Association of plasma aflatoxin with persistent detection of oncogenic human papillomaviruses in cervical samples from Kenyan women enrolled in a longitudinal study.

BACKGROUND: Cervical cancer is caused by oncogenic human papillomaviruses (HR-HPV) and is common among Kenyan women. Identification of factors that increase HR-HPV persistence is critically important. Kenyan women exposed to aflatoxin have an increased risk of HR-HPV detection in cervical specimens. This analysis was performed to examine associations between aflatoxin and HR-HPV persistence. METHODS: Kenyan women were enrolled in a prospective study. The analytical cohort for this analysis included 67 HIV-uninfected women (mean age 34 years) who completed at least two of three annual study visits and had an available blood sample. Plasma aflatoxin was detected using ultra-high pressure liquid chromatography (UHPLC)-isotope dilution mass spectrometry. Annual cervical swabs were tested for HPV (Roche Linear Array). Ordinal logistic regression models were fitted to examine associations of aflatoxin and HPV persistence. RESULTS: Aflatoxin was detected in 59.7% of women and was associated with higher risk of persistent detection of any HPV type (OR = 3.03, 95%CI = 1.08-8.55, P = 0.036), HR-HPV types (OR = 3.63, 95%CI = 1.30-10.13, P = 0.014), and HR-HPV types not included in the 9-valent HPV vaccine (OR = 4.46, 95%CI = 1.13-17.58, P = 0.032). CONCLUSIONS: Aflatoxin detection was associated with increased risk of HR-HPV persistence in Kenyan women. Further studies, including mechanistic studies are needed to determine if aflatoxin synergistically interacts with HR-HPV to increase cervical cancer risk.

Substantial Decline in Vaccine-Type Human Papillomavirus (HPV) Among Vaccinated Young Women During the First 8 Years After HPV Vaccine Introduction in a Community.

BACKGROUND: Human papillomavirus (HPV) vaccine effectiveness and herd protection are not well established in community settings. Our objective was to determine trends in vaccine-type HPV in young women during the 8 years after vaccine introduction, to assess changes in HPV prevalence and characterize herd protection in a community. METHODS: We recruited 3 samples of sexually experienced, 13-26-year-old adolescent girls and young women (hereafter women; N = 1180) from 2006-2014: before widespread vaccine introduction (wave 1) and 3 (wave 2) and 7 (wave 3) years after vaccine introduction. We determined the prevalence of vaccine-type HPV (HPV-6, -11, -16, and -18) among all, vaccinated, and unvaccinated women at waves 1, 2, and 3, adjusted for differences in participant characteristics, then examined whether changes in HPV prevalence were significant using inverse propensity score-weighted logistic regression. RESULTS: Vaccination rates increased from 0% to 71.3% across the 3 waves. Adjusted vaccine-type HPV prevalence changed from 34.8% to 8.7% (75.0% decline) in all women, from 34.9% to 3.2% (90.8% decline) in vaccinated women, and from 32.5% to 22.0% (32.3% decline) in unvaccinated women. Among vaccinated participants, vaccine-type HPV prevalence decreased significantly from wave 1 to wave 2 (adjusted odds ratio, 0.21; 95% confidence interval, .13-.34) and from wave 1 to wave 3 (0.06; .03-.13). The same decreases were also significant among unvaccinated participants (adjusted odds ratios, 0.44; [95% confidence interval, .27-.71] and 0.59; [.35-.98], respectively). CONCLUSIONS: The prevalence of vaccine-type HPV decreased >90% in vaccinated women, demonstrating high effectiveness in a community setting, and >30% in unvaccinated women, providing evidence of herd protection.

Impact and Effectiveness of the Quadrivalent Human Papillomavirus Vaccine: A Systematic Review of 10 Years of Real-world Experience.

Prophylactic human papillomavirus (HPV) vaccination programs constitute major public health initiatives worldwide. We assessed the global effect of quadrivalent HPV (4vHPV) vaccination on HPV infection and disease. PubMed and Embase were systematically searched for peer-reviewed articles from January 2007 through February 2016 to identify observational studies reporting the impact or effectiveness of 4vHPV vaccination on infection, anogenital warts, and cervical cancer or precancerous lesions. Over the last decade, the impact of HPV vaccination in real-world settings has become increasingly evident, especially among girls vaccinated before HPV exposure in countries with high vaccine uptake. Maximal reductions of approximately 90% for HPV 6/11/16/18 infection, approximately 90% for genital warts, approximately 45% for low-grade cytological cervical abnormalities, and approximately 85% for high-grade histologically proven cervical abnormalities have been reported. The full public health potential of HPV vaccination is not yet realized. HPV-related disease remains a significant source of morbidity and mortality in developing and developed nations, underscoring the need for HPV vaccination programs with high population coverage.

Episodic detection of human papillomavirus within a longitudinal cohort of young women.

Redetection of a type-specific human papillomavirus (HPV) infection may represent reinfection. However, a growing body of literature suggests that reactivation of HPV is common and that episodic detection of a HPV infection may represent reactivation of a persistent virus. A cohort of prospectively followed adolescent women (N = 150), ages 14-17, was observed on average 6.4 years. The authors describe the redetection of 37 HPV types and associated factors of redetection of high-risk (HR) and low-risk (LR) types using Cox proportional hazard models. Of 1,248 HPV type-specific infections, 286 (22.9%) were associated with redetection after apparent clearance. Chlamydia infections (HR = 1.99 [95%CI, 1.15-3.49]) and non-condom use (HR = 1.1 [95%CI, 1.04-1.99]) were associated with increased redetection of HR-HPV infections. Oral contraceptive pills (HR = 2.73 [95%CI, 1.52-4.90]) and number of sexual partners (HR = 1.44 [95%CI, 1.04-1.99]) were associated with increased redetection of LR-HPV infections. Episodic detection of HPV is common for HR- and LR-HPV types. This finding and identified factors or redetection have clinical implications and enhances the understanding of HPV natural history.

DNA detection and seroprevalence of human papillomavirus in a cohort of adolescent women.

OBJECTIVES: Human papillomavirus (HPV) infections are common in adolescent women, while the rare cancerous sequelae of HPV infections do not generally occur until the 4th or 5th decades of life. This prospective study of a cohort of adolescent women was performed to further our knowledge of the natural history of incident and prevalent HPV infections. METHODS: Self-vaginal swabs collected from high-risk, unvaccinated adolescent women in a longitudinal study were analysed for HPV DNA. Sera were collected at enrolment and later tested for HPV antibodies. Statistical analysis was performed to determine the HPV genotype distribution and duration of detection, and to determine rates of seropositivity and seroconversion for HPV types represented in the assays. RESULTS: 146 subjects (mean enrolment age=15.4 years; mean duration of follow-up=5.8 years) had samples adequate for analysis of HPV detection, and 95 of these subjects had paired sera available. The cumulative prevalence for high-risk and low-risk HPV types was 95.9% and 91.1%, respectively. HPV types 6, 11, 16 and 18 (HPV types represented in the quadrivalent vaccine) were found at some point in 40.4%, 6.2%, 48% and 24% of participants, respectively. Serological data confirmed exposure to these vaccine-covered types, as well as to other high-risk HPV types. CONCLUSIONS: In this cohort of adolescent women, high- and low-risk HPV types were frequently detected, and serological data confirmed exposure in most subjects. The high-prevalence HPV types represented in the quadrivalent HPV vaccine further support vaccination of women at an age well before sexual debut.

High frequency of human papillomavirus detection in the vagina before first vaginal intercourse among females enrolled in a longitudinal cohort study.

BACKGROUND: Genital human papillomavirus (HPV) infection is believed to be primarily sexually transmitted. Few studies have documented the detection of HPV in the vagina before first vaginal intercourse. METHODS: We used a longitudinally followed cohort of adolescent females without prior vaginal intercourse to examine the frequency of detection of vaginal HPV and the association between first reported HPV detection and noncoital sexual behaviors. RESULTS: HPV was detected in 45.5% of subjects (10 of 22) before first vaginal sex. Seven of these 10 subjects reported noncoital behaviors that, in part, might have explained genital transmission. CONCLUSIONS: HPV can be detected in the vagina before first sexual intercourse, highlighting the need for early vaccination.

Association of Chlamydia trachomatis infection with redetection of human papillomavirus after apparent clearance.

BACKGROUND: Persistent infection with oncogenic human papillomavirus (HPV) is associated with an increased risk of cervical malignancy. Redetection of type-specific HPV after a period of nondetection may be caused by reactivation of a low-level persistent infection. Little is known about factors associated with type-specific HPV redetection. METHODS: For a longitudinal cohort of adolescent women with frequent behavioral and sexually transmitted infection (STI) information (every 3 months), Cox proportional hazard models were used to assess the influence of sexual behaviors and STIs on the redetection of oncogenic or high-risk HPV infections. RESULTS: A total of 210 type-specific high-risk HPV detection episode periods were identified in this longitudinal cohort; 71 (33.8%) were characterized by a period of nondetection followed by redetection. Chlamydia trachomatis (hazard ratio [HR], 3.14; 95% confidence interval [CI], 1.44-6.86) was associated with redetection; redetection was >2 times more likely with each additional self-reported sex partner in the past 3 months (HR, 2.26; 95% CI, 1.35-3.78). CONCLUSIONS: This study demonstrates the role of C. trachomatis and number of recent sexual partners in type-specific HPV redetection. Given that persistent oncogenic HPV infections are associated with cancer-related outcomes, understanding the potential role of such factors in the pathogenesis of HPV-related outcomes is important.

The fanconi anemia pathway limits human papillomavirus replication.

High-risk human papillomaviruses (HPVs) deregulate epidermal differentiation and cause anogenital and head and neck squamous cell carcinomas (SCCs). The E7 gene is considered the predominant viral oncogene and drives proliferation and genome instability. While the implementation of routine screens has greatly reduced the incidence of cervical cancers which are almost exclusively HPV positive, the proportion of HPV-positive head and neck SCCs is on the rise. High levels of HPV oncogene expression and genome load are linked to disease progression, but genetic risk factors that regulate oncogene abundance and/or genome amplification remain poorly understood. Fanconi anemia (FA) is a genome instability syndrome characterized at least in part by extreme susceptibility to SCCs. FA results from mutations in one of 15 genes in the FA pathway, whose protein products assemble in the nucleus and play important roles in DNA damage repair. We report here that loss of FA pathway components FANCA and FANCD2 stimulates E7 protein accumulation in human keratinocytes and causes increased epithelial proliferation and basal cell layer expansion in the HPV-positive epidermis. Additionally, FANCD2 loss stimulates HPV genome amplification in differentiating cells, demonstrating that the intact FA pathway functions to restrict the HPV life cycle. These findings raise the possibility that FA genes suppress HPV infection and disease and suggest possible mechanism(s) for reported associations of HPV with an FA cohort in Brazil and for allelic variation of FA genes with HPV persistence in the general population.

Association of HPV types 6, 11, 16, and 18 DNA detection and serological response in unvaccinated adolescent women.

Antibodies directed against the human papillomavirus (HPV) L1 protein are detected in approximately 70% of individuals with HPV infections. The factors associated with a serological response are not characterized. It is hypothesized that the HPV viral load, duration of detection, or both would be associated with seropositivity in adolescent women. Adolescent women (n = 117), ages 15-17 at enrolment were followed for a mean of 6.2 years. Quarterly vaginal swabs (mean 22 per participant) were used to identify HPV 6, 11, 16, or 18 DNA (Roche PCR/Linear Array). Type-specific HPV infection was defined as ≥2 positive assays. To approximate viral load, Roche PCR/Linear Array test strips were scored visually based on the strength of signal relative to beta-globin controls. Sera collected near the end of study were tested by cLIA. Regression models were fit to assess associations between strength of signal (as represented by mean and cumulative strength of signal), duration of HPV detection, seropositivity, and serotiter. Detection of HPV DNA was associated with seropositivity for four types combined and for types 6, 16, and 18. Overall, 70.1% of DNA positive episodes were associated with type-specific seropositivity. The cumulative HPV DNA signal strength during periods of HPV detection for types 6, 11, 16, and 18 combined was associated with seropositivity (OR = 1.21, 95% CI 1.02-1.44 P = 0.026). No other HPV DNA predictors were found to be associated with seropositivity or serotiter.

Human papillomavirus seroprevalence and seroconversion following baseline detection of nine human papillomavirus types in young women.

BACKGROUND: Estimates of the humoral immune response to incident human papillomavirus (HPV) infections are limited. METHODS: In this post hoc analysis of 3875 women aged 16-23 years from a 4-valent HPV vaccine trial (NCT00092482), HPV seroprevalence on day 1 was measured with a 9-valent HPV (HPV 6/11/16/18/31/33/45/52/58) competitive Luminex immunoassay and compared with cervical/external genital HPV detection by polymerase chain reaction. In the control group, among women who were HPV DNA‒negative on day 1, seroconversion following initial HPV detection was estimated using Kaplan-Meier methods. RESULTS: Type-specific HPV seropositivity among women with no day 1 cervical/external genital HPV detection was 0.6%-3.6%. Women with any 9-valent HPV (9vHPV) cervical/external genital detection (796/3875; 20.5%) had concordant seropositivity ranging from 13.4% (HPV 45) to 38.5% (HPV 6). Among women in the control group who were negative for all HPV types on day 1, seroconversion by month 30 after initial detection ranged from 29% (HPV 45) to 75% (HPV 16). CONCLUSIONS: Humoral immune response to HPV is variable and dynamic, depending on type-specific exposure. This longitudinal analysis provides insight into the relationship between incident infection and seropositivity. CLINICALTRIALS: gov; NCT00092482 https://clinicaltrials.gov/ct2/show/NCT00092482.

Impact of an HPV6/11/16/18 L1 virus-like particle vaccine on progression to cervical intraepithelial neoplasia in seropositive women with HPV16/18 infection.

The impact of a human papillomavirus (HPV) vaccine on development of cervical intraepithelial neoplasia grade 2-3 or adenocarcinoma in situ (CIN2-3/AIS) in women with ongoing HPV16 or 18 infections prevaccination is reported. Seventeen thousand six-hundred and twenty-two women aged 16-26 were enrolled in 1 of 2 randomized, placebo-controlled, efficacy trials (Protocols 013 and 015). Vaccine or placebo was given at day 1, month 2 and 6. Women were tested for HPV6/11/16/18 DNA and antibodies at day 1. We focus on the subset of women who were seropositive and DNA positive to HPV16 or HPV18 prevaccination. Incidence is expressed as the number of women with an endpoint per 100 person-years-at-risk. In total, 419 vaccine and 446 placebo recipients were both seropositive and DNA positive to HPV16 or HPV18 prevaccination and had at least one follow-up visit. In Protocol 013, the incidence of HPV16/18-related CIN2-3/AIS among these women was 10.9 in the vaccine arm and 7.0 in the placebo arm (vaccine efficacy = -54.9; 95% CI: -181.7, 13.0). In Protocol 015, the incidence of HPV16/18-related CIN2-3/AIS was 5.5 in the vaccine arm and 6.2 in the placebo arm (vaccine efficacy = 12.2%; 95% CI: -29.8, 40.9). These data suggest HPV vaccination neither reduces nor enhances progression to HPV16/18-related high grade cervical lesions, and cervical cytology screening and corresponding management should continue as per local recommendations. Ultimately, population-based surveillance of vaccinated individuals beyond these clinical trials will be required to further address questions regarding the impact of vaccination in women exposed to vaccine HPV types before vaccination.

Adenocarcinoma in situ and associated human papillomavirus type distribution observed in two clinical trials of a quadrivalent human papillomavirus vaccine.

The primary objective of this report is to describe the detection of adenocarcinoma in situ (AIS) and associated human papillomavirus (HPV) type distribution that was observed in the context of two phase 3 clinical trials of a quadrivalent HPV6/11/16/18 vaccine. In this intention-to-treat analysis, we include all women who had at least one follow-up visit postenrollment. Healthy women (17,622) aged 15-26 with no history of HPV disease and a lifetime number of less than five sex partners (average follow-up of 3.6 years) were randomized (1:1) to receive vaccine or placebo at day 1, months 2, and 6. Women underwent colposcopy and biopsy according to a Papanicolaou triage algorithm. All tissue specimens were tested for 14 HPV types and were adjudicated by a pathology panel. During the trials, 22 women were diagnosed with AIS (six vaccine and 16 placebo). There were 25 AIS lesions in total, with HPV16/18 present in 96% (24 of 25 with 15 of 25 as single infections). Only two of 22 women had concomitant cytology results suggesting glandular abnormality. Colposcopic impressions (25 total) were either negative or indicated squamous lesions only. Of women with AIS, all six in the vaccine cohort and seven of 16 in the placebo cohort were infected at baseline with the same HPV type that was detected in the AIS lesion. Concurrent squamous lesions were detected in 20 of these 22 women. In summary, our findings show that AIS evades colposcopic and cervical cytologic detection. As most AIS lesions were HPV16/18-related, prophylactic HPV vaccination should reduce the incidence of invasive adenocarcinoma.

The humoral response to Gardasil over four years as defined by total IgG and competitive Luminex immunoassay.

Safe and effective vaccines against anogenital human papillomaviruses (HPV) are now available. These vaccines, composed of virus-like particles (VLPs) made from the L1 major capsid protein of specific HPV types, induce a polyclonal antibody response directed against specific conformational and linear epitopes displayed on the VLP. Numerous studies indicated the importance of neutralizing antibodies in protection from infection. However, our understanding of the antibody responses to these vaccines is not complete, and there is no established immune correlate of protection nor antibody threshold that correlates with protection against HPV infection or disease. In the current study, antibody responses of young women to Gardasil®, the quadrivalent HPV 6, 11, 16 and 18 L1 VLP vaccine (qHPV), were assessed through 48 months (M) in total IgG and competitive Luminex immunoassays (total IgG LIA and cLIA). The total IgG LIA was developed as a research assay to evaluate preclinical multivalent HPV VLP vaccine formulations. The cLIA simultaneously evaluates the antibody response to a unique conformational, neutralizing epitope on each of the four HPV types present in the quadrivalent vaccine; HPV 6, 11, 16 and 18. The same sera from women vaccinated with the qHPV vaccine were tested in both the total IgG LIA and the cLIA assays. The proportion of vaccinated women achieving seropositivity and the anti-HPV VLP total IgG and cLIA geometric mean titers (GMTs) were summarized at M7, M24, M48 based on the serostatus cut-points defined for each immunoassay. Overall, greater than 99% of subjects seroconverted to all four vaccine types in both assays; GMTs peaked at M7. For all four HPV types, regardless of the immunoassay used, the most significant decline in GMTs was observed between M7 and M24. By M24, the antibody titers had reached a plateau and minimal declines in antibody titers were observed between M24 and M48 for all four HPV types in both immunoassays. Testing the same sera, seropositivity for M48 HPV18 remained high (96.7%) in the total IgG LIA, but was 64.8% in the cLIA. The current study illustrates potential important differences in serologic assays utilized in the clinical trials of the two currently available HPV VLP vaccines (quadrivalent and bivalent). Differences in seropositivity status are attributed to the measurement parameters and sensitivity of the individual immunoassays and do not indicate reduced anti-HPV18 protective antibodies.

Systematic literature review of neutralizing antibody immune responses to non-vaccine targeted high-risk HPV types induced by the bivalent and the quadrivalent vaccines.

INTRODUCTION: Studies on the cross-protective effect of HPV bivalent and quadrivalent vaccines demonstrated inconsistent findings against additional HPV types covered by the nonavalent vaccine. The objective of this study was to conduct a systematic literature review to assess the consistency and durability of the cross-protective neutralizing antibody immune responses of the currently licensed bivalent and quadrivalent vaccines to non-vaccine HPV types targeted by the nonavalent vaccine (HPV 6, 11, 31, 33, 45, 52, and 58). METHODS: PubMed and EMBASE databases were searched from 2008 to 2019 to identify studies reporting antibody/immune response after vaccination with either the bivalent, quadrivalent, or nonavalent vaccine. Key outcomes were seroconversion, seropositivity or geometric mean titers against HPV types 6, 11, 31, 33, 45, 52, and 58. RESULTS: Eighteen publications met inclusion criteria, reporting on 14 interventional and five observational studies. Across all studies, immune responses to non-vaccine high-risk HPV types after bivalent vaccination were higher than baseline or quadrivalent vaccine. Nonavalent vaccine elicited near total seroconversion to HPV types 31, 33, 45, 52, and 58, with seropositivity remaining near 100% up to 24 months post-dose 1. In contrast, bivalent and quadrivalent vaccination resulted in lower seroconversion levels for non-vaccine types, which waned over time. CONCLUSIONS: The cross-protection antibody/immune response among participants having received all three doses of bivalent or quadrivalent vaccine is not comparable to the specific response elicited by HPV vaccine types. Even in cases where a statistically significant cross-reactive immunological response is reported, long-term data on the duration of the response beyond two years are very limited. Further, the lack of a standard for assays limits comparability of results between studies.

Systematic literature review of cross-protective effect of HPV vaccines based on data from randomized clinical trials and real-world evidence.

BACKGROUND: The extent of cross-protection provided by currently licensed bivalent and quadrivalent HPV vaccines versus direct protection against HPV 31-, 33-, 45-, 52-, and 58-related disease is debated. A systematic literature review was conducted to establish the duration and magnitude of cross-protection in interventional and observational studies. METHODS: PubMed and Embase databases were searched to identify randomized controlled trials (RCT) and observational studies published between 2008 and 2019 reporting on efficacy and effectiveness of HPV vaccines in women against non-vaccine types 31, 33, 45, 52, 58, and 6 and 11 (non-bivalent types). Key outcomes of interest were vaccine efficacy against 6- and 12-month persistent infection or genital lesions, and type-specific genital HPV prevalence or incidence. RCT data were analyzed for the according-to-protocol (bivalent vaccine) or negative-for-14-HPV-types (quadrivalent vaccine) efficacy cohorts. RESULTS: Data from 23 RCTs and 33 observational studies evaluating cross-protection were extracted. RCTs assessed cross-protection in post-hoc analyses of small size subgroups. Among fully vaccinated, baseline HPV-naïve women, the bivalent vaccine showed statistically significant cross-protective efficacy, although with wide confidence intervals, against 6-month and 12-month persistent cervical infections and CIN2+ only consistently for HPV 31 and 45, with the highest effect observed for HPV 31 (range 64.6% [95% CI: 27.6 to 83.9] to 79.1% [97.7% CI: 27.6 to 95.9] for 6-month persistent infection; maximal follow-up 4.7 years). No cross-protection was shown in extended follow-up. The quadrivalent vaccine efficacy reached statistical significance for HPV 31 (46.2% [15.3-66.4]; follow-up: 3.6 years). Similarly, observational studies found consistently significant effectiveness only against HPV 31 and 45 with both vaccines. CONCLUSIONS: RCTs and observational studies show that cross-protection is inconsistent across non-vaccine HPV types and is largely driven by HPV 31 and 45. Furthermore, existing data suggest that it wanes over time; its long-term durability has not been established.

Longer duration of anti-retroviral therapy is associated with decreased risk of human papillomaviruses detection in Kenyan women living with HIV.

OBJECTIVE: A longitudinal study was conducted among women living with HIV in Kenya to determine if duration of anti-retroviral (ART) usage altered detection and persistence of oncogenic (high-risk) human papillomaviruses (HR-HPV). METHODS: Women living with HIV without cervical dysplasia were enrolled at a cervical cancer screening clinic. Three cervical swabs, HIV viral loads, and CD4 cell counts were obtained at enrollment and at two annual visits. HPV genotyping was performed on swabs (Roche Linear Array). Linear regression models assessed effects of ART duration on HR-HPV detection and persistence. RESULTS: Seventy-seven women, median age 38 years, completed three study visits and were included in the analysis. The mean time from HIV diagnosis to enrollment was 9.6 years (SD 3.9 years). The mean ART duration was 6.2 years (SD 3.1 years). Most women had undetectable HIV viral loads and CD4 cell counts above 500 cells/L. Each additional year of ART use reduced the likelihood of detection of HR-HPV by 10-15% and persistent detection of A9 HR-HPV by 20%. CONCLUSION: Among Kenyan women living with HIV, longer duration of ART use was associated with significantly reduced risk of all detection and persistent detection of HR-HPV.

Human Papillomavirus Oral- and Sero- Positivity in Fanconi Anemia.

High-risk human papillomavirus (HPV) is prevalent and known to cause 5% of all cancers worldwide. The rare, cancer prone Fanconi anemia (FA) population is characterized by a predisposition to both head and neck squamous cell carcinomas and gynecological cancers, but the role of HPV in these cancers remains unclear. Prompted by a patient-family advocacy organization, oral HPV and HPV serological studies were simultaneously undertaken. Oral DNA samples from 201 individuals with FA, 303 unaffected family members, and 107 unrelated controls were tested for 37 HPV types. Serum samples from 115 individuals with FA and 55 unrelated controls were tested for antibodies against 9 HPV types. Oral HPV prevalence was higher for individuals with FA (20%) versus their parents (13%; p = 0.07), siblings (8%, p = 0.01), and unrelated controls (6%, p ≤ 0.001). A FA diagnosis increased HPV positivity 4.84-fold (95% CI: 1.96-11.93) in adjusted models compared to unrelated controls. Common risk factors associated with HPV in the general population did not predict oral positivity in FA, unlike unrelated controls. Seropositivity and anti-HPV titers did not significantly differ in FA versus unrelated controls regardless of HPV vaccination status. We conclude that individuals with FA are uniquely susceptible to oral HPV independent of conventional risk factors.

Persistence of oncogenic and non-oncogenic human papillomavirus is associated with human immunodeficiency virus infection in Kenyan women.

OBJECTIVES: Cervical cancer is caused by persistent infection with oncogenic, or "high-risk" types of human papillomaviruses, and is the most common malignancy in Kenyan women. A longitudinal study was initiated to investigate factors associated with persistent human papillomavirus detection among HIV-infected and HIV-uninfected Kenyan women without evidence of cervical dysplasia. METHODS: Demographic/behavioral data and cervical swabs were collected from HIV-uninfected women (n = 82) and HIV-infected women (n = 101) at enrollment and annually for 2 years. Human papillomavirus typing was performed on swabs (Roche Linear Array). Logistic regression models of human papillomavirus persistence were adjusted for demographic and behavioral characteristics. RESULTS: HIV-infected women were older and less likely to be married and to own a home and had more lifetime sexual partners than HIV-uninfected women. All HIV-infected women were receiving anti-retroviral therapy at enrollment and had satisfactory CD4 cell counts and HIV viral loads. One- and two-year persistent human papillomavirus detection was significantly associated with HIV infection for any human papillomavirus, high-risk human papillomavirus, International Agency for the Research on Cancer-classified high-risk human papillomavirus, and non-oncogenic "low-risk" human papillomavirus. CONCLUSION: Persistent detection of oncogenic and non-oncogenic human papillomavirus was strongly associated with HIV infection in Kenyan women with re-constituted immune systems based on satisfactory CD4 cell counts. In addition to HIV infection, factors associated with an increased risk of human papillomavirus persistence included a higher number of lifetime sex partners. Factors associated with decreased risk of human papillomavirus persistence included older age and being married. Further studies are needed to identify the immunological defects in HIV-infected women that allow human papillomavirus persistence, even in women receiving effective anti-retroviral therapy. Further studies are also needed to determine the significance of low-risk human papillomavirus persistence in HIV-infected women.

Prevalence, incidence, and natural history of HPV infection in adult women ages 24 to 45 participating in a vaccine trial.

OBJECTIVES: The natural history of human papillomavirus (HPV) infection has been studied extensively in young women; this study investigated HPV infection in adult women. METHODS: Data from 3817 women aged 24-45 years in a global trial of the 4-valent HPV (6/11/16/18) vaccine were used to calculate prevalence of anogenital infections containing 9-valent (9v) HPV vaccine types (6/11/16/18/31/33/45/52/58) and five non-vaccine types (35/39/51/56/59). Incidence of infections and persistent infections was estimated for 989 placebo recipients naive to all 14 HPV types at baseline. Age-adjusted hazard ratios were calculated for various sociodemographic factors. RESULTS: Prevalence of anogenital infection was highest in France at 29.2% (9vHPV types) and 21.7% (non-vaccine types) and lowest in the Philippines at 7.6% (9vHPV types) and 5.1% (non-vaccine types). Overall, HPV incidence (per 100 person-years) was 5.2 (9vHPV types) and 4.7 (non-vaccine types), and incidence of persistent infection was 2.7 (9vHPV types) and 2.1 (non-vaccine types). Factors associated with new HPV infections included younger age, younger age at first intercourse, being single, current use of tobacco, and higher number of past and recent sex partners. CONCLUSIONS: Because mid-adult women acquire new HPV infections, administration of the 9vHPV vaccine could reduce HPV-related morbidity and mortality in this population.

Evaluation of quadrivalent HPV 6/11/16/18 vaccine efficacy against cervical and anogenital disease in subjects with serological evidence of prior vaccine type HPV infection.

OBJECTIVE: In the quadrivalent (types 6/11/16/18) HPV vaccine (GARDASIL/SILGARD) clinical program, 73% of women aged 16-26 were naïve to all vaccine HPV types. In these women, prophylactic administration of the vaccine was highly effective in preventing HPV 6/11/16/18-related cervical disease. Of the remaining women, 15% of had evidence of past infection with one or more vaccine HPV types (seropositive and DNA negative) at the time of enrollment. Here we present an analysis in this group of women to determine the efficacy of the HPV 6/11/16/18 vaccine against new cervical and external anogenital disease related to the same vaccine HPV type which had previously been cleared. Vaccine tolerability in this previously infected population was also assessed. METHODS: 18,174 women were enrolled into 3 clinical studies. The data presented comprise a subset of these subjects (n = 2,617) who were HPV seropositive and DNA negative at enrollment (for >or=1 vaccine type). In each study, subjects were randomized in a 1:1 ratio to receive HPV 6/11/16/18 vaccine or placebo at day 1, month 2 and month 6 (without knowledge of baseline HPV status). Procedures performed for efficacy data evaluation included detailed genital examination, Pap testing, and collection of cervicovaginal and external genital specimens. Analyses of efficacy were carried out in a population stratified by HPV serology and HPV DNA status at enrollment. RESULTS: Subjects were followed for an average of 40 months. Seven subjects in the placebo group developed cervical disease, and eight subjects developed external genital disease related to a vaccine HPV type they had previously encountered. No subject receiving HPV 6/11/16/18 vaccine developed disease to a vaccine HPV type to which they were seropositive and DNA negative at enrolment. CONCLUSIONS: These results suggest that natural HPV infection-elicited antibodies may not provide complete protection over time, however the immune response to the HPV 6/11/16/18 vaccine appears to prevent reinfection or reactivation of disease with vaccine HPV types. Vaccine-related adverse experiences were higher among subjects receiving vaccine, mostly due to increased injection site adverse experiences.