Introduction

Tuberculosis (TB) is a significant global health problem especially given the continuing high levels of morbidity and mortality associated with the disease particularly in low- and middle-income countries where it often exacerbates the effects of HIV.1 The causative agent, Mycobacterium tuberculosis,2 is an airborne bacterial pathogen that primarily affects the lungs but can also attack other bodily organs.3 Prior to the COVID-19 pandemic, TB was the leading infectious disease killer, accounting for over 10 million cases annually and an estimated 1.3 million deaths in 2022.4 The mortality rate from TB can reach as high as 50% in the absence of treatment.1 5

While TB is both preventable and curable, effective disease control hinges on early diagnosis, timely initiation of appropriate treatment, and strict adherence to the prescribed regimens. The recommended treatment protocol typically involves a combination of antibiotics, including isoniazid, rifampicin, ethambutol, and pyrazinamide,6 with a mean treatment duration of 4–6 months, depending on disease severity.1 6 Patients with multidrug-resistant (MDR) TB require longer courses of treatment of up to a year.7 Since its introduction in 1994, the World Health Organization (WHO) directly observed treatment short course (DOTS) strategy—a comprehensive five-component plan that includes the administration of standardised short-course chemotherapy under directly observed treatment conditions, where a provider observes the patient taking their medications—has proven effective in global tuberculosis control.8 9 This approach significantly enhances adherence to the treatment regimen in both timing and dosage.9

Adherence to treatment is critical for achieving favourable treatment outcomes, preventing the development of drug resistance, and effectively managing TB disease and its transmission within communities.10 Non-adherence can lead to treatment failure, relapse, and the emergence of MDR and extensively drug-resistant strains, which are more difficult and costly to treat.1 Treatment adherence is a primary determinant of MDR TB,11 a significant global health problem, with nearly half a million cases reported in 2022.1 Factors influencing treatment adherence are complex and multifaceted, including patient-related factors (eg, knowledge, attitudes, beliefs, socioeconomic status), treatment-related factors (eg, duration, side effects, pill burden), healthcare system-related factors (eg, accessibility, patient-provider relationship) and socioeconomic factors (eg, stigma, social support, costs).12–16

The global burden of TB is unevenly distributed, with high-burden settings—primarily in low- and middle-income countries—accounting for a disproportionate share of cases and deaths.1 According to the WHO, high-TB burden settings are defined as countries or distinct parts of countries characterised by a high burden of TB, with disease incidence exceeding 100 cases per 100 000 population.17 These settings often face significant challenges in TB prevention and control, including resource constraints, inadequate healthcare infrastructure, poverty and stigma associated with the disease.13 14 18–20 Conversely, low-TB burden settings, defined by a TB incidence below 10 cases per 100 000 population and typically in high-income countries,17 face different challenges. These include delayed diagnosis, rising rates due to international migration dynamics, and potential complacency in TB control and surveillance efforts as a result of the low disease incidence.21–24 While the barriers and facilitators to treatment adherence may differ between low- and middle-income country settings where the majority of TB patients live, and high-income country settings with substantially lower-TB burden, it is unclear how the adherence levels compare between these settings.

Although adherence to TB treatment has been extensively studied, the existing literature is heterogeneous, particularly in terms of the varying study designs, populations, and definitions of adherence.10–12 Moreover, the comparative levels of adherence to TB treatment in high- and low-TB burden settings remain to be comprehensively evaluated. To address this evidence gap, this systematic review will collate available data on TB adherence to assess and compare adherence levels between high-TB burden countries and low-burden countries, which typically have more resources for TB care. By synthesising evidence on this topic, the findings from this study have the potential to inform the development of tailored interventions and policies to improve TB treatment outcomes across different contexts and contribute to global efforts towards eliminating this disease.

Objective

The aim of this systematic review protocol is to describe the methodological process that will be used to gather data and comparatively assess the evidence on TB treatment adherence levels in high-burden versus low-burden countries.

Review questions

How do tuberculosis treatment adherence levels among individuals with active TB in high-burden countries (HBCs) compare to those in low-burden countries (LBCs)?

What are the main facilitators and barriers to tuberculosis treatment adherence in HBCs compared with LBCs, and how do they differ?

MethodsProtocol development and registration

This protocol was developed following guidance in the Preferred Reporting Items for Systematic Review and Meta-analysis Protocols (PRISMA-P) Statement.25 The protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) (registration number CRD42021273336).

Data sources and search strategy

A systematic search will be conducted across the following databases: Medline, Embase, CINAHL, Scopus, Global Health and the Cochrane Database of Systematic Reviews.

The search strategy will be developed in consultation with a medical librarian. Search terms will include key medical subject headings and free-text terms relevant to the review’s topic and clinical focus. Using appropriate Boolean operators, we will create a comprehensive search string that combines keywords such as ‘adherence’, ‘treatment’, ‘treatment adherence’, ‘treatment completion’, ‘compliance’, ‘concordance’, ‘tuberculosis’, ‘TB’ and ‘multidrug-resistant TB’. Variations of terms and truncation will be applied as necessary. No age, gender or publication date restrictions will be imposed; however, only studies published in English will be considered. A draft search strategy for the Medline (Ovid) database is included in the online supplemental materials. Additionally, we will conduct manual hand searches of reference lists from relevant articles and explore grey literature sources through Google Scholar and the WHO website to identify further relevant studies.

Study eligibility criteria

To facilitate the identification of relevant articles for inclusion in the review and minimise the potential for bias, study selection will follow the guidance outlined in Chapter 3 of the Cochrane Handbook for Systematic Reviews of Interventions, defining the criteria for including studies.26 The following eligibility criteria will be applied:

Population

Eligible studies will involve individuals with either clinically or microbiologically diagnosed active TB. To maintain a focus on active TB and ensure consistency in assessing treatment adherence, studies exclusively reporting on cases of relapse or suspected TB will be excluded. We will consider studies involving subjects with both drug-resistant and drug-susceptible TB. If the data from the included studies permits, subgroup analysis will be conducted to identify potential differences.

Intervention/exposure

The intervention/exposure of interest is TB treatment. Included studies must focus on individuals with active TB who are receiving medication, with adherence monitored either directly or indirectly. As treatment duration depends on disease severity, we will report the duration of treatment as documented in the included studies.

Comparator/control

There is no comparator or control group in this review

Outcome

The primary outcome of this review is adherence to TB treatment. Studies will be included if they define and assess adherence as a proportion or rate of TB medication completion or compliance, providing data that enables the estimation of adherence levels (eg, 100%, 90%, 80%). Various methods of evaluating adherence, including self-reports and directly observed therapy, will be considered. Secondary outcomes of interest include the barriers and facilitators of TB medication adherence.

Study design

This review will consider empirical studies, including both randomised and non-randomised (observational) studies involving human populations that examine adherence (or non-adherence) to TB treatments. Case reports and case series, although observational, will not be eligible for inclusion given their typically small sample sizes.

Context

We will include studies conducted in populations from high- or low-TB burden countries.17 27–29 For high-TB burden countries, we will focus on the 30 countries classified as high-burden countries for TB according to the WHO’s high-burden country list from the post-2015 era (2015–2025). These 30 countries, most of which are low- and middle-income countries, account for 86–90% of the global tuberculosis burden.27 28 Low-burden countries will be defined as countries with an estimated incidence of fewer than 10 cases per 100 000 population.17 29

Exclusion criteria

Studies that do not meet the eligibility criteria outlined above will be excluded from this review. This includes studies involving individuals with latent TB, as well as those that do not report data on adherence to TB treatment. Using the high- or low-TB burden countries list from the WHO as reference,17 27–29 studies conducted outside high- or low-burden TB country settings will be screened out and excluded. Non-English language studies will also be excluded due to resource constraints. Additionally, conference proceedings, newsletters and editorials will not be included, as these sources typically present preliminary results or lack the detail needed to assess methodological rigour.

Selection process

In an initial step, two reviewers will independently screen the titles and abstracts of the retrieved search results to assess their relevance against the established inclusion and exclusion criteria. The full-text articles of records that meet the initial screening criteria will then be retrieved and independently reviewed by the same two reviewers for relevance to the research questions and potential inclusion. Any disagreements during the study selection process will be resolved through discussion between the two reviewers, and where necessary, a third reviewer will be invited to assist in achieving consensus.

Data extraction

Data will be extracted and summarised into a predesigned Excel data abstraction table by the same two reviewers. Extracted data from each eligible study will include information such as study descriptors, setting, sample characteristics, study methods, quality assessment features and outcomes data relevant to the review objectives (eg, adherence proportion, TB treatment timeframe).

In addition to extracting data on the adherence levels, information on the type of adherence measurement used will also be extracted. This will include data on whether objective adherence measures such as DOTS in both virtual and face-to-face formats, medication monitoring systems, ingestible biosensors, and metabolites, were used, as well as subjective self-report measures, including the use of valid and reliable surveys. The two reviewers will cross-check the table to ensure that all essential data were accurately retrieved.

Using the extracted data on study setting, countries will be categorised into low-income, lower-middle-income, upper-middle-income and high-income groups based on the gross national income (GNI) per capita thresholds for the fiscal year 2023, as established by the World Bank. According to the World Bank Atlas method, low-income countries are defined as those with a GNI of US$1145 or less; lower-middle-income countries have a GNI ranging from US$1146 to US$4515; upper-middle-income countries fall between US$4516 and US$14 005 and high-income countries are those with GNI greater than US$14 005).30 31

Risk of bias quality assessment

The quality of individual studies included in the review will be assessed according to the type of study design. For randomised trials, we will use the Cochrane Risk of Bias tool.32 Key domains of bias will be used to appraise the included studies on the aspects of trial design, conduct and reporting, including on randomisation, allocation concealment, blinding, use of intention-to-treat analyses, and other potential sources of bias.

We will appraise included observational studies using the Newcastle-Ottawa Scale with a ‘star scoring system’ that will assess study design features including participant/group selection and characteristics, comparability of groups, exposure and outcome information and definition.33 Qualitative data will be appraised using the Critical Appraisal Skills Programme tool for qualitative research and will evaluate key domain features such as the appropriateness of qualitative data for the research objectives, as well as methods of participant recruitment, data collection, and analyses.34 35 The quality appraisal process is not intended to exclude studies from the review but rather to ensure that meaningful interpretations and conclusions are drawn from the findings based on the reliability of the included studies.

Strategy for data synthesis

Our approach to the conduct and reporting of the data synthesis will follow the guidelines in the PRISMA-P Statement. We will generate a flow diagram to illustrate the study selection process. Data synthesis will involve both quantitative and qualitative analysis. Descriptive statistics will summarise the study-level information from the included studies.

A meta-analysis will be conducted only if the extracted data from at least three studies demonstrate sufficient homogeneity to allow for synthesis. If feasible, we will pool studies within a meta-analytical framework using the DerSimonian-Laird random-effects model,36 as we anticipate some variability among the studies to be included. Subgroup analyses will be performed based on different study designs, populations (eg, age group: children vs adults; gender differences), contextual settings (low-income vs other settings), adherence measurement methodologies (self-report vs objective measures) and criteria for labelling populations as adherent or non-adherent. If the data permits, we will also conduct meta-regression analyses to assess the potential effect of study-level covariates on the pooled estimates. We will assess heterogeneity using the Cochran Q test and I² statistics, provided there are enough eligible studies, and will complement this with a visual inspection of the forest plots.37 Funnel plots will be used to check for publication bias.

Qualitatively, we will undertake a meta-synthesis of the qualitative data from the included studies to generate common emergent themes regarding facilitators and barriers to TB treatment adherence in HBCs and LBCs. Noblit and Hare’s meta-ethnography steps will be followed by identifying common themes (and subthemes) across studies, assessing differences and systematically comparing study differences, and interpreting the research data within the realm of the generated themes.38

Strength of evidence

The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach will be used to assess the quality and strength of the evidence.39 The evidence will be categorised into four levels: high, moderate, low and very low.

Patients and public involvement

No patients or members of the public were involved in this study.

Ethics and dissemination

Ethics clearance is not required for this study since it does not involve recruiting or collecting data from participants. The study protocol for this systematic review describes the process that will be used to gather, review, and synthesise information that is publicly available through medical databases. The findings of the proposed systematic review and meta-analysis will be presented at a relevant scientific conference and published in a peer-reviewed journal. To ensure our study results get to non-scientific circles and other outlets particularly in the programmatic and policy spheres, we will also share our findings via social media including on X (formerly Twitter) and Facebook. This study is significant because it is the first systematic review to our knowledge that will comparatively assess TB treatment adherence levels between high- and low-TB burden countries, therefore contributing to the body of evidence and improving our understanding of medication adherence patterns according to the intensity of TB disease burden. The meta-synthesis of themes relating to barriers and facilitators of TB medication adherence will generate valuable insights into the factors influencing treatment adherence across different contexts, which may inform the development of tailored interventions and policies to improve treatment outcomes and support global efforts to eliminate TB.