Elsevier

The Lancet

Volume 357, Issue 9271, 9 June 2001, Pages 1831-1836
The Lancet

Articles
Natural history of cervical human papillomavirus infection in young women: a longitudinal cohort study

https://doi.org/10.1016/S0140-6736(00)04956-4Get rights and content

Summary

Background

Laboratory and epidemiological research suggests an association between human papillomavirus (HPV) and cervical intraepithelial neoplasia (CIN). We studied the natural history of incident cervical HPV infection and its relation to the development of CIN.

Methods

We recruited 2011 women aged 15–19 years who had recently become sexually active. We took a cervical smear every 6 months and stored samples for virological analysis. We immediately referred all women with any cytological abnormality for colposcopic assessment, but postponed treatment until there was histological evidence of progression to high-grade CIN.

Findings

In 1075 women who were cytologically normal and HPV negative at recruitment, the cumulative risk at 3 years of any HPV infection was 44% (95% CI 40–48): HPV 16 was the most common type. The cumulative risk at 3 years of detecting an HPV type not present in the first positive sample was 26% (20–32). 246 women had an abnormal smear during follow-up, of whom 28 progressed to high-grade CIN. The risk of high-grade CIN was greatest in women who tested positive for HPV 16 (risk ratio 8·5 [3·7-19·2]); this risk was maximum 6–12 months after first detection of HPV 16. All HPV types under consideration were associated with cytologically abnormal smears. Although abnormality was significantly less likely to be associated with low-viral-load samples, the cumulative risk at 3 years of a high-viral-load sample after a low-viral-load sample was 45% (95% CI 35–56). Five women who progressed to high-grade CIN consistently tested negative for HPV.

Interpretation

Our findings suggest that attempts to exploit the association between cervical neoplasia and HPV infection to improve effectiveness of cervical screening programmes might be undermined by the limited inferences that can be drawn from the characterisation of a woman's HPV status at a single point in time, and the short lead time gained by its detection.

Introduction

Laboratory-based research has firmly established a role for human papillomavirus (HPV) infection in cervical cancer. The epidemiological evidence that lends support to this finding is largely based on case-control studies, which have consistently revealed a strong association between cervical neoplasia and the detection of HPV DNA in samples of exfoliated cervical cells taken at, or subsequent to, diagnosis of disease.1 However, there is always ambiguity about the temporal relation between exposure and outcome with case-control studies, which, for example, does not allow us to eliminate the possibility that the presence of disease could itself increase the ability to detect HPV.2 Only cohort studies that include women who are cytologically normal at enrolment can provide direct evidence of temporality. Even with these studies, however, time of onset of infection has to be known to describe the incubation curve for HPV-associated abnormality; this detail cannot be established when the cohort includes women who are HPV positive on study entry, because the duration of infection before recruitment is unknown. To address this issue we recruited a cohort of young women who had recently become sexually active and were therefore unlikely to have had a previous cervical HPV infection. Here we describe the natural history of incident HPV infection and its temporal relation to the occurrence of cytological abnormality and development of high-grade cervical intraepithelial neoplasia (CIN).

Section snippets

Patients

We recruited women aged 15–19 years who visited one Birmingham Brook Advisory Centre between 1988 and 1992. The women were likely to be available for long-term follow-up because of their continuing need for contraceptive supplies. At study entry, we obtained a detailed social, sexual, and behavioural risk-factor profile for each participant and took a cervical smear. We stored cervical and serum samples for future virological testing. We asked women to reattend at intervals of 6 months when we

Results

We enrolled 2011 women, 530 (26%) of whom were excluded from analyses because they had abnormal smears (148) or were HPV positive on study entry (244), or both (138). We also excluded 406 women who gave only one sample that could be tested both cytologically and virologically. The final cohort comprises 1075 women who were cytologically normal and HPV negative on study entry and who had more than one evaluable sample. Table 1 shows baseline characteristics of our cohort at study entry. The

Discussion

As far as we know, this is the first cohort study to describe the natural history of incident cervical HPV infection in a UK population. The prevalence at recruitment and the incidence of HPV infection in our population were high. Our estimate of the cumulative risk at 3 years is similar to that reported for a cohort of North American college students, where HPV 16 was also the most common infecting type.9 We intended to recruit women before, or soon after, they had become sexually active, to

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