Nonlinear relationship between viral load and TCT in single/multiple HPV52 infection.

PURPOSE: To determine the correlation between HPV (human papillomavirus) 52 viral load, multiple infections and ThinPrep cytology test (TCT), to inform clinical management of HPV52-positive women after cervical cancer screening. METHODS: A total of 1,882 female patients who had positive quantitative HPV tests at Yuebei People's Hospital from January 2020 to December 2022, of whom 533 tested positive for HPV52. We excluded patients who combined HPV16 and/or HPV 18 positivity and whom HPV52 viral load could not be calculated. The final enrollment was 488 patients, including 400 NILM, 48 ASC-US, 28 LSIL and 12 HSIL. The HPV test is a quantitative multiplexed fluorescent PCR assay that provides both HPV genotyping and viral load. RESULTS: In our study, there were differences in the median distribution of viral loads among various cytological class categories. The risk of TCT results (LSIL or worse) was increased with the increase of HPV52 viral load, for every LOG unit increase in HPV52 viral load, the risk increased by 26.6%. More importantly, we found a nonlinear relationship between HPV52 viral load and TCT results (LSIL or worse) in both single and multiple infections. When the viral load reaches a threshold, the risk of abnormal cytological results increases significantly. CONCLUSION: HPV52 viral load is an independent risk factor for TCT results (LSIL or worse). The relationship between HPV52 viral load and TCT results (LSIL or worse) is not linear. Viral load may be used as a triage indicator for HPV52-positive patients, thus improving the post-screening clinical management of HPV52-positive women.

A prospective multicentre controlled study of Gaoweikang (Chinese multiherb extract-based tincture) used in high-risk HPV infections.

OBJECTIVE: The aim of the study was to investigate the safety and antiviral efficacy of a Chinese multiherb extract-based tincture (GWK) on a population of patients with high-risk human papilloma (hrHPV) infections and hrHPV-caused cervical low-grade squamous intraepithelial lesions (LSILs). PATIENTS AND METHODS: Patients with persistent hrHPV infection were enrolled in Group A, including A1 subjects, who received the intervention, and A2 subjects, who received the control. Patients with hrHPV infection causing cervical LSIL were enrolled in Group B, which included B1 subjects, who received the intervention, and B2 subjects, who served as the control. For Groups A1 and B1, hrHPV was tested at 3 months (M3) and 6 months (M6) after the intervention. The side effects were also analyzed. RESULTS: At baseline (D0), a total of 99 patients were enrolled in Group A, with 50 subjects in Group A1 and 49 subjects in Group A2. A total of 91 patients were enrolled in Group B, with 45 subjects in Group B1 and 46 subjects in Group B2. There was no significant difference in the characteristics, including average age, age stratification, and HPV genotype. At M6, both Group A1 and Group B1 had a higher hrHPV clearance rate than the control group (A1/A2: 80.0% vs. 20.4%; B1/B2: 64.4% vs. 15.2%, p<0.001). At M6, the effective rates of Group A1 and Group B1 were 84% (42/50) and 68.9% (31/45), respectively. The side effect rates of Groups A1 and B1 were 11.5% (6/52) and 11.1% (5/45), respectively. Most adverse reactions involved local discomfort, including vulvar erythema, vulvar itch, increased vaginal discharge, cervical bleeding, and mild pain in the lower abdomen. Univariate logistic regression analysis showed that the intervention had an OR of 12 (95% CI 4.431-32.50) for clearing persistent HPV infection (p<0.001). For cervical LSIL, the intervention had an OR of 10.1 for clearing persistent HPV infection (95% CI 3.68-27.7) (p<0.001). CONCLUSIONS: The results of this study suggest that the Chinese multiherb extract-based tincture GWK is safe and well tolerated. Furthermore, this preliminary study showed that this Chinese multiherb extract-based tincture is helpful for promoting HPV clearance in cases of persistent HPV and HPV-induced LSIL.

Analysis of HPV prevalence among individuals with reproductive tract infections in a Chinese population.

The previous research has found that human papillomavirus (HPV) infection is the main cause of cervical cancer, but it is still unclear whether HPV infection, as well as the HPV genotypes, are related to reproductive tract infections in the Chinese population. Patients who underwent HPV screening at Shandong Maternal and Child Health Hospital were selected, and the HPV infection status was analyzed among patients with cervical lesions, bacterial vaginosis, cervical inflammation, fungal vaginitis, and pelvic infections. SPSS 22 statistical analysis was used to analyze the differences in HPV infection types and rates between the control group and the experimental group. The HPV infection rate of bacterial vaginosis (χ2 = 13.4; P < .001) and fungal vaginitis (χ2 = 3.3; P < .045) are both significantly different from the control group. The single HPV infections reveals significant differences from control group in bacterial vaginosis (χ2 = 7.3; P = .004), fungal vaginitis (χ2 = 4.5; P = .023), and cervical lesions (χ2 = 58.8; P < .001). In the bacterial infection group, HPV51 (1.9%; χ2 = 6.0; P = .008) and HPV58 (4.7%; χ2 = 3.3; P = .044) showed significant differences in infection compared to the control group. In the fungal infection group, HPV39 (2.7%; χ2 = 4.7; P = .032) showed a significant difference in infection compared to the control group. Cervical lesions, bacterial vaginosis, fungal vaginitis, and cervical lesions among Chinese population exhibit age-specified distribution. HPV infection rate in bacterial vaginitis, fungal vaginitis and cervical lesions was higher than that in normal group. HPV52 and HPV16 infection are different, and HPV39 is different between bacterial vaginitis and fungal vaginitis.

Cervical Cancer Screening: A Review.

Importance: Each year in the US, approximately 100 000 people are treated for cervical precancer, 14 000 people are diagnosed with cervical cancer, and 4000 die of cervical cancer. Observations: Essentially all cervical cancers worldwide are caused by persistent infections with one of 13 carcinogenic human papillomavirus (HPV) genotypes: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68. HPV vaccination at ages 9 through 12 years will likely prevent more than 90% of cervical precancers and cancers. In people with a cervix aged 21 through 65 years, cervical cancer is prevented by screening for and treating cervical precancer, defined as high-grade squamous intraepithelial lesions of the cervix. High-grade lesions can progress to cervical cancer if not treated. Cervicovaginal HPV testing is 90% sensitive for detecting precancer. In the general population, the risk of precancer is less than 0.15% over 5 years following a negative HPV test result. Among people with a positive HPV test result, a combination of HPV genotyping and cervical cytology (Papanicolaou testing) can identify the risk of precancer. For people with current precancer risks of less than 4%, repeat HPV testing is recommended in 1, 3, or 5 years depending on 5-year precancer risk. For people with current precancer risks of 4% through 24%, such as those with low-grade cytology test results (atypical squamous cells of undetermined significance [ASC-US] or low-grade squamous intraepithelial lesion [LSIL]) and a positive HPV test of unknown duration, colposcopy is recommended. For patients with precancer risks of less than 25% (eg, cervical intraepithelial neoplasia grade 1 [CIN1] or histologic LSIL), treatment-related adverse effects, including possible association with preterm labor, can be reduced by repeating colposcopy to monitor for precancer and avoiding excisional treatment. For patients with current precancer risks of 25% through 59% (eg, high-grade cytology results of ASC cannot exclude high-grade lesion [ASC-H] or high-grade squamous intraepithelial lesion [HSIL] with positive HPV test results), management consists of colposcopy with biopsy or excisional treatment. For those with current precancer risks of 60% or more, such as patients with HPV-16-positive HSIL, proceeding directly to excisional treatment is preferred, but performing a colposcopy first to confirm the need for excisional treatment is acceptable. Clinical decision support tools can facilitate correct management. Conclusions and Relevance: Approximately 100 000 people are treated for cervical precancer each year in the US to prevent cervical cancer. People with a cervix should be screened with HPV testing, and if HPV-positive, genotyping and cytology testing should be performed to assess the risk of cervical precancer and determine the need for colposcopy or treatment. HPV vaccination in adolescence will likely prevent more than 90% of cervical precancers and cancers.

Prevalence of HPV infection and cervical intraepithelial lesions in HIV positive and negative women in the city of Florianopolis / Prevalência da infecção pelo HPV e lesões intraepiteliais cervicais em mulheres HIV positivas e negativas na cidade de Florianópolis

Introduction: HPV infection is the most frequent sexually transmitted infection in women. The high oncogenic risk HPV, associated with others factors, there are a risk of progressing to a precancerous lesion of the cervix and even cancer. This evolution is related to the persistence of the infection and other factors, mainly those that interfere with the woman's immunity. The immunosuppression caused by HIV infection is an important factor for viral persistence and the appearance of these lesions. Objectives: To compare the prevalence of HPV infection and cervical intraepithelial lesions in HIV-positive and negative women and describe the possible associated risk factors. Methods: The sample consisted of 50 HIV positive women (study group) and 50 HIV negative women (control group) recruited from the public health system of Florianópolis during the months of January to April 2022. Cervical samples were collected for cytological analysis and for detection of high-risk oncogenic HPV DNA by polymerase chain reaction (PCR). Categorical variables were compared using the chi-square test, with a significance level set at 5% Results: HPV infection was more prevalent in the control group, however, HIV positive women had a higher frequency of intraepithelial lesions diagnosed on cytology. Factors such as greater number of sexual partners, depression and smoking were more frequent in the group of HIV positive women. The number of CD4 T cells less than 200 cels/mm3 was associated with a higher number of altered Pap smears and a positive HPV DNA test. The use of combination antiretroviral therapy and undetectable viral load were associated with a greater number of normal cytology and undetected HPV DNA. Conclusion: The prevalence of cervical intraepithelial lesions in HIV-infected women is higher than in women without infection. The presence of HIV infection was the most important risk factor associated with the development of cervical lesions. (AU)

Introdução: O Papilomavírus Humano (HPV) é a infecção de transmissão sexual mais frequente na mulher. O HPV de alto risco oncogênico, associado a outros fatores, apresenta risco de evoluir para uma lesão pré-cancerosa do colo de útero e até mesmo para o câncer. Essa evolução está relacionada à persistência da infecção e outros fatores, principalmente os que interferem na imunidade da mulher. A imunossupressão causada pela infecção HIV é um fator importante para a persistência viral e o aparecimento destas lesões. Objetivos: Comparar a prevalência da infecção pelo HPV e das lesões intraepiteliais do colo de útero em mulheres HIV positivas e negativas, e descrever os possíveis fatores de risco associados. Métodos: A amostra foi composta por 50 mulheres HIV positivas (grupo de estudo) e 50 mulheres HIV negativas (grupo controle) recrutadas no sistema público de saúde de Florianópolis durante os meses de janeiro a abril de 2022. Foram coletadas amostras cervicais para análise citológica e para detecção do DNA HPV de alto risco oncogênico por reação em cadeia da polimerase (PCR). As variáveis categóricas foram comparadas pelo teste qui-quadrado, com nível de significância estabelecido em 5%. Resultados: A infecção pelo HPV foi mais prevalente no grupo controle, entretanto, as mulheres HIV positivas tiveram uma maior frequência de lesões intraepiteliais diagnosticadas na citologia. Os fatores como maior número de parceiros sexuais, depressão e tabagismo foram mais frequentes no grupo de mulheres HIV positivas. O número de células TCD4 inferior a 200 células/mm3 esteve associado a maior número de colpocitologias alteradas e teste DNA HPV positivo. O uso da terapia antirretroviral combinada e a carga viral indetectável estiveram associadas a um número elevado de citologias normais e DNA HPV não detectado. Conclusão: A prevalência de lesões intraepiteliais do colo do útero em mulheres infectadas pelo HIV foi maior que em mulheres soronegativas. A presença de infecção pelo HIV foi o fator de risco mais importante associado ao desenvolvimento de lesões cervicais.Palavras-chave: HPV. HIV. coinfecção. lesões intraepiteliais escamosas cervicais. prevalência.. (AU)

HPV E6/E7mRNA association with interleukin 10 (rs1800872) polymorphism in a group of Macedonian women.

Interleukin 10 (IL-10) is an immunosuppressive cytokine and its genetic variants could have an indirect impact on viral biology and human papillomavirus (HPV) E6/E7 messenger RNA (mRNA) expression as well. This study evaluates the association between IL-10-592 C/A (rs1800872) single-nucleotide polymorphism and HPV E6/E7 mRNA expression in a group of women from the Republic of North Macedonia. Using a commercial test, 272 women's cervical samples were analyzed for HPV E6/E7 mRNA and HPV DNA presence. The cases were stratified into three groups: double-positive (n = 108, positive for both tests), negative (n = 51, negative for HPV E6/E7 mRNA and HPV DNA positive), and the control group (n = 113, negative for both tests). The IL-10-592 C/A polymorphism was analyzed using polymerase chain reaction-restriction fragment length polymorphism. The results showed the CC genotype and the C allele frequencies of IL-10-592C/A were significantly higher in double-positive (59.3% and 78.2%) compared to negative group (39.2% and 65.7%), (p = 0.018, confidence interval [CI] = 2.25; 1.14-4.45 and p = 0.016, CI = 1.88; 1.11-3.16, respectively). The CC genotype and C allele of rs1800872 polymorphism were shown to be associated with HPV E6/E7 mRNA but not with HPV DNA positivity, which implies a possible role of this polymorphism in the course of the infection only after HPV onset, and lack of association with the susceptibility to HPV.

The eight-year long-term follow-up on the effectiveness of the quadrivalent human papillomavirus vaccine in Chinese women 20-45 years of age.

The quadrivalent human papillomavirus (4vHPV) vaccine has shown confirmative effectiveness in preventing HPV-related diseases among women and men around the globe. The phase III, randomized, double-blind efficacy study (Base study, NCT00834106) conducted in China showed 100% efficacy against HPV 16/18-related cervical intraepithelial neoplasia and efficacy against HPV persistent infection for 78 months. Participants aged 20-45 years who received three doses of 4vHPV vaccine or placebo during the base study were selected and invited for this long-term follow-up (LTFU) study to assess the long-term effectiveness of the 4vHPV vaccine in preventing HPV-related diseases. A total of 368 participants were included in this LTFU study with a median follow-up of 94 months. Among 27 participants (Vaccine vs. Placebo: 8 vs. 19) who underwent colposcopy and biopsy due to cervical cytological abnormalities or HPV infection, no HPV-16/18-related cases of cervical intraepithelial neoplasia (CIN), vulvar intraepithelial neoplasia (VIN), or vaginal intraepithelial neoplasia (VaIN) was observed in the vaccine group while two HPV-16-related cases (CIN1/VaIN) were observed in the placebo group. There were another two HPV-related cases (non-vaccine HPV types) found in the placebo group. Consistent with the findings from global studies that suggested long-term efficacy of 4vHPV vaccine, our study showed continued protective effect of 4vHPV vaccine against HPV-related precancerous diseases through a median follow-up time of 94 months with the longest follow-up time of 125 months after completing three doses of vaccination among Chinese women 20-45 years of age.

Changes of the vaginal microbiota in HPV infection and cervical intraepithelial neoplasia: a cross-sectional analysis.

This study aimed to explore the changes of the vaginal microbiota and enzymes in the women with high-risk human papillomavirus (HR-HPV) infection and cervical lesions. A total of 448 participants were carried out HPV genotyping, cytology tests, and microecology tests, and 28 participants were treated as sub-samples, in which vaginal samples were characterized by sequencing the bacterial 16S V4 ribosomal RNA (rRNA) gene region. The study found the prevalence of HR-HPV was higher in patients with BV (P = 0.036). The HR-HPV infection rate was 72.73% in G. vaginalis women, which was significantly higher than that of women with lactobacillus as the dominant microbiota (44.72%) (P = 0.04). The positive rate of sialidase (SNA) was higher in women with HR-HPV infection (P = 0.004) and women diagnosed with cervical intraepithelial neoplasia (CIN) (P = 0.041). In HPV (+) women, the α-diversity was significantly higher than that in HPV (-) women. The 16S rRNA gene-based amplicon sequencing results showed that Lactobacillus was the dominant bacteria in the normal vaginal microbiota. However, the proportion of Gardnerella and Prevotella were markedly increased in HPV (+) patients. Gardnerella and Prevotella are the most high-risk combination for the development of HPV (+) women. The SNA secreted by Gardnerella and Prevotella may play a significant role in HPV infection progress to cervical lesions.

Roles of extended human papillomavirus genotyping and multiple infections in early detection of cervical precancer and cancer and HPV vaccination.

BACKGROUND: The aim of the study was to investigate the risk of human papillomavirus (HPV) genotyping particularly vaccine genotypes and multiple infections for cervical precancer and cancer, which might contribute to developing genotype-specific screening strategy and assessing potential effects of HPV vaccine. METHODS: The HPV genotypes were identified using the Seq HPV assay on self-collected samples. Hierarchical ranking of each genotype was performed according to positive predictive value (PPV) for cervical intraepithelial neoplasia 2/3 or worse (CIN2+/CIN3+). Multivariate logistic regression model was used to estimate the odds ratios (ORs) with 95% confidence interval (CI) of CIN2+ according to multiplicity of types and vaccine types. RESULTS: A total of 2811 HPV-positive women were analyzed. The five dominant HPV genotypes in high-grade lesions were 16/58/52/33/18. The overall ranking orders were HPV16/33/35/58/31/68/18/ 56/52/66/51/59/45/39 for CIN2+ and HPV16/33/31/58/45/66/52/18/35/56/51/68/59/39 for CIN3+. The risks of single infection versus co-infections with other types lower in the hierarchy having CIN2+ were not statistically significant for HPV16 (multiple infection vs. single infection: OR = 0.8, 95%CI = 0.6-1.1, P = 0.144) or other genotypes (P > 0.0036) after conservative Bonferroni correction. Whether HPV16 was present or not, the risks of single infection versus multiple infection with any number (2, ≥2, or ≥ 3) of types for CIN2+ were not significantly different. In addition, HPV31/33/45/52/58 covered by nonavalent vaccine added 27.5% of CIN2, 23.0% of CIN3, and 12.5% of cancer to the HPV16/18 genotyping. These genotype-groups were at significantly higher risks than genotypes not covered by nonavalent vaccine. Moreover, genotypes covered by nonavalent vaccine contributed to 85.2% of CIN2 lesions, 97.9% of CIN3 and 93.8% of cancers. CONCLUSIONS: Partial extended genotyping such as HPV33/31/58 but not multiplicity of HPV infections could serve as a promising triage for HPV-positive self-samples. Moreover, incidence rates of cervical cancer and precancer were substantial attributable to HPV genotypes covered by current nonavalent vaccination.

Human Papillomavirus (HPV) seroprevalence, cervical HPV prevalence, genotype distribution and cytological lesions in solid organ transplant recipients and immunocompetent women in Sao Paulo, Brazil.

INTRODUCTION: Solid organ transplant (SOT) recipients are at increased risk of Human Papillomavirus (HPV) persistent infection and disease. This study aimed to evaluate HPV seroprevalence, cervical HPV prevalence, genotype distribution, and frequency of HPV-related cervical lesions in SOT recipients in comparison to immunocompetent women. METHODS: Cross-sectional study including SOT and immunocompetent women aged 18 to 45 years who denied previous HPV-related lesions. Cervical samples were screened for HPV-DNA by a polymerase chain reaction (PCR)-based DNA microarray system (PapilloCheck®) and squamous intraepithelial lesions (SIL) by liquid-based cytology. A multiplexed pseudovirion-based serology assay (PsV-Luminex) was used to measure HPV serum antibodies. RESULTS: 125 SOT and 132 immunocompetent women were enrolled. Cervical samples were collected from 113 SOT and 127 immunocompetent women who had initiated sexual activity. HPV-DNA prevalence was higher in SOT than in immunocompetent women (29.6% vs. 20.2%, p = 0.112), but this difference was not statistically significant. High-risk (HR)-HPV was significantly more frequent in SOT than in immunocompetent women (19.4% vs. 7.9%, p = 0.014). Simultaneous infection with ≥2 HR-HPV types was found in 3.1% of SOT and 0.9% of immunocompetent women. HPV seropositivity for at least one HPV type was high in both groups: 63.8% of 105 SOT and 69.7% of 119 immunocompetent women (p = 0.524). Low-grade (LSIL) and high-grade SIL (HSIL) were significantly more frequent in SOT (9.7% and 5.3%, respectively) than in immunocompetent women (1.6% and 0.8%, respectively) (p = 0.001). CONCLUSIONS: These results may reflect the increased risk of HPV persistent infection and disease progression in SOT women due to chronic immunosuppression.

Comparative accuracy of cervical cancer screening strategies in healthy asymptomatic women: a systematic review and network meta-analysis.

To compare all available accuracy data on screening strategies for identifying cervical intraepithelial neoplasia grade ≥ 2 in healthy asymptomatic women, we performed a systematic review and network meta-analysis. MEDLINE and EMBASE were searched up to October 2020 for paired-design studies of cytology and testing for high-risk genotypes of human papillomavirus (hrHPV). The methods used included a duplicate assessment of eligibility, double extraction of quantitative data, validity assessment, random-effects network meta-analysis of test accuracy, and GRADE rating. Twenty-seven prospective studies (185,269 subjects) were included. The combination of cytology (atypical squamous cells of undetermined significance or higher grades) and hrHPV testing (excepting genotyping for HPV 16 or 18 [HPV16/18]) with the either-positive criterion (OR rule) was the most sensitive/least specific, whereas the same combination with the both-positive criterion (AND rule) was the most specific/least sensitive. Compared with standalone cytology, non-HPV16/18 hrHPV assays were more sensitive/less specific. Two algorithms proposed for primary cytological testing or primary hrHPV testing were ranked in the middle as more sensitive/less specific than standalone cytology and the AND rule combinations but more specific/less sensitive than standalone hrHPV testing and the OR rule combination. Further research is needed to assess these results in population-relevant outcomes at the program level.

Development of cervical intraepithelial lesions and cervical cancer is not influenced by SOD2 RS4880 polymorhism.

Some of the more than 200 known HPV types are essential for cervical cancer development, the third type of cancer most incident in the female population. However, for the malignant transformation occur, some cofactors are needed, as the reactive oxygen species (ROS), which can be neutralized by the antioxidant system. The SOD2 enzyme, encoded by the same name gene, is found in mitochondria and is part of the first line of defense against oxidative stress damage. Genetic polymorphisms can act by altering the efficiency of the enzyme, among which the most studied is the rs4880. Thus, the purpose of the present study was to evaluate the association of this polymorphism with HPV infection and the development of low and high grade squamous intraepithelial lesions (LSIL and HSIL) and cervical cancer, in 407 women attended by the public health system in Brazil. HPV detection in cervical secretion samples was carried out by polymerase chain reaction (PCR) and blood samples were used for polymorphism genotyping through PCR followed by restriction fragment length polymorphism (RFLP). PCR and restriction products were subjected to 10% polyacrylamide gel electrophoresis. HPV negative group (control) included 158 women and the HPV positive group (case) 249 women. The infected group was divided into No Lesion (n = 90), LSIL (n = 20), HSIL (n = 67) and cervical cancer (n = 72). The data found on socio-epidemiological characteristics and habits corroborated with data found in the literature. The distribution of genotypes in the control group was 51.9% women TC, 29.8% TT and 18.3% CC. In the case group, the distribution was 55.0% women TC, 26.1% TT and 18.9% CC. This is the first study evaluating the influence of SOD2 rs4880 polymorphism on HPV infection, the development of cervical intraepithelial lesions and cervical cancer in a Brazilian population, although additional studies are needed to corroborate the results.

The Improving Risk Informed HPV Screening (IRIS) Study: Design and Baseline Characteristics.

BACKGROUND: Cervical cancer screening with high-risk human papillomavirus (HrHPV) testing is being introduced. Most HrHPV infections are transient, requiring triage tests to identify individuals at highest risk for progression to cervical cancer. Head-to-head comparisons of available strategies for screening and triage are needed. Endometrial and ovarian cancers could be amenable to similar testing. METHODS: Between 2016 and 2020, discarded cervical cancer screening specimens from women ages 25 to 65 undergoing screening at Kaiser Permanente Northern California were collected. Specimens were aliquoted, stabilized, and stored frozen. Human papillomavirus (HPV), cytology, and histopathology results as well as demographic and cofactor information were obtained from electronic medical records (EMR). Follow-up collection of specimens was conducted for 2 years, and EMR-based data collection was planned for 5 years. RESULTS: Collection of enrollment and follow-up specimens is complete, and EMR-based follow-up data collection is ongoing. At baseline, specimens were collected from 54,957 HPV-positive, 10,215 HPV-negative/Pap-positive, and 12,748 HPV-negative/Pap-negative women. Clinical history prior to baseline was available for 72.6% of individuals, of which 53.9% were undergoing routine screening, 8.6% recently had an abnormal screen, 30.3% had previous colposcopy, and 7.2% had previous treatment. As of February 2021, 55.7% had one or more colposcopies, yielding 5,563 cervical intraepithelial neoplasia grade 2 (CIN2), 2,756 cervical intraepithelial neoplasia grade 3 (CIN3), and 146 cancer histopathology diagnoses. CONCLUSIONS: This robust population-based cohort study represents all stages of cervical cancer screening, management, and posttreatment follow-up. IMPACT: The IRIS study is a unique and highly relevant resource allowing for natural history studies and rigorous evaluation of candidate HrHPV screening and triage markers, while permitting studies of biomarkers associated with other gynecologic cancers.

An Evaluation of Dose-Related HPV Vaccine Effectiveness Using Central Registries in Michigan.

BACKGROUND: Human papillomavirus (HPV) vaccine effectiveness (VE) evaluations provide important information for vaccination programs. We established a linkage between statewide central registries in Michigan to estimate HPV VE against in situ and invasive cervical lesions (CIN3+). METHODS: We linked females in Michigan's immunization and cancer registries using birth records to establish a cohort of 773,193 women with known vaccination history, of whom 3,838 were diagnosed with CIN3+. Residential address histories from a stratified random sample were used to establish a subcohort of 1,374 women without CIN3+ and 2,900 with CIN3+ among continuous Michigan residents. VE and 95% confidence intervals (CI) were estimated using cohort and case-cohort methods for up-to-date (UTD) vaccination and incomplete vaccination with 1 and 2 doses, and stratified by age at vaccination. RESULTS: Both analytic approaches demonstrated lower CIN3+ risk with UTD and non-UTD vaccination vs. no vaccination. The cohort analysis yielded VE estimates of 66% (95% CI, 60%-71%) for UTD, 33% (95% CI, 18%-46%) for 2 doses-not UTD, and 40% (95% CI, 27%-50%) for 1 dose. The case-cohort analysis yielded VE estimates of 72% (95% CI, 64%-79%) for UTD, 39% (95% CI, 10%-58%) for 2 doses-not UTD, and 48% (95% CI, 25%-63%) for 1 dose. VE was higher for vaccination at age <20 than ≥20 years. CONCLUSIONS: The statewide registry linkage found significant VE against CIN3+ with incomplete HPV vaccination, and an even higher VE with UTD vaccination. IMPACT: Future VE evaluations by number of doses for women vaccinated at younger ages may further clarify dose-related effectiveness.

Accuracy of different triage strategies for human papillomavirus positivity in an Italian screening population.

How to manage human papillomavirus (HPV)-positive women in cervical cancer screening remains debated. Our study compared different strategies to triage HPV positivity in a large cohort of women participating in a population HPV-based screening program. Women were tested for HPV (Cobas 4800; Roche), and those positive were triaged with cytology; cytology-positives were referred to colposcopy, while negatives were referred to 1-year HPV retesting. All HPV-positive women were also evaluated with p16/ki67 dual staining (Roche). All lesions found within 24 months of follow-up were included in the analyses. Of the 70 146 women tested, 4757 (6.8%) were HPV-positive. Of these, 1090 were cytology-positive and were referred to colposcopy. Of the 2958 HPV-positive/cytology-negative women who presented at 1-year retesting, 1752 (59.9%) still tested positive. Cumulatively, 532 CIN2+ (including 294 CIN3+) were found. The sensitivity of cytology, HPV16/18 and p16/ki67 as triage test for CIN3+ was 67.9%, 56.0% and 85.0%, respectively. The positive predictive value (PPV) for immediate colposcopy referral was 21.0%, 15.8% and 22.9%, respectively. Combining cytology with typing increased sensitivity to 83.9% and lowered PPV to 14.8%, while combining p16/ki67 and typing increased sensitivity to 91.1%, lowering the PPV to 15.9%. Women negative to p16/ki67 triage presented a cumulative 1-year CIN3+ risk of about 1%. In conclusion, when triaging HPV positivity, p16/ki67 performed better than cytology with or without HPV16/18 genotyping. The strategies that included dual staining achieved sensitivity and low 1-year risk for CIN3+ sufficiently high enough to permit considering extending the surveillance interval to 2 to 3 years for HPV-positive/triage-negative women.

The use of biomarkers and HPV genotyping to improve diagnostic accuracy in women with a transformation zone type 3.

BACKGROUND: Twenty percent of women referred to colposcopy have a type 3 transformation zone-where colposcopic assessment for high-grade dysplasia (CIN2+) is not possible. This study examines the effectiveness of HPV biomarkers and genotyping in combination with techniques that sample an endocervical TZ. METHODS: A prospective diagnostic accuracy study. Women booked for large-loop excision (LLETZ) with squamous dyskaryosis, high-risk HPV and a TZ3 were recruited. Immediately prior to LLETZ samples were collected for p16/Ki-67 dual-stained cytology, HPV genotyping and H&E, p16- and Ki-67-stained endocervical curettings. RESULTS: In women with low-grade screening (n = 64), 35.9% had CIN2+; dual-stained cytology had the greatest effect on the PPV of routine screening (76.1% vs 35.9%) and perfectly predicted the absence of CIN2+. In women with a high-grade screening result (n = 37); 75.6% had CIN2+ and dual-stained curettings improved the PPV (96.5 vs 75.6%). CONCLUSIONS: With high-grade screening and a TZ3, LLETZ appears safest as three quarters have CIN2+ . Women with low-grade screening and a TZ3 have a twofold increased risk of CIN2+ when compared to women where the TZ is visible. The use of dual-stained cytology may help identify those women who can be safely offered surveillance and those who require treatment.

Risk-stratification of HPV-positive women with low-grade cytology by FAM19A4/miR124-2 methylation and HPV genotyping.

BACKGROUND: The introduction of primary HPV screening has doubled the number of colposcopy referrals because of the direct referral of HPV-positive women with a borderline or mild dyskaryosis (BMD) cytology (ASC-US/LSIL) triage test. Further risk-stratification is warranted to improve the efficiency of HPV-based screening. METHODS: This study evaluated the discriminative power of FAM19A4/miR124-2 methylation, HPV16/18 genotyping and HPV16/18/31/33/45 genotyping in HPV-positive women with BMD (n = 294) in two Dutch screening trials. Absolute CIN3+ risks and colposcopy referrals within one screening round were calculated. RESULTS: Methylation analysis discriminated well, yielding a CIN3+ risk of 33.1% after a positive result and a CIN3+ risk of 9.8% after a negative result. HPV16/18 and HPV16/18/31/33/45 genotyping resulted in a 27.6% and 24.6% CIN3+ risk after a positive result, and a 13.2% and 9.1% CIN3+ risk after a negative result. Colposcopy referral percentages were 41.2%, 43.2%, and 66.3% for FAM19A4/miR124-2 methylation, HPV16/18 and HPV16/18/31/33/45 genotyping, respectively. The CIN3+ risk after a negative result could be lowered to 2.8% by combining methylation and extended genotyping, at the expense of a higher referral percentage of 75.5%. CONCLUSION: The use of FAM19A4/miR124-2 methylation and/or HPV genotyping in HPV-positive women with BMD can lead to a substantial reduction in the number of direct colposcopy referrals.

A retrospective study of cytology and HPV genotypes results of 3229 vaginal intraepithelial neoplasia patients.

To analyze the distribution of human papillomavirus (HPV) genotype, cytology, and the clinical characteristics of vaginal intraepithelial neoplasia (VaIN). All patients with histological-proven VaIN at West China Second University Hospital, between January 1, 2014, and October 1, 2020, were retrospectively identified. The demographics, medical history, HPV genotype, viral load, and cytology results were retrieved. Standard statistical analyses were conducted. Of 3229 patients included, 42.3% were diagnosed with VaIN 1, 30.3% with VaIN 2% and 27.4% with VaIN 3. Patients with VaIN 3 were the oldest (p < 0.001). The leading HPV genotypes were HPV 16, 52, 58, 53, 56 and 81. The positive rate of HPV 16 was positively correlated with the grade of VaIN and infected most VaIN 3 patients (76.0%). The sensitivities of cytology for VaIN only, concomitant VaIN, and VaIN after hysterectomy were 75.6%, 78.8%, and 82.9%, respectively (p = 0.013), and the sensitivities of HPV were 91.1%, 93.5%, and 91.7%, respectively (p = 0.205). Cotesting improved the sensitivities, up to 96.9%, 97.1%, and 98.1%, respectively. VaIN can occur alone or be concomitant with cervical or vulvar intraepithelial neoplasia. Most of those with VaIN 2/3 are infected with HPV 16. The sensitivity of cytology and HPV testing is non-inferior to that of cervical intraepithelial neoplasia 2+. Therefore, these testings might be helpful in the early detection of VaIN.