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Rapport fra Kunnskapssenteret nr 05 - 2007 - Systematisk oversikt

Prophylactic vaccines against human papillomavirus

( 21.04.2008 )
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Nilsen E , Alfsen C G, Feiring B , Skjeldestad F E, Steen R , Sæterdal I. Rapport fra Kunnskapssenteret nr 05 - 2007. ISBN 978-82-8121-145-2 ISSN 1890-1298

3-page executive summary

Background
The Norwegian Knowledge Centre for the Health Service (NOKC) was requested by the Norwegian Institute of Public Health to do a health technology assessment (HTA) on the effectiveness of prophylactic vaccines against human papillomavirus (HPV) infection. This part of the report, has evaluated the effectiveness and safety of such vaccines. Part two evaluates the cost-effectiveness and will be published at a later stage.

More than 120 subgroups of HPV have been identified, and at least 14 of these are oncogenic types. Persistent HPV infections are necessary, but not sufficient for development of cervical cancers. HPV types 16 and 18 cause about 70% of cervical cancers and HPV 6 and 11 cause 90% of anogenital warts.

HPV infection is common in sexually active women. Infections with HPV and cellular abnormalities in the cervix are dynamic processes. Most infections are incidental but sometimes the infections become persistent and the risk to generate cellular abnormalities is higher.

Two vaccines against human papillomavirus are developed, Gardasil® and Cervarix®. Gardasil is developed by Merck and is marketed in Europe by Sanofi Pasteur MSD, while Cervarix is developed by GlaxoSmith Kline. Both vaccines are type specific and are directed against the two most common causes of cervical cancer in the world, type 16 and 18. Gardasil, in addition, includes HPV 6 and 11 that are related to anogenital warts.

Objective
This report is a systematic review of the literature on effect and safety of prophylactic vaccines against human papillomavirus infection. The report will be part of the basis for a working group at the Norwegian Institute of Public Health. The working group shall advice the Ministry of Health and Care Services on the issue if vaccines against HPV will be implemented in the Norwegian vaccination program.

Methods
The work was carried out together with a review team of external professionals. Systematic searches were performed after published systematic reviews and randomized controlled trials in international databases. The literature was evaluated in a stepwise manner according to general principles of HTA. Studies that fulfilled our predetermined inclusion criteria were assessed and summarized.

Results
Ten randomized controlled trials are included in the report, of which two are follow-up studies. More than 5000 participants are included. Four of the publications evaluated immunogenicity and safety, while six publications in addition evaluate the efficacy of the vaccines against incident/persistent infection, cytological abnormalities (ASC-US, LSIL, HSIL) and/or cervical intraepithelial neoplasia (CIN 1, 2 and 3). In addition to analysis performed in the per protocol population (PPP); the studies on Cervarix includes results based on Intention-To-Treat (ITT) population, while the studies on Gardasil includes results based on modified ITT (MITT) population. These two populations (ITT and MITT) are almost identical and include participants who received at least one vaccination. In summary the results for Cervarix and Gardasil are as follows:

Efficacy of the vaccine against HPV 16/18 (Cervarix)
In the ITT analyses, vaccine efficacy was 83% (62.0-92.4%) and 94.4% (77.9-99.3) against incident infection after 27 and 48 months, respectively. In the PPP analyses, vaccine efficacy was 91.6% (64.5-98%) and 96.9% (81.3-99.3%) against incident infection after 18 and 48 months, respectively.
In the ITT analyses, vaccine efficacy was 95.1% (63.5-99.3%) and 100% (57.0-100%) against persistent infection (at least two positive HPV-DNA PCR assays for the same viral genotype separated by at least five or ten months) after 27 and 48 months, respectively. In the PPP analyses, vaccine efficacy was 100% (47.0-100%) and 100% (33.6-100%) against persistent infection after 18 and 48 months, respectively.

In the PPP analyses, no cases of CIN 2/3 were found in the vaccine group compared to five in the control group. There were not possible to calculate any meaningful estimates for this endpoint.

Efficacy of the vaccine against HPV 6/11/16/18 (Gardasil)
After 36 months follow-up, vaccine efficacy was 88% (72-96%) against persistent infection (at least two positive HPV-DNA PCR assays for the same viral genotype separated by at least four months or positive test during the last visit before lost to follow-up ) in the MITT cohort and 89% (70-97%) in the per protocol cohort. In the PPP analyses, no cases of CIN 2/3 were found in the vaccine group compared to three in the control group. There were not possible to calculate any meaningful estimates for this endpoint.

Safety
No serious adverse events related to vaccination, occurred in either vaccine or control groups. Most included participants, both in the vaccine and control group, had injection site adverse events as pain, swelling and redness. Most adverse events were of mild or moderate intensity.

Comments
The included studies show high HPV type specific vaccine efficacy against incident/ persistent infections, in addition to cytological and histological endpoints within the tested time interval. The follow-up time is too short (< 4 years) to conclude about the duration of the vaccine effect. The requirements of booster doses are still unknown. The longterm data regarding effects and sideeffects of the two vaccines will be important.


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Prophylactic vaccines against human papillomavirus
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