Sepehr N. Tabrizi

Population-level impact and herd effects following human papillomavirus vaccination programmes: a systematic review and meta-analysis.

BACKGROUND Human papillomavirus (HPV) vaccination programmes were first implemented in several countries worldwide in 2007. We did a systematic review and meta-analysis to assess the population-level consequences and herd effects after female HPV vaccination programmes, to verify whether or not the high efficacy reported in randomised controlled clinical trials are materialising in real-world situations. METHODS We searched the Medline and Embase databases (between Jan 1, 2007 and Feb 28, 2014) and conference abstracts for time-trend studies that analysed changes, between the pre-vaccination and post-vaccination periods, in the incidence or prevalence of at least one HPV-related endpoint: HPV infection, anogenital warts, and high-grade cervical lesions. We used random-effects models to derive pooled relative risk (RR) estimates. We stratified all analyses by age and sex. We did subgroup analyses by comparing studies according to vaccine type, vaccination coverage, and years since implementation of the vaccination programme. We assessed heterogeneity across studies using I(2) and χ(2) statistics and we did trends analysis to examine the dose-response association between HPV vaccination coverage and each study effect measure. FINDINGS We identified 20 eligible studies, which were all undertaken in nine high-income countries and represent more than 140 million person-years of follow-up. In countries with female vaccination coverage of at least 50%, HPV type 16 and 18 infections decreased significantly between the pre-vaccination and post-vaccination periods by 68% (RR 0·32, 95% CI 0·19-0·52) and anogenital warts decreased significantly by 61% (0·39, 0·22-0·71) in girls 13-19 years of age. Significant reductions were also recorded in HPV types 31, 33, and 45 in this age group of girls (RR 0·72, 95% CI 0·54-0·96), which suggests cross-protection. Additionally, significant reductions in anogenital warts were also reported in boys younger than 20 years of age (0·66 [95% CI 0·47-0·91]) and in women 20-39 years of age (0·68 [95% CI 0·51-0·89]), which suggests herd effects. In countries with female vaccination coverage lower than 50%, significant reductions in HPV types 16 and 18 infection (RR 0·50, 95% CI 0·34-0·74]) and in anogenital warts (0·86 [95% CI 0·79-0·94]) occurred in girls younger than 20 years of age, with no indication of cross-protection or herd effects. INTERPRETATION Our results are promising for the long-term population-level effects of HPV vaccination programmes. However, continued monitoring is essential to identify any signals of potential waning efficacy or type-replacement. FUNDING The Canadian Institutes of Health Research.

Web-Based Recruiting for Health Research Using a Social Networking Site: An Exploratory Study

Background Recruitment of young people for health research by traditional methods has become more expensive and challenging over recent decades. The Internet presents an opportunity for innovative recruitment modalities. Objective To assess the feasibility of recruiting young females using targeted advertising on the social networking site Facebook. Methods We placed an advertisement on Facebook from May to September 2010, inviting 16- to 25-year-old females from Victoria, Australia, to participate in a health study. Those who clicked on the advertisement were redirected to the study website and were able to express interest by submitting their contact details online. They were contacted by a researcher who assessed eligibility and invited them to complete a health-related survey, which they could do confidentially and securely either at the study site or remotely online. Results A total of 551 females responded to the advertisement, of whom 426 agreed to participate, with 278 completing the survey (139 at the study site and 139 remotely). Respondents’ age distribution was representative of the target population, while 18- to 25-year-olds were more likely to be enrolled in the study and complete the survey than 16- to 17-year-olds (prevalence ratio = 1.37, 95% confidence interval 1.05–1.78, P = .02). The broad geographic distribution (major city, inner regional, and outer regional/remote) and socioeconomic profile of participants matched the target population. Predictors of participation were older age, higher education level, and higher body mass index. Average cost in advertising fees per compliant participant was US

Etiologies of nongonococcal urethritis: bacteria, viruses, and the association with orogenital exposure

20, making this highly cost effective. Conclusions Results demonstrate the potential of using modern information and communication technologies to engage young women in health research and penetrate into nonurban communities. The success of this method has implications for future medical and population research in this and other demographics.

Fall in Human Papillomavirus Prevalence Following a National Vaccination Program

BACKGROUND The purpose of the present study was to determine pathogens and behaviors associated with nongonococcal urethritis (NGU) and the usefulness of the urethral smear in predicting the presence of pathogens. METHODS We conducted a case-control study of men with and without symptoms of NGU. Sexual practices were measured by questionnaire. First-stream urine was tested for Chlamydia trachomatis, Mycoplasma genitalium, Ureaplasma parvum, U. urealyticum, herpes simplex virus (HSV)-1, HSV-2, adenoviruses, and Gardnerella vaginalis by polymerase chain reaction. RESULTS C. trachomatis (20%), M. genitalium (9%), adenoviruses (4%), and HSV-1 (2%) were more common in cases with NGU (n = 329) after age and sexual risk were adjusted for (P< or =.01); U. urealyticum, U. parvum, and G. vaginalis were not. Infection with adenoviruses or HSV-1 was associated with distinct clinical features, oral sex, and male partners, whereas infection with M. genitalium or C. trachomatis was associated with unprotected vaginal sex. Oral sex was associated with NGU in which no pathogen was detected (P < or = .001). Fewer than 5 polymorphonuclear leukocytes (PMNLs) per high-power field (HPF) on urethral smear were present in 32%, 37%, 38%, and 44% of cases with C. trachomatis, M. genitalium, adenoviruses, and HSV, respectively. CONCLUSION We identified adenoviruses and HSV-1 as significant causes of NGU with distinct clinical and behavioral characteristics and highlighted the association between insertive oral sex and NGU. A urethral PMNL count of > or =5 PMNLs/HPF is not sufficiently sensitive to exclude pathogens in men with urethral symptoms.

Azithromycin Treatment Failure in Mycoplasma genitalium–Positive Patients with Nongonococcal Urethritis Is Associated with Induced Macrolide Resistance

BACKGROUND In April 2007, Australia became the first country to introduce a national government-funded human papillomavirus (HPV) vaccination program. We evaluated the programs impact on genotype-specific HPV infection prevalence through a repeat survey of women attending clinical services. METHODS HPV genoprevalence in women aged 18-24 years attending family planning clinics in the prevaccine period (2005-2007) was compared with prevalence among women of the same age group in the postvaccine period (2010-2011). The same recruitment and testing strategies were utilized for both sets of samples, and comparisons were adjusted for potentially confounding variables. RESULTS The prevalence of vaccine HPV genotypes (6, 11, 16, and 18) was significantly lower in the postvaccine sample than in the prevaccine sample (6.7% vs 28.7%; P < .001), with lower prevalence observed in both vaccinated and unvaccinated women compared with the prevaccine population (5.0% [adjusted odds ratio, 0.11; 95% confidence interval, 0.06-0.21] and 15.8% [adjusted odds ratio, 0.42; 95% confidence interval, 0.19-0.93], respectively). A slightly lower prevalence of nonvaccine oncogenic HPV genotypes was also found in vaccinated women (30.8% vs 37.6%; adjusted odds ratio, 0.68; 95% confidence interval, 0.46-0.99). CONCLUSIONS Four years after the commencement of the Australian HPV vaccination program, a substantial decrease in vaccine-targeted genotypes is evident and should, in time, translate into reductions in HPV-related lesions.

Assessment of herd immunity and cross-protection after a human papillomavirus vaccination programme in Australia: a repeat cross-sectional study

BACKGROUND Mycoplasma genitalium is a common cause of nongonococcal urethritis. Treatment trials have shown that doxycycline is inefficient, whereas a 5-day course of azithromycin eradicates the bacterium from 95% of infected men. The aim of the study was to establish the reason for the occasional treatment failures. METHODS Seven M. genitalium strains isolated from men who experienced azithromycin treatment failure were tested for in vitro susceptibility to macrolides with use of a cell culture-based method. The genetic basis for the drug resistance was established by sequencing parts of the 23S ribosomal RNA gene and the genes encoding the L4 and L22 proteins. Nine sets of specimens obtained before and after treatment from patients who experienced azithromycin treatment failure were examined with use of sequencing of polymerase chain reaction products. RESULTS The 7 strains that were isolated from patients who experienced treatment failure with azithromycin had minimum inhibitory concentrations >8 microg/mL for azithromycin and erythromycin. Three different mutations at positions 2058 and 2059 (Escherichia coli numbering) in region V of the 23S rRNA gene were found. Of the 9 patients with specimens obtained before and after treatment, only 2 had an initial specimen in which the mutation was present, indicating that drug resistance was induced as the result of an inappropriate dosage of azithromycin. CONCLUSION Development of macrolide resistance was shown to correlate with subsequent azithromycin treatment failure. The genetic basis for the drug resistance was shown to be mutations in region V of the 23S rRNA gene, which is well described in other Mollicutes. These findings raise concern about the use of single-dose azithromycin treatment of nongonococcal urethritis of unknown etiology.

Azithromycin failure in Mycoplasma genitalium urethritis.

BACKGROUND After the introduction of a quadrivalent human papillomavirus (HPV) vaccination programme in Australia in April, 2007, we measured the prevalence of vaccine-targeted and closely related HPV types with the aim of assessing direct protection, cross-protection, and herd immunity. METHODS In this repeat cross-sectional study, we recruited women aged 18-24 years who attended Pap screening between October, 2005, and July, 2007, in three major metropolitan areas of Australia to form our prevaccine-implementation sample. For our postvaccine-implementation sample, we recruited women aged 18-24 years who attended Pap screening in the same three metropolitan areas from August, 2010, to November, 2012. We compared the crude prevalence of HPV genotypes in cervical specimens between the prevaccine and the postvaccine implementation groups, with vaccination status validated against the National HPV Vaccination Program Register. We estimated adjusted prevalence ratios using log linear regression. We estimated vaccine effectiveness both for vaccine-targeted HPV types (16, 18, 6, and 11) and non-vaccine but related HPV types (31, 33, and 45). FINDINGS 202 women were recruited into the prevaccine-implementation group, and 1058 were recruited into the postvaccine-implementation group. Crude prevalence of vaccine-targeted HPV genotypes was significantly lower in the postvaccine-implementation sample than in the prevaccine-implementation sample (58 [29%] of 202 vs 69 [7%] of 1058; p<0·0001). Compared with the prevaccine-implementation sample, adjusted prevalence ratios for vaccine-targeted HPV genotypes were 0·07 (95% CI 0·04-0·14; p<0·0001) in fully vaccinated women and 0·65 (0·43-0·96; p=0·03) in unvaccinated women, which suggests herd immunity. No significant declines were noted for non-vaccine-targeted HPV genotypes. However, within the postvaccine-implementation sample, adjusted vaccine effectiveness against vaccine-targeted HPV types for fully vaccinated women compared with unvaccinated women was 86% (95% CI 71-93), and was 58% (26-76) against non-vaccine-targeted but related genotypes (HPV 31, 33, and 45). INTERPRETATION 6 years after the initiation of the Australian HPV vaccination programme, we have detected a substantial fall in vaccine-targeted HPV genotypes in vaccinated women; a lower prevalence of vaccine-targeted types in unvaccinated women, suggesting herd immunity; and a possible indication of cross-protection against HPV types related to the vaccine-targeted types in vaccinated women. FUNDING Australian National Health and Medical Research Council and Cancer Council Victoria.

The Association of Atopobium vaginae and Gardnerella vaginalis with Bacterial Vaginosis and Recurrence after Oral Metronidazole Therapy

We report significant failure rates (28%, 95% confidence interval 15%–45%) after administering 1 g azithromycin to men with Mycoplasma genitalium–positive nongonococcal urethritis. In vitro evidence supported reduced susceptibility of M. genitalium to macrolides. Moxifloxacin administration resulted in rapid symptom resolution and eradication of infection in all cases. These findings have implications for management of urethritis.

Probiotic Effects on Late-onset Sepsis in Very Preterm Infants: A Randomized Controlled Trial

BACKGROUND We investigated associations between Atopobium vaginae and bacterial vaginosis (BV) and the role that A. vaginae plays in recurrent BV after oral metronidazole therapy. METHODS Women with abnormal vaginal discharge or odor were enrolled in a cross-sectional study (n=358); the proportion of those infected with Gardnerella vaginalis and A. vaginae was determined by polymerase chain reaction. Women with BV (Nugent score [NS] 7-10 or 4-6 with > or =3 Amsel criteria; n=139) were treated with oral metronidazole (400 mg twice a day for 7 days) and examined at 1, 3, 6, and 12 months or until they reached an NS of 7-10 and recurrence of A. vaginae and G. vaginalis infection was established. RESULTS A. vaginae and G. vaginalis were highly sensitive for BV--96% (95% confidence interval [CI], 91%-98%) and 99% (95% CI, 97%-100%), respectively. However, A. vaginalis was more specific for BV (77% [95% CI, 71%-82%]) than was G. vaginalis (35% [95% CI, 29%-42%]). G. vaginalis was detected in 100% and A. vaginae in 75% of women with recurrent BV; higher organism loads were present in women with recurrent BV. A. vaginae was rarely detected without G. vaginalis, and women in whom both organisms were detected had higher rates of recurrent BV (83%) than women infected with G. vaginalis only (38%) (P<.001). CONCLUSIONS Infection with A. vaginae is more specific for BV than infection with G. vaginalis. The higher recurrence rates in women in whom both A. vaginae and G. vaginalis were detected suggest that A. vaginae makes a significant contribution to BV. However, its etiological role remains unclear.

Evaluation of self-collected samples in contrast to practitioner-collected samples for detection of Chlamydia trachomatis, Neisseria gonorrhoeae, and Trichomonas vaginalis by polymerase chain reaction among women living in remote areas.

BACKGROUND AND OBJECTIVE: Late-onset sepsis frequently complicates prematurity, contributing to morbidity and mortality. Probiotics may reduce mortality and necrotizing enterocolitis (NEC) in preterm infants, with unclear effect on late-onset sepsis. This study aimed to determine the effect of administering a specific combination of probiotics to very preterm infants on culture-proven late-onset sepsis. METHODS: A prospective multicenter, double-blinded, placebo-controlled, randomized trial compared daily administration of a probiotic combination (Bifidobacterium infantis, Streptococcus thermophilus, and Bifidobacterium lactis, containing 1 × 109 total organisms) with placebo (maltodextrin) in infants born before 32 completed weeks’ gestation weighing <1500 g. The primary outcome was at least 1 episode of definite late-onset sepsis. RESULTS: Between October 2007 and November 2011, 1099 very preterm infants from Australia and New Zealand were randomized. Rates of definite late-onset sepsis (16.2%), NEC of Bell stage 2 or more (4.4%), and mortality (5.1%) were low in controls, with high breast milk feeding rates (96.9%). No significant difference in definite late-onset sepsis or all-cause mortality was found, but this probiotic combination reduced NEC of Bell stage 2 or more (2.0% versus 4.4%; relative risk 0.46, 95% confidence interval 0.23 to 0.93, P = .03; number needed to treat 43, 95% confidence interval 23 to 333). CONCLUSIONS: The probiotics B infantis, S thermophilus, and B lactis significantly reduced NEC of Bell stage 2 or more in very preterm infants, but not definite late-onset sepsis or mortality. Treatment with this combination of probiotics appears to be safe.