This month’s clinically appraised topic looks at a major study’s findings into the long-term effectiveness of the HPV vaccine
CLINICAL BOTTOM LINE:
HPV vaccination has excellent long-term efficacy with few adverse effects.
CLINICAL SCENARIO:
A young woman asks whether she should have the vaccine to prevent cervical cancer. She wants to know the effect of the vaccine on preventing infection by human papillomavirus (HPV).
QUESTION:
Among young women, does the HPV vaccine reduce infection by HPV, compared to those who have not been vaccinated?
SEARCH STRATEGY:
Pubmed – Advanced search: cervical vaccination. Limits: RCT and last three years.
CITATION:
Romanowski B, et al. Sustained efficacy and immunogenicity of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine: analysis of a randomised placebo-controlled trial up to 6.4 years. Lancet 2009; 374:1975-85.
STUDY SUMMARY:
A blinded, multicentre, randomised, placebo-controlled trial in 27 sites in three countries (Brazil, Canada, and USA), involving an initial study and a follow-up study. Of the initial 1113 women randomised in the initial study, 560 were randomised to the vaccine group, and 553 to the placebo group. Of those initial women 393 from the vaccine group and 383 from the placebo group continued on to the follow-up study. Participants were women aged 15-25 years, with normal cervical cytology – that is HPV-16/18 seronegative, and oncogenic HPV DNA-negative at screening. Exclusion criteria included: administration of other HPV vaccine; randomisation failure; randomisation code broken; did not receive three doses; protocol violations; administration of protocol-prohibited drug; non-compliance with vaccine schedule (received outside of protocol-specified intervals); missing HPV DNA, serology, or cytology at month 0 or at screening; seropositive for HPV 16 or HPV 18 or abnormal cytology at screening; initially seropositive or unknown antibody status; intercurrent infection with HPV 16 or HPV 18; non-compliance with blood sampling schedule; essential serological data missing.
Women in the initial study were followed for up to 18 months, and were eligible for the three year follow-up study if they had received three doses of vaccine or placebo (at baseline, one and six months after randomisation), and remained masked from treatment allocation. The total amount of time women were followed for the initial and follow-up study after initial vaccination dose was up to 6.4 years. Cervical samples were tested for HPV DNA every six months.
Intervention (n=560 randomised, n=393 in follow-up study): three doses of HPV-16/18 AS04-adjuvanted vaccine.
Control (n=553 randomised, n=383 in follow-up study): equivalent number of doses with placebo.
Outcomes:
Primary outcome was effect of the vaccine in preventing infection by HPV 16, HPV 18 or both, up to 6.4 years. Secondary outcomes included long-term safety and immunogenicity of the vaccine, long-term effect against new and persistent infections, and cytological and histopathological abnormal changes associated with oncogenic HPV types.
Validity:
Randomisation by stratified block with centralised internet-based allocation. Investigators and women participating in the long-term follow-up study remained blinded to allocation. Follow-up of women participating in follow-up study was similar in both arms (90% vs 91%). Primary analysis of efficacy for virological outcomes (new and persistent infection) was done on the according-to-protocol (ATP) cohort, and for cytohistological outcomes on the total-vaccinated cohort (TVC). Only those women who received at least one dose of placebo or vaccine, and for whom outcome measures were available, were included in the TVC combined analysis for the initial and follow-up studies. The TVC was referred to as an intention-to-treat (ITT) cohort in previous publications of this study. Demographic profile of participants was similar.
RESULTS:
There were significantly fewer infections of HPV 16/18 in the vaccine group and efficacy remained high up to 6.4 years (table). Vaccine efficacy for persistent infections was 100 per cent. There was no significant difference between the groups for serious adverse events.
Comments:
The study was conducted on participants naïve to oncogenic HPV infection at the time of vaccination, and therefore accurately represents the target population of adolescents not yet sexually active who are most likely to benefit from such a vaccination.
The results for the HPV-16/18 AS04-adjuvanted vaccine can be used as a comparison for the HPV vaccine being introduced in New Zealand, as it also focuses on HPV type 16 and 18. ✚
Reviewers: Kirsten Lovell, 3rd year nursing student, University of Auckland; Dr Andrew Jull, associate professor, University of Auckland and nurse advisor – quality, Auckland District Health Board.
|
Results with 95% confidence intervals for up to 6.4 years Follow-up |
|||||
|
|
Vaccine |
Placebo |
AD (95% CI) |
RRR (95% CI) |
NNT (95% CI) |
|
New infection |
4 (1.0%) [n=401] |
70% (18.8%) |
17.8% (13.9% to 22.2%) |
95% (87.4% to 98.7%) |
6% (5% to 7%) |
|
Serious adverse events |
30 (8.0%) |
37 (10.0%) |
2.0% (-2.1% to 6.1%) |
– |
NS |
NS = not significant
