Prospective study of HPV16 viral load and risk of in situ and invasive squamous cervical cancer.

Background: A strong association has been shown between high viral DNA load (VL) of human papillomavirus (HPV) type 16 and risk for cervical cancer in situ (CIS). However, little data is available for the significance of VL in invasive squamous cell carcinoma (SCC).

Methods: In 2 nested case-control studies among women participating in cervical screening, with a cytologically normal first smear, we collected 5,665 smears from 621 women with CIS, 457 with SCC, and individually matched controls. All smears were tested for HPV, and VLs of HPV16 positive smears were quantified using real time-PCR. The median follow-up until diagnosis of CIS or SCC was 6.1 to 7.7 years.

Results: Low VL's were common among both CIS and SCC case women, until 1 to 2 years before diagnosis when a surge in VL occurred. The relative risk (RR) associated with low viral load of HPV16 was around 10 for CIS, and 10 to 20 for SCC throughout 10 years before diagnosis, compared with HPV16-negative women. For women with medium to high VL, the risk for CIS was greatly increased from 5 years before diagnosis [RR, 19; 95% confidence interval (CI), 7-48]. In SCC, a high VL conferred an increased risk, but only from 3 years before diagnosis [RR, 60; 95% CI, 6-580].

Conclusions: We show differing risk functions associated with HPV16 viral load in CIS and SCC, respectively. We further show that viral loads were unexpectedly low early in the SCC disease process.

Impact: HPV16 viral load appears highly complex which may limit its use in cervical screening.