Human papillomavirus vaccination: where to now?

INTRODUCTION Extraordinary developments have occurred since molecular and epidemiological tools have proven that oncogenic human papillomaviruses (HPVs) cause virtually all cervical cancers, as well as a proportion of other anogenital cancers (vulvar, vaginal, anal, penile) and some oropharyngeal cancers (particularly tonsillar). 2 In addition, lowrisk HPV types 6 and 11 are the causative agents of the majority of genital warts, a benign but very common sexually transmitted disease, estimated to occur in up to 10% of the population and with an estimated annual burden of new cases worldwide of 30 million. With the development of viral-like particles and the relatively short translation to phase 3 clinical vaccine trials showing that prophylactic HPV vaccines targeting the two most common causes of cervix cancer, HPV 16 and 18, are safe, immunogenic and efficacious, we now observe the outcome of these vaccines implemented as public health tools in those countries that can afford such programmes. Where coverage has been high to the appropriate target population, reduction in disease has already been seen for those HPV-related diseases with the shortest incubation periods. For example, in Australia the quadrivalent HPV (6, 11, 16, 18) vaccine was started in April 2007 in a comprehensive, national, government-funded, school-based, ongoing programme for girls 12 years of age, with a catch-up program to 26 years of age until December 2009. In this real-life situation, a statistically significant reduction has already been reported in genital warts of almost 60% in young women of vaccine-eligible age. These findings are most likely related to the catch-up component of the programme, rather than the school-based programme. However, with time and continued good vaccine coverage, one would expect a change in sexual health clinics, where treatment of genital warts currently makes up a large component of the work. Genital warts not only carry a huge financial burden, but also cause substantial psychosocial burden and, in immunocompromised patients such as those with HIV infection, can be recalcitrant to standard treatment and difficult to manage. Moreover, although initial registration of HPV vaccines in Australia allowed vaccination of boys 10e15 years of age, there is currently no government or health insurance subsidy for males: consequently only a very small proportion of males have received vaccination. Yet, with the high coverage in young women of around 70%, a significant reduction (28%) in genital warts in males has also been seenda herd immunity effect. Perhaps with the recent phase 3 clinical trial data showing effectiveness of a quadrivalent vaccine in reducing genital warts in males, as well as HPV16/18-related anal intraepithelial neoplasia, the precursor lesion to anal cancer, a case for vaccinating boys as well as girls could ultimately translate into true declines in genital warts, as well as other HPV-related diseases worldwide. In addition, such an approach would take the stigma away from just vaccinating girls and would ultimately decrease HPV-related diseases in men who have sex with men, as well as reducing any potential influence that genital warts and/or HPV infection may have on HIV transmission. Next in the time sequence of HPV-related diseases, one expects to see a reduction in incidence of abnormal Pap cytology in a vaccinated cohort. In a review of cervical Pap smear abnormalities recorded on the Victorian Cervical Cytology Registry, one of Australia’s population-based Pap test registers, a modest and significant decrease in high-grade abnormalities was demonstrated in women aged <18 years (<16 years at vaccination), during 2007e2009 when the HPV vaccination programme was delivered, compared with the prevaccination period. We expect to see similar reduced changes in Pap abnormalities in those countries with high coverage of school-based programmes with the bivalent vaccine, such as the UK. Such changes will bring along other challenges, as, ultimately, reduction in cytology screening abnormalities will translate into a reduced positive predictive value for Pap cytology for abnormalities, requiring more sensitive assays for screening such as HPV DNA assays, with triage to cytology for those found positive for HPV infection. As the success of Pap screening programmes has relied on extensive education of clinicians as well as consumers, such potential changes in practice will need to be well articulated at all levels, reinforced, audited and modified to ensure effective outcomes. Ultimately, and it will take decades given the natural history of HPV infection, a decline in HPVrelated cancers due to types 16 and 18 will be seen. But what does all this mean for the rest of the world, especially in low and middle income countries where much of the burden of disease is seen globally? First, in considering the fact that the currently licensed cervical cancer vaccines are relatively new and aimed at preadolescent and adolescent girls (an age group not commonly targeted for vaccination), as well as being vaccines for prevention of diseases occurring years later, and the necessary infrastructure for vaccine rollout is lacking, we should take a step back and learn from hepatitis B vaccination programmes. Inclusion of HPV vaccination in national immunisation programmes, possibly ‘piggybacking’ on the well-established WHO expanded programme on immunisation (EPI) for even the most resource-poor countries would be one way to achieve such a goal. This potential use of the Department of Microbiology and Infectious Diseases, The Royal Women’s Hospital, Parkville, Australia Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, Australia Infectious Disease and Microbiology, Murdoch Childrens Research Institute, University of Melbourne, Parkville, Australia Department of Microbiology, Royal Children’s Hospital, Parkville, Australia