Prospective evaluation of longitudinal changes in human papillomavirus genotype and phylogenetic clade associated with cervical disease progression

Abstract

Objective: Changes in the HPV genotype detected in patients over time could alter cervical disease progression. Identification of patterns in the alteration of HPV genotype should also be related to cytological and histological findings. Thus, we assessed the risk for low-grade squamous intraepithelial lesion (LSIL) or high-grade SIL (HSIL)/squamous cell carcinoma (SCC) associated with alterations in the HPV genotype detected, presence of multiple HPV genotypes, and individual genotyping or HPV clade grouping.

Methods: The 1052 participants were monitored by HPV chip and Pap smear. We calculated odds ratios and applied sequential association analysis (SAA) and decision tree analysis (DTA).

Results: We classified HPV alteration as persistence, regression (spontaneous vs. therapeutic), or metatyping (progressive vs. regressive). Spontaneous regression occurred in 71.9% of patients. Metatyping was strongly associated with progression (RR: 3.9, p=0.0242), with progressive metatyping showing a higher risk of progression (RR: 31.49, p=0.00448). Few patients with multiple infections were identified in the initial screen but 30.8% of patients had multiple infections in the final analysis. HPV-16, -35, -52, and -58 were commonly associated with HPV persistence. Univariate analysis determined that final diagnosis significantly associated with HPV type at the endpoint (p<0.0001), persistence (p=0.0001), and progressive metatyping (p=0.0022). SAA determined that HPV-66, -68, and -69 were significantly associated with HSIL, and HPV-16 and -18 persistence significantly association with SCC. DTA indicated an age less than 28 years had a peak in LSIL, and an age between 32 and 48 years had a peak in HSIL. A bimodal peak in SCC for HR-2 at the endpoint was observed in participants less than 32 and greater than 48 years of age.

Conclusions: The alteration patterns of HPV infection detected included persistence, regression, and metatyping. HPV persistence and progressive metatyping are significant signatures of disease progression.