Prophylactic vaccination against human papillomavirus infection and disease in women: a systematic review of randomized controlled trials.

BACKGROUND Human papillomavirus (HPV) is now known to be a necessary cause of cervical cancer, and prophylactic HPV vaccines aimed at preventing genital warts, precancerous cervical lesions and cervical cancer are now available. To gauge the potential impact on disease burden, we performed a systematic review of the evidence from randomized controlled trials. METHODS We conducted a systematic search of the literature to identify all randomized controlled trials of prophylactic HPV vaccination. Reports in 5 electronic databases covering 1950 to June 2007 (MEDLINE, MEDLINE in process, EMBASE, the Cochrane Central Registry of Controlled Trials and the Cochrane Library), bibliographies of all included studies and of narrative reviews (2006-2007), clinical trial registries, Google Scholar, public health announcements, selected conference proceedings (2004-2007) and manufacturers' information on unpublished data or ongoing trials were screened against predefined eligibility criteria by 2 independent reviewers. Vaccines had to contain coverage against at least 1 oncogenic HPV strain. The primary outcome of interest was the frequency of high-grade cervical lesions (high-grade squamous intraepithelial lesion, or grade 2 or 3 cervical intraepithelial neoplasia). The secondary outcomes were persistent HPV infection, low-grade cervical lesions (low-grade squamous intraepithelial lesion or grade 1 cervical intraepithelial neoplasia), external genital lesions, adverse events and death. Meta-analysis of the data was done in all cases where adequate clinical and methodological homogeneity existed. RESULTS Of 456 screened reports, 9 were included in the review (6 were reports of randomized controlled trials and 3 were follow-up reports of initial trials). Findings from the meta-analysis showed that prophylactic HPV vaccination was associated with a reduction in the frequency of high-grade cervical lesions caused by vaccine-type HPV strains compared with control groups: Peto odds ratio 0.14 (95% confidence interval [CI] 0.09-0.21) from combined per-protocol analyses, and 0.52 (95% CI 0.43-0.63) from modified intention-to-treat analyses. Vaccination was also highly efficacious in preventing other HPV-related infection and disease outcomes, including persistent HPV infection, low-grade lesions and genital warts. The majority of adverse events were minor. The incidence of serious adverse events and death were balanced between the vaccine and control groups. INTERPRETATION Among women aged 15-25 years not previously infected with vaccine-type HPV strains, prophylactic HPV vaccination appears to be highly efficacious in preventing HPV infection and precancerous cervical disease. Long-term follow-up is needed to substantiate reductions in cervical cancer incidence and mortality.