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Chlamydia

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)).

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.

 

Trialling innovative approaches to STI partner services: Partner-Delivered vv. Accelerated Partner Therapy

26 Feb, 15 | by Leslie Goode, Blogmaster

It is vital to treat partners of patients with curable STIs as quickly as possible.  But the effectiveness of interventions to achieve this proves hard to measure – and the case for increasing resources correspondingly difficult to make.  The inadequacy of the resources available to existing partner services has led some investigators in the US and UK to seek out innovative approaches to ensuring the treatment of partners which are less expensive.  One option – Patient-Delivered Partner Therapy (PDPT) – is to provide treatment for partners via the patient and without prior medical assessment of the partner.  The problems with this are: first, that PDPT may not conform to legal (Cramer & Leichliter (STI)) or professional guidelines; second, that concomitant infections (e.g. HIV) in the partner may go undiagnosed and untreated. An alternative solution – Accelerated Partner Therapy (APT) – is to treat the partner via the patient, but only after a medical assessment conducted by telephone or with a pharmacist (Golden & Estcourt (STI); Dombrowski & Golden (STI)).

The option of PDPT has been trialled in various US clinics (Mickievicz & Rietmeijer (STI); Sanchez & Schillinger (STI); but its impact is difficult to evaluate on a local level. Now, for the first time, Golden & Holmes have attempted a population-level randomized control trial of uptake and impact across 23 out of the 25 counties of Washington State.  This impressively large-scale operation had two elements.  The first was the provision of free PDPT, and involved: 1. informing all clinicians about the programme; 2. making stocks of free PDPT available to clinicians who had reported ≥ one case of Chlamydia or Gonorrhoea, and to certain large pharmaceutical chains; 3. visiting clinicians reporting frequent cases for the purpose of educating staff about the programme.  The second element was the possibility offered to diagnosing practitioners via routine report forms of having the provision of partner services handled by the state public health department. This intervention was rolled out in four successive waves to different counties in turn, thus enabling the impact of the intervention to be controlled against the default situation in the counties of each wave.

As regards uptake, percentage of persons receiving PDPT from clinicians rose in intervention periods from 18% to 34%, and percentage receiving partner services from 25% to 45%.  This is broadly comparable with what has been achieved by more local interventions in the US.  Unfortunately, it is one thing for a pack to be accepted by the index patient, another for a partner to be successfully treated.  Hence the interest of G&S’s attempt to evaluate population-level impact – through testing in sentinel clinics in the case of Chlamydia, and through incidence of reported infection in the case of Gonorrhoea. It was undoubtedly ambitious of G&S to seek an indicator of population level impact for a comparatively brief intervention.  It is no surprise that the results are less than overwhelming. Chlamydia test positivity and gonorrhoea incidence in women declined respectively from 8.2% to 6.5% and from 59.6 to 26.4 per 100,000. The latter more impressive reduction is unfortunately hard to distinguish from a strong secular trend in the same direction in various states.

There are more general problems, however – such as knowing whether the handing over of PDPT packs is resulting in the successful treatment of disease, or whether it may even be contributing to an ongoing failure to diagnose concomitant partner infections.  These might weigh in favour of the alternative approach recently developed in UK clinics: APT.  Estcourt & Johnson (STI) report uptakes of 66% and 59% for versions of APT as against 36% for conventional PS.  Sending a treatment pack following a telephone interview would seem to offer a better guarantee of partner treatment, than offering a pack on the basis of nothing more than a stated willingness of the index patient to deliver it.  At the same time, interviewing the partner averts the risk of doing harm by pre-empting consultations at which a fuller diagnosis of the partner’s condition would have been possible.  A population-level trial of the impact of APT has yet to be undertaken.

Could Chlamydia treatment failure be the result of genital contamination from persistent gut infection

6 Mar, 14 | by Leslie Goode, Blogmaster

The persistence of Chlamydia trachomatis  (Ct) infection in treated patients is generally attributed either to re-infection or poor treatment adherence.  To some, however, the evidence has suggested the operation of an additional factor – such as treatment failure (STIs/ Goetz & Bruisten; STIs/ Pitt & Ison; STIs/ Horner).

A recent study (Rank & Yeruva (R&Y)) develops an interesting hypothesis, based on evidence of Ct. infection in the gastro-intestinal (GI) tract of mice.  This supports the possibility that Ct. persistence in humans might be a result of ongoing Ct. infection of the gut, and re-infection of the genital via the lower GI tract (Yeruva & Rank).  According to R&Y’s research on animals, Ct. of the GI tract does not elicit an inflammatory response, and never resolves.  It provokes an immune response – but not at a level that would cure the GI infection.  The orthodoxy states that Ct. found in the human GI tract is “non-replicating”.  R&Y claim this not based on evidence.  So they see nothing to exclude the possibility that, in humans, as in mice, treatment failure may be due to auto-innoculation from the lower GI tract.

This hypothesis is highly relevant to discussion of Ct. persistence in this journal, which has arisen around such questions as: whether persistence is due to some factor other than re-infection or poor adherence, such as anti-microbial resistance (STIs/ Goetz & Bruisten; STIs/ Pitt & Ison); how important that factor is, and what it means for Chlamydia screening programs (STIs/ Regan & Hocking).  If R&Y’s hypothesis proves valid for humans as for mice, then that other factor – or, at least, some element of it – is explained, and would certainly need to be taken account of when modelling the effectiveness of screening programs.

The idea that persistence of Ct. in humans results from contamination from persistent GI tract infection seems to be a new one in the STI literature (though apparently cases have been documented by the veterinary literature in numerous animals as early as the 1950s).  It is certainly worthy of further investigation, given the implications that it would have, if proven, for diagnosis and management of human Ct. infection.  In that event, it would be necessary to consider, for example, what importance to attach to the clearing Ct. from the GI tract – and, supposing this to be necessary, how this would affect the nature and duration of treatment given for genital Ct..  In treating rectal Ct., for example, treatment with Azithromycin (≤13%) has been claimed to be inadequate (STIs/ Drummond & Donovan), while Hathorn & Goold find treatment with doxycycline to be a more effective alternative (STIs/ Hathorn & Goold).

Prospects for a high sensitivity point-of-care test for Chlamydia

14 Feb, 14 | by Leslie Goode, Blogmaster

A recent paper (Krölov&Langel) describes a technique for the diagnosis of Chlamydia trachomatis which, if developed into a point-of-care test (POCT), could be performed in just twenty minutes and would achieve a considerably greater sensitivity (83%) than any of the POCT alternatives to the current laboratory testing process using Polymerase Chain Reaction (PCR).  The technique – Recombinase Polymerase Amplification – is a Nuclear Acid Amplification (NAAT) test (like PCR), but one that allows a simplification of the complex stage of sample preparation such that it can be accomplished swiftly outside a laboratory setting.

The problem with PCR is that because it depends on a laboratory process, patients have to make a second visit to their health care provider in order to receive their diagnosis and treatment – and, some may fail to make that visit.  Existing POCT alternatives, however, seriously under-perform on the score of sensitivity (generally under 60% – and in many cases much worse).

Some researchers – including contributors to STIs (STIs/Skidmore; STIs/Gaydos; STIs/Dommelen&Hoebe) – have viewed the availability of such poorly performing tests as entirely detrimental.  On the other hand, the scale of the problem of patients lost to follow-up no doubt varies with place and time – and what is required of POCT may not be the same in all contexts (STIs/Rompalo&Gaydos).  Others, therefore, have taken a more positive view of the impact of less than perfect POCTs – to extent of acknowledging their potential role in certain contexts, or in combination with other interventions (Swain&Singh).  A recent modelling study (STIs/Huang&Barnes) has sought to set the conditions of cost-effectiveness for such a POCT in terms of thresholds for sensitivity, cost of POCT, and “willingness to wait” for the result.

Above all, however, the potential of the less than perfect POCT depends on the size of the “lost to follow up” problem.  The Swain and Singh (S&S) model assumes a 93.5% rate of return for treatment achieved for their sample by the Baltimore STD clinics engaged in their study in 2010.  This rate does not seem higher that than would be expected in STD clinics in developed countries nowadays (e.g. the UK).  It is certainly a good deal better than the 80% given by Schwebke & Hook for Alabama in 1994 – which has since been cited by Swain & Singh (2004) and Krölov & Langel (2014).  Assuming the rate of 93.5% lost to follow-up, Swain and Singh estimate degrees of sensitivity that would be needed at a given cost per test for the POCT to achieve a cost-effectiveness that would equal that of the current PCR tests.  Thus for a cost per test of $30 a POCT with approx. 85% sensitivity would be required; for a cost per test of $35, a sensitivity of 90%.  All of these predictions assume a POCT that would require the patient to wait 40’, and fairly low stated levels of “readiness to wait” (e.g. only 48% on the basis of a patient questionnaire).  On the basis of such admittedly rather rough and ready assumptions, the sensitivity of the proposed POCT seems to come at least range of parity with PCR as regards cost-effectiveness.

But these estimates all assume levels of “lost to follow up” such as we find in an STD clinic in developed countries.  This situation could, of course, be very different – and more favourable to POCTs – amongst specific populations and less developed countries where rates of return for follow-up could be much lower.  A more interesting and relevant modelling study than that of Swain and Singh would have shown the relation between proportion of “lost to follow up” and sensitivity for a given cost per test, rather than treating proportion of “lost to follow up” as the fixed parameter.

How does neighbourhood impact on STI (Chlamydia) risk?

19 Jun, 13 | by Leslie Goode, Blogmaster

The influence of neighbourhood on STI (and more particularly Chlamydia) acquisition is widely recognized fact.  Biello & Nikkolai argue for UK urban populations that neighbourhood socio-economic status (SES) is more closely correlated with Chlamydia risk than individual SES (http://sti.bmj.com/content/87/7/560.abstract?sid=88b6a7a5-11c9-472d-bd9a-39664d4142b7).  In another UK study (Birmingham), Shahmanesh & Ross find residence in neighbourhoods having certain SES characteristics to be  strongly predictive of both Chlamydia and Gonorrhoea (http://sti.bmj.com/content/76/4/268.abstract?sid=88b6a7a5-11c9-472d-bd9a-39664d4142b7).

But what is it exactly about these neighbourhoods that places their residents at far greater risk of STI acquisition than other neighbourhoods?  Is it, as some sociologists have proposed, the general level of social disorganization that heightens the risk, or is it poverty itself, or maybe the degree of residential instability?  Ford & Browning, in a recent study using data on a sample of 11,460 young adults from the US National Longitudinal Study of Adolescent Health, waves 1 and 3 (1994-2002), attempt to establish the pathway whereby neighbourhood influences the risk of acquiring Chlamydia (http://link.springer.com/article/10.1007%2Fs11524-013-9792-0).

The nature of the data allows the researchers to capture the association of Chlamydia acquisition amongst young people in their twenties, not only to various characteristics of their current neighbourhoods (i.e. at wave 3 of the study), but also the characteristics of those neighbourhoods in which they accomplished their transition into adulthood some years before (i.e. at wave 1).  The main finding of Ford & Browning is that characteristics of the current neighbourhood show no statistically significant correlation with Chlamydia acquisition, but characteristics of neighbourhoods at the time of adolescence – especially  “poverty” (on different models OR 1.23 & 1.25 respectively) – do show a correlation.  The obvious explanation is that these associations are mediated through individual variables such as sexual behaviour or psychological factors (e.g. depression).  Yet multi-variate findingsdid not confirm this mediation.

So what potential mechanisms are there for the influence of neighbourhood on STI acquisition?  While stressing the need for further research, the authors point principally to two.  The first of these is a “network” explanation.  Maybe neighbourhood of residence during adolescence could influence opportunities for future partner selection;  young adults who lived in an impoverished neighbourhood during adolescence may have a pool of higher risk sexual partners to choose from compared to their peers from more advantaged neighbourhoods.  The other interesting possibility is the influence of chronic stress associated with adverse neighbourhood conditions resulting in impaired immune system function and increased infectious disease risk through increased inflammation and cortisol secretion.

Either way, structural factors that are largely refractory even to the most ambitious public health interventions.  I am reminded of Wilkinson and Picket’s argument in The Spirit Level (http://www.amazon.com/The-Spirit-Level-Equality-Societies/dp/1608193411): the determinants of health outcomes are effectively located at a level that is presumably beyond of the reach of any but the most radical (indeed revolutionary) political interventions.  “The poor you will always with you.”  At the same time, sociological explanations of this kind provide justification for careful targeting of public health resources on needy populations and help us counter the “inverse care” law.

 

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