Effectiveness of self-sampling human papillomavirus test on precancer detection and screening uptake in Japan: The ACCESS randomized controlled trial.

Japan is lagging in cervical cancer prevention. The effectiveness of a self-sampling human papillomavirus (HPV) test, a possible measure to overcome this situation, has not yet been evaluated. A randomized controlled trial was performed to evaluate the effectiveness of a self-sampling HPV test on detection of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and screening uptake. Women between 30 and 58 years old who did not participate in the cervical cancer screening program for ≥3 years were eligible and assigned to the intervention group (cytology or self-sampling HPV test) or control group (cytology). Participants assigned to the intervention group were sent a self-sampling kit according to their ordering (opt-in strategy). A total of 7337 and 7772 women were assigned to the intervention and control groups, respectively. Screening uptake in the intervention group was significantly higher than that in the control group (20.0% vs. 6.4%; risk ratio: 3.10; 95% confidence interval [CI]: 2.82, 3.42). The compliance rate with cytology triage for HPV-positive women was 46.8% (95% CI: 35.5%, 58.4%). CIN2+ was detected in five and four participants in the intervention and control groups, respectively; there was no difference for intention-to-screen analysis (risk ratio: 1.32; 95% CI: 0.36, 4.93). Self-sampling of HPV test increased screening uptake; however, no difference was observed in the detection of CIN2+, probably due to the low compliance rate for cytology triage in HPV-positive women. Efforts to increase cytology triage are essential to maximize precancer detections.

Cost-effectiveness analysis of alternative screening strategies for the detection of cervical cancer among women in rural areas of Western Kenya.

While the incidence of cervical cancer has dropped in high-income countries due to organized cytology-based screening programs, it remains the leading cause of cancer death among women in Eastern Africa. Therefore, the World Health Organization (WHO) now urges providers to transition from widely prevalent but low-performance visual inspection with acetic acid (VIA) screening to primary human papillomavirus (HPV) DNA testing. Due to high HPV prevalence, effective triage tests are needed to identify those lesions likely to progress and so avoid over-treatment. To identify the optimal cost-effective strategy, we compared the VIA screen-and-treat approach to primary HPV DNA testing with p16/Ki67 dual-stain cytology or VIA as triage. We used a Markov model to calculate the budget impact of each strategy with incremental quality-adjusted life years and incremental cost-effectiveness ratios (ICER) as the main outcome. Deterministic cost-effectiveness analyses show that the screen-and-treat approach is highly cost-effective (ICER 2469 Int$), while screen, triage, and treat with dual staining is the most effective with favorable ICER than triage with VIA (ICER 9943 Int$ compared with 13,177 Int$). One-way sensitivity analyses show that the results are most sensitive to discounting, VIA performance, and test prices. In the probabilistic sensitivity analyses, the triage option using dual stain is the optimal choice above a willingness to pay threshold of 7115 Int$ being cost-effective as per WHO standards. The result of our analysis favors the use of dual staining over VIA as triage in HPV-positive women and portends future opportunities and necessary research to improve the coverage and acceptability of cervical cancer screening programs.

Cervical cancer screening program in Indonesia: is it time for HPV-DNA tests? Results of a qualitative study exploring the stakeholders' perspectives.

OBJECTIVES: Cervical cancer is a significant public health concern in Indonesia, and effective screening methods are necessary to improve the detection and reduce mortality. This study aimed to explore the perspectives of high-level stakeholders involved in cervical cancer screening in Indonesia and whether the use of human papillomavirus-deoxyribonucleic acid (HPV-DNA) methods for cervical cancer screening is acceptable in Indonesian settings. METHODS: A qualitative research approach guided by realist evaluation was applied using focus group discussions (FGDs) between December 2021 and February 2022, conducted with stakeholders involved in cervical cancer screening in Indonesia. They were representatives of practitioners and policymakers involved in the screening, and were recruited through purposive recruitment. The data were analysed using inductive approach of thematic analysis. RESULTS: The analysis of two FGDs with 29 participants identified four main themes: (i) Visual inspection with acetic acid (VIA) method as the most common modality used for cervical cancer screening, (ii) the applied screening programs in the community, (iii) the perceived challenges on the screening program, such as limitations of the National Health Insurance benefits package and a lack of regulations regarding screening procedures, and (iv) the possibilities of HPV-DNA testing as another modality for cervical cancer screening. Incorporating HPV-DNA testing also needs to ensure the capacity of the workers and the readiness of healthcare facilities. CONCLUSION: Although HPV-DNA testing is a promising modality, challenges on the cervical cancer screening in Indonesia remain on the coverage, accessibility of the tools in practice and the women's awareness towards the screening. Ultimately, the findings of this study would help inform policies to improve cervical cancer screening programs in Indonesia.

Joint detection of multiple HPV-testing technologies and evaluation of clinicopathological characteristics discriminate between HPV-independent and low-copy HPV-associated cervical squamous cell carcinoma (CSCC) -an analysis of 3869 cases.

OBJECTIVES: This study aimed to investigate the frequency and clinicopathological characteristics of HPV-independent cervical squamous cell carcinoma (CSCC). METHODS: A total of 3869 patients with CSCC from 2017 to 2021 were searched. p16INK4a immunochemistry (IHC), two HPV-DNA(L1) polymerase chain reactions and HPV mRNA in situ hybridization were performed. Viral copies were detected using the 21 HPV quantitative test. RESULTS: Six cases showed negative results in all four assays (group 1, 0.16%). Twenty-seven cases showed discordant results (group 2), and 3836 cases presented all-positive results (group 3). p16INK4a IHC showed similar sensitivity, specificity, and positive predictive value compared to the other three direct HPV assays. 21 HPV genotyping showed 100% of negative predictive value. HPV copies were extremely lower in Group 2 than in Group 3 (P < 0.01), but were not significantly different from those in Group 1. Older age, advanced FIGO stage (III-IV) and abnormal p53 (p53abn) IHC were independent predictors of HPV-negative status in univariate and multivariate logistic regression. Group 2 had similar proportions of age >60 years and p53abn IHC with Group 1, but had fewer cases with advanced FIGO stage (P < 0.05) and TILs (P < 0.05). Groups 1 and 2 had worse disease-free survival (DFS) and disease-specific survival (DSS) than Group 3 (P < 0.01), while no significant difference was found between these two groups. HPV-negative status was a risk factor for both DFS (P < 0.05) and DSS (P < 0.01) in univariate but not multivariate Cox regression. CONCLUSIONS: Joint detection of multiple technologies and evaluation of clinicopathological characteristics discriminate between HPV-independent and low-copy HPV-associated CSCC cases that present similar prognoses. Additional attention should be paid to these low-copy HPV-associated cases in clinical practice.

Incorporating HPV 33 and cytology into HPV 16/18 screening may be feasible. A cross-sectional study.

PURPOSE: The distribution of human papillomavirus (HPV) varies geographically, and each country is making its screening and vaccination program. This study questioned the need for colposcopy for HPV types other than HPV 16 and 18, and the need for cytology incorporated into HPV testing. METHODS: 1043 consecutive patients referred for colposcopy are included in this retrospective study. Logistic regression analysis, ANOVA, and Pearson's correlation were used for statistical analysis. The value of p < 0.05 was considered statistically significant. RESULTS: HPV 16 was the most common HPV type referred, followed by HPV 18, 52, 51, and 31, respectively. HPV 16 tends to be positive in younger patients than other HPV types (p < 0.05). Only HPV 16 (OR: 1.41, 1.06-1.88 95% CI) and HPV 33 (OR: 2.23; 1.06-4.64 95% CI) (p < 0.05) had significant prediction for CIN 2 + lesions. In patients with only a cytological abnormality, cytological abnormality with single other high-risk (hr) HPV (without HPV 16 or 18) or double other hrHPV positivity but without HPV 16 and 18 infections, we detected 159 (19%) CIN 2 + lesions. CONCLUSION: HPV 33 may be implemented in hrHPV screening protocols for direct colposcopy referral as well as HPV 16 and HPV 18 in specific regions. If we had opted for HPV-based screening only for HPV 16 and 18 without cytology, 19% of all CIN 2 + lesions would have been missed. HPV-based screening only with HPV 16 and 18 may not be feasible. Nonavalent vaccines should be considered for the vaccination of specific populations.

Presence of Human Papillomavirus DNA in Malignant Neoplasia and Non-Malignant Breast Disease.

Breast cancer is the leading cause of cancer death among women worldwide. Multiple extrinsic and intrinsic factors are associated with this disease's development. Various research groups worldwide have reported the presence of human papillomavirus (HPV) DNA in samples of malignant breast tumors. Although its role in mammary carcinogenesis is not fully understood, it is known that the HPV genome, once inserted into host cells, has oncogenic capabilities. The present study aimed to detect the presence of HPV DNA in 116 breast tissue biopsies and classify them according to their histology. It was found that 50.9% of the breast biopsies analyzed were malignant neoplasms, of which 74.6% were histologically classified as infiltrating ductal carcinoma. In biopsies with non-malignant breast disease, fibroadenoma was the most common benign neoplasm (39.1%). Detection of HPV DNA was performed through nested PCR using the external primer MY09/11 and the internal primer GP5+/6+. A hybridization assay genotyped HPV. HPV DNA was identified in 20.3% (12/59) of malignant neoplasms and 35% non-malignant breast disease (16/46). It was also detected in 27.3% (3/11) of breast tissue biopsies without alteration. However, there are no statistically significant differences between these groups and the existence of HPV DNA (p = 0.2521). Its presence was more frequent in non-malignant alterations than in malignant neoplasias. The most frequent genotypes in the HPV-positive samples were low-risk (LR) HPV-42 followed by high-risk (HR) HPV-31.

A unique Levey-Jennings control chart used for internal quality control in human papillomavirus detection.

OBJECTIVE: The purpose of this study was to provide an updated estimate of the prevalences of different types of human papillomavirus (HPV) in females in Chaoshan District and to establish an internal quality control (IQC) method for excluding false-positive results in HPV detection by using the Levey-Jennings control chart. METHOD: HPV types were detected in 23,762 cervical samples by using PCR membrane hybridization. The means and standard deviations (SDs) of the positive rates were calculated, the Levey-Jennings chart was plotted, and the rules for "out of control" and "warning" were established. A set of standardized IQC for HPV DNA tests was developed based on the values and Levey-Jennings charts. RESULT: In 466 batches, the positive rate exceeded the 1 + 2SD rule 24 times, but there was no consecutive exceedance, which was considered "in control". When the positive rate exceeded the 1 + 3SD rule 8 times with consecutive exceedance, it was considered "out of control". Further examination revealed that detections showing "out of control" had an undesirable random error, indicating that contamination may occur due to improper operation. CONCLUSION: This unique Levey-Jennings control chart is a practical method for eliminating false-positive results in HPV DNA detection and should be widely applicable in molecular diagnostic laboratories.

Accuracy of high-risk HPV DNA PCR, p16(INK4a) immunohistochemistry or the combination of both to diagnose HPV-driven oropharyngeal cancer.

BACKGROUND: The incidence of high-risk human papillomavirus (hrHPV)-driven head and neck squamous cell carcinoma, in particular oropharyngeal cancers (OPC), is increasing in high-resource countries. Patients with HPV-induced cancer respond better to treatment and consequently have lower case-fatality rates than patients with HPV-unrelated OPC. These considerations highlight the importance of reliable and accurate markers to diagnose truly HPV-induced OPC. METHODS: The accuracy of three possible test strategies, i.e. (a) hrHPV DNA PCR (DNA), (b) p16(INK4a) immunohistochemistry (IHC) (p16), and (c) the combination of both tests (considering joint DNA and p16 positivity as positivity criterion), was analysed in tissue samples from 99 Belgian OPC patients enrolled in the HPV-AHEAD study. Presence of HPV E6*I mRNA (mRNA) was considered as the reference, indicating HPV etiology. RESULTS: Ninety-nine OPC patients were included, for which the positivity rates were 36.4%, 34.0% and 28.9% for DNA, p16 and mRNA, respectively. Ninety-five OPC patients had valid test results for all three tests (DNA, p16 and mRNA). Using mRNA status as the reference, DNA testing showed 100% (28/28) sensitivity, and 92.5% (62/67) specificity for the detection of HPV-driven cancer. p16 was 96.4% (27/28) sensitive and equally specific (92.5%; 62/67). The sensitivity and specificity of combined p16 + DNA testing was 96.4% (27/28) and 97.0% (65/67), respectively. In this series, p16 alone and combined p16 + DNA missed 1 in 28 HPV driven cancers, but p16 alone misclassified 5 in 67 non-HPV driven as positive, whereas combined testing would misclassify only 2 in 67. CONCLUSIONS: Single hrHPV DNA PCR and p16(INK4a) IHC are highly sensitive but less specific than using combined testing to diagnose HPV-driven OPC patients. Disease prognostication can be encouraged based on this combined test result.

Comparison of self-collected versus clinician collected cervicovaginal specimens for detection of high risk human papillomavirus among HIV infected women in Ethiopia.

BACKGROUND: In order to meet the WHO 2030 cervical cancer elimination program, evaluation and utilization of sensitive testing method, and feasible sampling technique is a paradigm for enhancing cervical cancer screening coverage. Self-sampling for screening of HPV DNA testing is one of the easiest and sensitive techniques, though the evidence was limited in the Ethiopian context. This study aimed to compare the performance of self-collected vaginal specimen versus clinician collected cervical specimen for detection of HPV among HIV positive women in Ethiopia. METHODS: We conducted a comparative cross-sectional study design to collect cervicovaginal specimens among HIV positive women of age older than 24 years. Data were collected from six government hospitals from January to October 2021. A total of 994 cervicovaginal specimens was collected by clinicians and HIV positive women themselves in the cervical cancer screening unit using Abbott Cervi-Collect Specimen Collection Kit, and molecular HPV testing was conducted. Data were entered into an Excel spreadsheet and analyzed using SPSS version 25. Sensitivity, specificity and kappa were reported with p < 0.05 considered as statistically significant. RESULTS: The prevalence of high-risk HPV was 29.4% among self-sampled specimen and 23.9% among clinician collected specimens. The overall concordance of the test result was 87.3%. Oncogenic HPV types, other than HPV16&18 were predominant in both sampling techniques, 19.9% from vaginal self-collected specimen and 16.7% of clinician collected cervical specimens. The sensitivity and specificity of self-sampled HPV test was 84.0% and 88.4%, respectively. The level of agreement was good (k = 0.68) and statistically significant (p < 0.001). The discriminatory power of the test as true positive and negative was excellent with an area under the curve of 0.86. CONCLUSION: The magnitude of oncogenic HPV was higher in self-collected samples than the clinician collected specimen with good agreement between the two sampling methods. Thus, we recommend the Ministry of Health in Ethiopia to expand utilization of the self-sampled technique and enhance the coverage of screening in the country.

Acceptability, simplicity, and relevance of the new human papillomavirus/DNA test among 35-year-old ever-married women in a district of Sri Lanka: focus group discussions.

BACKGROUND: Two major drawbacks of the present cervical cancer screening programme in Sri Lanka are, the suboptimal sensitivity of the pap smear and the low coverage. The sensitivity of the HPV/DNA screening test is high. The objective of the study was to explore the acceptability relevance and simplicity of the new HPV/DNA screening implementation among ever-married women in a district of Sri Lanka. METHODS: Focus group discussions (FGD) (n = 3) in the public health divisions of the Kalutara district were used to collect data during December 2018. The study population comprised of ever-married women 35 years old, who, carried out an HPV/DNA test at a community Well Woman Clinics (WWCs) (n = 89). A list of WWCs was prepared according to an alphabetical order under urban, rural, and estate sector categories and allocated a number. One WWC was selected from each sector randomly for the three FGDs representing the estate, rural, and urban clinics. A convenient sampling technique was used to select participants for each FGD (n = 8). The information collected at each interview was summarized at the end of each interview. The analysis was done with manual content. RESULTS: Most of the participants were Sinhalese (n = 17, 70.9%), Buddhist (n = 18, n = 75%), and non-working (n = 18, n = 75%). The community awareness of HPV/DNA screening and field staff performance were highly appreciated by most of the participants. Most were aware of the high sensitivity of the HPV/DNA test, therefore the early detection rate of cervical cancer precursors is high. Most of the participants expressed the HPV/DNA test as a convenient and neutral test. Most were mentioned the necessity of repeated clinic visits for the pap test and colposcopy in HPV/DNA screened positive follow-up but there was marked acceptability (n = 23, 95.8%) for HPV/DNA test. CONCLUSIONS: Acceptability of the new HPV/DNA screening test was high. Most of the participants perceived the HPV/DNA test to be simple and also relevant. Therefore, the HPV/DNA screening test can be recommended to be incorporated into the National Cervical Cancer Screening Programme as its suitability was well explored in the Sri Lankan setting.