2-stage Cervical Cancer Screening in Botswana

Study Overview
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Brief Summary
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Cervical cancer is the leading cause of cancer death among women in Botswana. The burden of cervical cancer is largely related to the high prevalence of HIV in Botswana (22%), as HIV is known to be a significant risk factor for cervical cancer. Cervical cancer screening is life-saving and has been shown to reduce cervical cancer incidence in multiple settings. Yet, there is no consensus on appropriate screening algorithms for women living with HIV, across resource settings. Botswana is in a unique position, relative to its neighbors in Sub-Saharan Africa, in that there exists capacity for advanced screening modalities, including primary high risk human papilloma virus (hrHPV) testing and cytology-based screening. To address this issue, this study seeks to evaluate two-stage cervical cancer screening algorithms for women living with HIV in Botswana using hrHPV testing. The protocols include hrHPV testing followed by Pap Smear evaluation, VIA and colposcopy. These same participants will be invited back at one-year for cervical cancer screening using hrHPV testing (followed by triage testing) in order to inform guidelines on the frequency of HPV testing in women living with HIV. The evidence generated will be critical to guiding cervical cancer screening in HIV-infected women across resource settings.

Detailed Description
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Cervical cancer screening programs vary across settings and there is no clear guidance for effective screening programs for HIV-positive women. Evaluating the performance of algorithms that include human papillomavirus (HPV) DNA testing as first stage screening in high HIV prevalence settings like Botswana is essential for establishing an evidence-based strategy for cervical cancer screening in HIV-positive women. This study seeks to evaluate the performance of two-stage cervical cancer screening algorithms using primary HPV testing in women living with HIV in Botswana. Second stage screening modalities include Papanicolaou (Pap) smear, visual inspection with acetic acid (VIA) and colposcopy. The study will enroll 300 HIV positive women. For all 300 participants, gynecologic speculum exam will be performed and provider-collected cervical swabs will be collected for HPV testing and Pap smear preparation. HPV testing will be performed with either the commercially-available Cepheid Xpert® HPV Assay or a high throughput PCR platform. Pap smear will be prepared using standard technique at the site of collection. Participants who test HPV-negative will have their Pap smear sent to the National Health Lab (NHL) for staining and pathologist evaluation. If the Pap smear is abnormal, they will be referred to colposcopy per current Botswana Cervical Cancer Prevention Guidelines. Participants who test HPV-positive will also have their Pap smear reviewed, and will also be asked to return for colposcopy and will undergo further diagnosis and treatment for cervical cancer per national guidelines. At the colposcopy visit, a trained nurse will conduct VIA using the Botswana standard protocol. After application of acetic acid to the cervix, the nurse will record visual results as positive or negative. If VIA is positive based on assessment of the lesion(s), the nurse will record a recommendation for either cryotherapy or loop electrosurgical excision procedure (LEEP). Since all of these HPV-positive participants will undergo colposcopy, the participants will not be informed of the VIA results, as neither cryotherapy nor LEEP will be administered based on the VIA results. Rather, the participants will proceed to colposcopy and results of colposcopy will determine further diagnosis and treatment. This design enables us to assess the utility of the two-stage algorithms while providing the highest-quality follow-up to cervical cancer screening abnormalities in Botswana. These same participants will be invited back at one-year for repeat cervical cancer screening using the same screening methods as at baseline. The data will inform guidelines on the frequency of hrHPV testing in women living with HIV.

Official Title
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Development of a Two-stage Cervical Cancer Screening Algorithm for Botswana

Conditions
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Cervical Cancer, HIV/AIDS

Intervention / Treatment
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* Diagnostic Test: 2-stage screen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥25 years of age HIV-positive Competent to understand study procedures and give informed consent. Exclusion Criteria: Currently pregnant Currently menstruating or having persistent vaginal discharge Previous hysterectomy Previous diagnosis of cervical cancer

Ages Eligible for Study
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Minimum Age: 25 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Interventional Model Description: Prospective cohort
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 2-stage screen<br>All patients will be enrolled in the two-stage cervical cancer screening protocol | Diagnostic Test: 2-stage screen<br>* Pap smear is currently the standard of care for cervical cancer screening in Botswana. In this study, participants will undergo HPV DNA testing at the time of Pap smear collection. If HPV DNA test is positive, they will be referred for colposcopy. Patients who have an HPV negative test but positive Pap smear will be referred for colposcopy per Botswana cervical cancer screening guidelines.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Performance of HPV-Pap screening algorithm | Measurement of the sensitivity, specificity and positive predictive value of Pap smear in predicting cervical precancer and cancer in HPV positive, HIV positive women. | 2 months | 
| Performance of HPV-VIA screening algorithm | Measurement of the sensitivity, specificity and positive predictive value of VIA in predicting cervical precancer and cancer in HPV positive, HIV positive women. | 2 months | 
| Performance of HPV-Colposcopy screening algorithm | Measurement of the sensitivity, specificity and positive predictive value of Colposcopy in predicting cervical precancer and cancer in HPV positive, HIV positive women. | 6 months | 
| Incident and persistent HPV infection at one-year follow-up |  | 18 months | 
| Incidence, persistence and progression of histopathologic abnormality at one-year follow-up |  | 18 months |