Objectives To investigate the role of human papillomavirus (HPV) in the development of cervical neoplasia in women with no previous cervical cytological abnormalities; whether the presence of virus DNA predicts development of squamous intraepithelial lesion; and whether the risk of incident squamous intraepithelial lesions differs with repeated detection of the same HPV type versus repeated detection of different types. Design Population based prospective cohort study. Setting General population in Copenhagen, Denmark. Participants 10 758 women aged 20-29 years followed up for development of cervical cytological abnormalities; 370 incident cases were detected (40 with atypical squamous cells of undetermined significance, 165 with low grade squamous intraepithelial lesions, 165 with high grade squamous intraepithelial lesions). Main outcome measures Results of cervical smear tests and cervical swabs at enrolment and at the second examination about two years later. Results Compared with women who were negative for human papillomavirus at enrolment, those with positive results had a significantly increased risk at follow up of having atypical cells (odds ratio 3.2, 95% confidence interval 1.3 to 7.9), low grade lesions (7.5, 4.8 to 11.7), or high grade lesions (25.8, 15.3 to 43.6). Similarly, women who were positive for HPV at the second examination had a strongly increased risk of low (34.3, 17.6 to 67.0) and high grade lesions (60.7, 25.5 to 144.0). For high grade lesions the risk was strongly increased if the same virus type was present at both examinations (813.0, 168.2 to 3229.2). Conclusions Infection with human papillomavirus precedes the development of low and high grade squamous intraepithelial lesions. For high grade lesions the risk is greatest in women positive for the same type of HPV on repeated testing.

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In Greenland, the incidence of cervical cancer is 5.7 times higher than in Denmark among women aged 20-39. From Nuuk (Greenland) and Nykøbing Falster (Denmark) a sample of 800 women aged 20-39 years was drawn at random. A total of 586 and 661 women were investigated in Greenland and Denmark respectively. All women had a gynecological examination including a PAP-smear and cervical scrape for HPV-analysis (filter in situ hybridization). A blood sample was taken for analysis of HSV type-specific antibodies (ELISA). The percentage of normal smears was identical in the 2 areas (95%). The total HPV 16/18 infection rate was 13% in Denmark and 8.8% in Greenland, and the age-adjusted prevalence rate in Greenland was only 67% of that in Denmark (95% CI: 0.05-0.89). The proportion of HPV 6/11 positivity was the same in Greenland and in Denmark (6.7% vs. 7.5%). A significantly higher proportion of the Greenlandic women had HSV-2 antibodies (68.2%) in comparison with Danish women (30.9%) (p less than 0.01). The prevalence of HSV-1 was also higher in Greenland, especially in women aged 20 to 24. Our finding of a higher HPV infection rate in Denmark than in Greenland, opposed to cervical cancer rates, does not support a role for these viruses as determinants of cervical cancer incidence. In contrast, the rate of HSV-2 infection co-varies with the observed incidence of cervical cancer. This is in line with the notion that differences in cervical cancer incidence between Denmark and Greenland are determined by aspects of sexual behavior.

Summary The prevalence of human papillomavirus (HPV) infection and other risk factors were studied in a high risk area for cervical cancer (Greenland) Epidemiological research has long pointed to cancer of the cervix uteri as a sexually transmitted disease (Brinton & Fraumeni, 1986). For more than a decade, human papillomavirus (HPV) has been suggested to play an important role in cervical carcinogenesis (zur Hausen, 1989). Not only has HPV DNA been detected in more than 90% of all cervical carcinoma samples tested, but it has also recently been shown that human keratinocytes immortalised with HPV DNA, turn malignant after prolonged cultivation (Hurlin et al., 1991;Pecoraro et al., 1991). If HPV is a main causal agent, one would anticipate a geographical accordance between incidence of cervical cancer and prevalence of HPV infection. On this background we were surprised that our population-based comparison showed that the prevalence of HPV 16/18 detection was higher in Denmark (13.0%) than in Greenland (8.8%) in spite of the cervical cancer incidence being five times higher in Greenland (Kjaer et al., 1988). By contrast, the high risk Greenlandic women were characterised by e.g. a higher number of sexual partners and earlier age at first intercourse compared with Danish women (Kjaer et al., 1989). Because of the surprising lack of correspondence between HPV 16/18 prevalence and incidence of cervical cancer and in view of the further development of new DNA hybridisation techniques, we decided to undertake a renewed comparative study in the same geographical areas. In addition, we reinvestigated the association between HPV and HSV infection and the number of sexual partners like in the previous investigation (Kjaer et al., 1990

The study confirms the sexual transmission of the infection. There is also good concordance between risk factors for ever having had GW and cervical neoplasia. A close relationship between having had GW and an abnormal Pap smear was observed.