Cervical Cancer News Information Blog | HPV Vaccines, The Pap Smear Test, and the Latest Cervical Cancer Research

Helsinki, Finland

Department of Obstetrics and Gynecology, Helsinki University Hospital, Helsinki, Finland

In this article, the author offers a concise, practical summary of the research findings reported in Paavonen J, Naud P, Salmerón J, et al; the HPV PATRICIA study group. Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young women. Lancet. 2009;374(9686):301-314.

Key research findings

● The HPV-16/18 AS04-adjuvanted vaccine is highly efficacious against CIN2+ associated with HPV 16/18 and nonvaccine oncogenic HPV types

● The vaccine shows substantial overall efficacy in cohorts relevant to universal mass vaccination and catch-up programs

● The safety profile of the vaccine is favorable and the vaccine is well tolerated

The final analysis of the Papilloma Trial Against Cancer in Young Adults) study shows that the HPV-16/18 AS04-adjuvanted vaccine (Cervarix, GlaxoSmithKline) has high efficacy against the lesions that can eventually lead to cervical cancer. The vaccine also shows crossprotective efficacy against other oncogenic HPV types closely related to HPV-16/18. Furthermore, the vaccine has demonstrated efficacy in women and girls likely to benefit from universal mass vaccination and catch-up programs. The findings were recently reported in The Lancet.1

Protocol
In the PATRICIA study, females aged 15 to 25 years were randomly assigned to receive the HPV- 16/18 vaccine Cervarix (vaccine) or a hepatitis A vaccine (control). The primary end point was to assess vaccine efficacy against cervical intraepithelial neoplasia grade 2 or worse (CIN2+). Details on the collection of samples and other specifics were previously published.2 Results from 3 cohorts were considered as part of the final analysis. The according-to-protocol for efficacy (ATP-E) cohort included all participants who received 3 vaccine doses (at 0, 1, and 6 months), had normal or low-grade cytology at baseline, complied with the protocol, and were evaluable for the primary end point of CIN2+ (vaccine recipients = 8093, controls = 8069). The total vaccinated cohort (TVC) represented the young sexually active population and included all participants who received at least 1 vaccine dose regardless of their baseline HPV status (vaccine recipients = 9319, controls = 9325). The TVCnaïve cohort represented participants who have not yet had sex and who had no evidence of oncogenic HPV infection at baseline (vaccine recipients = 5822, controls = 5819).

Results
The mean follow-up was slightly less than 3 years after the third dose. In the primary analysis, which considered protection against CIN2+ that was associated with HPV-16/18, vaccine efficacy was 93%. In another analysis, which assigned the cause of lesions infected with multiple oncogenic HPV types (according to a type assignment algorithm) to a single type, vaccine efficacy was 98%. When the HPV type detected in the lesion was not considered in the analysis, vaccine efficacy was 30% in the TVC and 70% in the TVC-naive. Corresponding values against CIN3+ (the immediate precancer of invasive cervical cancer) were 33% and 87% in the TVC and TVC-naïve cohorts, respectively, an indication that HPV-16/18 plays a larger role in CIN3+. CIN3+ is considered to be a more reliable end point than CIN2+. Longer follow-up was required to observe the vaccine's effect on CIN2+ lesions resulting from newly acquired infections because no change in CIN2+ lesions derived from prevalent infections or low-grade lesions would be anticipated with the vaccine. Delayed separation of the Kaplan- Meier curves showing the cumulative incidences of CIN2+ in the study population support this finding.

The vaccine was also shown to be protective against other oncogenic HPV types—most notably HPV-31 (related to HPV-16), HPV-45 (related to HPV-18), and HPV-33. Overall, the vaccine efficacy was calculated at between 37% and 54% against 12 nonvaccine oncogenic HPV types. Worldwide, HPV-16/18 is thought to be responsible for 70% of cervical cancer, while other oncogenic HPV types cause the remaining 30%. The 5 HPV types previously named—HPV-16, 18, 31, 33, and 45—account for approximately 82% of all cases of cervical cancer. Given its cross-protective efficacy, this vaccine could provide protection against cervical cancer that is 11% to 16% greater than that which it provides against HPV-16/18.

Along with the reduced number of lesions, HPV-vaccine recipients in the TVC and TVC-naive cohorts received significantly fewer referrals for colposcopy and underwent significantly fewer cervical excision procedures. In the TVC-naïve cohort, colposcopy referrals were 26% lower and cervical excision procedures were 69% lower than in controls. Fewer cervical excision procedures could lead to a reduction in preterm births and other adverse pregnancy outcomes that have been associated with treatment of CIN.

Discussion
The strengths of the study include its duration; size; and diversity of participants, who came from North America, Latin America, Europe, and Asia-Pacific regions. Continued monitoring through Pap smears and HPV testing in all women, whether vaccinated or unvaccinated, is of vital importance and must be stressed. However, HPV vaccination has the potential to substantially reduce both the incidence of cervical cancer and precancer as well as the numbers of colposcopy referrals and cervical excision procedures. The results observed in the TVCnaive cohort give a good indication of the potential benefit of vaccinating adolescents before they become sexually active—ie, the population being targeted for universal mass vaccination.

The study has some limitations. First, because of the high efficacy of the vaccine against HPV-16/18, a larger number of colposcopy referrals were made in the control group than in the vaccine group. This could have led to detection of more lesions caused by nonvaccine HPV types. Data for persistent infection are not affected by this bias, however, and those results also indicate protection against important nonvaccine oncogenic HPV types. Other study limitations include possible underestimation of the true incidence of CIN2+ lesions from nonvaccine HPV types, since those lesions take longer to develop than lesions caused by HPV-16/18. Caution should be exercised in applying these results to the general population because they are based on completion of the 3-injection series by a high proportion of women (92%), a goal that might not be possible in real life.

In terms of safety, the HPV-16/18 AS04-adjuvanted vaccine and the control vaccine had similar profiles. When data from almost 30 000 girls and women taking part in phase 2 and 3 trials (including ours) were pooled, most recipients tolerated the vaccine well and the safety profile was favorable in participants of all ages.

Currently, the target population for HPV vaccination is girls and young women aged 11 to 26 years prior to their first sexual experience. The most efficient way to stop the virus is to also vaccinate the other half of the sexually active population: boys and men. Studies are now ongoing to develop the best vaccination strategy.

Summary
Our results show that the efficacy of the HPV-16/18 AS04-adjuvanted vaccine is high in protecting women and girls against CIN2+ lesions associated with HPV- 16/18 and nonvaccine oncogenic HPV types. The vaccine also has a substantial overall effect in populations that have been targeted for universal mass vaccination and catch-up programs.

References
1. Paavonen J, Naud P, Salmerón J, et al; the HPV PATRICIA Study Group. Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young women. Lancet. 2009;374(9686):301-314.
2. Paavonen J, Jenkins D, Bosch FX, et al; HPV PATRICIA study group. Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial. Lancet. 2007;369(9580):2161-2170.

Author disclosure: Funding for the study was provided by GlaxoSmithKline Biologicals. Dr Paavonen has received funding through the University of Helsinki to conduct HPV vaccine studies for Merck and GSK.