2021-2022 AMMI Canada guidance on the use of antiviral drugs for influenza in the COVID-19 pandemic setting in Canada.

We provide an update to the Association of Medical Microbiology and Infectious Disease Canada seasonal influenza foundation guideline on the use of antiviral drugs for influenza for the upcoming 2021-2022 influenza season in Canada. Peramivir and baloxavir marboxil were licensed in Canada in 2017 and 2020, respectively, but neither is currently marketed. Thus, this guidance continues to focus on further optimizing the use of oseltamivir and zanamivir. Important issues for this year include the implications of co-circulation of severe acute respiratory syndrome coronavirus 2 and influenza viruses; the role of diagnostic testing in relation to impact on patient management; and dosing and administration recommendations for neuraminidase inhibitors for various at-risk age groups.

Une mise à jour des lignes directrices de base d'AMMI Canada sur l'utilisation de médicaments antiviraux contre l'influenza au cours de la saison grippale 2021-2022 au Canada est présentée. Le péramivir et le baloxavir marboxil ont été homologués au Canada en 2017 et en 2020, respectivement, mais ni l'un ni l'autre n'est encore commercialisé. Les lignes directrices continuent donc d'être axées sur l'optimisation de l'oseltamivir et du zanamivir. Les enjeux importants cette année incluent les effets de la cocirculation du coronavirus 2 du syndrome respiratoire aigu sévère et des virus de l'influenza, le rôle des tests diagnostiques sur la prise en charge des patients, de même que les recommandations en matière de posologie et d'administration des inhibiteurs de la neuraminidase dans divers groupes d'âge à risque.

2020-2021 AMMI Canada guidance on the use of antiviral drugs for influenza in the setting of co-circulation of seasonal influenza and SARS-CoV-2 viruses in Canada.

We provide an update to the Association of Medical Microbiology and Infectious Disease Canada foundation guidance for the upcoming 2020-2021 influenza season in Canada. Important issues for this year include the implications of co-circulation of SARS-CoV-2, the role of diagnostic testing, and a restatement of dosing and administration recommendations for neuraminidase inhibitors in various age groups and underlying health conditions. Although peramivir and baloxivir are now licensed in Canada, neither is currently marketed, so this guidance focuses on further optimizing the use of oseltamivir and zanamivir.

Nous actualisons l'information sur les directives de la Fondation de l'Association pour la microbiologie médicale et l'infectiologie Canada en vue de la saison grippale 2020­2021 au Canada. Cette année, les enjeux importants touchent les conséquences de la co-circulation de la maladie à coronavirus 2019, le rôle des tests diagnostiques et la réaffirmation des recommandations relatives aux maladies sous-jacentes ainsi qu'à la posologie et à l'administration des inhibiteurs de la neuraminidase dans divers groupes d'âge. Même si le péramivir et le baloxivir sont désormais homologués au Canada, ces médicaments n'y sont pas encore commercialisés, et c'est pourquoi les présentes directives visent à optimiser l'utilisation de l'oseltamivir et du zanamivir.

Use of antiviral drugs for seasonal influenza: Foundation document for practitioners-Update 2019.

This document updates the previous AMMI Canada Foundation Guidance (2013) on the use of antiviral therapy for influenza.

Le présent document est une mise à jour des précédentes directives d'AMMI Canada (2013) sur l'utilisation des antiviraux contre la grippe.

Guidance for practitioners on the use of antiviral drugs to control influenza outbreaks in long-term care facilities in Canada, 2014-2015 season.

The AMMI Canada Guidelines document 'The use of antiviral drugs for influenza: A foundation document for practitioners', published in the Autumn 2013 issue of the Journal, outlines the recommendations for the use of antiviral drugs to treat influenza. This article, which represents the first of two updates to these guidelines published in the current issue of the Journal, aims to inform health care professionals of the increased risk for influenza in long-term care facilities due to a documented mismatch between the components chosen for this season's vaccine and currently circulating influenza strains. Adjusted recommendations for the use of antiviral drugs for influenza in long-term care facilities for this season are provided.

Guidance on the use of antiviral drugs for influenza in acute care facilities in Canada, 2014-2015.

This article represents the second update to the AMMI Canada Guidelines document on the use of antiviral drugs for influenza. The article aims to inform health care professionals of the increased risk for influenza in long-term care facilities due to a documented mismatch between the components chosen for this season's vaccine and currently circulating influenza strains. Adjusted recommendations for the use of antiviral drugs for influenza in the acute care setting for this season are provided.

Efficacy of human papillomavirus 16 and 18 (HPV-16/18) AS04-adjuvanted vaccine against cervical infection and precancer in young women: final event-driven analysis of the randomized, double-blind PATRICIA trial.

We report final event-driven analysis data on the immunogenicity and efficacy of the human papillomavirus 16 and 18 ((HPV-16/18) AS04-adjuvanted vaccine in young women aged 15 to 25 years from the PApilloma TRIal against Cancer In young Adults (PATRICIA). The total vaccinated cohort (TVC) included all randomized participants who received at least one vaccine dose (vaccine, n = 9,319; control, n = 9,325) at months 0, 1, and/or 6. The TVC-naive (vaccine, n = 5,822; control, n = 5,819) had no evidence of high-risk HPV infection at baseline, approximating adolescent girls targeted by most HPV vaccination programs. Mean follow-up was approximately 39 months after the first vaccine dose in each cohort. At baseline, 26% of women in the TVC had evidence of past and/or current HPV-16/18 infection. HPV-16 and HPV-18 antibody titers postvaccination tended to be higher among 15- to 17-year-olds than among 18- to 25-year-olds. In the TVC, vaccine efficacy (VE) against cervical intraepithelial neoplasia grade 1 or greater (CIN1+), CIN2+, and CIN3+ associated with HPV-16/18 was 55.5% (96.1% confidence interval [CI], 43.2, 65.3), 52.8% (37.5, 64.7), and 33.6% (-1.1, 56.9). VE against CIN1+, CIN2+, and CIN3+ irrespective of HPV DNA was 21.7% (10.7, 31.4), 30.4% (16.4, 42.1), and 33.4% (9.1, 51.5) and was consistently significant only in 15- to 17-year-old women (27.4% [10.8, 40.9], 41.8% [22.3, 56.7], and 55.8% [19.2, 76.9]). In the TVC-naive, VE against CIN1+, CIN2+, and CIN3+ associated with HPV-16/18 was 96.5% (89.0, 99.4), 98.4% (90.4, 100), and 100% (64.7, 100), and irrespective of HPV DNA it was 50.1% (35.9, 61.4), 70.2% (54.7, 80.9), and 87.0% (54.9, 97.7). VE against 12-month persistent infection with HPV-16/18 was 89.9% (84.0, 94.0), and that against HPV-31/33/45/51 was 49.0% (34.7, 60.3). In conclusion, vaccinating adolescents before sexual debut has a substantial impact on the overall incidence of high-grade cervical abnormalities, and catch-up vaccination up to 18 years of age is most likely effective. (This study has been registered at ClinicalTrials.gov under registration no. NCT001226810.).

Risk of newly detected infections and cervical abnormalities in women seropositive for naturally acquired human papillomavirus type 16/18 antibodies: analysis of the control arm of PATRICIA.

BACKGROUND: We examined risk of newly detected human papillomavirus (HPV) infection and cervical abnormalities in relation to HPV type 16/18 antibody levels at enrollment in PATRICIA (Papilloma Trial Against Cancer in Young Adults; NCT00122681). METHODS: Using Poisson regression, we compared risk of newly detected infection and cervical abnormalities associated with HPV-16/18 between seronegative vs seropositive women (15-25 years) in the control arm (DNA negative at baseline for the corresponding HPV type [HPV-16: n = 8193; HPV-18: n = 8463]). RESULTS: High titers of naturally acquired HPV-16 antibodies and/or linear trend for increasing antibody levels were significantly associated with lower risk of incident and persistent infection, atypical squamous cells of undetermined significance or greater (ASCUS+), and cervical intraepithelial neoplasia grades 1/2 or greater (CIN1+, CIN2+). For HPV-18, although seropositivity was associated with lower risk of ASCUS+ and CIN1+, no association between naturally acquired antibodies and infection was demonstrated. Naturally acquired HPV-16 antibody levels of 371 (95% confidence interval [CI], 242-794), 204 (95% CI, 129-480), and 480 (95% CI, 250-5756) EU/mL were associated with 90% reduction of incident infection, 6-month persistent infection, and ASCUS+, respectively. CONCLUSIONS: Naturally acquired antibodies to HPV-16, and to a lesser extent HPV-18, are associated with some reduced risk of subsequent infection and cervical abnormalities associated with the same HPV type.

Natural history of progression of HPV infection to cervical lesion or clearance: analysis of the control arm of the large, randomised PATRICIA study.

BACKGROUND: The control arm of PATRICIA (PApilloma TRIal against Cancer In young Adults, NCT00122681) was used to investigate the risk of progression from cervical HPV infection to cervical intraepithelial neoplasia (CIN) or clearance of infection, and associated determinants. METHODS AND FINDINGS: Women aged 15-25 years were enrolled. A 6-month persistent HPV infection (6MPI) was defined as detection of the same HPV type at two consecutive evaluations over 6 months and clearance as ≥2 type-specific HPV negative samples taken at two consecutive intervals of approximately 6 months following a positive sample. The primary endpoint was CIN grade 2 or greater (CIN2+) associated with the same HPV type as a 6MPI. Secondary endpoints were CIN1+/CIN3+ associated with the same HPV type as a 6MPI; CIN1+/CIN2+/CIN3+ associated with an infection of any duration; and clearance of infection. The analyses included 4825 women with 16,785 infections (3363 women with 6902 6MPIs). Risk of developing a CIN1+/CIN2+/CIN3+ associated with same HPV type as a 6MPI varied with HPV type and was significantly higher for oncogenic versus non-oncogenic types. Hazard ratios for development of CIN2+ were 10.44 (95% CI: 6.96-15.65), 9.65 (5.97-15.60), 5.68 (3.50-9.21), 5.38 (2.87-10.06) and 3.87 (2.38-6.30) for HPV-16, HPV-33, HPV-31, HPV-45 and HPV-18, respectively. HPV-16 or HPV-33 6MPIs had ~25-fold higher risk for progression to CIN3+. Previous or concomitant HPV infection or CIN1+ associated with a different HPV type increased risk. Of the different oncogenic HPV types, HPV-16 and HPV-31 infections were least likely to clear. CONCLUSIONS: Cervical infections with oncogenic HPV types increased the risk of CIN2+ and CIN3+. Previous or concomitant infection or CIN1+ also increased the risk. HPV-16 and HPV-33 have by far the highest risk of progression to CIN3+, and HPV-16 and HPV-31 have the lowest chance of clearance.

Rural practice and the personal and educational characteristics of medical students: survey of 1269 graduates of the University of Manitoba.

OBJECTIVE: To describe the relationships between rural practice and the personal and medical education characteristics of medical students and residents. DESIGN: Cross-sectional, mailed survey. SETTING: Manitoba. PARTICIPANTS: Of 2578 physician graduates of the University of Manitoba from 1965 to 2000 who were surveyed, 1269 (49%) responded. MAIN OUTCOME MEASURES: Whether physicians had ever practised in rural settings, and their demographic characteristics and adolescent, medical school, and residency training experiences. Multivariate logistic regression models were used to determine variables jointly and independently associated with rural practice. RESULTS: Of 1269 respondents, 39% had practised in rural settings, including 58% of the 362 respondents who identified family practice as their primary career activity, and 32% of the 907 respondents whose primary activities were other than family practice. For all graduates, being male (P = .0289), having lived in a rural community (P < .0001), having attended a rural high school (P < .0001), and having rural educational experiences during medical school (P = .0068) or during postgraduate training (P < .0001) were significantly related to a greater likelihood of rural practice. In the final multivariate model, graduates of rural high schools, compared with those from urban public schools, were 1.57 times (95% CI 1.09 to 2.26) more likely to have practised in rural settings. Graduates who undertook part of their undergraduate training in rural settings were 1.34 times (95% CI 1.09 to 1.75) more likely to practise in rural locations. For both undergraduates and residents, the distance of their rural education experiences from Winnipeg and the likelihood of rural practice were directly related. For both FPs and non-FPs, being male and undertaking rural education during residency training were associated with a greater likelihood of rural practice, as was the distance of the training experience from the urban setting. For non-FPs a similar association was observed with undergraduate rural experiences. CONCLUSION: This large survey of graduates from a Canadian medical school demonstrated that attending a rural high school (P < .0001) and having rural educational exposure during medical school and residency training (P = .0068) were significantly associated with a physician practising in a rural location. That is, rural educational experiences on the continuum from high school through residency training appeared to be associated with rural practice.

The use of antiviral drugs for influenza: Guidance for practitioners 2012/2013.

The present article addresses the use of antiviral drugs in the management of seasonal influenza illness for the 2012/2013 season. It updates the previous document published in 2011 (1). Noteworthy guidance updates since 2011 include the following: Seasonal influenza in 2012/2013 is predicted to be caused by two human influenza A and one influenza B strain, all of which are anticipated to remain generally susceptible to oseltamivir.The predicted strains are A/California/7/2009 (H1N1) pdm09-like, A/Victoria/361/2011 (H3N2)-like and B/Wisconsin/1/2010-like (Yamagata lineage). All are included in the seasonal influenza vaccine and are susceptible to oseltamivir.Swine-variant H3N2v, which has rarely caused infection in humans exposed to infected swine within the past year in the United States, is susceptible to oseltamivir. It is not included in the current seasonal influenza vaccine.It is still considered that initiation of antiviral therapy more than 36 h to 48 h after onset of symptoms is beneficial in patients hospitalized with complicated influenza and severe illness.Oseltamivir continues to be recommended for the treatment of influenza in pregnant women.The use of antiviral drugs among measures to control outbreaks of influenza in closed facilities such as correctional institutions is now included in the present document.

Le présent article porte sur l'utilisation d'antiviraux pour prendre en charge l'influenza pendant la saison 2012­2013. Il met à jour le document publié en 2011 (1). Les conseils qui méritent d'être soulignés depuis 2011 s'établissent comme suit : On prévoit qu'en 2012­2013, l'influenza saisonnière sera causée par deux souches de l'influenza humaine A et une souche de l'influenza B, qui devraient demeurer généralement susceptibles à l'oseltamivir.Les souches prévues sont le virus analogue à A/California/7/2009 (H1N1)pdm09, le virus analogue à A/Victoria/361/2011 (H3N2) et le virus analogue à B/Wisconsin/1/2010 (lignée Yamagata). Toutes sont incluses dans le vaccin contre l'influenza saisonnière et sont susceptibles à l'oseltamivir.La variante porcine du virus H3N2 (H3N2v), qui a causé peu d'infections chez des humains exposés à des porcs depuis un an aux États-Unis, est susceptible à l'oseltamivir. Elle n'est pas incluse dans le vaccin actuel contre l'influenza saisonnière.On considère encore que l'amorce des antiviraux plus de 36 heures à 48 heures après l'apparition des symptômes est bénéfique aux patients hospitalisés en raison d'une influenza complexe et d'une maladie grave.L'oseltamivir continue d'être recommandé pour le traitement de l'influenza chez les femmes enceintes.Le recours à des antiviraux parmi les mesures de contrôle des éclosions d'influenza dans des établissements fermés, tels que les établissements de détention, fait désormais partie de ce document.

Overall efficacy of HPV-16/18 AS04-adjuvanted vaccine against grade 3 or greater cervical intraepithelial neoplasia: 4-year end-of-study analysis of the randomised, double-blind PATRICIA trial.

BACKGROUND: Cervical intraepithelial neoplasia grade 2 or greater (CIN2+) is the surrogate endpoint used in licensure trials of human papillomavirus (HPV) vaccines. Vaccine efficacy against CIN3+, the immediate precursor to invasive cervical cancer, is more difficult to measure because of its lower incidence, but provides the most stringent evidence of potential cancer prevention. We report vaccine efficacy against CIN3+ and adenocarcinoma in situ (AIS) in the end-of-study analysis of PATRICIA (PApilloma TRIal against Cancer In young Adults). METHODS: Healthy women aged 15-25 years with no more than six lifetime sexual partners were included in PATRICIA, irrespective of their baseline HPV DNA status, HPV-16 or HPV-18 serostatus, or cytology. Women were randomly assigned (1:1) to receive an HPV-16/18 AS04-adjuvanted vaccine or a control hepatitis A vaccine via an internet-based central randomisation system using a minimisation algorithm to account for age ranges and study sites. The patients and study investigators were masked to allocated vaccine. The primary endpoint of PATRICIA has been reported previously. In the present end-of-study analysis, we focus on CIN3+ and AIS in the populations of most clinical interest, the total vaccinated cohort (TVC) and the TVC-naive. The TVC comprised all women who received at least one vaccine dose, approximating catch-up populations and including sexually active women (vaccine n=9319; control=9325). The TVC-naive comprised women with no evidence of oncogenic HPV infection at baseline, approximating early adolescent HPV exposure (vaccine n=5824; control=5820). This study is registered with ClinicalTrials.gov, number NCT00122681. FINDINGS: Vaccine efficacy against CIN3+ associated with HPV-16/18 was 100% (95% CI 85·5-100) in the TVC-naive and 45·7% (22·9-62·2) in the TVC. Vaccine efficacy against all CIN3+ (irrespective of HPV type in the lesion and including lesions with no HPV DNA detected) was 93·2% (78·9-98·7) in the TVC-naive and 45·6% (28·8-58·7) in the TVC. In the TVC-naive, vaccine efficacy against all CIN3+ was higher than 90% in all age groups. In the TVC, vaccine efficacy against all CIN3+ and CIN3+ associated with HPV-16/18 was highest in the 15-17 year age group and progressively decreased in the 18-20 year and 21-25 year age groups. Vaccine efficacy against all AIS was 100% (31·0-100) and 76·9% (16·0-95·8) in the TVC-naive and TVC, respectively. Serious adverse events occurred in 835 (9·0%) and 829 (8·9%) women in the vaccine and control groups, respectively; only ten events (0·1%) and five events (0·1%), respectively, were considered to be related to vaccination. INTERPRETATION: PATRICIA end-of-study results show excellent vaccine efficacy against CIN3+ and AIS irrespective of HPV DNA in the lesion. Population-based vaccination that incorporates the HPV-16/18 vaccine and high coverage of early adolescents might have the potential to substantially reduce the incidence of cervical cancer. FUNDING: GlaxoSmithKline Biologicals.

Cross-protective efficacy of HPV-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by non-vaccine oncogenic HPV types: 4-year end-of-study analysis of the randomised, double-blind PATRICIA trial.

BACKGROUND: We evaluated the efficacy of the human papillomavirus HPV-16/18 AS04-adjuvanted vaccine against non-vaccine oncogenic HPV types in the end-of-study analysis after 4 years of follow-up in PATRICIA (PApilloma TRIal against Cancer In young Adults). METHODS: Healthy women aged 15-25 years with no more than six lifetime sexual partners were included in PATRICIA irrespective of their baseline HPV DNA status, HPV-16 or HPV-18 serostatus, or cytology. Women were randomly assigned (1:1) to HPV-16/18 vaccine or a control hepatitis A vaccine, via an internet-based central randomisation system using a minimisation algorithm to account for age ranges and study sites. The study was double-blind. The primary endpoint of PATRICIA has been reported previously; the present analysis evaluates cross-protective vaccine efficacy against non-vaccine oncogenic HPV types in the end-of-study analysis. Analyses were done for three cohorts: the according-to-protocol cohort for efficacy (ATP-E; vaccine n=8067, control n=8047), total vaccinated HPV-naive cohort (TVC-naive; no evidence of infection with 14 oncogenic HPV types at baseline, approximating young adolescents before sexual debut; vaccine n=5824, control n=5820), and the total vaccinated cohort (TVC; all women who received at least one vaccine dose, approximating catch-up populations that include sexually active women; vaccine n=9319, control=9325). Vaccine efficacy was evaluated against 6-month persistent infection, cervical intraepithelial neoplasia grade 2 or greater (CIN2+) associated with 12 non-vaccine HPV types (individually or as composite endpoints), and CIN3+ associated with the composite of 12 non-vaccine HPV types. This study is registered with ClinicalTrials.gov, number NCT00122681. FINDINGS: Consistent vaccine efficacy against persistent infection and CIN2+ (with or without HPV-16/18 co-infection) was seen across cohorts for HPV-33, HPV-31, HPV-45, and HPV-51. In the most conservative analysis of vaccine efficacy against CIN2+, where all cases co-infected with HPV-16/18 were removed, vaccine efficacy was noted for HPV-33 in all cohorts, and for HPV-31 in the ATP-E and TVC-naive. Vaccine efficacy against CIN2+ associated with the composite of 12 non-vaccine HPV types (31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68), with or without HPV-16/18 co-infection, was 46·8% (95% CI 30·7-59·4) in the ATP-E, 56·2% (37·2-69·9) in the TVC-naive, and 34·2% (20·4-45·8) in the TVC. Corresponding values for CIN3+ were 73·8% (48·3-87·9), 91·4% (65·0-99·0), and 47·5% (22·8-64·8). INTERPRETATION: Data from the end-of-study analysis of PATRICIA show cross-protective efficacy of the HPV-16/18 vaccine against four oncogenic non-vaccine HPV types-HPV-33, HPV-31, HPV-45, and HPV-51-in different trial cohorts representing diverse groups of women. FUNDING: GlaxoSmithKline Biologicals.

Oseltamivir, an influenza neuraminidase inhibitor drug, does not affect the steady-state pharmacokinetic characteristics of cyclosporine, mycophenolate, or tacrolimus in adult renal transplant patients.

BACKGROUND: An influenza neuraminidase inhibitor drug, oseltamivir (Os) may be prescribed to renal transplant patients to prevent and treat influenza A and B illness. A pharmacokinetic (PK) interaction between Os and immunosuppressive drugs might adversely affect the efficacy and/or toxicity of the latter agents. This study was conducted to determine whether adverse symptoms and acute drug interactions occur during their coadministration. MATERIALS AND METHODS: A randomized, crossover study design was utilized to study the effect of a 75-mg dose of Os on the steady-state PK of cyclosporine A (CyA), mycophenolate mofetil, or tacrolimus (Tac) in a convenience sample of 19 adults with a renal allograft by measurement of total plasma or blood drug concentrations (C(p)) over one 12-hour dose interval. Os PK parameters were determined from its concentrations and those of its metabolite, Os carboxylate, in plasma and urine over 48 hours. RESULTS: Of 19 volunteers, 12 were men, with age (mean ± SD) 46 ± 11 years, weight 83 ± 19 kg, and calculated Cl(creatinine) 64 ± 27 mL/min. Adverse effects were minor and transient. Os did not affect the steady-state C(max), T(max), or area under the concentration versus time curve (AUC) over a 12-hour dose interval of CyA, mycophenolic acid, or Tac or the C(trough) of CyA or mycophenolate but increased the mean C(trough) of Tac by 13%. DISCUSSION: The increase in Tac mean C(trough) during coadministration with Os is not likely clinically important. Os and Os carboxylate PK were similar to those in subjects with native kidneys and similar renal function who have been described in the literature. CONCLUSIONS: These data from a single Os dose study suggest that coadministration is not expected to cause adverse symptoms nor alter the steady-state PK of CyA, mycophenolate mofetil, or Tac in stable adult renal transplant patients with mild renal insufficiency. The data enable a multiple-dose study that reflects clinical practice during influenza exposure and assesses the possibility that chronic exposure to Os might result in a different outcome.

Famciclovir: a focus on efficacy and safety.

IMPORTANCE OF THE FIELD: Famciclovir is the prodrug of penciclovir, a guanosine analogue that inhibits viruses of the alpha sub-family of the Herpesviridae, as well as hepatitis B virus. It is indicated for management of mucocutaneous herpes simplex virus disease and acute herpes zoster, and has been investigated for management of hepatitis B virus infection. AREAS COVERED IN THIS REVIEW: Data for this review were identified by searches of papers published in English on Medline and Scopus, spanning the years 1975 through 1 February 2010 with the key words: 'famciclovir', 'famvir', 'penciclovir', 'herpes', 'oral', 'genital', 'varicella', 'zoster' and 'virus' in association with 'safety', 'toxicity', 'tolerability', 'efficacy' and 'indications'. Relevant references were also obtained from articles acquired through the search strategy. WHAT THE READER WILL GAIN: Readers are also provided with up-to-date information on the use of famciclovir for infections due to herpes simplex, varicella zoster and hepatitis B viruses. Clinical data pertaining to the safety and tolerability of famciclovir are also reviewed. TAKE HOME MESSAGE: Famciclovir is a safe, convenient, and well-tolerated drug when used for its approved indications. The most common side effects indicated in the majority of studies were headache and nausea. Data for its use in childhood and pregnancy are limited.

Influenza virus susceptibility and resistance to oseltamivir.

Oseltamivir phosphate is a prodrug of oseltamivir carboxylate, a highly specific inhibitor of influenza virus neuraminidases. Given that oseltamivir carboxylate binds to highly conserved, essential amino acids in the catalytic site of the enzyme, and that the activity of neuraminidase is critical for virus release from infected cells and subsequent virus spread, the drug was expected to have a low propensity to select for viable resistant mutants. Indeed, viruses with neuraminidase (and haemagglutinin) substitutions conferring reduced susceptibility to oseltamivir have been generated with difficulty in vitro, and these mutants generally have reduced infectivity and transmissibility compared with wild-type virus in animal models. Studies of seasonal influenza isolates collected before the introduction of oseltamivir show an absence of naturally occurring resistance. Few resistant mutants have arisen during clinical trials of oseltamivir in seasonal influenza, with cumulative data from all Roche-sponsored studies indicating an incidence of resistance of 0.32% in adults (0.4%, including low-level mutants detected by genotyping alone in mixed virus populations) and 4.1% (5.4%) in children. Higher incidences of resistance were observed in two small Japanese studies, in which children received a different dosing schedule from their Western counterparts. In summary, the overall incidence of influenza virus resistance associated with the seasonal use of oseltamivir is currently low and resistant viruses might be of little clinical significance, except perhaps in immunocompromised individuals. However, continued vigilance, especially of emerging avian H5N1 strains, combined with careful, systematic laboratory-based monitoring, is essential.