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.

Effect of Influenza Vaccination of Children on Infection Rate in Hutterite Communities: Follow-Up Study of a Randomized Trial.

BACKGROUND: An earlier cluster randomized controlled trial (RCT) of Hutterite colonies had shown that if more than 80% of children and adolescents were immunized with influenza vaccine there was a statistically significant reduction in laboratory-confirmed influenza among all unimmunized community members. We assessed the impact of this intervention for two additional influenza seasonal periods. METHODS: Follow-up data for two influenza seasonal periods of a cluster randomized trial involving 1053 Canadian children and adolescents aged 36 months to 15 years in Season 2 and 1014 in Season 3 who received the study vaccine, and 2805 community members in Season 2 and 2840 in Season 3 who did not receive the study vaccine. Follow-up for Season 2 began November 18, 2009 and ended April 25, 2010 while Season 3 extended from December 6, 2010 and ended May 27, 2011. Children were randomly assigned in a blinded manner according to community membership to receive either inactivated trivalent influenza vaccine or hepatitis A. The primary outcome was confirmed influenza A and B infection using RT-PCR assay. Due to the outbreak of 2009 H1N1 pandemic, data in Season 2 were excluded for analysis. RESULTS: For an analysis of the combined Season 1 and Season 3 data, among non-recipients (i.e., participants who did not receive study vaccines), 66 of the 2794 (2.4%) participants in the influenza vaccine colonies and 121 of the 2301 (5.3%) participants in the hepatitis A colonies had influenza confirmed by RT-PCR, for a protective effectiveness of 60% (95% CI, 6% to 83%; P = 0.04); among all study participants (i.e., including both those who received study vaccine and those who did not), 125 of the 3806 (3.3%) in the influenza vaccine colonies and 239 of the 3243 (7.4%) in the hepatitis A colonies had influenza confirmed by RT-PCR, for a protective effectiveness of 63% (95% CI, 5% to 85%; P = 0.04). CONCLUSION: Immunizing children and adolescents with inactivated influenza vaccine can offer a protective effect among unimmunized community members for influenza A and B together when considered over multiple years of seasonal influenza. TRIAL REGISTRATION: Clinicaltrials.gov NCT00877396.

Herpes Simplex Encephalitis: Lack of Clinical Benefit of Long-term Valacyclovir Therapy.

BACKGROUND: Despite the proven efficacy of acyclovir (ACV) therapy, herpes simplex encephalitis (HSE) continues to cause substantial morbidity and mortality. Among patients with HSE treated with ACV, the mortality rate is approximately 14%-19%. Among survivors, 45%-60% have neuropsychological sequelae at 1 year. Thus, improving therapeutic approaches to HSE remains a high priority. METHODS: Following completion of a standard course of intravenous ACV, 87 adult patients with HSE (confirmed by positive polymerase chain reaction [PCR] for herpes simplex virus DNA in cerebrospinal fluid) were randomized to receive either valacyclovir (VACV) 2 g thrice daily (n = 40) or placebo tablets (n = 47) for 90 days (12 tablets of study medication daily). The primary endpoint was survival with no or mild neuropsychological impairment at 12 months, as measured by the Mattis Dementia Rating Scale (MDRS). Logistic regression was utilized to assess factors related to the primary endpoint. RESULTS: The demographic characteristics of the 2 randomization groups were statistically similar with no significant differences in age, sex, or race. At 12 months, there was no significant difference in the MDRS scoring for VACV-treated vs placebo recipients, with 85.7% and 90.2%, respectively, of patients demonstrating no or mild neuropsychological impairment (P = .72). No significant study-related adverse events were encountered in either treatment group. CONCLUSIONS: Following standard treatment with intravenous ACV for PCR-confirmed HSE, an additional 3-month course of oral VACV therapy did not provide added benefit as measured by neuropsychological testing 12 months later in a population of relatively high-functioning survivors. CLINICAL TRIALS REGISTRATION: NCT00031486.

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.).

Bacteremia caused by Eggerthella lenta in an elderly man with a gastrointestinal malignancy: A case report.

Eggerthella lenta is an anaerobic, Gram-positive bacillus commonly found in the human digestive tract. Occasionally, it can cause life-threatening infections. Bacteremia due to this organism is always clinically significant and is associated with gastrointestinal diseases and states of immune suppression. The authors report a case involving an elderly man with a newly diagnosed gastrointestinal malignancy who developed bacteremia caused by E lenta, treated successfully using empirical therapy with vancomycin and piperacillin-tazobactam, followed by directed therapy with metronidazole once the identity and antibiotic susceptibility of the organism was established. The present case reinforces the connection between E lenta bacteremia with gastrointestinal malignancy and highlights the importance of searching for a source of bacteremia due to this organism.

L'Eggerthella lenta est un bacille anaérobique à Gram positif présent dans le tube digestif humain. Il cause parfois des infections au potentiel mortel. La bactériémie attribuable à cet organisme est toujours grave sur le plan clinique et s'associe à des maladies gastro-intestinales et à des états immunosuppressifs. Les auteurs présentent le cas d'un homme âgé atteint d'un cancer gastro-intestinal diagnostiqué qui a souffert d'une bactériémie causée par l'E lenta et qui a reçu un traitement empirique fructueux à la vancomycine et à la pipéracilline-tazobactam, suivi d'une thérapie dirigée au métronidazole une fois l'organisme connu et la susceptibilité à l'organisme établie. Ce cas renforce le lien entre la bactériémie causée par l'E lenta et le cancer gastro-intestinal et fait ressortir l'importance d'en chercher la source.

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.

Utility of a writing station in the multiple mini-interview.

The multiple mini-interview (MMI) is a reliable and valid method of selecting applicants for admission to health professional schools on the basis of non-cognitive traits. Because the MMI is a series of short interview stations that applicants rotate through in coordinated sequence, it can potentially be resource intensive. However, the MMI design has room for innovation and efficiency. At the University of Manitoba Faculty of Medicine, a 10-minute unsupervised writing station (WS) was incorporated into the MMI to obtain a writing sample from each applicant, to increase the number of independent scores per applicant, and to increase the number of applicants interviewed per circuit without increasing interviewer numbers. One assessor evaluated all the writing samples and assigned a score ranging from 1 to 7. With the inclusion of a WS into an 11-station MMI, the faculty's capacity to interview applicants increased by 9% (from 297 to 324) without substantially increasing interviewer hours needed per day. For 1,257 applicants interviewed in 2008-2011, the mean WS score was 4.03 (SD=1.36), whereas applicants' mean of 10 oral station (OS) scores was 4.62 (SD=0.69). Correlations between WS score and mean OS score ranged from .16 to .27 (p<.01) over the four years. Because inter-station correlations for OS ranged from .01 to .37, the correlation of .21 between WS and mean OS scores for all four years combined appears reasonable. Institutions that want to effectively increase the capacity of their MMI process might consider adding a WS.

Multiple mini-interview scores of medical school applicants with and without rural attributes.

INTRODUCTION: Students from rural areas are under-represented in medical schools. Concerns have been raised about rural applicants' qualifications relative to those of their urban counterparts, and the impact such potential differences in competitiveness may have on their under-representation. Although studies have reported no differences in Grade Point Average (GPA) and Medical College Admission Test (MCAT) scores between applicants with and without rural attributes, to date no study has assessed if performance on the multiple mini-interview (MMI) varies between the two groups. METHODS: The MMI scores of 1257 interviewees for admission to the MD program at the Faculty of Medicine, University of Manitoba, in years 2008 to 2011, were studied for an association with graduation from a rural high school and attributes in the following three domains: rural connections, employment in rural areas, and rural community service. RESULTS: There were 205 (16.3%) rural high school graduates among interviewed applicants. Rural high school graduates scored significantly lower (mean of 4.4 on a scale of 1 to 7; p < 0.05) than urban high school graduates (4.6). Among rural-attribute domains, those with rural community service alone had the highest MMI scores (4.9) while those with rural connections alone had the lowest scores (4.3; p = 0.016). After adjusting for demographics, GPA, and MCAT scores in a multiple linear regression model, rural-attribute domains were not significant predictors of an applicant's MMI score. However, graduation from a rural high school was significantly associated with decreased MMI scores (a 0.122 decrease in predicted MMI scores on a scale of 1 to 7). CONCLUSION: Despite graduates from rural and urban high schools having comparable GPA, there exists a rural-urban divide in MMI scores that could exacerbate the under-representation of rural students in medical schools. Aboriginal applicants can also potentially be disproportionately affected, as they were more often from rural high schools than from urban high schools. Future studies need to determine systematic and institutional reasons, if any, for the differential in MMI scoring that can affect admission decisions for some rural applicants. It is also to be noted that the magnitude of difference is small enough that it may ultimately be irrelevant for future physician performance and practitioner outcomes.

Use of Z-scores to rank applicants to professional degree programs.

Criteria for assessing suitability of applicants for professional degree programs such as veterinary medicine are usually treated as distinct components of a composite scoring procedure that determines applicant ranking. Some components are valued more than others, which is reflected in the relative weights assigned to each component. However, the patterns of dispersal of individual components have the potential to alter the assigned relative weights. Components with larger variances can have greater influences on composite scores than intended. Such unintended altered weighting can be avoided through standardization. Yet non-standardized approaches continue to be used for admissions ranking in several programs. In this study, we documented the potential for differential selection of applicants when non-standardized scoring approaches are applied to admissions assessment components. At our medical school, applicants' component scores with differing variances are standardized by determining Z-scores with a mean of 0 and standard deviation of 1 before mathematically combining to calculate composite scores and admissions ranking. We retrospectively and hypothetically ranked one applicant cohort using non-standardized methods and identified differences in ranking between the standardized and non-standardized approaches. Most differences were observed for applicants in the second, third, and fourth quintiles of the admissions rank list, that is, those for whom admissions cut-off decisions make a marked difference. Observations were supported by lower Spearman's rank correlation coefficients in these quintiles. Although standardization of component scores is not a novel topic, we document the implications of using non-standardized scoring approaches for applicant ranking and underscore the importance of standardization of component scores.

Characteristics of respiratory viral infections during influenza season in Canadian Hutterite Communities.

OBJECTIVES: To determined the pathogen-specific incidence of respiratory virus infection in Hutterite communities occurring over the 2008-2009 influenza season and assess temporal characteristics of respiratory illness related to infection. METHODS: 3273 participants community members enrolled in a cluster randomized trial of influenza vaccine were studied. RESULTS: One hundred forty-nine participants had laboratory-confirmed influenza, and 595 had at least one episode of laboratory-confirmed respiratory viral infection other than influenza. Entero/rhinovirus had the highest incidence among children<5 years. CONCLUSIONS: A decline in the incidence of infections with age was observed for influenza as well as for most other respiratory viruses.

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.

Prevalence and risk factors for cervical HPV infection and abnormalities in young adult women at enrolment in the multinational PATRICIA trial.

OBJECTIVE: We evaluated baseline data from the PApilloma TRIal against Cancer In young Adults (PATRICIA; NCT00122681) on the association between behavioral risk factors and HPV infection and cervical abnormalities. METHODS: Women completed behavioral questionnaires at baseline. Prevalence of HPV infection and cervical abnormalities (detected by cytological or histological procedures) and association with behavioral risk factors were analyzed by univariate and stepwise multivariable logistic regressions. RESULTS: 16782 women completed questionnaires. Among 16748 women with data for HPV infection, 4059 (24.2%) were infected with any HPV type. Among 16757 women with data for cytological abnormalities, 1626 (9.7%) had a cytological abnormality, of whom 1170 (72.0%) were infected with at least one oncogenic HPV type including HPV-16 (22.7%) and HPV-18 (9.3%). Multivariable analysis (adjusted for age and region, N=14404) showed a significant association between infection with any HPV type and not living with a partner, smoking, age <15 years at first sexual intercourse, higher number of sexual partners during the past 12 months, longer duration of hormonal contraception and history of sexually transmitted infection (STI). For cervical abnormalities, only history of STI (excluding Chlamydia trachomatis) remained significant in the multivariable analysis after adjusting for HPV infection. CONCLUSIONS: Women reporting 3+ sexual partners in the past 12 months had the highest risk of HPV infection at baseline. HPV infection was the main risk factor for cervical abnormalities, and history of STIs excluding Chlamydia trachomatis increased risk to a lesser extent. Although behavioral factors can influence risk, all sexually active women are susceptible to HPV infection.

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.