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Outcome and associated factors of high-risk human papillomavirus infection without cervical lesions.BMC Women's Health Nov 2023To study the outcome of human papillomavirus (HPV) infection in women with cervical pathology results of non-cervical intraepithelial neoplasia (CIN) or cervical cancer...
OBJECTIVE
To study the outcome of human papillomavirus (HPV) infection in women with cervical pathology results of non-cervical intraepithelial neoplasia (CIN) or cervical cancer and positive high-risk HPV test, as well as analyze the associated risk factors affecting the outcome of infection.
METHODS
To investigate the outcome of high-risk (HR)-HPV infection in the female genital tract and analyze the associated risk factors affecting their outcome, a total of 196 women with positive HR-HPV test results and non-CIN or cervical cancer cervical pathology results were selected for follow-up at the Cervical Disease Clinic of the Obstetrics and Gynecology Hospital, Zhejiang University School of Medicine from January 2017 to March 2020. The follow-up interval was every 6 months, and both cervical cytology (TCT) and HR-HPV testing were performed at each follow-up visit. If the cervical cytology results were normal upon recheck and the HR-HPV test was negative, the woman was considered to be cleared of the HPV infection and was entered into the routine cervical screening population. When the repeat HR-HPV test remained positive after 6 months, the woman was defined as having a persistent HR-HPV infection. If HR-HPV persisted but the TCT results were normal, follow-up was continued. If HR-HPV persisted and the TCT results were abnormal, a colposcopy-guided biopsy was performed immediately. In this situation, if the histological results were still non-CIN or cervical cancer, the follow-up was continued. If the histological results confirmed the development of CIN or invasive cancer, then enter another study follow-up to further track its development and outcome, and the woman commenced the treatment process. The HPV infection clearance time was analyzed by the Kaplan-Meier method, and the comparison of the HPV clearance rate and infection clearance time between each of the different groups was performed using aχ test or Fisher's exact test, as appropriate. After the univariate analysis, several significant factors were included in the Cox model and independent risk factors were analyzed.
RESULTS
A total of 163 women were enrolled in this study. The median age was 40.0 years (22-67 years) and the median follow-up time was 11.5 months (6-31 months). The spontaneous clearance rate of HR-HPV infection was 51.5%, and the median time to viral clearance was 14.5 months. Age and the initial viral load were high risk factors affecting the spontaneous clearance of HR-HPV infection. The factors significantly associated with HPV clearance rate and time to HPV clearance consisted of menopause and full-term delivery (P < 0.05).
CONCLUSIONS
In women with normal or low-grade lesions on the cell smear, the spontaneous clearance rate of HR-HPV infection was 51.5% and the time to clearance was 14.5 months. Age and the initial viral load were independent associated factors affecting the spontaneous clearance of HR-HPV infection in the female genital tract. These findings suggest that non-young women or those with high viral loads have a higher rate of persistent HR-HPV infection. Thus, intensive screening should be recommended.
Topics: Pregnancy; Female; Humans; Adult; Uterine Cervical Neoplasms; Papillomavirus Infections; Human Papillomavirus Viruses; Early Detection of Cancer; Uterine Cervical Dysplasia; Vaginal Smears; Colposcopy; Papillomaviridae
PubMed: 37957634
DOI: 10.1186/s12905-023-02764-8 -
International Journal of Gynecological... Sep 2023Vulvar squamous cell cancer (VSC) accounts for 90% of vulvar cancers. Next-generation sequencing studies of VSC imply human papillomavirus (HPV) and p53 status play...
Vulvar squamous cell cancer (VSC) accounts for 90% of vulvar cancers. Next-generation sequencing studies of VSC imply human papillomavirus (HPV) and p53 status play separate roles in carcinogenesis and prognosis. We sought to describe the genomic landscape and analyze the immunologic profiles of VSC with respect to HPV and p53 status. A total of 443 VSC tumors underwent tumor profiling. Next-generation sequencing was performed on genomic DNA isolated from formalin-fixed paraffin-embedded tumor samples. PD-L1, microsatellite instability were tested by fragment analysis, IHC, and next-generation sequencing. Tumor mutational burden-high was defined as >10 mutations per MB. HPV 16/18 positive (HPV+) status was determined using whole exome sequencing on 105 samples. Three cohorts were identified from 105 samples with known HPV: HPV+, HPV-/p53wt, and HPV-/p53mt. Where HPV and p53 status were examined, TP53 mutations were exclusive of HPV+ tumors. In all, 37% of samples were HPV+. Among the 66 HPV- tumors, 52 (78.8%) were HPV-/p53mt and 14 (21.2%) were HPV-/p53wt. The HPV-/p53wt cohort had a higher rate of mutations in the PI3KCA gene (42.9% HPV-/p53wt vs 26.3% HPV+ vs. 5.8% HPV-/p53mt, q =0.028) and alterations in the PI3K/AkT/mTOR pathway (57.1% HPV-/p53wt vs. 34.2% HPV+ vs. 7.7% HPV-/p53mt, q =0.0386) than the other 2 cohorts. Ninety-eight VSC tumors with HPV16/18 information underwent transcriptomic analysis and immune deconvolution method. No differences were observed in immune profiles. The HPV-/p53wt VSC tumors had significantly higher rates of mutations in the PI3KCA gene and alterations in the PI3K/AkT/mTOR pathway, a potential target that merits further investigation in this subgroup.
Topics: Female; Humans; Vulvar Neoplasms; Tumor Suppressor Protein p53; Human papillomavirus 16; Papillomavirus Infections; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Human papillomavirus 18; Carcinoma, Squamous Cell; Genomics; Mutation; Papillomaviridae; Human Papillomavirus Viruses; TOR Serine-Threonine Kinases
PubMed: 37131274
DOI: 10.1097/PGP.0000000000000950 -
Frontiers in Public Health 2023Infections with human papillomaviruses (HPV) are sexually transmitted and can cause cancer. In Germany, vaccination against HPV is recommended for girls and boys aged...
BACKGROUND
Infections with human papillomaviruses (HPV) are sexually transmitted and can cause cancer. In Germany, vaccination against HPV is recommended for girls and boys aged 9-17 years. We aimed to investigate HPV DNA prevalence, genotype distribution and vaccine effectiveness (VE) in women aged 20-25 years 10 years after the introduction of HPV vaccination in Germany (2018-2019), and compared these data to an equally designed study from 2010-2012.
METHODS
Seventy six geographical clusters were randomly selected, followed by random selection of 61 women aged 20-25 years per cluster. Participants performed cervicovaginal self-sampling and answered questions on demographics, sexual behaviour and HPV vaccination. Samples were tested for 18 high risk and nine low risk HPV genotypes. We performed chi-square tests, Fisher's exact test, unpaired Student's -test and proportion -test, and calculated crude and adjusted prevalence ratios (PR) and 95% CIs.
RESULTS
Of 7,858 contacted women a total of 1,226 agreed to participate. Of these, 94 women were positive for HPV types 16 and/or 18. HPV16 prevalence was 7.0% (95% CI 5.6-8.6) and HPV18 prevalence was 0.8% (95% CI 0.4-1.5). HPV6 and HPV11 were rare with only five (0.4%; 0.1-0.9) and one (0%; 95% CI 0.0-0.5) positive tests. Seven hundred fifty-seven women (62%) had received at least one HPV vaccine dose and 348 (28%) were vaccinated as currently recommended. Confounder-adjusted VE was 46.4% (95% CI 4.2-70.1) against HPV16/18 infection and 49.1% (95% CI 8.2-71.8) against infection with at least one HPV genotype covered by the quadrivalent HPV vaccine. Compared with the 2010-2012 study results, HPV16/18 prevalence dropped from 22.5% (95% CI 19.0-26.3) to 10.3% (95% CI 7.5-13.9; < 0.0001) in unvaccinated participants.
CONCLUSION
Vaccine-covered HPV genotypes were rare among 20-25 years old women in Germany and decreased compared to the time point shortly after the start of the HPV vaccination program. HPV prevalence of almost all vaccine-covered genotypes was strongly reduced in vaccinated participants. A decrease of HPV16 and HPV18 was even observed in unvaccinated participants, compared to 2010-2012 data, suggesting indirect protection of unvaccinated women. Low VE against HPV16/18 and HPV6/11/16/18 in our study might be attributable to study design in combination with the endpoint selection of (mainly transient) HPV DNA positivity.
Topics: Adult; Female; Humans; Young Adult; Germany; Human papillomavirus 16; Human papillomavirus 18; Human Papillomavirus Viruses; Papillomaviridae; Papillomavirus Infections; Papillomavirus Vaccines; Prevalence; Vaccine Efficacy
PubMed: 37719724
DOI: 10.3389/fpubh.2023.1204101 -
EBioMedicine Jun 2024Despite numerous studies having evaluated the associations between human papillomavirus (HPV) infection and risk of specific cancers other than anogenital tract and... (Review)
Review
BACKGROUND
Despite numerous studies having evaluated the associations between human papillomavirus (HPV) infection and risk of specific cancers other than anogenital tract and oropharyngeal, the findings are inconsistent and the quality of evidence has not been systematically quantified. We aimed to summarise the existing evidence as well as to evaluate the strength and credibility of these associations.
METHODS
We conducted an umbrella review of systematic reviews and meta-analyses of observational studies. PubMed, EMBASE, and Web of Science were searched from inception to March 2024. Studies with systematic reviews and meta-analyses that examined associations between HPV or HPV-associated genotypes infection and specific cancers were eligible for this review. The quality of the methodology was evaluated using A Measurement Tool to Assess systematic Reviews (AMSTAR). The credibility of the evidence was assessed using GRADE. The protocol was preregistered with PROSPERO (CRD42023439070).
FINDINGS
The umbrella review identified 31 eligible studies reporting 87 associations with meta-analytic estimates, including 1191 individual studies with 336,195 participants. Of those, 29 (93.5%) studies were rated as over moderate quality by AMSTAR. Only one association indicating HPV-18 infection associated with an increased risk of breast cancer (odds ratio [OR] = 3.48, 95% confidence interval [CI] = 2.24-5.41) was graded as convincing evidence. There were five unique outcomes identified as highly suggestive evidence, including HPV infection increased the risk of oral squamous cell carcinoma (OR = 7.03, 95% CI = 3.87-12.76), oesophageal cancer (OR = 3.32, 95% CI = 2.54-4.34), oesophageal squamous cell carcinoma (OR = 2.69, 95% CI = 2.05-3.54), lung cancer (OR = 3.60, 95% CI = 2.59-5.01), and breast cancer (OR = 6.26, 95% CI = 4.35-9.00). According to GRADE, one association was classified as high, indicating that compared with the controls in normal tissues, HPV infection was associated with an increased risk of breast cancer.
INTERPRETATION
The umbrella review synthesised up-to-date observational evidence on HPV infection with the risk of breast cancer, oral squamous cell carcinoma, oesophageal cancer, oesophageal squamous cell carcinoma, and lung cancer. Further larger prospective cohort studies are needed to verify the associations, providing public health recommendations for prevention of disease.
FUNDING
National Key Research and Development Program of China, Natural Science Foundation of China, Outstanding Scientific Fund of Shengjing Hospital of China Medical University, and 345 Talent Project of Shengjing Hospital of China Medical University.
Topics: Humans; Papillomavirus Infections; Neoplasms; Risk Factors; Papillomaviridae; Female; Systematic Reviews as Topic
PubMed: 38744109
DOI: 10.1016/j.ebiom.2024.105155 -
Viruses Sep 2023The global incidence of sexually transmitted infections (STIs) remains high, with the World Health Organization (WHO) estimating that over 1 million people acquire STIs... (Review)
Review
The global incidence of sexually transmitted infections (STIs) remains high, with the World Health Organization (WHO) estimating that over 1 million people acquire STIs daily. STIs can lead to infertility, pregnancy complications, and cancers. Co-infections with multiple pathogens are prevalent among individuals with an STI and can lead to heightened infectivity and more severe clinical manifestations. (CT) is the most reported bacterial STI worldwide in both men and women, and several studies have demonstrated co-infection of CT with viral and other bacterial STIs. CT is a gram-negative bacterium with a unique biphasic developmental cycle including infectious extracellular elementary bodies (EBs) and metabolically active intracellular reticulate bodies (RBs). The intracellular form of this organism, RBs, has evolved mechanisms to persist for long periods within host epithelial cells in a viable but non-cultivable state. The co-infections of CT with the most frequently reported sexually transmitted viruses: human immunodeficiency virus (HIV), human papillomavirus (HPV), and herpes simplex virus (HSV) have been investigated through in vitro and in vivo studies. These research studies have made significant strides in unraveling the intricate interactions between CT, these viral STIs, and their eukaryotic host. In this review, we present an overview of the epidemiology of these co-infections, while specifically delineating the underlying mechanisms by which CT influences the transmission and infection dynamics of HIV and HSV. Furthermore, we explore the intricate relationship between CT and HPV infection, with a particular emphasis on the heightened risk of cervical cancer. By consolidating the current body of knowledge, we provide valuable insights into the complex dynamics and implications of co-infection involving CT and sexually transmitted viruses.
Topics: Male; Pregnancy; Humans; Female; Chlamydia trachomatis; Coinfection; Sexual Behavior; Human Papillomavirus Viruses; HIV Infections
PubMed: 37766360
DOI: 10.3390/v15091954 -
Journal of Obstetrics and Gynaecology :... Dec 2023High-risk (HR)-human papillomavirus (HPV) is the leading cause of precancerous cervical lesions in patients with chronic untreated infection. We investigated the...
High-risk (HR)-human papillomavirus (HPV) is the leading cause of precancerous cervical lesions in patients with chronic untreated infection. We investigated the relationships among several vaginal microbiological alterations, oncogene E6/E7 expression, and HR-HPV. A total of 1327 women who underwent HPV screening, vaginal microecology determination, and fluid-based thin-layer cytological test were enrolled and classified into the HPV-negative group, the low-risk (LR)-HPV-positive group, and the HR-HPV-positive group. The status of cervical HPV infection, vaginal microecology, and E6/E7 mRNA expression were examined sequentially. The effect of HR-HPV infection on cervical cancer (CC) was meticulously assessed, and associations between HR-HPV infection and vaginal microecology and E6/E7 mRNA were identified. In total 548/1327 patients were HPV positive, including LR-HPV infection ( = 132) and HR-HPV infection ( = 416). Patients in the HR-HPV positive group revealed higher detection rates of bacterial vaginosis (BV), trichomonal vaginitis (TV), and vulvovaginal candidiasis (VVC) relative to the HPV negative group. A higher E6/E7 mRNA expression was identified in HR-HPV patients compared to LR-HPV patients. BV and E6/E7 mRNA were classified as independent risk factors for HR-HPV infection. Patients with HR-HPV infection were more susceptible to CC development. Overall, BV and E6/E7 mRNA expression were identified as independent risk factors for HR-HPV infection.IMPACT STATEMENT Through literature review, we found that vaginal ecological changes increase the risk of HPV infection, and HPV persistent infection is an important risk factor for cervical precancerous lesions and cervical cancer. In addition, HPV gene E6/E7 is expressed in HPV-positive cervical cancer cells, which is related to cell malignant transformation and even tumorigenesis. This study further revealed that bacterial vaginosis (BV) and E6/E7 mRNA were independently correlated with HR-HPV infection, and HR-HPV infection increased the risk of cervical cancer. E6/E7 mRNA detection may be used as a new auxiliary diagnostic index for HR-HPV infection. In addition, this study provides a reference for whether the restoration of vaginal microecological balance in patients with BV undergoing clinical treatment is conducive to HR-HPV regression, and provides theoretical support for the prevention and control of cervical cancer microecological approach and the occurrence and development of cervical cancer.
Topics: Female; Humans; Human Papillomavirus Viruses; Oncogene Proteins, Viral; Oncogenes; Papillomaviridae; Papillomavirus Infections; RNA, Messenger; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms; Vaginosis, Bacterial; Review Literature as Topic
PubMed: 36645341
DOI: 10.1080/01443615.2022.2161349 -
Clinical Epigenetics Aug 2023Screening plays a key role in secondary prevention of cervical cancer. High-risk human papillomavirus (hrHPV) testing, a highly sensitive test but with limited... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Screening plays a key role in secondary prevention of cervical cancer. High-risk human papillomavirus (hrHPV) testing, a highly sensitive test but with limited specificity, has become the gold standard frontline for screening programs. Thus, the importance of effective triage strategies, including DNA methylation markers, has been emphasized. Despite the potential reported in individual studies, methylation markers still require validation before being recommended for clinical practice. This systematic review and meta-analysis aimed to evaluate the performance of DNA methylation-based biomarkers for detecting high-grade intraepithelial lesions (HSIL) in hrHPV-positive women.
METHODS
Hence, PubMed, Scopus, and Cochrane databases were searched for studies that assessed methylation in hrHPV-positive women in cervical scrapes. Histologically confirmed HSIL was used as endpoint and QUADAS-2 tool enabled assessment of study quality. A bivariate random-effect model was employed to pool the estimated sensitivity and specificity as well as positive (PPV) and negative (NPV) predictive values.
RESULTS
Twenty-three studies were included in this meta-analysis, from which cohort and referral population-based studies corresponded to nearly 65%. Most of the women analyzed were Dutch, and CADM1, FAM19A4, MAL, and miR124-2 were the most studied genes. Pooled sensitivity and specificity were 0.68 (CI 95% 0.63-0.72) and 0.75 (CI 95% 0.71-0.80) for cervical intraepithelial neoplasia (CIN) 2+ detection, respectively. For CIN3+ detection, pooled sensitivity and specificity were 0.78 (CI 95% 0.74-0.82) and 0.74 (CI 95% 0.69-0.78), respectively. For pooled prevalence, PPV for CIN2+ and CIN3+ detection were 0.514 and 0.392, respectively. Furthermore, NPV for CIN2+ and CIN3+ detection were 0.857 and 0.938, respectively.
CONCLUSIONS
This meta-analysis confirmed the great potential of DNA methylation-based biomarkers as triage tool for hrHPV-positive women in cervical cancer screening. Standardization and improved validation are, however, required. Nevertheless, these markers might represent an excellent alternative to cytology and genotyping for colposcopy referral of hrHPV-positive women, allowing for more cost-effective screening programs.
Topics: Female; Humans; Pregnancy; Uterine Cervical Neoplasms; DNA Methylation; Early Detection of Cancer; Colposcopy; Triage; Papillomavirus Infections; Referral and Consultation; Papillomaviridae; Cell Adhesion Molecule-1
PubMed: 37533074
DOI: 10.1186/s13148-023-01537-2 -
Cancer Medicine Aug 2023There is an alarming increase in human papillomavirus-associated head and neck cancer (HNC), reaching epidemic levels. While patient prognosis is generally good,...
BACKGROUND
There is an alarming increase in human papillomavirus-associated head and neck cancer (HNC), reaching epidemic levels. While patient prognosis is generally good, off-target treatment effects are associated with decreased quality of life. Thus, non-invasive strategies to predict treatment response and risk of recurrence could help de-escalate treatment. In this study, we tested circulating tumor (ct)DNA in liquid biopsies (blood/saliva) of HPV-positive HNC patients to assess treatment response and disease progression.
METHODS
A total of 235 blood and saliva samples were collected from 60 HPV-positive and 17 HPV-negative HNC patients (control group) before and/or after treatment. Samples were analyzed using ddPCR for HPV16/18/31/33/35/45 and correlated with imaging and pathological examination.
RESULTS
HPV-ctDNA detection was significantly higher prior to treatment (91%) than after treatment (8.0%) (χ p < 0.00001), with high concordance between saliva and blood (93%). In matched samples, all patients positive for ctDNA before treatment showed significant reductions in ctDNA levels post treatment (p < 0.0001). All but one patient with persistent ctDNA after treatment showed residual tumor and subsequent recurrence. Finally, fragmentomic analysis revealed shifts in cell-free DNA fragment size after treatment, suggesting a complementary biomarker for treatment response.
CONCLUSIONS
Blood and saliva were found to be good sources of HPV-ctDNA. The presence of ctDNA strongly correlated with treatment response, demonstrating clinical utility as a non-invasive biomarker to monitor tumor progression in HPV-positive HNC. Liquid biopsy based ctDNA testing could be an effective approach to predict recurrence and stratify patients for de-escalation of treatment, thereby improving quality of life.
Topics: Humans; Human Papillomavirus Viruses; Papillomavirus Infections; Human papillomavirus 16; Neoplasm, Residual; Saliva; Quality of Life; Human papillomavirus 18; Head and Neck Neoplasms; Circulating Tumor DNA; Biomarkers, Tumor; Neoplasm Recurrence, Local
PubMed: 37526056
DOI: 10.1002/cam4.6191 -
Human Vaccines & Immunotherapeutics Dec 2023Human papillomavirus (HPV) infection is associated with the risk of developing certain cancers, including cancers of the cervix, vulva, vagina, penis, anus, rectum, and...
Human papillomavirus (HPV) infection is associated with the risk of developing certain cancers, including cancers of the cervix, vulva, vagina, penis, anus, rectum, and oropharynx. In 2016, the bivalent HPV-16/18 vaccine was included in the Korea National Immunization Program. This vaccine protects against HPV types 16 and 18 and other oncogenic HPV types predominant in cervical and anal cancers. This post-marketing surveillance (PMS) study assessed the safety of the HPV-16/18 vaccine in Korea. The study was conducted in males and females aged between 9 and 25 years, from 2017 to 2021. Safety was measured in terms of frequency and intensity of adverse events (AEs), adverse drug reactions (ADRs), and serious adverse events (SAEs) after each vaccine dose. The safety analysis included all participants who were vaccinated as per prescribing information and who completed a 30-day follow-up after at least one dose. Data were collected using individual case report forms. The total safety cohort included 662 participants. A total of 220 AEs were reported in 144 subjects (21.75%), and there were 158 ADRs in 111 subjects (16.77%), with the most common being injection site pain in all cases. No SAEs or serious ADRs were reported. Most AEs were reported after the first dose and were injection site reactions with mild intensity that recovered. No individuals required hospitalization or an emergency department visit. Safety results showed that the HPV-16/18 vaccine was generally well tolerated in the Korean population, and no safety concerns were identified.ClinicalTrials.gov Identifier: NCT03671369.
Topics: Male; Female; Humans; Child; Adolescent; Young Adult; Adult; Human papillomavirus 16; Uterine Cervical Neoplasms; Papillomavirus Infections; Human papillomavirus 18; Papillomavirus Vaccines; Drug-Related Side Effects and Adverse Reactions; Injection Site Reaction; Product Surveillance, Postmarketing; Republic of Korea
PubMed: 36896702
DOI: 10.1080/21645515.2023.2184756 -
Cell Reports. Medicine Aug 2023Effective triage of high-risk human papillomavirus (hrHPV)+ women is warranted to avoid unnecessary referral and overtreatment. Molecular triage tests have recently...
Effective triage of high-risk human papillomavirus (hrHPV)+ women is warranted to avoid unnecessary referral and overtreatment. Molecular triage tests have recently begun to impact cervical intraepithelial neoplasia grade 3 (CIN3) or cervical cancer (CC), termed CIN3+, detection. We find that zinc finger protein 671 methylation (ZNF671) test has superior performance for CIN3+ detection in all single molecular triage tests, including HPV16/18 genotyping, paired box gene 1 methylation (PAX1), and ZNF671, in the training set. Using ZNF671 test instead of Thinprep cytologic test (TCT) as a single triage strategy or as a combined triage strategy with HPV16/18 genotyping has achieved comparable sensitivity but higher specificity for CIN3+ detection among 391 hrHPV+ women in the validation set. Little attention has been paid to the women with hrHPV- status but detected CIN3+. We find that the CIN3+ risk after a negative result could be reduced further by triage using ZNF671 in hrHPV- patients.
Topics: Humans; Female; Uterine Cervical Neoplasms; Human papillomavirus 16; DNA Methylation; Human papillomavirus 18; Uterine Cervical Dysplasia; Tumor Suppressor Proteins
PubMed: 37557178
DOI: 10.1016/j.xcrm.2023.101143