Richard J. Hillman

Efficacy of quadrivalent HPV vaccine against HPV Infection and disease in males.

BACKGROUND Infection with human papillomavirus (HPV) and diseases caused by HPV are common in boys and men. We report on the safety of a quadrivalent vaccine (active against HPV types 6, 11, 16, and 18) and on its efficacy in preventing the development of external genital lesions and anogenital HPV infection in boys and men. METHODS We enrolled 4065 healthy boys and men 16 to 26 years of age, from 18 countries in a randomized, placebo-controlled, double-blind trial. The primary efficacy objective was to show that the quadrivalent HPV vaccine reduced the incidence of external genital lesions related to HPV-6, 11, 16, or 18. Efficacy analyses were conducted in a per-protocol population, in which subjects received all three vaccinations and were negative for relevant HPV types at enrollment, and in an intention-to-treat population, in which subjects received vaccine or placebo, regardless of baseline HPV status. RESULTS In the intention-to-treat population, 36 external genital lesions were seen in the vaccine group as compared with 89 in the placebo group, for an observed efficacy of 60.2% (95% confidence interval [CI], 40.8 to 73.8); the efficacy was 65.5% (95% CI, 45.8 to 78.6) for lesions related to HPV-6, 11, 16, or 18. In the per-protocol population, efficacy against lesions related to HPV-6, 11, 16, or 18 was 90.4% (95% CI, 69.2 to 98.1). Efficacy with respect to persistent infection with HPV-6, 11, 16, or 18 and detection of related DNA at any time was 47.8% (95% CI, 36.0 to 57.6) and 27.1% (95% CI, 16.6 to 36.3), respectively, in the intention-to-treat population and 85.6% (97.5% CI, 73.4 to 92.9) and 44.7% (95% CI, 31.5 to 55.6) in the per-protocol population. Injection-site pain was significantly more frequent among subjects receiving quadrivalent HPV vaccine than among those receiving placebo (57% vs. 51%, P<0.001). CONCLUSIONS Quadrivalent HPV vaccine prevents infection with HPV-6, 11, 16, and 18 and the development of related external genital lesions in males 16 to 26 years of age. (Funded by Merck and others; ClinicalTrials.gov number, NCT00090285.).

HPV Vaccine against Anal HPV Infection and Anal Intraepithelial Neoplasia

BACKGROUND The rate of anal cancer is increasing among both women and men, particularly men who have sex with men. Caused by infection with human papillomavirus (HPV), primarily HPV type 16 or 18, anal cancer is preceded by high-grade anal intraepithelial neoplasia (grade 2 or 3). We studied the safety and efficacy of quadrivalent HPV vaccine (qHPV) against anal intraepithelial neoplasia associated with HPV-6, 11, 16, or 18 infection in men who have sex with men. METHODS In a substudy of a larger double-blind study, we randomly assigned 602 healthy men who have sex with men, 16 to 26 years of age, to receive either qHPV or placebo. The primary efficacy objective was prevention of anal intraepithelial neoplasia or anal cancer related to infection with HPV-6, 11, 16, or 18. Efficacy analyses were performed in intention-to-treat and per-protocol efficacy populations. The rates of adverse events were documented. RESULTS Efficacy of the qHPV vaccine against anal intraepithelial neoplasia associated with HPV-6, 11, 16, or 18 was 50.3% (95% confidence interval [CI], 25.7 to 67.2) in the intention-to-treat population and 77.5% (95% CI, 39.6 to 93.3) in the per-protocol efficacy population; the corresponding efficacies against anal intraepithelial neoplasia associated with HPV of any type were 25.7% (95% CI, -1.1 to 45.6) and 54.9% (95% CI, 8.4 to 79.1), respectively. Rates of anal intraepithelial neoplasia per 100 person-years were 17.5 in the placebo group and 13.0 in the vaccine group in the intention-to-treat population and 8.9 in the placebo group and 4.0 in the vaccine group in the per-protocol efficacy population. The rate of grade 2 or 3 anal intraepithelial neoplasia related to infection with HPV-6, 11, 16, or 18 was reduced by 54.2% (95% CI, 18.0 to 75.3) in the intention-to-treat population and by 74.9% (95% CI, 8.8 to 95.4) in the per-protocol efficacy population. The corresponding risks of persistent anal infection with HPV-6, 11, 16, or 18 were reduced by 59.4% (95% CI, 43.0 to 71.4) and 94.9% (95% CI, 80.4 to 99.4), respectively. No vaccine-related serious adverse events were reported. CONCLUSIONS Use of the qHPV vaccine reduced the rates of anal intraepithelial neoplasia, including of grade 2 or 3, among men who have sex with men. The vaccine had a favorable safety profile and may help to reduce the risk of anal cancer. (Funded by Merck and the National Institutes of Health; ClinicalTrials.gov number, NCT00090285.).

Prevalence of and Risk Factors for Human Papillomavirus (HPV) Infection Among HIV-Seronegative Men Who Have Sex With Men

BACKGROUND We examined the baseline prevalence of penile, scrotal, perineal/perianal, and intra-anal human papillomavirus (HPV) infection in human immunodeficiency virus (HIV)-seronegative men who have sex with men (MSM). METHODS Data were analyzed from 602 MSM aged 16-27 years with ≤ 5 lifetime sexual partners. Serum samples were tested for antibodies to HPV6/11/16/18. Swab samples were collected separately from several anogenital areas for detection of HPV6/11/16/18/31/33/35/39/45/51/52/56/58/59 DNA. RESULTS The prevalence of any tested HPV type was 18.5% at the penis, 17.1% at the scrotum, 33.0% at the perineal/perianal region, 42.4% in the anal canal, and 48.0% at any site. Overall, 415 MSM (69.7%) were negative to HPV 6, 11, 16, and 18 at enrollment by both serology and DNA detection. Men residing in Europe and Latin America had significantly increased risk of HPV infection at external genital sites and the anal canal compared to men from Australia. Tobacco use and greater number of lifetime sexual partners was associated with higher HPV infection prevalence. CONCLUSIONS The prevalence of HPV infection is high among young sexually active MSM, with the anal canal being the most common site of infection. Lifetime number of sexual partners was the most important modifiable risk factor for anogenital HPV infection.

Immunogenicity of the Quadrivalent Human Papillomavirus (Type 6/11/16/18) Vaccine in Males 16 to 26 Years Old

ABSTRACT Human papillomavirus (HPV) infection can lead to significant disease in males, including anogenital warts, intraepithelial neoplasias, and several types of oral and anogenital cancers. The quadrivalent HPV (type 6/11/16/18) L1 virus-like particle (VLP) vaccine (qHPV vaccine; Gardasil) has recently been demonstrated to prevent persistent infection and associated disease related to vaccine HPV types in males. We report the overall immunogenicity results from a trial of the quadrivalent HPV vaccine in males. Overall, 3,463 heterosexual men and 602 men who had sex with men were enrolled into a randomized, placebo-controlled, double-blind safety, immunogenicity, and efficacy study. Serum samples were collected prior to vaccination at day 1 and at months 7, 24, and 36 postvaccination. Immunogenicity was evaluated with a multiplex, competitive Luminex immunoassay. Almost all subjects (97.4 to 99.2%) seroconverted for vaccine HPV types by month 7. At month 36, 88.9%, 94.0%, 97.9%, and 57.0% of subjects were still seropositive for HPV-6, -11, -16, and -18, respectively. For all vaccine HPV types, black subjects had significantly higher antibody titers at month 7 than did both Caucasian and Asian subjects. An anamnestic antibody response was seen in men seropositive before vaccination. The vaccine was highly immunogenic in males 16 to 23 years of age; responses were comparable to those observed in women. Furthermore, the immune responses were consistent with the established efficacy of the vaccine in the prevention of incident and persistent HPV infection, anogenital warts, and anal intraepithelial neoplasia.

Anal human papillomavirus genotype diversity and co-infection in a community-based sample of homosexual men

Objectives: To determine the prevalence and risk factors for anal human papillomavirus (HPV) infection in community-based cohorts of homosexual men in Sydney, Australia. Methods: A cross-sectional study in consecutively presenting participants in the positive Health and Health in Men cohorts in 2005. HPV testing was performed on anal PreservCyt specimens collected from 316 homosexual men (193 HIV-negative, 123 HIV-positive) using the Digene Hybrid Capture 2 (HC-2) assay for detection of low-risk (LR) and high-risk (HR) genotypes. HPV genotype testing was also performed on a subset of 133 men (93 HIV-negative, 36 HIV-positive) using Roche Linear Array (LA) assay. Results: HC-2 detected HPV infection in 79% of men (LR 55%, HR 69%). HIV-positive men were more likely than HIV-negative men to have LR-HPV (OR 3.5, 95% CI 2.1 to 5.7) and HR-HPV (OR 5.5, 95% CI 3.0 to 10.2). LA detected HPV infection in 95% of men (LR 85%, HR 77%). HIV-positive men had a mean of 7.1 HPV types compared to 4.2 in HIV-negative men; the difference was significant for both LR-HPV (p<0.001) and HR-HPV (p<0.001). HPV-16 was detected in 36% of HIV-positive and 27% of HIV-negative men. There was no consistent trend in HPV prevalence with increasing age. HR-HPV detection was associated with anal bleeding for HIV-positive men and anal warts for HIV-negative men. Conclusions: Anal HPV infection was nearly universal in this community-based sample of homosexual men. A wide variety of HPV genotypes were detected, and co-infection with multiple genotypes was common. Anal HPV infection is more prevalent and more diverse in HIV-positive than HIV-negative homosexual men.

The epidemiology of anal cancer

Anal cancer comprises malignancies of the anal canal principally of two morphologic variants: squamous cell carcinoma (SCC) and adenocarcinoma. In most settings, SCC compromises more than 70% of cases. In the general population, anal cancer is uncommon, with age-standardised incidence rates mostly between 1 and 2 per 100000 per year. However, incidence of anal SCC is increasing by 1-3% per year in developed country settings. High-risk human papillomavirus (HPV) types can be detected in 80-90% of all anal SCC cases, making it second only to cervical cancer in the closeness of its association with this virus. HPV-16 can be detected in ~90% of HPV-positive cases of anal SCC. Case-control studies have demonstrated that sexual risk factors (homosexuality in men and multiple sexual partners in women) are strongly associated with anal cancer risk. Other risk factors include immune deficiency and tobacco exposure. Anal cancer rates are highest in homosexual men, particularly in those who are HIV-positive, in whom anal cancer is among the most common of all cancers. Vaccination against HPV holds great promise for anal cancer prevention for those not already HPV-infected. For the current generation of adult high-risk populations, screening programs to allow early detection and treatment are under investigation.

Anal and perianal squamous carcinomas and high‐grade intraepithelial lesions exclusively associated with “low‐risk” HPV genotypes 6 and 11

Anal squamous cell carcinomas are predominantly associated with high‐risk human papillomaviruses (HPVs), particularly HPV 16, similar to cervical, vaginal and vulvar cancers. Although the presence of “low‐risk” HPVs, in particular genotypes 6 and 11, have occasionally been reported in various HPV‐related anogenital cancers, the overall distribution of these genotypes in the anal canal and perianal tissue may differ to that in the cervix. In addition, although the majority of anal and perianal cancers are associated with HPV, some are not; hence, confirmation of direct association of the virus within a lesion is important. Using laser capture microdissection, anal and perianal invasive carcinomas and high‐grade squamous intraepithelial lesions (HSILs) in biopsies previously associated with HPV 6 or 11 alone were isolated from tissue sections and HPV genotype tested. Of seven cases tested, four invasive carcinomas were positive for HPV 6 only, one invasive carcinoma was negative for HPV and two HSILs were positive for HPV 11 only. All samples were confirmed as HPV 16/18 negative using two different DNA targets (E6 and L1). From these results, we confirm that HPV 6 and 11 can occasionally be associated with high‐grade lesion and anal cancer.

Blind sampling is superior to anoscope guided sampling for screening for anal intraepithelial neoplasia

Objectives: Anal cytology smears are either collected “blind” (swab inserted 4 cm into anal canal and rotated) or guided through an anoscope (transformation zone visualised and then sampled). We compared these smear techniques with respect to sample quality and patient acceptability. Methods: Using a paired, random sequence clinical trial, 151 homosexual men (n = 95 HIV positive) underwent both smear techniques at a single visit; smear order was randomised and specimens were read blind. Both techniques utilised a Dacron swab, with water lubrication. Cytological specimens were prepared using a liquid based collection method (ThinPrep). The outcome measures were cytological specimen adequacy, cytological classification, presence of rectal columnar, squamous and metaplastic cells, contamination, patient comfort and acceptability, and volume of fluid that remained after the ThinPrep procedure. Results: Regardless of smear order, guided smears were less likely to detect higher grade abnormalities than blind smears (15 v 27 cases, p = 0.001). Controlling for smear order, guided smears were more likely to be assessed as “unsatisfactory” for cytological assessment (OR 6.93, 95% CI 1.92 to 24.94), and contain fewer squamous (OR 0.20, 95% CI 0.04 to 0.94) and metaplastic cells (OR 0.12, 95% CI 0.03 to 0.54) than blind smears; there were no other statistically significant differences between techniques. Regardless of smear technique, first performed smears were more likely to detect a higher grade abnormality than second performed smears (23 v eight cases, p<0.001). Conclusions: Blind cytology smears are superior to anoscope guided smears for screening for anal neoplasia in homosexual men.

The Study of the Prevention of Anal Cancer (SPANC): design and methods of a three-year prospective cohort study

BackgroundThe incidence of human papillomavirus (HPV)-associated anal cancer is increasing in men who have sex with men (MSM). Screening for the presumed cancer precursor, high-grade anal squamous intraepithelial lesions (HSIL) in a manner analogous to cervical cancer screening has been proposed. Uncertainty remains regarding anal HPV natural history and the role of anal cytology and high-resolution anoscopy (HRA) as screening tests. Well-designed cohort studies are required to address these issues.Methods/designThe SPANC study is a prospective study of the epidemiology of low-risk and high-risk anal HPV infection and related cytological and histological abnormalities in HIV-negative and HIV-positive homosexual men aged 35 years and over. The study aims to recruit 600 men from community-based settings in Sydney, Australia. There are six study visits over three years. At the first five visits men undergo a digital ano-rectal examination (DARE), an anal “Papanicolaou” (Pap) test for HPV detection, genotyping and anal cytology, followed by HRA and directed biopsy of any visible abnormalities. The men also complete a behavioural questionnaire before each visit. Questions include a detailed history of sexual behaviour, of anal symptoms, possible anal cancer risk factors and validated quality of life and psychosocial questions. Questionnaires are also completed 2 weeks and 3 months following the provision of test results and include questions on participant experience during the procedure and post-procedure symptoms, including pain and bleeding in addition to quality of life/ psychosocial outcomes.DiscussionRecruitment for the study began in September 2010 and will conclude in mid-2015, with follow up continuing to 2018. Thus far, over 350 men have been recruited from a variety of community-based settings and are broadly representative of the target screening population. The SPANC study is one of only a small number of cohort studies globally to perform HPV, cytology and HRA screening on all participants over multiple time points. The study results will contribute to understanding of the natural history of anal HPV and inform the possible development of guidelines for implementing anal cancer screening programs in this population.

Progression to and spontaneous regression of high-grade anal squamous intraepithelial lesions in HIV-infected and uninfected men.

Objective:To quantify incidence of, and risk factors for, progression to and spontaneous regression of high-grade anal squamous intraepithelial lesions (ASILs). Design:Retrospective review of patients at St Vincents Hospital Anal Cancer Screening Clinic during a period when high-grade ASILs were not routinely treated (2004–2011). Methods:All patients who had an anal Papanicolaou smear or high-resolution anoscopy were included, except for patients with previous anal cancer. High-grade anal intraepithelial neoplasia (HGAIN) was defined as a composite of histologically confirmed grade 2 or 3 anal intraepithelial neoplasia (AIN2/3) and/or high-grade squamous intraepithelial lesion on anal cytology. Analyses were repeated restricting to histologically confirmed AIN3. Results:There were 574 patients: median age 45 years (interquartile range, IQR 36–51), 99.3% male and 73.0% HIV-infected [median HIV duration was 13.8 years (IQR 6.4–19.8), median CD4+ T-lymphocyte count was 500 cells/&mgr;l (IQR 357–662), 83.5% had undetectable plasma HIV viral load]. Median follow-up was 1.1 years (IQR 0.26–2.76). Progression rate to HGAIN was 7.4/100 person-years (95% confidence interval, CI 4.73–11.63). No risk factor for progression to HGAIN was identified; progression to AIN3 was more likely with increasing age (Ptrend = 0.004) and in those who were HIV-infected [hazard ratio 2.8 (95% CI 1.18–6.68) versus HIV-uninfected; P = 0.019], particularly in those whose nadir CD4+ T-lymphocyte count was less than 200 cells/&mgr;l (Ptrend = 0.003). In 101 patients with HGAIN, 24 (23.8%) patients had spontaneous regression [rate 23.5/100 person-years (95% CI 15.73–35.02)], mostly to AIN1. Regression was less likely in older patients (Ptrend = 0.048). Two patients with HGAIN developed anal cancer. Conclusion:High-grade ASILs frequently spontaneously regress. Longer-term, prospective studies are required to determine whether these regressions are sustained.