Human papillomavirus detection for diagnosis and vaccination for prevention
Cervical cancer is a leading cause of cancer deaths among women in developing countries and is also a major health problem in developed countries. The discovery that persistent infection with an oncogenic type of human papillomavirus (HPV) is necessary for the cancer to develop was arguably one of the most important advances in gynaecology of recent decades. On page 1001, Kitchener et al. report the findings of a three centre study in the UK in which women with cervical intraepithelial neoplasia grade 3 (CIN3) were investigated for their carriage of HPV to investigate its role in the decision as to whether further follow up was necessary following ablative treatment of their precancerous lesion. Of 917 treated women, 783 were HPV negative and 95.1% of these had entirely reassuring cytology at follow up. Only one woman had CIN3 and five women had CIN2. Of the 134 who were positive for HPV, 44% had persistent abnormal cytology at follow up. Even if they had normal cytology at 6 months, one had CIN3 and four had CIN2 detected during the subsequent 18 months. Kitchener et al. concluded that in women who are HPV negative at 6 months following treatment, the risk of residual CIN3 is negligible. They suggest that a woman who is cytology negative and HPV negative at 6 months can safely be recalled at 3-year intervals rather than undergo 10 years of annual follow up as currently recommended in UK national guidelines.
Recent years have seen the development of effective vaccines to prevent HPV infection. Such is the importance of this topic that on page 938, we publish a review article from an expert group in the Netherlands. Heideman et al. give us a detailed account of the mechanism of action of the vaccines, their clinical effects, and recommended implementation strategies. They point out that although a reduction of premalignant cervical lesions can be envisaged within 7 years following vaccination, it will take up to 20 years before we see the expected marked reduction in the incidence of cervical cancer, reflecting its long latent phase. The prevention of adenocarcinomas will be particularly welcome as these are often missed by current cervical screening. How long will immunity last? Antibody levels higher than those found in natural infections have been shown to persist for at least 5 years, but long-term effectiveness is as yet unclear. Accordingly, as the peak likelihood of acquiring HPV infection is during the 5–10 years following the commencement of sexual activity, the currently recommended age for vaccination is 9–14 years. The NHS in the UK, on the advice of the Joint Committee on Vaccination and Immunisation, is planning to introduce HPV vaccination nationwide for girls aged 12–13 years in September 2008. The NHS direct website (www.nhsdirect.nhs.uk/articles/article.aspx?articleId=2336) contains a good account of HPV vaccination and the UK government’s plans. There will also be a 2-year catch-up campaign, due to start in autumn 2009, which will include all girls who are up to 18 years of age. It is not yet clear which of the two currently available vaccines will be used. One of these, Gardasil, protects against HPV types 16 and 18, which can cause cervical cancer, and types 6 and 11, which cause genital warts. The second, Cervarix, protects only against HPV types 16 and 18. In some places, for example Nova Scotia, free HPV vaccination has already been introduced. In other parts of Canada, funding is being left to individual provincial governments. In the USA, plans vary considerably from state to state; a summary of them can be found in Wikipedia at http://en.wikipedia.org/wiki/HPV_vaccine, and an excellent account of the vaccine from the USA Centers For Disease Control and Prevention (CDC) at www.cdc.gov/std/Hpv/STDFact-HPV-vaccine.htm. Both the CDC and the Federal Drug Administration consider the vaccine to be safe, especially as it does not contain mercury or even any complete virus particles. The main obstacle to effective implementation may well be objections from parents that vaccination against what is essentially a sexually transmitted disease will encourage inappropriate early sexual activity. In one prospective study (Vallely et al., Vaccine 2008;26:2203–10), a Church of England school refused permission for the showing of a movie explaining the background to the vaccine. Some Muslim parents regarded HPV vaccination as unnecessary because ‘our daughters will remain monogamous and are required to trust their husband’s fidelity’. In some people’s minds, the wages of ‘sin’ are CIN, and preventing the punishment of the sexually ‘promiscuous’ is thwarting the will of God. Similar controversies dogged the introduction of treatments for syphilis in the 1930s. Unfortunately, even if a woman is monogamous, this is no guarantee that her husband will behave similarly. In a prospective study of 36 secondary schools in Manchester, UK, the vaccine uptake for the first dose of a three-dose schedule was only 70.6%, and this fell to 68.5% for the second dose (Brabin et al., BMJ 2008;336:1056–8). Uptake was significantly lower in schools with a higher proportion of ethnic minority girls or girls entitled to free school meals (indicating a low family income). Whether such a rate of uptake will be sufficient to provide ‘herd immunity’ remains to be seen. Unfortunately, HPV infection is influenced not by professed beliefs but only by actual behaviour. The likely epidemiological and economic impact of Gardasil in the UK is analysed in the paper by Dasbach et al. on page 947. They conclude that routine vaccination at 12 years of age, combined with a 12- to 24-year-old catch-up programme is the most effective strategy, with the cost per QALY ranging between £5,882 and £11,412, well within the range usually considered cost-effective (I discussed QALYs in detail in last month’s editor’s choice). However, they assumed that the percentage of girls aged 12 years receiving the full three dose of vaccine would be 80%. As Brabin et al. have suggested that the actual take-up may be significantly less than this, achieving cost-effectiveness is likely to require a substantial effort to convince the majority of the population that vaccination is in everyone’s interests. A high-level of ‘herd immunity’ will benefit everyone, except the manufacturers of colposcopes.