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Original Studies

High-risk Human Papillomavirus Messenger RNA Testing in Wet and Dry Self-collected Specimens for High-grade Cervical Lesion Detection in Mombasa, Kenya

Islam, Jessica Yasmine PhD, MPH∗,†; Mutua, Michael M. MBChB; Kabare, Emmanuel; Manguro, Griffins MBChB, MPH; Hudgens, Michael G. PhD§; Poole, Charles MPH, ScD; Olshan, Andrew F. PhD∗,†; Wheeler, Stephanie B. PhD, MSPH†,¶; McClelland, R. Scott MD, MPH‡,∥; Smith, Jennifer S. PhD, MPH∗,†

Author Information
Sexually Transmitted Diseases: July 2020 - Volume 47 - Issue 7 - p 464-472
doi: 10.1097/OLQ.0000000000001167

Invasive cervical cancer is caused by persistent infection with high-risk human papillomavirus (hr-HPV).1 Although highly preventable through early detection and treatment of precancerous lesions,2 cervical cancer remains the fourth most common cause of cancer-related morbidity and mortality among women worldwide.3 In high-resource countries, the successful implementation of cytology-based, or Papanicolaou test, screening has reduced cervical cancer incidence and mortality by at least 80%.4 However, there are several barriers to the implementation of cytology-based programs in low- and middle-income countries (LMICs), including limited health care infrastructure, reduced access to clinicians to conduct pelvic examinations, and fewer trained cytopathologists.5 Consequently, the burden of cervical cancer disproportionately impacts both never-screened and underscreened women in LMICs, where nearly 90% of the deaths attributable to cervical cancer occur.3 In Kenya, where the estimated population-based screening coverage is 13%,6 cervical cancer is the leading cause of cancer-related mortality among women.3

The development of molecular-based laboratory assays to detect hr-HPV has recently changed the approach to cervical cancer screening.7 Evidence from randomized controlled trials shows that primary hr-HPV screening is effective for the detection of high-grade precancerous lesions, with higher sensitivity and less frequent intervals required between screenings.7,8 Molecular hr-HPV testing has been associated with lower mortality attributable to cervical cancer9 and offers the potential to implement larger-scale cervical cancer screening programs using self-collected sampling.10 In accordance with World Health Organization recommendations,2 LMICs are implementing molecular HPV testing as a primary screening tool.11

Self-collection of cervicovaginal specimens for cervical cancer screening is a clinically valid method for hr-HPV testing, with the potential to circumvent barriers to clinic-based screening.12 In addition, sensitivity for the detection of high-grade cervical lesions using self-collected samples for HPV DNA detection is equivalent to physician-collected samples.13 However, hr-HPV DNA testing does have limitations. For example, in populations and geographical areas where hr-HPV prevalence is high, providing HPV DNA testing may have notably low specificity for high-grade cervical lesions detection,2 resulting in unnecessary follow-up procedures and overburdening of referral clinics for treatment.14

One potential strategy to improve the specificity of cervical cancer screening is to test for hr-HPV messenger RNA (mRNA) of the oncogenic proteins E6 and E7, which may more accurately predict progression to invasive disease.15 Few prior studies have evaluated the validity of using self-collected samples for HPV mRNA testing.14,16,17 Furthermore, currently available data evaluating self-collection for HPV mRNA testing have been generated using samples stored in liquid transport media, which is relatively more costly than dry self-collection.18

The feasibility of self-collected sampling for hr-HPV testing with dry swabs transported and stored at room temperature might facilitate more efficient and larger-scale screening strategies in LMICs. To date, there is a lack of data on the performance of self-collection using brushes stored dry (sc-DRY) compared with self-collected samples stored wet in transport media (sc-WET) to evaluate the clinical validity for high-grade cervical lesion detection. We present here results comparing the performance of Aptima hr-HPV mRNA testing (Hologic Corporation, San Diego, CA) using sc-DRY and sc-WET specimens for the detection of cytological high-grade cervical lesions or more severe (≥high-grade squamous intraepithelial lesion [HSIL]) among female sex workers (FSWs) in Mombasa, Kenya. Furthermore, we present results of the performance of Aptima hr-HPV mRNA testing for physician-collected specimens for the detection of ≥HSIL. We also evaluated participants' preferences for HPV sampling methods.

METHODS

Study Population

From August 2013 to April 2018, FSWs participating in a cohort study of women at high risk of acquiring sexually transmitted infections (STIs) and HIV in Mombasa, Kenya, were invited to participate in this cross-sectional cervical cancer screening study to compare the performance of self-collected sampling methods stored both dry and wet, physician-collected sampling, and visual inspection with acetic acid (VIA) for cervical cancer screening. Clinical procedures, including self-collection and physician collection of genital samples for HPV mRNA testing, were performed at the Ganjoni Clinic in Mombasa. The Ganjoni Clinic has been a primary research site for the Mombasa Cohort19 and venue for STI testing and treatment among at-risk and HIV-positive women in Mombasa for more than 25 years.

Study procedures were integrated into the ongoing follow-up procedures for the Mombasa Cohort, as previously described.20 Briefly, the Mombasa Cohort is an open cohort study of FSWs established in 1993 to provide high-quality care to at-risk women and supports research efforts of HIV prevention, treatment, and care. For participant recruitment, outreach meetings were conducted at major sex work venues 1 to 2 times each month. During these meetings, outreach staff provided counseling on a health topic requested by the women of the community, as well as general information about the research clinic. Interested women were provided with a referral card and invited to visit Ganjoni Clinic.

The criteria for inclusion into the Mombasa Cohort included the following: (1) women 18 years and older, (2) residing in the Mombasa area, (3) self-identifying as exchanging sex for payment in cash or in-kind at the time of enrollment, and (4) able to provide informed consent. Eligible women were invited to participate in this cervical cancer screening study during the visit for specimen collection for Chlamydia trachomatis and Neisseria gonorrhoeae testing. We used convenience sampling to enroll women who agreed to participate from among those who were eligible and carried out enrollment to ensure half of the participants were HIV positive. Women were excluded from this study if they were currently pregnant or had a history of hysterectomy or treatment of cervical precancer. Participating women were counseled on the risks and benefits of cervical cancers screening and administered a questionnaire to collect sociodemographic, reproductive, and sexual behavior data. The study was approved by the ethical review committees of the University of Nairobi/Kenyatta National Hospital and the University of North Carolina at Chapel Hill. All participants provided written informed consent before enrollment into the study.

Sample Collection

To perform self-collection of genital specimens, each woman was directed to a private room at the clinic. A study nurse provided verbal instructions and pictorial diagrams with detailed instructions on self-collection were available in the private room. Participants were instructed to squat and insert a cytobrush up into the vaginal vault, rotating it 3 to 5 times, and then withdrawing. Each woman performed self-collection using 2 different specimen brushes1: the Evalyn cytobrush (Rovers, Amsterdam, the Netherlands) for dry self-collection (sc-DRY) and2 the Viba cytobrush (Rovers) for wet self-collection (sc-WET), which included a plastic cryovial containing 1 mL of Aptima liquid transport media (Hologic) (Fig. 1). The Evalyn cytobrush consists of a pink plunger containing white bristles made of polyethylene at the tip, a transparent casing, and a transparent cap (https://www.roversmedicaldevices.com/cell-sampling-devices/evalyn-brush/). The Viba brush consists of a blue handle and a removable white tip (https://www.roversmedicaldevices.com/cell-sampling-devices/viba-brush/). The tip contains bristles made of similar material to the Evalyn brush. To minimize potential bias from the order of specimen collection, women assigned odd study numbers self-collected using the Evalyn brush first, whereas those with even study numbers self-collected using the Viba cytobrush first.

F1
Figure 1:
Cytobrushes used for self-collection: Rovers Evalyn Brush and Rovers Viba-Brush RT, Rovers Medical Devices, Oss, the Netherlands.

After self-collection, a study clinician performed a speculum-assisted pelvic examination to collect cervical specimens for hr-HPV mRNA testing. Physician collection of cervical specimens from the endocervix was performed using a cervical specimen collection brush (Hologic). Similar to the Viba brush (for sc-WET), physician-collected specimens were stored in Aptima media. After specimen collection, the clinician performed VIA and a conventional Papanicolaou test for cytology assessment. All study clinicians had extensive training and experience in genital examination and specimen collection as part of the procedures in the Mombasa Cohort. After the clinical examinations, women participated in a structured interview using a standardized questionnaire to assess their experiences undergoing self-collection and physician collection of specimens.

Conventional cytological smears were evaluated at the University of Nairobi and classified according to the 2001 Bethesda System. All smears were independently read by 2 cytopathologists who were blinded to HPV mRNA and VIA screening results. For discrepant cases, the final diagnosis was made after a consensus of the 2 reviewing cytopathologists. Women with high-grade lesions or above were referred to standard care and treatment at the Coast Provincial General Hospital (CPGH) in Kenya. All specimens were archived for external quality control and future testing.

HPV mRNA Laboratory Testing

The physician-collected sample and both self-collected samples were transported daily to the research laboratory at the CPGH for hr-HPV mRNA testing. The physician-collected sample and both self-collected samples were transported daily to the research laboratory at the CPGH for hr-HPV mRNA testing. The samples were transported by project personnel in a cooler box and kept at 8°C, which was monitored by an external temperature probe. On arrival at the research laboratory, the sc-DRY samples were first stored at room temperate and transferred into Aptima media no more than 12 hours after collection. All samples were stored in a freezer at −80°C until laboratory testing. Testing for HPV mRNA detection took place at CPGH laboratory.

Laboratory personnel were blinded to the results of the other screening tests. Self-sampled and physician-sampled genital specimens were tested for hr-HPV using the Food and Drug Administration–approved APTIMA HPV Assay (Hologic Inc), which detects mRNA encoding the E6/E7 oncoproteins from 14 high-risk HPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68). Specimen processing comprises 3 main steps, including target capture, target amplification by transcription-mediated amplification, and amplicon detection by the hybridization protection assay carried out according to the manufacturer's instructions. This process was automated using Hologic's Panther System platform by trained technologists.

Statistical Analyses

Of 400 FSWs, 1 woman was missing hr-HPV mRNA testing results and excluded from analyses, resulting in a final sample of 399. Sociodemographic and sexual behavioral characteristics were assessed for all women and stratified by HIV status using univariate analyses. Agreement between hr-HPV mRNA positivity in sc-WET specimens compared with sc-DRY and compared with physician collection was measured using percent agreement and the κ statistic with 95% confidence intervals (CIs),21 stratified by cytology diagnosis. Pairwise comparisons using the McNemar test were conducted to assess differences in hr-HPV mRNA prevalence in sc-DRY and sc-WET sample specimens and in sc-WET versus physician collection, which is included in the Appendix Table 1. Two-by-two tables were constructed to calculate sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) using conventional cytology as the reference standard (≥HSIL detection) with 95% CIs. Differences in sensitivity, specificity, and predictive values of screening tests were assessed using Wald-type CIs.22 We calculated prevalence differences (PDs) with 95% CIs to assess potential differences in preference of self-collection devices by age (<40 and ≥40 years).

Sensitivity analyses were conducted to estimate PPV and NPV values of sc-DRY and sc-WET specimens for varying prevalence of ≥HSIL to address concerns regarding generalizability and transportability of findings. Currently, the World Health Organization recommends cervical cancer screening to start as soon as a woman has tested positive for HIV, regardless of age.2 Therefore, we present results stratified overall and by HIV status. All statistical analyses were performed using SAS 9.4.

RESULTS

Participant Characteristics

Overall, the median age of women was 39 years (range, 19–66 years; Table 1). The prevalence of hr-HPV mRNA was generally similar in physician-collected (34%), sc-WET (37%), and sc-DRY (32%) samples. Most women had 8 or fewer years of education (57%) and reported being divorced or widowed (63%). A higher proportion of women reported using either no contraception (35%) or condoms only (21%) during sexual acts.

T1
TABLE 1:
Sociodemographic and Sexual Behavioral Characteristics of 399 Female Sex Workers in Mombasa, Kenya, 2013 to 2018

For all 3 individual HPV-mRNA screening test results, the prevalence of hr-HPV mRNA was higher among HIV-positive women compared with HIV-negative women (sc-WET: PD, 0.15 [95% CI, 0.06–0.24]; sc-DRY: PD, 0.14 [95% CI, 0.04–0.23]; physician: PD, 0.19 [95% CI, 0.10–0.28]). The prevalence of an abnormal cytology result (≥atypical squamous cells of undetermined significance) was 27% and was also higher among HIV-positive women (31%) than HIV-negative women (23%; PD: 0.06 [95% CI, 0.01–0.11]).

Concordance of hr-HPV mRNA Detection Between sc-WET and sc-DRY

Overall, approximately one-third of women tested positive for hr-HPV mRNA using the self-collected sampling stored wet (n = 147; 37%) or stored dry (n = 127; 32%). A quarter of women (97/387) were positive for hr-HPV mRNA with both sc-WET and sc-DRY samples; 12% (47/387) were hr-HPV mRNA positive using the sc-WET sample but not the sc-DRY sample; 6.9% (27/387) were positive for hr-HPV mRNA using the sc-DRY but not the sc-WET sample; and 56% (216/387) were negative for hr-HPV mRNA using both the sc-DRY and sc-WET samples (Table 2). Using the McNemar test for paired samples, hr-HPV mRNA positivity was higher in sc-WET samples compared with sc-DRY (P = 0.02). High risk-HPV mRNA concordance was determined between sc-WET and sc-DRY samples, stratified by cytology diagnosis. Twelve participants did not have cytology diagnoses available and were excluded from the stratification analyses.

T2
TABLE 2:
HPV mRNA Detection Agreement of Self-Collected Samples Stored Wet (sc-WET) and Self-Collected Stored Dry (sc-DRY) Samples, Stratified by Cytology Diagnosis (n = 387)

Performance of hr-HPV mRNA Testing of Self-Collected Stored Wet, Self-Collected Stored Dry, and Physician-Collected Specimens, and VIA for the Detection of ≥HSIL

The overall sensitivity estimates of hr-HPV mRNA for ≥HSIL of sc-WET (85% [95% CI, 66%–96%]) and sc-DRY (78% [95% CI, 58%–91%]) were comparable (difference, −0.07; Wald 95% CI, −0.21 to 0.07; Table 3). Physician-collected samples for hr-HPV mRNA testing showed a similar sensitivity for ≥HSIL detection (93% [95% CI, 76%–99%]) compared with sc-WET (difference, −0.07; Wald 95% CI, −0.19 to 0.09) and sc-DRY (difference, 0.15; Wald 95% CI, −0.02 to 0.32; Fig. 2). Overall, the specificity of hr-HPV mRNA for ≥HSIL detection was similar when comparing sc-WET to physician collection (difference, −0.03; 95% CI, −0.08 to 0.01). However, specificity was lower for sc-WET (66% [61%–71%]) than sc-DRY (71% [66%–76%]; difference, −0.05 [95% CI, −0.10 to −0.00). The specificity of VIA for ≥HSIL was 56% (95% CI, 51%–62%).

T3
TABLE 3:
Performance of HPV Testing of Physician-Collected, Wet Self-Collected, and Dry Self-Collected Specimens, and VIA for the Detection of Cytological High-Grade Cervical Lesions in 387 Female Sex Workers in Mombasa, Kenya (2013–2018)
F2
Figure 2:
Performance of HPV testing of physician-collected, wet self-collected, and dry self-collected specimens, and visual inspection with acetic acid (VIA) for the detection of cytological high-grade cervical lesions.

The PPVs were 16% (95% CI, 10%–23%) for sc-WET and 17% (95% CI, 11%–25%) for sc-DRY. The PPV for physician collection specimens was 19% (95% CI, 12%–26%). Sensitivity analyses showed that for all 3 test results, as the prevalence of ≥HSIL increases to 20%, the PPV increases to approximately 40% and the NPV only decreases slightly (Supplementary Fig. 1, https://links.lww.com/OLQ/A489). The summary of sensitivity analyses is provided in Appendix Table 2.

Acceptability of Self-Collection Methods

Overall, 144 (36%) of women reported preferring self-collection compared with physician collection. Preference for self-collection did not seem to vary by age (<40 years, 39%; ≥40 years, 32%; PD, 0.07; 95% CI, −0.03 to 0.16) or HIV status (HIV-positive, 44%; HIV-negative, 56%; PD, −0.07; 95% CI, −0.16 to 0.03). Women more frequently reported to prefer self-collection stored dry (46%) compared with storage in media (31%). Most women agreed that the Evalyn brush (used for dry storage) was comfortable to insert (88%) and came with instructions easy to understand (95%). Approximately half of participants were concerned that use of the Evalyn brush for self-collection may lead to pain (45%), and approximately 60% were concerned about properly using the Evalyn brush. Similar patterns were observed for the Viba brush (used for wet storage; Table 4).

T4
TABLE 4:
HPV Sampling Preference of Dry and Wet HPV mRNA Self-Collection (n = 399)

DISCUSSION

To our knowledge, this is the first study to directly compare hr-HPV mRNA testing on self-collected wet- and dry-stored specimens to detect ≥HSIL. Among 399 FSWs in Kenya, high-risk HPV mRNA testing using self-collected samples stored wet and dry demonstrated similar sensitivity for ≥HSIL detection, although the specificity of dry-stored samples seemed higher. High-risk HPV mRNA positivity was similar in self-collected wet (36%) compared with physician-collected (34%) specimens, but was lower in self-collected dry brushes (32%). Although we found high sensitivity and specificity of hr-HPV mRNA testing using self-collected samples for the detection of ≥HSIL, our cohort of Kenyan FSWs preferred physician collection of cervical samples over self-collection methods for cervical cancer screening.

Our results demonstrate that compared with wet-stored specimens, dry-stored specimens have similar test characteristics for the detection of high-grade cervical lesions, indicating that dry-stored samples are a viable option for home-based cervical cancer screening programs. Prior studies have directly compared HPV DNA testing using self-collected specimens stored dry and wet and report comparable sensitivities for the detection of CIN2+,23,24 and ≥HSIL.25 Sensitivity estimates of HPV DNA testing on dry-stored samples to detect high-grade cervical neoplasia or more severe were similar to our study and ranged from 76% to 90%.23,24 However, specificity for high-grade cervical neoplasia in prior studies of HPV DNA testing in dry- versus wet-stored samples was lower for both self-collection methods (46%–67%).23,24

The prevalence of hr-HPV mRNA based on self-collection specimens in our study was similar to other hr-HPV mRNA studies conducted in sub-Saharan Africa among high-risk groups. In a South African study of 325 HIV-infected women, the prevalence of hr-HPV mRNA based on self-collected samples was 43.5%,14 which is similar to the prevalence we found in HIV-positive women (44.6% for sc-WET and 38.9% for sc-DRY). Among a cohort of 344 FSWs in Nairobi, of which 25% were HIV positive, the prevalence of hr-HPV mRNA was 30%.16 Given that HPV DNA is typically detected at higher-prevalence proportions than HPV mRNA within various populations studied,26 our study population has a notably high prevalence of hr-HPV infection.

We observed low PPVs for HPV testing using sc-WET (16%) and sc-DRY (17%) for the detection of high-grade lesions, although these PPV values are higher than previous self-collection studies conducted in Kenya (8.2%).16,17 Here, PPV is an estimate of the proportion of women with a positive HPV mRNA test result, who actually have our outcome of interest ≥HSIL. The relatively low PPV is concerning, as it may lead to unnecessary treatment when women are offered treatment based on the results of their screening test (i.e., “HPV screen and treat” strategy2). However, in areas where women may screen only once in their lifetime, such as Kenya, the low PPV may not be as much of a concern because of a woman's lifetime risk of hr-HPV infection and persistence. In low-resource settings, the potential benefits of using a screen and treat strategy based on a test with low PPV may outweigh the harms of overtreatment,17 although further evidence is needed.

Among FSWs in Kenya, we found that physician collection was more frequently preferred than either self-collection method. These findings are inconsistent with prior studies that found that women generally reported preference of self-collection over physician-collected sampling for cervical cancer screening.27 A recent meta-analysis found that of 12,610 women, 59% (95% CI, 48%–69%) reported preference for self-sampling compared with physician collection.27 However, there was wide variability across individual studies (22%–95% of respondents). In our study, women frequently reported feeling concerned about hurting themselves when inserting the self-collection brush into their vaginal canal. They also expressed concerns of their ability to properly carry out self-collection. Our findings are similar to results of a Cameroonian study, which showed that, although women found self-collection more comfortable and less embarrassing, a greater proportion preferred physician collection (62% vs. 29%) as they were concerned about the reliability of results.28 Indeed, factors facilitating uptake of HPV self-collection among women in Kenya include confidence in the ability to complete HPV self-sampling, proximity to screening sites, and feelings of privacy and comfort conducting the HPV self-sampling.29 However, it is important to note that it is unknown whether a woman's preference for type of collection method would have a meaningful impact on uptake of self-collection when no alternative screening method is provided.30 It is critical that future research addresses barriers to self-collection uptake to better inform the successful implementation of cervical cancer screening programs in low-resource settings.

Our study approach has several advantages. First, this cross-sectional study was nested within an ongoing prospective study with established follow-up procedures, including HIV-positive women, a population at notably high-risk of cervical cancer. Second, conventional cervical cytology slides were independently read by 2 cytopathologists to improve the accuracy of cytological diagnoses. Third, screening collection methods were performed sequentially on the same day, allowing for direct comparison of the samples collected. In addition, we randomized each participant to either first complete self-collection for the dry- or the wet-stored sample to ensure the order of procedures did not affect our results. Finally, our study presents data on the preference of self-collection for cervical cancer screening, which builds on prior work conducted by our group on preferences of 199 FSWs30 and further underscores the potential obstacles to self-collection in settings with limited access to trained health care providers.

Among study limitations, women participating in the Mombasa Cohort volunteer for research visits with regular HIV and STI screening; as such, our findings may not be generalizable to all women eligible for cervical cancer screening in LMICs. Our small sample size also limited our ability to compare the agreement (using the κ statistic) between sc-DRY and sc-WET in women with <HSIL compared with those with ≥HSIL. The interpretation of our analyses is therefore limited because of few HSIL cases, although our results are comparable with prior cervical cancer screening studies conducted in sub-Saharan Africa.16 Further research is needed to assess the use of dry-stored specimens with HPV mRNA testing to detect high-grade cervical lesions in large cohorts to confirm our study findings.

In conclusion, based on our findings, the use of dry-stored specimens seems to be a viable option for hr-HPV mRNA testing owing to the similar sensitivity and specificity compared with wet-stored self-collected hr-HPV testing for ≥HSIL detection. The possibility of using dry-stored self-collected samples without the need of storage media would improve the utility of self-collection for hr-HPV testing and could reduce the costs needed for the storage and transport of samples. Limited resources may then be focused on follow-up and treatment services for women who screen positive for hr-HPV, which would be ideal for resource-constrained settings. Additional research to address patient and provider preferences and elimination of barriers to self-collection is crucial.

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