Linear viral load increase of a single HPV‐type in women with multiple HPV infections predicts progression to cervical cancer

• Published in: International journal of cancer 2016-11, Vol.139 (9), p.2021-2032
• Main Authors: Depuydt, Christophe E., Thys, Sofie, Beert, Johan, Jonckheere, Jef, Salembier, Geert, Bogers, Johannes J.
• Format: Article
• Language: English
• Subjects: Adult; Cancer; Cervical cancer; cervical cancer screening; cervical intraepithelial neoplasia; Cervical Intraepithelial Neoplasia - virology; clonal; Coinfection; Disease Progression; Female; Genotype & phenotype; Human papillomavirus; Humans; Infections; liquid‐based cytology leftover; Medical research; Papillomaviridae; Papillomaviridae - classification; Papillomaviridae - physiology; Papillomavirus Infections - virology; real‐time quantitative PCR; RNA, Viral - genetics; transient virion producing; Uterine Cervical Neoplasms - virology; viral doubling time; Viral Load
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.30238

Persistent high‐risk human papillomavirus (HPV) infection is strongly associated with development of high‐grade cervical intraepithelial neoplasia or cancer (CIN3+). In single type infections, serial type‐specific viral‐load measurements predict the natural history of the infection. In infections with multiple HPV‐types, the individual type‐specific viral‐load profile could distinguish progressing HPV‐infections from regressing infections. A case‐cohort natural history study was established using samples from untreated women with multiple HPV‐infections who developed CIN3+ (n = 57) or cleared infections (n = 88). Enriched cell pellet from liquid based cytology samples were subjected to a clinically validated real‐time qPCR‐assay (18 HPV‐types). Using serial type‐specific viral‐load measurements (≥3) we calculated HPV‐specific slopes and coefficient of determination (R2) by linear regression. For each woman slopes and R2 were used to calculate which HPV‐induced processes were ongoing (progression, regression, serial transient, transient). In transient infections with multiple HPV‐types, each single HPV‐type generated similar increasing (0.27copies/cell/day) and decreasing (−0.27copies/cell/day) viral‐load slopes. In CIN3+, at least one of the HPV‐types had a clonal progressive course (R2 ≥ 0.85; 0.0025copies/cell/day). In selected CIN3+ cases (n = 6), immunostaining detecting type‐specific HPV 16, 31, 33, 58 and 67 RNA showed an even staining in clonal populations (CIN3+), whereas in transient virion‐producing infections the RNA‐staining was less in the basal layer compared to the upper layer where cells were ready to desquamate and release newly‐formed virions. RNA‐hybridization patterns matched the calculated ongoing processes measured by R2 and slope in serial type‐specific viral‐load measurements preceding the biopsy. In women with multiple HPV‐types, serial type‐specific viral‐load measurements predict the natural history of the different HPV‐types and elucidates HPV‐genotype attribution. What's new? It is well known that individual high‐risk human papilloma virus (HPV) genotypes can cause cervical cancer, but the risk posed by infections with multiple viral genotypes is less clear. Here the authors examined genotype‐specific viral loads over time in women infected with multiple HPV genotypes. While in women with no cervical intraepithelial neoplasia (CIN), infection dynamics of multiple or single genotypes were similar, in women with advanced lesions