Six-year regression and progression of cervical lesions of different human papillomavirus viral loads in varied histological diagnoses

Objective: This study aims to evaluate human papillomavirus (HPV) viral loads as a biomarker for triage into colposcopy and cervical intraepithelial neoplasia grade 2 (CIN2) therapy to reduce the colposcopy referral rate and CIN2 overtreatment in low-resource settings. Methods: In 1999, 1997 women aged 35 to 45 years in Shanxi, China, received 6 cervical screenings with pathological confirmation. In 2005, 1461 histologically normalwomen, 99 with CIN grade 1 (CIN1), and 30 with CIN2 or worse (CIN2+) were rescreened in a follow-up study. Human papillomavirus was detected by Hybrid Capture 2. Viral load, estimated by the ratio of relative light units to standard positive control (RLU/PC),was categorized into 4 groups: negative (<1.0), low (≥1.0, <10.0), moderate (≥10.0, <100.0), and high (≥100.0). We estimated the cumulative incidence of CIN2+ by viral load subgroups and calculated adjusted hazard ratios for CIN2+ using Cox proportional hazards regression. Results: Cumulative incidence of CIN2+ increased with baseline HPV viral loads 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+ (adjusted hazard ratio, 188.8; 95% confidence interval, 41.2-864.1). Raising the ratio of relative light units to standard positive control 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 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 CIN grade 3 or worse. 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 older than 35 years. Viral loads may also predict CIN2 progression until additional biomarkers become available.