Six-Year Regression and Progression of Cervical Lesions of Different Human Papillomavirus Viral Loads in Varied Histological Diagnoses

Abstract

Objective This study aims to evaluate HPV viral load as a biomarker for triage into colposcopy and CIN2 therapy, in order to reduce the colposcopy referral rate and CIN2 over treatment in low resource settings. Methods In 1999, 1997 women aged 35–45 in Shanxi, China, received six cervical screenings with pathological confirmation. In 2005, 1461 histologically normal women, 99 with cervical intraepithelial neoplasia (CIN) grade 1 (CIN1), and 30 with CIN grade 2 or worse (CIN2+) were rescreened in a follow-up study. HPV was detected by Hybrid Capture 2. Viral load, estimated by the ratio of relative light units to standard positive control, was categorized into four groups: negative (<1.0), low (≥1.0, <10.0), moderate (≥10.0, <100.0) and high (≥100.0). We estimated cumulative incidence of CIN2+ by viral load subgroups and calculated adjusted hazard ratios (aHR) for CIN2+ using Cox proportional hazards regression. Results Cumulative incidence of CIN2+ increased with baseline HPV viral load among normal women and women with CIN1 at baseline (P-trend<0.001). Repeat moderate-high viral load was associated with the highest risk for CIN2+ (aHR=188.8, 95% confidence interval: 41.2–864.1). Raising the RLU/PC cutoff from 1.0 to 10.0 for colposcopy greatly reduced the referral rate from 18.1% to 12.9%. It also increased the specificity (84.8% vs. 90.4%), the positive predictive value (22.5% vs. 28.9%), and the positive likelihood ratio (6.4 vs. 8.9), yet with loss of the sensitivity by 12% (97.6% vs. 85.7%). Among women with CIN2 at baseline, 56% regressed to normal, 24% regressed to CIN1, 4% remained CIN2, and 16% progressed to CIN3+. Conclusions Locales using HPV testing as the primary screening method, and lacking high-quality cytology-based screening, should consider viral load as an alternative to colposcopy triage for women over age 35. Viral load may also predict CIN2 progression until additional biomarkers become available.

2019 ASCCP Risk-Based Management Consensus Guidelines for Abnormal Cervical Cancer Screening Tests and Cancer Precursors

“…Additionally, as more data has accumulated confirming the high regression rates of CIN2 lesions, especially for younger women [12,[23][24][25][26][27][28][29], it has increasingly become difficult to justify the inclusion of CIN2 lesions in the primary endpoint for cervical disease. These studies have indicated that almost half of all CIN2 lesions will regress spontaneously, with lesions that are negative for HPV types 16 and 18 having the highest rates of regression [25,29].…”

“…However, even for HR HPV infections, about 50% will spontaneously clear within 1-2 years [8]. HR HPV viral load has been identified as a major factor associated with cervical precancer, especially for the alpha 9 genotype family, which contains types 16,31,33,35,52, and 58 [9][10][11][12]. Therefore, HR HPV devices utilize a "clinical cutoff" (also known as a "clinical cutpoint"), where only HR infections with viral nucleic acid levels resulting in signals exceeding a certain threshold are reported as positive for HR HPV, in order to minimize identification of low viral load infections that have a high probability of spontaneous clearance.…”

Clinical course of untreated cervical intraepithelial neoplasia grade 2 under active surveillance: systematic review and meta-analysis

“…We identified 250 potentially eligible studies; 43 publications met the inclusion criteria (fig 1),6222324252627282930313233343536373839404142434445464748495051525354555657585960616263 but seven were duplicate reports of the same data 27283140505254. Of the 36 eligible studies (total of 3160 women), seven (19%) were randomised trials with suitable data in the non-experimental arm,22253339455762 16 (44%) were prospective cohort studies,6263032343536373841435155566063 and 13 (36%) were retrospective cohort studies23242942444647484953585961 (see supplementary table 2).…”

“…Of the 36 eligible studies (total of 3160 women), seven (19%) were randomised trials with suitable data in the non-experimental arm,22253339455762 16 (44%) were prospective cohort studies,6263032343536373841435155566063 and 13 (36%) were retrospective cohort studies23242942444647484953585961 (see supplementary table 2). The median follow-up was 16 months (range 3-72, interquartile range 7.6-27.4 months).…”

Risk Prediction of Cervical Cancer and Precancers by Type-Specific Human Papillomavirus: Evidence from a Population-Based Cohort Study in China

“…In 1999, 1,997 women aged 35 to 45 years were enrolled in Shanxi Province Cervical Cancer Screening Study I (SPOCCS I) study (14)(15)(16). They were nonpregnant and had no history of cervical screening or hysterectomy.…”