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Cervical screening and HPV

Does it ever make sense to target HPV screening at HIV-infected individuals?

4 Jul, 17 | by Leslie Goode, Blogmaster

A number of recent studies have considered the case for HPV-related cancer prevention interventions that are targeted at specific populations. In the developed world, interventions of cervical screening and teenage vaccination aim to cover the female, or male and female, population (at a certain age) in order to prevent cervical cancer.  The question of more targeted interventions generally arises in relation to MSM – and especially HIV+ MSM – on account of their heightened risk of HPV-induced anal cancers.  There has been a marked rise in these cancers since the 1980s.  Unlike cervical cancers in heterosexual women (which decline with age), anal cancers are prevalent in MSM of all ages (Poynton & Grulich (STI)) – possibly reflecting higher rates of exposure through new partners.  Particularly high rates of anal cancer in older MSM living with HIV may be attributable to long-term immunologic defects in this population (van der Laar & Richel (STI)).  Elevated HPV rates have also been shown in sexual minority women (Reiter & McRee (STI)).  Of course, the problem of anal cancers in MSM could be resolved through vaccination of adolescent boys.  However, a recent UK study has investigated the feasibility of delivering a targeted HPV vaccination programme to adult MSM through STI clinics (Bayley & Soldan (STI)).

In developing countries, there could also be a case for targeting HPV screening – but for the prevention of cervical cancer in heterosexual women, rather anal cancer amongst MSM.  In most parts of sub-Saharan African, and other limited resource settings, neither cervical screening nor widespread adolescent vaccination have proved feasible, and rates of cervical cancer are relatively high (WJCO: Cervical Screening in Limited Resource Settings).  Here, Whitham & Kulasingam (W&K) have argued in a recent analysis of the evidence from six longitudinal studies undertaken in Senegal from 1994-2010, that some targeting of the available resources towards women who are HIV+ is justified given their considerably elevated levels of risk.  Like the HIV+ MSM in the studies mentioned above, HIV+ heterosexual women, according to W&K, have much higher rates of progression from HPV to high-grade squamous intraepithelial lesions (HSIL) (HR 2.55 times), as well as higher levels of progression from normal to HPV, and from normal to HSIL (respectively, HR 1.53 and 1.58). These rates corroborate the results of earlier studies (e.g. Mayaud & Lacey (STI)) that suggest high-risk HPV types and a tendency to HSIL in HIV+ in the older female population.

These findings prompt W&K to recommend, in the sub-Saharan setting, the policy of targeting of HPV vaccination to the HIV+ population recently proposed in the developed world for HIV+ MSM.  Unfortunately, various problems make such an intervention considerably less feasible in the case of sub-Saharan HIV+ women.  First, the sheer prevalence of HPV amongst the target population make HPV testing inefficient as a stand-alone screening strategy and tends to reduce its positive predictive value.  Second, the tests current in the West (cytology and Hybrid Capture 2) require laboratory equipment and technician expertise not likely to be available in Africa.  On the latter point, however, W&K note that the recently developed careHPV test may offer a more effective alternative to Visual Inspection with Acetic acid (VIA).

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.

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