Adjunct screening of cervical or vaginal samples using careHPV testing with Pap and aided visual inspection for detecting high-grade cervical intraepithelial neoplasia

Highlights

• To study the combined performance of careHPV with Pap and VIA as a model for LRCs.

• Cervical careHPV in parallel with VIA detected high-grade CIN best.

• Parallel testing of CHPV with Pap was a second option and may not be for LRCs.

• VHPV in parallel with Pap or VIA resulted in a similar yield as a third option.

• Sequential testing of careHPV with Pap or VIA tests is not an option for LRCs.

Abstract

Objective

To evaluate the performance of careHPV DNA testing for human papillomavirus (HPV) on cervical and vaginal samples (CHPV and VHPV respectively) in adjunct screening together with visual inspection of the cervix by acetic acid (VIA) or Papanicolaou (Pap) tests in the detection of high-grade cervical intraepithelial neoplasia (CIN).

Subjects and methods

A cross-sectional study examined 4658 women 30–59 years of age by performing screening tests for HPV using careHPV on cervical and vaginal samples together with Pap and VIA. The CHPV and VHPV test results were presented as a ratio of viral load expressed in relative light units (RLUs) to the mean RLU from a positive control set at 1 pg/mL cut-off (CO). Performances of various pairs of screening tests in parallel and sequential settings were computed through the detection rates of CIN, percentages of unnecessary colposcopic referrals of screen positives, and compared with stand-alone tests.

Results

The screening positivity of CHPV, VHPV, Pap and VIA ranged from 2.4% to 5.5%. The highest sensitivity (72%) was observed for the combination of CHPV and VIA in parallel, followed by 65.6% for CHPV and Pap, and 59% for all other combinations (VHPV and Pap, VHPV and VIA, and VIA and Pap). The percentage of unnecessary colposcopic referrals in the parallel setting of CINII+ detection ranged from 2.8% to 6.0%. Sequential testing of CHPV or VHPV with other tests yielded very low sensitivities with a reduction in unnecessary colposcopic referrals.

Conclusion

Cervical careHPV testing (CHPV) in parallel with VIA was the option that performed best in the detection of high-grade CIN and could be a feasible option for low-resource countries (LRCs).

Introduction

Cervical cancer is a preventable disease with a very high incidence (85%) in low-resource countries (LRCs) [1]. The methods of screening – such as visual inspection of the cervix with acetic acid (VIA), the Papanicolou (Pap) smear, and human papillomavirus (HPV) DNA testing on cervical and vaginal samples – for the detection of cervical intraepithelial neoplasia (CIN) have been reported in various study settings [2], [3], [4], [5], [6]. Nationwide Pap screening programmes are not possible in LRCs. Although VIA offers important potential advantages for screening in LRCs, subjectivity and quality control are still major issues for this as a stand-alone screening test [7]. Definite improvements have been demonstrated for HPV DNA testing, either by hybrid capture II (HCII) [5] or by careHPV [8], over conventional tests of cervical screening. There are review-based studies [9], [10] using self-sampling and physician-collected samples in HPV DNA testing for LRCs. One study assessed optimal screening strategies for cervical cancer using stand-alone tests and their combinations among low- and middle-income populations of Latin America and Eastern Europe [11]. Another study from India compared Pap and HPV tests for the detection of high-grade CIN among VIA-positive cases [12]. A recent study [13] demonstrated the need for triage testing on the primary self-sample HPV testing to identify clinically significant pre-cancers or cancers. Several other studies have reported comparative performances of various screening tests in various combinations [14], [15], [16], [17], [18], [19].

The approach of adopting a single cervical screening test in isolation often lacks adequate performance in the detection of high-grade CIN. Combined visual screening tests (as compared to stand-alone tests) evaluated estimation of the extra false-positive results per additional high-grade CIN detected with the combined tests [20] There is still a definite need for the eventual introduction of more sensitive and affordable screening tests for LRCs. The community-level demonstrations of careHPV testing [21], [22] and VIA demonstration [6] in Uttar Pradesh, and pilot-based implementation of VIA in the Tamil Nadu state of India, to assess the appropriateness of the tests [23] indicate that the ground is being prepared for control of the disease, especially in LRCs. At this juncture, assessment of adjunctive tests for a better yield in LRCs would be helpful. The comparative performance of each of the screening tests in isolation – such as self-collected (VHPV) and clinician-collected (CHPV) samples with careHPV testing, Pap and VIA – has previously been reported by us from our rural and multi-country settings [21], [22]. Combined evaluation of these tests in parallel as well as sequentially in the detection of high-grade CIN has to our knowledge not yet been reported. However, a recent study [18] reported on careHPV evaluated only in sequential testing of selected screening tests. We analysed the combined performance of careHPV testing on clinician-collected cervical samples or self-collected vaginal samples with Pap and VIA screening tests. The aim was to evaluate the combined performance of CHPV, VHPV, Pap and VIA screening tests both in parallel and in sequential use for the detection of high-grade CIN.