Dorothy J. Wiley

Efficacy of Human Papillomavirus-16 Vaccine to Prevent Cervical Intraepithelial Neoplasia A Randomized Controlled Trial

OBJECTIVE: Human papillomavirus (HPV) virus-like particle (VLP) vaccines have demonstrated effectiveness in preventing persistent HPV infections. Whether protection lasts longer than 18 months and, thus, impacts rates of cervical intraepithelial neoplasia (CIN) 2–3 has not yet been established. We present results from an HPV16 L1 VLP vaccine trial through 48 months. METHODS: A total of 2,391 women, aged 16–23 years, participated in a randomized, double-blind, placebo-controlled trial. Either 40 &mgr;g HPV16 L1 VLP vaccine or placebo was given intramuscularly at day 1, month 2, and month 6. Genital samples for HPV16 DNA and Pap tests were obtained at day 1, month 7, and then 6-monthly through month 48. Colposcopy and cervical biopsies were performed if clinically indicated and at study exit. Serum HPV16 antibody titer was measured by radioimmunoassay. RESULTS: Among 750 placebo recipients in the per protocol population, 12 women developed HPV16-related CIN2–3 (6 CIN2 and 6 CIN3). Among 755 vaccine recipients, there were no cases (vaccine efficacy 100%, 95% confidence interval [CI] 65–100%). There were 111 cases of persistent HPV16 infection in placebo recipients and 7 cases in vaccine recipients (vaccine efficacy 94%, 95% CI 88–98%). After immunization, HPV16 serum antibody geometric mean titers peaked at month 7 (1,519 milli-Merck units [mMU]/mL), declined through month 18 (202 mMU/mL), and remained relatively stable between month 30 and month 48 (128–150 mMU/mL). CONCLUSION: The vaccine HPV16 L1 VLP provides high-level protection against persistent HPV16 infection and HPV16-related CIN2–3 for at least 3.5 years after immunization. Administration of L1 VLP vaccines targeting HPV16 is likely to reduce risk for cervical cancer. LEVEL OF EVIDENCE: I

External genital warts: diagnosis, treatment, and prevention.

External genital warts (EGWs) are visible warts that occur in the perigenital and perianal regions. They are due primarily to non-oncogenic human papillomavirus (HPV) types, usually types 6 and 11. Physical examination assisted by bright light and magnification is the recommended approach for primary diagnosis. Biopsy is indicated when EGWs are fixed to underlying structures or discolored or when standard therapies are not effective. Recurrences are common, and there is no single treatment that is superior to others. Among women with atypical squamous cells, molecular HPV testing may be useful in determining who should be referred for colposcopy. Condoms may provide some protection against HPV-related diseases and thus are recommended in new sexual relationships and when partnerships are not mutually monogamous. Because the efficacy of cesarean section in preventing vertical transmission of HPV infection from women with EGWs to their progeny has not been proved, it is not recommended.

Incidence and epidemiology of anal cancer in the multicenter AIDS cohort study.

Objective:To examine the incidence and risk factors for anal cancer in a multicenter cohort of human immunodeficiency virus (HIV) positive and HIV-negative men who have sex with men followed between 1984 and 2006 (Multicenter AIDS Cohort Study). Methods:Prospective analysis using Poisson regression and Cox proportional hazard models and a nested case-control study using conditional logistic regression. Results:There were 28 cases of anal cancer among the 6972 men who were evaluated. The incidence rate was significantly higher in HIV-positive men than in HIV-negative men (incidence rate = 69 vs 14 per 100,000 person-years). Among HIV-positive men, anal cancer incidence was higher in the highly active antiretroviral therapy (HAART) era than the pre-HAART era (incidence rate = 137 vs 30 per 100,000 person-years). In multivariate analysis restricted to the HAART era, anal cancer risk increased significantly with HIV infection (relative hazard = 4.7, 95% confidence interval = 1.3 to 17) and increasing number of unprotected receptive anal sex partners at the first 3 study visits (P trend = 0.03). Among HIV-positive men, current HAART use did not decrease anal cancer risk. Conclusions:HIV-positive men had increased risk of anal cancer. Improved survival of HIV-positive individuals after HAART initiation may allow for sufficient time for human papillomavirus-associated anal dysplasias to develop into malignancies, thus explaining the increased incidence of anal cancer in the HAART era.

Synaptic Changes in Alzheimer’s Disease : Increased Amyloid-β and Gliosis in Surviving Terminals Is Accompanied by Decreased PSD-95 Fluorescence

In an effort to examine changes that precede synapse loss, we have measured amyloid-beta and a series of damage markers in the synaptic compartment of Alzheimers disease (AD) cases. Because localization of events to the terminal region in neurons is problematic with conventional methods, we prepared synaptosomes from samples of cryopreserved human association cortex, and immunolabeled terminals with a procedure for intracellular antigens. Fluorescence was quantified using flow cytometry. The viability dye calcein AM was unchanged in AD terminals compared to controls, and the fraction of large synaptosome particles did not change, although a striking loss of large terminals was observed in some AD cases. The percent positive fraction for a series of pre- and postsynaptic markers was not affected by AD in this cohort. However, the amyloid-beta-positive fraction increased from 16 to 27% (P < 0.02) in terminals from AD cortex. The expression level on a per-terminal basis is indicated in this assay by fluorescence (relative fluorescence units). The fluorescence of presynaptic markers did not change in AD terminals, but PSD-95 fluorescence was decreased by 19% (P < 0.03). Amyloid-beta fluorescence was increased by 132% (P < 0.01), and glial fibrillary acidic protein labeling by 31% (P < 0.01). These results suggest that synapse-associated amyloid-beta is prominent in regions relatively unaffected by AD lesions, and that amyloid accumulation in surviving terminals is accompanied by gliosis and alteration in the postsynaptic structure.

Conserved Methylation Patterns of Human Papillomavirus Type 16 DNA in Asymptomatic Infection and Cervical Neoplasia

ABSTRACT DNA methylation contributes to the chromatin conformation that represses transcription of human papillomavirus type16 (HPV-16), which is prevalent in the etiology of cervical carcinoma. In an effort to clarify the role of this phenomenon in the regulation and carcinogenicity of HPV-16, 115 clinical samples were studied to establish the methylation patterns of the 19 CpG dinucleotides within the long control region and part of the L1 gene by bisulfite modification, PCR amplification, DNA cloning, and sequencing. We observed major heterogeneities between clones from different samples as well as between clones from individual samples. The methylation frequency of CpGs was measured at 14.5%. In addition, 0.21 and 0.23%, respectively, of the CpA and CpT sites, indicators of de novo methylation, were methylated. Methylation frequencies exceeded 30% in the CpGs overlapping with the L1 gene and were about 10% for most other positions. A CpG site located in the linker between two nucleosomes positioned over the enhancer and promoter of HPV-16 had minimal methylation. This region forms part of the HPV replication origin and is close to binding sites of master-regulators of transcription during epithelial differentiation. Methylation of most sites was highest in carcinomas, possibly due to tandem repetition and chromosomal integration of HPV-16 DNA. Methylation was lowest in dysplasia, likely reflecting the transcriptional activity in these infections. Our data document the efficient targeting of HPV genomes by the epithelial methylation machinery, possibly as a cellular defense mechanism, and suggest involvement of methylation in HPV oncogene expression and the early-late switch.

Risk Factors for Oral HPV Infection among a High Prevalence Population of HIV-Positive and At-Risk HIV-Negative Adults

Introduction: Human papillomavirus (HPV) is an important risk factor for oropharyngeal cancer. Individuals with human immunodeficiency virus (HIV) have higher oral HPV prevalence but the risk factors for oral HPV infection are not well understood for either HIV-positive or HIV-negative individuals. Methods: This study was nested within the Multicenter AIDS Cohort Study (MACS; men) and Women Interagency HIV Study (WIHS; women) cohorts. Exfoliated oral epithelial cells were collected from 379 HIV-positive and 266 at-risk HIV-negative individuals using a rinse and gargle with Scope mouthwash. Samples were tested for 36 types of HPV DNA using PGMY09/11 consensus primers and reverse line blot hybridization. Risk factors for oral HPV infection were explored using logistic regression with generalized estimating equations in this cross-sectional analysis. Results: Prevalent oral HPV infection was common (34%), including HPV16 infection in 5.7% of participants. HIV-positive individuals had increased odds of prevalent oral HPV infection compared with HIV-negative individuals [adjusted OR = 2.1; 95% confidence interval (CI), 1.6–2.8]. Risk factors for prevalent oral HPV differed in HIV-positive and HIV-negative participants. Among HIV-negative individuals, higher number of recent oral sex or rimming partners were strong risk factors for prevalent oral HPV infection (each Ptrend < 0.01). In contrast, among HIV-positive individuals, lower CD4 T-cell count (Ptrend < 0.001) and higher number of lifetime sexual partners (Ptrend = 0.03) were strong risk factors. Conclusions: Oral HPV prevalence was elevated in HIV-positive individuals after controlling for differences in cigarette smoking and sexual behavior, supporting the possibility that HIV may affect the natural history of oral HPV. Impact: Immunosuppression may contribute to increased persistence or progression of oral HPV infection. Cancer Epidemiol Biomarkers Prev; 21(1); 122–33. ©2011 AACR.

Risk factors for hepatitis C virus infection among homeless adults

OBJECTIVE: To describe the prevalence of hepatitis C virus (HCV) infection in a sample of homeless and impoverished adults and examine risk factors for HCV infection in the overall sample and as a function of injection drug use.DESIGN: Assays were conducted on stored sera. Socio-demographic characteristics and risky sexual activity were measured by content-specific items. Substance use was measured by a structured questionnaire. HCV antibodies were tested by enzyme-linked immunosorbent assay; a confirmatory level was defined by recombinant immunoblot assay.SETTINGS: Shelters (N=36) and outdoor locations in Los Angeles.PARTICIPANTS: Eight hundred eighty-four homeless women and/or partners or friends.RESULTS: Among this sample of 884 homeless and impoverished adults, 22% were found to be HCV infected. Lifetime injection drug users (IDUs) (cocaine, crack, and methamphetamine) and recent daily users of crack were more likely than nonusers or less-frequent users of these drugs to be HCV-infected. Similar results were found for those who had been hospitalized for a mental health problem. Among non-injection drug users and persons in the total sample, those who reported lifetime alcohol abuse were more likely than those who did not to be HCV infected. Controlling for socio-demographic characteristics, multiple logistic regression analyses revealed IDUs have over 25 times greater odds of having HCV infection than non-IDUs. HCV infection was also predicted by older age, having started living on one’s own before the age of 18, and recent chronic alcohol use. Males and recent crack users had about one and a half times greater odds of HCV infection when compared to females and non-chronic crack users.CONCLUSIONS: Targeted outreach for homeless women and their partners, including HCV testing coupled with referrals to HCV and substance abuse treatments, may be helpful.

Cancer incidence in the multicenter aids cohort study before and during the HAART era: 1984 to 2007

The incidence of Kaposi sarcoma (KS) and non‐Hodgkin lymphoma (NHL) among human immunodeficiency virus (HIV)‐infected individuals declined after the introduction of highly active antiretroviral therapy (HAART) in the mid‐1990s, but the cancer risk associated with HIV infection during the HAART era remains to be clarified.

Reversible Deficiency of Antimicrobial Polypeptides in Bacterial Vaginosis

ABSTRACT Bacterial vaginosis is a common condition associated with increased risk of sexually transmitted diseases, including human immunodeficiency virus infections. In contrast, vulvovaginal candidiasis has a much weaker association with sexually transmitted diseases. We found that vaginal lavage fluid from women with bacterial vaginosis is deficient in antimicrobial polypeptides and antimicrobial activity compared to fluid from healthy women or women with vulvovaginal candidiasis. Effective treatment normalized the concentrations of antimicrobial polypeptides in both bacterial vaginosis and in vulvovaginal candidiasis, suggesting that the abnormalities were a result of the diseases. Unlike in vulvovaginal candidiasis, the neutrophil attractant chemokine interleukin-8 (IL-8) was not increased in bacterial vaginosis, accounting for low concentrations of neutrophil-derived defensins in vaginal fluid. In organotypic cultures of human vaginal epithelium containing dendritic cells, treatment with Lactobacillus jensenii, a typical vaginal resident, induced the synthesis of IL-8 mRNA and the epithelial human β-defensin-2 mRNA, but a typical bacterial vaginosis pathogen, Gardnerella vaginalis, had no effect. When the two bacteria were combined, Gardnerella vaginalis did not interfere with the immunostimulatory effect of Lactobacillus jensenii. The loss of normal immunostimulatory flora in bacterial vaginosis is thus associated with a local deficiency of multiple innate immune factors, and this deficiency could predispose individuals to sexually transmitted diseases.

External Genital Warts: Report of the American Medical Association Consensus Conference

A consensus process was undertaken to describe and evaluate current information and practice regarding the diagnosis, treatment, and evaluation of patients with external genital warts (EGWs) and their sex partners. This process developed a number of key statements that were based on strong evidence in the literature or reasonable suppositions and opinions of experts. Key statements included the following. In most cases, EGWs can be diagnosed clinically by visual inspection. No one treatment is ideal for all patients or all warts. Women with EGWs and female sex partners of men with EGWs are at increased risk for human papillomavirus-related cervical disease and, like all women, should be screened for cervical cancer. The diagnosis of EGWs in children requires a sexual abuse evaluation. Clinicians who treat EGWs have a responsibility to counsel patients and to provide information about the infectivity, diagnosis, treatment, and natural history of EGWs and general information about sexual health and other sexually transmitted diseases.