High load for most high risk human papillomavirus genotypes is associated with prevalent cervical cancer precursors but only HPV16 load predicts the development of incident disease

Abstract

Cervicovaginal human papillomavirus (HPV) viral load has been purported as a potential marker for the detection of high-grade cervical intraepithelial neoplasia or cancer (>/=CIN2). To examine disease association with type-specific viral load for the full-range of anogenital HPV infections, we conducted cross-sectional and prospective analyses of approximately 2,000 HPV-infected women from a 10,000-woman population-based study in Guanacaste, Costa Rica with 7 years of follow-up. Cervical specimens were tested for >40 HPV types using a MY09/MY11 L1 consensus primer PCR method with type-specific dot blot hybridization and PCR signal intensity as a measure of viral load. A positive association was observed between prevalent >/=CIN2 and high viral load compared to low viral load for women with baseline single HPV16 infections (OR = 19.2, 95% CI = 4.4-83.2) and single non-16 carcinogenic infections (OR = 9.2, 95% CI = 2.1-39.9). Inclusion of women with multiple HPV types did not substantially change these associations. In prospective follow-up, only women infected with HPV16 alone (OR = 27.2, 95% = 3.5-213.5) had a strong association between high viral load and incident >/=CIN2; non-16 carcinogenic high viral load was not associated with incident >/=CIN2 (OR = 0.7, 95% CI = 0.2-1.9). Single noncarcinogenic type viral load was not associated with increased risk of prevalent or incident >/=CIN2 (OR = 1.2 and 1.1, respectively). In conclusion, carcinogenic high viral load was associated with prevalent >/=CIN2; however HPV16 was uniquely associated with incident >/=CIN2. The extent to which these observations can be translated into clinical practice must be rigorously examined in the context of the method of viral load measurement and the type-specific differences observed for incident >/=CIN2.

Figure 1

Box plots of log10-transformed HPV16 (a and b) and HPV18 (c and d) normalized viral load (viral load per 20,000 GAPDH copies) by oligonucleotide hybridization signal intensity in the original 5 (a and c) and collapsed 2 (b and d) categories. The median crude HPV copy number (and interquartile range) by hybridization signal intensity, HPV 16: 1 = 10 (1–48), 2 = 6 (1–240), 3 = 144 (27–1661), 4 = 2538 (294–12,610), 5 = 14,382 (2988–61,936); HPV 18: 1 = 2 (1–7), 2 = 221 (1–5682), 3 = 745 (154–6137), 4 = 1387 (172–4881), 5 = 5001 (1803–175,651). [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

Figure 2

Schematic representation of underlying trajectory of HPV infection from cross-sectional viral load measurements. A similar baseline viral load measurement (t0) is found in subject (a) and subject (b). However, longitudinal characterization of the subsequent natural history of the infection demonstrates that the high viral load could reflect one of two underlying states (a) the peak viral replication prior to immune recognition and clearance, or (b) a persistently high viral load, inclusive of a persistent neoplasia. To the extent that women with HPV 16 may be more likely at cross-section to be in state (b) relative to other genotypes, this could explain the unique predictive value of HPV 16 viral load for incident CIN2+.