Sexual Health

Background Human papillomavirus (HPV) DNA is present in the majority of squamous cell cancers of the anus. ADXS11-001 immunotherapy is a live attenuated Listeria monocytogenes (Lm) bioengineered to secrete an HPV-16-E7 fusion protein targeting HPV-transformed cells. The Lm vector infects antigen-presenting cells, stimulating both MHC class 1 and 2 pathways resulting in specific T-cell immunity to tumours. The Brown University Oncology Research Group has initiated a phase I/II study evaluating two treatment schedules of ADXS11-001 with standard chemoradiation for anal cancer. Methods: Patients with newly diagnosed anal cancer with a primary tumour >4cm or lymph node involvement, without distant metastases, are eligible. All patients receive two courses of mitomycin, 5-FU with concurrent radiation (54Gy in 30 fractions by IMRT). Patients receive four treatments of ADXS11-001, 1×10(9) colony-forming units intravenously once approximately every 28 days. In treatment schedule 1, the first dose is given before chemoradiation and the second to fourth doses are given every 28 days after completion of radiation. In treatment schedule 2, the second dose of ADXS11-001 is administered during chemoradiation. Results: Three patients have been treated with ADXS11-001 and chemoradiation on treatment schedule 1. One patient developed grade 3 chills and one patient experienced grade 2 flu-like symptoms post-infusion, both resolved with symptomatic treatment. Conclusions: ADXS11-001 is a highly novel form of immunotherapy designed to generate an immune response against HPV transformed cells. Accrual is continuing to evaluate safety and efficacy for patients with anal cancer.

Background: Chlamydia trachomatis prevalence among 12-17-year-old adolescents in Germany was determined in the present study. Methods: A random age-stratified sample of 1815 urine specimens of boys and girls was selected from a population-based nationwide health survey conducted in 2003-06. Urine samples were pooled and tested for chlamydia using strand displacement amplification. Positive pools were individually retested. Prevalence, prevalence ratios (PR) and corresponding 95% confidence intervals (CI) were calculated. Associations between infection and socio-demographic factors (age, sex, place of residence), sexual activity (defined by oral contraceptive use or gynaecologist visits) and abdominal pain among females were examined in univariate analysis. Results: Sixteen samples (0.9% 95% CI: 0.5-1.3%), all from 15-17-year olds, were positive for chlamydia. Prevalence increased with age to 2% (95% CI: 0.8-3.2%) among 17 year olds and was higher among girls than boys (1.8% v. 0.1%; P < 0.001). A total of 4.6% (95% CI: 1.4-7.7%) of sexually active girls aged 17 were infected and 5/7 of them had no regular abdominal pain. Of all girls with abdominal pains, 52% had visited gynaecologists. Prevalence of infection was higher among those with pains than those without (PR = 3.8, 95% CI: 1.3-11.0). Conclusions: This is the first nationwide study based on a representative sample of boys and girls to measure chlamydia prevalence among adolescents in Germany. Prevalence in Germany is consistent with other countries. Among sexually active females, prevalence was comparable to screening thresholds. As gynaecological visits were common among females, we recommend that gynaecologists should actively offer screening to sexually active females, which would strengthen the newly implemented screening for females under 25 years.

Background: There are few population-based data on the disease burden of cervical cancer from developing countries, especially South Pacific islands. This study aimed to determine the incidence and mortality associated with cervical cancer and the coverage of Papanicolaou (Pap) cervical cytology in 20- to 69-year-old women in Fiji from 2004 to 2007. Methods: National data on the incident cases of histologically confirmed cervical cancer and the associated deaths, and on Pap smear results were collected from all pathology laboratories, and cancer and death registries in Fiji from 2004 to 2007. Results: There were 413 incident cases of cervical cancer and 215 related deaths during the study timeframe. The annualised incidence and mortality rates in 20- to 69-year-old Melanesian Fijian women, at 49.7 per 100?000 (95% confidence interval (CI): 43.7-56.4) and 32.3 per 100?000 (95% CI: 26.9-38.4) respectively, were significantly higher than among 20- to 69-year-old Indo-Fijian women at 35.2 per 100?000 (P<0.001, 95% CI: 29.5-41.7) and 19.8 per 100?000 (P=0.002, 95% CI: 15.1-25.5) respectively. Of 330 cases diagnosed between 2004 and 2006, 186 (56%) had died by 31 December 2006. Pap smear coverage for this period was 8.0% (95% CI: 7.9-8.1) of the target population. Conclusions: The incidence and mortality related to cervical cancer in Fiji is high, whereas Pap smear coverage is very low. Greater investment in alternative screening strategies and preventive measures should be integrated into a comprehensive, strategic cervical cancer control program in Fiji.

To describe the frequency of the 3-month test for re-infection among sexual health service patients in Australia. We assessed the re-testing rates at 30-120 days after chlamydia infection in men who have sex with men (MSM), heterosexual males and females attending sexual health services across Australia between 2004 and 2008. A χ(2)-test was used to determine significant differences in re-testing rates according to demographic characteristics and trends over time. In the 5-year period, 10207 MSM, 28530 heterosexual males and 31190 heterosexual females were tested for chlamydia. Of those tested, 9057 (13.0%) were positive. The proportion of patients with chlamydia infection who were re-tested in 30-120 days was 8.6% in MSM, 11.9% in heterosexual males and 17.8% in heterosexual females. Among MSM, chlamydia re-testing rates were lower in men aged <30 years (8.4%) than ≥30 years (12.5%) (P=0.04) and lower in travellers and migrants (2.9%) than non-travellers (9.9%) (P=0.002). In heterosexual males, chlamydia re-testing rates were lower in men in regional and rural areas (10.5%) than metropolitan areas (13.5%) (P=0.017). There was no increasing trend in re-testing rates between 2004 and 2008 (P=0.787). Of the patients re-tested, 44.1% of MSM were positive, 21.0% of heterosexual males and 16.1% of females. The high chlamydia positivity at 30-120 days support recommendations that call for a 3-month test for re-infection following a positive test. The low re-testing rates highlight the need for innovative strategies to increase re-testing.

Background Anal cancer accounts for 4% of all lower gastrointestinal tract malignancies in the US. One of the most important predictors of prognosis among anal cancer patients is the size of the primary tumour. Tumours with diameters >5cm have poorer disease-free survival than those with smaller tumours. Understanding the biological changes associated with tumour growth may provide information to guide therapy and improve patient outcomes. DNA methylation changes are critical epigenetic events in cancer development. Methods: In this study we sought to characterise the epigenomic signatures associated with anal cancer tumour size (≤5cm vs >5cm) in FFPE tissues from 121 patients (≤5cm=88; >5cm=33) who participated in the RTOG 98-11 cooperative group anal cancer clinical trial. Differential methylation, examined at >450000 CpG loci using the Illumina Human Methylation 450 Array, were compared between the two groups using Mann-Whitney test (significance=P<0.001 and difference in methylation β-value >0.1). Results: This study included 74 women and 47 men with a median age of 54 years. A total of 86 CpG loci were differentially methylated (78 increased and 8 decreased) in large vs small tumours. Genes harbouring CpG sites that were among the most highly differentially methylated included those associated with WNT signalling (FZD10, WNT9A), microRNAs (MIR200A) and novel methylated targets (PON3). Conclusions: These data provide evidence that epigenetic events likely play a significant role in the progression of anal SCC and may serve as biomarkers of prognosis. Similar epigenomic approaches may be useful at earlier stages of anal neoplastic progression for application in screening and early detection.

Background Although anal HPV infection and cytological abnormalities are highly prevalent among HIV-infected MSM patients, there is limited data on HIV-infected heterosexual men and women. Since November 2010 at our clinic, anal cancer screening with both hr-HPV and cytology was routinely performed in all HIV-infected patients. The purpose of the study was to evaluate the prevalence of anal hr-HPV infection and cytological abnormalities among our cohort of HIV-infected MSM, heterosexual men and women. We also evaluated the performance of hr-HPV and abnormal cytology in detecting high-grade dysplasia (AIN2+). Methods: A retrospective cohort study was conducted in HIV patients who underwent routine screening for anal cancer from January 2011 to January 2013. The hr-HPV test is done concomitantly on an anal cytology specimen using the Hybrid Capture 2 assay (Digene Corporation). Medical records of patients who underwent high-resolution anoscopy (HRA) because of abnormal cytology (ASCUS and above) or positive hr-HPV were reviewed. Results: A total of 221 HIV patients underwent screening with both hr-HPV and anal cytology. Among them, 67% were men (73% MSM vs 27% heterosexual). hr-HPV was positive in 43% (54% MSM, 28% non-MSM and 27% women). Anal cytology was abnormal in 39% (48% MSM, 28% non-MSM and 34% of women). Among 117 (53%) patients with an abnormal screening test, 27% had both hr-HPV infection and abnormal cytology, 14% had only hr-HPV infection and 13% had only abnormal cytology. Cytology results were normal in 50%, non-diagnostic in 10%, ASCUS in 23%, LSIL in 14% and HSIL in 2%. Among 68 HIV patients who underwent HRA because of either abnormal anal cytology or hr-HPV infection, 22 patients had AIN2+ (17 were MSM) and all had hr-HPV. None of 14 patients with negative hr-HPV who underwent HRA for abnormal cytology had AIN2+. Paired results of cytology and biopsy did not correlate (rs=-0.13). Conclusions: Anal hr-HPV infection, cytological abnormalities and AIN2+ are prevalent among our cohort of HIV-infected heterosexual men and women. We suggest anal cancer screening for all HIV-infected patients. In our limited sample, hr-HPV performed better than anal cytology in detecting and ruling out AIN2+.

Background High-grade dysplasia (HSIL) is the anal squamous cell carcinoma (ASCC) precursor. Ablation with surgery, electro cautery (ECA) and infrared coagulation (IRC) might prevent ASCC. We endeavoured to determine long-term effectiveness of HSIL ablation and progression to ASCC. Methods: A retrospective chart review of patients undergoing HSIL ablation by any modality between February 1998 until May 2012. Results: In 456 HIV+ MSM (mean age 45 ± 9 years) and 271 HIV- MSM (mean age 41 ± 11years) followed for a mean of 3 (range 0.2-13) years, 1673 HSILs were treated by laser, IRC and/or ECA. ASCC developed in 5 (0.7%) MSM but only one (0.1%) was undergoing active treatment. For HIV+ MSM, recurrence after 1st, 2nd, 3rd and 4th treatment was 66%, 64%, 62% and 54%, respectively. For HIV- MSM, HSIL recurrence after the 1st, 2nd, 3rd and 4th treatment was 59%, 44%, 46% and 50%, respectively. Median number of recurrent lesions was never greater than 2 for HIV+ MSM and 1 for HIV- MSM. The cure rate of lesions treated once in HIV+ and HIV- MSM was 73% and 84%, respectively. KM curves demonstrate that most recurrence occurs within the first 12 months after treatment. Recurrence increased with HIV infection (HR 1.3; 95% CI: 1.1-1.6) and each additional lesion treated (HR 1.6; 95% CI: 1.1-1.2). Age and treatment modality did not affect recurrence. Conclusions: Patients undergoing active ablation for cure of intra-anal HSIL appear to have limited progression to ASCC. Recurrence remains high but falls over time and repeated treatment.

The nef gene from HIV-1 has been shown to be an important pathogenic factor when considering development of AIDS. Detection of nef variants with an effect on immune modulation is important to understand HIV-1 pathogenesis and has possible impact on treatment strategies. The nef gene of HIV-1 isolates from patients in a long-term non-progressor (LTNP) cohort and a slow-progressor (SP) cohort (n = 11) was analysed and compared with isolates from a control patient group of progressors (n = 18). Most of the patients with delayed disease progression had extensive medical records, providing an insight into the LTNP disease profile and allowing for the stratification of patients based on their CD4 cell decline. In sequences from nine patients, most of the functional domains of HIV-1 Nef appeared intact, and no major deletions were observed to possibly account for an effect on the delayed disease status. However, the results demonstrate a high incidence of a single amino acid polymorphism (cysteine 138) in HIV-1 Nef. The allelic frequency of cysteine 138 between the delayed disease progression group and the progressor group was found to be statistically significant (P = 0.0139). The phylogeny of isolates was investigated and the variants harbouring the cysteine 138 mutation clustered independently. The present study describes a viral genetic polymorphism related to AIDS disease progression. The polymorphism (cysteine 138) has previously been reported to confer decreased viral replication (Premkumar DR, et al. AIDS Res Hum Retroviruses 1996; 12(4): 337-45). A sequence database search for comparative mutations revealed a high frequency of cysteine 138 in patients with reported SP AIDS.

Background Screening for the anal cancer precursor HSIL is not recommended in national guidelines. A recent Cochrane review of HSIL treatment concluded there is no evidence of efficacy. In this context, we aimed to describe the natural history of anal HSIL, and association with human papillomavirus (HPV), in a community-recruited cohort of Australian homosexual men. Methods: The SPANC study is a three-year prospective study in men aged ≥35 years. At each visit, men undergo an anal swab for cytology and HPV genotyping (Roche Linear Array), followed by high-resolution anoscopy-aided biopsy. Anal HSIL is defined as having either anal intraepithelial neoplasia grade 2/3 on histology and/or HSIL/ASC-H on cytology. Results: Among 342 men recruited by March 2013, median age was 49 with 29% HIV positive. At baseline, prevalence of anal HSIL was 50% and 44% in the HIV-positive and HIV-negative groups, respectively (P=0.303). Among those without HSIL at baseline, HSIL incidence was 28/100 person-years in both the HIV-positive and HIV-negative groups (P=0.920). Among those with HSIL at baseline, the incidence of change to non-HSIL was 41 and 43/100 person-years (P=0.851). Men with anal HPV16 at baseline were more likely to develop incident HSIL (57 vs 23/100 person-years, P=0.010), and less likely to change to non-HSIL (18 vs 61/100 person-years, P=0.001). Conclusions: Anal HSIL was highly prevalent in these homosexual men. Both incidence of HSIL and change to non-HSIL were common, and were closely associated with HPV16 status. HPV16 positivity may identify men with HSIL at higher risk of anal cancer.

Background: Home-based sampling is a strategy to enhance uptake of sexually transmissible infection (STI) screening. This review aimed to compare the screening uptake levels of home-based self-sampling and clinic-based specimen collection for STIs (chlamydia (Chlamydia trachomatis), gonorrhoea (Neisseria gonorrhoeae) and trichomoniasis) in females aged 14-50 years. Acceptability and effect on specimen quality were determined. Methods: Sixteen electronic databases were searched from inception to September 2012. Randomised controlled trials (RCTs) comparing the uptake levels of home-based self-sampling and clinic-based sampling for chlamydia, gonorrhoea and trichomoniasis in females aged 14-50 years were eligible for inclusion. The risk of bias in the trials was assessed. Risk ratios (RRs) for dichotomous outcomes were meta-analysed. Results: Of 3065 papers, six studies with seven RCTs contributed to the final review. Compared with clinic-based methods, home-based screening increased uptake significantly (P=0.001-0.05) in five trials and was substantiated in a meta-analysis (RR: 1.55; 95% confidence interval: 1.30-1.85; P=0.00001) of two trials. In three trials, a significant preference for home-based testing (P=0.001-0.05) was expressed. No significant difference was observed in specimen quality. Sampling was rated as easy by a significantly higher number of women (P=0.01) in the clinic group in one trial. Conclusions: The review provides evidence that home-based testing results in greater uptake of STI screening in females (14-50 years) than clinic-based testing without compromising quality in the developed world. Home collection strategies should be added to clinic-based screening programs to enhance uptake.

In Australia, data for induced abortions (IA) is unreliable, although accurate information is essential for the development of policy and funding for services relating to IA. The rate of induced abortion was an incidental finding from questionnaire data collected for a longitudinal study of chlamydia in young women in Australia. We found a pregnancy rate of 7.2/100 woman years (95% confidence interval (CI): 5.7-9.0) (n=76) and IA rate of 2.1/100 women years (95% CI: 1.4-3.2) (n=22). Differences were found between States and Territories, information which might influence the development of services in regions of Australia.

Background Anal Pap tests have been advocated as a screening tool for anal precancerous lesions. We aimed to ascertain prevalence and correlates of UAPT among homosexual men. Methods: SPANC is a 3-year prospective study of homosexual men aged ≥35 years in Sydney. At baseline, data were collected and study procedures, including an anal swab for ThinPrep(®) cytology, were performed. Results: UAPT initially occurred in 40 (11.7%) of 342 participants (median age 49 years; 28.7% HIV positive) enrolled by the end of March 2013. There was no difference in UAPT by collecting clinician (P=0.669) or reporting pathologist (P=0.267). UAPT occurred more than twice as often among HIV-negative compared with -positive men (13.9% vs 6.1%, P=0.048) and were less likely than satisfactory smears to contain transformation zone (TZ) cells (4.6% vs 35.4%, P<0.001). Having a UAPT was associated with more anal Pap swab discomfort (P=0.037) and feeling more tense during the exam (P=0.008), but not with haemorrhoids or past anal surgery. On multivariate analysis, never douching (P<0.001), soapy water douching (among those who douched; P=0.003), fewer anal HPV types (P=0.005) and feeling more tense during the exam (P=0.039) remained independently associated with UAPT. All UAPT were repeated within a month and results were: 21 (52.5%) again unsatisfactory, 13 (32.5%) negative, 2 (5.0%) ASCUS/LSIL and 4 (10%) ASC-H/HSIL. Conclusions: UAPT are more common among men with less receptive anal sexual experience. Causes of UAPT may be a combination of sampling, behavioural and biological factors.

Background: A high incidence of vulvar cancer, and its precursor lesion, high-grade vulvar intraepithelial neoplasia (VIN) has been identified in young Indigenous women living in the Arnhem Land region of the Northern Territory (NT) of Australia. This clustering is restricted to women aged <50 years, suggesting that oncogenic human papillomavirus (HPV) is a key causal factor. This study compared the HPV genotype prevalence, HPV-16 variant distribution and p16(INK4a)expression in stored vulvar cancer and high-grade VIN biopsy specimens from women residing in Arnhem Land, with specimens taken from Indigenous and non-Indigenous women in other regions of NT where there is no observed increase in vulvar cancer incidence. Methods: Twenty high-grade VIN and 10 invasive cancer biopsies were assessed from Arnhem Land along with 24 high-grade VIN and 10 invasive cancer biopsies from other regions of NT. Results: Biopsies from Arnhem Land were similar to those from other regions in the detection of high-risk (HR) or possible HR HPV (VIN: 95% and 84% respectively for Arnhem Land and other regions, P=0.356; invasive cancer: 100% and 80%, P=0.473), HPV-16 (VIN: 60% and 80%, P=0.364; invasive cancer: 70% and 70%, P=1.0) and p16(INK4a) expression (VIN: 90% and 84%, P=0.673; invasive cancer: 100% and 80%, P=0.474). All HPV-16 variants were of the European prototype. Conclusion: Comparison of biopsies revealed no significant difference in the frequency of oncogenic HPVs or HPV-16 variant types between Arnhem Land and other regions, suggesting another cofactor in this cluster.

Background Human papillomavirus (HPV) types 16/18 are significant causes of female cervical cancers and likely cause most anal cancers. Oestrogen influences HPV-related cervical malignancies; however, the role of testosterone in anal HPV16/18 infections is unknown. Methods: 340 men who have sex with men (MSM) enrolled in the Multicenter AIDS Cohort Study were tested for serum free testosterone (SFT) and, ~24 months later, anal HPV16/18-DNA. Poisson regression with robust error variance analyses estimated prevalence ratios for HPV16/18 infections with the following exposures: log10-transformed SFT, exogenous and supraphysiological testosterone measures, race, age, self-reported number of anal receptive intercourse partnerships ≤24 months before testing, enrolment period, body mass index, hepatitis C infection, tobacco and alcohol, HIV infection, and CD4+ T-cell counts among the HIV-infected. Stratified-tabular analyses also evaluated blood draw timing (AM/PM), study site, and time on study. Results: 89% (304/340) of men provided complete data for all covariates. On average, men were White (263/304), 60 years old (s.d. 5.3; median 60.1 years) with 76.2ngdL(-1) (s.d. 57.1; median 69.0ngdL(-1)) SFT, and 43% (132/304) were HIV infected; 25% (75/304) tested HPV16/18-DNA positive. The fully adjusted model suggests each half-log10 increase of SFT is associated with a 1.69-fold (95% confidence interval (CI): 1.08, 2.64) higher HPV16/18 prevalence. Compared with HIV-uninfected men, HPV16/18 prevalence was 1.81-fold higher (95% CI: 1.08, 3.03) for HIV-infected men with ≤500 CD4+ T-cells mm(-3). No other covariates were significantly associated with HPV16/18 prevalence. Conclusions: Higher free testosterone is associated with increased HPV16/18 prevalence in MSM, independent of sexual behaviour and other potential confounders. The mechanisms underlying this association remain unclear and warrant further study.

Background The nucleotide analogue cidofovir has been shown to be effective in treating precancerous HPV-associated lesions located in the respiratory tract, cervix, vulva and anus. Cidofovir has been shown to have a 51% efficacy in the short-term treatment of high-grade perianal squamous intraepithelial lesions in HIV-infected persons. Less is known about the effect of cidofovir in treating more advanced stages of HPV-associated disease such as invasive cancer. Methods: We established an immortalised anal keratinocyte cell line (AKC2) following transfection of the HPV-16 genome into primary anal keratinocytes and long-term culture. AKC2 cells were invasive using in vitro collagen invasion assays. To determine the effect of cidofovir on invasion, AKC2 cells were treated for up to 7 days with different concentrations of cidofovir (10, 25 and 50 µg mL(-1)) and studied using the collagen invasion assays. Untreated cells served as a control. Results: We detected a decrease in invasion of AKC2 cells (50%, 70% and 90% decrease) with 10, 25 and 50 µg mL(-1) cidofovir, respectively. Cellular toxicity was not detected in any of the cidofovir-treated samples. Preliminary data suggest that cidofovir directly or indirectly impairs the formation of actin filaments and cellular filopodia, which are known to play a role in cellular invasion. Conclusions: Cidofovir inhibits invasion of HPV-16-transformed anal keratinocytes potentially through affecting pathways that are involved in actin filament formation. Cidofovir could potentially be useful as an adjuvant treatment for invasive anal cancers, and its mechanism of action in inhibiting cellular invasion requires further study.

Previous studies have concluded that transgender people are a marginalised and stigmatised group, with high rates of sexually transmissible infections (STI), sex work, injecting drug use and multiple sexual partners. To our knowledge, this is the first study in Australia to focus on the sexual behaviour and sexual health needs of transgender people attending an urban sexual health clinic. A retrospective case note review was undertaken of the transgender attendees of the Sydney Sexual Health Centre between 1990 and 2006. Demographics, gender characteristics, risk behaviours, sexual health morbidity, psychosocial information and other significant features of the transgender population were assessed. Forty clients were identified as transgender, of whom 36 (90%) were male-to-female and four (10%) were female-to-male. Seventeen (43%) had a history of sex work, 16 (40%) had injected drugs, 14 (35%) had had unprotected anal or vaginal sex in the past 3 months. Twenty (50%) clients had histories of a STI, including three (7.5%) that were HIV positive, and two were co-infected with hepatitis C. Genital warts and chlamydia were the most common diagnoses made during the study period. Physical examination was inadequately documented in 53% of first visits. Psychosocial morbidity was common. Transgender clients presented infrequently at this clinic. Although half reported few risks, the other half reported multiple risk behaviours and had most STI. These findings suggest that there needs to be improved sexual health service for transgender clients at our clinic.

Background In this prospective study we evaluate the sampling performance of HPV16 DNA E6 and L1 levels in detecting anal intraepithelial neoplasm using either a moistened Dacron swab (DS) or cytobrush (CB). Methods: We recruited HIV-infected (n=57) and organ-transplanted subjects (n=3) with an abnormal anal Pap smear who presented for high-resolution anoscopy (HRA). Prior to HRA, the first 30 subjects underwent sampling with a moistened DS, and the next 30 with a CB. HRA was then performed in the usual fashion. Samples were tested for HPV16 DNA E6 and L1 DNA using a validated qPCR technique. Anal biopsies were taken as per standard-of-care and categorised as negative, AIN 1/warts, or AIN 2 or 3. Results: 59 of 60 samples had adequate DNA and were evaluated for the comparison of HPV16 E6 and L1 DNA levels. A CB performed better than the DS in detecting low positive and positive levels of HPV16 E6 DNA (P=0.01). We then further evaluated the correlation of HRA-directed biopsies and HPV16 DNA E6 levels. There was a positive correlation of HRA-directed biopsy results stratified by increasing histological levels with HPV16 E6 DNA (P=0.018, Kruskal-Wallis test). Conclusions: A CB performed better than DS for molecular HPV testing. If molecular testing is included in anal cancer screening, consideration should be made for co-sampling with both a DS for cytology and CB for HPV testing. Further studies evaluating the sample yields should be performed to assist in implementation of anal cancer screening programs in defined populations of at-risk individuals.

Vaccines are now available to prevent the development of cervical cancer from genital human papillomavirus (HPV) infection. The decision to vaccinate depends on a vaccine's cost-effectiveness. A rigorous cost-effectiveness model for vaccinated individuals is presented in a companion paper; this paper investigates the additional benefits the community might receive from herd immunity. A mathematical model was developed to estimate the impact of a prophylactic vaccine on transmission of HPV type 16 in Australia. The model was used to estimate the expected reduction in HPV incidence and prevalence as a result of vaccination, the time required to achieve these reductions, and the coverage required for elimination. The modelled population was stratified according to age, gender, level of sexual activity and HPV infection status using a differential equation formulation. Clinical trials show that the vaccine is highly effective at preventing persistent infection and pre-cancerous lesions. These trials do not, however, provide conclusive evidence that infection is prevented altogether. The possible modes of vaccine action were investigated to see how vaccination might change the conclusions. The model predicts that vaccination of 80% of 12-year-old girls will eventually reduce HPV 16 prevalence by 60-100% in vaccinated and 7-31% in unvaccinated females. If 80% of boys are also vaccinated, reductions will be 74-100% in vaccinated and 86-96% in unvaccinated females. A campaign covering only 12-year-old girls would require 5-7 years to achieve 50% of the eventual reduction. With a catch-up campaign covering 13-26-year-olds, this delay would be reduced to only 2 years. Unrealistically high coverage in both sexes would be required to eliminate HPV 16 from the population. Under pessimistic assumptions about the duration of vaccine-conferred immunity, HPV 16 incidence is predicted to rise in some older age groups. Mass vaccination with a highly effective vaccine against HPV 16 has the potential to substantially reduce the incidence and prevalence of infection. Catch-up vaccination offers the potential to substantially reduce the delay before the benefits of vaccination are observed. A booster vaccination might be required to prevent an increase in incidence of infection in women over 25 years of age.

Reproductive control refers to the ability of a man or woman to control his or her own reproduction. Unintended pregnancy is a commonly used proxy measure for reproductive control. Using heterosexually active women participating in the National Survey of Family Growth Cycle 6 (n = 4521), we evaluated unintended pregnancy as a proxy measure for reproductive control. We identified four categories of women by self-reported pregnancy intention: (1) women reporting one unintended pregnancy, (2) women reporting two or more unintended pregnancies, (3) women reporting intentionally having no pregnancies and (4) women who reported that all pregnancies were intended (reference category). Polytomous logistic regression, weighted for the complex sampling design, provided estimates of odds ratios (OR) and 95% confidence intervals (CI). Fifty-one percent of women who reported having one unintended pregnancy went on to experience at least one additional unintended pregnancy. Being black, Hispanic, born to a mother who was <18 years at first birth, having multiple partners and age of first sexual debut (consensual or non-consensual) were significant predictors of multiple unintended pregnancies. Relative to sexual debut after 18 years of age, women reporting a sexual debut at less than 15 years were at increased risk of multiple unintended pregnancies (adjusted OR (reported as consensual): 6.96; 95% CI: 4.26 to 11.39; adjusted OR (reported as non-consensual: 27.10; 95% CI: 11.03-66.57)). Efforts to delay sexual debut and to protect girls from non-consensual sex are sorely needed to prevent a lifelong trajectory of lack of reproductive control.

Background Treatment of anal high-grade squamous intraepithelial lesions (aHSIL) may prevent anal cancer. Options for treatment of diffuse lesions include staged ablation, often requiring surgery, although in-office treatment is preferable. Topical 5% 5-fluorouracil (t5FU) has been used to treat diffuse female genital HPV-associated disease. We report our experience using t5FU for treatment of diffuse aHSIL considered unsuitable for ablation, to evaluate its tolerability and efficacy. Methods: Patients were given t5FU for treatment of diffuse aHSIL in doses of 0.5 mL self-applied 2× daily for 5 days followed by 9 days off. Patients were assessed on average following 4-8 cycles for complete response (CR), defined as the absence of HSIL on exam, cytology and/or histology, or partial response (PR), defined as a reduction in the amount of disease. Patients with PR then received ablative therapy. Results: 73 patients (55 HIV infected, 18 uninfected) were treated, including 13 women and 60 men. In 69 patients who used t5FU for at least one cycle, CR occurred in 8 (~11%) patients, 53 (~77%) had a partial response indicating reduction of disease, 6 (9%) had no response, and 1 had more widespread disease, 1 chart was not evaluable. Treatment was discontinued after <1 cycle in 4 patients due to side effects. Patients with PR were treated successfully with in-office ablation, except 2 patients referred for surgery. Conclusions: t5FU was well tolerated although side effects occur. Most patients had clinical improvement, suggesting that t5FU may play an important role in aHSIL treatment. Further studies may determine its optimal use.

Background: Although the dramatic increase in the incidence of squamous cell carcinoma of the anal canal (SCCA) has been reported in recent publications, changes in the incidence and demographic patterns of adenocarcinoma of the anal canal (AAC) are unknown. Methods: The 1973-2009 SEER public use dataset was analysed to determine incidence trends for and demographic factors characterising AAC. Joinpoint analysis identified time points when the incidence rates changed. Results: Joinpoint analyses identified 1989 as the single inflection point among 1791 AAC cases at which the slope of incidence rates significantly decreased. Annual per cent change (APC) decreased from 3.5% to -1.4% overall. Analysis of demographic factors did not identify specific variables that accounted for the decrease in incidence over time. Conclusions: The incidence of AAC has declined since 1989. No demographic or clinical factor was identified that may account for change in incidence. We postulate that increasing sophistication in diagnostic studies differentiating low rectal cancers from AAC may contribute to the decrease in incidence.

Background: Numerous social determinants of health are associated with violent crime rates and sexually transmissible infection (STI) rates. This report aims to illustrate the potential usefulness of violent crime rates as a proxy for the social determinants of STI rates. Methods: For each year from 1981 to 2010, we assessed the strength of the association between the violent crime rate and the gonorrhoea (Neisseria gonorrhoeae) rate (number of total reported cases per 100?000) at the state level. Specifically, for each year, we calculated Pearson correlation coefficients (and P-values) between two variables (the violent crime rate and the natural log of the gonorrhoea rate) for all 50 states and Washington, DC. For comparison, we also examined the correlation between gonorrhoea rates, and rates of poverty and unemployment. We repeated the analysis using overall syphilis rates instead of overall gonorrhoea rates. Results: The correlation between gonorrhoea and violent crime was significant at the P<0.001 level for every year from 1981 to 2010. Syphilis rates were also consistently correlated with violent crime rates. In contrast, the P-value for the correlation coefficient exceeded 0.05 in 9 of the 30 years for the association between gonorrhoea and poverty, and in 17 of the 30 years for that between gonorrhoea and unemployment. Conclusions: Because violent crime is associated with many social determinants of STIs and because it is consistently associated with STI rates, violent crime rates can be a useful proxy for the social determinants of health in statistical analyses of STI rates.

To investigate changes in mortality following HIV and AIDS in Australia. The results of a linkage between HIV/AIDS diagnoses and the National Death Index (NDI) to the end of 2003 were used to estimate mortality rates following HIV/AIDS. Standardised Mortality Ratios (SMRs) were calculated for deaths following HIV, with and without AIDS, in three periods of treatment; before antiretroviral therapy (< or =1989), pre- and early-HAART (1990-1996) and HAART (1997-2003). Crude mortality rates were calculated as the number of deaths per 1000 person-years. The total number of people living with HIV/AIDS was estimated. There were 1789 deaths following HIV without AIDS and 6730 deaths after AIDS. For deaths following HIV without AIDS, the SMRs were 2.99, 1.22 and 1.6 during the periods before 1990, 1990-1996 and 1997-2003. For deaths after AIDS the SMRs were 137.84, 28.64 and 4.55 in the periods one to three, respectively. The crude death rate following HIV without AIDS increased from 16.8 before 1986 to 19.6 in 2003. Death rates after AIDS decreased from 958.7 up to 1986 to 60.4 in 2003. The number of new HIV diagnoses increased to 1276 in 1990 then decreased to 780 in 2003, while AIDS diagnoses increased to 950 in 1994 then decreased to 252 in 2003. The total number of people living with HIV was estimated to be 7873 in 1989, and 12828 in 2003. Mortality following AIDS decreased while deaths before AIDS remained low. The number of people living with HIV/AIDS has increased.