Qualitative evidence for the use of Mycobacterium tuberculosis antigen-based skin tests

Abstract

Background New Mycobacterium tuberculosis specific antigen-based skin tests (TBST) have been developed. However, end-user values and preferences, acceptability and feasibility for use in clinical care, and possible impact on health equity outcomes are unknown. Understanding the factors that affect these key outcomes may help to improve utilisation and programmatic implementation.

Methods Objective 4 was informed by three work packages – A, B, C. This Executive Summary draws on the findings from all three work packages: A-Systematic Review, B-User Interviews), C End-user values and preferences: Discrete Choice Experiment (DCE).

For work package A, two systematic reviews were conducted that synthesized the qualitative research evidence on end-user values and preferences for the use of specific TBST for latent TB infection, compared to existing tests (IGRA, TST). One review aimed to capture data on TBST specifically as compared to IGRA and /or TSTs (Review A), and another focused on IGRA and TST only because we anticipated few studies on novel TBST (Review B). A public call for data relating to TBST was also announced by the WHO. Data were extracted from eligible studies, synthesised then analysed thematically. Study quality and confidence in the evidence was evaluated in accordance with the GRADE-CERQual. The reviews were registered in PROSPERO: Systematic review A, specific TBST compared to the IGRA and/or the TST (CRD42021273744); Systematic review B, IGRA and TST compared to each other or without a comparator (CRD42021273952). A qualitative coding framework was developed from the themes and subthemes that emerged from these reviews. This was then used for analysis of data from work package B.

For work package B, 20 semi-structured interviews were conducted with a diverse range of clinicians, laboratory staff, programme officers, and individuals living with LTBI (referred to as ‘consumers’ throughout this report), with the aim of understanding their experiences of using TBI tests, including the IGRA, TST, and TBST. Findings from these interviews were synthesised and analysed thematically using the coding framework from work package A, with adaptations to accommodate additional key themes and subthemes influencing TBST acceptability, feasibility and health equity identified from the interviews.

For work package C, an online cross-sectional discrete choice experiment (DCE) survey was conducted drawing from themes derived in work packages A and B. DCE methodology was used to elicit stated values and preferences from participants (end users) without directly asking them to state their preferred options. Consumers (people living with TBI/eligible for TB infection testing or underwent testing previously) or providers (healthcare providers involved in the TB care pathway) were invited to participate via global networks of TB advocates, researchers and policy makers. The survey was delivered in English and required access to the internet to complete. Different designs were developed for consumers and providers to represent the different potential determinants of choice to either, and a minimum sample size of 45 was deemed sufficient to draw statistical inference in both designs. Choice data were analysed using multinomial logistic regression models, and willingness-to-accept analyses used to compare results within and across designs.

Results Characteristics of data included in each work packages For work package A, four studies were identified that met the inclusion criteria for both systematic reviews. From Review A on specific TBSTs, only one data sources was identified from the Russian Federation, which came from a WHO public call for data relating to the feasibility and acceptability of antigen-based TB skin tests. Participants were parents of children with TBI. From Review B on current IGRA and TST, 3 peer-reviewed articles were found to meet the inclusion criteria; these 3 papers were from the United States, South Africa and the Netherlands. Participants included a range of health professionals involved in TB care (US and Netherlands) and people living with HIV (South Africa). The overall confidence in the quality of the evidence from the studies was low to moderate based on the GRADECerQual assessments, as the data lacked richness, with most studies reporting only summaries of participant quotes or limited direct quotes. All studies were conducted on specific subgroups (e.g. people living with HIV, or parents of children and adolescents with TBI).

For work package B (user interviews), we recruited 20 participants– 13 were TB healthcare providers (8 from low middle-income countries) and 7 TB consumers (3 from low-middle income countries). Healthcare providers included program executives and decision-makers, public health practitioners and advocates, physicians, researchers and lab technicians, and a nurse.

For work package C (End-user values and preferences: DCE), we had a total of 234 participants complete the DCE (186 providers and 48 consumers). Overall, 59% of respondents were female, 56% were aged 36–55 years, and the main countries in which respondents were based were India (26%), the United States (16%), South Africa (9%), Pakistan (8%) and Zimbabwe (7%).

End-user values and preferences Qualitative data from the systematic reviews and end-user interviews, and quantitative data from the DCE, indicated that healthcare consumers and providers had similar values and preferences in terms of TBI tests. Key end-user values included test accuracy, convenience, positive patient experience, cost, and resource requirements. In particular, end-users valued tests with high accuracy such as the TBSTs and IGRA (i.e., low false-positive and negative rates), as they reduce the risk of downstream consequences associated with false positive and negative results (e.g., anxiety, the need for additional testing or unnecessary treatment). End users also preferred having a test that was convenient to administer and access. This included valuing tests that can be accessed in a community or primary care setting, that avoid follow-up visits to read test results, and that can be administered without the need for additional systems or infrastructure to be developed. These findings were initially identified from themes emerging from the systematic reviews and end-user interviews, and confirmed by the DCE findings.

From the qualitative data from the reviews and interviews, all TBI test options were found to have strengths and limitations in terms of convenience. A positive consumer experience was valued by end-users. This meant that tests with fewer psychological (e.g., anxiety, stigma, stress) and physical consequences (e.g., discomfort) were preferred. Tests that were more accurate tended to be associated with better consumer experience, although some aspects of consumer experience were worse in skin tests (e.g., stigma from the welt, discomfort) compared to non-skin-based tests. Low-cost tests were generally preferred due to greater accessibility in resource-limited contexts (e.g., the TBSTs, TST). Tests with lower resource requirements were preferred in resource-limited settings (e.g., the TBSTs, TST), however, this appeared to be less of a consideration in high-income countries. End users showed a preference toward TBI tests that used existing infrastructure in their healthcare setting. Data from the DCE confirmed that a lack of a need for an in-person follow-up appointment and not requiring specialist staff or equipment to interpret or administer the test, were important end-user preferences for TB testing.

Acceptability Qualitative data from systematic reviews and end-user interviews suggests TBST were perceived to have greater specificity and sensitivity than the TST. Having greater test accuracy was deemed desirable to avoid the negative consequences of false positives or negatives. However, the TBST was expected to have many of the same limitations as skin tests in terms of patient experience (e.g., a return visit required, discomfort, a welt on the arm, stigma) compared to the IGRA. The IGRA was deemed the preferred test option in countries which already have the IGRA in use, as the required supporting infrastructure are already in place, and because the TBST would have comparable accuracy and performance, thus not adding value. There were also concerns about skin tests as these tests were viewed as a dated, basic technology subject to human error and/or interpretation. Suggestions for improving the acceptability of TBST included careful communication during its implementation with endorsement by healthcare providers and organizations (e.g., the WHO). Data from the DCE found strong and consistent preferences among both healthcare providers and consumers for tests which minimize false positive and negative results. The DCE also found that consumers had a strong preference for testing in the community and primary care settings compared to hospital locations.

Feasibility Findings from the qualitative evidence synthesis (reviews and end-user interviews) support the feasibility of use of the TBST but only in settings where the TST is already in use, as the required resourcing and training is already in place. The TBST is likely to be a low-cost, portable test that can be well-suited for low-resource healthcare settings, which may not be able to support the IGRA, due to the comparably greater cost and resources required to implement the IGRA. However, if healthcare settings already have the necessary infrastructure in place to implement the IGRA, then the IGRA are a more feasible test option than either skin tests because they do not require a return visit to read the result, a step where patients may be lost to follow-up. Results from the DCE found that lack of a need for an in-person follow-up appointment and not requiring specialist staffor equipment to interpret or administer the test, were important preferences for TB testing that would influence feasibility. There was some suggestion that providers preferred more expensive tests (when offered a choice based on a hypothetical cost of USD 50 compared to USD 25), though test cost was the least important determinant of test choice.

Health equity Qualitative evidence from reviews and end-user interviews indicate that it is unlikely that specific TBST would create any new equity issues. Rather, the TBST are likely to improve health equity through the provision of a more accurate, low-cost test for resource-limited settings where the PPD-TST is already in use. Moreover, their portability and low cost make them suited to use in large scale screening programs in vulnerable, hard-to-reach communities. However, it is possible that TBST may not affect health equity in low-resource settings that do not already use the TST, as barriers to accessing skin and other healthcare tests in these settings exist, which would need to be addressed first, regardless of the type of TB test available. In terms of test accessibility, the data from the DCE found that consumers had a strong preference for testing in the community and primary care settings compared to hospital locations, which could have health equity implications.

Conclusion Findings across the three work packages were consistent with each other in the themes, and subthemes identified that would influence TBST acceptability and feasibility. The qualitative evidence synthesis from the systematic reviews and the user interviews, as well as the quantitative findings from the DCE highlight the potential for novel antigen-based skin tests (TBST) as an acceptable alternative to the TST. The findings from the DCE support the data from the reviews and interviews, even though published review data from work package A were limited. Our findings were generally consistent across both healthcare providers and consumers.

In conclusion, specific TBST were found to be more acceptable and equally feasible to the TST, with greater benefits for health equity driven by higher sensitivity and specificity. TBST may be more preferrable for use in more resource-limited settings compared to the TST due to the higher accuracy whilst retaining portability and ability to administer in a community / primary care setting. Test preferences were influenced by end-user values such as test accuracy, convenience, cost, positive patient experience, and resource requirements. IGRA remain the preferred test option in high-income countries with existing infrastructure to support their use; it is unlikely that widespread use of the IGRA would change in these settings where IGRA is mostly the standard of care, particularly due to the strong provider preference for less of a need for an in-person follow-up appointment for all tested individuals, so resources can focus on those who do require follow-up such as those who test positive.