Review 2: "Sputum and Tongue Swab Molecular Testing for the In-Home Diagnosis of Tuberculosis in Unselected Household Contacts: A Cost and Cost-Effectiveness Analysis"

Septiara Putri; Mardiati Nadjib

doi:doi:10.1162/2e3983f5.847d4261

Sputum and tongue swab molecular testing for the in-home diagnosis of tuberculosis in unselected household contacts: a cost and cost-effectiveness analysis

by Charl Bezuidenhout, Lawrence Long, Brooke Nichols, Gesine Meyer-Rath, Matthew P Fox, Grant Theron, Bernard Fourie, Sharon Olifant, Adam Penn-Nicholson, Morten Ruhwald, and Andrew Medina-Marino

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Published on Oct 18, 2024
www.medrxiv.org

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ABSTRACT Background Delayed and missed diagnosis are a persistent barrier to tuberculosis control, partly driven by limitations associated with sputum collection and an unmet need for decentralized testing. Household contact investigation with point-of-care testing of non-invasive specimens like tongue swabs are hitherto undescribed and may be a cost-effective solution to enable community-based active case finding.Methods In-home, molecular point-of-care testing was conducted using sputum and tongue specimens collected from all household contacts of confirmed tuberculosis cases. A health economic assessment was executed to estimate and compare the cost and cost-effectiveness of different in-home, point-of-care testing strategies. Incremental cost effectiveness ratios of strategies utilizing different combination testing algorithms using sputum and/or tongue swab specimens were compared.Findings The total implementation cost of delivering the standard of care for a 2-year period was $84 962. Strategies integrating in-home point-of-care testing ranged between $87 844 - $93 969. The cost-per-test for in-home, POC testing of sputum was the highest at $20·08 per test. Two strategies, Point-of-Care Sputum Testing and Point-of-Care Combined Sputum and Individual Tongue Swab Testing were the most cost-effective with ICERs of $543·74 and $547·29 respectively, both below a $2,760 willingness-to-pay threshold.Interpretation An in-home, point-of-care molecular testing strategy utilizing combination testing of tongue swabs and sputum specimens would incur an additional 10.6% program cost, compared to SOC, over a 2-year period. The increased sample yield from tongue swabs combined with immediate result notification following, in-home POC testing would increase the number of new TB cases detected and linked to care by more than 800%.Research in context Evidence before this study We searched PubMed for original research published between January 1, 1950 and June 30, 2024 that evaluated the cost-effectiveness of in-home POC molecular testing, as part of HCI strategies for tuberculosis. PubMed search terms used included [“household contact investigation” OR “household contact tracing”] AND “tuberculosis” AND “cost-effectiveness”. The search revealed 8 studies, of which one was removed as HCIs were leveraged for the provision of short course preventative therapy and not tuberculosis testing. None of the studies were conducted in South Africa. All seven remaining studies relied on a hub-and-spoke model of sputum collection and transportation with sputum tested at a centralized laboratory facility. Although active case finding strategies like HCIs are endorsed by the WHO to improve early case detection and treatment initiation, limited research has been done to assess its cost-effectiveness in low- and middle-income countries.Added value of this study To our knowledge, this is the first example of in-home molecular point-of-care (POC) testing as part of HCI. The use of primary data to estimate and compare the incremental cost effectiveness of different combination, in-home testing strategies utilizing alternative sample types equips policy makers with a selection of strategy options to choose from. The tradeoff between sample types with high collection yield and those with increased accuracy becomes evident in the economic analysis, highlighting the need to consider both yield and accuracy in effective clinical decision making and use-case development. The success of in-home, POC tongue swab testing of all contacts, irrespective of symptom presentation shows great promise for universal testing programs.Implications of all available evidence Results from our economic modeling provide evidence in support for the integration of in-home, POC tuberculosis (TB) testing during HCI. The use of less invasive tongue swab samples to increase sample yield in the absence of sputum expectoration highlights the value of combination testing strategies. Immediate result notification resulting from rapid, in-home POC testing shows great promise for increasing early case detection and improving treatment uptake. In-home, POC testing strategies, when incorporated into HCI could curb ongoing community transmission and reduce the overall burden of TB. Considerations for adopting novel POC testing strategies in future active case finding programs like HCI should strongly be considered.Summary We evaluated the cost-effectiveness of in-home, point-of-care TB testing of household contacts. The findings indicate that combined testing strategies using tongue swab and sputum specimens could significantly increase TB case detection, with modest additional program costs.

RR\ID Evidence Scale rating by reviewer:

Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.

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Review: Overall, this manuscript with the focus on combining sputum and tongue swab molecular testing is novel and offers practical implications for settings with limited access to centralised health care facilities. This manuscript offers significant contributions to the field of TB diagnostics but requires broader contextualisation and methodological refinements to maximise its policy impact and academic rigor.

Comments below:

In the abstract section, please kindly state the model type and perspective in health economic assessment.
The use of “HCI” and “POC” without consistent elaboration may confuse readers unfamiliar with these terms.
Need to add the method used in the abstract i.e costing method and outcome measurement. Interpretation in the abstract is not clear enough, whether the authors are quite sure with cost-effectiveness results .
The threshold used in this study is $2,760 per HHC, newly diagnosed and linked to treatment is not common, please add your assumption/ reference case . (line 227: the USD 2760 threshold used in this analysis was far more conservative than the prescribed WHO_CHOICE threshold). In addition, a 2 year period is set to reflect “time horizon” but it is unclear what the impact of this is to the outcome (it seems no analysis on Life Year Gain), please clarify your assumption.
The prevalence of TB among HHCs was estimated at 4.5%. Please clarify how this data was used for for outcome analysis.
The inclusion of both fixed and variable costs under a provider's perspective provides detailed insights into resource allocation and financial implications. It is challenging to combine top-down and bottom up approaches and readers could learn from the process you have done. For programmatic HCI testing cost the driver was salary, but driver for Xpert is cost per test (attributable to cost of the cartridge). How have the authors combined the two approaches to reflect this?
Limited generalisability: While the study uses empirical data from South Africa, its applicability to other LMIC settings with varying TB prevalence, health care system, and economic conditions is not sufficiently addressed. Authors can add this in discussion section.
Some cost estimates (e.g., cost-per-test of tongue swabs and sputum) rely on negotiated or generalised data without providing a breakdown or sensitivity to local variations. In addition, the reliance on a single source for device and consumable costs may overlook price variability in different procurement settings.
The primary outcome—new TB cases detected and linked to treatment—is relevant but excludes downstream benefits, such as secondary transmission reduction or quality-adjusted life years (QALYs). This limits comparability with other cost-effectiveness studies, authors could discuss this
Author briefly mentions a 1:1 DALY ratio but does not validate this assumption with robust evidence or alternative modelling.
The exclusion of paediatric populations, despite their relevance to TB burden, is noted but not adequately explored in terms of implications.
Table 1. How to interpret effectiveness 0.0003, 0.014, 0.029 as well as ICER as compared to threshold (ref case for WTP used in the study)

Review 2: "Sputum and Tongue Swab Molecular Testing for the In-Home Diagnosis of Tuberculosis in Unselected Household Contacts: A Cost and Cost-Effectiveness Analysis"

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