Savings from the introduction of BPaL and BPaLM regimens at the country level

SUMMARY BACKGROUND In 2022, the WHO recommended the 6-month regimens BPaL (bedaquiline + pretomanid + linezolid) and BPaLM (BPaL + moxifloxacin) as treatment options for most forms of drug-resistant TB. SLASH-TB estimates the cost-saving and cost-effectiveness for the healthcare system and patients when a country switches from current standard-of-care treatment regimens to BPaL/BPaLM. METHODOLOGY Country data from national TB programmes (NTP) are used to calculate the costs for all regimens and treatment outcomes. Where BPaL/BPaLM is not currently used, clinical trial outcomes data are used to estimate cost-effectiveness. DALYs are calculated using the Global Burden of Disease (GBD) database. RESULTS We present the results of four countries that have used the tool and shared their data. When shorter and longer regimens are replaced with BPaL/BPaLM, the savings per patient treated in Pakistan, the Philippines, South Africa, and Ukraine are $746, $478, $757, and $2,636, respectively. An increased number of patients would be successfully treated with BPaL/BPaLM regimens, with 411, 1,025, 1,371 and 829 lives saved and 20,179, 27,443, 33,384 and 21,924 DALYs averted annually in the four countries, respectively. CONCLUSION Through BPaL/BPaLM regimens, drug-resistant TB treatment has become more effective, shorter, less burdensome for patients, cheaper for both health systems and patients, and saves more lives.

Globally, there were an estimated 410,000 incident cases of drug-resistant TB (DR-TB) in 2022.An estimated 57% of patients were not enrolled in adequate treatment for DR-TB. 1 Apart from case finding, the cost of treatment of DR-TB patients is a key healthcare challenge for most low-and middle-income countries.Cost-saving and cost-effective DR-TB treatment options are critically needed to reduce the economic pressure on the currently strained healthcare system.
Until recently, the WHO recommended treatments for DR-TB were a 9-11-month standard short oral regimen (SSOR) and .18-monthstandard long oral regimen (SLOR).In 2022, the WHO updated its guidelines to recommend 6-month all-oral BPaL (bedaquiline þ pretomanid þ linezolid) and BPaLM (BPaL þ moxifloxacin) regimens (BPaL/BPaLM) for most forms of DR-TB. 2 Wide use of BPaL/BPaLM has the potential to substantially improve the DR-TB treatment landscape by reducing treatment costs, alleviating the burden on health systems, and saving patient-incurred costs.The Swiss Tropical and Public Health Institute and TB Alliance have developed a tool called SLASH-TB (Savings from Leveraging & Adopting Shorter & Highly Effective TB Treatments 3 ) that calculates the value added from transitioning the current standard of care to the BPaL/BPaLM regimens at the country level.The tool calculates the costs and cost-effectiveness when a country continues with the standard regimens compared with when the country's DR-TB patients are treated with BPaL/BPaLM.The tool was applied to data from four countries: Pakistan, the Philippines, South Africa, and Ukraine.This paper describes the tool and presents results from these countries.

METHODOLOGY
SLASH-TB and its structure SLASH-TB compares current shorter or longer regimens with BPaLM for MDR-TB (multidrug-resistant TB) and BPaL for pre-extensively drug-resistant TB (pre-XDR-TB; MDR-TB with additional resistance to fluoroquinolones).The tool also allows for the comparison of individualised treatment regimens.The tool output shows what a country could expect regarding cost savings, cost-effectiveness, and budget impact over 5-10 years.As this was a retrospective study using data obtained from records and estimates, and no patients were interviewed, no institutional approval was required.
SLASH-TB is MS Excel-based (Microsoft, Redmond, WA, USA) for ease of application by countries where data can be provided by the National Tuberculosis Programme and/or other stakeholders.It consists of 1) guidance on how to fill the data sheets, 2) two data sheets in which the user is required to fill in country data, 3) calculation sheets, which include TBrelated data extracted from the GBD databank 4 and 4) the output dashboard.
Of the two worksheets that need to be filled, the first one, called 'TB data', requires data on DR-TB treatment and outcomes, such as regimens used in the previous year latest available treatment outcomes of DR-TB cohorts, and the projected number of patients in the country over the next 10 years to be treated with different regimens (BPaL, BPaLM, SSOR, SLOR).Patient-related data required for each regimen are as follows: the average number of patient visits to health facilities during treatment, the proportion of patients hospitalised and average duration of hospitalisation, daily hospitalisation costs for the health system and the patient, and other costs to calculate direct patient costs, namely minimal daily wage and average local travel costs to hospital/ clinic.
The second worksheet captures the following costs for each regimen used in the country: 1) TB medicines, 2) ancillary medicines, and 3) tests for baseline and treatment monitoring (such as sputum examinations, blood tests, etc); 4) hospitalisation costs; and 5) patient costs.For the first four categories, an estimate of the proportion of patients who need them (e.g.100% need bedaquiline under BPaL regimen, while a much lower percentage of patients may be using delamanid under the longer regimen) and the number of units needed for the treatment must be estimated.Patient costs include an average estimate for travel costs to the clinic/ hospital, lost productive time (assuming minimum wages), daily hospitalisation costs borne by the patient, and other costs where available, such as childcare or caregiver costs.
When desired by a country and if data are available, other costs can be added, such as social support (cash or food baskets), capital costs, and others.SLASH-TB has the flexibility to include additional costs for both patients and service providers where such data are available.

The treatment outcomes of SLASH-TB
For the cost-effectiveness analysis, treatment outcomes are crucial; hence, the latest available data are requested by regimen from each country.It is noted that if the country does not yet have treatment outcome data for BPaL, the treatment outcomes presented in the relevant trial (ZeNix for BPaL 5 and TB-PRACTECAL for BPaLM 6 ) are used.Data presented at The Union Conference in 2023 7 show that countries implementing BPaL under operational research achieved similar outcomes as those in clinical trials.Treatment success is defined as the sum of patients cured and treatment completed. 8Patients experiencing unfavourable outcomes during post-treatment followup in clinical trials were not included in the assessment.

Outputs of SLASH-TB
The outputs are presented in a table format for ease of use by countries.Table 1 presents the total costs for service providers and patients under each regimen and the average per-patient cost for each regimen.The table also presents the annual and per-patient savings for patients and providers resulting from the switch from current regimens to BPaL/BPaLM.
Table 2 presents the incremental benefit for three periods: the year before the analysis and the 5-and 10-year horizons using BPaL/BPaLM.The following were calculated: successful treatment outcomes; lives saved; treatment failures averted; patients lost to follow-up averted; months of treatment saved; disability-adjusted life-years (DALYs) averted; years of life lost (YLL) due to premature mortality averted; and years lived with a disability (YLDs) averted.
A scenario analysis was conducted to explore the impact of different treatment outcomes on incremental effectiveness (Table 3).The Philippines is already using BPaL, and SLASH-TB uses the actual treatment outcomes for BPaL and TB-PRACTECAL results for BPaLM 5 to calculate the effectiveness -captured as Scenario A. For Scenario B, we used the Zenix trial results for BPaL 4 and interim published results for BPaLM in TB-PRACTECAL, 9 both showing a lower treatment success rate.
Table 4 presents a budget impact analysis showing cost savings for service providers and patients resulting from switching to the new regimens over 5 and 10 years.

RESULTS
We present the results of the four countries that have provided their data in 2023 to use SLASH-TB fully.

Service provider and patient costs
Table 1 presents the computed costs for each country for SSOR and SLOR, as per the reported use of these regimens in 2022, stratified by total costs and costs per patient.The costs for the countries per patient ranged from $1,256 to $3,394 for SSOR and $2,602 to $6,920 for SLOR.It should be noted that the costs were the highest in Ukraine, where all patients are hospitalised for a certain period according to national treatment guidelines.If these patients were to use BPaL/BPaLM instead of SSOR or SLOR, the cost would be between $996 and $2,573 per patient, indicating savings in each country.These costs and savings are disaggregated by service provider costs and patient costs and detailed in Supplementary Data 1.

Incremental effectiveness
In the four analysed countries, the treatment success rates for SSOR ranged between 67-81%; for SLOR, it was between 53% and 73%.In comparison, BPaL/ BPaLM have ~90% success in clinical trials and operational research in countries.Supplementary Data 2 provides detailed treatment outcome data from the four countries.

Scenario analysis: Incremental effectiveness under different treatment outcome scenarios
Scenario A is the actual treatment outcomes in the Philippines for BPaL (Supplementary Data 2) and those of TB-PRACTECAL 5 for BPaLM.Scenario B uses less favourable treatment outcomes and shows that with a lower success rate, as reported in ZeNix 4 and interim TB-PRACTECAL trial results, 8 the number of additional successful treatments using BPaL/BPaLM in the Philippines remains high at 1,001 compared with 1,307.Although the lives saved and failures averted remain similar due to the similarity in outcomes from various studies, the number of patients lost to followup increases but remains 367 fewer than when using current regimens (Table 3).

DISCUSSION
One of the main challenges with the tool is the collection of data that countries may not routinely gather.However, with the ongoing efforts to use WHO guidelines directly and digitise data, including Cost-effectiveness of BPaL/BPaLM the guide on 'Electronic recording and reporting for tuberculosis care and control', 10 such information is becoming more readily available.While SLASH-TB has the flexibility to include additional costs for both patients and service providers where such data are available, the flexibility also extends to unavailable data.For example, among the analysed countries, South Africa and Ukraine failed to procure data on ancillary medicines.In these cases, we removed the cost of ancillary medicines from the analysis for current regimens and BPaL/BPaLM.SLASH-TB uses GBD country data based on TB disease and is not disaggregated for DR-TB.This likely leads to an underestimation of the burden of DR-TB disease and, hence, an underestimation of the number of lives saved through the new regimens.
The outcome 'years lived with disability' was adjusted by the number of patient treatment months saved when using the shorter BPaL/BPaLM regimens.In reality, the issue of disability is far more complex -TB, especially DR-TB, often results in post-TB sequelae and disabilities, 11,12 and this is not captured adequately in SLASH-TB.
Regarding the cost borne by the patients, SLASH-TB considers the average costs of transportation, hospitalisation expenses and days of lost income due to trips to a clinic in the frame of DR-TB treatment.For lost income, the country's minimum wage was used, likely resulting in an underestimation of lost income.Out-of-pocket expenditures are also likely underestimated for a certain proportion of patients.On the other hand, it was assumed that all patients were wage earners.
SLASH-TB also does not consider the indirect benefits of reduced duration of treatment and a lower pill burden.Long-term treatment and a high pill burden can have a strong negative impact on the patient's quality of life.Also not considered are the potentially substantial positive effects of lower failure and relapse rates (such as the positive effects of less transmission, lower re-treatment rates, and lower re-hospitalisation rates) through the use of BPaL/ BPaLM.
The evidence to support better outcomes for DR-TB when using BPaL/BPaLM regimens is impressive but not extensive.More studies on the real-world treatment outcomes of BPaL and BPaLM are currently being conducted, and additional data are expected to be published soon.Data informing SLASH-TB outcomes can be adjusted if warranted, and countries will be able to use the programmatic outcomes data when they start implementing BPaL/BPaLM.
Clinical trials and emerging data from programmatic implementation 6,13 prove that the shorter BPaL/ BPaLM regimens are more effective and more easily implementable for DR-TB.SLASH-TB calculates that implementing these treatments would lead to significant cost savings with a long-term impact on the governmental health budget, in addition to better treatment outcomes resulting in more people successfully completing treatment, fewer cases of treatment failure, and more lives saved due to the positive impact on patient cohorts.5][16] Operational research in the Philippines shows a higher treatment success than the clinical trials on which SLASH-TB is based.However, the scenario analysis indicates that even when the worst outcomes from all trials are considered, the use of BPaL/BPaLM would still result in substantially more lives saved and fewer failures or losses to follow-ups than when continuing the SSOR and SLOR; thus, these interventions would remain highly cost-effective.Therefore, there is a strong economic and treatment outcome-based case for the rapid implementation of BPaL/BPaLM regimens.The expected monetary savings could be used to improve diagnostic access and treatment support.This will contribute to closing the enormous gap that exists between the incidence cases of DR-TB and those enrolled in adequate treatment: only approximately 43% of the estimated number of people who developed DR-TB in 2022 were enrolled in treatment. 1

CONCLUSION
By implementing the BPaL/BPaLM regimens, DR-TB treatment has become more effective, shorter, less burdensome for patients, and cheaper for both health systems and patients.SLASH-TB expresses this in numbers; therefore, it is helpful for country planning, advocacy, and budgeting.Countries will benefit from using SLASH-TB for planning purposes and advocacy by presenting concrete figures that show the benefit of the newly recommended BPaL/BPaLM regimens.The results from SLASH-TB support the case for rapid implementation of BPaL/BPaLM made in published advocacy documents, such as the Call to Action of WHO and partners 17 and the Global Fund's advocacy guide on six-month treatments for DR-TB. 18he main challenge now is to scale up the use of BPaL/BPaLM regimens rapidly.There is an epidemiological, economic, and moral imperative to adequately support countries in these scaling-up efforts.SLASH-TB provides countries with an accessible tool to rapidly conduct cost-effectiveness and budget impact analyses to support policy decisions, at no to minimal cost.TB Alliance intends to disseminate information on the tool widely so that countries worldwide can benefit from it.
This research was supported by TB Alliance (Global Alliance for TB Drug Development; New York, NY, USA) with funding from Australia's Department of Foreign Affairs and Trade; the Bill & Melinda Gates Foundation (Seattle, WA, USA; Grant Number: INV-042457; the UK Foreign, Commonwealth and Development Office; Germany's Federal Ministry of Education and Research through KfW; Irish Aid (Dublin, Ireland); and the United States Agency for International Development (Washington DC, USA).The funders played no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.R É S U M É C O N T E X T E : En 2022, l'OMS a préconisé l'utilisation des schémas thérapeutiques (bedaquiline + pretomanid + linezolid) et BPaLM (BPaL + moxifloxacin), d'une durée de 6 mois, comme alternatives pour traiter la plupart des formes de TB résistante aux médicaments.SLASH-TB a réalisé une estimation des économies et de la rentabilité pour le système de santé et les patients lorsqu'un pays décide de passer des schémas thérapeutiques standards actuels au BPaL/BPaLM.M É T H O D O L O G I E : Les programmes nationaux de lutte contre la TB (NTP) utilisent les données nationales pour évaluer les coûts des différents schémas thérapeutiques et des résultats des traitements.Si le BPaL/BPaLM n'est pas utilisé actuellement, les données des essais cliniques sont utilisées pour estimer le rapport coût-efficacité.Les années de vie ajustées sur l'incapacité (DALYs, pour l'anglais « disability-adjusted life-years ») sont calculées à l'aide de la base de données Global Burden of Disease (GBD).R É S U L T A T S: Nous présentons les résultats de quatre pays qui ont utilisé l'outil et partagé leurs données.Lorsque les schémas plus courts et plus longs sont remplacés par BPaL/BPaLM, les économies par patient traité au Pakistan, aux Philippines, en Afrique du Sud et en Ukraine sont respectivement de 746, 478, 757 et 2 636 dollars.L'utilisation des schémas BPaL/BPaLM permettrait de traiter un plus grand nombre de patients avec succès, ce qui sauverait respectivement 411, 1 025, 1 371 et 829 vies et éviterait 20 179, 27 443, 33 384 et 21 924 DALYs par an dans les quatre pays.C O N C L U S I O N : Les schémas BPaL/BPaLM ont révolutionné le traitement de la tuberculose pharmacorésistante en le rendant plus efficace, plus rapide, moins contraignant pour les patients, plus économique pour les systèmes de santé et les patients, et en sauvant un plus grand nombre de vies.

Table 3 .
Scenario analysis: Incremental effectiveness for 2022, The Philippines.

Table 4 .
Budget impact analysis: savings when switching from SSOR and SLOR to BPaL/BPaLM.