Four year efficacy of prophylactic human papillomavirus quadrivalent vaccine against low grade cervical, vulvar, and vaginal intraepithelial neoplasia and anogenital warts: randomised controlled trial

Objectives To evaluate the prophylactic efficacy of the human papillomavirus (HPV) quadrivalent vaccine in preventing low grade cervical, vulvar, and vaginal intraepithelial neoplasias and anogenital warts (condyloma acuminata). Design Data from two international, double blind, placebo controlled, randomised efficacy trials of quadrivalent HPV vaccine (protocol 013 (FUTURE I) and protocol 015 (FUTURE II)). The trials were to be 4 years in length, and the results reported are from final study data of 42 months’ follow-up. Setting Primary care centres and university or hospital associated health centres in 24 countries and territories around the world. Participants 17622 women aged 16-26 years enrolled between December 2001 and May 2003. Major exclusion criteria were lifetime number of sexual partners (>4), history of abnormal cervical smear test results, and pregnancy. Intervention Three doses of quadrivalent HPV vaccine (for serotypes 6, 11, 16, and 18) or placebo at day 1,month 2, and month 6. Main outcome measures Vaccine efficacy against cervical, vulvar, and vaginal intraepithelial neoplasia grade I and condyloma in a per protocol susceptible population that included subjects who received all three vaccine doses, tested negative for the relevant vaccine HPV types at day 1 and remained negative throughmonth 7, and had nomajor protocol violations. Intention to treat, generally HPV naive, and unrestricted susceptible populations were also studied. Results In the per protocol susceptible population, vaccine efficacy against lesions related to the HPV types in the vaccine was 96% for cervical intraepithelial neoplasia grade I (95% confidence interval 91% to 98%), 100% for both vulvar and vaginal intraepithelial neoplasia grade I (95% CIs 74% to 100%, 64% to 100% respectively), and 99% for condyloma (96% to 100%). Vaccine efficacy against any lesion (regardless of HPV type) in the generally naive population was 30% (17% to 41%), 75% (22% to 94%), and 48% (10% to 71%) for cervical, vulvar, and vaginal intraepithelial neoplasia grade I, respectively, and 83% (74% to 89%) for condyloma. Conclusions Quadrivalent HPV vaccine provided sustained protection against low grade lesions attributable to vaccineHPV types (6, 11, 16, and18) and a substantial reduction in the burden of these diseases through 42 months of follow-up. Trial registrations NCT00092521 and NCT00092534. INTRODUCTION Human papillomaviruses (HPVs) are responsible for about 500 000 cases of cervical cancer a year globally and 10 million further cases of high grade cervical intraepithelial neoplasias (grades II or III), immediate precursors to malignancy. It is estimated that 30 million women and men acquire anogenital warts (condyloma acuminata) or low grade cervical intraepithelial neoplasia each year, which may be an underestimation given the inadequacy of reporting in many countries and evidence of a rising incidence over time. Although many low grade lesions of the lower genital tract resolve spontaneously in immunocompetent subjects, this type of lesion contributes greatly to the clinical and economic burden of HPV disease in women. The psychosocial 4 and economic implications of condyloma are substantial and reflect, in part, the high transmission rates and inadequacyof available treatment options in achieving prolonged response rates. Cervical intraepithelial neoplasia grade I can contain a variety of low or high risk HPV types, whereas anogenital warts are (in up to 90% of cases) caused by either of two low risk HPV types—namely, 6 and 11. 13 14 The quadrivalent HPV vaccine (for types 6, 11, 16, and 18) has the potential to prevent about 70% of cervical cancers and 90% of condyloma by targeting HPV types 16 and 18 and types 6 and 11, respectively. Clinical trials have shown that in the per protocol population (that is, subjects naive to a given HPV type(s) at baseline and throughout the three dose vaccination) vaccine efficacy against cervical intraepithelial neoplasia grade II-III or adenocarcinoma in situ was 99% (95% confidence interval 93% to Correspondence to: J Dillner, Department of Medical Microbiology, Lund University, Malmö University Hospital, SE20502 Malmö, Sweden [email protected] Cite this as: BMJ 2010;340:c3493 doi:10.1136/bmj.c3493 BMJ | ONLINE FIRST | bmj.com page 1 of 9 100%). Efficacy against vulvar and vaginal intraepithelial neoplasia grade II-III was 100% (72% to 100%). High efficacy against condyloma has also been demonstrated (100% (92% to 100%)). These data have led to regulatory approval of the vaccine in roughly 100 countries for the prevention of cervical cancer, cervical cancer precursor lesions, and condyloma in girls and women aged 9-26 years. In some countries, the approved indication also includes vulvar and vaginal cancers. The contribution of HPV types 6, 11, 16, and 18 to low grade neoplasias has not beenwell elucidated. The HPV types have been found in 25-50% of low grade cervical and vulvovaginal neoplasias, but assigning causality is difficult because most of these lesions containmultipleHPV types.Whether elimination of some of the HPV types in a multiple infection will prevent disease can be proved only through vaccination. This report represents a combined analysis of quadrivalent HPV vaccine protocols 013 (FUTURE I trial) and 015 (FUTURE II trial), focusing on the efficacy of the vaccine in preventing low grade cervical and vulvovaginal lesions (grade I neoplasias and condyloma) after an average of 42 months of follow-up. We also sought to describe the proportion of the low grade disease burden that can be prevented by vaccination against HPV types 6, 11, 16, and 18. METHODS Study designs Data are considered from two international, double blind, placebo controlled, randomised efficacy trials of the quadrivalent HPV vaccine (protocol 013 (FUTURE I, NCT00092521) and protocol 015 (FUTURE II, NCT00092534)). These trials were similar in design and infrastructure and were conducted among women aged 16-26 years fromNorth America, Latin America, Europe, and Asia Pacific. Primary efficacy end points assessed in protocol 013 included (a) condyloma, vulvar and vaginal intraepithelial neoplasia, or vulvar and vaginal cancer related to HPV types 6, 11, 16, or 18; and (b) cervical intraepithelial neoplasia, adenocarcinoma in situ, or cervical cancer related toHPV types 6, 11, 16, or 18. The primary efficacy end points assessed in protocol 015 were cervical intraepithelial neoplasia grades II-III and cervical cancer related to HPV types 16 or 18. Pregnant women and those with a history of >4 lifetime sexual partners or history of an abnormal cervical smear test result were not eligible to participate in these trials. The institutional review board at each participating centre approved the protocol, and informed consent was obtained from all participants. The current report details the complete follow-up data from protocols 013 and 015, representing a mean follow-up period of 42 months. Vaccine In each of the studies, eligible subjectswere randomised in a 1:1 ratio to receive three doses of the quadrivalent (HPV types 6, 11, 16, and 18) LI virus-like particle vaccine (Gardasil,Merck,Whitehouse Station,NJ,USA) or placebo at day 1,month 2, andmonth 6 (additional vaccination regimens included as part of protocol 013 did not contribute to the data reported here). Study procedures Detailed cervicovaginal examinationswere performed at the scheduled day 1 and month 7 visits, including cervical collections for cervical smear testing (ThinPrep, Cytyc Corporation, Boxborough, MA, USA), Details of different patient populations analysed for efficacy of quadrivalent human papillomavirus (HPV) vaccine Per protocol susceptible population