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HPV

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)

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.

 

Population-based evidence for the preventative efficacy of quadrivalent HPV in Australia

30 Sep, 14 | by Leslie Goode, Blogmaster

The HPV vaccination programmes introduced by many countries over the last few years (since 2007) reveal considerable diversity in the coverage they have achieved, the mode of access (i.e. school, public health, private clinics) and responsibility for cost (i.e. publically vv. privately funded) – even in Europe (see ECDC Guidance).  In the light of the known efficacy of the vaccine, implementation has seemed frustratingly slow – partly, in some cases, due to ungrounded negative public perceptions around safety (e.g. in Japan where the national programme was actually suspended) and the impact on sexual mores (e.g. in the US).  Early indicators of its positive health impacts in countries like Australia – where implementation was early (2007) and wholehearted – are therefore to be welcomed, as favouring the implementation of programmes in the future.  In the absence of evidence of the reduction of cervical and other cancers, evidence of the effectiveness of the quadrivalent vaccine against warts – from clinics (STI/Donovan & Fairley; STI/Garland & Jayasinghe; STI/Fairley & Bradshaw), or pharmacists (STI/Wilson & Baker) – or evidence for the reduction of cervical abnormalities (STI/blogs/Brogly & Yang) – may offer a proxy.

Smith & Canfell (S&C), recently published in Journal of Infectious Diseases, claim to provide the first whole population analysis of the impact on genital warts of a national HPV vaccination programme – and this may be the best predictor of the longer-term, and more important, cancer prevention benefits to be seen in future years.  It is no surprise it derives from Australia, the first (2007) country to introduce routine school-based vaccination of 12-13 yr girls, plus catch-up through to 2009 for girls 13-17 yrs in schools, and young women 18-26 yrs in primary care. Earlier studies in Australia largely relied on data from sexual health clinics; this study is based on national data of all hospital episodes 1999-2011 involving a diagnosis of genital warts.

The findings of S&C show a decline of 89.9% in admissions involving warts from 2006/7 to 2010/11 for girls aged 12-17 yrs, a decline of 72.7% for women aged 18-26, and a decline of 38% for men aged 18-14 (the indirect effect of female vaccination).  The decline of cases in the 18-28 age group occurs from mid-2008. Other age groups do not show the same sharp decline, nor do MSM – to judge from the fact that the decline exclusively concerns warts in non-anal location.

An issue of particular concern to Australia, and one that consequently receives considerable attention in this study, is the impact on the indigenous population, where incidence and mortality rates for cervical cancer are, respectively, 2.8 and 4.7 times higher for the indigenous as for the non-indigenous population.  Reductions for indigenous and non-indigenous females appear to be similar (86.7% and 76.1% respectively) – which is curious, given that data for two Australian states indicate lower rates of course completion (3 doses) by indigenous females.  If the same tendency in uptake were replicated in the other Australian states (which we don’t know) this might suggest the efficacy of ≤2 dose courses of therapy.  Such a result would corroborate the findings of a recent study covered in this blog (STI/blogs/”Catch up” and incomplete HPV vaccination), which investigates the efficacy of ≤2 dose courses of therapy also in the context of socially disadvantaged groups.

 

“Catch-up” and incomplete HPV vaccination better than nothing

26 Aug, 14 | by Leslie Goode, Blogmaster

Quadrivalent HPV vaccine (HPV4) has been shown to protect against HPV types 16 & 18, which cause 70% of cervical cancers, and HPV types 6 & 11, which cause 90% of genital warts.  Health authorities in the US and elsewhere have therefore recommended routine vaccination of girls (and more recently boys) at ages 11 & 12, and “catch-up” vaccination for women aged 13 to 26. Vaccination programmes in New Zealand (STIs/Read & Fairley) and Australia (STIs/Fairley and Bradshaw) have indicated what can be achieved, given adequate coverage.

For the US and elsewhere there remains a problem of ensuring coverage.  Recent figures from the US Centers for Disease Control and Prevention National Immunization Survey-Teen (NIS-Teen) for 13-17 year-olds ≥1 dose quadrivalent or bivalent vaccine, CDC/MMWR 25.7.14, show levels that remain obstinately low despite year on year improvement, rising from 53.8% to 57.3% (girls), and from 20.8% to 34.6% (boys) between 2012 and 2013.  By comparison, UK uptake on the first 3 years of its programme was 66% (STIs/Sacks & Robinson).  The low US rate is of particular concern because there is considerable evidence from the US and UK that it is often those who are most at risk, such as racial and ethnic minorities, who are most likely to miss out on vaccination (STIs/Niccola & Hadler; STIs/Sacks & Robinson; STIs/Liddon & Hadler).  Tantalizingly, the Report estimates at 91.3% the coverage for ≥1 dose by age 13, if HPV vaccine had been administered to adolescent girls born in 2000 during health care visits when they received another vaccine.

This, of course, raises the question why this opportunity is being missed.  The authors cite the disquieting datum that, when NIS-Teen asked parents to identify reasons for non-vaccination, one third of parents of girls and over half of parents of boys reported that their child’s clinician had not recommended  that their child receive an HPV vaccination.  They therefore point to the need to address gaps in clinician knowledge and communication skills as well as parental knowledge.  A discussion of apparent difficulty of ensuring the conformity of providers to HPV guidelines has already been discussed by STIs/Kepka & Seraya.

 

Given poor levels of uptake at age 11-12, especially among some of the needier populations, it becomes important to know the effectiveness of catch-up vaccination and incomplete vaccination.  This is made very evident in a recent US cross-sectional study, Brogly & Shi Yang (B&Y), of the relation of cervical abnormalities to HPV vaccination status amongst 235 minority women undergoing routine cervical cytology testing.  Only 54% of these had initiated, and only 33% completed, vaccination – and of those vaccinated, only 3% had received the vaccination before sexual debut.  Their results appear to show that even a tardy, and frequently incomplete, HPV vaccination confers significant benefits on individual women.  Abnormalities (ASCUS, LSIL or HSIL) proved to be considerably reduced amongst the vaccinated group, even where participants had not completed the full course of three injections – RR 0.35 for ≥1 dose as against no vaccination; RR 0.45 for 1-2 doses as against no vaccination; RR 0.26 for completed vaccine as against no vaccination.  If corroborated in further studies, these findings could reinforce argument in favour of the effectiveness of HPV catch-up against those have placed this in doubt (STs/Chesson & Markowitz).

The study also aimed to examine the relationship between vaccination status and HPV genotype, but the sample size was too small to establish anything very conclusive.  STIs/Nielsen & Kjaer claim to demonstrate, with a far larger Danish sample, that low-risk types are frequent in ASCUS lesions, but scarcely ever occur in isolation from high-risk HPV types, where the lesions are more severe.

Sexual health in the post-HPV vaccination era: implications for genital warts and cervical screening

2 May, 13 | by Leslie Goode, Blogmaster

Quadrivalent HPV vaccination (qHPV) for adolescent girls is recommended and publicly financed in a number of countries.  This intervention promises to prevent up to 70% of HPV generated cancers in those vaccinated, as well as vastly reducing the burden of genital warts (GW).  In relation to prevention of HPV generated cancer and cancerous lesions, its effective contribution will need to be evaluated in relation to cervical screening, and as part of an overall cancer prevention strategy: the question of the right mix of interventions, including vaccination and its relation to the method and interval of screening, are questions of ongoing debate.  Regarding HPV generated GW, however, it may already be possible to score up certain gains.

A recent Swedish national cohort study of 2.2 million women aged 10-44 years offers evidence of the effectiveness of qHPV in relation to genital warts (GW) that complements the findings of clinical trials regarding its therapeutic efficacity (http://jnci.oxfordjournals.org/content/105/7/469.abstract?sid=e0d178cd-8985-42e4-b934-201c858ca42e). The results of efficacity trials follow pre-specified inclusion criteria and are consequently not generalizable.  Now, however, thanks to the rigorous registration of patients and treatment in Sweden, these researchers have been able, so they claim, to gain an insight into the effectiveness of the vaccine – better than would been possible in many other countries.  Results are stratified by age: vaccine effectiveness was 93% against GW where administered at under 14 years;  80% for girls aged 14-16 years; 71% for those aged 17-19; 48% for those aged 20-22 years; and effectively zero for those above 22 years.  This study confirms at the level of national surveillance the general picture offered, at the level of the STI clinic, by Read & Fairley’s account of the “near disappearance” of heterosexually transmitted GW from  vaccinated <21 years, four years after the introduction of a qHPV program in Melbourne, Australia (vaccination restricted for three years to girls ≤26 years and thereafter to 12-13 years) (http://sti.bmj.com/content/87/7/544.abstract?sid=58e7950b-ccdf-4899-b67b-c7ad3b00081d).

Given the steep decline in effectiveness of qHPV for girls aged >13 years as indicated by these studies, it is disquieting to discover in a recent study of US parents expressing their non-intention to have their teens vaccinated with qHPV that as many as 11% of them gave as the reason that their children were “not yet sexually active”.  The study (Darden & Jacobson) was initiated on the basis of data from the National Immunization Survey, and involved asking parents of children who were “not-up-to-date” with qHPV (along with Tdap and MCV4) and who further indicated their non-intention to vaccinate, the reasons for their decision (http://pediatrics.aappublications.org/content/131/4/645.abstract?sid=082b138f-5a8d-47c5-bf41-5c45d343b129).  The percentage of US girls in the immunization cohort taking up the full three doses of qHPV has increased over the three years 2008-2010 from 17.9% to 32%, but remains substantially below that for Tdap and MCV4 (81.2% & 62.7% for 2010 as against 32%); there is a rising percentage giving as reason for non-vaccination “safety concerns/side effects” – rising over the three years from 4.5% to 16.4%.

The long term implications of incorporating qHPV into the STI toolkit are very unclear, though the reduction of GW is, of course, very welcome.  Aside from the much discussed question of how the choice of cervical screening method should complement vaccination in a post qHPV era (http://sti.bmj.com/content/87/Suppl_1/A14.3.abstract?sid=190a5031-ecc8-4f7f-a4bc-1411d34798f1) there is the question of how a woman’s knowledge that she has been vaccinated is likely to impact on her behaviour in relation to cervical screening (http://jms.rsmjournals.com/content/18/1/41.full.pdf+html?sid=9162f5ac-9762-43c5-bcd8-5e09044c2368;

http://ruizscience.webs.com/HPVvaccineCervicalCancerScreening.pdf).  If we suppose a moderate level of HPV cover combined with a partial collapse in cervical screening compliance what will be effect on the incidence of cervical cancer? Given many health systems are already embarked on the route of qHPV vaccination, it is imperative to maximize the vaccination uptake.  The study of Darden and Jacobson may indicate the challenge posed, with the integration of qHPV into the toolkit, by the urgent need to ensure we communicate the right public health messages.

HPV re-activation in older women: an increased cancer risk unrelated to sexual behaviour?

11 Feb, 13 | by Leslie Goode, Blogmaster

Older women who have had ≥5 lifetime sexual partners could turn out to be a relatively high-risk group for Human Papilloma Virus (HPV) and associated cervical lesions – regardless of declining sexual activity.  If – that is – Gravitt, Viscidi et al. (http://jid.oxfordjournals.org/content/207/2/272.full.pdf+html?sid=4bc8141c-9b7c-4a13-8a43-451d6fa85fcf; http://jid.oxfordjournals.org/content/207/2/211.full.pdf+html?sid=4bc8141c-9b7c-4a13-8a43-451d6fa85fcf) are correct to see the results of their cohort study of Baltimore women attending obstetric-gynaecology clinic as supportive of the hypothesis that the HPV experienced by these older high-risk women is a reactivated form of the infection.  The virus, they suggest, may remain undetectable in the body for years in order to emerge in later years with immune-senescence – like the varicella zoster virus that reactivates as shingles.  This would explain the double peak in age-specific HPV prevalence (debut and menopause) in some cultures; while the absence of this pattern in the US and N. Europe, they hypothesize, may be an effect of the more restrictive sexual mores of the pre-sixties generation.

What is the evidence?  When the results are stratified according to number of lifetime sexual partners, it is discovered that the Population Attributable Risk (PAR) of high-risk (HR) variants of HPV (i.e. those causing cancerous lesions) due to ≥5 lifetime partners is 87% among the older study participants, and 28% among the younger ones; while the PAR of HR-HPV due to a new sex partner is 7.7% among the older group and 28% among the younger.  This, as the authors argue, is consistent with reactivation of the virus in later life, though they admit reactivation is difficult to prove.

If this hypothesis is supported by further research, it will certainly impact on a number of issues that have been a concern for our readers and contributors.  First, the question of women’s perceived risk of cervical cancer – important because it has been shown to predict cancer screening attendance and has been associated with HPV vaccination uptake (http://sti.bmj.com/content/88/6/400.abstract?sid=2f5a46a3-43d9-4648-a3f6-9f1a46384f61, pp.1-2).  If Gravitt et al. are right, then currently less sexually active older women, who are nevertheless in the higher-risk group on account of past sexual activity, are in serious danger of underestimating their risk; furthermore, that risk could, in reality, be greater that we imagined owing to the behavioural impact of the sexual revolution.  Second, the question of stigmatization, especially in relation to HPV testing at routine “smear” tests (http://sti.bmj.com/content/82/2/169.abstract?sid=2f5a46a3-43d9-4648-a3f6-9f1a46384f61).  If HPV is often present, but undetected, and, when detected, may turn out to have no relation to current sexual activity, then the stigmatizing link between HPV status and current sexual behaviour is, at least, weakened – which ought to have a de-stigmatizing effect.  Third, HPV vaccination, and the concern of certain parents that it might lead to sexual disinhibition (http://sti.bmj.com/content/87/4/349.abstract?sid=44f0f0a6-c872-4cb1-9ca1-afa0aa8db872).  Here, again, the idea that sexually inactive, or less active, people can be at serious risk runs counter to the public perception of a direct link between current sexual behaviour and cervical cancer risk – which ought to make HPV vaccination easier to justify to a public concerned about sexual disinhibition.

 

Widespread abuses of HPV testing in the US?

26 Jul, 11 | by Leslie Goode, Blogmaster

The US-based journal Obstetrics and Gynecology carries a front-page editorial: “Abuses in Human Papillomavirus DNA Testing”. A study featuring in July’s issue based on a survey of nationally representative samples of smear-test (pap test) providers reports widespread overuse of HPV testing in the context of routine smear tests. The editorial dramatically concludes that this “seriously wastes government, payer, and patient dollars, but also potentially harms patients, therefore violating the first tenet of the Hippocratic oath”.

To understand the problem, we need to bear in mind:
i. that only some of the HPV genotypes are associated with cervical carcinogenesis, and that HPV DNA tests have recently become available capable of screening for exclusively “high-risk” strains;
ii. that US national guidelines recommend HPV testing (“reflex testing”) of women with atypical squamous cells of undertermined significance (ASC-US): HPV-positive women are referred to colposcopy and HPV-negative women rescreened in 12 months;
iii. that US national guidelines also recommend HPV testing in the context of a routine three-yearly smear-test (“co-testing”), but only in the case of women aged 30 years and older. (In the younger age-groups occurrences have been shown to be pervasive but transient). Negative cytology and positive HPV – or, conversely, ASC-US cytology and negative HPV – triggers re-screening after a year; ASC-US cytology plus positive HPV warrants referral for colposcopic evaluation. More abnormal cytology (i.e. low-grade intra-epithelial lesions and anything more serious) triggers colposcopic evaluation

This study discovered three areas of widespread “abusive” testing:
1. 28.5% of routine test providers employed HPV DNA tests for “low-risk”, as well as “high-risk strains of HPV. The low-risk HPV test is not recommended in this setting – or, for that matter, in any other health setting – though for some reason the test remains widely available;
2. 60% of health-care providers, and 66% of clinics, used routine HPV co-testing in women aged under 30. This presumably leads to over-testing and unnecessary referrals;
3. health care providers performed reflex testing in cases of intra-epithelial lesions, warranting immediate referral for colposcopy. This might indicate that women were being put at unnecessary risk of cervical cancer.

So why is practice so frequently in breach of current (2006) guidelines? The authors mention amongst possible factors: the availability of low-risk HPV DNA tests, test marketing, health care provider confusion over the difference between high-risk and low-risk tests, financial gain in the form of liberal test reimbursement of private practice by private insurance, patient requests to test HPV status. They point to the need for wide-reaching interventions such as limiting test reimbursement to facilitate recommended uses of HPV DNA tests and eliminate low-risk HPV testing, and education materials for patients and health care providers to address patient demand for HPV testing.

Jennifer Wai-Yin Lee et al., “Low-Risk Human Papillomavirus Testing and Other Nonrecommended Human Papillomavirus Testing Practices Among U.S. Health Care Providers”, Obstetrics and Gynecology, vol. 118, no.1, July 2011
Editorial, Philip E. Castle, “Abuses in Human Papillomavirus DNA Testing”, Obstetrics and Gynecology, vol. 118, no.1 July 2011
http://journals.lww.com/greenjournal/pages/currenttoc.aspx

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