Evaluation of Sulfasalazine as an Adjunctive Therapy in Treating Pulmonary Pre-XDR-TB: Efficacy, Safety, and Treatment Implication

Abstract

Background

The rising prevalence and limited efficacy of treatments for pre-extensively drug-resistant tuberculosis (pre-XDR-TB) underscore an immediate need for innovative therapeutic options. A combination of host-directed therapy (HDT) and anti-TB treatment presents a viable alternative for pre-XDR-TB management. Sulfasalazine (SASP), by targeting the amino acid transport system xc (xCT), potentially reduces the intracellular Mycobacterium tuberculosis load and mitigates lung pathology, positioning it as a promising TB HDT agent. This study aims to assess the efficacy of SASP as a supplementary therapy for pre-XDR-TB.

Methods

A pilot study examined the safety and effectiveness of two 9-month short-course, all-oral regimens for pre-XDR-TB treatment: Bdq-regimen (consisting of Bdq, linezolid, cycloserine, clofazimine, and pyrazinamide) and SASP-regimen (comprising SASP, linezolid, cycloserine, clofazimine, and pyrazinamide). The primary endpoint was the incidence of unfavorable outcomes 12 months post-treatment.

Results

Of the 44 participants enrolled, 43 were assessable 12 months post-treatment. Culture conversion rates stood at 73.2% by Month 2 and escalated to 95.1% by Month 6. Overall, 88.4% (38/43) of the participants exhibited favorable outcomes, 85.2% (19/23) for the Bdq-regimen and 93.8% (14/15) for the SASP-regimen. The SASP-regimen group recorded no deaths or treatment failures.

Conclusion

Both 9-month short-course, all-oral regimens manifested commendable primary efficacy in treating pre-XDR-TB patients. The SASP-regimen emerged as effective, safe, well-tolerated, and cost-effective.

Plain language summary

This study explored a new way to treat a hard-to-treat type of tuberculosis (TB) using a medicine called Sulfasalazine, alongside usual TB treatments. Over 9 months, two groups of patients were given different sets of medicines, one including Sulfasalazine. The results, checked 12 months after treatment, showed that most patients improved, especially those given Sulfasalazine. No one in the Sulfasalazine group died or had their treatment fail, suggesting that Sulfasalazine could be a promising addition to current treatments for this tough-to-treat TB.

Keywords:

• Sulfasalazine
• host-directed therapy
• pre-extensive drug-resistant tuberculosis
• short-course
• treatment

Abbreviations

AEs, adverse events; ALT, alanine aminotransferase; AST, aspartate aminotransferase; Bdq, bedaquiline; BMI, body mass index; CFDA, China Food and Drug Administration; CC, culture conversion; Cfz, clofazimine; ChiCTR, Chinese Clinical Trials Registry; CT, computed tomography; Cs, cycloserine; DST, drug susceptibility testing; FQs, fluoroquinolones; FR-6, favorable treatment response at Month 6; gDST, genotypic drug susceptibility tests; HDT, host-directed therapy; IQR, interquartile range; Lzd, linezolid; M. tb, Mycobacterium tuberculosis; MIC, minimum inhibitory concentration; MDR-TB, multi-drug resistant tuberculosis; pDST, phenotypic drug susceptibility tests; pre-XDR-TB, pre-extensively drug-resistant tuberculosis; Pza, pyrazinamide; QTcF, Fridericia-corrected QT interval; SAEs, serious adverse events; SASP, sulfasalazine; SNP, single nucleotide polymorphism; Tb, tuberculosis; WHO, World Health Organization; XDR-TB, extensively drug-resistant tuberculosis; Xpert, Xpert MTB/RIF assay.

Data Sharing Statement

The raw/processed forms of the data presented in this manuscript cannot be shared at this time as they constitute part of an ongoing study.

Ethical Approval and Consent

The Ethical Committee of the Shenzhen Third People’s Hospital approved this study (number: 2020-019-03, date: 2020-05-23). After providing a clear explanation of their rights and duties, written informed consent was obtained from all study participants or a guardian in the case of minors before screening and assignment. The study was conducted according to the principles of the World Medical Association Declaration of Helsinki, Good Clinical Practice Guidelines, and local laws and regulations.

Acknowledgments

We thank all the physicians and assistants who participated in this study and enrolled patients. We thank the Haibo Wang for assistance in data management and analysis.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

All authors declare that they have no competing interests in this work.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China (82070016), the National Key Research and Development Program of China (2023YFC2306700, 2023YFC2306703), the Guangdong Provincial Clinical Research Center for Tuberculosis Project (2020B1111170014), the Shenzhen High-level Hospital Construction Fund (XKJS-CRGRK-008), the Shenzhen Clinical Research Center for Tuberculosis (20210617141509001), the Shenzhen Scientific and Technological Foundation (KCXFZ20211020163545004), Shenzhen Third People’s Hospital Research Fund (G2021010, G2021015, G2021023, G2022155).