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HPV and cancer

What is the future of cervical screening in the era of HPV vaccination?

20 Feb, 17 | by Leslie Goode, Blogmaster

With the introduction of HPV child vaccination programmes, there will have to be a shift from cytology to HPV testing as the main technology involved in primary cervical screening, say the contributors to an on-coming special issue of Preventive Medicine (Tota & Ratnam I) (T&R). Why?  Well, first, because of the inevitable decline in the positive predictive value of the test (i.e. proportion of positive results that are true positives) that comes with declining prevalence of HPV sequelae.  This is an important consideration given the reality of the potential ‘harm’ resulting from false positive diagnoses.  But it is also necessary to take into account the impact on diagnosis (which, of course, in the case of cytology, takes place through the judgment of fallible human cytotechnologists) of the ever-dwindling proportion of abnormalities – an effect well described by T&R as a reduced ‘signal-to-noise ratio’.  This, our authors argue, will inevitably lead to ‘fatigue’.

Yet the transition to HPV primary screening is very much to be welcomed, it seems.  Tota & Ratnam I comprehensively review recent trials – in Canada, US and Europe – which all demonstrate that primary HPV screening (in combination with various ‘triage’ regimes for positive cases) offers more security, even at more distant testing intervals, than a cytology-based regime.  Also one that is less prone to human error, more cost-effective, as well as capable (unlike cytology) of being adapted to ‘self-testing’ regimes that could allow wider access (especially in limited resource settings).

Another paper in this on-coming special issue reviews trials (Canadian HPV FOCAL, and Montreal-based VASCAR) testing different ‘triage’ regimes (Tota & Ratnam II).  These involve cytology, with or without HPV genotyping.  Genotyping allows the discrimination of different levels of risk according to HPV genotype, giving health services the option of a differentiated approach to more or less ‘high risk’ strains (i.e. retesting after a year, referral to cytology, or to colposcopy). Whether or not genotyping is included in the regime, the combination of primary HPV screening in combination with triage seems to offer a much more reliable test than cytology – at the possible cost of some relatively minor increase in needless colposcopy referral.

Yet cervical screening policy must, in practice, be informed by more than epidemiological evidence – as the editor of this special issue (Schiffman) reminds us.  It will also depend on available resources and the willingness of a particular system to assume a degree of risk.  The US is particularly good example.  As Kinney & Huh show, in another study in this issue same special issue, the very marginal increment in safety demonstrated by five-yearly co-testing over stand-alone HPV is one that US appears not to be willing to relinquish, even at considerable cost both economic and in terms of ‘harms from screening’.

At the other extreme, of course, are the medium and limited-resource settings in which, for various reasons the aspiration to offer affordable protection through traditional forms of screening (e.g.  visual inspection with acetic acid (VIA)), may currently be delivering ‘sub-optimal’ results (see, for example, Sibanda & Cowan (STIs)).  (For an evaluation of HPV screening as against VIA, see Mitchell & Ogilvie (STIs).)  The special issue includes papers that consider the possibility of diverse screening algorithms in limited resource settings (Maza & Gage; Kuhn & Denny).  Where there are problems of access, the self-collection of samples, which becomes a possibility with HPV primary screening may offer a more feasible alternative to clinician based approaches.  Vallely & Caldor (STIs) makes the case for screening based on self-sampling using CepheidXpert.  Nelson & Arnold (STIs)  review 24 studies of HPV self-sampling across five continents.

Where HPV vaccination loses the battle for public support: calculating the health implications for Japan

9 Nov, 16 | by Leslie Goode, Blogmaster

A recent brief contribution to The Lancet-Oncology (Tanaka & Ueda) uses predictions of the probable health outcomes of the suspension of the Japanese HPV vaccination programme to make the case for an urgent reassessment of the current policy.  This intervention is very timely.  The approved age for HPV vaccination for Japanese girls is a window of four years from 13-16 yrs, and the current year (2016-17) constitutes the fourth since the suspension of the programme (June 2013); so the current year is the last opportunity for a return to the initial HPV vaccination policy before the effects of the suspension (for the oldest in the cohort) become irrevocable.   From the following year on (2017-8), the authors argue, every additional year of suspension will exclude an additional age group from the protective effects of HPV vaccination – unless, that is, the eligibility period is extended to include older girls).  With a view to maximizing the impact of this message, they assess the impact of restarting vaccination in 2020 as against restarting in the current year.  They do this on two scenarios depending on whether or not vaccination, when resumed, is given to those who would have missed out in 2013-2017 as well as to those currently eligible.

So how great are these effects?   On the first scenario (no catch-up for missed years), risk of HPV 16/18 infection at 20yrs is estimated for the 2013-6 year groups at around a steady 1.0%, given resumption of vaccination 2020, as against the 0.3-0.4% risk, with resumption in 2016; on the second, that steady 1% risk over the four missed years is replaced by an evenly paced decline from 1.0% to previous levels (0.3-0.4%) over the four-year period.

Of course, it is the long-term health impact of these HPV infections that constitutes the cost of the current Japanese policy, and, were it recognized, the strongest incentive for a resumption of vaccination.  Unfortunately, the full impact is very long term, and hard to quantify.  But some advanced indication of its potential scale is provided by the recent Finish ‘FUTURE’ trial that demonstrated an absence of CIN3 and ICC lesions in vaccinated participants (Paavonen/3/STIs), as well as, more indirectly, the enormous (c.90%) declines in genital wart presentations in Australia (Chow & Fairley/STIs; Ali & Donovan (STIs)) and New  Zealand (Wilson & Baker/STIs).  The benefits foregone by the unvaccinated will also include protection against head and neck – especially oropharyngeal – cancers (Field & Lechner/STIs; King & Sonnenberg/STIs), and against a small, but significant range of anogenital cancers in women (Prevention of anogenital cancers in women/STIs/blogs).  On a more positive note, however, there is some evidence for the benefit of ‘catch-up’ and incomplete vaccination (“Catch-up” and incomplete vaccination/STIs/blogs) as against those who have hitherto put this in doubt (STs/Chesson & Markowitz).

An important lesson of the Japanese experience for everyone concerned with HPV is the importance of public education.  The very poor levels of understanding revealed by a recent systematic review (Patel & Moss/STIs) amongst European adolescents is a timely warning that uninformed attitudes to HPV vaccination are not restricted to the Japanese.

Prevention of anogenital cancers in women may be an additional benefit of HPV vaccination

14 Oct, 16 | by Leslie Goode, Blogmaster

Cervical cancer is evidently the most important, but by no means the only, health risk that vaccination against HPV aims to avert. The potential impact of vaccination on other cancers (not to mention genital warts) may also be a factor in estimating the cost benefit of achieving higher vaccination coverage, as well as determining priorities for vaccination programmes (e.g. the relative importance of achieving high coverage for males).  Recent studies have investigated the role of HPV in the rising incidence of head and neck – especially oropharyngeal – cancers (Field & Lechner/STIs; King & Sonnenberg/STIs), and in the development of anal cancers amongst MSM (Poynten & Garland/STIs).  The dramatic impact of vaccination programmes on the prevalence of genital warts has already been attested both in Australia, where vaccination was introduced in 2007 (Chow & Fairley/STIs ), and, more recently in the UK (Canvin & Mesher/STIs ).

In addition to these benefits of HPV vaccination, a recent Danish nationwide cohort study (Sand & Kjaer (S&K)) draws attention to another relatively limited, but nevertheless significant, benefit in the shape of a range of anogenital cancers in women – i.e. anal, vaginal and vulvar cancers.  These seem to be strongly associated with the occurrence of high grade cervical intraepithelial neoplasia (CIN2 & 3), and should therefore be numbered amongst the adverse effects of HPV that vaccination may help to prevent.  Given the relative rarity of these cancers (total yearly incidence in UK, both male and female, is currently about a quarter of that of oropharyngeal cancers), an important advantage of S&K’s study is its impressive scale.  It investigates no less than 2.8 million women born 1918-1990 over the period from 1978 to 2012. Also, unlike similar studies, it is able to control not only for age, but for a range of potential confounders such as socio-economic status and smoking.  The use of CIN2/CIN3 as a proxy for HPV infection seems well supported by the evidence (Tachezy & Vonka/STIs; Azwa & Harun (STIs)).

The key findings of the study were as follows.  Relative risk of anal, vulvar and vaginal cancers following CIN2/3 as against no such history was found to be greatly increased: RR 2.8, 2.5, 8.3 after CIN2; 4.1, 3.9, 17.4 after CIN3.  Risk was particularly high in the first year after CIN; but the increased risk persisted, suggesting the effect could not be attributed to surveillance bias.  So, for example, analysis showed increased risks of anal, vulvar and vaginal cancers at ≥25 years after CIN3 diagnosis of RR 4.8, 3.2, and 5.5, respectively.  In non-cervical anogenital cancer, HPV16 was the most frequently detected HPV type.  The fact that cancer risk following CIN3 is substantially greater than it was following CIN2 suggests to the authors that the cause of both may be attributable to an inadequate immune response to HPV in certain women, leading to a failure to clear the infection.  The propensity of persistent HPV to spread to the entire anogenital region explains the range of cancers (anal, vaginal, vulvar) in respect to which these women seem to be at heightened risk (see Simpson & Turner/STIs ).

Mathematical models say: switching to HPV nonavalent vaccine brings cost benefits.

20 Jun, 16 | by Leslie Goode, Blogmaster

STI journal issues of nearly a decade ago, when HPV vaccination was a relatively new thing, hosted a discussion on the issue of which vaccine to choose. The choice at that time, readers will remember, was between GSK’s Cervarix 2vHPV and Merck’s Gardasil 4vHPV (Morris/STIs)*.  Now, the introduction of a third alternative, Gardasil (9vHPV), seems to have fuelled a similar burst of activity amongst mathematical modellers – at least in the US, where the new vaccine was licensed in 2014.

Gardasil 9vHPV elicits immunity to nine oncogenic (i.e. associated with cancer) serotypes – i.e. five more serotypes than Gardasil 4vHPV, and seven more than Cervatrix 2vHPV.  The nonavalent vaccine (9vHPV) is expected to extend protection from >66% to 80% of cervical cancers.  It will also, it should not be forgotten, have some benefit in preventing HPV-related oropharygneal cancers (Field and Lechner/STIs).  However, Gardasil 9vHPV is approximately $13 per dose more expensive than Gardasil 4vHPV, and $18 more expensive than Cervatrix 2vHPV.  In 2015 the US Centers for Disease Control and Prevention (CDC) recommended vaccination with any of the three alternatives for females aged 9-26yrs, and with 4vHPV or 9vHPV for males aged 11-21yrs.

Once again, then, the question of the relative cost-effectiveness of HPV vaccines raises its head – this time in the US, and in connection with a possible switch from 4vHPV and 2vHPV to 9HPV as the vaccine of choice. Mathematical modellers in the US have risen to the challenge in at least two recent studies.  Brisson & Markowitz conclude that making the switch would be cost-effective ‘under most scenarios’ (Chesson & Saraiya/STIs; Brisson & Markowitz).  Now, Durham and Galvani (D&G), in another US modelling study, have reached the same conclusion.  Not content, however, with a response for current levels of vaccination coverage, they also consider the impact on cost-effectiveness of raising national coverage with 9vHPV to higher levels.  This requires them to take into account the effect of herd-immunity, which ensures that returns on investment diminish to the extent that higher levels of coverage have already been achieved.  They also consider the relative cost-effectiveness of distributing the investment in 9vHPV vaccination in such a way as to bring up the vaccination levels in states where it is low (e.g. Arkansas, Missisipi, Missouri, Kansas) towards the levels already achieved in other states (e.g. Illinois, Montana, N. Carolina, Washington DC), as against that of an even distribution.  (At present, state vaccination rates vary between 20-57% for females, and between 9-43% for males – though inter-state migration rates are such that 29-84% of the long-term health benefits of vaccination will be realized by beyond the boundaries of the state where vaccination took place).

The findings of the study are as follows.  9vHPV is cost-effective – as compared with the alternatives – at any level of coverage.  Comprehensively switching to 9vHPV would yield the same benefit as raising levels of coverage with existing vaccines across the population of the US by 11%.  Second, assuming a comprehensive switch to 9vHPV: a national increase in coverage of 10% would show an incremental cost-effectiveness ratio (ICER) corresponding to a willingness to pay (WTP) of $40,000 per QALY, and increases of 20%, or 40%, ICERs equivalent to WTPs of $53,000 and $106,000, respectively.  Finally, the figure of $40,000 WPT per QALY given above represents only an average, since, in practice, the cost-benefit of an increase of 10% in coverage would differ widely between states with low current levels of coverage, like Arkansas, where the cost-benefit would be around $13,500, and states with high levels, like California, where it would be around $56,400. The authors therefore advocate focussing the investment needed to achieve increases in coverage on states that currently have low levels of coverage.

  • a previous version of this blog mistakenly mistakenly gave the names of the manufacturers of Gardasil and Cervarix as GSK and Merck respectively.  The mistake has recently been brought to our attention, and the manufacturers as given in the emended blog (23.6.16) are the correct ones. (Blogmaster)

Achieving HPV herd immunity cost-effectively. When does it make sense to allocate resources preferentially to boys?

23 Apr, 15 | by Leslie Goode, Blogmaster

Recent empirical studies of HPV vaccination have provided evidence that marginal vaccination costs increase with coverage.  Let us take into account – they argue – not just the vaccine price, but the cost of education and outreach programmes that would be needed so as to reach the yet unvaccinated population.  If we do so, we are likely to find that raising the vaccination rate for pre-adolescent girls, let us say, from 40-41%, proves considerably more expensive than raising it from 20-21%.  This, in turn, raises the question whether – given the achievement of herd immunity is the ultimate goal – resources are necessarily best allocated when directed to the female rather than the male pre-adolescent population. Could it even be that – at certain levels of coverage and a certain rates of increase in marginal vaccination cost (for girls and for boys) – resources might be more effectively allocated to the vaccination of pre-adolescent boys? Ryser & Myers in a recent study seek to model the impact of marginal cost increase in order to answer this question.  In the case of US, at least – with rates of vaccination standing currently, for girls and boys, at, respectively 37% and 13.9% – they argue in cost benefit terms for re-directing resources to boys.  However, the question is no doubt relevant to other countries in which HPV has been introduced, but levels sufficient for herd immunity, have not yet been achieved.

Optimal allocation of new resources as between girls and boys for a given level of vaccination is indicated in the diagrams on p.40.  Marginal vaccination cost increase is estimated at a higher, a lower, and zero level.  What is striking is the radically different patterns of optimal allocation between girls and boys in those three scenarios.  At the very least, the results challenge the orthodoxy of the superior cost benefit of female vaccination. They also indicate the importance of further empirical research into marginal vaccination cost increase.

The limitations of the study are largely due to the assumption of a closed sexual network of 14-18 yr old heterosexual adolescents.  The attempt is made to factor in the impact of various complicating factors, such as the assortativity of vaccine uptake with sexual activity, the likely presence of additional relationships between females inside, and older males outside, the network, and asymmetric vaccination cost curves as between girls and boys.  But the most serious limitation was beyond the power of the study to address.  This is the restriction of the modelled network to heterosexual relations, and the exclusion from consideration of a large number of HPV-related conditions such as anal and oro-pharyngeal cancers which have higher incidence among MSM and HIV-infected individuals (Lawton & Asboe (STIs); English & Pourbohloul (STIs)).  One wonders, therefore, whether the case for male HPV vaccination is not a great deal stronger than might appear from this paper.  At all events, a case is made that, even when these conditions are excluded, a greater allocation of HPV vaccination resources to males may be justifiable – e.g. currently in the US.  For the impact of the recent extension of the HPV vaccination programme to males in Australia (the first country to have taken this step (2013)), see Korostil & Donovan (STIs).

Population-based study concludes: HPV vaccination does not cause sexual disinhibition

19 Jan, 15 | by Leslie Goode, Blogmaster

HPV is known to be the cause of various types of cancer, including cervical cancer. Routine vaccination before the onset of sexual activity ought therefore to be effective in reducing the incidence of these cancers, and has been adopted by many countries.  The impact of such programmes will not be apparent for years; but the sharp reduction of cases of genital warts in several countries where vaccination has been introduced, is an encouraging indicator of the likely effectiveness of cancer prevention over the longer term (STI/blog/Smith & Canfell).  Unfortunately, however, vaccination coverage has often been sub-optimal ( STI/Sacks & Robinson).  A number of recent contributions to STIs have attempted to identify parental (and provider) concerns that may be responsible for poor uptake of vaccination (STI/Schuler & Brewer; STI/Javanbakht & Guerry;  STI/Krupp & Madhivanan).

One concern frequently mentioned by these studies is that HPV vaccination could lead to sexual disinhibition.  The results of a large population-based cohort study in Canada (Smith & Levesque (S&M)), where HPV vaccination was introduced in 2006, may help to offer some assurance on this matter.  The study was based on administrative health data relating to a cohort of 260,493 girls, of whom approximately half were in the first two school year-groups offered the vaccine (2006-7; 2007-8), and the other half in the previous two year groups (2004-5;2005-6). The study compared data from the two groups in respect to the incidence of pregnancy and non-HPV-related STIs over the four years following vaccination.  Earlier studies addressing the question of vaccination-related disinhibition have focussed on risk perception or reported sexual behaviour.   S&M use objective medical outcomes – pregnancy and STi diagnoses.  Moreover, the definition of the groups on the basis of eligibility for vaccination, as opposed to vaccination itself, circumvents the potential confounding bias which might have been expected to arise from the fact that the same beliefs and behaviours influencing the decision to vaccinate would likely also have affected the outcome of pregnancy and STI infection.

The results are entirely reassuring.  In respect to pregnancy they show precisely no difference between the eligible as opposed to ineligible girls (RR = 1.0 0); in regard to non-HPV related STI diagnoses, they show a small reduction among eligible girls, which the authors plausibly attribute to the likely eventuality of some HPV-related warts having being categorized in the data as non-HPV-related.  These findings corroborate, on a population wide basis, those of earlier studies (e.g. Bednarczyk & Omer) which indicate that fears of vaccination-related disinhibition are unwarranted.

 

Heterosexual transmission of HPV to male oral tract via oral/genital route indicated by partner data

15 Dec, 14 | by Leslie Goode, Blogmaster

The UK Joint Committee for Vaccination and Immunization (JCVI) has not so far decided to extend HPV vaccination to boys, but this possibility remains under consideration (Public Health England Guidance on HPV 2014-15). The potential benefit of protecting males from face and neck cancer will be an important consideration, both in the UK and in other countries contemplating this extension of HPV vaccination programs (STI/Conway & Adams).  Some have attributed the recent tripling in number of cases of these cancers to oral HPV, thus transforming what was formerly a smokers’ disease into an STI outcome.  A figure of 2,000.has been placed on the total of HPV attributable cases in UK males.  Such claims – and their public health policy implications – confer a new importance on research into the risk factors of oral HPV infection among young men.

A recently reported sub-study taking place in the framework of the Montreal based HPV Infection and Transmission among Couples through Heterosexual Activity (HITCH) cohort study claims to be the first to have established the association of oral infection in males with sexual behaviour, not just on the basis of their reported sexual behaviour, but through the collection of data from their partners (Dahlstrom & Franco).   The study administered questionnaires and tests to 222 young men and their partners at baseline and four-months.

Prevalence of oral HPV among male study participants was 7.2%.  Of these 28.6% (2) were found to have a partner with oral HPV infection, and 11.5% (15) to have a partner with genital infection.  The study also investigated type-specific HPV prevalences.  The prevalence among the young men of oral HPV16 (especially associated with head and neck cancer) was 2.3% (5); among the 33 men who had a partner with genital HPV, prevalence was (6.1%) (2/33).  In a rough and ready way, this study also establishes a correlation of oral HPV prevalence in males with frequency of oral sex (RR 1.47 as between rarely/sometimes having oral sex & rarely/never having oral sex).  The potential advance on previous studies is that this correlation is seen to hold only where the partner is genital HPV positive.

The importance of these findings is, first, to corroborate, on the basis of partner data, the conclusion drawn by earlier studies of the relation of oral HPV with reported oral sex, that there is indeed transmission of HPV from the female partner to the male partner’s oral tract, whether through oral or genital routes.  Second, the association of deep kissing with oral HPV infection seen in earlier studies would seem to be confirmed by the higher prevalence among men with oral HPV of female partners with oral HPV.  However, the alternative explanation of auto-inoculation, indicated in the study data by the high prevalence of genital HPV in self, cannot be excluded (STI/Hernandez & Ning).  Third, the possibility of oral sex as a route of transmission is suggested by the increased prevalence of oral HPV among men with a genital HPV partner, and its relationship to frequency of oral sex.

 

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