Impact of donor CYP3A5 genotype on pharmacokinetics of tacrolimus in South African paediatric liver transplant patients.

BACKGROUND: In the paediatric liver transplant programme in Johannesburg, South Africa (SA), tacrolimus is the calcineurin inhibitor of choice, comprising an essential component of the immunosuppression regimen. It is characterised by a narrow therapeutic index and wide interpatient variability, necessitating therapeutic drug monitoring of whole-blood concentrations. Pharmacogenetic research, although not representative of SA population groups, suggests that single-nucleotide polymorphisms within the cytochrome P450 3A5 (CYP3A5) gene contribute to the variability in tacrolimus dosing requirements. The rs776746 polymorphism, CYP3A5*3, results in a splice defect and a non-functional enzyme. Clinically, to reach the same tacrolimus concentration-to-dose ratio (CDR), expressors (CYP3A5*1/*1 and *1/*3) require a higher tacrolimus dose than non-expressors (*3/*3). OBJECTIVES: To compare the pharmacokinetics of tacrolimus in paediatric liver transplant recipients with their donors' CYP3A5 genotypes, considering both donor and recipient characteristics. METHODS: Blood samples from 46 living liver donors were collected, their genomic DNA was extracted, and their CYP3A5 genotype was established (polymerase chain reaction and restriction fragment length polymorphism analysis, validated by Sanger sequencing). The relationship of donor and recipient characteristics with the mean tacrolimus CDR was analysed using a general linear model. Non- confounding significant variables were included in a multiple regression model. RESULTS: The study showed that all expressor donors genotyped as CYP3A5*1/*1 were of black African self-reported race and ethnicity. During the first 15 days post-transplant, we found that children who received grafts from donor CYP3A5 expressors (CYP3A5*1/*1 and *1/*3) had significantly lower mean tacrolimus CDRs compared with those who received grafts from donor CYP3A5 non-expressors (*3/*3); the recipients of CYP3A5 expressor grafts therefore require higher doses of oral tacrolimus to achieve the same therapeutic target range. In addition, graft-to-recipient weight ratio and the CYP3A5 donor genotypes were independent factors that significantly (p<0.05) affected mean tacrolimus CDRs in recipients. CONCLUSION: In this study, we showed that all CYP3A5*1 homozygote donors were of black African self-reported race and ethnicity, and tacrolimus CDRs in paediatric living-donor liver transplant recipients were significantly affected by donor graft size and donor CYP3A5 genotypes. Information from this study may inform the development of an Afrocentric tacrolimus precision-medicine algorithm to optimise recipient safety and graft outcomes.

Imaging spectrum of amyloid-related imaging abnormalities associated with aducanumab immunotherapy.

Alzheimer's Disease (AD) is a leading cause of morbidity. Management of AD has traditionally been aimed at symptom relief rather than disease modification. Recently, AD research has begun to shift focus towards disease-modifying therapies that can alter the progression of AD. In this context, a class of immunotherapy agents known as monoclonal antibodies target diverse cerebral amyloid-beta (Aß) epitopes to inhibit disease progression. Aducanumab was authorized by the US Food and Drug Administration (FDA) to treat AD on June 7, 2021. Aducanumab has shown promising clinical and biomarker efficacy but is associated with amyloid-related imaging abnormalities (ARIA). Neuroradiologists play a critical role in diagnosing ARIA, necessitating familiarity with this condition. This pictorial review will appraise the radiologic presentation of ARIA in patients on aducanumab.

Outbreak of Legionnaires' disease associated with cooling towers at a California state prison, 2015.

A large outbreak of Legionnaires' disease occurred at a California state prison in August 2015. We conducted environmental and epidemiological investigations to identify the most likely source of exposure and characterise morbidity. Sixty-four inmates had probable Legionnaires' disease; 14 had laboratory-confirmed legionellosis. Thirteen (17%) inmates were hospitalised; there were no deaths. Ill inmates were more likely to be ⩾65 years old (P < 0.01), have the chronic obstructive pulmonary disease (P < 0.01), diabetes mellitus (P = 0.02), hepatitis C infection (P < 0.01), or end-stage liver disease (P < 0.01). The case-patients were in ten housing units throughout the prison grounds. All either resided in or were near the central clinical building (for appointments or yard time) during their incubation periods. Legionella pneumophila serogroup 1 was cultured from three cooling towers on top of the central medical clinic (range, 880-1200 cfu/ml). An inadequate water management program, dense biofilm within the cooling towers, and high ambient temperatures preceding the outbreak created an ideal environment for Legionella sp. proliferation. All state prisons were directed to develop local operating procedures for maintaining their cooling towers and the state health department added a review of the maintenance plans to their environmental inspection protocol.

Outbreak epidemiologically linked with a composite product of beef, mechanically separated chicken and textured vegetable protein contaminated with multiple serotypes of Salmonella enterica including multidrug-resistant Infantis, California 2016.

A salmonellosis outbreak occurred at a California prison in April and May 2016. In a cohort study of 371 inmates, persons who consumed dishes from the prison kitchen made from ground meat had a higher attack rate (15%) than those who did not (4%) (risk ratio 3.4, 95% CI 1.1-10.6). The ground meat product was composed exclusively of beef, mechanically separated chicken (MSC) and textured vegetable protein; eight of eight lots of the product collected from the prison and processing facility were contaminated with Salmonella enterica of eight serotypes and 17 distinct PFGE patterns, including multidrug-resistant S. Infantis. Either the MSC or the beef could have been the source of the particular strains of S. enterica isolated from patients or the product. The microbiological evidence is most consistent with MSC as the source of the high levels of S. enterica in the epidemiologically linked meat product. Our findings contribute to the growing body of evidence about the hazard posed by the use of products containing raw mechanically separated poultry in kitchens in institutions.

Plasma N-Terminal Probrain Natriuretic Peptide, Vascular Endothelial Growth Factor, and Cardiac Troponin I as Novel Biomarkers of Hypertensive Disease and Target Organ Damage in Cats.

BACKGROUND: In the absence of ocular target organ damage (ocular-TOD), diagnosis of hypertension is challenging in cats. Biomarkers would provide additional support for the diagnosis of hypertension. HYPOTHESIS: Vascular endothelial growth factor (VEGF), N-terminal probrain natriuretic peptide (NT-proBNP), cardiac troponin I (cTnI), and urine protein-to-creatinine ratio (UPC) are predictors of systemic hypertension, will be increased in cats with hypertension with or without ocular-TOD, and will decrease with antihypertensive treatment. METHODS: Plasma VEGF, NT-proBNP, and cTnI concentrations and UPC were determined in healthy geriatric cats, normotensive cats with chronic kidney disease (CKD), hypertensive cats with evidence of hypertensive retinopathy (HT-ocular-TOD), and hypertensive cats without hypertensive ocular-TOD (HT-noTOD). Comparisons among groups were performed. Multivariable binary logistic regression models were built to identify independent biomarkers of hypertension and ocular-TOD. Receiver operator characteristic (ROC) curves were drawn to assess clinical use. RESULTS: Cats with HT-ocular-TOD had significantly higher VEGF than all other groups (P < .05) and significantly higher NT-proBNP than healthy cats (P < .001). Healthy cats had significantly lower cTnI than all other groups (P < .05). No differences were found among groups for UPC (P = .08). Cardiac troponin I and VEGF were independent predictors of hypertension (P < .05), but none of the biomarkers were independent predictors of ocular-TOD. N-terminal probrain natriuretic peptide concentrations decreased with antihypertensive treatment (P < .001). The ROC curves indicated that none of the biomarkers met the criteria to function as diagnostic tests for the diagnosis of hypertension or associated ocular-TOD. CONCLUSIONS AND CLINICAL SIGNIFICANCE: Despite statistical significance and changes with ocular-TOD, antihypertensive treatment, or both, VEGF, NT-proBNP, and cTnI did not function as useful diagnostic tests for hypertension. Persistently increased systolic blood pressure (SBP) measurements in combination with fundoscopy remains the preferred method for diagnosis of feline hypertension.

Does the North American Society for Pediatric and Adolescent Gynecology Short Curriculum Increase Resident Knowledge in Pediatric and Adolescent Gynecology?

STUDY OBJECTIVE: To determine if the North American Society for Pediatric and Adolescent Gynecology (NASPAG) Short Curriculum improves self-reported knowledge in pediatric and adolescent gynecology (PAG) among obstetrics and gynecology (Ob/Gyn) residents, at programs without PAG-trained faculty. DESIGN: Prospective, cross-sectional exposure to the NASPAG short curriculum with a follow-up questionnaire. SETTING: Ob/Gyn residency training programs without PAG faculty. PARTICIPANTS: Ob/Gyn residents in training from February 2015 to June 2015. INTERVENTIONS: Exposure to the NASPAG Short Curriculum. MAIN OUTCOME MEASURES: Improvement in self-perceived knowledge after completion of curriculum. RESULTS: Two hundred twenty-seven residents met inclusion criteria; 34 completed the study (15% response). Less than 50% of residents reported adequate knowledge in the areas of prepubertal vaginal bleeding, vulvovaginitis, precocious and delayed puberty, Home environment, Education and Employment, Eating, peer-related Activities, Drugs, Sexuality, Suicide/depression, Safety from injury and violence (HEEADSSS) interview, pelvic pain, and bleeding management in teens with developmental delay. After completion of the curriculum, self-reported knowledge improved in 8 of 10 learning objectives, with no significant improvement in bleeding disorders or Müllerian anomalies. There was no association between pretest knowledge and level of residency training, type of residency program, previous exposure to PAG lectures, and previous exposure to patients with PAG complaints. CONCLUSION: Significant deficiencies exist regarding self-reported knowledge of core PAG topics among Ob/Gyn residents at programs without PAG-trained faculty. Use of the NASPAG Short Curriculum by residents without access to PAG-trained faculty resulted in improved self-reported knowledge in PAG.

Prevalent high-risk HPV infection and vaginal microbiota in Nigerian women.

In this study, we evaluated the association between high-risk human papillomavirus (hrHPV) and the vaginal microbiome. Participants were recruited in Nigeria between April and August 2012. Vaginal bacterial composition was characterized by deep sequencing of barcoded 16S rRNA gene fragments (V4) on Illumina MiSeq and HPV was identified using the Roche Linear Array® HPV genotyping test. We used exact logistic regression models to evaluate the association between community state types (CSTs) of vaginal microbiota and hrHPV infection, weighted UniFrac distances to compare the vaginal microbiota of individuals with prevalent hrHPV to those without prevalent hrHPV infection, and the Linear Discriminant Analysis effect size (LEfSe) algorithm to characterize bacteria associated with prevalent hrHPV infection. We observed four CSTs: CST IV-B with a low relative abundance of Lactobacillus spp. in 50% of participants; CST III (dominated by L. iners) in 39·2%; CST I (dominated by L. crispatus) in 7·9%; and CST VI (dominated by proteobacteria) in 2·9% of participants. LEfSe analysis suggested an association between prevalent hrHPV infection and a decreased abundance of Lactobacillus sp. with increased abundance of anaerobes particularly of the genera Prevotella and Leptotrichia in HIV-negative women (P < 0·05). These results are hypothesis generating and further studies are required.

The rare DAT coding variant Val559 perturbs DA neuron function, changes behavior, and alters in vivo responses to psychostimulants.

Despite the critical role of the presynaptic dopamine (DA) transporter (DAT, SLC6A3) in DA clearance and psychostimulant responses, evidence that DAT dysfunction supports risk for mental illness is indirect. Recently, we identified a rare, nonsynonymous Slc6a3 variant that produces the DAT substitution Ala559Val in two male siblings who share a diagnosis of attention-deficit hyperactivity disorder (ADHD), with other studies identifying the variant in subjects with bipolar disorder (BPD) and autism spectrum disorder (ASD). Previously, using transfected cell studies, we observed that although DAT Val559 displays normal total and surface DAT protein levels, and normal DA recognition and uptake, the variant transporter exhibits anomalous DA efflux (ADE) and lacks capacity for amphetamine (AMPH)-stimulated DA release. To pursue the significance of these findings in vivo, we engineered DAT Val559 knock-in mice, and here we demonstrate in this model the presence of elevated extracellular DA levels, altered somatodendritic and presynaptic D2 DA receptor (D2R) function, a blunted ability of DA terminals to support depolarization and AMPH-evoked DA release, and disruptions in basal and psychostimulant-evoked locomotor behavior. Together, our studies demonstrate an in vivo functional impact of the DAT Val559 variant, providing support for the ability of DAT dysfunction to impact risk for mental illness.

A UK retrospective observational study of clinical outcomes and healthcare resource utilisation of infliximab treatment in Crohn's disease.

BACKGROUND: Crohn's disease (CD) places a substantial burden on healthcare systems, with the majority of costs arising from hospitalisation and surgery. AIM: To evaluate the 'real-world' clinical effectiveness, impact on healthcare utilisation and cost of infliximab for the treatment of CD in UK practice. METHODS: A non-interventional, retrospective analysis of medical records from patients with CD treated with infliximab at 18 hospital centres across the UK. The primary objective was to compare cumulative clinical outcomes and healthcare resource utilisation for the 0- to 24-month post-infliximab period with the 12 months preceding infliximab treatment. Predefined outcomes included the number of elective surgical procedures, hospitalisations and healthcare provider consultations. Costs associated with healthcare utilisation were collected from the perspective of the UK National Health Service (NHS). RESULTS: The study involved 380 patients. Infliximab significantly reduced the mean number of elective (from 0.18 to 0.11; P = 0.0035) and non-elective (from 0.46 to 0.29; P < 0.0001) hospitalisations, and the number of consultations with gastroenterologists, gastrointestinal surgeons and radiologists (from 4.0 to 3.5, from 0.7 to 0.5 and from 0.5 to 0.2, respectively; all P < 0.001); all decreases were associated with significant cost reductions. The mean number of elective surgical procedures (including correction of severe anal fistulae and abscess drainage) was significantly reduced. CONCLUSIONS: The observed reductions in numbers of hospitalisations, surgical procedures and consultations with healthcare professionals are key indicators of the clinical effectiveness of infliximab for the treatment of CD. These benefits result in overall decreases in healthcare resource utilisation, which translate into cost savings for the NHS.

Immune responses elicited by a fourth dose of the HPV-16/18 AS04-adjuvanted vaccine in previously vaccinated adult women.

BACKGROUND: Vaccines are now available for the prevention of HPV-16/18-related cervical infections and pre-cancers, primarily targeting adolescent girls. Since the risk of HPV exposure potentially persists throughout a woman's sexual life, vaccine-derived immunity should be long-term. The current study, HPV-024 (NCT00546078, http://clinicaltrials.gov), assessed the immune memory in North American women who received three doses of HPV-16/18 AS04-adjuvanted vaccine 7 years earlier in HPV-001 (NCT00689741). METHODS: Women vaccinated in HPV-001 received a 4th-dose of the HPV-16/18 vaccine (024-4DV group, N=65). Post 4th-dose immune responses were compared with post 1st-dose immune responses in cross-vaccination controls (024-3DV group, N=50). Reactogenicity was compared between the 4th-dose and the 1st-dose administration. RESULTS: Pre 4th-dose, 100% of subjects in the 024-4DV group remained seropositive for anti-HPV-16/18 antibodies (ELISA). Compared to pre 4th-dose, GMTs for anti-HPV-16 and anti-HPV-18 antibodies were respectively 9.3-fold and 8.7-fold higher at day 7, and 22.7-fold and 17.2-fold higher at month 1. Compared to post 1st-dose, GMTs for anti-HPV-16 and anti-HPV-18 were respectively 80.5-fold and 205.4-fold higher at day 7, and 11.8-fold and 20.5-fold higher at month 1. Furthermore, 68.2% and 77.3% of women had HPV-16/18 specific memory B-cells, respectively, pre 4th-dose, rising to 100% one month post 4th-dose vaccination. The 4th-dose was generally well tolerated. CONCLUSION: A 4th-dose of HPV-16/18 AS04-adjuvanted vaccine triggered a rapid and strong anamnestic response in previously vaccinated women, demonstrating vaccine-induced immune memory.

Evaluation of treatment options for patients with advanced renal cell carcinoma: assessment of appropriateness, using the validated semi-quantitative RAND corporation/University of California, Los Angeles methodology.

A diverse range of treatment options and interventions are available for the management of renal cell carcinoma (RCC), allowing clinicians to tailor therapy to best meet their patient's needs and situation. However, choosing from the plethora of options can be problematic. RCC treatment guidelines advise on the most efficacious agents based upon specific clinical trial populations, but these do not always take into account all the patient factors that influence the suitability of treatment options for individual patients. This study used the validated RAND/UCLA (RAND corporation/University of California, Los Angeles) 'appropriateness methodology' to integrate clinical efficacy data with expert opinion concerning the use of specific RCC treatment options for particular patient scenarios, in an attempt to facilitate the widespread implementation of patient-focussed treatment choices. Use of the methodology has allowed us to develop treatment algorithms for patients with locally-advanced RCC and for those with metastatic disease post-nephrectomy or with primary tumour in situ. The algorithms take into account patient-specific characteristics such as tumour histology, prior treatment and known risk factors to advise whether a particular treatment intervention is appropriate, not appropriate or of uncertain appropriateness. Use of this methodology aims to develop a formalised process by which expert opinion can be integrated with clinical data and used as an additional source of information that can provide further guidance concerning difficult treatment decisions when data are absent or sparse.

Efficacy of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine in women aged 15-25 years with and without serological evidence of previous exposure to HPV-16/18.

In the Phase III PATRICIA study (NCT00122681), the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine (Cervarix(®), GlaxoSmithKline Biologicals) was highly efficacious against HPV-16/18 infections and precancerous lesions in women HPV-16/18 deoxyribose nucleic acid (DNA) negative and seronegative at baseline. We present further data on vaccine efficacy (VE) against HPV-16/18 in the total vaccinated cohort including women who may have been exposed to HPV-16/18 infection before vaccination. In women with no evidence of current or previous HPV-16/18 infection (DNA negative and seronegative), VE was 90.3% (96.1% confidence interval: 87.3-92.6) against 6-month persistent infection (PI), 91.9% (84.6-96.2) against cervical intraepithelial neoplasia (CIN)1+ and 94.6% (86.3-98.4) against CIN2+ [97.7% (91.1-99.8) when using the HPV type assignment algorithm (TAA)]. In women HPV-16/18 DNA negative but with serological evidence of previous HPV-16/18 infection (seropositive), VE was 72.3% (53.0-84.5) against 6-month PI, 67.2% (10.9-89.9) against CIN1+, and 68.8% (-28.3-95.0) against CIN2+ [88.5% (10.8-99.8) when using TAA]. In women with no evidence of current HPV-16/18 infection (DNA negative), regardless of their baseline HPV-16/18 serological status, VE was 88.7% (85.7-91.1) against 6-month PI, 89.1% (81.6-94.0) against CIN1+ and 92.4% (84.0-97.0) against CIN2+ [97.0% (90.6-99.5) when using TAA]. In women who were DNA positive for one vaccine type, the vaccine was efficacious against the other vaccine type. The vaccine did not impact the outcome of HPV-16/18 infections present at the time of vaccination. Vaccination was generally well tolerated regardless of the woman's HPV-16/18 DNA or serological status at entry.

Monitoring infection with Epstein-Barr virus among seromismatch adult renal transplant recipients.

Patients who undergo Epstein-Barr virus (EBV) seromismatch (D+/R-) transplants have a higher risk for the development of post-transplant lymphoproliferative disorder (PTLD). Adult renal transplant recipients at a single institution were prospectively monitored for EBV during the first year post-transplant. Over a 2-year period, 34 patients (7.78%) were identified as being EBV D+/R-recipients. Patients who developed symptoms or had persistent viremia were pre-emptively administered rituximab. Six recipients were discharged without monitoring on the protocol. Of those six, three (50%) developed PTLD and all three lost their grafts. Twenty (60.6%) of the 34 recipients developed viremia during the first year post-transplant. Of the recipients who became viremic, six (30%) received rituximab. None of the six who received rituximab-developed PTLD. We found that recipients who were not monitored on the protocol were more likely to have PTLD and graft loss compared to those who were (p = 0.008). Post-transplant monitoring of adults who undergo EBV D+/R-kidney transplants for viremia and symptoms associated with EBV infection may prompt intervention which reduces the incidence of PTLD within the first year. Use of rituximab in preventing PTLD among patients with primary EBV infection requires further prospective study to determine its overall safety and efficacy.

Point-source outbreak of coccidioidomycosis in construction workers.

Coccidioidomycosis results from inhaling spores of the fungus Coccidioides spp. in soil or airborne dust in endemic areas. We investigated an outbreak of coccidioidomycosis in a 12-person civilian construction crew that excavated soil during an underground pipe installation on Camp Roberts Military Base, California in October 2007. Ten (83.3%) workers developed symptoms of coccidioidomycosis; eight (66.7%) had serologically confirmed disease, seven had abnormal chest radiographs, and one developed disseminated infection; none used respiratory protection. A diagnosis of coccidioidomycosis in an eleventh worker followed his exposure to the outbreak site in 2008. Although episodic clusters of infections have occurred at Camp Roberts, the general area is not associated with the high disease rates found in California's San Joaquin Valley. Measures to minimize exposure to airborne spores during soil-disrupting activities should be taken before work begins in any coccidioides-endemic area, including regions with only historic evidence of disease activity.

Sustained efficacy and immunogenicity of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine: analysis of a randomised placebo-controlled trial up to 6.4 years.

BACKGROUND: Prophylactic human papillomavirus (HPV) vaccines have to provide sustained protection. We assessed efficacy, immunogenicity, and safety of the HPV-16/18 AS04-adjuvanted vaccine up to 6.4 years. METHODS: Women aged 15-25 years, with normal cervical cytology, who were HPV-16/18 seronegative and oncogenic HPV DNA-negative (14 types) at screening participated in a double-blind, randomised, placebo-controlled initial study (n=1113; 560 vaccine group vs 553 placebo group) and follow-up study (n=776; 393 vs 383). 27 sites in three countries participated in the follow-up study. Cervical samples were tested every 6 months for HPV DNA. Management of abnormal cytologies was prespecified, and HPV-16/18 antibody titres were assessed. The primary objective was to assess long-term vaccine efficacy in the prevention of incident cervical infection with HPV 16 or HPV 18, or both. We report the analyses up to 6.4 years of this follow-up study and combined with the initial study. For the primary endpoint, the efficacy analysis was done in the according-to-protocol (ATP) cohort; the analysis of cervical intraepithelial neoplasia grade 2 and above (CIN2+) was done in the total vaccinated cohort (TVC). The study is registered with ClinicalTrials.gov, number NCT00120848. FINDINGS: For the combined analysis of the initial and follow-up studies, the ATP efficacy cohort included 465 women in the vaccine group and 454 in the placebo group; the TVC included 560 women in the vaccine group and 553 in the placebo group. Vaccine efficacy against incident infection with HPV 16/18 was 95.3% (95% CI 87.4-98.7) and against 12-month persistent infection was 100% (81.8-100). Vaccine efficacy against CIN2+ was 100% (51.3-100) for lesions associated with HPV-16/18 and 71.9% (20.6-91.9) for lesions independent of HPV DNA. Antibody concentrations by ELISA remained 12-fold or more higher than after natural infection (both antigens). Safety outcomes were similar between groups: during the follow-up study, 30 (8%) participants reported a serious adverse event in the vaccine group versus 37 (10%) in the placebo group. None was judged related or possibly related to vaccination, and no deaths occurred. INTERPRETATION: Our findings show excellent long-term efficacy, high and sustained immunogenicity, and favourable safety of the HPV-16/18 AS04-adjuvanted vaccine up to 6.4 years. FUNDING: GlaxoSmithKline Biologicals (Belgium).

Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young women.

BACKGROUND: The human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine was immunogenic, generally well tolerated, and effective against HPV-16 or HPV-18 infections, and associated precancerous lesions in an event-triggered interim analysis of the phase III randomised, double-blind, controlled PApilloma TRIal against Cancer In young Adults (PATRICIA). We now assess the vaccine efficacy in the final event-driven analysis. METHODS: Women (15-25 years) were vaccinated at months 0, 1, and 6. Analyses were done in the according-to-protocol cohort for efficacy (ATP-E; vaccine, n=8093; control, n=8069), total vaccinated cohort (TVC, included all women receiving at least one vaccine dose, regardless of their baseline HPV status; represents the general population, including those who are sexually active; vaccine, n=9319; control, n=9325), and TVC-naive (no evidence of oncogenic HPV infection at baseline; represents women before sexual debut; vaccine, n=5822; control, n=5819). The primary endpoint was to assess vaccine efficacy against cervical intraepithelial neoplasia 2+ (CIN2+) that was associated with HPV-16 or HPV-18 in women who were seronegative at baseline, and DNA negative at baseline and month 6 for the corresponding type (ATP-E). This trial is registered with ClinicalTrials.gov, number NCT00122681. FINDINGS: Mean follow-up was 34.9 months (SD 6.4) after the third dose. Vaccine efficacy against CIN2+ associated with HPV-16/18 was 92.9% (96.1% CI 79.9-98.3) in the primary analysis and 98.1% (88.4-100) in an analysis in which probable causality to HPV type was assigned in lesions infected with multiple oncogenic types (ATP-E cohort). Vaccine efficacy against CIN2+ irrespective of HPV DNA in lesions was 30.4% (16.4-42.1) in the TVC and 70.2% (54.7-80.9) in the TVC-naive. Corresponding values against CIN3+ were 33.4% (9.1-51.5) in the TVC and 87.0% (54.9-97.7) in the TVC-naive. Vaccine efficacy against CIN2+ associated with 12 non-vaccine oncogenic types was 54.0% (34.0-68.4; ATP-E). Individual cross-protection against CIN2+ associated with HPV-31, HPV-33, and HPV-45 was seen in the TVC. INTERPRETATION: The HPV-16/18 AS04-adjuvanted vaccine showed high efficacy against CIN2+ associated with HPV-16/18 and non-vaccine oncogenic HPV types and substantial overall effect in cohorts that are relevant to universal mass vaccination and catch-up programmes. FUNDING: GlaxoSmithKline Biologicals.