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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.

Cochrane says: Chlamydia screening may have very limited impact, but more research is needed

3 Oct, 16 | by Leslie Goode, Blogmaster

There is a strong rationale for systematic Chlamydia screening, and it is widely recommended and practised. Yet there are harms associated with the screening process (Low(STIs)), and, of course, serious concerns about its cost-effectiveness (De Wit & Kretzschmar (STIs)).  This lends urgency to the question of whether Chlamydia screening works – addressed in a recently published systematic review for the Cochrane Database:  ‘Screening for genital chlamydia infection’.

It all depends, the authors claim, on what we want screening to do: whether it’s a general reduction of prevalence in the population that we’re aiming at, or the prevention of serious sequelae such as PID (Pelvic Inflammatory Disease) in individuals.  The strict Cochrane exclusion criteria (especially that of ‘reporting a pre-specified primary outcome’) reduce the pool of evaluated studies to just two addressing the impact of screening on Chlamydia prevalence – only one of which (not, as it happens, an RCT) addresses impact on prevalence in the general population (Schmid & Kretzschmar (STIs)).  Regarding the impact of screening on reduction of PID incidence, the field narrows to just four RCTs (Andersen & Olesen (STIs);  Ostergaard & Olesen; Oakeshott & Hay; Scholes & Stamm).

Respecting the impact on prevalence, Schmid & Kretzschmar (STIs) observe very little effect (RR 0.96), but the quality of evidence is rated, on Cochrane criteria, as ‘low’.  As for PID prevention, an effect was observed (overall RR 0.68), but unfortunately was considerably less pronounced in the two studies with low risk of selection bias (Andersen & Olesen (STIs) and Oakeshott & Hay) (RR 0.80) than with the other two studies ((RR 0.42).  This evidence was consequently downgraded from ‘high’ to ‘moderate’.

So there continues to be no evidence at present for a positive impact of screening on general prevalence, though further research could possibly modify this assessment.  As regards the incidence of PID, some limited degree of positive impact may have been demonstrated – though whether systematic screening interventions will turn out to be cost-effective is another question (De Wit & Kretzschmar (STIs)).  The reviewers point out there is another important trial that is still on-going (hence not eligible for inclusion): Hocking (STIs).  The latter – a study being undertaken in Australian GP practices – involves ‘opportunistic’ testing (as defined by Low (Low(STIs)) rather than screening proper (i.e. ‘systematic’ screening).  However, given that this is the form of intervention being undertaken in many places including the UK, its final results will no doubt be of great interest.  On the basis of the study’s findings to date, the verdict seems unlikely to be favourable (Yeung & Temple-Smith (STIs)).

Is increasing gonorrhoea resistance in MSM is a result of more treatment, rather than greater sexual activity?

20 Jul, 16 | by Leslie Goode, Blogmaster

Emerging antibiotic resistance to the last-ditch treatment of Neisseria gonorrhoeae compels health policy-makers to balance opposing concerns.  On the one hand, successfully combating spread of the infection requires targeted treatment of core-group individuals.  On the other, a focus on the core-group causes a rebound in core-group incidence, with maximal dissemination of resistance (Chan & McCabe/STIs (C&M); Chan & Fisman/STIs).

Recent public health orthodoxy has tended to favour the more intensive screening of core-group individuals (Ison & Unemo (STI); Giguere & Alary/STIs; Lewis/STIs).  However Fingerhut & Althaus (F&A), in a recent modelling study, seek to shift the balance in the opposite direction.  They claim their model demonstrates that the wide disparity in the spread of resistance spread as between populations of MSM and of HMW (heterosexual men and women) reflects differing levels of treatment rather than differences in sexual behaviour (‘more sexual partners’).

So far as concerns the first part of the claim (‘gonorrhoea spreads faster with more treatment’), F&A’s findings corroborate those of C&M.  However, in coupling this with the claim that gonorrhoea spread is not the result of sexual behaviour (‘gonorrhoea (does not) spread faster with more sexual partners’) they place the balance of responsibility for spread with the prevailing policy of treatment.  This is presumably intended to push policy makers in the direction of a more conservative attitude to targeting testing and screening.

But can F&A really justify this  change of emphasis by differentiating the respective contributions of ‘more treatment’ as against ‘greater sexual activity’ to the difference in resistance between MSM and MSW popultions ?  We are wrong, the authors argue, to assume that ‘more partners’ amongst the MSM population necessarily entails more transmissions (p. 11) – and their model apparently demonstrates this.   A common sense response, however, would be to object that ‘more partners’ presumably implies ‘more sex acts with more partners’ – and that, even if ‘more partners’ does not in itself entail more transmissions, ‘more sex acts with more partners’ might certainly be expected to do so.

Interestingly, Althaus in another paper (see Althaus & Alizon) – admittedly, in connection with heterosexual groups – corroborates our common sense expectation by showing that the number of partners displays, if not a proportional, then at least a linear, relation  to number of sex acts. So can it really be the case that there is not a greater number of transmissions amongst the MSM population, given the greater number of partners? The authors evidently believe not.

Nevertheless, it would be interesting – as well as pertinent, I suspect, to the goals of the study – to have a more satisfying explanation of why, here, as elsewhere, common sense turns out to be wrong.




Can a case be made for opportunistic testing for Chlamydia?

6 May, 16 | by Leslie Goode, Blogmaster

Last month saw the publication of a revised Guidance on Chlamydia Control in Europe (2016) by the European Centre for Disease Prevention and Control.  This replaces the earlier Guidance on Chlamydia Control in Europe (2009) – though the 2016 document refers the reader to the 2009 one for more detailed descriptions of the epidemiology of the infection in Europe, and of prevention programmes in the various states.  The 2016 Guidance displays a distinct change in tone from the earlier document, reflecting greater scepticism as to the feasibility of an ‘effective Chlamydia control strategy’ and abandoning the earlier ‘step-by-step’ presentation with its suggestion of ascending levels culminating in register-based screening.  The changes concern primarily opportunistic testing and screening (formerly levels C and D in the ascending sequence).  These interventions are now recommended only ‘if resources are available’.

So what sort of case can be made for Chlamydia prevention interventions that go beyond primary prevention to at-risk individuals, evidence-based case management, and partner notification?

In favour of asymptomatic testing it is sometimes argued that the sequelae of Chlamydia such as Pelvic Inflammatory Disease (PID), ectopic pregnancy and tubal infertility largely occur in patients who have experienced only asymptomatic infection; so interventions restricted to treating symptomatic patients and their partners are likely to have limited impact on the prevention of complications (see Low, and response by Joan M. Chow).  On the other hand, it has proved very difficult, in practice, to come up with opportunistic testing interventions that can be shown to be effective (see Low).  As far as concerns the population level impact of such interventions, it seems unreasonable, on current evidence, to expect that they would ever be able to achieve sufficiently high levels of coverage.  However, If we limit our interest to their impact at the individual level, the effectiveness of opportunistic testing turns out to be very difficult to evaluate, because insufficient is known, amongst other things, about the risk of Chlamydia progressing to complications.  And without knowing more about the effectiveness of interventions, it is difficult to produce a robust evaluation of their cost effectiveness.

Some attempts have been made, however.  De Wit & Kretzschmar/STIs (D&K) model various screening scenarios on the basis of data from a three year annual screening programme in an area of the Netherlands that was genuinely register-based – as opposed to the opportunistic testing undertaken by the so-called ‘screening’ programme in the UK.  Andersen & Valkengoed/STIs (A&V) report on the Danish ‘register’ study which randomly assigned 9000 from the public register either to be invited or not invited for a Chlamydia test, and then followed up both arms for Chlamydia sequelae over a nine-year period.  From neither study are the results particularly encouraging.  D&K estimate cost effectiveness, on the most favourable scenario, at over $50,000 per QALY; while A&V report no benefit from participation in the intervention arm which received invitation to a Chlamydia test.

As for opportunistic testing, Johnson & Cassell/STIs (J&C) compare the various institutional settings involved in UK national programme in respect to the number of tests performed and the rates of positivity – as do den Heijer & Dukers- Muijrers/STIs (d&D) for the South Limburg area of the Netherlands in study on a registered based intervention (see also Woodhall & Saunders/STIs).  J&C remark on the relative importance for women of healthcare-based settings along with youth centres, both as regards number of tests performed and positivity.  This happens to agree with the findings of d&D who report 71% of female positive diagnoses in healthcare settings.  For men, non-healthcare related institutional settings were popular, but had considerably lower rates of positivity than healthcare-related settings.

Overall, these papers seem to indicate the likely effectiveness of opportunistic testing through enhanced testing services in healthcare-related settings –a solution that might be achievable without undue cost through existing health services.


Health professionals violate human rights of sex workers in Kenya

10 Feb, 16 | by Leslie Goode, Blogmaster


‘Key’ populations – such as sex workers – are now seen as crucial to turning the tide of the HIV epidemic. Given the recognized epidemiological potential of such marginalized groups to act as ‘bridging populations’ into the wider population, much importance has rightly been attached to countering the kind of routine violations of human rights that can effectively exclude such vulnerable populations from participation in health interventions designed to deal most effectively with the causes of the epidemic (UNAIDS Gap Report; UNAIDS (STI/blog). Amidst the talk of public health ‘strategies’, Speaking Out, a recent report based on the personal testimonies of 30 Kenyan sex workers, offers a powerful reminder that the problem of HIV in key populations is a cultural and social challenge before it is a technical one.  It is also a corrective to any strategy that would underestimate, in these days of expanded ART provision, the apparently softer but more complex challenge of cultural interventions to protect human rights. The report offers the results of one of the local community-led research projects supported in eleven countries by the Global Network for People Living with AIDS (GNP+).

At the heart of the problem of violations to the human rights of sex workers is the behaviour of health professionals. Officially, the human rights of such minorities are protected in Kenya by robust constitutional and legislative provisions; in practice, they are routinely flouted by everybody – including health workers. The authors of the report place violations in the following categories. Around HIV diagnosis. An attendee at an ante-natal clinic is HIV tested without her knowledge, and informed of the result in the presence of her current partner, who subsequently separates from her. Breach of confidentiality. On discovering the sex worker status of a positive-diagnosed attendee, a doctor scrolls down to ‘mama’ on the patient’s mobile and summons her mother to the hospital. Discrimination. A health worker who recognizes the status of a women attending with a stab injury announces to colleagues: ‘This is a sex worker who has been stealing other men’s husbands. Just stitch her. If it heals, well and good. If not, so be it’. Denial of services. A sex worker attending a facility following rape, is abused for her status, laughed at for claiming rape, and refused PEP on the grounds that it was not for ‘people like her’.

Such total disregard for the human rights of sex workers is shared by law enforcement officers who refuse to take seriously accusations or rape, refuse protection before the law for human rights violations, summarily arrest, then extort from, and sexually harass, their sex workers, inflict degrading treatment on them while they are in custody, and deny them access to treatment for the duration of their stay.

It is difficult to see how much progress is likely to be made in turning the tide of HIV in this particular ‘key population’ without a wholesale transformation of attitudes. The kind of abuses this study reveals are evidently paralleled in many countries. For example, Ndondo & Dlovu (STIs) and Jose & Nathan (STIs) draw attention, on the basis of qualitative survey evidence, to similar kinds of violations to sex workers’ human rights by law enforcement officers in Zimbabwe and East Timor, respectively. Mayhew & Hawkes (STIs) discuss violations in respect to a number of vulnerable groups including sex workers by both law enforcement officers and health professionals in Pakistan. It would seem that in many countries the UNAIDS strategy of controlling HIV in key bridging populations will encounter stiff cultural challenges.

Incidental gonorrhoea screening in the general population via dual NAAT is no benefit

12 Jun, 15 | by Leslie Goode, Blogmaster

Fifer & Ison (STIs) express concern over the use of the “dual” nucleic acid amplification tests (NAATs) for the detection of chlamydia and gonorrhoea in the context of chlamydia screening in the UK.  Additional testing for gonorrhoea, when the real target is chlamydia, does not necessarily confer an additional net benefit.   This is because even a high specificity test such as Cobas 4800 (Perry & Corden (STIs); Rockett & Limnios (STIs)) will generate a high proportion of false positives when the infection tested for has extremely low prevalence, as in the  case of gonorrhoea in the general population.  And the potential disbenefit of the additional test in terms of the psychological impact, and the impact on relationships, of false positive diagnoses could easily outweigh the medical benefit represented by the diagnoses which are accurate (Dixon-Woods & Shukla (STIs); McCaffery & Wardle (STIs)).

The potential impact of the adoption of the dual NAAT as a stand-alone test – if not confirmed by further testing using either a second NAAT or else culture – is illustrated by a recent Australian study published in the Medical Journal of Australia (MJA).  Chow & Fairley perform a retrospective analysis of insurance and notification data from Melbourne over the years 2008-2013.  They seek to demonstrate that the apparent rise in identified gonorrhoea cases amongst the general female – non-indigenous – population (from 98 to 343) is at least partly an “artefact” of the growing employment by laboratories of the dual NAAT.  They do this by eliminating the alternative possibility of a genuine increase in gonorrhoea in the general population.  To this purpose they use their data to investigate changes in the proportion of positive dual NAAT gonorrhoea diagnoses to the number of dual NAAT test ordered, over the period during which dual NAATs were being introduced.  They also investigate rates of positive gonorrhoea diagnoses over this period at a “sentinel” clinic in Victoria where culture alone was used as a means ofgGonorrhea diagnosis.  They find that the proportion of positive dual NAAT diagnoses in Victoria remained relatively constant over time (around 0.2-0.3%), as did the proportion of positive culture diagnoses at the Melbourne clinic (around 0.4-0.6%).  Of 25 untreated women who had a positive NAAT result for gonorrhoea and were referred to the Melbourne clinic, only 10/25 were confirmed by culture.  The authors comment that this is in line with what might be expected in the light of the published specificity of the various NAAT tests employed.

C&F recommend that laboratories suppress gonorrhoea diagnoses from the dual NAATs.  An MJA editorial in the same issue questions the feasibility of this.  Instead, the editors propose that the NAAT should, in the case of Gonorrhoea, be used as either a triage, with positive diagnoses confirmed by culture, or as an add-on where high prevalence populations are first tested by culture.  They also consider the possibility of confirming the initial NAAT with a NAAT using a different target.  However, they come down in favour of retaining culture in the diagnostic pathway on account of its value as a means of assessing resistance.  They also question whether even the double NAAT would guarantee adequate predictive value in very low prevalence populations.

Evidently, further studies are required.

Universal vv. targeted HIV screening in US EDs

3 Sep, 13 | by Leslie Goode, Blogmaster

The US Centres for Disease Control and Prevention (CDC) recommends universal “opt-out” HIV screening in all health care settings, including emergency departments and primary care settings (CDC 2006 HIV testing guidelines); the UK Guidelines for HIV Testing (BHIVA, BASHH, BIS) have, since 2008, recommended universal “opt-out-screening” in communities where HIV prevalence ≥ 2 per 1000 (HPA 2011 Time to test for HIV).  “Universal” screening is, of course, easier to recommend, than to implement.  However, a recent US study, Lyons & Fichtenbaum (L&F), raises the question whether, given adequate resources for implementation of universal screening, it is even the right goal to aim for. Isn’t some degree of targeting always bound to have a beneficial influence on the yield of screening?

This randomized control study conducted over two years in a US emergency department within a low HIV prevalence area and in the context of an ongoing HIV screening program, compared the yield of universal and targeted HIV screening.  Sufficient resources were provided to ensure that within the targeted arm, eligibility criteria could be targeted as broadly as possible, and would be implemented effectively.  The researchers were thus able to investigate the possibility that some degree of targeting would increase the yield of screening even in the ideal situation where it was not being forced on them by inadequate resourcing.

The answer of the study is that, even in the context of this low-prevalence area (0.23% in the surrounding county), targeting conferred no detectable clinical advantage. Of the 4,692 eligible visits in the universal arm 40.8% consented with 6 new diagnoses resulting (0.31%); of the 4880 eligible visits in the targeted arm 47.4% consented with 3 new diagnoses (0.22%).  The lower level of consent that might have been expected in the universal arm was not accompanied by any decrease in yield.  So even in this optimal situation for targeting, it seems to have brought no advantage.

What is the relevance of this finding, we might ask – especially outside the US, where emergency departments may not have the same role within the health system as the first and last resort of the uninsured? A large trial of universal HIV screening in Paris emergency departments, for example, generated an entirely negative result (STI Blogs 28/11/11); whereas the 2009-10 UK screening pilots of the HINT study picked up rather more cases (4/3433), though not as many as L&F (HPA 2011 Time to test for HIV).  A more generalizable message of this study may be the difficulty of using targeting effectively to reach the undiagnosed.  Palfreeman & McNally, in a short report on a pilot screening study at a UK acute medical unit (Leicester), undertaken concurrently with the HINT study, comments that 3/10 diagnosed did not have an indicator condition, and that many would have been missed but for the pilot.  This might be a point in favour of universal screening.

The findings of L&F have decreasing relevance to the extent that screening operates in situations where resources are constrained.  The authors themselves comment, in connection with the clinical screening program into which their study was inserted, that its high positivity rate (1%) before and after the study reflects the degree to which health workers were forced by limited resources to operate more selective targeting than the study itself.  Of course, L&F do not mean to imply that, in the more straitened context of the program prior to the study intervention, health workers should not have been applying more restrictive criteria.  Their point is simply that, where such constraints do not apply, targeted screening should not be assumed to offer any greater benefit than universal screening.  The relevance of such a finding, supposing it to be well-founded, will depend on how far, in the particular context considered, real-life conditions approximate those of the study itself, rather than those of the screening program as it operated prior to and after the study!




Cervical cancer prevention in low-resource settings: could self-testing be the answer?

26 Feb, 12 | by Leslie Goode, Blogmaster

A recent paper (Qiao et al.) – Journal of National Cancer Institute (JNCI) 104:3 – reports the findings of a series of 5 population-based studies of self-screening for cervical cancer in rural China, involving 13,140 participants.  They are particularly relevant to STI readers on account of issues they raise about the effectiveness of screening programs in low-resource settings.  An editorial in the same issue of JNCI (Patrick Petignat) provides an interesting discussion of these issues.

While a seventh of the world’s cases of cervical cancer (the third most common type of cancer in women) occur in China, a high proportion of these will be in low-resource rural settings where access to healthcare is very limited, and the kind of screening (smear or pap test) conducted in developed countries is not feasible.  The last few years have seen the development of a promising alternative to the smear test, which involves screening for the strains of Human Papilloma Virus (HPV) that can lead to cervical cancer (HPV DNA).  So far as low-resource settings are concerned, the latter test has the notable advantage that it can be administered by patients on themselves, and need not require significant medical resources and laboratory infrastructure.

Could self-administered HPV DNA testing provide a practicable mode of screening in areas, like rural, China where trained medical practitioners are scarce?              Petignat, in his JNCI editorial, helpfully distinguishes between the issue of diagnostic performance, and the wider issue of the likely efficacy of self-testing interventions outside the research setting.

The paper (Qiao et al.) addresses the first issue.  Participants in the five studies were all tested with HPV DNA administered by physician and with self-administered HPV DNA, as well as with  two other tests – liquid-based cytology (LBC) and visual inspection with acetic acid (VIA) (a test that has been proposed for low-resource settings).   Sensitivity and specificity of self-administered HPV DNA in detecting biopsy-confirmed cervical intraepithelial neoplasia grade 2 or more severe (CIN2+) proved to be 86.2% and 80.07% respectively as against 97% and 82.7% for HPV DNA performed by physician.  Sensitivity of self-administered HPV DNA at 86.2% was actually superior to sensitivity of LBC at 80.7% and VIA at 50.3%. So far so good.  The real problem with HPV DNA, whether self-administered or administered by physician, proved to be its relatively low specificity of 80.7%.  Without further triage, screening with HPV DNA would result in an altogether unfeasible 15.6% of women being referred for colposcopy.  A combination of self-HPV with triage using LBC or VIA might offer the most feasible solution.  Computer models for the impact of these combinations were developed in the course of the study, and produced levels of referral for colposcopy of 4.8% and 4.5% respectively.  Given LBC requires laboratory facilities and a medical infrastructure not likely to be achievable in a low-resource context, self-HPV combined with VIA comes out as the most feasible option.

There remains, however, the issue of the likely feasibility of self-testing interventions outside the research setting. The authors comment on the willingness of participants (70% of those invited) and the almost 100% compliance of participants with instructions.  This is promising. But compliance on the part of volunteer participants is one thing: likely take-up of self-testing interventions outside such a framework is quite another, and would no doubt depend on the delivery of the intervention, as well as on a range of cultural factors.  The authors refer to a relatively inexpensive testing kit – care HPV.  Ultimately, however, cost-effectiveness will depend on take-up.  Petignat concludes with a salutary note of warning: “Self-HPV per se is only a part of a secondary prevention program, and obstacles to program participation might not only result in program failure but also be harmful for women”.  In view of this, further research seems called for.

Fang-Hui Zhao, You-Lin Qiao et al., “Pooled Analysis of a Self-Sampling HPV DNA Test as a Cervical Cancer Primary Screening Method”, Journal of the National Cancer Institute, 104:3, 8th Feb., 2012

Patrick Petignat, Pierre Vassilakos, “Is It Time to Introduce HPV Self-Sampling for Primary Cervical Cancer Screening?” (Editorial) Journal of the National Cancer Institute, 104:3, 8th Feb., 2012

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