Point-of-care testing and treatment of sexually transmitted and genital infections during pregnancy in Papua New Guinea (WANTAIM trial): protocol for an economic evaluation alongside a cluster-randomised trial.

INTRODUCTION: Left untreated, sexually transmitted and genital infections (henceforth STIs) in pregnancy can lead to serious adverse outcomes for mother and child. Papua New Guinea (PNG) has among the highest prevalence of curable STIs including syphilis, chlamydia, gonorrhoea, trichomoniasis and bacterial vaginosis, and high neonatal mortality rates. Diagnosis and treatment of these STIs in PNG rely on syndromic management. Advances in STI diagnostics through point-of-care (PoC) testing using GeneXpert technology hold promise for resource-constrained countries such as PNG. This paper describes the planned economic evaluation of a cluster-randomised cross-over trial comparing antenatal PoC testing and immediate treatment of curable STIs with standard antenatal care in two provinces in PNG. METHODS AND ANALYSIS: Cost-effectiveness of the PoC intervention compared with standard antenatal care will be assessed prospectively over the trial period (2017-2021) from societal and provider perspectives. Incremental cost-effectiveness ratios will be calculated for the primary health outcome, a composite measure of the proportion of either preterm birth and/or low birth weight; for life years saved; for disability-adjusted life years averted; and for non-health benefits (financial risk protection and improved health equity). Scenario analyses will be conducted to identify scale-up options, and budget impact analysis will be undertaken to understand short-term financial impacts of intervention adoption on the national budget. Deterministic and probabilistic sensitivity analysis will be conducted to account for uncertainty in key model inputs. ETHICS AND DISSEMINATION: This study has ethical approval from the Institutional Review Board of the PNG Institute of Medical Research; the Medical Research Advisory Committee of the PNG National Department of Health; the Human Research Ethics Committee of the University of New South Wales; and the Research Ethics Committee of the London School of Hygiene and Tropical Medicine. Findings will be disseminated through national stakeholder meetings, conferences, peer-reviewed publications and policy briefs. TRIAL REGISTRATION NUMBER: ISRCTN37134032.

Assessment of attribution algorithms for resolving CIN3-related HPV genotype prevalence in mixed-genotype biopsy specimens using laser capture microdissection as the reference standard.

To make accurate determinations regarding potential and actual impact of HPV vaccine programs, precise estimates of genotype-specific contributions to disease are required for pre- and post-vaccine populations. Definitive determination of lesion-specific genotypes, particularly where multiple genotypes are detected in a sample, can be technically demanding and resource intensive; therefore, most prevalence studies use mathematical algorithms to adjust for multiple genotype detections. There are currently several algorithms, which can produce genotype estimates within a wide range of variability. The use of these for cervical cytology samples has recently been assessed for accuracy against a definitive reference standard, but none have yet been assessed for multiple-genotype-containing whole biopsy specimens. Using laser capture microdissection (LCM) on biopsy samples, lesion-specific genotype prevalence data were generated for a cohort of 516 young Australian women (aged 18-32 years) with cervical intraepithelial neoplasia grade 3 or adenocarcinoma in situ. Using whole tissue section genotype data from the same cohort, including 71 (13.7%) with multiple genotypes, lesion-associated genotype prevalence was estimated using four different attribution algorithms. The proportion of lesions attributable to HPV16 and HPV18 by LCM were 58.4% and 5%, respectively; hierarchical, proportional, single type/minimum and any type/maximum attribution estimates were comparable across genotypes. For analyses utilising whole tissue biopsy cervical specimens, attribution estimates are appropriate for estimating the proportional contribution of individual genotypes to lesions in a population.

Reduced dose human papillomavirus vaccination: an update of the current state-of-the-art.

Human papillomavirus (HPV) infection is the primary cause of genital warts, some oropharyngeal cancers and anogenital cancers, including cervical, vagina, vulvar, anal and penile cancers. Primary prevention of cervical cancer requires the prevention of high-risk HPV infections, particularly HPV genotypes 16 and 18. Both Gardasil® and Cervarix® vaccines when administered by a three-dose schedule have been demonstrated to be effective against cervical, vulva, and vaginal cancer precursors from vaccine genotypes in phase III clinical trials, and post-marketing studies; Gardasil® vaccine also offers additional protection against anal cancer precursors. However, high costs of HPV vaccines and the logistics of delivering a three-dose schedule over 6 months are challenging in countries with limited resources. Several studies have demonstrated non-inferiority in antibody response between adolescents (9-15 years old) who received two doses (6 months apart) and women (>15 years old) who received the standard three-dose schedule. These studies provided evidence for the World Health Organization and European Medical Association to revise its recommendation to give two instead of three doses of HPV vaccine to adolescents below 15 years of age, provided the 2nd dose is given 6 months apart. Although reduced dose schedules can alleviate costs and logistics associated with HPV vaccination, especially in resource-poor countries, there are still gaps in this area of research, particularly regarding long-term protection. This review discusses the findings on antibody response and clinical outcomes in studies evaluating reduced dose HPV schedules, and highlights the important considerations of its implementation. In addition, other important immunological biomarkers that may be associated with long-term protection are highlighted and discussed.

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.

In vitro assessment of the effect of vaccine-targeted human papillomavirus (HPV) depletion on detection of non-vaccine HPV types: implications for post-vaccine surveillance studies.

In populations where the prevalence of vaccine-targeted HPV types has been reduced significantly due to widespread vaccination of the target population, the sensitivity of some consensus PCR-based assays to detect remaining HPV types may be altered, leading to misrepresentations of prevalence. Importantly, this may lead to false indications of type replacement in vaccinated populations. To assess whether excess vaccine-targeted HPV DNA resulted in reduced detection of other genotypes on the Roche HPV linear array genotype assay, simulated samples containing 1000 copies of one or two high-risk HPV DNA genomes in the presence and the absence of 10,000 copies of the HPV16 genome were tested. HPV16 alone did not affect detection of other high-risk genotypes; however when HPV16 and an additional genotype were present, detection of HPV31, 33, 51 or 59 was impeded, indicating potential for misrepresentation of population-based prevalence of these genotypes and false evidence for type replacement following vaccination.

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

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.

Rationale and design of REACT: a randomised controlled trial assessing the effectiveness of home-collection to increase chlamydia retesting and detect repeat positive tests.

BACKGROUND: Repeat infection with Chlamydia trachomatis is common and increases the risk of sequelae in women and HIV seroconversion in men who have sex with men (MSM). Despite guidelines recommending chlamydia retesting three months after treatment, retesting rates are low. We are conducting the first randomised controlled trial to assess the effectiveness of home collection combined with short message service (SMS) reminders on chlamydia retesting and reinfection rates in three risk groups. METHODS/DESIGN: The REACT (retest after Chlamydia trachomatis) trial involves 600 patients diagnosed with chlamydia: 200 MSM, 200 women and 200 heterosexual men recruited from two Australian sexual health clinics where SMS reminders for retesting are routine practice. Participants will be randomised to the home group (3-month SMS reminder and home-collection) or the clinic group (3-month SMS reminder to return to the clinic). Participants in the home group will be given the choice of attending the clinic if they prefer. The mailed home-collection kit includes a self-collected vaginal swab (women), UriSWAB (Copan) for urine collection (heterosexual men), and UriSWAB plus rectal swab (MSM). The primary outcome is the retest rate at 1-4 months after a chlamydia diagnosis, and the secondary outcomes are: the repeat positive test rate; the reinfection rate; the acceptability of home testing with SMS reminders; and the cost effectiveness of home testing. Sexual behaviour data collected via an online survey at 4-5 months, and genotyping of repeat infections, will be used to discriminate reinfections from treatment failures. The trial will be conducted over two years. An intention to treat analysis will be conducted. DISCUSSION: This study will provide evidence about the effectiveness of home-collection combined with SMS reminders on chlamydia retesting, repeat infection and reinfection rates in three risk groups. The trial will determine client acceptability and cost effectiveness of this strategy. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ACTRN12611000968976.

Sexual behaviors and risk for sexually transmitted infections among teenage men who have sex with men.

OBJECTIVES: To report on sexual behaviors and sexually transmitted infections (STIs) among men who have sex with men (MSM) in their teens, when many MSM engage in their first sexual experiences. METHODS: MSM aged 16 to 20 years were recruited via community and other sources. Men completed a questionnaire about their sexual behaviors and were screened for gonorrhea, chlamydia, syphilis, and HIV. RESULTS: Two hundred men were included. The median age was 19 years. The median age at first insertive or receptive anal intercourse was 17 years. Half of men reported sex with mainly older men: these men were more likely to engage in receptive anal intercourse (48% vs. 25%, p < .001) than other men. Most men had engaged in insertive (87%) and receptive (85%) anal intercourse in the prior 12 months with 60% and 53% reporting inconsistent condom use with insertive and receptive anal intercourse partners, respectively. The median number of insertive anal intercourse partners was 3 and 1.5 (p < .001) among men reporting inconsistent and consistent condom use with insertive anal intercourse over the prior 12 months. The median number of receptive anal intercourse partners was 3 and 2 (p = .006) among men reporting inconsistent and consistent condom use with receptive anal intercourse over the prior 12 months. Pharyngeal gonorrhea, rectal gonorrhea, urethral chlamydia, rectal chlamydia, and syphilis were detected in 3.0%, 5.5%, 3.0%, 4%, and 2.0% of men, respectively. All men were HIV negative. CONCLUSION: Many of the teenage MSM in this study were at risk for STI. Preventative messages and STI screening interventions that are age appropriate need to be developed to reduce HIV and STI risk in this under-recognized group.

A randomised trial of point-of-care tests for chlamydia and gonorrhoea infections in remote Aboriginal communities: Test, Treat ANd GO- the "TTANGO" trial protocol.

BACKGROUND: High prevalence rates of Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) have been reported in Aboriginal people in remote and regional areas of Australia for well over two decades, and repeat positivity rates are high. To interrupt disease transmission and reduce the risk of complications, early diagnosis and treatment is important. However in many remote and regional areas there are long delays between testing for these curable sexually transmissible infections and providing treatment, due to both physical distance from laboratories and difficulties when recalling patients for subsequent management once results are available. Point-of-care (POC) tests have the potential to provide more timely diagnosis, to increase treatment and contact tracing, and in turn reduce CT and NG infection rates. METHODS/DESIGN: TTANGO (Test, Treat, ANd GO) is a cross-over cluster randomised controlled trial in 12 regional or remote Australian health services, which predominantly provide clinical services to Aboriginal people. The overall aim of TTANGO is to measure the clinical effectiveness, cost-effectiveness and cultural and operational acceptability of molecular POC testing for CT and NG infection. The primary outcome is repeat positivity at three months after treatment of an initial CT or NG infection. Participating health services will undertake the clinical management of CT and NG under two different modalities for one year each. In the first year, six health services will be randomly assigned to manage these infections under current diagnostic guidelines. The other six will supplement current diagnostic guidelines with POC testing, whereby diagnosis is made and subsequent treatment for those with positive POC tests is offered at the initial consultation. In the second year, the health services will cross over to the opposite management modality. TTANGO will be conducted over four years; 1.5 years of trial initiation and community consultation, 2 years of trial conditions and evaluation, and 6 months of data analysis and feedback. DISCUSSION: TTANGO is the first cluster randomised trial of POC testing for CT and NG internationally. The results of this trial will provide crucial information to guide sexual health clinical practice in remote Aboriginal communities and other high prevalence settings. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ACTRN12613000808741.

Quality assessment for human papillomavirus testing.

There are over 30 commercial, as well as numerous in-house assays, available for human papillomavirus testing. Laboratories performing such assays would need to assess accuracy and reproducibility of their results by incorporating ongoing internal control as well as participating in external quality-assurance schemes (EQAS) as part of their quality assurance program. Several EQAS are available and participation in which is a requirement for laboratories engaged in HPV testing. It is important that laboratories select the appropriate panels for detection of targeted types covered by assay used. Failure to do so can possibly alter patient management and increase the cost of treatment.

Assessment of MagNA pure LC extraction system for detection of human papillomavirus (HPV) DNA in PreservCyt samples by the Roche AMPLICOR and LINEAR ARRAY HPV tests.

Roche Molecular Systems recently released two PCR-based assays, AMPLICOR and LINEAR ARRAY (LA), for the detection and genotyping, respectively, of human papillomaviruses (HPVs). The manual specimen processing method recommended for use with both assays, AmpliLute, can be time-consuming and labor-intensive and is open to potential specimen cross-contamination. We evaluated the Roche MagNA Pure LC (MP) as an alternative for specimen processing prior to use with either assay. DNA was extracted from cervical brushings, collected in PreservCyt media, by AmpliLute and MP using DNA-I and Total Nucleic Acid (TNA) kits, from 150 patients with histologically confirmed cervical abnormalities. DNA was amplified and detected by AMPLICOR and the LA HPV test. Concordances of 96.5% (139 of 144) (kappa=0.93) and 95.1% (135 of 142) (kappa=0.90) were generated by AMPLICOR when we compared DNA extracts from AmpliLute to MP DNA-I and TNA, respectively. The HPV genotype profiles were identical in 78.7 and 74.7% of samples between AmpliLute and DNA-I or TNA, respectively. To improve LA concordance, all 150 specimens were extracted by MP DNA-I protocol after the centrifugation of 1-ml PreservCyt samples. This modified approach improved HPV genotype concordance levels between AmpliLute and MP DNA-I to 88.0% (P=0.043) without affecting AMPLICOR sensitivity. Laboratories that have an automated MP extraction system would find this procedure more feasible and easier to handle than the recommended manual extraction method and could substitute such extractions for AMPLICOR and LA HPV tests once internally validated.

Comprehensive clinical care on-site in men-only saunas: confidential STI/HIV screening outreach clinic.

During 2001 and 2002 an anonymous outreach-screening programme in Melbourne, Australia, offered testing for gonorrhoea and chlamydia on-site at men-only saunas. Modifications were made to this screening programme to offer a comprehensive testing clinic for sexually transmissible infections (STIs), including HIV. The comprehensive clinic was evaluated after one year of operation, and comparisons were made with the earlier anonymous screening programme. The comprehensive outreach clinic made contact with fewer men (n = 557), however, men tested had a higher prevalence of gonorrhoea and chlamydia (17%), and all men tested positive for STIs/HIV were followed up. The findings and comparisons outlined in this paper may be used for different communities to decide what screening programme model best suits their individual situation: anonymous programme with fewer tests offered, confidential and comprehensive STI/HIV testing programme, or both. On the basis of our evaluation, we have opted to continue the comprehensive STI/HIV testing programme in local men-only saunas.