Genotype Distribution of Human Papillomaviruses & HPV E6/E7 mRNA Test for the Detection of High-Grade Cervical Intraepithelial Neoplasia (CIN2+) Among Gynecology Complaints in Northwest Ethiopia
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Date
2023-07
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Addis Ababa University
Abstract
Background: In developing nations, cervical cancer (CC) is the main cause of cancer-related
fatalities in women due to the absence of well-established vaccination and screening programs.
Exploring the best triage test for women with cervical abnormalities is a timely area of research
to advance cervical screening and management. Further, the distinct proportional impact of
each HR-HPV on the distribution of cervical lesions varies geographically. There is a shortage
of data regarding the clinical value of high-risk human papillomaviruses (HR-HPV) E6/E7
mRNA test and their molecular epidemiology in cervical samples from Ethiopia, particularly
in the current study area. Moreover, despite the fact that HR-HPV infection is an essential
biological cause of CC, other socio-demographic factors are not well studied in the nation.
Therefore, this study aimed to fill these data gaps.
Objectives: The aim of the study was to determine the HPV genotype involved in cervical
lesions, to evaluate the clinical use of HR-HPV E6/E7 mRNA for the early detection of CIN2+,
and to explore factors associated with it among gynecology complaints in northwest Ethiopia.
Methods: Between March 2019 and October 2021, a cross-sectional study was carried out at
Felege Hiwot Compressive Specialized Hospital (FHCSH). Among women who visited the
hospital for gynecological examination, those who were eligible for visual inspection (VIA)-
based screening were included. Cervical punch samples were obtained by a gynecologist for
histological analysis. Cervical swabs collected and analyzed for HR-HPV DNA and HPV
E6/E7 mRNA using the Abbott Alinity m system and real-time PCR, respectively at the
Institute of Virology, Leipzig University, Germany. Demographic and gynecologic-related
history were collected using a structured questionnaire. The distribution and frequency of HR-
HPVs described using descriptive statistics. Histology was used as the reference test to
determine how well the E6/E7 mRNA detected CIN2+.
Results: Of the 355 study participants (aged 30 to 80 years), more than half, 211 (59.4%), were
unaware of CC, and their previous cervical screening practice was approximately 25%.
Cervical biopsies from 41.8% (140/335; 95% CI: 36.6-47.1%) participants were diagnosed as
cancer. The proportion of HR-HPV was 53%(188/355; 95%CI: 47.8-58.1%), with 13 different
genotypes identified. HPV16 was predominant at 50.4% (95%CI: 29.4-39.2%), followed by
HPV31 (9.7%), HPV33 (8.5%), HPV39 and HPV68 (5.8% each), and HPV18 at 4.7%. The
iv
E6/E7 mRNA test was positive in 35.8% (127/355; 95%CI: 30.0-40.9) of cases for HPV16, 16
& 45. The proportion of positive HPV DNA test results for these three HR-HPVS was 42%
(149/355). The total agreement of DNA and mRNA tests in the detection of these HPVs was
at 92.7% (95%CI: 89.5-94.9) with a kappa value of 0.821. HPV16, at 108 (85%), was the most
common genotype expressing E6/E7 mRNA. The mRNA assay had sensitivity, specificity,
positive and negative predictive values (PPV and NPV) of 65.2% (95%CI: 57.5-72.2%), 90%
(95%CI: 84.6-93.4%), 85.8% (95%CI: 78.5-91.0%), & 73.6% (95%CI: 67.2-79.1%),
respectively for detecting histologically confirmed CIN2+. Specifically, the sensitivity and
specificity of this assay in the detection of CIN2+ were 92.7% & 47%, respectively among
HPV16, 18, & 45 DNA-positive cases. Likewise, the analytical sensitivity and specificity of
the HPV-DNA test were 84.8% & 74.1%, respectively. CC increased steadily with participant
age, with women older than 50 years about four times more likely to develop CIN2+ (AOR:
3.68 95%CI: 1.75-7.72, p < 0.001). Similarly, no cervical screening in the past five years
(AOR: 2.04; 95%CI: 1.04-4004; p = 0.038), infection with HR-HPVs (AOR: 5.28; 95%CI:
2.66-10.47; p < 0.001) and tested positive for E6/E7 mRNA (AOR: 5.78; 95%CI: 2.73-12.24,
p < 0.001) were statistically associated with CIN2+.
Conclusions: CC is still a significant issue for women's health in northwest Ethiopia that
requires evidence-based interventions. The E6/E7 mRNA test and the HPV DNA test
demonstrated good agreement and showed better diagnostic relevance in detecting CIN2+.
Therefore, the test can be considered for colposcopy and biopsy triage. In particular, the mRNA
test may be regarded as a potential triage for women who are HPV-positive , mainly in regions
with a shortage of pathologists and colposcopy facilities. Vaccination and future HPV-based
screening methods in Ethiopia should consider the important HR-HPV genotypes identified in
such studies. To better assess the HPVs circulating in northwestern Ethiopia, community-based
surveys should be conducted. Likewise, to optimize the E6/E7 mRNA analytical sensitivity
and specificity , large-scale studies targeting major HR-HPVs should be considered. Finally,
in accordance with the WHO recommendation women who are eligible for cervical screening
need to be screened with a high-precision test, including HPV-based tests.
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Keywords
Cervical cancer, CIN2+, HPV E6/E7 mRNA, HR-HPV DNA, northwest Ethiopia