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Chlamydia Screening

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.

 

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.

No rise in UK Chlamydia; but disquieting trends for MSM

29 Jun, 11 | by Leslie Goode, Blogmaster

The annual report of the UK Health Protection Agency (17th June, 2011) offers a concise and accessible statistical overview of recent trends in STIs (not including HIV/AIDS), as well as details of the UK Chlamydia screening programme and the recent epidemic of lymphogranuloma venereum (LGV).
The overall picture suggests a slight decline (1%) in STIs in 2010, and – for the first time since records began – no rise in chlamydia diagnosis (despite the continued scale-up of testing). The overall decline conceals a continued rise in gonorrhoea (3%) and herpes (8%) diagnosis, partly attributable to more sensitive diagnostic tests.
Those aged under 25 account for 63% of chlamydia diagnosed, 54% of genital warts, 47% of gonorrhoea, 41% of genital herpes. Trends since 2008 differ somewhat according to sex. Among women the 15-24 year olds are very considerably the most severely affected group, and have seen a continued slight decline in gonorrhoea and genital warts diagnosis. Among men cases seems less unevenly spread overall, but with 20-24 years old the most affected. These have seen a continued rise in gonorrhoea diagnosis.
Men who have sex with men (MSM) are the other key population. These account for 64% of syphilis and 40% of gonorrhoea. Here there is less cause for cheer. Gonorrhoea diagnosis has continued to rise (up by a third in the past year), while Syphilis continues on its upward trajectory. Given the high risk of exposure to HIV/AIDS in the MSM population (a dimension of the STIs picture that is absent from this report, which fails to make the link between STI and HIV), these figures are particularly worrying.
The report concludes with statistics for the epidemic of lymphogranuloma venereum (LGV). This began in the late 2004 and has intensified considerably, with a third of the total number of 1,665 cases having been diagnosed since 2010 – largely among white HIV positive MSM.

HPA, Health Protection Report, HIV/Sexually Transmitted Infections (STIs), vol. 5, no.24, 17th June 2011

http://www.hpa.org.uk/hpr/infections/hiv_sti.htm

Chlamydia screening at the crossroads

11 Jan, 10 | by Jackie Cassell, Editor of STI

As financial screws tighten, and a general election approaches, British clinical readers are expecting lean times ahead.   Services for sexually transmitted infections (STI) are unlikely to get major billing in party manifestoes, and political support tends to be driven by committed individuals rather than public demand.

These are particularly interesting times for England’s National Chlamydia Screening Programme (NCSP).  The programme has been the subject of a report by the National Audit Office, followed by a hearing of Parliament’s Public Accounts Committee before the Christmas break.

The NCSP was announced in 2003, and differed from pilot studies in several respects.  Both English pilots(1,2,3) had achieved high rates of coverage within their single year of operation, with general practice a predominant setting, and using some form of payment for general practitioners who participated, while only one(3) had included males in the target group.

During the financial year April 2008-2009 an estimated 15.9% of England’s 6.7M 15-24 year old population had been tested for Chlamydia outside specialist genitourinary medicine clinics – still far short of the estimated one third which was achieved in the pilots and thought to be needed to achieve a real impact on incidence.    However, whatever happens now the programme will continue to have a major impact on the organisation of sexual health services.  The dissemination of testing into family planning (contraception) clinics, other young people’s services and increasingly into general practice has already mainstreamed awareness of STIs among the public and professionals. The next few months will be crucial in defining public policy on the balance and relationship between the NCSP (simple service, high throughput) and specialist STI services (complex and expensive, and focussing on the needs of individuals of higher than average risk behaviour or worse than average luck).

The NCSP was criticised by the National Audit Office(4 ) for multiple and weak branding, disorganised and cost-inefficient commissioning, and highly variable partner notification (and even treatment) rates. The report is definitely worth a read, along with its sister publication – a report on the NCSP to the Department of Health by Dr Ruth Hussey. The NCSP was implemented in a period of increasing devolution of a wide range of healthcare resource decisions to local areas, with pressure applied where needed by blunt instruments such as the “Vital Signs Indicator” which last year set a standard of 17% coverage for the NCSP .  In this respect, its difficulties  are likely to be a wider sign of the times as suggested by the Chair of the Public Accounts Committee, who remarked in closing: “What went wrong? You ploughed ahead with local, fragmented implementation, the programme has been inefficient, it has wasted public funds and each programme has been buying its own kit, devising its own marketing and websites.

Although the Public Accounts Committee’s recommendations are not yet published, a flavour of what we can expect can be inferred from a webcast of the hearing at http://www.parliamentlive.tv/Main/Player.aspx?meetingId=5227 or, if you prefer the written word, at http://www.publications.parliament.uk/pa/cm/cmpubacc.htm#uncorr

A more coherent branding and commissioning of the NCSP will have implications for the branding, and prioritisation, of more specialist STI services. Clinicians and providers will need to think and advocate long and hard for a locally effective the future balance between the NCSP (whatever form it may take), and the broader picture of services for STIs, including specialist services. Who and what will they be for, if everyone offers a yearly chlamydia test?

4. National Audit Office:  Young People’s Sexual Health. http://www.nao.org.uk/publications/0809/young_peoples_sexual_health.aspx
5. Dr Ruth Hussey.  Review of the National Chlamydia Screening Programme.  Crown publication, London, 2009. http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_108285
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