Human papillomavirus (HPV) is considered the most common sexually transmitted agent worldwide and more than 100 types of HPV have been identified. Persistent infection with oncogenic HPV is recognized as a necessary cause of cervical cancer. Approximately 70% of cervical cancers in the world are attributed to two of the most common HPV types, 16 and 18.
This systematic review was carried out to assess whether the HPV vaccines currently offered to 11 to 12 year-old girls in Norway are also effective as a catch-up vaccination for women up to age 26 in preventing HPV-related diseases.
For HPV vaccination of women aged 16 and older:
- The results show a protective effect of HPV vaccination against Cervical intraepithelial neoplasia grade 2 and higher (CIN2+) associated with the HPV types included in the vaccines (high quality of the evidence), and indicate a protective effect against all CIN2+ lesions (independent of HPV types in the lesions) (moderate quality of evidence).
- The quadrivalent HPV vaccine protects against genital warts (high quality evidence).
- Long-term (up to 8 years) follow-up after HPV vaccination indicates little or no difference in the occurrence of serious adverse events when compared to the control groups (moderate quality of evidence).
Human papillomavirus (HPV) is considered the most common sexually transmitted agent worldwide and more than 100 types of HPV have been identified. However, a small number of HPV types contribute to a large proportion of HPV-related diseases. Persistent infection with oncogenic HPV is recognized as a necessary cause of cervical cancer. Approximately 70% of cervical cancers in the world are attributed to two of the most common HPV types, 16 and 18.
Efficient prophylactic vaccines can have an important public health impact. Under several plausible assumptions, an economic evaluation suggest that introduction of HPV 16/18 type vaccination to current screening in Norway may be a cost-effective strategy for further reductions in cervical cancer incidence and mortality. Prophylactic HPV vaccination was introduced in the Norwegian childhood immunization program in 2009. It is unclear whether vaccinating older girls will also be beneficial, and The Norwegian Institute of Public Health requested a Health Technology Assessment to ascertain the potential effectiveness of a catch-up vaccination of females up to 26 years of age.
To carry out a systematic review in order to assess whether HPV vaccines currently offered to 11- to 12-year-old girls in Norway are also effective as a catch-up vaccination for women up to age 26 in preventing HPV-related diseases.
We have conducted this systematic review in accordance with the Handbook for the Norwegian Knowledge Center for the Health Services.
Two review authors reviewed all citations to identify relevant publications according to pre-specified criteria. Full text publications of potentially eligible references were retrieved, and we assessed all included references for risk of bias according to the Handbook. We extracted data from the included references using a pre-designed data recording form. These steps were done independently and then jointly by two review authors or by one of the review authors and then checked by one of the others.
We entered and analyzed data using the Review Manager software and calculated risk ratios and the associated 95 % confidence interval for the estimate of effect. We applied the GRADE method (Grading of Recommendations Assessment, Development and Evaluation) to assess the overall quality of evidence for each outcome.
The literature search for randomized controlled trials on HPV vaccines was conducted in October 2012. We identified 616 references. In addition, we received 12 references from the pharmaceutical companies with marketing authorization for HPV vaccines in Norway. After reading titles and abstracts and full texts, we included 46 references in the present report.
The main findings of the review are:
The pooled estimate for cervical intraepithelial neoplasia grade 2 and higher (CIN2+) show a borderline statistically significant difference in CIN2+ risk between the vaccine and the control groups (intention-to treat population, four-year follow-up ) (RR= 0.80; 95% CI= 0.62, 1.02). The quality of the evidence for this outcome is moderate.
The pooled estimate for CIN2+ lesions associated with the HPV types in the vaccine shows a statistically significant difference in the risk of these lesions between the vaccine and control groups (intention-to treat population, four-year follow-up ) (RR= 0.54; 95 % CI= 0.44, 0.67). The quality of the evidence for this outcome is high.
The pooled estimate for serious adverse events shows that there is no statistically significant difference between the vaccine and the control groups (safety population, longest reported follow-up) (RR= 0.99; 95 % CI= 0.91, 1.08). The quality of the evidence for this outcome is moderate.
When combining the data for all pre-cancerous cervical lesions (CIN2+) in young women our results indicated a protective effect of these lesions. However, there is some uncertainty about the effectiveness of prophylactic HPV vaccination. The uncertainty is due to borderline significant results for CIN2+ lesions in the intention-to-treat and the per protocol population after a four-year follow-up.
Examining CIN2+ lesions independent of HPV type may reflect the possible wider public health impact of a HPV vaccination. Previous meta-analyses presented mostly results for lesions containing the HPV types included in vaccines under study (64;65). In line with previous meta-analyses, we found that assumed risk in the placebo group for HPV type related CIN2+ lesions is 22 per 1000, and the corresponding risk in the vaccine group is 12 per 1000. The confidence in this estimate (quality of the evidence) is high. High grade cervical lesions were chosen as the outcome of interest because they are immediate precursors to cervical cancer, and because they were described as the best outcome to use when examining the effect of HPV vaccination.
There is some uncertainty regarding the long-term effect of the vaccines due to the relatively short follow-up periods of the clinical trials. Since we will only know the true effect of HPV vaccination on cervical cancer and mortality outcomes in 20-30 years, long-term follow-up data for the vaccinated populations are important.
No statistically significant difference in serious adverse events between the vaccination and the placebo groups were found. Nevertheless, the number of cases within the clinical studies is not sufficient to determine the occurrence of rarely occurring (severe) adverse events in a reliable way. Long-term safety needs to be assessed in future trials and in possible follow-up publications of existing trials.
We have conducted a systematic review based on primary clinical trials of a randomized controlled design. Randomized controlled trials are expected to be more robust against bias than observational studies, and are therefore the preferred design for studies of effect of an intervention. However, to assess long-term follow-up data and outcomes related to harm, observational and registry studies might be more appropriate.
National vaccination programs have already been started in many countries, but the true effect on cervical cancer outcomes of this vaccine will be observed 20-30 years from now. It remains to be seen whether we will see a dramatic reduction in HPV- associated diseases, such as cervix, vulva, vagina, anus, oral cavity, and oropharynx and tonsil cancers, as a result of a national vaccination programs.
Our systematic review of the effect of a catch-up HPV vaccination of young women demonstrates that:
There is a protective effect of HPV vaccination against CIN2+ lesions associated with the HPV types in the vaccines (high quality of the evidence) and against all CIN2+ lesions (independent of HPV types in the lesions) (moderate quality of evidence).
Long-term (up to 8 years) follow-up after HPV vaccination indicates little or no difference in the occurrence of serious adverse events in the vaccine group when compared to the control group (moderate quality of evidence).
Further research is needed to demonstrate if there is an association between HPV vaccination and incidence of HPV related cancers, cancer related mortality and long-term safety.