Published: 8 December 2016
Prescriber Update 37(4): 52-53
Gardasil 9, the next generation human papillomavirus (HPV) vaccine, provides protection against the four HPV subtypes found in Gardasil (HPV 6, 11, 16 and 18) and an additional five subtypes (HPV 31, 33, 45, 52 and 58).
HPV is the most common sexually transmitted infection worldwide. The lifetime risk for HPV infection is greater than 50%. Most HPV infections are asymptomatic and 90% of HPV infections are cleared within 24 months1.
Infection with one of the numerous low-risk HPV types may result in genital warts. Infection with high-risk types can cause cancer, particularly in the 10% of infections that are not cleared. The risk of cancer is increased with smoking and infection with multiple cancer-causing HPV subtypes1.
The different cancer types where at least some cases can be associated with HPV infection and the incidence rate in New Zealand are shown in Table 1.
|Cancer||Incidence per 100,000 per year||Number of registrations 2013|
|Cervical cancer||6.3 (Mortality rate 1.4)||158|
|Anal||1.0 in men, 1.2 in women||32 in men, 38 in women|
|Oropharyngeal||0.4 in men, 0.1 in women||11 in men, 5 in women|
|Tonsil||1.6 in men, 0.3 in women||48 in men, 9 in women|
Infection with HPV can be avoided by vaccinating with the HPV vaccine and/or using condoms. Although there is a screening programme for cervical cancer, there are no screening programmes for other cancers caused by HPV infection. The screening programme is not 100% effective, and women still die from cervical cancer (Table 1).
The prevalence of different subtypes of HPV varies between regions. For Australia and New Zealand, 86.5% of HPV-induced cervical cancer is caused by the HPV subtypes included in the Gardasil 9 vaccine1.
Gardasil 9 was approved for use in New Zealand based on clinical studies which included more than 15,000 subjects who received at least one dose of Gardasil 93,4,5,6,7,8,9. Medsafe’s assessment of these studies has been published (www.medsafe.govt.nz/publications/OIAContents.asp).
In the pivotal study, Gardasil 9 was compared with Gardasil using a three-dose regimen in females aged 16 to 26 years3. Gardasil was used as the comparator since it would have been unethical to use a placebo. The study was conducted at multiple sites, including sites in New Zealand. Gardasil 9, like Gardasil, is only effective if given prior to first sexual contact/exposure to HPV. Therefore, the results of this study were analysed according to whether there was evidence that the clinical trial subjects were HPV-uninfected. The incidence of high-grade cervical, vulvar and vaginal disease in the HPV-uninfected group was 2.4 per 1,000 person-years in the Gardasil 9 group and 4.2 per 1,000 person-years in the Gardasil group3.
The efficacy results from the pivotal study were extrapolated (immunologically bridged) to younger girls and boys4,5. Gardasil may also be administered at the same time as meningococcal and Tdap vaccines6,8.
The immunogenicity of Gardasil 9 in females who had already been vaccinated with Gardasil was also assessed7. In this study, saline was used as the placebo comparator. The frequency of injection site reactions was 9.1 in every 10 subjects given Gardasil 9 and 4.4 in every 10 subjects given the placebo. The frequencies of systemic adverse events were 3.1 in every 10 of the Gardasil 9 subjects and 2.6 in every 10 of the placebo group7.
The immunological response to a two-dose schedule of Gardasil 9 has also been investigated in a non-inferiority trial. Two timing intervals were assessed at 6 months and 12 months. Non-inferiority was demonstrated for both time points. Antibody titres were higher when the two doses were separated by a period of 12 months rather than 6 months10.
The long-term efficacy of Gardasil 9 is still to be determined. Of interest, studies on Gardasil have now reported data for up to nine years since vaccination with no decrease in efficacy11.
An integrated safety analysis of all the clinical studies has been published12. The most common adverse events were injection site reactions, headache and pyrexia. Twenty of the 15,875 subjects given Gardasil 9 discontinued the vaccination course because of an adverse event. Recent safety concerns with Gardasil have focused on postural orthostatic tachycardia syndrome (POTS) and complex regional pain syndrome (CRPS). Two subjects were diagnosed with POTS, one did not have recurrent episodes, and in the other subject, the events occurred more than three years after vaccination. The two cases of CRPS were attributed to a previous injury.
Other concerns have been raised regarding the use of Gardasil. It has been suggested that vaccination with HPV vaccine may promote promiscuity. Several studies have been conducted, and to date, none has reported any change in sexual behaviour after vaccination13,14.
Overall, Gardasil 9 has improved efficacy, and the safety profile is consistent with that for Gardasil. There was an increase in the number of injection site reactions compared to Gardasil, but this is expected as the vaccine contains an increased number of antigens.
Please continue to report all suspected adverse reactions to CARM (https://nzphvc.otago.ac.nz/).