Oncogenic Human Papillomavirus Infection Research Articles

Evaluation of changes caused by HR-HPV infection in squamous cell carcinoma of the head and neck using Raman microspectroscopy in combination with multivariate statistical analysis

Abstract Introduction: Squamous cell carcinoma of the head and neck region (HNSCC), with a positive status for high oncogenic potential human papillomavirus (HR-HPV), represents a clinically distinct disease entity compared to HPV-independent cases. Patients exhibit variations in prognosis and proposed therapy regimens. A prompt and reliable diagnosis of the presence of HPV infection could optimize the treatment for these patients. Currently employed treatment methods are long-term, expensive, and lack specificity, especially when administered separately. Material and methods: The research objective of this study is to explore significant differences in the Raman spectra of biological samples taken from patients with HNSCC, facilitating the confirmation of HPV virus presence. Study groups were delineated based on histopathological diagnosis and molecular biology tests, confirming the biological activity of the virus and the presence of the HR-HPV form with a diagnosis of a specific subtype. Results: To identify high oncogenic potential human papillomavirus (HR-HPV) infection as a crucial factor in squamous cell carcinoma of the head and neck region, an effective automatic data analysis system was established, relying on Raman microspectroscopy and multivariate analysis. Our results showed clear ranges of the Raman spectrum that differentiated between HPV-associated and non-HPV-associated cancers. Conclusions: In conclusion, our experience shows a great diagnostic potential of Raman confocal microscopy with multidimensional statistical analysis. In the future, the use of this method may allow for the creation of an effective and automated HR-HPV detection system in neoplastic tissue.

Prevalence of anal HPV infection and anal HSIL among MSM 50 years and older living with or without HIV

Background: Anal cancer is caused by human papillomavirus (HPV), particularly HPV-16, and is preceded by anal high-grade squamous intraepithelial lesions (HSIL). The incidence of anal cancer is highest among men who have sex with men (MSM) living with HIV (MSMLWH) and increases with age. However, most previous studies of anal HPV infection and anal HSIL were performed on men under 50 years of age, and relatively little is known about HSIL among older MSMLWH or MSM not living with HIV (MSM-Not-LWH). Setting: We enrolled MSM who were aged 50+ during 2018-2022 in San Francisco, California. Methods: 129 MSMLWH and 109 MSM-not-LWH participated. All participants had anal HPV DNA testing (Atila Biosystems) and high-resolution anoscopy with biopsy of visible lesions. Results: Among MSMLWH, 47% had anal HSIL, 19% had HPV-16, and 51% had other oncogenic anal HPV types (excluding HPV-16). Among MSM-not-LWH, 37% had anal HSIL, 22% had HPV-16, and 34% had other oncogenic anal HPV types. Increasing age was not statistically associated with prevalent HSIL, HPV-16, or other oncogenic HPV infections in MSMLWH or MSM-not-LWH. HPV-16 (OR:45.1, 95% CI:15.8-129), other oncogenic HPV types (OR:5.95, 95% CI:2.74-12.9) were associated with increased odds of anal HSIL, adjusted for age, income, education, and HIV status. Conclusion: The prevalence of oncogenic anal HPV, anal HPV-16, and anal HSIL remain very high in older MSMLWH and MSM-not-LWH. With recent evidence showing that treating anal HSIL prevents anal cancer, MSM aged 50+ should be considered for anal cancer screening.

P16 overexpression identifies oncogenic high-risk HPV infection in non-oropharyngeal squamous cell carcinoma of the head and neck.

Human papillomavirus (HPV) is an increasing risk factor for cancer. HPV-associated oropharyngeal squamous cell carcinoma (OPSCC) is associated with a favorable outcome. Blockstaining for p16 is a surrogate marker for HPV+ OPSCC. In oral and laryngeal squamous cell carcinoma (OSCC/LSCC), the relevance of p16 immunohistochemistry, alone or in combination with other cell cycle-related proteins, to identify HPV-driven non-OPSCC is less well understood. We stained for p16, pRb, cyclin D1, and p53 in 327 HNSCC. In 310 OPSCC, HPV-status was assessed by HPV DNA PCR. In 119 non-OPSCC, RNA in situ hybridization was additionally performed. HPV-status was correlated with staining patterns, p53 and clinical data. The OPSCC showed blockstaining for p16 in 36%, 8% were equivocal. Of these, HPV-testing was performed in 57%, and 53% were positive for HPV DNA. HPV-association correlated with absence of pRb and cyclin D1 and favorable outcome. In non-OPSCC, 18% showed p16-blockstaining, and 13% showed E6/E7 RNA. Six of seven HPV+ OSCC and 8/8 LSCC lost pRb and cyclin D1. Compared to HPV-negative counterparts, patients with HPV+ cancers had lower rates of alcohol consumption and keratinizing morphology. HPV-positive OSCC had a longer overall survival (p < 0.05). HPV subtype 16 was the most common. We conclude that HPV-positive non-OPSCC are associated with p16 overexpression and low levels of pRb and cyclin D1. High expression of pRb and cyclin D1 indicates HPV-negativity.

Incidence of oncogenic HPV infection in women with and without mental illness: A population-based cohort study in Sweden.

Women with mental illness experience an increased risk of cervical cancer. The excess risk is partly due to low participation in cervical screening; however, it remains unknown whether it is also attributable to an increased risk of infection with human papillomavirus (HPV). We aimed to examine whether women with mental illness had an increased infection rate of HPV compared to women without mental illness. Using a cohort design, we analyzed all 337,116 women aged 30 to 64 and living in Stockholm, who had a negative test result of 14 high-risk HPV subtypes in HPV-based screening, during August 2014 to December 2019. We defined women as exposed to mental illness if they had a specialist diagnosis of mental disorder or had a filled prescription of psychotropic medication. We identified incident infection of any high-risk HPV during follow-up and fitted multivariable Cox models to estimate hazard ratios (HR) with 95% confidence intervals (CI) for HPV infection. A total of 3,263 women were tested positive for high-risk HPV during follow-up (median: 2.21 years; range: 0 to 5.42 years). The absolute infection rate of HPV was higher among women with a specialist diagnosis of mental disorder (HR = 1.45; 95% CI [1.34, 1.57]; p < 0.001) or a filled prescription of psychotropic medication (HR = 1.67; 95% CI [1.55, 1.79]; p < 0.001), compared to women without such. The increment in absolute infection rate was noted for depression, anxiety, stress-related disorder, substance-related disorder, and ADHD, and for use of antidepressants, anxiolytics, sedatives, and hypnotics, and was consistent across age groups. The main limitations included selection of the female population in Stockholm as they must have at least 1 negative test result of HPV, and relatively short follow-up as HPV-based screening was only introduced in 2014 in Stockholm. Mental illness is associated with an increased infection rate of high-risk HPV in women. Our findings motivate refined approaches to facilitate the WHO elimination agenda of cervical cancer among these marginalized women worldwide.

Serum oxidative biomarkers associated with genital HPV infection and cervical lesions in women.

Human papillomavirus (HPV) infection is a major cause of cervical cancer. Studies showed HPV carcinogenesis may be induced by oxidative stress affecting the host immune system. The objective of this study is to evaluate levels of four circulating oxidative stress biomarkers associated with the HPV infection, persistence, and cervical lesion status in women. The three serum biomarkers measuring oxidative damage to biomolecules (8-oxodG, 8-oxo-7,8-dihydro-2'-deoxyguanosine [8-oxodG] for DNA, 4-hydroxy-2-nonenal [4-HNE] for lipid, and protein carbonyl [PC] for protein) and one antioxidant (glutathione, GSH) collected from 38 women were evaluated. The PC levels were significantly higher for women with oncogenic HPV infection (p = 0.047) and persistence (p = 0.053) based on the unadjusted linear model. In particular, women with ≥3 oncogenic HPV types had a higher PC level than those without HPV infection (p = 0.041). Women with low-grade squamous intraepithelial lesions showed an elevated PC (p = 0.058). These trends remained similar after adjusting for age. The GSH levels were lower for women infected with ≥3 oncogenic HPV types based on age-adjusted results (p = 0.061). This study supported that serum PC was associated with HPV infection, persistence, and cervical lesions, so it can potentially be used to monitor HPV carcinogenesis. Further large-scale studies will be needed to confirm these findings.

Risk factors of oncogenic HPV infection in HIV-positive men with anal condyloma acuminata in Shenzhen, Southeast China: a retrospective cohort study.

Human immunodeficiency virus (HIV)-positive patients with anal condyloma acuminata (CA) present an increased risk of anal cancer progression associated with oncogenic human papillomavirus (HPV) infection. It is essential to explore determinants of anal infection by oncogenic HPV among HIV-positive patients with CA. A retrospective cohort study was performed in HIV-positive patients with CA between January 2019 to October 2021 in Shenzhen, Southeast China. Exfoliated cells were collected from CA lesions and the anal canal of HPV genotypes detected by fluorescence PCR. Unconditional logistic regression analysis was used to probe associations of independent variables with oncogenic HPV infection. Among HIV-positive patients with CA, the most prevalent oncogenic genotypes were HPV52 (29.43%), HPV16 (28.93%), HPV59 (19.20%), and HPV18 (15.96%). Risk of oncogenic HPV infection increased with age at enrollment (COR: 1.04, 95% CI: 1.01-1.07, p = 0.022). In the multivariable analysis, age ≥ 35 years (AOR: 2.56, 95% CI: 1.20-5.70, p = 0.02) and history of syphilis (AOR: 3.46, 95% CI: 1.90-6.79, p < 0.01) were independent risk factors statistically associated with oncogenic HPV infection. History of syphilis (AOR: 1.72, 95% CI: 1.08-2.73, p < 0.02) was also an independent risk factor statistically associated with HPV16 or HPV18 infection. In clinical practice, HIV-positive CA patients aged ≥35 years or with a history of syphilis should carry out HR-HPV testing and even anal cancer-related examinations to prevent the occurrence of anal cancer.

Prevalence and risk factors of anal human papillomavirus infection among men with anal condyloma acuminata by HIV status in ShenZhen, Southeast China: A retrospective cohort study.

Patients with anal condyloma acuminatum (CA) are at risk of developing anal cancer which is associated with oncogenic human papillomavirus (HPV) infection. Investigation of anal HPV prevalence and risk factors can provide effective strategies for the prevention of anal cancer. A retrospective study was conducted among 549 patients with anal CA in the Third People's Hospital of Shenzhen between January 2019 and October 2021. HPV prevalence and HIV antibodies were detected by fluorescent PCR and ELISA, respectively. Logistic regression model and structural equation modeling (SEM) were conducted to analyzed the risk factors of oncogenic HPV infection. The overall prevalence of HPV was 96.72%. Both HPV6 (N = 285, 51.91%) and HPV11 (N = 300, 54.64%) were more than half infected and the most frequent Hr-HPV genotype was HPV16 (N = 138, 25.14%). HIV-positive (AOR: 5.02, 95% CI: 2.98-8.60, p < 0.0001) and history of syphilis (AOR: 4.24, 95% CI: 2.31-8.46, p < 0.0001) were independent risk factors statistically associated with oncogenic HPV infection. Ever had anal sex (AOR: 3.40, 95% CI: 1.28-11.81, p = 0.0267) and age 35 years and older (AOR: 2.79, 95% CI: 1.53-5.15, p = 0.0009) were associated with HPV16 and HPV52, respectively. SEM analyses showed that HIV-positive (b = 1.549, p < 0.001) and history of syphilis (b = 1.450, p < 0.001) had significant positive effects on oncogenic HPV infection. Ever had anal sex (b = 1.243, p = 0.025) and Age (b = 0.043, p = 0.002) positively drived HPV16 and HPV52 infection, respectively. Anal CA patients who are HIV-positive, have a history of syphilis, or at least 35 years old should be considered for Hr-HPV, cytology and other anal cancer related tests to reduce the risk of cancer development.

Findings from a Malaysian multicentre study on oropharyngeal squamous cell carcinoma

BackgroundIn addition to the conventional aetiologic agents of oropharyngeal squamous cell carcinoma (OPSCC) such as tobacco usage, alcohol consumption and betel quid usage, it has been established that a proportion of OPSCC are driven by persistent oncogenic human papillomavirus (HPV) infections. Currently, there is a lack of data on the burden of HPV- associated OPSCC in Asian countries including Malaysia.MethodsA cross-sectional multicentre study with tissue analysis of Malaysian patients diagnosed with primary OPSCC within a five-year period, from 2015 to 2019 between 01/01/2015 to 31/12/2019 was undertaken. Determination of HPV status was carried out using p16INK4a immunohistochemistry on tissue microarrays constructed from archived formalin-fixed paraffin-embedded tissue.ResultsFrom the cases identified, 184 cases had sufficient tissue material for analysis. Overall, median age at diagnosis was 63.0 years (IQR = 15) and 76.1% of patients were males. In our cohort, 35.3% of patients were Indian, 34.2% were Chinese, 21.2% were Malay and 9.2% were from other ethnicities. The estimated prevalence of HPV-associated OPSCC in our cohort was 31.0% (CI 24.4–38.2%). The median age for the HPV-associated OPSCC sub-group of patients was not significantly lower than the median age of patients with HPV-independent OPSCC. More than half of HPV-associated OPSCC was seen in patients of Chinese ethnicity (54.4%). Patients with HPV-associated OPSCC had a much better overall survival than patients with HPV-independent OPSCC (Log rank test; p < 0.001). Patients with HPV-associated OPSCC with no habit-related risk factors such as smoking, were found to have much better overall survival when compared to all other sub-groups.ConclusionsThe findings from our study suggests that prevalence of HPV-associated OPSCC in Malaysia, though not as high as some developed countries, is however on an upward trend. HPV-associated OPSCC appears to be more frequently encountered in patients of Chinese ethnicity. Conventional risk-factors associated with OPSCC such as smoking, alcohol consumption and betel quid chewing should still be considered when estimating prognosis of patients with HPV-associated OPSCC.

The Prevalence of Human Papillomavirus in Women Living with HIV in Mukono General Hospital, Uganda

Background and aims: High-risk oncogenic genotype human papillomavirus (HPV) infection induces cervical cancer (CaCx), a common cancer in women globally. Women living with human immunodeficiency virus (WLHIV) have a greater risk of hr-HPV infection and perseverance, enhancing the risk of defects in the cells of the cervix and aggressive CaCx. However, its prevalence in WLHIV is not apparent. The main objective of this research was to explore the types and prevalence of HPV infection by genotyping HPV among a cohort of WLHIV attending an antiretroviral therapy (ART) clinic in Mukono, Uganda. Methods: A cross-sectional study was conducted among women aged 25 to 49 years attending an ART clinic in a public health facility in Mukono, Uganda. Systematic random sampling was used to select 342 WLHIV from a target population of 3000. Only participants who had an Xpert HPV test between July 2021 and December 2022 were selected and interviewed, and their responses were analyzed using descriptive statistics. Results: Slightly more than half (56.7%) of the participants were under 35 years old, married (52.6%), and with a primary level of education (51.2%). The prevalence of hr-HPV was 39.8% (95% CI: 34.40-44.78). Of the total participants, 136 (39.8%) were high-risk HPV positive, with HPV 16, HPV18/45, and other hr-HPV types (31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68) being positive in 23 (6.7%), 21 (6.1%), and 110 (32.2%), respectively, while 17 (12.5%) had mixed hr-HPV infections. Conclusion: There is a high prevalence of HPV infection among WLHIV, underscoring the need to frequently screen and diagnose CaCx pre-cancerous lesions for its effective prevention.

Impact of Dietary Quality on Genital Oncogenic Human Papillomavirus Infection in Women.

Most cervical cancers are directly linked to oncogenic or high-risk human papillomavirus (HR-HPV) infection. This study evaluates associations between diet quality and genital HPV infection in women. This study included 10 543 women from the 2003-2016 National Health and Nutrition Examination Survey. The outcome was the genital HPV infection status (HPV-negative, low-risk [LR] HPV, and HR-HPV). Dietary quality was evaluated using the Healthy Eating Index (HEI), in which a higher score indicates a better diet quality. Women who did not consume total fruits (15.8%), whole fruits (27.5%), or green vegetables and beans (43%) had a significantly higher risk of HR-HPV infection than women who complied with the Dietary Guidelines for Americans (HR-HPV odds ratio = 1.76, 1.63, and 1.48 for a HEI score of 0 vs 5, respectively) after adjusting confounding factors. Similar results of these food components on LR-HPV infection were found. In addition, intake of whole grains and dairy was inversely associated with LR-HPV infection. This study showed that women who did not eat fruits, dark-green vegetables, and beans had a higher risk of genital HR-HPV infection. Intake of these food components is suggested for women to prevent HPV carcinogenesis.

HPV-induced host epigenetic reprogramming is lost upon progression to high-grade cervical intraepithelial neoplasia.

The impact of a pathogen on host disease can only be studied in samples covering the entire spectrum of pathogenesis. Persistent oncogenic human papilloma virus (HPV) infection is the most common cause for cervical cancer. Here, we investigate HPV-induced host epigenome-wide changes prior to development of cytological abnormalities. Using cervical sample methylation array data from disease-free women with or without an oncogenic HPV infection, we develop the WID (Women's cancer risk identification)-HPV, a signature reflective of changes in the healthy host epigenome related to high-risk HPV strains (AUC=0.78, 95% CI: 0.72-0.85, in nondiseased women). Looking at HPV-associated changes across disease development, HPV-infected women with minor cytological alterations (cervical intraepithelial neoplasia grade 1/2, CIN1/2), but surprisingly not those with precancerous changes or invasive cervical cancer (CIN3+), show an increased WID-HPV index, indicating the WID-HPV may reflect a successful viral clearance response absent in progression to cancer. Further investigation revealed the WID-HPV is positively associated with apoptosis (ρ=0.48; P < .001) and negatively associated with epigenetic replicative age (ρ=-0.43; P < .001). Taken together, our data suggest the WID-HPV captures a clearance response associated with apoptosis of HPV-infected cells. This response may be dampened or lost with increased underlying replicative age of infected cells, resulting in progression to cancer.

Determinants of Acquisition, Persistence, and Clearance of Oncogenic Cervical Human Papillomavirus Infection in the Philippines Using a Multi-Omics Approach: DEFEAT HPV Study Protocol

HPV infection is one of the most studied risk factors in cervical cancer-the second most common cancer site and cause of death due to cancer in the Philippines. However, there is a lack of population-based epidemiological data on cervical HPV infection in the Philippines. Local reports on co-infections with other lower genital tract pathogens, commonly reported globally, are also lacking, which emphasizes the need to increase efforts in targeting HPV prevalence, genotype, and distribution. Hence, we aim to determine the molecular epidemiology and natural history of HPV infection among reproductive-age Filipino women using a community-based prospective cohort design. Women from rural and urban centers will be screened until the target sample size of 110 HPV-positive women (55 from rural sites and 55 from urban sites) is reached. Cervical and vaginal swabs will be collected from all screened participants. For HPV-positive patients, HPV genotypes will be determined. One hundred ten healthy controls will be selected from previously screened volunteers. The cases and controls will comprise the multi-omics subset of participants and will be followed up after 6 and 12 months for repeat HPV screening. Metagenomic and metabolomic analyses of the vaginal swabs will also be performed at baseline, after 6 months, and after 12 months. The results of this study will update the prevalence and genotypic distribution of cervical HPV infection among Filipino women, determine whether the current vaccines used for HPV vaccination programs capture the most prevalent high-risk HPV genotypes in the country, and identify vaginal community state types and bacterial taxa associated with the natural history of cervical HPV infection. The results of this study will be used as the basis for developing a biomarker that can help predict the risk of developing persistent cervical HPV infection in Filipino women.

Stepped Behavioral and Biological Screening for Oral Oncogenic HPV DNA in Middle-aged and Elderly Adults: A Feasibility Study.

Novel preventive interventions are needed to address the rising incidence of HPV+ OPC. In this feasibility study, we characterized barriers to a two-step, behavioral and biological screening program for oral oncogenic HPV infection, an intermediate outcome for HPV+ OPC.

The association of HPV infection and vaginal microbiota of reproductive women in China: A multicenter cohort study protocol

Cervical cancer is a global health concern. Persistent oncogenic human papillomavirus (HPV) infection is a prerequisite for the development of cervical cancer. Emerging research indicates that the vaginal microbiota may play both protective and harmful roles in the acquisition and persistence of HPV and the development of cervical cancer. This multicenter cohort study mainly aims to reveal the association of vaginal microbiota with the outcome of HPV infection in six months in women of reproductive age. We will recruit 50 research centers and enroll a total of about 10,000 female volunteers with a series of strict inclusion and exclusion criteria across China, including HPV positive and HPV negative women. A unified questionnaire will be used to obtain the sociodemographic information, clinical data and lifestyle of all volunteers. Specimens including vaginal secretions swabs and cervical exfoliated cells will be collected at the first visit and follow-up after six months. We will use 16S rRNA sequencing to characterize the vaginal microbiota of volunteers’ vaginal swabs. Twenty-one HPV genotypes and other sexually transmitted pathogens, including Neisseria gonorrhoeae, Chlamydia trachomatis, Ureaplasma urealyticum, Mycoplasma hominis, Mycoplasma genitalium and Herpes simplex virus type Ⅱ will be examined using flow-through hybridization and gene chip. The association of HPV infection and vaginal microbiota will be investigated, and the core microbiota attributes to the persistent HPV infection will be analyzed in this study.

Vaginal microbiota associated with oncogenic HPV in a cohort of HPV-vaccinated women living with HIV.

BackgroundWomen living with HIV (WLWH) experience higher rates of human papillomavirus (HPV) infection and cervical cancer than women without HIV. Changes in the vaginal microbiome have been implicated in HPV-related disease processes such as persistence of high-risk HPV infection but this has not been well defined in a population living with HIV.MethodsFour hundred and 20 girls and WLWH, age ≥9, across 14 clinical sites in Canada were enrolled to receive three doses of quadrivalent HPV vaccine for assessment of vaccine immunogenicity. Blood, cervical cytology, and cervico-vaginal swabs were collected. Cervico-vaginal samples were tested for HPV DNA and underwent microbiota sequencing.ResultsPrincipal component analysis (PCA) and hierarchical clustering generated community state types (CSTs). Relationships between taxa and CSTs with HPV infection were examined using mixed-effects logistic regressions, Poisson regressions, or generalized linear mixed-effects models, as appropriate. Three hundred and fifty-six cervico-vaginal microbiota samples from 172 women were sequenced. Human papillomavirus DNA was detected in 211 (59%) samples; 110 (31%) contained oncogenic HPV. Sixty-five samples (18%) were taken concurrently with incident oncogenic HPV infection and 56 (16%) were collected from women with concurrent persistent oncogenic HPV infection.ConclusionsNo significant associations between taxa, CST, or microbial diversity and HPV-related outcomes were found. However, we observed weak associations between a dysbiotic microbiome and specific species, including Gardnerella, Porphyromonas, and Prevotella species, with incident HPV infection.

Performance of HPV E4 and p16INK4a biomarkers in predicting regression of cervical intraepithelial neoplasia grade 2 (CIN2): protocol for a historical cohort study

IntroductionCervical intraepithelial neoplasia grade 2 (CIN2) represents a spectrum of lesions with variable progression and regression. Pathological diagnosis of CIN2 is subjective and poorly reproducible. Accurate diagnosis and identification of...

Abstract 2264: Co-infection with Epstein-Barr virus impacts oral HPV persistence

Abstract Rates of oropharyngeal cancer (OPC) associated with human papillomavirus (HPV) infection are increasing in men. The obligate precursor to OPC is a persistent infection with an oncogenic HPV type that is unable to be cleared via natural immunity alone. However, the factors that influence HPV persistence at the oral cavity are unknown. It is plausible that long-term infection with other pathogens at the same anatomic site indicates an overall inability to clear an oral infection. Epstein-Barr virus (EBV) is a saliva-transmitted gamma herpesvirus that infects 90% of the population by adulthood and replicates in the epithelial cells of the oropharynx. This study aimed to investigate whether oral EBV shedding, a marker of active viral replication, could serve as a biomarker for persistent, oncogenic oral HPV infection in men. Men with an HPV16 or 18 oral infection present at the baseline visit of the HPV Infection in Men (HIM) Study were included (n=63). Briefly, men from Tampa, FL, U.S.; Cuernavaca, Mexico; and Sao Paolo, Brazil were followed every 6 months for a median of 4.1 years. Men completed a risk factor questionnaire and provided an oral gargle sample at each visit. For this study, the baseline, 6-month, and 12-month oral specimens were HPV genotyped using the SPF10 PCR-DEIA-LiPA25 system. Presence of EBV was evaluated in the baseline specimen using PCR to amplify and quantify the EBV DNA on the Rotor-Gene Q MDx instrument. Men with the same oral HPV type present at the 6-month and 12-month visit were categorized as 6-month and 12-month oral HPV persistent, respectively. The association between EBV and persistent HPV infection was investigated using a logistic regression model adjusted for age, country, and smoking. Among 63 men with oral HPV 16/18 infection at baseline, 44 HPV infections did not persist, 19 persisted to at least 6-months and 11 persisted to at least 12 months. Among the total sample, 32 also had EBV detected in the oral gargle at baseline. Among men who did not have a persistent HPV infection, 21 (47.7%) had EBV detected at baseline while 11 (57.9%) men with an HPV infection that persisted at least 6 months had detectable EBV at baseline; and 9 (81.8%) of the men who persisted to 12 months had EBV detected. Mean EBV viral load was highest among men who persisted to at least 12 months (5.0 log copies/ml) and was significantly higher than men who did not persist (2.5 log copies/ml; p=0.047). Detection of oral EBV at baseline was significantly associated with elevated risk of ≥12-month oral HPV 16/18 persistence (aOR: 9.90; 95% CI: 1.38-70.96), but not ≥6-month HPV 16/18 persistence (aOR: 1.62; 95% CI: 0.52-5.06).These data support the hypothesis that EBV reactivation may be a biomarker of poor immune control leading to increased risk of oral HPV persistence. The use of a biomarker that identifies men whose HPV infection may persist would be a useful tool to allow for screening and early detection of OPC. Citation Format: Brittney L. Dickey, Anna R. Giuliano, Bradley Sirak, Martha Abrahamsen, Eduardo Lazcano-Ponce, Luisa L. Villa, Anna E. Coghill. Co-infection with Epstein-Barr virus impacts oral HPV persistence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2264.

Efficacy of Single-Dose Human Papillomavirus Vaccination among Young African Women

BackgroundSingle-dose human papillomavirus (HPV) vaccination, if efficacious, would be tremendously advantageous, simplifying implementation and decreasing costs.MethodsWe performed a randomized, multicenter, double-blind, controlled trial of single-dose nonavalent (HPV 16/18/31/33/45/52/58/6/11 infection) or bivalent (HPV 16/18 infection) HPV vaccination compared with meningococcal vaccination among Kenyan women 15 to 20 years of age. Enrollment and 6-monthly cervical swabs and a month 3 vaginal swab were tested for HPV deoxyribonucleic acid (DNA). Enrollment sera were tested for HPV antibodies. The modified intent-to-treat (mITT) cohort comprised participants who had an HPV antibody-negative result at enrollment and an HPV DNA-negative result at enrollment and month 3. The primary outcome was incident persistent vaccine-type HPV infection by month 18.ResultsBetween December 2018 and June 2021, 2275 women were randomly assigned and followed. A total of 758 participants received the nonavalent HPV vaccine, 760 received the bivalent HPV vaccine, and 757 received the meningococcal vaccine; retention was 98%. Thirty-eight incident persistent infections were detected in the HPV 16/18 mITT cohort: one each among participants assigned to the bivalent and nonavalent groups and 36 among those assigned to the meningococcal group. Nonavalent vaccine efficacy (VE) was 97.5% (95% confidence interval [CI], 81.7 to 99.7%; P≤0.0001), and bivalent VE was 97.5% (95% CI, 81.6 to 99.7%; P≤0.0001). Thirty-three incident persistent infections were detected in the HPV 16/18/31/33/45/52/58 mITT cohort: four in the nonavalent group and 29 in the meningococcal group. Nonavalent VE for HPV 16/18/31/33/45/52/58 was 88.9% (95% CI, 68.5 to 96.1; P<0.0001). The rate of serious adverse events was 4.5% to 5.2% by group.ConclusionsOver the 18-month timeframe we studied, single-dose bivalent and nonavalent HPV vaccines were each highly effective in preventing incident persistent oncogenic HPV infection, similar to multidose regimens. (Funded by the National Institutes of Health, the Bill and Melinda Gates Foundation, and the University of Washington; ClinicalTrials.gov number, NCT03675256.)

Therapeutic DNA Vaccines against HPV-Related Malignancies: Promising Leads from Clinical Trials.

In 2014 and 2021, two nucleic-acid vaccine candidates named MAV E2 and VGX-3100 completed phase III clinical trials in Mexico and U.S., respectively, for patients with human papillomavirus (HPV)-related, high-grade squamous intraepithelial lesions (HSIL). These well-tolerated but still unlicensed vaccines encode distinct HPV antigens (E2 versus E6+E7) to elicit cell-mediated immune responses; their clinical efficacy, as measured by HSIL regression or cure, was modest when compared with placebo or surgery (conization), but both proved highly effective in clearing HPV infection, which should help further optimize strategies for enhancing vaccine immunogenicity, toward an ultimate goal of preventing malignancies in millions of patients who are living with persistent, oncogenic HPV infection but are not expected to benefit from current, prophylactic vaccines. The major roadblocks to a highly efficacious and practical product remain challenging and can be classified into five categories: (i) getting the vaccines into the right cells for efficient expression and presentation of HPV antigens (fusion proteins or epitopes); (ii) having adequate coverage of oncogenic HPV types, beyond the current focus on HPV-16 and -18; (iii) directing immune protection to various epithelial niches, especially anogenital mucosa and upper aerodigestive tract where HPV-transformed cells wreak havoc; (iv) establishing the time window and vaccination regimen, including dosage, interval and even combination therapy, for achieving maximum efficacy; and (v) validating therapeutic efficacy in patients with poor prognosis because of advanced, recurrent or non-resectable malignancies. Overall, the room for improvements is still large enough that continuing efforts for research and development will very likely extend into the next decade.

Progression from human papillomavirus (HPV) infection to cervical lesion or clearance in women (18–25 years): Natural history study in the control arm subjects of AS04-HPV-16/18 vaccine efficacy study in China between 2008 and 2016

ABSTRACT Background Cervical cancer is the third most frequent cancer in Chinese women aged 15–44 years old. Human papillomavirus (HPV) is recognized as the main etiologic agent of cervical carcinomas. This study aims to better understand the natural history of HPV infections in Chinese women aged 18–25 years. Research Design and Methods Data from 3,025 control arm women (AS04-HPV-16/18 vaccine trial) were analyzed to assess the probability of progression or clearance from a 6-month persistent infection (6MPI) to a cervical intraepithelial neoplasia grade 2 or greater (CIN2+), and the association with clinical determinants. Data were analyzed using univariate and multivariable Cox models. Results A total of 1,324 women with 3,814 HPV infections were included, and 65.7% of the women had at least one 6MPI. Among those 6MPI, 5.0% progressed to CIN2+, while 61.0% cleared within 6 months. The risk of progression from 6MPI to CIN2+ was substantially higher for oncogenic versus non-oncogenic HPV types. Conclusions Oncogenic HPV infections showed lower clearance and higher risk to progress to CIN2 +. These findings observed in a population of Chinese women, confirmed previous findings from multinational studies. Trial Registration The PATRICIA and AS04-HPV-16/18 vaccine trials are registered at ClinicalTrials.gov (NCT00779766 and NCT00122681).