Human papillomavirus (HPV) is the most common sexually transmitted agent worldwide and more than 100 types of HPV have been identified.
This systematic review was carried out to assess whether vaccinating boys with the same HPV vaccines currently offered to 11 to 12-year-old girls in Norway would be effective in preventing HPV-related diseases among males.
The five included references represent two different clinical trials. The efficacy data is from one large randomized study that examined the efficacy of prophylactic vaccination of males aged 16 to 26 with the quadrivalent HPV vaccine.
- This study shows that the quadrivalent vaccine is efficacious in preventing external genital lesions, caused by infection with HPV 6, 11, 16 or 18, in males aged 16-26 (moderate quality of evidence).
- Genital warts are the main type of genital lesions prevented by vaccinating males (moderate quality evidence).
- Effect data on precancerous lesions such as penile intraepithelial neoplasia (PIN2+) are sparse because of limited (three years) follow-up, and the results are not conclusive (low quality evidence). Assessement of precancerous lesions probably needs longer follow-up time.
- In the subpopulation of men who have sex with men, the vaccine reduced the risk of anal intraepithelial neoplasia (AIN2+) (low quality evidence).
- Three years follow-up after HPV vaccination indicated little or no difference in the occurrence of serious adverse events in the vaccine group compared to the control group (moderate quality of evidence).
Long-term follow-up studies are required to demonstrate if there is an effect of HPV vaccination on cancer related mortality and cancer prevalence (i.e. penile, anal or oropharyngeal cancer).
Human papillomavirus (HPV) is the most common sexually transmitted agent worldwide and more than 100 types of HPV have been identified. The WHO International Agency for Research on Cancer concluded that there was sufficient evidence to support a causal role of certain types of HPV infection in carcinoma of the cervix, vulva, vagina, penis, anus and oropharynx. HPV16 and 18 cause more than 90% of the HPV-related cancers. Variable proportions of certain non-cervical cancers (e.g. anal, penis and oropharyngeal) are HPV-related. Oncogenic HPVs, particularly HPV 16, are associated with anogenital cancers (anus, vagina, vulva and penis), and oropharyngeal cancers.
Efficient prophylactic vaccines could possibly have an important public health impact. Under several plausible assumptions, an economic evaluation from 2007 suggested that introduction of HPV 16/18 type vaccination of 12-year-old girls in Norway may be a cost-effective strategy for further reductions in cervical cancer incidence and mortality. Norway introduced prophylactic HPV vaccination in the childhood immunization program in 2009. It is unclear whether vaccinating boys will also be beneficial, and The Norwegian Institute of Public Health requested a Health Technology Assessment to ascertain the potential effectiveness of vaccinating males aged 12.
To carry out a systematic review in order to assess whether vaccinating boys with the same HPV vaccines currently offered to 12-year-old girls in Norway would be effective in preventing HPV-related diseases among boys.
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 prespecified criteria. We retrieved full text publications of potentially eligible references, and 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. One review author extracted data from the included references and another review author verified the data.
We entered and analysed data using the Review Manager software and calculated risk ratios and associated 95% confidence intervals for the estimates 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 five included references represent two different clinical trials. One large randomized study (n=4055) that shows results of prophylactic administration of quadrivalent HPV vaccine is the basis for the efficacy data in this systematic review. This study shows that the HPV vaccine is efficacious in preventing external genital lesions with infection of HPV 6, 11, 16 and 18 in males aged 16 to 26 (RR 0.33 (CI 0.25-0.44). Among the external genital lesions, the outcome that predominates is genital warts, and a prevented by vaccinating was observed (RR 0.39 (CI 0.25-0.58). Other precancerous lesions probably need studies with a longer follow up time. So far with only 3 years follow up, there was very sparse data on the precancerous penile lesions (PIN2+) and the results are not conclusive (RR1.2 (CI 0.37-3.94). For the subpopulation of men who have sex with men, the vaccine reduced precancerous anal lesions (AIN2+) (RR 0.46 (CI 0.27-0.79) (low quality evidence).
Three years follow-up after HPV vaccination indicate little or no difference in the occurrence of serious adverse events in the vaccine group compared to the control group (RR 0.81 (CI 0.16-0.87) (moderate quality of evidence).
There is some uncertainty regarding the long-term effects of the HPV vaccines for males due to the relatively short follow-up periods in the clinical trials. Since we will only know the true effect of HPV vaccination on cancer prevalence and cancer mortality in 20-30 years, long-term follow-up data for the vaccinated populations are important.
There was no statistically significant difference in serious adverse events between the vaccination and the placebo groups. Nevertheless, the number of cases within the clinical studies is not sufficient to determine the occurrence of rarely occurring (and potentially severe) adverse events in a reliable way. Future trials and possible follow-up publications of existing trials should assess long-term safety.
We have conducted a systematic review based on randomized controlled clinical trials. Randomized controlled trials have lower risk of bias than observational studies, and are therefore the preferred design to study the effects of an intervention. However, observational studies will be appropriate to assess long-term follow-up data and monitor outcomes related to harm.
Many countries have already started national vaccination programs for girls, but we will only have evidence on the true effect on cancer outcomes of these programs 20-30 years from now. It remains to be seen whether we will see a dramatic reduction in HPV- associated cancers, such as cervix, vulva, vagina, anus, and oropharyngeal because of the national vaccination program.
HPV vaccine is efficacious in preventing external genital lesions with infection of HPV 6, 11, 16 and 18 in boys and men aged 16-26 years. The main genital lesion prevented is genital warts. There are very sparse data on precancerous lesions (PIN2+) and the results are so far not conclusive with 3 years follow up. HPV vaccination reduced the risk of anal intraepithelial neoplasia (AIN2+) in a subpopulation of men who have sex with men. There is little or no difference in the occurrence of serious adverse events when compared to the control groups.
Further research is needed to demonstrate whether HPV vaccination reduces the incidence of HPV related cancers and cancer related mortality and to get data on long-term safety.