Periodic Reporting for period 1 - MEsHH (DNA MEthylation for HPV-related disease among women living with HIV)
Reporting period: 2018-09-05 to 2020-09-04
Women living with human immunodeficiency virus (WLHIV) have an increased risk of cervical cancer and precancer. The majority of WLHIV live in low- and middle-income countries where access to cervical cancer screening, and treatment of precancerous cervical lesions is limited. Cervical cancer screening strategies have previously shown variable sensitivity (visual inspection methods) or low specificity (HPV-DNA based tests) for the detection of cervical precancer among WLHIV. Novel strategies are required to more effectively screen WLHIV with or without an effective triage strategy without resulting in unnecessary referrals. The precise diagnostic accuracy of various cervical cancer screening strategies in WLHIV remains uncertain and varies widely across studies.
The aim of the MEsHH study was to evaluate novel cervical cancer screening strategies, including DNA methylation assays compared to other existing cervical cancer screening methods, including visual inspection, cervical cytology and HPV DNA for detection of cervical precancer among a cohort of WLHIV in Sub-Saharan Africa. Secondary objectives were to gain an understanding on how HIV disease progression (measured using ART status and CD4+ count) impacts the diagnostic accuracy of cervical cancer screening strategies.
The aim of the MEsHH study was to evaluate novel cervical cancer screening strategies, including DNA methylation assays compared to other existing cervical cancer screening methods, including visual inspection, cervical cytology and HPV DNA for detection of cervical precancer among a cohort of WLHIV in Sub-Saharan Africa. Secondary objectives were to gain an understanding on how HIV disease progression (measured using ART status and CD4+ count) impacts the diagnostic accuracy of cervical cancer screening strategies.
A DNA methylation approach using HPV16 was evaluated in 151 HPV16 positive WLHIV in Burkina Faso and South Africa enrolled in the HPV in Africa Research Partnership study. HPV16 infection was common in WLHIV with and without precancer, although prevalence of precancer was higher in women with HPV16 infection compared to those without HPV16 infection. DNA methylation of HPV16 L1/L2 genes did not distinguish women with and without cervical precancer, but HPV16 viral load was significantly higher in women with precancer compared to those without. In this study, HPV16 viral load (E6/E7) test had higher diagnostic accuracy to detect cervical precancer in women with HPV16 infection, compared to DNA methylation of HPV16.
To address the secondary objective, several meta-analyses were conducted during this study to evaluate the diagnostic accuracy of current and novel cervical cancer screening strategies in women living with HIV. In a meta-analysis of the diagnostic accuracy of cervical cancer screening strategies in WLHIV including 31 studies and 17,676 WLHIV which evaluated screen strategies (VIA, HPV-DNA tests, cervical cytology) and screen-triage (VIA, cytology, HPV16/18 genotyping in HPV positive women) strategies for precancer, VIA had variable sensitivity and specificity for precancer due to heterogeneity in study design and training and experience of operators. Less variability was observed for HPV-DNA based tests which had high sensitivity for precancer but low specificity which is possibly a reflection of the high prevalence of non-clinically relevant HR-HPV infections, thereby suggesting the need for a triage test for HPV positive women. Modifications to HPV tests to increase threshold for test positivity as well as restricted genotype approach increased specificity. In a separate meta-analysis of the evidence on diagnostic accuracy of currently available DNA methylation assays for precancer, 16,336 women in 43 studies provided data on the mostly studied human genes (CADM1, MAL, MIR-124-2, FAM19A4, POU4F3, EPB41L3, PAX1, SOX1) and HPV genotypes (HPV16 L1/L2 genes). Most (81%) studies evaluated methylation assays following a high-risk (HR)-HPV-positive or abnormal cytology result. As a triage test, DNA methylation has higher specificity than cervical cytology and higher sensitivity than HPV16/18 genotyping.
To address the secondary objective, several meta-analyses were conducted during this study to evaluate the diagnostic accuracy of current and novel cervical cancer screening strategies in women living with HIV. In a meta-analysis of the diagnostic accuracy of cervical cancer screening strategies in WLHIV including 31 studies and 17,676 WLHIV which evaluated screen strategies (VIA, HPV-DNA tests, cervical cytology) and screen-triage (VIA, cytology, HPV16/18 genotyping in HPV positive women) strategies for precancer, VIA had variable sensitivity and specificity for precancer due to heterogeneity in study design and training and experience of operators. Less variability was observed for HPV-DNA based tests which had high sensitivity for precancer but low specificity which is possibly a reflection of the high prevalence of non-clinically relevant HR-HPV infections, thereby suggesting the need for a triage test for HPV positive women. Modifications to HPV tests to increase threshold for test positivity as well as restricted genotype approach increased specificity. In a separate meta-analysis of the evidence on diagnostic accuracy of currently available DNA methylation assays for precancer, 16,336 women in 43 studies provided data on the mostly studied human genes (CADM1, MAL, MIR-124-2, FAM19A4, POU4F3, EPB41L3, PAX1, SOX1) and HPV genotypes (HPV16 L1/L2 genes). Most (81%) studies evaluated methylation assays following a high-risk (HR)-HPV-positive or abnormal cytology result. As a triage test, DNA methylation has higher specificity than cervical cytology and higher sensitivity than HPV16/18 genotyping.
This data will contribute to the evidence on choice of screening strategies for detection of cervical precancer among WLHIV in low- and middle-income setting. The research findings will create an awareness of magnitude of the problem of cervical cancer among WLHIV populations, and the need, importance and limitations of current screening modalities, in addition to the possible incorporation of more novel screening approaches, including DNA methylation assays in national cervical cancer screening guidelines if shown to be effective in future studies. Molecular based strategies can play an important role in cervical cancer screening, especially in the universal ART era and in COVID-19 era where options for self-sampling will facilitate screening participation.