The Prevalence of HPV Genotypes Detected by Cobas HPV in Cervical Samples among Unvaccinated Women from Isfahan Province, Iran

doi:10.21203/rs.3.rs-1752706/v1

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The Prevalence of HPV Genotypes Detected by Cobas HPV in Cervical Samples among Unvaccinated Women from Isfahan Province, Iran

https://doi.org/10.21203/rs.3.rs-1752706/v1

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Purpose: Human papillomavirus is suggested as a well-known risk factor for cervical cancers and nowadays, primary HPV typing is recommended as an alternative test to cervical cytology.

Methods: This cross-sectional study evaluated the liquid-based cervical smears of 700 women with no history of HPV vaccination and cervical dysplastic disease from 2017 to 2020 in Isfahan, Iran. Here, we try to compare the prevalence of HPV genotypes using COBAS (@roch) with the results of pap smear cytology in evaluating the most appropriate test for cervical cancer screening, especially in low-resource societies.

Results: The prevalence of HPV infection was 23.3%, including 8.7% with HPV 16/18 and 14.6% with other HR (high-risk) HPVs. Considering positive HPV genotypes, the frequency of HR HPV decreases in older age groups; 42.1% compared to 6.8%. In cytology reports, 8 out of 16 individuals with high-risk lesions were negative for any type of HPV; on the other hand, there were 129 HR HPV-positive patients out of 570 negative or low-risk pap smear results.

Conclusion: It assumed that there is no superiority for HPV genotyping over cytology or vice versa in detecting high-risk patients for cervical cancer; As only 26.8% of women with HPV show abnormal cytology; and from those with normal cytology, 17.9% were positive for HR HPV. Screening with one method had a rare but high risk of delay in the timely detection of cervical cancer. Above that, the high prevalence of HPV infection in unvaccinated women also reveals the need for studies on the cost-effectiveness of universal vaccination.

Human Papilloma Virus

Cobas

Cervical Cancer

screening

cervical cytology

Cervical cancer is the most common gynecological cancer in women and the fourth leading cause of cancer death in developing countries. According to the latest global statistics in 2018, 570,000 new cases and about 311,000 deaths due to cervical cancer have been recorded, with Asia having the largest share [1]. The World Health Organization (WHO) announced 917 cases of cervical cancer in Iran, more than half of which died due to advanced disease, In 2019 [2]. Unfortunately, only 48% of Iranian women have participated in cervical cancer screening, and more than half of the newly diagnosed cases are those who have not been screened [3–5]. Human papillomavirus (HPV) is the leading risk factor in developing nearly all cervical cancers [6]. It is estimated that at least half of sexually active women will be infected with HPV in their lifetime [7].

According to the WHO statistics, an increasing trend of all cancers is predicted by 2040, especially in developing countries with low screening and diagnostic resources. This adds to the importance of paying attention to cervical cancer screening programs [8].

WHO recommended two priorities for countries intending to decrease the burden of cervical cancer: Vaccination of adolescents against HPV and encouraging women to participate in screening programs [9, 10]. According to a cost-effectiveness study, the implementation of national HPV vaccination is not cost-effective in Iran [11]. As a low-middle income county, Iran falls in the category of countries with less than 30% coverage of HPV vaccination. Therefore, it is necessary to focus on screening programs and defining the most valuable and effective methods based on local situations [12].

There are two standard screening methods for cervical cancer: Pap smear test, a cytological test to find abnormal cervical cells, and HPV genotyping, which detects the HPV virus but is incapable of finding cellular changes. The 2019 American society of cancer prevention (ASCCP) guidelines suggest that HPV testing is more valuable than cytology in identifying cervical cancer [13, 14].

Iran's national screening program for cervical cancer includes a non-mandatory pap smear examination every five years for 30-50-year-old women. The cost of pap smear screening in this program is covered by basic health insurance. However, there is no governmental funding support for HPV screening.

This study examines the prevalence of the HPV infection and its genotype in unvaccinated women and compares it with cervical cytology reports in Isfahan, Iran.

This cross-sectional study evaluated the liquid-based cervical smears of 700 women with no history of HPV vaccination and cervical dysplastic disease from 2017 to 2020 in Isfahan, Iran. Gynecologists obtained smears by cytobrush and analyzed them for HPV genotyping and Pap smear in two pathology laboratory centers.

After obtaining smeared cell slides for a liquid-based cytology test, the remaining cell samples on the cytobrush were stored at room temperature for further HPV analysis. Roche COBAS® HPV test 4800 (Roche Molecular Systems, Pleasanton, CA), approved by the United States Food and Drug Administration, was used for HPV DNA typing. The COBAS® HPV test utilizes amplification of target DNA by the polymerase Chain reaction (PCR) and nucleic acid hybridization and can detect 14 high-risk HPVs. This HPV DNA testing method separately detects HPV 16 and HPV 18, and a pool of 12 other HR HPVs (31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68).

We categorize HPV genotyping results into five groups: negative, positive HPV 16, positive HPV 18, positive HPV 16 or 18 and other types, and positive for other HR HPVs. The Pap smear result was categorized as normal (including negative result, atrophy, or mild inflammation), moderate to severe inflammation, low-risk malignant cells (including Atypical Squamous Cell with Undetermined Significance (ASCUS), Low-Grade Squamous Intraepithelial Lesion (LSIL), and (HSIL)), and high-risk malignant cells (High-Grade Squamous Intraepithelial Lesion (HSIL)).

Data were analyzed using SPSS software version 22 (IBM Corp. Armonk, New York, USA). To describe continuous and categorical variables, mean (standard deviation) and frequency were used. Independent sample t-test and chi-square were used to compare continuous and categorical variables between groups. The significance level was set at 0.05.

The Ethics Committee of Isfahan University of Medical Sciences approved this study (IR.MUI.MED.REC.1399.1047).

This cross-sectional study included 700 cervical smear specimens from 700 healthy women. The mean (± SD) age of the study population was 37.3 (± 8.62), of which 19 (47.1%) were under 25 years old, and 4 (0.6%) were above 65 years old.

The Prevalence of HPV infection was 23.3%, including 8.7% with HPV 16 and/ or 18 and 14.6% with other HR HPVs. The distribution of HPV genotypes in the study population and age groups is provided in Table 1. Considering positive HPV genotypes, the frequency of HR HPV decreases in older age groups; 42.1% of women under 25 years old and only 6.8% of women in the age group of 55–64 years old were positive for HR HPVs (supplementary Fig. 1).

From 700 samples in our study, 586 samples were also examined for cytology, in which malignant cervical cells, including ASCUS, LSIL, and HSIL, were reported in 113 (19.3%) cases. HPV was detected in 18.8% of patients with normal cytology and 23.5% of those with moderate to severe inflammation. The HPV prevalence in low-risk and high-risk individuals was 32.0% and 50.0%, respectively. The Prevalence of other HR HPVs in all Pap smear categories except the high-risk category is higher than the Prevalence of HPV 16 or 18. In cytology reports, 16 individuals were reported as HSIL, from which eight individuals were negative for any types of HPV; four of them were positive for HPV 16, one for HPV 18, and two for other HR HPVs (Table 2).

In the age group of 25–34 years old, the Prevalence of HPV in three groups of negative, low-risk, and high-risk cytology was 26.3%, 34.2%, and 71.4%, respectively (p-value, 0.02). Details on the Prevalence of HPV in different cytology categories are presented in Table 3.

Table 1

Distribution of HPV genotypes based on age categories
	Whole sample N = 700	Age group N (%)
	Whole sample N = 700	under 25 N = 19	25–34 N = 291	35–44 N = 248	45–54 N = 109	55–64 N = 29	65 and higher N = 4
Negative	537 (76.7)	11 (57.9)	214 (73.5)	189 (76.2)	92 (84.4)	27 (93.1)	4 (100)
HPV 16 or 18 with or without other types	61 (8.7)	2 (10.5)	27 (9.3)	21 (8.5)	10 (9.2)	1 (3.4)	0
Other high-risk HPVs	102 (14.6)	6 (31.6)	50 (17.2)	38 (15.3)	7 (6.4)	1 (3.4)	0

Table 2

Distribution of HPV genotypes based on cervical cytology reports
Pap smear reports	Total n = 586	HPV genotypes					p-value
Pap smear reports	Total n = 586	negative	HPV 16	HPV 18	HPV 16 or 18 and other	Other types	p-value
NL (mild inflammation or negative or atrophy)	112 (19.1)	91 (81.3)	0.01	0	4 (3.6)	9 (8.0)	0.01
moderate to severe inflammation	361 (61.6)	276 (76.5)	12 (3.3)	0	14 (3.9)	59 (16.3)
Low-risk malignant cells (ASCUS, LSIL)	97 (16.6)	66 (68.0)	6 (6.2)	0	6 (6.2)	19 (19.6)
High-risk malignant cells (HSIL)	16 (2.7)	8 (50.0)	4 (25.0)	1 (6.3)	1 (6.3)	2 (12.5)

Table 3

Prevalence of HPV in different cytology categories based on age groups
	Age categories	Pap smear reports
	Age categories	Negative for malignant cells (normal, inflammation, or atrophy)	Low-risk malignant cell (ASCUS, LSIL)	High-risk malignant cells (HSIL)	p-value
Hpv genotype	under 25 yo				0.3
	Negative	5 (45.5)	5 (71.4)	-
	Positive	6 (54.5)	2 (28.6)	-
	25–34 yo				0.02
	Negative	143 (73.7)	25 (65.8)	2 (28.6)
	Positive	51 (26.3)	13 (34.2)	5 (71.4)
	35–44 yo				0.1
	Negative	133 (78.2)	21 (63.6)	5 (71.4)
	Positive	37 (21.8)	12 (36.4)	2 (28.6)
	45–54 yo				0.03
	Negative	66 (86.8)	11 (73.3)	-
	Positive	10 (13.2)	4 (26.7)	1 (100)
	55–64 yo				0.5
	Negative	18 (90)	3 (100)	-
	Positive	2 (10)	-	-
	65 yo and above				-
	Negative	2 (100)	1 (100)	1 (100)
	Positive	-	-	-

Cervical cancer is the leading cause of young age mortality in Asian countries. Declining the incidence and mortality of cervical cancer is a global goal that could achieve by manipulating HPV infection persistence, as the leading risk factor, by using effective screening or vaccination [12]. According to the last cancer epidemiologic reports in Iran, the estimated incidence rate of cervical cancer infection and mortality is about 2.3 and 1.2 in 100000, respectively. Although the rate of infection is almost low, the mortality rate is significant [12, 15–18]. It is of great importance to consider the report of Karimi et al. about the high rate of cervical cancer detection in non-screened females in approximately 80% of cases [19]. There are limited epidemiological studies investigating the accurate prevalence of different HPV types in the Iranian population, which is necessary for planning the most appropriate preventive and screening program based on the patterns of HPV subtypes prevalence.

The results of COBAS-HPV genotyping show that 23.3% of unvaccinated women were infected by HR HPV. Based on the results of our study, there is no superiority for HPV genotyping over cytology or vice versa in detecting high-risk patients for cervical cancer; As only 26.8% of women with HPV show abnormal cytology; and from those with normal cytology, 17.9% were positive for HPV 16 or 18.

Screening with one method had a rare but high risk of delay in the timely detection of cervical cancer [20]. In our study, high-grade dysplasia was detected in 50% of women with a negative HPV test. This percent is unneglectable as they would be missed if only HPV genotyping was done. Though not all cases of HSIL would develop into cervical cancer, the rapid progression potential of these lesions has been confirmed and require a timely and aggressive approach [21].

In this regard, a Turkish study revealed the presence of some unclassified HPV infections in patients with abnormal cytology. At the same time, numerous cases of positive HR HPV with normal cytology were detected [22]. Interestingly, Wolday et al. confirmed the presence of HPV infection in all of the abnormal pap smears and in nearly 49% of cases with a normal Pap smear compared to 18.8% in the present study. They had tested not only HR HPV types but also some other probable HR HPV genotypes based on the IARC study [23, 24]. Yuan et al. showed the presence of HPV infection in only 13.5% of patients with any abnormal cytology, although they did not differentiate between low and high-risk cytology [25]. The study of Kovacevic et al. demonstrated the possibility of high-grade lesions despite normal HPV. It concluded that there is no guarantee for detecting all high-risk patients with a single screening method. They also find a probable correlation between other types of HPV, even the noncarcinogenic subtypes, with cancer progression [26].

Based on a study by Meloni et al., the rate of HPV infection among women with cytological diagnosis of ASCUS, LSIL, and HSIL was 37.3%, 60.1%, and 57.9%, respectively. In our study, the rate of HPV infection was 18.8% in normal pap smears, 32% in low-risk abnormalities (ASCUS, LSIL), and 50% in the HSIL group. Other studies show no significant difference in the frequency of HPV infection based on cytology results [27]. In the present study, we found a high rate of HR HPV in patients with moderate to severe inflammation (23.5%). Other studies reported that the Prevalence of HPV infection in those with abnormal cytology is higher than in those with normal cytology [28–30]. It is not suggested to triage patients with persistent inflammation in pap smear with the HPV test, and there is an absolute need to exclude pre-malignant pathology with colposcopic evaluation [31].

The present study demonstrated a higher proportion of HPV infection among patients under 35 years old, mostly younger than 25 years old, which shows the need for an educational program on sexually transmitted diseases. Although cervical cancer is not considered one of the most common cancers in our province, there is a significant transition in HPV prevalence throughout the country due to changes in lifestyle behavior and socioeconomic factors [32].

Although the investigational study by the COBAS method considers one of the most valid methods of detecting high-risk HPV, especially in the primary setting, it does not permit recognition of non-HPV16 and 18 subtypes, which restricts the authors of the present study from analyzing the most prevalent subtype in infected cases. According to the International Agency for Research on Cancer (IARC) classification, there are twelve HPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59) with "carcinogenic potential to humans," which is the basic knowledge to introducing the present high-risk HPV testing. However, recently, there has been some evidence on additional "possibly cancer-causing HPV types" (HPV 26, 53, 66, 67, 70, 73, 82 30, 34, 69, 85, 97) and several other unclassified HPVs [26], which bring a question on replacing pap smear screening with HPV typing. Based on our findings, the most prevalent subtype among infected cases with high-risk HPV was other HR HPVs with or without HPV 16 or 18. Although this finding was in line with the results of another study in North Iran [33], it was inconsistent with two studies of other provinces that showed HPV genotypes 18 and 53 as the most dominant subtypes [34, 35]. This difference could be due to the sampling method and the study population. Our population's most common HPV genotypes were HPV16 in women with HSIL and other HR HPVs in low-risk cases (ASCUS and LSIL).

Although Iran is not one of the 70 countries that have a national HPV immunization program for girls, based on the present study and the high Prevalence of HPV at young ages, a national study to evaluate the cost-effectiveness of HPV vaccination and integration of this vaccine in the national vaccination program is recommended.

In conclusion, the results of COBAS-HPV genotyping show that 23.3% of unvaccinated women were infected by HR HPV%, including 8.7% with HPV 16 and/ or 18 and 14.6% with other HR HPVs. Based on the results of our study, there is no superiority for HPV genotyping over cytology or vice versa in detecting high-risk patients for cervical cancer; As only 26.8% of women with HPV show abnormal cytology; and from those with normal cytology, 17.9% were positive for HPV 16 or 18. Screening with one method had a rare but high risk of delay in the timely detection of cervical cancer and using molecular methods and routine Pap smear tests simultaneously has more value in detecting high-risk patients for cervical cancer.

The high prevalence of HPV infection in unvaccinated women also reveals the need for studies on other prevention programs such as universal vaccination.

ASCCP: American society of cancer prevention guidelines,

ASCUS: Atypical Squamous Cell with Undetermined Significance,

HSIL: High-Grade Squamous Intraepithelial Lesion,

HR: High-risk,

HPV: Human papillomavirus,

LSIL: Low-Grade Squamous Intraepithelial Lesion,

PCR: Polymerase Chain reaction,

WHO: World Health Organization.

Ethics approval: This study was reviewed and approved by the Ethics Committee of Isfahan University of Medical Sciences (Grant No: IR.MUI.MED.REC.1399.1047). Informed consent was also obtained from all subjects. All methods were carried out in accordance with relevant guidelines and regulations.
Consent for publication: Not applicable.
Availability of data and materials: All data generated or analyzed during this study are included in this published article [and its supplementary information files].
Competing interests: The authors declare that there have no competing interests.
Funding: Not applicable.
Authors' contributions: LMS, AZ, MS, FB conceived and designed the evaluation and drafted the manuscript. LMS, AZ, MS, AV participated in designing the evaluation, performed parts of the statistical analysis and helped to draft the manuscript. LMS, AV, AZ, MS re-evaluated the clinical data, revised the manuscript and performed the statistical analysis and revised the manuscript. LMS, AZ, MS. collected the clinical data, interpreted them and revised the manuscript. AV, LMS, FB re-analyzed the clinical and statistical data and revised the manuscript. All authors read and approved the final manuscript.
Acknowledgements: We would also like to show our gratitude to Parvin Rajabi(MD), professor of pathology, Isfahan university of medical science, Isfahan, Iran and Mohammadreza Azizi (DCLD), the head of research center, Erythron, pathobiology institute, Isfahan, Iran for sharing their pearls of wisdom with us during the course of this research, although any errors are our own and should not tarnish the reputations of these esteemed persons
Authors' information: LMS and AV had conducted prior study on HPV prevelance, cost-effectivness of HPV vaccination in low-resources countries like Iran, and the baseline microbiology of HPV. AZ and FB had worked on cervical cancer screening validity in Iran. LMS, AZ, FB and AV are assistant professor, full professor, and researcher in Isfahan medical university of Iran. MS works as a researcher and MD. pathologist in the clinical pathology department of Erythron laboratory which is equipped with a COBAS PCR system in Isfahan, Iran.

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No competing interests reported.

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The Prevalence of HPV Genotypes Detected by Cobas HPV in Cervical Samples among Unvaccinated Women from Isfahan Province, Iran

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