Abstract
Drug-resistant tuberculosis (DR-TB) poses a significant public health challenge, particularly in resource-limited settings. The prevalence and management of DR-TB in African countries require comprehensive strategies to improve patient outcomes and control the spread of the disease. Aggregated routine data (from 2018 to 2022) on multidrug-resistant TB (MDR-TB) were collected from the National TB Programs (NTPs) from all six countries. The diagnostic capacity for MDR-TB was globally insufficient. The system for collecting and transporting samples was sometimes inoperative. A total of 2353 cases of MDR-TB were reported, with 86.4% receiving treatment. The gap between the expected number of MDR-TB cases and the number reported per country varied from 51.5% to 88.0%, depending on the year. Fifty-two extensively drug-resistant (XDR) TB cases received treatment regimens over five years, with variations across countries. All patients received free follow-up examinations, nutritional and financial support for travel expenses to the outpatient care and treatment centers. The MDR-TB treatment success rates for all regimens between 2018 and 2021 ranged from 44.4 to 90.9%, varying by country and year. The information system relied on primary tools, reporting tools, and digital solutions. Progress has been made in MDR-TB management; however, challenges persist, necessitating resources to enhance access to rapid molecular screening tests.
1. Introduction
Tuberculosis (TB) remains a global health challenge, exacerbated by the emergence of drug-resistant strains. Drug-resistant TB (DR-TB) is a person with TB disease who is infected with a strain of Mycobacterium tuberculosis complex that is resistant to any TB medicines tested [1]. DR-TB includes (1) Isoniazid-resistant and rifampicin-susceptible TB (Hr-TB; the strain of M. tuberculosis complex is resistant to isoniazid but susceptible to rifampicin); (2) Rifampicin-resistant TB (RR-TB; the strain of M. tuberculosis complex is resistant to rifampicin); (3) Multidrug-resistant TB (MDR-TB; the strain of M. tuberculosis complex is resistant to both rifampicin and isoniazid); (4) Pre-extensively drug-resistant TB [pre-XDR-TB; the strain of M. tuberculosis complex is resistant to rifampicin (and which may also be resistant to isoniazid), and which is also resistant to at least one fluoroquinolone (either levofloxacin or moxifloxacin)]; (5) Extensively drug-resistant TB [XDR-TB; the strain of M. tuberculosis complex is resistant to rifampicin (and which may also be resistant to isoniazid), as well as resistant to at least one fluoroquinolone (levofloxacin or moxifloxacin) and at least one other “Group A” drug (bedaquiline or linezolid)] [1]. MDR-TB is a subset of RR-TB, and the two are often grouped together using the term MDR/RR-TB [1]
In 2022, the World Health Organization (WHO) estimated that there would be around 410,000 new cases of multidrug-resistant tuberculosis (MDR-TB) and rifampin-resistant TB (RR-TB) worldwide (95% uncertainty interval [UI]: 370,000–450,000) [2]. In the same year, 22,495 cases were reported in the African region, 97% of which were under treatment [2]. The 2020 cohort of MDR-TB patients in the African region showed that 71% were successfully treated [2]. Despite the funding mobilized for TB, improved drug availabilitý and quality, technical assistance, and capacity building, drug-resistant TB (DR-TB) remains a threat to public health worldwide.
The reasons for the persistence of TB in the world, including Africa, encompass poverty, demographic growth, and human migration, as well as HIV infection, which is particularly prevalent in impoverished nations, where 95% of TB cases are concentrated [2]. The true burden of MDR-TB remains poorly understood in certain sub-Saharan countries due to the lack of routine surveillance, inter-country coordination, and poor reporting. In response to this situation, the WHO has put in place strategies to combat TB and MDR-TB in particular [2]. Against this backdrop, the International Union Against TB and Lung Disease (The Union) has been implementing the Contributing to the Elimination of TB in Africa (CETA) project since 2019 in eight French-speaking African countries. One of the components aims to enhance care provision, particularly for patients suffering from MDR-TB. Conducted within the framework of the CETA project, this study offers an overview of the DR-TB management landscape and an in-depth analysis of its strengths and weaknesses, aimed at enhancing program management in French-speaking Africa.
2. Materials and Methods
2.1. Study Design, Study Site, and Study Population
This is a cross-sectional analysis of DR-TB surveillance data from 1 January 2018 to 31 December 2022.
This study was carried out in six of the eight French-speaking African countries in the CETA project (Benin, Burkina Faso (BF), Cameroon, Niger, Senegal, Togo). All states, except Cameroon, are included in the list of Priority Poor Countries that France is prioritizing as part of its solidarity efforts [3]. The selection of these countries is determined by a thorough assessment of their needs, their willingness to engage in the project, the EU’s familiarity with them, alongside their capacity to effectively manage financing from the Global Fund.
2.2. Data Collection
Using a standardized file, we collected and compiled routine data on DR-TB from the monitoring and evaluation departments of the National TB Programs (NTPs) of the countries participating in this study.
This study looked at key indicators of DR- TB, including case notification, treatment initiation rates, and treatment outcomes, along with the inherent strengths and weaknesses in managing this disease within each country. All countries adhere to the WHO operational definitions, which have been incorporated into their national guidelines for managing MDR-TB [4].
2.3. Data Analysis
Aggregate data were collected using standardized forms designed for the CETA project. The data were compiled by country and by year using Microsoft Excel 2016 for Windows. Statistical analyses and tables were produced using Microsoft Excel 2016 for Windows.
2.4. Ethics
This study was conducted under programmatic conditions, relying on aggregated instead of personal data. Formal approval from ethics committees of the respective countries was not necessary for this purpose. The data provided by NTPs were used with the consent of program managers.
3. Results
3.1. Screening Strategy
3.1.1. Diagnostic Tests and Indications
Screening strategies depend on the target population and the countries’ diagnostic capacities in terms of the availability of diagnostic tests for MDR-TB (Table 1 and Table 2).
Table 1.
Availability of diagnostic tests for MDR-TB by country, December 2022.
Table 2.
Distribution of the number of microscopy units and GeneXpert by country from 2018 to 2021.
The indications for Xpert MTB/RIF tests in the six countries were as follows: (1) presumed DR-TB patients (contact subjects of DR-TB; patients treated after having been lost to follow-up; relapse cases; positive controls at M2, M3, M5, and M6; (2) presumed TB patients from populations at high risk of TB (people living with HIV; children; prisoners; gold miners; people aged 65 and over; individuals with diabetes; people with kidney failure; health workers); (3) new smear-positive patients; and (4) any patient suspected of having TB (laboratory with Xpert MTB/RIF test).
Xpert MTB/RIF test deployment as the primary screening method for all presumptive TB patients started in Benin in 2018, followed by BF in 2020, Togo and Senegal in 2021, and Cameroon and Niger in 2022.
3.1.2. Sample Collection and Transport System
Depending on the country, samples were transported either by health workers or NGOs, supported financially by partners, notably the Global Fund. Alternatively, an integrated system facilitated the transportation of biological samples from district laboratories to those equipped with a GeneXpert MTB/RIF device, using postal services or private carriers. Sample referral in the six countries was organized as follows: (1) from health facilities lacking a laboratory to CDTs with a bacilloscopy laboratory; (2) from laboratories conducting bacilloscopy to GeneXpert sites; and (3) from GeneXpert sites to the National Reference Laboratory (NRL).
3.1.3. Drug-Resistant TB Notification
Number of Confirmed MDR-TB Cases Treated from 2018 to 2022 in the Six Countries
Over the span of five years, a total of 2353 cases of MDR-TB were reported in the six countries, with 2033 patients (86.4%) receiving treatment. The number of confirmed MDR-TB cases ranged from 72 in Togo to 854 in Cameroon. The proportion of treated MDR-TB cases ranged from 77.4% in Togo to 91.6% in Senegal (Table 3).
Table 3.
Number of confirmed MDR-TB cases put on treatment from 2018 to 2022.
The gap between the expected number of MDR-TB cases and the number of cases reported per country ranged from 51.5% to 88.0%, depending on the year (Table 4).
Table 4.
Gap between the expected number of cases and the number of cases reported by country from 2018 to 2022.
Number of Confirmed XDR-TB Cases Put on Treatment from 2018 to 2022
In the past five years, all 57 confirmed XDR-TB cases have been put on treatment. The number of confirmed XDR-TB cases ranged from one 1 case in Benin to 17 cases in Niger (Table 5).
Table 5.
Number of confirmed XDR-TB cases put on treatment from 2018 to 2022 *.
3.2. Treatment Strategy
3.2.1. Treatment Protocols
Standardized treatment is routinely applied to all patients across countries. The treatment regimens differ for MDR-TB and XDR-TB. All countries have switched to a short, all-oral regimen (Table 6).
Table 6.
Treatment protocols by country *.
3.2.2. Organization of Care
The number of treatment centers for MDR-TB varied from one center (in Benin and Togo) to eleven centers in Cameroon. Across all countries, there was a predominant shift towards decentralization and outpatient follow-up, except for Benin, where strict hospitalization was enforced throughout the treatment period. Additionally, in all countries, patients benefited from complementary follow-up examinations and received nutritional and financial support to cover travel expenses related to outpatient care (Table 7).
Table 7.
Care organization by country.
3.2.3. MDR-TB and Extensively DR-TB (XDR-TB) Treatment Results
The overall therapeutic success was 71.5% in 2018 and decreased to 62.7% in 2020. Togo and Benin were the only countries which witnessed an increase in therapeutic success, 81.8% and 90.9%, respectively (Table 8 and Table 9).
Table 8.
Treatment outcome for MDR-TB for all schemes, 2018–2021.
Table 9.
Outcome of TB-XDR treatment from 2018 to 2021.
3.3. Information System
The information system is based on the country’s health pyramid (central level, intermediary level, and peripherical level). The information system is based on primary tools, reporting tools, and paperless solutions. All the NTPs have a data management department, which is closely linked to the intermediary and peripheral level (Table 10). Aggregated data are collected quarterly at TB clinics and then sent to the regional level, where checking is carried out before transmission to the central level.
Table 10.
Tools used in the countries.
4. Discussion
The emergence of resistance to anti-TB drugs is a global threat to TB control efforts. This descriptive study shows a gap of 77% to 79.1% between the reported number of MDR-TB cases and the estimated number of cases in the six countries from 2018 to 2021, falling below the WHO’s estimated incidence rates [2,4,5,6,7,8]. Notably, a consistent disparity persists between WHO estimates and the number of MDR-TB cases detected [2,4,5,6,7,8].
Challenges in accessing services, including geographical and financial barriers, poverty, and limited education, along with patient attrition between services (laboratory, clinical, and follow-up), appeared to contribute to the under-reporting of cases [9,10]. The CETA project aims to share best practice and innovative approaches for enhancing MDR-TB notification. One component involved active case finding among presumed TB patients at all entry points to TB Diagnostic and Treatment Centers (DTCs) within the community, offering the potential to bridge current gaps in MDR-TB case detection and reporting in these six countries, which were likely impacted by the COVID-19 pandemic. The decrease in MDR-TB case detection and reporting from 2019 to 2020 reflects disruptions to TB diagnosis and treatment services caused by the pandemic, affecting healthcare delivery on both the supply and demand sides. According to the WHO, in 2020, only 71% (2.1/3.0 million) of people diagnosed with pulmonary TB worldwide were tested for rifampicin resistance. This led to the diagnosis of 132,222 cases of MDR or RR-TB and 25,681 cases of pre-XDR TB (resistance to rifampin, isoniazid and fluoroquinolones, or Pre-XDR-TB), amounting to 157,903 cases. This is a sharp decrease (22%) from the 201,997 people detected with DR-TB in 2019 [8].
Enhancing the notification rate of MDR-TB hinges on promptly diagnosing cases. Following WHO guidelines, diagnosing MDR or RR-TB requires both the bacteriological confirmation of TB and the identification of DR using rapid molecular tests or culture methods [11]. The WHO recommends that all individuals with signs and symptoms of TB should first receive a rapid molecular diagnostic test and specifically Xpert MTB/RIF Ultra and Truenat [11], given their superior accuracy in detecting both simple and DR-TB.
All six countries in our study had access to Xpert tests (Xpert MTB/RIF, Xpert MTB/RIF Ultra, Xpert MTB XDR); Hain tests (LPA1 or GenoType MTBDR plus 2.0, LPA2 or GenoType MTBDR plus); and culture with phenotypic drug susceptibility testing. The use of the Xpert MTB/RIF test as a first-line screening test for all presumed TB patients in laboratories with Xpert MTB/RIF tests began in 2018 in Benin, in 2020 in Burkina Faso, in 2021 in Togo, and in 2022 in Cameroon and Niger. However, there has been a shortage of GeneXpert equipment in all countries. In Cameroon, only 36 out of 306 laboratories have access to GeneXpert equipment, which has hindered the diagnosis of MDR-TB, consequently leading to low case reporting. Additionally, another hindrance to diagnosis was the underdeveloped state of sample transport systems in most countries, which require closer assessment to determine their effectiveness. Potential differences in identification and treatment between countries and across years may be attributed to disparity in the availability of diagnostic tools, healthcare workers, distribution and capacity of healthcare facilities, and challenges posed by rural versus urban settings. Furthermore, there was no harmonized protocol across the countries.
Indeed, there is a centralized system in place for transporting samples from peripheral health facilities lacking laboratories to DTCs equipped with bacilloscopy laboratories, then from these laboratories to GeneXpert sites, and finally from GeneXpert sites to the National Reference Laboratory for Mycobacteria. However, this sample transport system still faces logistical challenges, especially concerning the time required for sample transportation and the timely delivery of results. The implementation of Xpert platform interconnection software, particularly DataToCare, aims to link national laboratory networks by gathering diagnostic and patient data at the TB center level. This software displays information in real-time on a dashboard, aiding central-level decision-making, and promptly reporting test results to medical teams and patients. While applications are available, they do not consistently operate optimally in BF, Cameroon, Niger, and Togo.
The proportion of MDR-TB cases among those detected in our study who received treatment varied from 77.4% in Togo to 91.6% in Senegal. However, there was a huge gap between the expected number of MDR-TB cases and the number of cases reported by country, which varied from 51.5% to 88.0% depending on the year. Worldwide, only around a third of people with DR-TB had access to treatment by 2021. The cumulative total number of people with MDR/XDR-TB worldwide, who were actually receiving treatment in 2018–2020 was 482,683, or only 32% of the five-year target (2018–2022) of 1.5 million [8]. For children, the cumulative number was 12,219, or only 11% of the five-year target of 115,000 [8]. In 2020, 150,359 individuals diagnosed with MDR/XDR-TB were put on treatment, marking a 15% decrease from the total of 177,100 in 2019. This decline may be attributed to the impact of the COVID-19 pandemic [8]. The main reasons for not starting treatment were refusal of care and death, and thus, the need for awareness-raising initiatives to combat stigma to improve treatment uptake is evident.
Standardized treatment is routinely applied to all patients across countries. All countries have switched to a short, all-oral regimen in line with WHO recommendations [12]. In 2022, new WHO guidelines recommended a six-month BPaLM/BPaL treatment regimen for eligible patients [12]. The shorter duration, reduced number of doses, and high efficacy of this new treatment regimen have the potential to alleviate the burden on healthcare systems and conserve valuable resources. As a corollary, extending diagnostic and therapeutic coverage to all individuals in need would become feasible, whereas previously, treating a patient with MDR-TB required nine to twenty months [13]. However, a potential challenge in implementing this recommendation would be their capacity to conduct the bedaquiline (Bdq) sensitivity test before initiating the new short oral regimen. The emergence of strains that are resistant to Bdq is a notable concern, with a recent study conducted in Moldova reporting a 15% prevalence of resistance to Bdq within their MDR-TB cohort [14].
The number of MDR-TB treatment centers varies from one country to another, with one center in Benin and Togo to eleven centers in Cameroon. Recognizing the reluctance of some patients to visit treatment centers, often due to prejudice or limited resources, there is an emerging trend in all countries towards decentralization and outpatient treatment.
However, this decentralization effort faces challenges in effectively supporting patients to ensure consistent TB care, potentially fostering the emergence of new forms of resistance. Another obstacle lies in the insufficient identification and management of adverse effects caused by anti-TB drugs, resulting in treatment interruptions and attrition. In Cameroon, patients are required to pay upfront for drugs to manage adverse effects. Nevertheless, despite these challenges, patients in all countries receive free follow-up examinations and access to nutritional and financial support.
Furthermore, the under-reporting of adverse drug reactions to national pharmacovigilance committees is a prevalent issue across countries. Consequently, with the implementation of decentralization, it is expected that most countries experience a potential decline in key indicators related to MDR-TB management, and thus, the implementation a well-conceived decentralization model may require increased resource allocation.
To effectively combat TB, key indicators of success include ongoing research, treatment of individuals with TB, including MDR-TB, improved accessibility to high-quality DTCs, and intensified prevention initiatives [15]. The global targets are treatment coverage for MDR-TB and a treatment success rate of 90% by 2025 [15]. In our study, treatment success rates exhibited variability both between countries and across years, ranging from 44.4% in Cameroon in 2020 and Togo in 2021 to 86.2% in Benin in 2019. Worldwide, the treatment success rate for patients who were initiated on MDR-TB treatment displayed an upward trend, increasing from 48% in 2009 to 58% for the 2017 cohort [6].
Our study warrants careful consideration of both its strengths and limitations. By examining multiple countries over five years, we were able to provide an overview of regional trends, challenges, and progress in MDR-TB diagnosis and treatment. This approach allowed us to identify cross-country patterns and potential regional strategies for improvement. Furthermore, analyzing data over several years helps us understand the impact of interventions and policy changes, generating hypotheses for future sub-analyses.
However, apart from these abovementioned strengths, a key limitation is that the study is programmatic and descriptive, serving as preliminary research rather than an in-depth analysis. Thus, only aggregate data were collected, precluding us from assessing which socio-economic and clinical factors were associated with MDR-TB. This limitation underscores the need for further detailed studies to explore the underlying mechanisms driving spatial variations, which could help tailor strategies to address specific local constraints. Additionally, future research should collect data on HIV patients and other vulnerable populations to better understand their impact on MDR TB and XDR TB outcomes.
5. Conclusions
Considerable progress has been made in the management of MDR-TB in the various CETA project countries. Nevertheless, MDR-TB remains a challenge in terms of screening and management, which requires significant technical and financial resources to improve access to rapid molecular screening tests. Additional support holds promise for improving existing systems and outcomes. Emphasizing knowledge exchange and skill pooling between countries through collaborative frameworks is essential. Despite the recommendation of new treatment regimens such as BPaL/BPaLM in 2023, their adoption has yet to materialize in the region.
Author Contributions
Conceptualization, G.B., A.R.O. and K.G.K.; Data curation, G.B., A.R.O., A.A.F., A.K.K., A.S., Y.M.D. and M.F.D.; Formal analysis, G.B., A.R.O. and K.G.K.; Funding acquisition, K.G.K.; Investigation, G.B., A.R.O., A.A.F., A.K.K., A.S., Y.M.D., M.F.D. and K.G.K.; Methodology, G.B., A.R.O. and K.G.K.; Project administration, G.B., A.R.O., D.R.A. and K.G.K.; Software, G.B. and A.R.O.; Supervision, G.B., A.R.O., O.B.M., A.C., G.A., D.A., A.B. and K.G.K.; Validation, K.G.K.; Visualization, G.B., A.R.O., A.A.F., A.K.K., A.S., Y.M.D., M.F.D., O.B.M. and K.G.K.; Writing—original draft, G.B., A.R.O. and K.G.K.; Writing—review and editing, G.B., A.R.O., A.A.F., A.K.K., A.S., Y.M.D., M.F.D., O.B.M., A.C., G.A., D.A., A.B., S.M. and K.G.K. All authors have read and agreed to the published version of the manuscript.
Funding
This research was funded by The Agence Française de Développement (AFD) Group funds, grant number CZZ2579 01 L, Paris, France.
Institutional Review Board Statement
No individual data were collected. Only aggregated information was collected by those providing care for TB patients and their contacts, and no individual identifiers were provided to individuals outside the health service.
Informed Consent Statement
All participants signed informed consent forms.
Data Availability Statement
The data that support the findings of the study are available from the National Tuberculosis Programme Department of each country upon reasonable request.
Acknowledgments
The authors thank established staff working in TB control in the six countries of the project.
Conflicts of Interest
The authors declare no conflicts of interest.
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