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HPV E6/E7 mRNA test for the detection of high grade cervical intraepithelial neoplasia (CIN2+): a systematic review

HPV E6/E7 mRNA test for the detection of high grade cervical intraepithelial neoplasia (CIN2+): a... Background: Genital infection with certain types of Human papillomavirus (HPV) is a major cause of cervical cancer globally. For early detection of premalignant dysplasia, evidences are coming out on the usefulness of HPV E6/E7 mRNA test as a potential tool compared with cytology and HPV DNA testing. Taking into account shortage of compiled data on this field, the aim of this systematic review was to describe the latest diagnostic performance of HPV E6/E7 mRNA testing to detect high grade cervical lesions (CIN2+) where by histology was taken as a gold standard. Methods: Articles published in English were systematically searched using key words from PubMed/Medline and SCOPUS. In addition, Google Scholar and the Google database were searched manually for grey literature. Two reviewers independently assessed study eligibility, risk of bias and extracted the data. We performed a descriptive presentation of the performance of E6/E7 mRNA test (in terms of sensitivity, specificity, negative and positive predictive values) for the detection of CIN2 + . Results: Out of 231 applicable citations, we have included 29 articles that included a total of 23,576 study participants (age range, 15–84 years) who had different cervical pathologies. Among the participants who had cervical histology, the proportion of CIN2+ was between 10.6 and 90.6%. Using histology as a gold standard, 11 studies evaluated the PreTect HPV Proofer, 7 studies evaluated the APTIMA HPV assay (Gen-Probe) and 6 studies evaluated the Quantivirus® HPV assay. The diagnostic performance of these three most common mRNA testing tools to detect CIN2+ was; 1) PreTect Proofer; median sensitivity 83%, specificity 73%, PPV 70 and NPV 88.9%. 2) APTIMA assay; median sensitivity 91.4%, specificity 46.2%, PPV 34.3% and NPV 96.3%. 3) Quantivirus®: median sensitivity 86.1%, specificity 54.6%, PPV 54.3% and NPV was at 89.3%. Further, the area under the receiver operating characteristics (AU-ROC) curve varied between 63.8 and 90.9%. Conclusions: The reported diagnostic accuracy implies that HPV mRNA based tests possess diagnostic relevance to detect CIN2+ and could potentially be considered in areas where there is no histology facility. Further studies including its cost should be considered. Keywords: HPV E6/E7 mRNA test, Diagnostic performance, CIN2+ * Correspondence: awoke.derbie@bdu.edu.et Department of Medical Microbiology, College of Medicine and Health Sciences, Bahir Dar University, Bahir Dar, Ethiopia Centre for Innovative Drug Development and Therapeutic Trials for Africa (CDT-Africa), Addis Ababa University, Addis Ababa, Ethiopia Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Derbie et al. Infectious Agents and Cancer (2020) 15:9 Page 2 of 10 Background high grade cervical lesion (CIN2+) enabling detection of According to the Global Cancer Statistics report of the the HPV infection and simultaneously predicting the year 2018, cervical cancer ranks 4th for both incidence change of cervical lesions [32–40]. This is because con- and mortality with over 570,000 cases and 311,000 tinuous expression of E6/E7 oncogenes of HR-HPVs is deaths worldwide [1]. The global burden of cervical can- necessary for the development and maintenance of the cer (close to 85%) occurs in developing countries, where dysplastic phenotype [41]. it accounts for about 12% of all female cancers [1, 2]; It is known that the synergistic effect of the E6 and E7 and nine out of ten cervical cancer deaths disproportion- proteins results in a disturbance of cell cycle regulation, ately occur in developing countries [3–9]. apoptosis prevention, and the transformation and main- About 95–99% of cervical cancer cases are associated tenance of neoplastic and dysplastic cells [42]. The over- with genital infection with High risk (HR)-HPV, which is expression of the E6 and E7 proteins, which inactivate the most common viral infection of the reproductive tract the p53 and pRB respectively, can be detected by testing globally [10, 11] that most women are experiencing soon for the E6/E7 mRNA transcripts which is a potential after they become sexually active [12]. Persistent infection biomarker (proxy indicator) for an increased risk of dis- with HR-HPV is the primary cause of cervical cancer and ease progression to the level of cancer [43–46]. The E6/ its precursor lesion, called the cervical intraepithelial E7 mRNA test can therefore help in avoiding aggressive neoplasia (CIN) [13, 14]. Next to cervical cancer, the HR- procedures (biopsies and over-referral of transient HPV HPV has also been linked to a large proportion of other infections) as well as lowering patient’s anxiety and the kinds of cancers (anus, vulva, vagina and penis) and a follow-up period as well [34]. growing number of head and neck tumors [15–19]. So far, The detection of HR-HPV E6/E7 mRNA is being > 150 different HPVs have been characterized and com- tested as the potential biomarker to elucidate the onco- pletely sequenced. Of all types, about 40 are sexually genic role of HPV in cancer of the cervix and other kind transmitted and infect the genitalia [17, 20–23]. HPV of tumors in general [30, 35, 36, 39, 40, 42]. However, types 16 and 18 are notably responsible for > 70% of all there is quite limited systematically reviewed data on the cervical cancer cases worldwide [15, 24, 25]. diagnostic role of different HPV E6/E7 mRNA tests for Cervical cancer is curable if detected at its early stage. detection of CIN2+, using histology as a gold standard Premature detection cervical lesion is valuable as it de- test. Specifically, the test performance of Aptima, Quan- velops slowly preceding cervical cancer which typically tivirus and PreTect Proofer was assessed. The two tests takes over a period 10 years [26]. These precursor lesions (Aptima, Quantivirus) are able to detect the E6/7 mRNA called the cervical intraepithelial neoplasia (CINs) could from the same 14 HPV types, however, one of these tests be detected by a variety of methods [27]; the most fre- (Aptima) is FDA approved and has a number of publica- quently used one is cytology, but there are other alterna- tions in the literature, whereas the other one (Quanti- tive methods such as HPV DNA tests and visual virus) has no clinical population based study published inspection with acetic acid (VIA) [15], the latter being so far and only few entries in the web. The third test practiced primarily in resource limited settings [15]. (PreTect Proofer) is only able to detect the E6/7 mRNA However, cytology and HPV-DNA based tests are widely of five HPV types. available in most developed nations [28, 29]. HPV DNA testing is being introduced in some countries as an ad- Main text junct to cytology (‘co-testing’) or as the primary screen- Methods ing test to be followed by a secondary test such as Protocol registration cytology or measurement of HR-HPV E6/E7 gene prod- In accordance with the PRISMA guidelines, our sys- ucts [15, 30, 31]. tematic review protocol was submitted to the Inter- Getting tools with reasonable diagnostic performance national Prospective Register of Systematic Reviews remains a challenge in the fight against cervical cancer (PROSPERO) and registered with a registration num- globally. Given the inadequacy of existent methods, plus ber ‘CRD42019123382’. limitations in the use of both cytology and HPV DNA test (including but not limited to the sensitivity/specifi- Eligibility criteria city issues and the inability to indicate the risk of pro- Studies were selected based on the following criteria; gression to cancer), there has long been interest in the Study design: we considered observational quantitative development of new screening tools in cervical cancer studies, like cross-sectional and cohort studies that re- [28, 29]. Many discovery approaches to find HPV associ- ported the diagnostic performance of HPV E6/E7 mRNA ated cervical cancer screening biomarkers are currently assays for the detection of CIN2+. (CIN2+ refers to: his- underway, of which the HR-HPV E6/E7 mRNA test is a tologically confirmed high grade lesions (CIN2, CIN3 promising non-invasive biomarker for the detection of and cancer)). Participants: We included studies that Derbie et al. Infectious Agents and Cancer (2020) 15:9 Page 3 of 10 included women (cervical sample) having different kinds studies of diagnostic test accuracy was independently of cervical pathology. Language and publication:we used by the first two authors. Of the twelve criterion of included peer-reviewed journal articles published in the tool, we eliminated three items because we felt that English in the period of 2011 to 14 Jan 2019 with the their scoring is difficult and rating the items would be outcome of interest reported in different countries. more of subjective. Assessment of quality results was categorized but not summarized into a score as the Information sources and search strategy method has little validity [48]. This review was done following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Proto- Data synthesis col (PRISMA) guideline [47]. Research papers were sys- The extracted data were fed into a Microsoft Excel and tematically searched in PubMed/Medline and SCOPUS presented in terms of 1) CIN profile of the study sub- using key words by combing using Boolean operator. jects, 2) the proportion of CIN2+, 3) the proportion of Manual search from Google scholar and Google data- mRNA test result 4) diagnostic performance of mRNA bases was also performed for grey literature; the last test to detect CIN2+ (sensitivity, specificity, PPV and search was done on 14th of Jan, 2019. The reference NPV). Owing to the presence of a large amount of clin- lists of retrieved articles were probed (forward and back ical heterogeneity of the included articles and as most of ward searching) to identify articles that were not re- the papers didn’t present the 2 × 2 table, pooling of the trieved from databases and our manual search. The first diagnostic performance of mRNA tests was not possible. two authors; AD and DM searched the articles Instead, we performed a descriptive presentation of these independently. elements (using range) to compile a best evidence syn- The domains of the search terms were Human Papillo- thesis for E6/E7 mRNA HPV testing in the detection of maviruses, HPV, E6/E7 mRNA, and Cervical Intraepithe- CIN2+. A systematic narrative synthesis was provided in lial Neoplasia. We combined Human Papillomaviruses which summary results were presented using text, table and HPV with the Boolean operator “OR”, and the result and figures. Descriptive statistics, such as: simple counts, was combined with the other terms with “AND”. Full ranges and percentages were used to describe the search strategy for the two databases is annexed in findings. Additional file 1. Results Study selection Search results Research papers that reported the type of HPV E6/E7 From the systematically searched databases and other mRNA diagnostic performance for the detection of sources, a total of 231 articles were retrieved and CIN2+ were included. Searched articles were directly sequentially screened. After removing 88 duplicates, the imported and handled using EndNote X5 citation man- 143 were screened by title then 52 were removed. Con- ager (Thomson Reuters, New York, USA). Based on the sequently, 53 were removed by abstract and 9 by full text PRISMA protocol, duplicated articles were excluded and with justifiable reasons. Finally, a total of 29 studies met the titles and abstracts of the remaining papers were our inclusion criteria. Screening was based on the screened independently for inclusion in full text evalu- PRISMA flow chart which was adapted from the ation by the first two authors. Differences between the PRISMA guidelines [49] (Fig. 1). reviewers were resolved through discussion. Characteristics of the included studies Data collection process and data items The characteristic of the included articles is summarized Data such as the name of the first author, year of publi- in (Table 1 and Table 2). The studies were reported cation, country where the study was conducted, age from 13 different countries in Europe, Asia and the group of the study participants, type of women included United States of America. We didn’t find articles re- in the study, CIN profile of the study participants, the ported in Latin America and Africa, in particular. The proportion of CIN2+, type of HPV E6/E7 mRNA test number of participants in each included study varied used, the positivity rate of the mRNA test and its diag- from 60 to 9451. Seven studies did not report the age of nostic performance (in terms of sensitivity, specificity, the study participants. The included studies employed a Positive Predictive value (PPV) and Negative Predictive total of 23,576 study participants (age range, 15–84 Value (NPV)) were extracted from the included articles. years) who had different cervical pathologies. The stud- ies were of varying methodological quality, and were Quality appraisal predominately performed in a secondary screening set- To assess the risk of bias, the Critical Appraisal Skills ting (i.e women or cervical samples were subjected to Programme (CASP) tool [48] that developed to evaluate HPV E6/E7 mRNA testing secondary to having positive Derbie et al. Infectious Agents and Cancer (2020) 15:9 Page 4 of 10 Fig. 1 The PRISMA flow diagram of literature selection cervical cytology and/or positive HPV DNA test). Simi- Risk of bias larly, diverse histological findings were reported ranging Ratings of the study quality for each of the nine domain- from normal histology to cervical cancer (Table 1). based critical appraisal skills program (CASP) [48] Among those participants who had cervical histo- criteria to make sense of a diagnostic test study are pre- logical examination, the proportion of CIN2+ was be- sented in Additional file 2. The risk of bias for each indi- tween 10.6 and 90.6%. The reported proportion of vidual domain was rated as ‘Yes’, ‘No’ or ‘Can’t tell’. The positive mRNA test varied from 10.3 to 74.2%. With re- assessment of quality results was categorized not scored gard to the type of HPV E6/E7 test methods, 11 studies otherwise. The mRNA test predictive values were not evaluated the PreTect Proofer, 7 studies evaluated the reported by Clad et al. [56]. Otherwise we felt that all APTIMA HPV assay, 6 studies evaluated the Quanti- the included studies had no major methodological virus® HPV assay and the remaining studies each evalu- uncertainties. ated Fluorescence in situ hybridization (FISH), Optimygene HR-HPV RT-qDx assay, HPV OncoTect, Diagnostic performance of HPV E6/E7 mRNA testing to RT-PCR assay based on consensus primers and real- detect CIN2+ time PCR assay. A study [50] evaluated both real-time Due to the difference in clinical presentation of subjects PCR assay and PreTect Proofer. On top of this, about 13 (considerable clinical heterogeneity of the study partici- studies compared HPV E6/E7 mRNA testing to the Hy- pants by the included studies), pooling the diagnostic brid Capture 2 (HC2) DNA test (Digene/Qiagen), two performance data was not possible. In its place, we com- studies compared the mRNA test to Linear Array (Roche piled a best evidence synthesis for HPV E6/E7 mRNA Diagnostics), two studies compared the mRNA test to HPV testing to detect high grade cervical lesions DNA PCR testing, one study used SepaGene kit, one (CIN2+) using descriptive statistics. study used HPV DNA chip test and one study used The diagnostic performance of the three most com- QuantiVirus®HPV DNA Diagnostic Kit. The rest didn’t mon mRNA testing tools as compared with histologi- compare the mRNA test with HPV DNA test. The cally confirmed high-grade cervical intraepithelial agreement between HPV-DNA and HPV-E6/E7 mRNA neoplasia (CIN2+) as an endpoint was as follows; 1) Pre- test in the detection of cervical lesions (which varied Tect Proofer; median sensitivity 83%; ranged 72–95%, from 77.6 to 92.5%) was reported by only 8 studies [39, median specificity 73%; range 45–92.5%, median PPV 51–57] (Table 2). 70%; range 39–90.9%, median NPV 88.9%; range 81– Derbie et al. Infectious Agents and Cancer (2020) 15:9 Page 5 of 10 Table 1 Characteristics of the included studies, 2011–18 Author (s), Year Country #Partici- Age group, Study population characteristics Histology profiles pants median Ratnam, 2011 Canada 1418 15–80, 30.6 Women referred to colposcopy and those Normal = 651, CIN1 = 366, CIN2 = routinely screened 120, CIN2 + =401, CIN3 = 281 Waldstrom, Denmark 405 16–65, 32 Three years archived liquid-based samples, all CIN2 + =67, CIN3 + =33 2011 with a diagnosis of LSIL Fan, 2018 China 192 No data Patients with abnormal cytology results and/or CIN1- = 41, CIN1 = 54, CIN2 = 28, high-risk HPV infection CIn3 = 53, cancer = 16 Han,2018 China 197 No data Women with abnormal cytological or HPV CIN1- = 80, CIN1 = 16, CIN2/3 = 50, test results Caner = 51 Binnicker,2014 USA 350 No data Residual specimens with a cytologic result of CIN2 + =81, CIN3 + =41 ≥ atypical squamous cells of undetermined significance (ASC-US) Broccolo,2013 Italy 308 20–65 A retrospective study on cervical cytology specimens Normal = 70, CIN1 = 159, CIN2 + =79 Waldstrom, Denmark 235 30–69, 42.2 Women with ASC-US cytology Normal = 86, CIN1 = 35, CIN2 = 21, 2012 CIN3 = 26, Cancer = 1 Li,2017 China 318 No data Women with ASCUS cytology attending routine Normal = 169, CIN1 = 74, CIn2 = 40, outpatient primary cervical screening CIN3 = 16, cancer = 19 Benevolo,2011 Italy 464 17–78, 32 Hybrid Capture 2 (HC2)-positive patients, <CIN2 = 49, CIN2 + =49, SCC = 9 who underwent colposcopy Wang, 2019 Korea 563 20–84, no Liquid-based cytology samples Normal = 51, CIN1 = 75, CIN2 = 16, CIN3 = 40, cancer = 38 Liu, 2014 China 335 No data Women who underwent outpatient Normal = 30, CIN1 = 5, CIN2 = 1, hospital-based gynecological screening CIn3 = 15, Cancer 41 Iftner, 2015 Germany 9451 30–60 Women undergoing routine cervical screening <CIN2 = 513, CIN2 = 47, CIN3 + =43 Sorbye, 2011 Norway 520 25–69 Post-colposcopy follow-up of women with CIN2- = 396, CIN2 + = 124 negative or low-grade biopsy Duvlis, 2015 Macedonian 413 19–78 Women that come for cervical cancer screening Normal = 10, CIN1 = 22, CIN2 = 20, CIN3 = 9 Castro, 2013 Spain 165 18–75, 34.8 Women with endocervical samples harboring CIN2- = 93, CIN2 + = 72 HPV 16 and/or 18 DNA Pierry, 2012 USA 246 19–75 Women in a higher risk urban screening population Normal = 137, CIN1 = 64, CIN2 = 25, CIN3 = 20 Alaghehbandan, Canada 1360 15–80, 30.7 women with a history of abnormal cytology Normal = 635, CIN1 = 345, 2013 referred to colposcopy CIN2 + =380, Cancer = 10 Clad, 2011 Germany 424 No data Women referred to colposcopy due to an Normal = 108, CIN1 = 64, CIN2 = 89, abnormal Pap smear CIN3 = 150, Cancer = 13 Varnai, 2018 Germany 66 21–66, 34.6 Office based screening population who were Normal = 6, CIN2 = 5, CIN3 = 22 HPV-DNA positive for at least one of the following HR- HPV types: HPV 16, 18, 31, 33 and 45 Coquillard, 2011 USA 2049 No data Women both low and high risk Normal = 1694, CIN1 = 78 CIN2 + =73 Shen, 2013 China 272 16–77, 37 Women with abnormal colposcopy CIN1- = 80, CIN2 = 6, CIN3 + =25 Li, 2016 China 186 22–68 Patients underwent colposcopy Normal = 32, CIN1 = 51, CIN2/3 = 71, cancer = 32 Liu, 2017 China 380 > 30 Women who were associated with high risk Normal = 159, CIN1 = 68, CIN2 = 74, of cervical virus infection CIN3 = 68, cancer = 11 Benevolo, 2011 Italy 1610 18–83, 39.5 Retrospective analysis of women underwent Normal = 74, CIN1 = 282, CIN2 = 120, an E6/E7 mRNA test on cervical samples CIN3 = 86, cancer = 24 Liu, 2018 Japan 171 22–76, 33 Women with pathologically-diagnosed CIN or CIN1 = 16, CIN2 = 33, CIN3 = 83, cervical carcinoma SCC = 39 Persson, 2014 Sweden 219 23–60, 32 HR-HPV-positive women diagnosed with atypical Normal = 56, CIN1 = 69, CIn2 = 37, squamous cells of undetermined significance CIN3+ 36 (ASCUS) and low-grade squamous intraepithelial lesions (LSIL) Derbie et al. Infectious Agents and Cancer (2020) 15:9 Page 6 of 10 Table 1 Characteristics of the included studies, 2011–18 (Continued) Author (s), Year Country #Partici- Age group, Study population characteristics Histology profiles pants median Sorbye, 2011 Norway 297 25–69 Women with ASC-US and LS CIN1- = 53, CIN2 + =69 Andersson, Sweden 204 21–79, 32 Women who were undergoing gynecological Normal = 45, CIN1 = 33, CIn2 = 28, 2011 screening or had been admitted to a referral center CIN3 = 31, Cancer 28 Oliveira, 2013 Portugal 554 18–73, 33 Women were referred for opportunistic screening and Normal = 131, CIN1 = 128, CIn2 = 129, for evaluation of HPV associated lesions CIN3 = 146, Cancer = 14 98%, 2) APTIMA assay; median sensitivity 91.4%; range reflects the diverse spectrum of cervical pathologies of 78.1–96.3%, median specificity 46.2%; range 25–96.1%, the participants employed by the included articles. Due median PPV 34.3%; range 21–40.8% and median NPV to this heterogeneity of the employed participants by the 96.3%; range 67.4–99.8% and 3) Quantivirus®: median included studies, the results of the HPV E6/E7 mRNA sensitivity 86.1%; range 71.9–93.4%, median specificity test performance have limited generalizability and con- 54.6%; range 36.4–85%, median PPV 54.3%; range 22.2– clusion should be considered with caution. Moreover, 82%, median NPV 89.3%; range 61.9–97.3%. extreme diagnostic results were also reported, for ex- Only six studies [51, 58–62] reported the area under ample, the test specificity reported by Sorbye et al. [64] the receiver operating characteristic (ROC) curve for was at (92.5%) and Persson et al. [65] was at (25%). Simi- diagnosing high-grade cervical lesions (CIN2+) by HPV larly, extreme positive predicative values (PPVs) of the E6/E7 mRNA tests considering histology as a gold stand- mRNA test were reported by Iftner et al. at 21.1% [55] ard. The reported area under the curve varied from 63.8 and Liu et al. at 91% [66] in which the disparity might to 90.9% (the curve was to the left of the diagonal) with be resulted from a difference in the type of included overall mRNA test median sensitivity, 87.7%, range 55– study participants who had different cervical pathologies. 96.3%; median specificity 70.7%, range 25.5–96.1%; Our review report proved that the E6/E7 mRNA tests median PPV 67%, range 21.1–91%; and median NPV have diagnostic relevance to detect CIN2+, especially 83.7%, range 77–99.8% (Table 2). with good test specificity. This is consistent with a previ- ous study [63]. Recent evidences also showed that detec- Discussion tion of the HPV E6/E7 mRNA transcripts may provide a There is a previous review on the performance of HPV higher specificity for the detection of high grade cervical mRNA test by Burger et al. [63] which was published in lesions, since the oncogenic potential of HPV infection 2010. Our review is an update of the latest knowledge depends on the over expression of these two transcripts on the test performance of HPV E6/E7 mRNA test, [57] but the test methods lack either detection of all compiled from articles published since 2011. We high-risk HPV genotypes (like, PreTect HPV-Proofer) or included double number of studies with varying meth- the capacity to specify the detected genotypes (like, odological quality but our finding is in line with this APTIMA) [50]. In general a high specificity and NPV of review. Hence, together with the previous review [63], the E6/E7 HPV mRNA test [35] can be translated into a our finding would be considered for further large scale low referral rate for colposcopy [61], which is not com- studies to generate bold data on the clinical applicability monly available, particularly in resource limited settings. of the test. There are several HPV testing kits/products available In the present review, women were tested for the HPV [67]. In our review, studies used the following kind of E6/E7 mRNA predominately secondary to having posi- HPV E6/E7 mRNA testing products; PreTect Proofer tive cervical cytology and/or positive HPV DNA test. (NorChip AS)/NucliSENS-EasyQ® (Biomerieux), APTIMA Similarly, diverse histological findings were reported HPV assay, Quantivirus® HPV assay, Fluorescence in situ ranged from normal histology to cervical cancer. The hybridization (FISH), Optimygene HR-HPV RT-qDx HPV E6/E7 mRNA tests detected 10.3 to 74.2% propor- assay, HPV OncoTect, RT-PCR assay based on consensus tions of cervical lesions from participants who had primers and real-time PCR assay. The first two methods different level of cervical pathology. A study by Liu et al. are commonly utilized tests in the field of HPV mRNA showed that the positivity rate of HPV E6/E7 mRNA test test; hence in this review out of 29 included studies 18 increased with the severity of cytological or histological used these two methods. findings [60] in which all samples with high-grade Taking histology confirmed CIN 2+ as the disease lesions were positive for the HPV mRNA test as endpoint to assess the clinical performance of the test, described previously [40]. All grades of histological find- the sensitivity of APTIMA at (78.1–96.3%) was better ings were reported in this review. Specifically, the than the PreTect HPV-Proofer (72 to 95%) and Quanti- proportion of CIN2+ was between 10.6 and 90.6%. This virus® (71.9–93.4%). However, in terms of specificity Derbie et al. Infectious Agents and Cancer (2020) 15:9 Page 7 of 10 Table 2 The proportion of HPV E6/E7 mRNA test result and its diagnostic performance of against histology, 2011–18 Author (S) Prevalence HPV DNA test HPV E6/E7 mRNA test mRNA test Performance of E6/E7 mRNA test of CIN2+, n (%) positivity Sen% Spe% PPV% NPV% AU-ROC% rate, n(%) Ratnam, 2011 28.30% Hybrid Capture 2 (HC2) Aptima 964 (68%) 96.3 46.2 40.0 96.7 Waldstrom, 67(16.5) none Aptima 271 (67%) 92.5 38.2 22.9 96.3 Fan, 2018 97 (50.5) HC2 Fluorescence in situ no data 91.5 81.6 82.7 90.9 90.9 hybridization (FISH) Han,2018 101 (51.3) No data No data No data 85.2 66.7 72.9 81 74.95 Binnicker,2014 81(23.1) HC2 APTIMA 230 91.4 42 32.1 94.2 (65.7%) Broccolo,2013 79 (25.6) Quantitative real-time PreTect HPV-Proofer 115 (37.3) 77 81.7 66.9 88 PCR Waldstrom, 48 (55.8) Linear Array Aptima 103 87.5 78 40.8 97.3 2012 (31.7%) Li,2017 85 (26.7) HC2 QuantiVirus HPV E6/E7 177 (70.2) 88.2 36.4 33.9 89.3 68.5 RNA 3.0; Benevolo,2011 49 (10.6) HC2 Pretect HPV-Proofer 165 (36%) 72 73 39 92 Wang, 2019 104 (47.3) HPV DNA chip test Optimygene HR-HPV 219 (38.9) 85.9 82.5 78.2 87.4 RT-qDx assay, Liu, 2014 57 (61.9) No Quantivirus® 135 (40.3) 71.9 74.3 82 61.9 78 Iftner, 2015 90 (14.9) HC2 Aptima 464 (4.9%) 87.8 96.1 21.1 99.8 Sorbye, 2011 124 (23.8) No PreTect HPV-Proofer 52 (27.1) 89.1 92.5 77.3 96.4 Duvlis, 2015 29 (47.5) No NucliSENS-EasyQ® 74 (17.9) 93.1 50 62 88.9 (PreTect Proofer) Castro, 2013 72 (43.6) Nested PCR NucliSENS-EasyQ® 96 (58.2) 84.1 80 90.9 88.9 (PreTect Proofer) Pierry, 2012 45 (18.3) none (HPV OncoTect 89 92 71 Alaghehbandan, 380 (27.9) HC2 PreTect HPV-Proofer 525 (38.6) 76.1 68.7 55 89.1 Clad, 2011 252 (59.4) HC2 Aptima 274 (65) 91.7 75 Varnai, 2018 27 (81.8) PCR-based typing PreTect HPV-Proofer 38 (58) 95 55 81 86 Coquillard, 2011 73 (28.1) HC2 Quantivirus® No data 84 85 78 – Shen, 2013 31 (27.9) HC2 Quantivirus® 200 (73.5) 82.4 15.5 22.2 75 63.8 Li, 2016 103 (55.4) HC2 Quantivirus® 138 (74.2) 91.3 47 68.1 81.3 75.9 Liu, 2017 153 (40.3) none Quantivirus® 275 (72.4) 93.4 62.1 40.5 97.3 Benevolo, 2011 230 (39.2) HC2 PreTect HPV-Proofer 166 (10.3) 83 45 80 91 Liu, 2018 155 (90.6) SepaGene kit RT-PCR assay 95 (55.6) 55 50 91 77 Persson, 2014 73 (36.9) Linear Array Genotyping APTIMA 162 (74) 78.1 25 36.5 67.4 Sorbye, 2011 69 (23.2) None PreTect HPV-Proofer 97 (32.7) 94.2 86 67 98 Andersson, 87 (56.1) None Real-time PCR No data 91 68 67 91 Andersson, 87 (56.1) None PreTect HPV-Proofer No data 75 77 70 81 Oliveira, 2013 295 (53.8) HC2 NucliSENS EasyQ® (PreTect 305 (55.1) 79.3 72.6 76.7 75.5 Proofer) (45–92.5%) the PreTect HPV-Proofer was much better hence is more specific than the APTIMA and Quanti- than these two tests. This might partly because, the Pre- virus® assays which detect mRNA of more genotypes. Tect HPV-Proofer detects only the mRNA of the five Targeting more genotypes makes the latter two methods most common HPV types (HPV16, 18, 31, 33, and 45) rather more sensitive than the PreTect Proofer [50]. Our Derbie et al. Infectious Agents and Cancer (2020) 15:9 Page 8 of 10 review result is in line with this argument. On top of Limitations this, the reported AU-ROC curve by six of the articles This systematic review presents the latest developments [51, 58–62] varied from 63.8 to 90.9% which reflects the in the field of HPV E6/E7 mRNA test accuracy. We have usefulness of the test in discriminating women having included relatively adequate number of articles published CIN2 + . in different countries employing a large number of study In our review 8 studies [39, 51–57] reported the agree- participants. However, our review result should be inter- ment between HPV-E6/E7 mRNA and HPV-DNA test- preted in light of a couple of shortcomings. The main ing for the detection of cervical lesions at 77.6–92.5%. drawback of our review is the lack of studies that Compared to DNA-based tests (the most common one employed similar and well-defined population with same was Digene Hybrid Capture 2 HPV DNA test) which cervical pathology characteristics. Hence, the review was indicate only the presence or absence of the virus, de- suffered from heterogeneity of the studies and was not tecting HPV E6/E7 mRNAs gives more insight into viral possible to pool the performance of the mRNA tests. activity and by implication, clinical relevance (correlate Moreover, the decisive aim of cervical cancer screening better with the severity of the lesion). Hence, the latter is to detect cervical lesions that will develop into cancer. is a potential marker for the identification of women at However, the use of histologically confirmed CIN2+ risk of developing cervical carcinoma. Our review sup- endpoint when evaluating mRNA accuracy represents a port the argument that the HPV E6/E7 mRNA assay challenge because of the regression (false positive) or could overcome the shortcoming of low specificity of progression (false negative) of many confirmed lesions DNA assays for clinical detection of high-grade cervical [63]. Confining our inclusion criteria to include only ar- lesions [35, 68–75]. ticles published in English languages may introduce The Burger et al. [63] review on HPV mRNA test for missing of relevant studies and reduced the precision of the detection of cervical intraepithelial neoplasia, the our results. reported sensitivities varied between 41 and 86% and 90–95% for the PreTect Proofer/Easy Q and APTIMA Conclusions assay, respectively. Similarly, the reported specificities The reported test performance and the receiving operat- vary from 63 to 97% and 42–61% for the PreTect ing characteristics curves implies that HPV E6/E7 mRNA Proofer/Easy Q and APTIMA assay, respectively. These testing has a diagnostic relevance to detect CIN2+ and figures are almost in line with our reports. It is good to could be considered in areas where there is no histological note that a higher specificity, especially in a triage setting test facility. Further studies including its cost should be may reduce the number of women that would be considered. Moreover, future research in the field should subjected to unnecessary conizations and expensive emphasis on the clinical translation (utility) of HPV E6/E7 follow-up [63, 71] and patients psychologic burden asso- mRNA tests using large consecutive cohorts of women, ciated with repeated HPV-DNA testing [72]. However, including participants from developing nations, represent- an individual study by Shen et al. does not support the ing a well-defined population for a specific type of cervical use of this assay in screening for cervical cancer preven- pathology. tion alone [61]. A study by Yang et al. also showed that a woman Supplementary information tested positive for HPV E6/E7 mRNA had a higher risk Supplementary information accompanies this paper at https://doi.org/10. of progressing to high grade cervical lesions. Whereas, 1186/s13027-020-0278-x. women with a negative HPV E6/E7 mRNA can increase follow-up interval, by comprehensively considering their Additional file 1. Search strategy situation, thus, avoiding unnecessary colposcopy and re- Additional file 2. Risk of bias summary result: review authors’ judgements about each risk of bias item for included studies, 2011–18 ducing the rate of colposcopy and biopsy [76]. In our re- view the overall mRNA test performance in terms of negative predicative value (NPV) was at (77–99.8%) Abbreviations ACS: American Cancer Society; ASCUS: Atypical squamous cells of which is in line with the above statement in which undetermined significance; CI: Confidence Interval; CIN: Cervical Intra mRNA test had a very good negative prediction of Neoplasia; DNA: Deoxyribonucleic Acid; E6/7: Early protein 6/7; HIV: Human women for high grade cervical lesions if they get tested Immunodeficiency virus; HPV: Humanpapillom Virus; HR-HPV: High-risk Humanpapilloam virus; Kb: Kilo base pair; L1/2: Late Protein ½; LCR: Long negative. These help patients from unnecessary follow- Control Region; mRNA: messenger ribonucleic acid; NA: Nucleic Acid; up including the expensive colposcopy, diagnostic and NPV: Negative Predictive Value; ORF: Open Reading Frame; Pap : Papaniculo therapeutic procedures [64]. In contrary, women tested test; PCR : Polymerase Chain Reaction; pHR: Probable High Risk; PPV: Positive Predictive Value; pRb: Retinoblastoma Protein; qPCR: quantitative Polymerase positive in the HPV E6/E7 mRNA test have a greater Chain Reaction; ROC: Receiver Operating Characteristic curve; SCC: Squamous risk of malignant progression of cervical lesions and Cell Carcinoma; VIA: Visual Inspection with Acetic acid; WHO: World Health therefore needs more care and earlier check-ups [77]. Organization Derbie et al. Infectious Agents and Cancer (2020) 15:9 Page 9 of 10 Acknowledgments 12. Maine D, Hurlburt S, Greeson D. Cervical Cancer prevention in the 21st We would like to thank Bahir Dar and Addis Ababa Universities and CDT- century: cost is not the only issue. Am J Public Health. 2011;101(9):1549–55. Africa for the provided opportunity to undertake this review. 13. Santos-Lopez G, et al. General aspects of structure, classification and replication of human papillomavirus. Rev Med Inst Mex Seguro Soc. 2015; 53(2):S166–71. Authors’ contributions 14. WHO. Human papillomavirus (HPV) and cervical cancer. 2016 [cited 2018 13 AD and TA conceived the review topic and objectives. AD and DM April]; Available from: http://www.who.int/mediacentre/factsheets/fs380/en/. participated in the study selection and data extraction. TA, YM and XVO 15. Bruni, L., et al. ICO/IARC Information Centre on HPV and Cancer (HPV reviewed the manuscript critically for its scientific content. All authors Information Centre). Human Papillomavirus and Related Diseases in the reviewed and approved the manuscript. World. Summary Report 2017. 2017 [cited 2018 13 April]; Available from: http://www.hpvcentre.net/statistics/reports/XWX.pdf. Funding 16. Chow LT, Broker TR, Steinberg BM. The natural history of human We have received no fund for this particular review. papillomavirus infections of the mucosal epithelia. Apmis. 2010;118(6–7): 422–49. Availability of data and materials 17. Doorbar J, et al. The biology and life-cycle of human papillomaviruses. All the generated data in this review are included in the manuscript. Vaccine. 2012;20(30):083. 18. Wallace NA, Galloway DA. Novel functions of the human papillomavirus E6 Ethics approval and consent to participate Oncoproteins. Annu Rev Virol. 2015;2(1):403–23. Not applicable in this section. 19. Centre, I.I.I.C.o.H.a.C.H.I. Human Papillomavirus and Related Diseases Report. 2017 [cited 2018 28 Sep ]; Available from: http://www.hpvcentre.net/ Consent for publication statistics/reports/XWX.pdf. Not applicable in this section. 20. Münger K, et al. 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HPV E6/E7 mRNA test for the detection of high grade cervical intraepithelial neoplasia (CIN2+): a systematic review

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Abstract

Background: Genital infection with certain types of Human papillomavirus (HPV) is a major cause of cervical cancer globally. For early detection of premalignant dysplasia, evidences are coming out on the usefulness of HPV E6/E7 mRNA test as a potential tool compared with cytology and HPV DNA testing. Taking into account shortage of compiled data on this field, the aim of this systematic review was to describe the latest diagnostic performance of HPV E6/E7 mRNA testing to detect high grade cervical lesions (CIN2+) where by histology was taken as a gold standard. Methods: Articles published in English were systematically searched using key words from PubMed/Medline and SCOPUS. In addition, Google Scholar and the Google database were searched manually for grey literature. Two reviewers independently assessed study eligibility, risk of bias and extracted the data. We performed a descriptive presentation of the performance of E6/E7 mRNA test (in terms of sensitivity, specificity, negative and positive predictive values) for the detection of CIN2 + . Results: Out of 231 applicable citations, we have included 29 articles that included a total of 23,576 study participants (age range, 15–84 years) who had different cervical pathologies. Among the participants who had cervical histology, the proportion of CIN2+ was between 10.6 and 90.6%. Using histology as a gold standard, 11 studies evaluated the PreTect HPV Proofer, 7 studies evaluated the APTIMA HPV assay (Gen-Probe) and 6 studies evaluated the Quantivirus® HPV assay. The diagnostic performance of these three most common mRNA testing tools to detect CIN2+ was; 1) PreTect Proofer; median sensitivity 83%, specificity 73%, PPV 70 and NPV 88.9%. 2) APTIMA assay; median sensitivity 91.4%, specificity 46.2%, PPV 34.3% and NPV 96.3%. 3) Quantivirus®: median sensitivity 86.1%, specificity 54.6%, PPV 54.3% and NPV was at 89.3%. Further, the area under the receiver operating characteristics (AU-ROC) curve varied between 63.8 and 90.9%. Conclusions: The reported diagnostic accuracy implies that HPV mRNA based tests possess diagnostic relevance to detect CIN2+ and could potentially be considered in areas where there is no histology facility. Further studies including its cost should be considered. Keywords: HPV E6/E7 mRNA test, Diagnostic performance, CIN2+ * Correspondence: awoke.derbie@bdu.edu.et Department of Medical Microbiology, College of Medicine and Health Sciences, Bahir Dar University, Bahir Dar, Ethiopia Centre for Innovative Drug Development and Therapeutic Trials for Africa (CDT-Africa), Addis Ababa University, Addis Ababa, Ethiopia Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Derbie et al. Infectious Agents and Cancer (2020) 15:9 Page 2 of 10 Background high grade cervical lesion (CIN2+) enabling detection of According to the Global Cancer Statistics report of the the HPV infection and simultaneously predicting the year 2018, cervical cancer ranks 4th for both incidence change of cervical lesions [32–40]. This is because con- and mortality with over 570,000 cases and 311,000 tinuous expression of E6/E7 oncogenes of HR-HPVs is deaths worldwide [1]. The global burden of cervical can- necessary for the development and maintenance of the cer (close to 85%) occurs in developing countries, where dysplastic phenotype [41]. it accounts for about 12% of all female cancers [1, 2]; It is known that the synergistic effect of the E6 and E7 and nine out of ten cervical cancer deaths disproportion- proteins results in a disturbance of cell cycle regulation, ately occur in developing countries [3–9]. apoptosis prevention, and the transformation and main- About 95–99% of cervical cancer cases are associated tenance of neoplastic and dysplastic cells [42]. The over- with genital infection with High risk (HR)-HPV, which is expression of the E6 and E7 proteins, which inactivate the most common viral infection of the reproductive tract the p53 and pRB respectively, can be detected by testing globally [10, 11] that most women are experiencing soon for the E6/E7 mRNA transcripts which is a potential after they become sexually active [12]. Persistent infection biomarker (proxy indicator) for an increased risk of dis- with HR-HPV is the primary cause of cervical cancer and ease progression to the level of cancer [43–46]. The E6/ its precursor lesion, called the cervical intraepithelial E7 mRNA test can therefore help in avoiding aggressive neoplasia (CIN) [13, 14]. Next to cervical cancer, the HR- procedures (biopsies and over-referral of transient HPV HPV has also been linked to a large proportion of other infections) as well as lowering patient’s anxiety and the kinds of cancers (anus, vulva, vagina and penis) and a follow-up period as well [34]. growing number of head and neck tumors [15–19]. So far, The detection of HR-HPV E6/E7 mRNA is being > 150 different HPVs have been characterized and com- tested as the potential biomarker to elucidate the onco- pletely sequenced. Of all types, about 40 are sexually genic role of HPV in cancer of the cervix and other kind transmitted and infect the genitalia [17, 20–23]. HPV of tumors in general [30, 35, 36, 39, 40, 42]. However, types 16 and 18 are notably responsible for > 70% of all there is quite limited systematically reviewed data on the cervical cancer cases worldwide [15, 24, 25]. diagnostic role of different HPV E6/E7 mRNA tests for Cervical cancer is curable if detected at its early stage. detection of CIN2+, using histology as a gold standard Premature detection cervical lesion is valuable as it de- test. Specifically, the test performance of Aptima, Quan- velops slowly preceding cervical cancer which typically tivirus and PreTect Proofer was assessed. The two tests takes over a period 10 years [26]. These precursor lesions (Aptima, Quantivirus) are able to detect the E6/7 mRNA called the cervical intraepithelial neoplasia (CINs) could from the same 14 HPV types, however, one of these tests be detected by a variety of methods [27]; the most fre- (Aptima) is FDA approved and has a number of publica- quently used one is cytology, but there are other alterna- tions in the literature, whereas the other one (Quanti- tive methods such as HPV DNA tests and visual virus) has no clinical population based study published inspection with acetic acid (VIA) [15], the latter being so far and only few entries in the web. The third test practiced primarily in resource limited settings [15]. (PreTect Proofer) is only able to detect the E6/7 mRNA However, cytology and HPV-DNA based tests are widely of five HPV types. available in most developed nations [28, 29]. HPV DNA testing is being introduced in some countries as an ad- Main text junct to cytology (‘co-testing’) or as the primary screen- Methods ing test to be followed by a secondary test such as Protocol registration cytology or measurement of HR-HPV E6/E7 gene prod- In accordance with the PRISMA guidelines, our sys- ucts [15, 30, 31]. tematic review protocol was submitted to the Inter- Getting tools with reasonable diagnostic performance national Prospective Register of Systematic Reviews remains a challenge in the fight against cervical cancer (PROSPERO) and registered with a registration num- globally. Given the inadequacy of existent methods, plus ber ‘CRD42019123382’. limitations in the use of both cytology and HPV DNA test (including but not limited to the sensitivity/specifi- Eligibility criteria city issues and the inability to indicate the risk of pro- Studies were selected based on the following criteria; gression to cancer), there has long been interest in the Study design: we considered observational quantitative development of new screening tools in cervical cancer studies, like cross-sectional and cohort studies that re- [28, 29]. Many discovery approaches to find HPV associ- ported the diagnostic performance of HPV E6/E7 mRNA ated cervical cancer screening biomarkers are currently assays for the detection of CIN2+. (CIN2+ refers to: his- underway, of which the HR-HPV E6/E7 mRNA test is a tologically confirmed high grade lesions (CIN2, CIN3 promising non-invasive biomarker for the detection of and cancer)). Participants: We included studies that Derbie et al. Infectious Agents and Cancer (2020) 15:9 Page 3 of 10 included women (cervical sample) having different kinds studies of diagnostic test accuracy was independently of cervical pathology. Language and publication:we used by the first two authors. Of the twelve criterion of included peer-reviewed journal articles published in the tool, we eliminated three items because we felt that English in the period of 2011 to 14 Jan 2019 with the their scoring is difficult and rating the items would be outcome of interest reported in different countries. more of subjective. Assessment of quality results was categorized but not summarized into a score as the Information sources and search strategy method has little validity [48]. This review was done following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Proto- Data synthesis col (PRISMA) guideline [47]. Research papers were sys- The extracted data were fed into a Microsoft Excel and tematically searched in PubMed/Medline and SCOPUS presented in terms of 1) CIN profile of the study sub- using key words by combing using Boolean operator. jects, 2) the proportion of CIN2+, 3) the proportion of Manual search from Google scholar and Google data- mRNA test result 4) diagnostic performance of mRNA bases was also performed for grey literature; the last test to detect CIN2+ (sensitivity, specificity, PPV and search was done on 14th of Jan, 2019. The reference NPV). Owing to the presence of a large amount of clin- lists of retrieved articles were probed (forward and back ical heterogeneity of the included articles and as most of ward searching) to identify articles that were not re- the papers didn’t present the 2 × 2 table, pooling of the trieved from databases and our manual search. The first diagnostic performance of mRNA tests was not possible. two authors; AD and DM searched the articles Instead, we performed a descriptive presentation of these independently. elements (using range) to compile a best evidence syn- The domains of the search terms were Human Papillo- thesis for E6/E7 mRNA HPV testing in the detection of maviruses, HPV, E6/E7 mRNA, and Cervical Intraepithe- CIN2+. A systematic narrative synthesis was provided in lial Neoplasia. We combined Human Papillomaviruses which summary results were presented using text, table and HPV with the Boolean operator “OR”, and the result and figures. Descriptive statistics, such as: simple counts, was combined with the other terms with “AND”. Full ranges and percentages were used to describe the search strategy for the two databases is annexed in findings. Additional file 1. Results Study selection Search results Research papers that reported the type of HPV E6/E7 From the systematically searched databases and other mRNA diagnostic performance for the detection of sources, a total of 231 articles were retrieved and CIN2+ were included. Searched articles were directly sequentially screened. After removing 88 duplicates, the imported and handled using EndNote X5 citation man- 143 were screened by title then 52 were removed. Con- ager (Thomson Reuters, New York, USA). Based on the sequently, 53 were removed by abstract and 9 by full text PRISMA protocol, duplicated articles were excluded and with justifiable reasons. Finally, a total of 29 studies met the titles and abstracts of the remaining papers were our inclusion criteria. Screening was based on the screened independently for inclusion in full text evalu- PRISMA flow chart which was adapted from the ation by the first two authors. Differences between the PRISMA guidelines [49] (Fig. 1). reviewers were resolved through discussion. Characteristics of the included studies Data collection process and data items The characteristic of the included articles is summarized Data such as the name of the first author, year of publi- in (Table 1 and Table 2). The studies were reported cation, country where the study was conducted, age from 13 different countries in Europe, Asia and the group of the study participants, type of women included United States of America. We didn’t find articles re- in the study, CIN profile of the study participants, the ported in Latin America and Africa, in particular. The proportion of CIN2+, type of HPV E6/E7 mRNA test number of participants in each included study varied used, the positivity rate of the mRNA test and its diag- from 60 to 9451. Seven studies did not report the age of nostic performance (in terms of sensitivity, specificity, the study participants. The included studies employed a Positive Predictive value (PPV) and Negative Predictive total of 23,576 study participants (age range, 15–84 Value (NPV)) were extracted from the included articles. years) who had different cervical pathologies. The stud- ies were of varying methodological quality, and were Quality appraisal predominately performed in a secondary screening set- To assess the risk of bias, the Critical Appraisal Skills ting (i.e women or cervical samples were subjected to Programme (CASP) tool [48] that developed to evaluate HPV E6/E7 mRNA testing secondary to having positive Derbie et al. Infectious Agents and Cancer (2020) 15:9 Page 4 of 10 Fig. 1 The PRISMA flow diagram of literature selection cervical cytology and/or positive HPV DNA test). Simi- Risk of bias larly, diverse histological findings were reported ranging Ratings of the study quality for each of the nine domain- from normal histology to cervical cancer (Table 1). based critical appraisal skills program (CASP) [48] Among those participants who had cervical histo- criteria to make sense of a diagnostic test study are pre- logical examination, the proportion of CIN2+ was be- sented in Additional file 2. The risk of bias for each indi- tween 10.6 and 90.6%. The reported proportion of vidual domain was rated as ‘Yes’, ‘No’ or ‘Can’t tell’. The positive mRNA test varied from 10.3 to 74.2%. With re- assessment of quality results was categorized not scored gard to the type of HPV E6/E7 test methods, 11 studies otherwise. The mRNA test predictive values were not evaluated the PreTect Proofer, 7 studies evaluated the reported by Clad et al. [56]. Otherwise we felt that all APTIMA HPV assay, 6 studies evaluated the Quanti- the included studies had no major methodological virus® HPV assay and the remaining studies each evalu- uncertainties. ated Fluorescence in situ hybridization (FISH), Optimygene HR-HPV RT-qDx assay, HPV OncoTect, Diagnostic performance of HPV E6/E7 mRNA testing to RT-PCR assay based on consensus primers and real- detect CIN2+ time PCR assay. A study [50] evaluated both real-time Due to the difference in clinical presentation of subjects PCR assay and PreTect Proofer. On top of this, about 13 (considerable clinical heterogeneity of the study partici- studies compared HPV E6/E7 mRNA testing to the Hy- pants by the included studies), pooling the diagnostic brid Capture 2 (HC2) DNA test (Digene/Qiagen), two performance data was not possible. In its place, we com- studies compared the mRNA test to Linear Array (Roche piled a best evidence synthesis for HPV E6/E7 mRNA Diagnostics), two studies compared the mRNA test to HPV testing to detect high grade cervical lesions DNA PCR testing, one study used SepaGene kit, one (CIN2+) using descriptive statistics. study used HPV DNA chip test and one study used The diagnostic performance of the three most com- QuantiVirus®HPV DNA Diagnostic Kit. The rest didn’t mon mRNA testing tools as compared with histologi- compare the mRNA test with HPV DNA test. The cally confirmed high-grade cervical intraepithelial agreement between HPV-DNA and HPV-E6/E7 mRNA neoplasia (CIN2+) as an endpoint was as follows; 1) Pre- test in the detection of cervical lesions (which varied Tect Proofer; median sensitivity 83%; ranged 72–95%, from 77.6 to 92.5%) was reported by only 8 studies [39, median specificity 73%; range 45–92.5%, median PPV 51–57] (Table 2). 70%; range 39–90.9%, median NPV 88.9%; range 81– Derbie et al. Infectious Agents and Cancer (2020) 15:9 Page 5 of 10 Table 1 Characteristics of the included studies, 2011–18 Author (s), Year Country #Partici- Age group, Study population characteristics Histology profiles pants median Ratnam, 2011 Canada 1418 15–80, 30.6 Women referred to colposcopy and those Normal = 651, CIN1 = 366, CIN2 = routinely screened 120, CIN2 + =401, CIN3 = 281 Waldstrom, Denmark 405 16–65, 32 Three years archived liquid-based samples, all CIN2 + =67, CIN3 + =33 2011 with a diagnosis of LSIL Fan, 2018 China 192 No data Patients with abnormal cytology results and/or CIN1- = 41, CIN1 = 54, CIN2 = 28, high-risk HPV infection CIn3 = 53, cancer = 16 Han,2018 China 197 No data Women with abnormal cytological or HPV CIN1- = 80, CIN1 = 16, CIN2/3 = 50, test results Caner = 51 Binnicker,2014 USA 350 No data Residual specimens with a cytologic result of CIN2 + =81, CIN3 + =41 ≥ atypical squamous cells of undetermined significance (ASC-US) Broccolo,2013 Italy 308 20–65 A retrospective study on cervical cytology specimens Normal = 70, CIN1 = 159, CIN2 + =79 Waldstrom, Denmark 235 30–69, 42.2 Women with ASC-US cytology Normal = 86, CIN1 = 35, CIN2 = 21, 2012 CIN3 = 26, Cancer = 1 Li,2017 China 318 No data Women with ASCUS cytology attending routine Normal = 169, CIN1 = 74, CIn2 = 40, outpatient primary cervical screening CIN3 = 16, cancer = 19 Benevolo,2011 Italy 464 17–78, 32 Hybrid Capture 2 (HC2)-positive patients, <CIN2 = 49, CIN2 + =49, SCC = 9 who underwent colposcopy Wang, 2019 Korea 563 20–84, no Liquid-based cytology samples Normal = 51, CIN1 = 75, CIN2 = 16, CIN3 = 40, cancer = 38 Liu, 2014 China 335 No data Women who underwent outpatient Normal = 30, CIN1 = 5, CIN2 = 1, hospital-based gynecological screening CIn3 = 15, Cancer 41 Iftner, 2015 Germany 9451 30–60 Women undergoing routine cervical screening <CIN2 = 513, CIN2 = 47, CIN3 + =43 Sorbye, 2011 Norway 520 25–69 Post-colposcopy follow-up of women with CIN2- = 396, CIN2 + = 124 negative or low-grade biopsy Duvlis, 2015 Macedonian 413 19–78 Women that come for cervical cancer screening Normal = 10, CIN1 = 22, CIN2 = 20, CIN3 = 9 Castro, 2013 Spain 165 18–75, 34.8 Women with endocervical samples harboring CIN2- = 93, CIN2 + = 72 HPV 16 and/or 18 DNA Pierry, 2012 USA 246 19–75 Women in a higher risk urban screening population Normal = 137, CIN1 = 64, CIN2 = 25, CIN3 = 20 Alaghehbandan, Canada 1360 15–80, 30.7 women with a history of abnormal cytology Normal = 635, CIN1 = 345, 2013 referred to colposcopy CIN2 + =380, Cancer = 10 Clad, 2011 Germany 424 No data Women referred to colposcopy due to an Normal = 108, CIN1 = 64, CIN2 = 89, abnormal Pap smear CIN3 = 150, Cancer = 13 Varnai, 2018 Germany 66 21–66, 34.6 Office based screening population who were Normal = 6, CIN2 = 5, CIN3 = 22 HPV-DNA positive for at least one of the following HR- HPV types: HPV 16, 18, 31, 33 and 45 Coquillard, 2011 USA 2049 No data Women both low and high risk Normal = 1694, CIN1 = 78 CIN2 + =73 Shen, 2013 China 272 16–77, 37 Women with abnormal colposcopy CIN1- = 80, CIN2 = 6, CIN3 + =25 Li, 2016 China 186 22–68 Patients underwent colposcopy Normal = 32, CIN1 = 51, CIN2/3 = 71, cancer = 32 Liu, 2017 China 380 > 30 Women who were associated with high risk Normal = 159, CIN1 = 68, CIN2 = 74, of cervical virus infection CIN3 = 68, cancer = 11 Benevolo, 2011 Italy 1610 18–83, 39.5 Retrospective analysis of women underwent Normal = 74, CIN1 = 282, CIN2 = 120, an E6/E7 mRNA test on cervical samples CIN3 = 86, cancer = 24 Liu, 2018 Japan 171 22–76, 33 Women with pathologically-diagnosed CIN or CIN1 = 16, CIN2 = 33, CIN3 = 83, cervical carcinoma SCC = 39 Persson, 2014 Sweden 219 23–60, 32 HR-HPV-positive women diagnosed with atypical Normal = 56, CIN1 = 69, CIn2 = 37, squamous cells of undetermined significance CIN3+ 36 (ASCUS) and low-grade squamous intraepithelial lesions (LSIL) Derbie et al. Infectious Agents and Cancer (2020) 15:9 Page 6 of 10 Table 1 Characteristics of the included studies, 2011–18 (Continued) Author (s), Year Country #Partici- Age group, Study population characteristics Histology profiles pants median Sorbye, 2011 Norway 297 25–69 Women with ASC-US and LS CIN1- = 53, CIN2 + =69 Andersson, Sweden 204 21–79, 32 Women who were undergoing gynecological Normal = 45, CIN1 = 33, CIn2 = 28, 2011 screening or had been admitted to a referral center CIN3 = 31, Cancer 28 Oliveira, 2013 Portugal 554 18–73, 33 Women were referred for opportunistic screening and Normal = 131, CIN1 = 128, CIn2 = 129, for evaluation of HPV associated lesions CIN3 = 146, Cancer = 14 98%, 2) APTIMA assay; median sensitivity 91.4%; range reflects the diverse spectrum of cervical pathologies of 78.1–96.3%, median specificity 46.2%; range 25–96.1%, the participants employed by the included articles. Due median PPV 34.3%; range 21–40.8% and median NPV to this heterogeneity of the employed participants by the 96.3%; range 67.4–99.8% and 3) Quantivirus®: median included studies, the results of the HPV E6/E7 mRNA sensitivity 86.1%; range 71.9–93.4%, median specificity test performance have limited generalizability and con- 54.6%; range 36.4–85%, median PPV 54.3%; range 22.2– clusion should be considered with caution. Moreover, 82%, median NPV 89.3%; range 61.9–97.3%. extreme diagnostic results were also reported, for ex- Only six studies [51, 58–62] reported the area under ample, the test specificity reported by Sorbye et al. [64] the receiver operating characteristic (ROC) curve for was at (92.5%) and Persson et al. [65] was at (25%). Simi- diagnosing high-grade cervical lesions (CIN2+) by HPV larly, extreme positive predicative values (PPVs) of the E6/E7 mRNA tests considering histology as a gold stand- mRNA test were reported by Iftner et al. at 21.1% [55] ard. The reported area under the curve varied from 63.8 and Liu et al. at 91% [66] in which the disparity might to 90.9% (the curve was to the left of the diagonal) with be resulted from a difference in the type of included overall mRNA test median sensitivity, 87.7%, range 55– study participants who had different cervical pathologies. 96.3%; median specificity 70.7%, range 25.5–96.1%; Our review report proved that the E6/E7 mRNA tests median PPV 67%, range 21.1–91%; and median NPV have diagnostic relevance to detect CIN2+, especially 83.7%, range 77–99.8% (Table 2). with good test specificity. This is consistent with a previ- ous study [63]. Recent evidences also showed that detec- Discussion tion of the HPV E6/E7 mRNA transcripts may provide a There is a previous review on the performance of HPV higher specificity for the detection of high grade cervical mRNA test by Burger et al. [63] which was published in lesions, since the oncogenic potential of HPV infection 2010. Our review is an update of the latest knowledge depends on the over expression of these two transcripts on the test performance of HPV E6/E7 mRNA test, [57] but the test methods lack either detection of all compiled from articles published since 2011. We high-risk HPV genotypes (like, PreTect HPV-Proofer) or included double number of studies with varying meth- the capacity to specify the detected genotypes (like, odological quality but our finding is in line with this APTIMA) [50]. In general a high specificity and NPV of review. Hence, together with the previous review [63], the E6/E7 HPV mRNA test [35] can be translated into a our finding would be considered for further large scale low referral rate for colposcopy [61], which is not com- studies to generate bold data on the clinical applicability monly available, particularly in resource limited settings. of the test. There are several HPV testing kits/products available In the present review, women were tested for the HPV [67]. In our review, studies used the following kind of E6/E7 mRNA predominately secondary to having posi- HPV E6/E7 mRNA testing products; PreTect Proofer tive cervical cytology and/or positive HPV DNA test. (NorChip AS)/NucliSENS-EasyQ® (Biomerieux), APTIMA Similarly, diverse histological findings were reported HPV assay, Quantivirus® HPV assay, Fluorescence in situ ranged from normal histology to cervical cancer. The hybridization (FISH), Optimygene HR-HPV RT-qDx HPV E6/E7 mRNA tests detected 10.3 to 74.2% propor- assay, HPV OncoTect, RT-PCR assay based on consensus tions of cervical lesions from participants who had primers and real-time PCR assay. The first two methods different level of cervical pathology. A study by Liu et al. are commonly utilized tests in the field of HPV mRNA showed that the positivity rate of HPV E6/E7 mRNA test test; hence in this review out of 29 included studies 18 increased with the severity of cytological or histological used these two methods. findings [60] in which all samples with high-grade Taking histology confirmed CIN 2+ as the disease lesions were positive for the HPV mRNA test as endpoint to assess the clinical performance of the test, described previously [40]. All grades of histological find- the sensitivity of APTIMA at (78.1–96.3%) was better ings were reported in this review. Specifically, the than the PreTect HPV-Proofer (72 to 95%) and Quanti- proportion of CIN2+ was between 10.6 and 90.6%. This virus® (71.9–93.4%). However, in terms of specificity Derbie et al. Infectious Agents and Cancer (2020) 15:9 Page 7 of 10 Table 2 The proportion of HPV E6/E7 mRNA test result and its diagnostic performance of against histology, 2011–18 Author (S) Prevalence HPV DNA test HPV E6/E7 mRNA test mRNA test Performance of E6/E7 mRNA test of CIN2+, n (%) positivity Sen% Spe% PPV% NPV% AU-ROC% rate, n(%) Ratnam, 2011 28.30% Hybrid Capture 2 (HC2) Aptima 964 (68%) 96.3 46.2 40.0 96.7 Waldstrom, 67(16.5) none Aptima 271 (67%) 92.5 38.2 22.9 96.3 Fan, 2018 97 (50.5) HC2 Fluorescence in situ no data 91.5 81.6 82.7 90.9 90.9 hybridization (FISH) Han,2018 101 (51.3) No data No data No data 85.2 66.7 72.9 81 74.95 Binnicker,2014 81(23.1) HC2 APTIMA 230 91.4 42 32.1 94.2 (65.7%) Broccolo,2013 79 (25.6) Quantitative real-time PreTect HPV-Proofer 115 (37.3) 77 81.7 66.9 88 PCR Waldstrom, 48 (55.8) Linear Array Aptima 103 87.5 78 40.8 97.3 2012 (31.7%) Li,2017 85 (26.7) HC2 QuantiVirus HPV E6/E7 177 (70.2) 88.2 36.4 33.9 89.3 68.5 RNA 3.0; Benevolo,2011 49 (10.6) HC2 Pretect HPV-Proofer 165 (36%) 72 73 39 92 Wang, 2019 104 (47.3) HPV DNA chip test Optimygene HR-HPV 219 (38.9) 85.9 82.5 78.2 87.4 RT-qDx assay, Liu, 2014 57 (61.9) No Quantivirus® 135 (40.3) 71.9 74.3 82 61.9 78 Iftner, 2015 90 (14.9) HC2 Aptima 464 (4.9%) 87.8 96.1 21.1 99.8 Sorbye, 2011 124 (23.8) No PreTect HPV-Proofer 52 (27.1) 89.1 92.5 77.3 96.4 Duvlis, 2015 29 (47.5) No NucliSENS-EasyQ® 74 (17.9) 93.1 50 62 88.9 (PreTect Proofer) Castro, 2013 72 (43.6) Nested PCR NucliSENS-EasyQ® 96 (58.2) 84.1 80 90.9 88.9 (PreTect Proofer) Pierry, 2012 45 (18.3) none (HPV OncoTect 89 92 71 Alaghehbandan, 380 (27.9) HC2 PreTect HPV-Proofer 525 (38.6) 76.1 68.7 55 89.1 Clad, 2011 252 (59.4) HC2 Aptima 274 (65) 91.7 75 Varnai, 2018 27 (81.8) PCR-based typing PreTect HPV-Proofer 38 (58) 95 55 81 86 Coquillard, 2011 73 (28.1) HC2 Quantivirus® No data 84 85 78 – Shen, 2013 31 (27.9) HC2 Quantivirus® 200 (73.5) 82.4 15.5 22.2 75 63.8 Li, 2016 103 (55.4) HC2 Quantivirus® 138 (74.2) 91.3 47 68.1 81.3 75.9 Liu, 2017 153 (40.3) none Quantivirus® 275 (72.4) 93.4 62.1 40.5 97.3 Benevolo, 2011 230 (39.2) HC2 PreTect HPV-Proofer 166 (10.3) 83 45 80 91 Liu, 2018 155 (90.6) SepaGene kit RT-PCR assay 95 (55.6) 55 50 91 77 Persson, 2014 73 (36.9) Linear Array Genotyping APTIMA 162 (74) 78.1 25 36.5 67.4 Sorbye, 2011 69 (23.2) None PreTect HPV-Proofer 97 (32.7) 94.2 86 67 98 Andersson, 87 (56.1) None Real-time PCR No data 91 68 67 91 Andersson, 87 (56.1) None PreTect HPV-Proofer No data 75 77 70 81 Oliveira, 2013 295 (53.8) HC2 NucliSENS EasyQ® (PreTect 305 (55.1) 79.3 72.6 76.7 75.5 Proofer) (45–92.5%) the PreTect HPV-Proofer was much better hence is more specific than the APTIMA and Quanti- than these two tests. This might partly because, the Pre- virus® assays which detect mRNA of more genotypes. Tect HPV-Proofer detects only the mRNA of the five Targeting more genotypes makes the latter two methods most common HPV types (HPV16, 18, 31, 33, and 45) rather more sensitive than the PreTect Proofer [50]. Our Derbie et al. Infectious Agents and Cancer (2020) 15:9 Page 8 of 10 review result is in line with this argument. On top of Limitations this, the reported AU-ROC curve by six of the articles This systematic review presents the latest developments [51, 58–62] varied from 63.8 to 90.9% which reflects the in the field of HPV E6/E7 mRNA test accuracy. We have usefulness of the test in discriminating women having included relatively adequate number of articles published CIN2 + . in different countries employing a large number of study In our review 8 studies [39, 51–57] reported the agree- participants. However, our review result should be inter- ment between HPV-E6/E7 mRNA and HPV-DNA test- preted in light of a couple of shortcomings. The main ing for the detection of cervical lesions at 77.6–92.5%. drawback of our review is the lack of studies that Compared to DNA-based tests (the most common one employed similar and well-defined population with same was Digene Hybrid Capture 2 HPV DNA test) which cervical pathology characteristics. Hence, the review was indicate only the presence or absence of the virus, de- suffered from heterogeneity of the studies and was not tecting HPV E6/E7 mRNAs gives more insight into viral possible to pool the performance of the mRNA tests. activity and by implication, clinical relevance (correlate Moreover, the decisive aim of cervical cancer screening better with the severity of the lesion). Hence, the latter is to detect cervical lesions that will develop into cancer. is a potential marker for the identification of women at However, the use of histologically confirmed CIN2+ risk of developing cervical carcinoma. Our review sup- endpoint when evaluating mRNA accuracy represents a port the argument that the HPV E6/E7 mRNA assay challenge because of the regression (false positive) or could overcome the shortcoming of low specificity of progression (false negative) of many confirmed lesions DNA assays for clinical detection of high-grade cervical [63]. Confining our inclusion criteria to include only ar- lesions [35, 68–75]. ticles published in English languages may introduce The Burger et al. [63] review on HPV mRNA test for missing of relevant studies and reduced the precision of the detection of cervical intraepithelial neoplasia, the our results. reported sensitivities varied between 41 and 86% and 90–95% for the PreTect Proofer/Easy Q and APTIMA Conclusions assay, respectively. Similarly, the reported specificities The reported test performance and the receiving operat- vary from 63 to 97% and 42–61% for the PreTect ing characteristics curves implies that HPV E6/E7 mRNA Proofer/Easy Q and APTIMA assay, respectively. These testing has a diagnostic relevance to detect CIN2+ and figures are almost in line with our reports. It is good to could be considered in areas where there is no histological note that a higher specificity, especially in a triage setting test facility. Further studies including its cost should be may reduce the number of women that would be considered. Moreover, future research in the field should subjected to unnecessary conizations and expensive emphasis on the clinical translation (utility) of HPV E6/E7 follow-up [63, 71] and patients psychologic burden asso- mRNA tests using large consecutive cohorts of women, ciated with repeated HPV-DNA testing [72]. However, including participants from developing nations, represent- an individual study by Shen et al. does not support the ing a well-defined population for a specific type of cervical use of this assay in screening for cervical cancer preven- pathology. tion alone [61]. A study by Yang et al. also showed that a woman Supplementary information tested positive for HPV E6/E7 mRNA had a higher risk Supplementary information accompanies this paper at https://doi.org/10. of progressing to high grade cervical lesions. Whereas, 1186/s13027-020-0278-x. women with a negative HPV E6/E7 mRNA can increase follow-up interval, by comprehensively considering their Additional file 1. Search strategy situation, thus, avoiding unnecessary colposcopy and re- Additional file 2. Risk of bias summary result: review authors’ judgements about each risk of bias item for included studies, 2011–18 ducing the rate of colposcopy and biopsy [76]. In our re- view the overall mRNA test performance in terms of negative predicative value (NPV) was at (77–99.8%) Abbreviations ACS: American Cancer Society; ASCUS: Atypical squamous cells of which is in line with the above statement in which undetermined significance; CI: Confidence Interval; CIN: Cervical Intra mRNA test had a very good negative prediction of Neoplasia; DNA: Deoxyribonucleic Acid; E6/7: Early protein 6/7; HIV: Human women for high grade cervical lesions if they get tested Immunodeficiency virus; HPV: Humanpapillom Virus; HR-HPV: High-risk Humanpapilloam virus; Kb: Kilo base pair; L1/2: Late Protein ½; LCR: Long negative. These help patients from unnecessary follow- Control Region; mRNA: messenger ribonucleic acid; NA: Nucleic Acid; up including the expensive colposcopy, diagnostic and NPV: Negative Predictive Value; ORF: Open Reading Frame; Pap : Papaniculo therapeutic procedures [64]. In contrary, women tested test; PCR : Polymerase Chain Reaction; pHR: Probable High Risk; PPV: Positive Predictive Value; pRb: Retinoblastoma Protein; qPCR: quantitative Polymerase positive in the HPV E6/E7 mRNA test have a greater Chain Reaction; ROC: Receiver Operating Characteristic curve; SCC: Squamous risk of malignant progression of cervical lesions and Cell Carcinoma; VIA: Visual Inspection with Acetic acid; WHO: World Health therefore needs more care and earlier check-ups [77]. Organization Derbie et al. Infectious Agents and Cancer (2020) 15:9 Page 9 of 10 Acknowledgments 12. Maine D, Hurlburt S, Greeson D. Cervical Cancer prevention in the 21st We would like to thank Bahir Dar and Addis Ababa Universities and CDT- century: cost is not the only issue. Am J Public Health. 2011;101(9):1549–55. Africa for the provided opportunity to undertake this review. 13. Santos-Lopez G, et al. General aspects of structure, classification and replication of human papillomavirus. Rev Med Inst Mex Seguro Soc. 2015; 53(2):S166–71. Authors’ contributions 14. WHO. Human papillomavirus (HPV) and cervical cancer. 2016 [cited 2018 13 AD and TA conceived the review topic and objectives. AD and DM April]; Available from: http://www.who.int/mediacentre/factsheets/fs380/en/. participated in the study selection and data extraction. TA, YM and XVO 15. Bruni, L., et al. ICO/IARC Information Centre on HPV and Cancer (HPV reviewed the manuscript critically for its scientific content. All authors Information Centre). Human Papillomavirus and Related Diseases in the reviewed and approved the manuscript. World. Summary Report 2017. 2017 [cited 2018 13 April]; Available from: http://www.hpvcentre.net/statistics/reports/XWX.pdf. Funding 16. Chow LT, Broker TR, Steinberg BM. The natural history of human We have received no fund for this particular review. papillomavirus infections of the mucosal epithelia. Apmis. 2010;118(6–7): 422–49. Availability of data and materials 17. Doorbar J, et al. The biology and life-cycle of human papillomaviruses. All the generated data in this review are included in the manuscript. Vaccine. 2012;20(30):083. 18. Wallace NA, Galloway DA. Novel functions of the human papillomavirus E6 Ethics approval and consent to participate Oncoproteins. Annu Rev Virol. 2015;2(1):403–23. Not applicable in this section. 19. Centre, I.I.I.C.o.H.a.C.H.I. Human Papillomavirus and Related Diseases Report. 2017 [cited 2018 28 Sep ]; Available from: http://www.hpvcentre.net/ Consent for publication statistics/reports/XWX.pdf. Not applicable in this section. 20. Münger K, et al. 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