322070  PMID: 21888784
cross-sectional study; pandemic (H1N1) 2009; family characteristics; secondary transmission; quarantine; antiviral prophylaxis; influenza; viruses; Australia; research

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