Intricacies of Global Tuberculosis Management—EndTB-2035 on the Fence?

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This manuscript succinctly summarizes information about current issues with tuberculosis treatment, treatment methods, drugs, and social factors that lead to it, and will be useful to readers who want to know more about this information.

The "Conclusion" of this article is a summary of the main text, so it may be appropriate to include a brief summary of any points that the author considers particularly important along with his or her own issues.

Author Response

We thank the reviewer and editor for valuable feedback that helped to improve the clarity and content of our perspective article. We have added several new sections and included a new table and a new figure as suggested by the reviewers and editor.  

We have incorporated all the edits and revisions as track changes in red in the “highlighted version” of the original article.  This file is submitted as Supplemental Information for reference. A clean version that has all the corrections but without highlights is submitted as the revised article.

REVIEWER-1

Comment: This manuscript succinctly summarizes information about current issues with tuberculosis treatment, treatment methods, drugs, and social factors that lead to it, and will be useful to readers who want to know more about this information.

The "Conclusion" of this article is a summary of the main text, so it may be appropriate to include a brief summary of any points that the author considers particularly important along with his or her own issues.

Response: We thank the reviewer for the suggestion. We have added a summary as follows: “In summary, a considerable improvement has been seen globally among the different lines of TB management strategies, such as diagnosis, treatment, and prevention. Over the years, TB diagnosis has been progressively shifting away from conventional smear microscopy towards more rapid molecular tests including the most advanced sequencing techniques, particularly in high-TB burden countries such as India, China, and South Africa. However, TB diagnosis is very challenging for EP-TB, and TB among children and in individuals with underlying health conditions, including HIV infection and diabetes, owing to the paucibacillary status and/or difficulty in sample collection. To overcome these hurdles, alternatives to sputum samples, such as urine and feces, are considered for TB diagnosis, along with specialized techniques for multi-modal diagnosis. In addition to the improvements in diagnosis, TB treatment has made significant progress recently with an oral regimen with a shortened duration for DR-TB; thus, promising better patient compliance. Though BCG is still the only vaccine approved by WHO, several candidate TB vaccines are in the pipeline that are being evaluated for their safety and/or efficacy in clinical trials. Advancement has also been made in identifying LTBI cases with a wide choice of TB preventive therapy for broader coverage of contacts and high-risk groups. Similarly, the nationwide UHC with increased service coverage and reduced catastrophic costs to patients is planned to be achieved with better funding. Economic evaluation among high TB burden countries indicates increasing contribution by domestic funds, which can be improved by international resource mobilisation and funding from developed countries through the various United Nations health programs. The efficacy of TB management in routine health care can be improved by using a multisector approach over a vertical line, thereby including PHC as well as private-public partnership as elaborated in a recent publication (42). By addressing the gaps and challenges in TB management discussed thus far, the END-TB goal may be achieved by 2035 as set by the WHO ” (lines 470-496).

Reviewer 2 Report

Comments and Suggestions for Authors

This paper portrait an overview of the Tuberculosis management in the context of the WHO EndTB-2035 initiative goals. The paper is well written with detailed description of the tools available at each step of TB management. The structure of the paper maps the key issues posed by TB management including prevention, diagnosis, treatment and resistances. The paper highlight the huge progress in diagnostic tools with nucleic acid amplification technologies (NAAT) and for the treatment of MDR and XDR-TB. The diagnosis of extra-pulmonary TB is still challenging, and require complex testing techniques, which are scarcely available in TB-high burden countries with limited resources.  Access to the new drugs, which are active on MDR and XDR-TB, is also challenging in most of TB-high burden countries. The paper addressed also operational challenges including social determinants and health coverage.

Comments and suggestions

1)      In the light of the progress in testing and treatment, the main challenge remaining to achieve WHO EndTB-2035 goals is improving access to TB healthcare in TB-high burden countries. This implies promoting actions to improve funding for TB care from international donors but also countries domestics contribution. The paper discussed the effect of individual financial issues such catastrophic cost but did not address the global issues related to TB healthcare financial mechanisms in TB-high burden countries. Discussing economic and health economic analyses addressing strategies to implement the new testing tools and treatment regimens in resource-limited countries should be interesting

2)      Authors could also discuss global initiatives at country level to increase the proportion of the country GDP allocated to the healthcare system. Viewing TB management issues as isolated from the overall healthcare challenges faced by resource-limited countries will not help fully identify the keys determinants of TB-care low coverage.

Author Response

We thank the reviewer and editor for valuable feedback that helped to improve the clarity and content of our perspective article. We have added several new sections and included a new table and a new figure as suggested by the reviewers and editor.  

We have incorporated all the edits and revisions as track changes in red in the “highlighted version” of the original article.  This file is submitted as Supplemental Information for reference. A clean version that has all the corrections but without highlights is submitted as the revised article.

REVIEWER-2

This paper portrait an overview of the Tuberculosis management in the context of the WHO EndTB-2035 initiative goals. The paper is well written with detailed description of the tools available at each step of TB management. The structure of the paper maps the key issues posed by TB management including prevention, diagnosis, treatment and resistances. The paper highlight the huge progress in diagnostic tools with nucleic acid amplification technologies (NAAT) and for the treatment of MDR and XDR-TB. The diagnosis of extra-pulmonary TB is still challenging, and require complex testing techniques, which are scarcely available in TB-high burden countries with limited resources.  Access to the new drugs, which are active on MDR and XDR-TB, is also challenging in most of TB-high burden countries. The paper addressed also operational challenges including social determinants and health coverage.

Response: We thank the reviewer for the suggestion. We have added the following: “The diagnosis of EP-TB is still challenging and requires specialized diagnostic techniques, which are limited in high TB burden countries with low resource settings” (lines 175-176).

Comments and suggestions

1)      In the light of the progress in testing and treatment, the main challenge remaining to achieve WHO EndTB-2035 goals is improving access to TB healthcare in TB-high burden countries. This implies promoting actions to improve funding for TB care from international donors but also countries domestics contribution.

The paper discussed the effect of individual financial issues such catastrophic cost but did not address the global issues related to TB healthcare financial mechanisms in TB-high burden countries. Discussing economic and health economic analyses addressing strategies to implement the new testing tools and treatment regimens in resource-limited countries should be interesting

Response: We thank the reviewer for the suggestion and have added a new section: 5.4. Economic evaluation and improving finance for TB management: From the nation-level TB management aspect, the government bodies and policymakers need to realize that issues in TB management should be paralleled with the overall healthcare challenges of their nation, necessitating an economic evaluation and ways to improve finance, particularly in resource-limited countries to improve TB-care coverage. A recent study provided insights into the financial profile of TB management in many countries during the financial years 2006-2021. This WHO report-based report analysed the funding from various sources like domestic, global and grants across 131 countries in the Americas, Europe, Asia, Africa and Oceania (Australia), and estimated the year-wise financial burden for TB management [34]. Accordingly, the overall domestic fund was 3.75 times more than the global fund and 17 times more than the grant between the years 2006-2021, peaking particularly in the years 2010-2013. The domestic funding for TB management was highest in all countries across all continents except Africa where the global funds were higher than domestic, probably due to global attention, since Africa hosts nearly half of the high-TB burden countries globally, as listed by WHO [34]. Countries with high TB burden, such as India, have ramped up the efforts on the commitment of central to local stakeholders/government bodies for effective TB management [35]. In countries with high TB burden, such as India, Indonesia, and China, the national TB program contributes to TB management as part of their routine health care services and financing system. In these countries, either a private-public partnership or largely public sector remains as the point-of-care for TB, primarily offering symptom checks and radiology, and up to treatment adherence once TB is diagnosed and treatment started. Geographical inaccessibility, lack of knowledge, proper incentives, and supervision; high out-of-pocket expenses; limited coverage of diagnostics and drugs; non-coverage of health insurance for outpatient services, and lack of multi-sector engagement, social and cultural stigmatism towards TB, and health-seeking behaviour of individuals are beyond those vertical driven programs mentioned previously [27,36]. (lines 354 – 378).

And

“Economic evaluation with increased financial profiling is required for improved TB management, particularly in resource-limited countries. Domestic funding contributes to the majority of national TB management costs with additional scope for resource mobilization and disease tracking as well as planned budgeting. In addition to the vertical national TB program, private-public partnerships, and the role of PHC are vital for effective TB management” (lines 465-469).

2)      Authors could also discuss global initiatives at country level to increase the proportion of the country GDP allocated to the healthcare system. Viewing TB management issues as isolated from the overall healthcare challenges faced by resource-limited countries will not help fully identify the keys determinants of TB-care low coverage.

Response: We thank the reviewer for the suggestion and added the following: “Studies have shown a positive correlation between a country’s GDP and spending per incident TB case globally. In addition, the GDP has increased in recent years among several high TB-burden countries, including India and China, which also resonates in their corresponding spending on per-incident TB cases. However, the average spending per incident TB case was lower in the low and middle-income group countries (LMIC), compared to the upper and middle-income group countries (MIC), with government spending more on managing TB care among other infectious diseases, which are already short funded [40,41]. Among the WHO list of indicators for sustainable development growth (SDG), the GDP per capita was included with a recommendation of sustaining the per capita growth according to national accordance and increasing GDP growth by 7% at least in the least developed countries [16]” (lines 393-402).

Reviewer 3 Report

Comments and Suggestions for Authors

It is a well-written perspective with all the available technical evidence. These information are well known and to avoid “analysis paralysis” the authors can add a few perspectives on solutions regarding: the role of social science, regulatory agencies/professional bodies in the TB high burdened countries, the health system approach/PHC, the concept of integration considering that TB has been a vertical program for too long, implementation of programs in fragile environment, and most importantly efficiencies and role of domestic funding.

Author Response

We thank the reviewer and editor for valuable feedback that helped to improve the clarity and content of our perspective article. We have added several new sections and included a new table and a new figure as suggested by the reviewers and editor.  

We have incorporated all the edits and revisions as track changes in red in the “highlighted version” of the original article.  This file is submitted as Supplemental Information for reference. A clean version that has all the corrections but without highlights is submitted as the revised article.

REVIEWER-3

Comments: It is a well-written perspective with all the available technical evidence. These information are well known and to avoid “analysis paralysis” the authors can add a few perspectives on solutions regarding: the role of social science, regulatory agencies/professional bodies in the TB high burdened countries, the health system approach/PHC, the concept of integration considering that TB has been a vertical program for too long, implementation of programs in fragile environment, and most importantly efficiencies and role of domestic funding.

Response: We thank the reviewer for the suggestions and added the following: “A recent study provided insights into the financial profile of TB management in many countries during the financial years 2006-2021. This WHO report-based report analysed the funding from various sources like domestic, global and grants across 131 countries in the Americas, Europe, Asia, Africa and Oceania (Australia), and estimated the year-wise financial burden for TB management [34]. Accordingly, the overall domestic fund was 3.75 times more than the global fund and 17 times more than the grant between the years 2006-2021, peaking particularly in the years 2010-2013. The domestic funding for TB management was highest in all countries across all continents except Africa where the global funds were higher than domestic, probably due to global attention, since Africa hosts nearly half of the high-TB burden countries globally, as listed by WHO [34]. Countries with high TB burden, such as India, have ramped up the efforts on the commitment of central to local stakeholders/government bodies for effective TB management [35]. In countries with high TB burden, such as India, Indonesia, and China, the national TB program contributes to TB management as part of their routine health care services and financing system. In these countries, either a private-public partnership or largely public sector remains as the point-of-care for TB, primarily offering symptom checks and radiology, and up to treatment adherence once TB is diagnosed and treatment started. Geographical inaccessibility, lack of knowledge, proper incentives, and supervision; high out-of-pocket expenses; limited coverage of diagnostics and drugs; non-coverage of health insurance for outpatient services, and lack of multi-sector engagement, social and cultural stigmatism towards TB, and health-seeking behaviour of individuals are beyond those vertical driven programs mentioned previously [27,36]. (lines 358-378).

And

“In several TB endemic countries, domestic funding is a major contributor to the cost of TB management, with promise for further increase through resource mobilisation, planning budget cycle, and efficient resource tracking [36]. Apart from the exclusive vertical approach owing to finance for TB, the involvement of primary health centres as well as the private-public partnership approach are documented to improve TB management. Importantly, the primary health care (PHC) setting can provide equitable access to quality and affordable health services followed by effective referral to the next level and continuity of care wherever required. Furthermore, the WHO has underpinned the adoption of PHC to achieve the standard of UHC by offering community-based health services along with social protection [37]. In countries with large private sectors, the private and informal sectors become the point of care for about 60-80% of health-seeking behavior among women and the ill; however, the disengagement of such private/informal sectors with national TB programs in high TB burden setting is alarming for the overall TB management strategies. Indeed, epidemiological studies conducted among countries experiencing a good public-private mix (PPM) have demonstrated better TB detection and treatment outcomes [38,39]. (lines 379-392).