Although an exciting advance, there remain many questions about the role of the HPV vaccine in preventing cervical cancer. These largely revolve around the issue of cost benefit and feasibility of vaccinating a sufficiently large number of young girls/young women and possibly boys in the world to make a difference. At present, the answers to many of the questions remain unknown, and it would probably be a mistake to avoid making clear that HPV vaccine is unlikely to be the (sole) solution – certainly in the next several decades – to the problem of cervical cancer in low income countries particularly, but also to the control of cervical cancer in general.
Some of the issues that are appropriate points for debate include:
1. The Issue of the requirement that many women are vaccinated who are will never develop cervical cancer. Estimates of the crude incidence of cervical cancer, although variable in different parts of the world, tends to be less than 30 per 100,000, even in high incidence regions – see figure cervix uteri incidence crude rate . It should be born in mind that cervical cancer is more common in lower socioeconomic groups, and that registry data is particularly sparse in these populations, such that these figures may be underestimates. It means that, even with the most optimistic picture, very large numbers of girls must be vaccinated in order to prevent cervical. This has implications both for the distribution (requiring a cold-chain) and administration of the vaccine, as well as the requirement that side effects are very few and not serious. Unfortunately, many people may believe that if, for example, 1000 women are vaccinated against Cx cancer, they will be prevented from developing this form of cancer (or others related to HPV). While not incorrect at one level, what this does not take into consideration is that the chance that any one of these 1000 women would develop cervical cancer is less than 1 in 100 per year, with a cumulative lifetime risk of 2-3%. Thus, to prevent one woman from developing cancer over 90 need to be vaccinated. Where the incidence is much lower (e.g. because of screening programs), the number of cases prevented is correspondently fewer. Another way of looking at this is that 95% or more of women vaccinated receive no benefit.
What is the significance of this? It means that the cost benefit ratio is high – the financial cost of preventing cervical cancer (this will be lessened by adding in other genital cancers and even oral cancers associated with HPV, although these are much lower in incidence than cervical cancer) at several hundred dollars for a course of vaccination compares poorly with, for example, measles (according to the WHO, it costs less than one dollar to immunize a child against measles, a disease which affects 20 million children per year and results in almost 200,000 annual deaths. Cervical cancer affects some 500-600,000 women per year and causes some 300,000 annual deaths).
Financial cost, however, is only one issue to be considered. More important is the fact that a high number of women must be put at risk to protect a few. What is this risk?
The following abstract from (http://www.lifesitenews.com/ldn/2008/jul/08070316.html), which relates to Gardasil, the quadrivalent vaccine against types 16, 18 (the two most prevalent HPV types in cervical cancer), 6 and 11 (associated with genital worts) made by Merck, provides some information, but suggest that much more is needed:
Judicial Watch, a public interest group that campaigns against government corruption, uncovered documents through the Freedom of Information Act that show the US Food and Drug Administration (FDA) received reports of 10 deaths associated with Gardasil since September 2007, and 140 "serious" reports of adverse reactions, including 27 "life threatening" cases, 10 spontaneous abortions, and 6 cases of the debilitating Guillain-Barre Syndrome since January 2008. Judicial Watch also found 8,864 Vaccine Adverse Event Reporting System (VAERS) records associated with Gardasil, more than double the 3,461 events that had been reported with the HPV vaccine in Fall 2007. Many experienced outbreaks of genital warts from the HPV vaccine. The watchdog group says the number of deaths associated with the vaccine is at least 18 and possibly as many as 20. The full report from Judicial Watch is available at the following website: http://www.judicialwatch.org/documents/2008/JWReportFDAhpvVaccineRecords.pdf
Adverse events also include vascular thrombosis, seizures, anaphylactic shock and genital warts and possibly an increase in the incidence of grade 2 and 3 CIN lesions in women previously exposed to HPV). What is not reported by Judicial Watch is the denominator, i.e., the size of the population in which these deaths occurred. The FDA has stated that by July 2008 over 16 million women had been vaccinated with gardasil with almost 10,000 adverse events reported (http://www.cdc.gov/vaccinesafety/vaers/FDA_and_CDC_Statement.htm). This would indicate an incidence of 10 adverse events per 16,000 vaccinated persons – which must be interpreted in the context of the anticipated number of cervical cancer cases and the seriousness of the adverse events. Screening has dramatically lowered the incidence in high income countries, but it remains much higher in most low and middle income countries. The FDA reports that more than 90% of adverse events are not serious. If the Judicial Watch numbers of perhaps 20 deaths among women vaccinated in the USA so far is accepted, then one can extrapolate that there could be 1 vaccine-related death for every 175 cases of cervical cancer in high incidence regions. This may be acceptable, if the alternative is late presentation and a very poor prognosis. However, given that there is little or no information on vaccine related side-effects in girls and young women in developing countries, where the high incidence of other prevalent infections and poor hygiene could influence the pattern, it would seem premature to attempt to vaccinate large numbers of girls/young women in developing countries with any HPV vaccine. In the meantime, the FDA concludes: Based on the review of available information by FDA and CDC, Gardasil continues to be safe and effective, and its benefits continue to outweigh its risks. It also concludes that the vaccine will potentially benefit the health of millions of women by providing protection against the types of HPV that cause the majority of cervical cancer, genital warts, and other HPV-related diseases. This statement will be correct over many years - the global burden of cervical cancer is estimated to be somewhere between 500 and 600,000 – approximately half a million per year. Thus, the prevention of 100% of cases would translate into approximately 5 million prevented from developing cervical cancer every 10 years. This would be an extremely valuable result. However, in high income countries and middle eastern countries, the incidence of cervical cancer is quite low – in the former, largely due to cervical cancer screening (the incidence is of the order of 4 cases per 100,000 women per year and cumulative incidence rates that are often less than 1%). Thus, cost benefit analyses of the vaccine would need to take into consideration the cost and toxicity of present methods of preventing cervical cancer, particularly screening and treatment, as well as the issue of choice on the part of women.
2. The issue of the age at which the vaccine should be given. Published reports indicate a very high degree of effectiveness for vaccines against HPV16 and 18 in the prevention of CIN lesions in females previously unexposed to HPV. The protective effect against the development of high grade CIN lesions and invasive cancer in previously exposed women is minimal at best, and probably non-existent. This means that the vaccine must be given prior to exposure to HPV – in effect, prior to sexual activity. While the age at which sexual activity is initiated in females varies markedly from one country to another (although the quality of data in this regard is likely to be questionable, especially from countries where pre-marital sex is considered extremely negatively) this means that HPV vaccine should probably be given at the age of 12. Some countries recommend that the vaccine be given to women up to the age of 25 years. Such a practice will greatly increase the cost while having a small impact on efficacy (depending, again, upon the fraction of girls at ages above 12 years who have not commenced sexual activity (been infected with HPV).
3. The duration of the protective effect. Clinical studies with HPV vaccines were performed in the last few years. ^ "Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions". N. Engl. J. Med. 356 (19): 1915–27. May 2007. doi:10.1056/NEJMoa061741. PMID 17494925. As such, it is not yet possible to know how long protection against uninfected individuals lasts. It could be just a few years or significantly more. This information is crucial, however, both to a cost-effectiveness analysis and also to the strategy for protecting women against cervical cancer. If the protective effect is short lived – even 10 years – such that revaccination is necessary, the cost and inconvenience will be markedly greater while the probability that a considerable proportion of the population will be unprotected during their most sexually active years must be considered. Further, deciding the optimal interval between vaccination will be difficult. Protection will not abruptly end, and will vary from one individual to another. To avoid the situation where all protection is lost, women may need to be vaccinated significantly before the average duration of protection is reached.
4. Vaccination of Males. There are several reasons to consider vaccination of males. Firstly, various genital cancers in males (and females) are are associated with HPV (as well as oral cancers, particularly tonsillar cancer) and could be prevented by an efficient, minimally toxic HPV vaccine. Moreover, males infected with HPV are able to infect women such that the dynamics of protection of the entire population will depend, to a significant degree, assuming that protection lasts for several years, on the proportion of males who have also been vaccinated. However, vaccinating males would considerably increase the cost of vaccination programs while efficacy of the vaccine against HPV-related cancers other than cervical cancer requires further research.
5. Vaccination of HIV Positive Individuals. A number of cancers associated with viruses are increased in incidence in individuals infected with HIV. This includes cancers associated with HPV. The only HIV positive population that should be considered for vaccination is, again, children, since adults will invariably have been infected with HPV. Efficacy and toxicity will need to be carefully explored in this population and could differ markedly from that in HIV negative individuals. In addition, the benefits and toxicities of HPV vaccination may differ in HPV negative populations who subsequently become infected with HIV – such information is particularly important in an African context. However, given the increased incidence of HPV associated cancers in HIV positive individuals, exploring use of the the vaccine in girls with non-sexually acquired HIV with reasonable CD4 counts and receiving anti-retroviral therapy may be something to be considered.
6. The issue of the time-interval until the population is protected. Since the peak age of cervical cancer is generally between 50 and 60 years in high incidence regions (see figure cervix uteri incidence), then it will be several decades before significant benefit from the vaccine accrues. During this time, and for many years afterwards, it will be necessary to continue to control cervical cancer by methods currently in use. Indeed, whether it will ever be possible to stop cervical cancer screening in high income countries, or to rely solely upon HPV vaccine in the prevention of cervical cancer in low income countries is another important question that must be posed and which will influence cost benefit ratios of the vaccine. More research regarding the period of protection and the possibility that other high risk strains of HPV may become more prevalent will need to be performed before such questions can be answered.
7. The issue of other high risk HPV strains. Both of the presently available vaccines – made by Merck and GlaxoSmithKline, only two HPV types which are high risk viruses for the development of cervical cancer are protected against. While these appear, on the basis of all published data, to be by far the most frequent types associated with cervical cancer, there are many other types that can cause this disease. Although present vaccines may well have some protective effects against other strains, the possibility still exists that the incidence of cervical cancer will not be influenced as much as is hoped by vaccines against HPV types 16 and 18 must be considered.
8. Logistics. Globocan has estimated that the burden of cervical cancer (this will be augmented by other HPV associated cancers) is approximately 48,500 cases per year in Africa, although this figure is increasing, and cervical cancer occurs at particularly high incidence in HIV infected individuals, being considered as an AIDS defining cancer. This number is likely to increase in the coming years – even the rapidly growing population (presently 500-600 million) will result in an increased tumor burden. Cost effective studies clearly need to take into consideration the fact that more than 95% of vaccinated women will receive no benefit, but some, at least, of these will develop harmful effects, fatal in a (presumably) very small minority. The observation that cervical cancer occurs predominantly in socioeconomically deprived populations will also have a significant impact on logistics.
While the development of HPV vaccines represents a major technological advance, it is important to examine the cost benefit ratio of using the vaccine as well as the fact that there are many remaining unknowns. It will be important to ensure that evaluation of efficacy and toxicity continues, particularly in low and middle income countries where differences in customs and environments may influence the cost-benefit ratio. It is also important that measures to control cervical cancer by early detection are continued and, wherever feasible, increased. It should be made clear that vaccinating a few thousand girls will not have a significant impact on mortality from cervical cancer since the HPV vaccine differs considerably from vaccines against common infectious diseases insofar that the vast majority of vaccinated women will not benefit from the vaccine. This makes issues of cost and toxicity of even greater importance than in diseases where, even when mortality rates are low, the disease is of high prevalence and associated with significant morbidity and sequelae.