Elsevier

The Lancet

Volume 355, Issue 9222, 24 June 2000, Pages 2194-2198
The Lancet

Articles
Consistent high viral load of human papillomavirus 16 and risk of cervical carcinoma in situ: a nested case-control study

https://doi.org/10.1016/S0140-6736(00)02402-8Get rights and content

Summary

Background

Persistent infection with certain types of human papillomavirus (HPV) is believed to be a prerequisite for the development of cervical neoplasia. Persistence may depend on certain characteristics, such as viral load, which has so far been given little attention. We investigated the association between HPV 16 viral load and cervical carcinoma in situ.

Methods

We did a nested case-control study of women participating in cytological screening in Sweden. We used a sensitive quantitative PCR assay to estimate HPV 16 load in multiple smears for each woman, taken during a period of up to 26 years before diagnosis. We calculated Ct values, which decrease as the number of viral DNA copies increases.

Findings

2081 smears from 478 cases and 1754 smears from 608 controls were tested. Among cases, we found a consistently increased load of HPV 16 already 13 years or more before diagnosis, and when many smears were still cytologically normal. Women with high HPV 16 viral loads were at least 30 times the relative risk of HPV-16-negative women more than a decade before diagnosis. The increase in relative risk was constant over time. About 25% of women (95% CI 0·12–0·32) infected with a high viral load before age 25 years developed cervical carcinoma in situ within 15 years.

Interpretation

Cervical carcinoma in situ associated with HPV 16 occurs mainly in HPV-16-positive women who have consistently high viral loads long term. Women at high risk could be identified by use of a quantitative HPV test in addition to cytological screening.

Introduction

Viral persistence of oncogenic human papillomaviruses (HPV) seems essential for the development of cervical neoplasia. A high viral load resulting from productive viral replication might support viral persistence.1 All studies but one that have estimated HPV load, have shown an increased risk for cervical carcinoma in relation to high viral load.2, 3, 4, 5, 6, 7 These investigations did not, however, quantify viral load, which was estimated crudely from the signal intensity in the hybridisation assay or by comparison of results from different HPV detection methods. We did a nested case-control study to investigate the temporal relation between HPV 16 load and cervical carcinoma in situ by quantitative PCR assay to try to achieve better understanding of the role of HPV load in the development of cervical carcinoma.

Section snippets

Participants

We selected women from a cohort in a cytological screening programme that covered women aged 30–49 years (and, later, 25-49 years), started in Uppsala County, Sweden in 1967.8 732 287 smears from 146 889 women were stored at the University Hospital, and all information was stored on computer from 1969 to 1995. From this cytology register we identified all registered women who had at least one smear. We required that the first smear was cytologically normal (PAP=1) and that the women were born

Characteristics of participants

462 smears for cases and 386 smears for controls were excluded because of negative β-actin Ct values. Therefore, 2081 smears from the cases and 1754 smears from the controls were analysed (table 1). 871 (42%) smears were HPV 16 positive among cases and 117 (7%) among controls. The median β-actin Ct values were similar at different times before diagnosis (table 1), with no change over time.15 By contrast, the median HPV 16 Ct values were strikingly lower (indicating high viral load) in cases

Discussion

Viral load of HPV 16 determines a woman's risk of developing cervical carcinoma in situ many years in advance of the event. A substantial excess risk could already be predicted in women with a high viral load of HPV 16a decade before diagnosis of cervical carcinoma in situ, compared with HPV-16-negative women. By contrast, women with low viral load of HPV 16 were not at increased risk of cervical carcinoma in situ. Quantitative measurement of low, medium, high, and no HPV 16 viral load added

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