Primary HPV-based Cervical Cancer Screening Algorithms in Botswana

NCT04242823Active, Not RecruitingNAINTERVENTIONAL

Summary

Primary high-risk human papillomavirus (HPV) testing has become first line screening for cervical cancer in high-income countries. The feasibility of this approach in low- and middle-income countries (LMICs) is less clear, as is the role of HPV testing among women living with human immunodeficiency virus (HIV). The proposed study seeks to evaluate the accuracy of cervical cancer screening algorithms using primary HPV testing followed by various forms of visual evaluation, including visual inspection with acetic acid (VIA), colposcopy and automated visual evaluation (AVE) for the detection of high-grade cervical dysplasia, using histology as the gold standard. We will validate the AmpFire Assay for HPV self-sampling in our setting. We will determine safe screening intervals in women living with HIV (WLHIV) in an HPV-based cervical cancer screening program and compare triage strategies for positive HPV results at WHO recommended screening intervals for WLHIV. We also seek to understand in-depth the attitudes, acceptability and preferences regarding cervical cancer screening, HPV testing, and self-sampling, for women in Botswana through interviews of a sub-set of women recruited for the cervical cancer screening study. Finally, we will analyze the cost of two-stage cervical cancer screening algorithms using high-risk HPV testing in Botswana.

Key Facts

Lead Sponsor

Beth Israel Deaconess Medical Center

Enrollment

3000

Start Date

2021-02-22

Completion Date

2026-12-31

Study Type

INTERVENTIONAL

Official Title

Performance of Two-stage Cervical Cancer Screening Algorithms Using Primary High-risk Human Papillomavirus Testing in Botswana

Interventions

8-type HPV genotype restriction

Conditions

Cervical CancerPrevention

Eligibility

Age Range

25 Years – 100 Years

Sex

FEMALE

Inclusion Criteria:

1. Cis-gender female or transgender male (must have a cervix)
2. ≥25 years of age
3. Competent to understand study procedures and give informed consent.

Exclusion Criteria:

1. Currently pregnant (as diagnostic procedures for cervical cancer are often deferred during pregnancy)
2. Previous hysterectomy
3. Previous diagnosis of cervical cancer

Outcome Measures

Primary Outcomes

Compare the sensitivity, specificity, PPV and NPV of triage of primary human papillomavirus testing with 8-type HPV genotype restriction to visual inspection with acetic acid and colposcopy

Time frame: 3 years

Determine the persistence of HPV infection in WLHIV at the pre-specified follow-up interval

Time frame: 5 years

Determine the clearance of HPV infection in WLHIV at the pre-specified follow-up interval

Time frame: 5 years

Determine the incidence of HPV infection in WLHIV at the pre-specified follow-up interval

Time frame: 5 years

Quantify the incidence of cervical intraepithelial lesion grade 3 or worse in women living with HIV who were baseline HPV positive but with benign pathology at 2 year interval screening

Time frame: 5 years

Quantify the incidence of cervical intraepithelial lesion grade 3 or worse in women living with HIV who were baseline HPV negative at 3 year interval screening

Time frame: 5 years

Analyze the cost of two-stage cervical cancer screening algorithms using high-risk HPV testing in Botswana.

Time frame: 5 years

Secondary Outcomes

Understand in-depth the attitudes, acceptability and preferences regarding cervical cancer screening, HPV testing, and self-sampling, for women in Botswana through interviews of a sub-set of women recruited for the cervical cancer screening study.

Time frame: 6 years

Evaluate the performance of a novel HPV assay as a stand-alone screening tool in our high-prevalence HIV population

Time frame: 3 years

Evaluate the impact of patient demographic and clinical factors, such as number of sexual partners, smoking, HIV status and related HIV immune markers, on risk of cervical dysplasia

Time frame: 5 years

Evaluate the impact of patient characteristics and and risk factors on the risk for cervical disease

Time frame: 5 years

Locations

Bamalete Lutheran Hospital, Ramotswa, Botswana

Linked Papers

2024-10-29

High-grade cervical disease and cervical cancer in women aged 50 years and older compared with younger women: examining prevalence by HIV status in two large prospective cohorts in Botswana

Objectives International guidelines recommend cervical screening cessation at age 50 following two consecutive negative screens. However, many women aged 50 and older in low-income and middle-income countries (LMICs) have not had prior opportunity to screen. We examine the prevalence of cervical dysplasia and cervical cancer stage in Botswana women aged 50+ compared with 30–49, stratified by HIV status. Design Secondary analysis of data from two prospective cohort studies. Setting The screening cohort was recruited at health facilities in South East District. The cancer cohort was recruited from the primary public tertiary referral hospital and a private hospital in Gaborone, Botswana. Participants The screening cohort included 2570 women aged 30 and older recruited from February 2021 to August 2022. Screening eligibility included anyone with a cervix and without a prior history of cervical cancer. The cancer cohort included 1520 patients diagnosed with cervical cancer who sought care at the facilities where recruitment took place from January 2015 to December 2022. Primary and secondary outcome measures The prevalence of cervical intraepithelial neoplasia (CIN)2+ and cancer stage at diagnosis was compared across age groups, stratified by HIV status. Prevalence ratios were calculated for the association between age and CIN2+/CIN3+via log-binomial regression. Results The prevalence of CIN2+ was similar between 30–49 years old and 50+, both among women with HIV (WWH, 15.9% and 19.3%, respectively) and without HIV (13.3% and 10.4%, respectively). Similar findings were found when CIN3+ was used as the outcome. There were no statistically significant differences in prevalence ratios (PRs) across age groups for CIN2+ (adjusted PR (aPR) WWH 1.1 (95% CI 0.80 to 1.6); aPR HIV− 0.78 (95% CI 0.45 to 1.4) nor CIN3+ (aPR WWH 1.1 (95% CI 0.70 to 1.6); aPR HIV− 0.81 (95% CI 0.40 to 1.7)). Nearly half of cervical cancer diagnoses were made in women 50+; three-quarters of cases in women without HIV were diagnosed at 50+ years. Conclusions Our findings demonstrate the prevalence of high-grade cervical dysplasia and cervical cancer remains high beyond age 50 in both women with and without HIV in an LMIC context with high HIV prevalence. Screening women 50+ will allow treatment for cervical dysplasia and may provide early diagnosis of curable cervical cancer. These findings support the rapid introduction of high-performance cervical screening to increase access for women 50+. Trial registration number NCT04242823.

2023-11-10

Triage of HPV positivity in a high HIV prevalence setting: A prospective cohort study comparing visual triage methods and HPV genotype restriction in Botswana

AbstractObjectiveGuidelines for effective triage following positive primary high‐risk human papillomavirus (HPV) screening in low‐ and middle‐income countries with high human immunodeficiency virus (HIV)‐prevalence have not previously been established. In the present study, we evaluated the performance of three triage methods for positive HPV results in women living with HIV (WLHIV) and without HIV in Botswana.MethodsWe conducted baseline enrollment of a prospective cohort study from February 2021 to August 2022 in South‐East District, Botswana. Non‐pregnant women aged 25 or older with an intact cervix and no prior diagnosis of cervical cancer were systematically consented for enrollment, with enrichment of the cohort for WLHIV. Those who consented completed a questionnaire and then collected vaginal self‐samples for HPV testing. Primary HPV testing for 15 individual genotypes was conducted using Atila AmpFire® HPV assay. Those with positive HPV results returned for a triage visit where all underwent visual inspection with acetic acid (VIA), colposcopy, and biopsy. Triage strategies with VIA, colposcopy and 8‐type HPV genotype restriction (16/18/31/33/35/45/52/58), separately and in combination, were compared using histopathology as the gold standard in diagnosing cervical intraepithelial neoplasia (CIN) 2 or worse (CIN2+).ResultsAmong 2969 women enrolled, 1480 (50%) tested HPV positive. The cohort included 1478 (50%) WLHIV; 99% were virologically suppressed after a mean of 8 years on antiretroviral therapy. In total, 1269 (86%) women had histopathology data for analysis. Among WLHIV who tested positive for HPV, 131 (19%) of 688 had CIN2+ compared with 71 (12%) of 581 in women without HIV. Screening by 8‐type HPV genotype restriction was more sensitive as triage to detect CIN2+ in WLHIV 87.79% (95% CI: 80.92–92.85) and women without HIV 85.92% (95% CI: 75.62–93.03) when compared with VIA (WLHIV 62.31% [95% CI: 53.39–70.65], women without HIV 44.29% [95% CI: 32.41–56.66]) and colposcopy (WLHIV 70.77% [95% CI: 62.15–78.41], women without HIV 45.71% [95% CI: 33.74–58.06]). However, 8‐type HPV genotype restriction had low specificity in WLHIV of 30.88% (95% CI: 27.06–34.90) and women without HIV 37.06% (95% CI: 32.85–41.41). These results were similar when CIN3+ was used as the outcome. When combining 8‐type HPV genotype restriction with VIA as the triage strategy, there was improved specificity to detect CIN2+ in WLHIV of 81.65% (95% CI: 78.18–84.79) but dramatically reduced sensitivity of 56.15% (95% CI: 47.18–64.84).ConclusionsEight‐type HPV genotype restriction is a promising component of effective triage for HPV positivity. However, novel triage strategies in LMICs with high HIV prevalence may be needed to avoid the trade‐off between sensitivity and specificity with currently available options.Clinical trials registrationThis study is registered on Clinicaltrials.gov no. NCT04242823, https://clinicaltrials.gov/ct2/show/NCT04242823.

Linked Investigators

Bessie X Zhang

Matthys H. Botha

Gynecological oncology

Rebecca Luckett