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Diagnostics

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.

“Fast-tracking” the end of the HIV epidemic

8 Oct, 14 | by Leslie Goode, Blogmaster

At a high-level event on the margin of the UN General Assembly meeting in New York last month, convened with the support of UNAIDS, world leaders agreed that ending the AIDS epidemic as a global threat by 2030 was possible, and should be placed at the centre of health development goals.  The brochure, Fast Track (7 pages), sets out the agreed proposals.  The context of the agreement is the General Assembly’s discussion of 17 Sustainable Development Goals for 2015-2030 to replace the Millenium Development Goals that are due to expire in 2015 – and, more specifically, the formulation of targets to accompany the Sustainable Development Goal for health: “To ensure health lives and promote well-being for all at all ages”.  The week before the UN General Assembly saw the early online publication of a paper by 16 international experts (Norheim & Peto)  proposing as a “feasible goal” the overall reduction of pre-mature deaths by 40% – including, as an important element, a reduction by two-thirds of deaths due to HIV.

The proposals contained in Fast Track are in line with the most radical response scenario set out in pp.291-3 of the UNAIDS GAP report (July 2014), involving reduction of new adult infections to 500,000 by 2020, and 200,000 by 2030.  Also reminiscent of the earlier document is the sense of the tide of the epidemic having turned, and of its increasing concentration within the cities of 30 or so nations – and, more specifically, within fairly specific populations of those cities, such as sex workers, intravenous drug-users, etc..  This concentration represents both a challenge and an opportunity (STI/blogs/UNAIDS GAP report).  The new element in Fast Track is a three-fold target of 90%: for the proportion of those infected should know their HIV status, the proportion of those knowing their HIV status who receive anti-retroviral therapy, and the proportion of those on therapy who achieve undetectable levels of viral load – all by 2030.  A glance back at the GAP report itself reveals what a challenge this is likely to be (e.g. at present, 3 in 5 of HIV infected not receiving ART).

Also timed to coincide with the proposals (25th September) was the announcement of a scheme to expand access to viral load testing through an agreement affecting the pharmaceutical Roche’s COBAS® AmpliPrep/COBAS TaqMan HIV-1 Test version 2.0 (see STI/Hatzakis & Kantzanou).  Access to viral load testing is essential to monitoring of HIV-infected people (STI/Hill & Minton), and its high cost has been an obstacle to progress in low and middle income companies up until now.  The new agreement may smooth the way to the achievement of the ambitious targets set out in Fast Track.

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.

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