Point-of-care testing with Xpert HPV for single-visit, screen-and-treat for cervical cancer prevention: a demonstration study in South Africa.

Human papillomavirus (HPV)-based screen-and-treat (SAT) is recommended but implementation presents operational challenges. We implemented HPV-SAT at a research site in Khayelitsha, South Africa, screening 3062 women aged 30-65 years (44% women living with HIV [WHIV]). All were screened using point-of-care Xpert HPV and almost all received their HPV results on the same day. HPV-positivity occurred in 41.5% of WHIV and 17.4% of women without HIV (WNoH) reducing to 26.2% in WHIV and 10.4% in WNoH applying treatment eligibility criteria based on high viral load in the channels detecting HPV16, 18, 45, 16, 18, 31, 33, 35, 52, 58. Among those eligible for treatment, 91.3% were considered suitable for ablative therapy, and 94.6% underwent thermal ablation on the same day, with no serious adverse events. Twelve months later, 39.0% of WHIV and 65.2% of WNoH treated with ablative therapy were clear of HPV. In women who were HPV-positive but ineligible for treatment, 19.1% and 12.9% had histologically-confirmed cervical intraepithelial neoplasia grade 2 or worse (CIN2+) at 12 months. SAT programs need to weigh trade-offs between overtreatment versus delayed or no treatment for women who test positive for HPV. Treatment modalities for precancerous lesions need to be improved.

Clinical Utility of Reflex Testing with Cancer Biomarkers to Improve Diagnostic Accuracy of Primary Human Papillomavirus Screening.

BACKGROUND: Human papillomavirus (HPV) testing is the cornerstone of cervical cancer screening, with outstanding sensitivity but only moderate specificity. We evaluated whether reflex testing for cancer biomarkers improves the sensitivity/specificity balance of screening. METHODS: Cervical samples from women in Cape Town, South Africa, ages 30-65 years, were collected and tested with Xpert HPV and with real-time PCR to detect mRNA for cyclin-dependent kinase inhibitor 2A (CDKN2A), topoisomerase 2 alpha (TOP2A), and Ki67 (MKi67). Women with histologically confirmed cervical intraepithelial neoplasia grade 2 or worse (CIN2+; 85 women without and 166 with HIV) and women with no cervical disease (331 without and 257 with HIV) were included. RESULTS: When used as reflex tests after a positive HPV result, biomarkers discriminated well between women with and without CIN2+. The inclusion of both CDKN2A and MKi67 had the best performance, with area under the curve (AUC) of 0.9171 and 0.8734 in women without and with HIV, respectively. Although excellent, these performance parameters did not improve on an approach utilizing only HPV testing with more stringent cycle threshold cutoffs and HPV genotype selection, which achieved AUC of 0.9059 and 0.8705 in women without and with HIV, respectively. CONCLUSIONS: Biomarkers can be used as triage after positive HPV results but do not outperform an approach utilizing higher viral load cutoffs on selected high-risk genotypes. IMPACT: A screening approach using HPV testing alone can be more easily implemented at the point of care.

Assessment of the implementation context in preparation for a clinical study of machine-learning algorithms to automate the classification of digital cervical images for cervical cancer screening in resource-constrained settings.

Introduction: We assessed the implementation context and image quality in preparation for a clinical study evaluating the effectiveness of automated visual assessment devices within cervical cancer screening of women living without and with HIV. Methods: We developed a semi-structured questionnaire based on three Consolidated Framework for Implementation Research (CFIR) domains; intervention characteristics, inner setting, and process, in Cape Town, South Africa. Between December 1, 2020, and August 6, 2021, we evaluated two devices: MobileODT handheld colposcope; and a commercially-available cell phone (Samsung A21ST). Colposcopists visually inspected cervical images for technical adequacy. Descriptive analyses were tabulated for quantitative variables, and narrative responses were summarized in the text. Results: Two colposcopists described the devices as easy to operate, without data loss. The clinical workspace and gynecological workflow were modified to incorporate devices and manage images. Providers believed either device would likely perform better than cytology under most circumstances unless the squamocolumnar junction (SCJ) were not visible, in which case cytology was expected to be better. Image quality (N = 75) from the MobileODT device and cell phone was comparable in terms of achieving good focus (81% vs. 84%), obtaining visibility of the squamous columnar junction (88% vs. 97%), avoiding occlusion (79% vs. 87%), and detection of lesion and range of lesion includes the upper limit (63% vs. 53%) but differed in taking photographs free of glare (100% vs. 24%). Conclusion: Novel application of the CFIR early in the conduct of the clinical study, including assessment of image quality, highlight real-world factors about intervention characteristics, inner clinical setting, and workflow process that may affect both the clinical study findings and ultimate pace of translating to clinical practice. The application and augmentation of the CFIR in this study context highlighted adaptations needed for the framework to better measure factors relevant to implementing digital interventions.

Performance of Xpert HPV on Self-collected Vaginal Samples for Cervical Cancer Screening Among Women in South Africa.

OBJECTIVES: Self-sampling may increase access to cervical cancer screening in low-resource settings. Using Xpert HPV, we compared test performance of self- and clinician-collected samples in HIV-positive and HIV-negative women in South Africa. MATERIALS AND METHODS: Three hundred thirty HIV-positive and 375 HIV-negative women in the screening group and 202 HIV-negative and 200 HIV-positive women in the referral group, aged 30-65 years, participated in the study. All women self-collected a vaginal sample, and then, a cervical sample was collected by a clinician (both tested using Xpert HPV), followed by colposcopic examination and collection of histologic specimens. RESULTS: There was good agreement between self- and clinician-collected samples for detection of any high-risk human papillomavirus (HPV, κ = 0.72 [95% CI = 0.669-0.771]). Prevalence of HPV and sensitivity of the test to detect cervical intraepithelial neoplasia 2+ was similar in self- and clinician-collected samples. Specificity was lower in self-collected than in clinician-collected samples in both HIV-negative (self: 77.5% [95% CI = 72.8-81.8] vs clinician: 86.9% [95% CI = 82.9-90.2]) and HIV-positive (self: 44.0% [95% CI = 38.0-50.1] vs clinician: 59.7% [95% CI = 53.6-65.6]) women. Restricting the definition of screen-positive to 3 of 5 channels on HPV Xpert improved specificity in both HIV-negative (self: 83.2% [95% CI = 78.8-87.0] vs clinician: 89.7% [95% CI = 86.1-92.7]) and HIV-positive (self: 54.2% [95% CI = 48.1-60.2] vs clinician: 67.4% [95% CI = 61.5-72.9]) women. CONCLUSIONS: The self-collected sample had good agreement with the clinician-collected sample for the detection of HPV, and restricting the HPV types may improve the specificity in HIV-positive women.

Selecting human papillomavirus genotypes to optimize the performance of screening tests among South African women.

Human papillomavirus (HPV) testing is highly sensitive compared to cytology, with the trade-off of being less specific. We investigated whether select combinations of HPV genotypes, ascertained by Linear Array (LA) and Xpert HPV (GX), can optimize sensitivity/specificity trade-offs to detect high-grade cervical intraepithelial neoplasia (CIN2+). In a study in Cape Town, South Africa, 586 women living without and 535 living with HIV, aged 30-65 years, were recruited. Each woman underwent a pelvic exam to collect cervical samples (tested by LA and GX for 14 high-risk HPV genotypes) and underwent colposcopy with histological sampling to determine CIN2+. In multivariable logistic regression of LA results, only HPV genotypes 16, 18, 31, 33, 35, 52, 58 were significantly associated with CIN2+ (P < .05). Xpert includes these seven types along with HPV 45 within three of the test's five channels and we defined these eight types as restricted genotyping (ie 16, 18, 31, 33, 35, 45, 52, 58). Full genotyping was defined as all 14 high-risk types. Sensitivity estimates for full genotyping using LA were similar to that of restricted genotyping: 83.9% (full) vs 79.0% (restricted) in women without HIV and 93.0% (full) vs 88.9% (restricted) in women living with HIV. Specificity estimates improved for restricted vs full genotyping: 87.4% (full) vs 90.8% (restricted) in women without HIV and 63.7% (full) vs 71.4% (restricted) in women living with HIV. To optimize the performance of HPV testing for cervical cancer screening in high-burden, under-resourced settings like South Africa, only HPV 16, 18, 31, 33, 35, 45, 52, 58 could be included to define screen-positive. We recommend the inclusion of HPV45 for its known link to adenocarcinoma.

Clinical evaluation of modifications to a human papillomavirus assay to optimise its utility for cervical cancer screening in low-resource settings: a diagnostic accuracy study.

BACKGROUND: HPV-based screen and treat is the recommended approach for cervical cancer screening in low-resource settings, but quite low specificity of human papillomavirus (HPV) testing, particularly in women living with HIV, leads to overtreatment. We evaluated whether HPV type restriction and more stringent cutoffs on Xpert HPV optimise performance characteristics of this assay for screen and treat. METHODS: We recruited HIV-negative and HIV-positive women aged 30-65 years from a primary care facility and a referral colposcopy clinic in Cape Town, South Africa. Women included had no history of any anogenital cancer or treatment for cervical dysplasia, had no hysterectomy, and were not pregnancy at the time of recruitment. All women had cervical samples collected for Xpert HPV (an assay that detects high-risk HPV types in five channels: HPV type 16; HPV types 18 or 45, or both; HPV types 31, 33, 35, 52, or 58, or more than one of these types; HPV types 51 or 59, or both; and HPV types 39, 56, 66, or 68, or more than one of these types) and underwent colposcopy and histological sampling with consensus pathology review. Logistic regression and receiver operating characteristic curves were used to evaluate improvements in specificity attained by modifying cycle threshold cutoffs to define screen-positive results. RESULTS: We recruited 1121 women aged 30-65 years, 586 of whom were HIV-negative and 535 HIV-positive. Sensitivity of detecting cervical intraepithelial neoplasia grade 2 or greater in HIV-negative women using manufacturer-defined cycle threshold cutoffs for all channels was 88·7% (95% CI 83·1-94·3), and specificity was 86·9% (83·4-90·4). Sensitivity was 93·6% (90·0-97·3) and specificity 59·9% (54·1-65·7) in HIV-positive women. Cycle threshold values from channels detecting HPV type 16, HPV types 18 or 45 (or both), and HPV types 31, 33, 35, 52, or 58 (or more than one of these types) were informative to predict cervical intraepithelial neoplasia grade 2 or greater. Shifting cycle threshold cutoffs on these three channels allowing sensitivity to decline to 75-85%, led to specificities of 91·3-95·3% in HIV-negative women and 77·0-85·8% in HIV-positive women. INTERPRETATION: More stringent cycle threshold cutoffs on selected channels in Xpert HPV improve specificity with only modest losses in sensitivity, making this assay an optimal choice for HPV-based screen and treat in settings with a high prevalence of HIV. These modifications can be made from standard output with no need for new engineering. Decision making about performance characteristics of HPV testing can be shifted to programme implementers and cutoffs selected according to resource availability and community preferences. FUNDING: Supported by the National Cancer Institute UH2/3 CA189908.

Psychosexual health in gynecologic cancer.

More people are living with the long-term effects of cancer owing to improvements in cancer treatments and an aging population. Many people diagnosed with cancer report a negative impact on sexual identity, sexual functioning, and their sexual relationship. Gynecologic cancer survivors are often the most severely affected. These cancers involve cancers of the ovaries, uterus, cervix, vagina, and vulva. The impact of these cancers on sexual health results not only from the disease process itself, but may also be due to the necessary treatments required. These can have a profound impact on psychological, physiological, and social well-being both in the short and long term, which may result in negative impact on the quality of life of the patient as well as her partner. Although most patients express that they would like to be more informed about sexual health and would like to have the opportunity to discuss these issues with their therapeutic team, sexual health is often not discussed with the patient.

Human papillomavirus infection and cervical disease in human immunodeficiency virus-1-infected women.

OBJECTIVE: To report on the natural history of high-risk human papillomavirus (HPV) infection and cervical disease in human immunodeficiency virus (HIV)-1-infected women living in Cape Town, South Africa. METHODS: This was a prospective study of 400 untreated, HIV-1-infected women who underwent high-risk HPV DNA testing, cytology, colposcopy, histology, and CD4 count testing every 6 months for 36 months. Human immunodeficiency virus viral loads and HPV type distribution were determined at entry and after 18 months. RESULTS: Sixty-eight percent of the women were high-risk HPV DNA positive at entry, 35% had a cytologic diagnosis of low-grade squamous intraepithelial lesion (LSIL), and 13% had high-grade squamous intraepithelial lesion (HSIL). There were no cancers. Abnormal cytology and high-risk HPV positivity were strongly correlated with low CD4 counts and high HIV viral loads. The most prevalent types of HPV were HPV-16, -52, -53, -35, and -18. Incident high-risk HPV infection occurred in 22%, and of those infected with high-risk HPV, 94% of infections persisted over an 18-month period, and 6% cleared their infections. Cytologic progression to SIL from normal/atypical squamous cells of undetermined significance cytology occurred in 17% of cases, but only 4% of cases of LSIL progressed to HSIL. CONCLUSION: There is a high level of high-risk HPV infection in HIV-1 infected women, but progression to HSIL over 36 months occurred in the minority of cases. We recommend an initial colposcopy for an abnormal test, and if no high-grade lesion is identified, triennial screening would be appropriate. Human papillomavirus type 16 was the commonest, and HPV-18 was the fifth commonest, suggesting that vaccination against these two types would have a significant effect. LEVEL OF EVIDENCE: II.