Advancements in DS-TB Short Course Treatment and CLO-FAST Study Review

Between June 2021 and April 2023, when the trial was terminated due to ineffectiveness based on DSMB recommendations, 58 of the planned 110 participants were included in Group 1, 31 of the planned 55 participants in Group 2, and 15 of the planned 20 participants in Group C. The majority of participants were male (79%), and 29% were HIV-positive (median baseline CD4+ cell count 265 cells/mm³, IQR 185-379 cells/mm³). Seventy-one percent of patients had radiological advanced tuberculosis, and 25% were 3+ smear positive at enrollment. The median study follow-up time (IQR) was 50.2 weeks (39.7, 57.6 weeks). By week 12, 89% (n=48) of participants in Group 1 and 90% (n=28) of participants in Group 2 achieved stable culture conversion (adjusted HR 1.17, 90%CI: 0.79 to 1.73, adjusted for baseline HIV status and presence of advanced disease). Influenced by changes in creatinine clearance rates in Group 1, the cumulative proportion of participants with ≥ grade 3 adverse events in Group 1 (46%) was higher than in Group 2 (16%) (difference 30%, 90%CI: 14-45%). The cumulative incidence of adverse outcomes in Groups 1 and 2 was 49% (95%CI: 34-67%) and 34% (95%CI: 19-58%) respectively (difference -15%, 95%CI: -41% to 11%). The table below describes the clinical/bacteriological adverse outcome events.

The 13-week treatment regimen containing CFZ and Rifapentine showed poor efficacy for DS-TB. Despite a high culture conversion rate at week 12, the incidence of adverse events in the SOC group was also high.

In recent years, a significant trend in tuberculosis research has been to explore shorter and more effective drug combinations for treating drug-sensitive tuberculosis (DS-TB). The key motivations and goals behind this trend include: (1) Enhancing patient adherence: Standard treatment regimens (HRZE) typically last 6 months or longer, placing a significant burden on patients and leading to treatment interruptions or incompleteness, which may result in treatment failure and the development of drug resistance. Shorter regimens aim to alleviate this burden and improve treatment completion rates. (2) Reducing adverse reactions: Long-term use of anti-tuberculosis drugs may increase the risk of adverse reactions, particularly hepatotoxicity and other side effects. Shorter regimens are expected to mitigate these risks. (3) Improving treatment efficiency and resource utilization: Shorter treatment regimens can enhance the efficiency of healthcare resource usage, which is particularly significant in resource-limited settings for public health improvement.

Successful cases of shorter treatment regimen research include: (1) Study 31/A5349: By using high-dose Rifapentine instead of Rifampicin and replacing Ethambutol with Moxifloxacin, the treatment duration was shortened to 4 months. (2) SHINE study: For children and adolescents with milder conditions, the standard regimen was shortened to 4 months. (3) TRUNCATE-TB study: Using Bedaquiline + Linezolid instead of Rifampicin for a 2-month intensive treatment, or adjusting to 3 months based on treatment response, with a total duration reduced to 86 days if results were unsatisfactory. These three studies were published in 2021, 2022, and 2023 respectively, representing significant progress in shorter treatment regimens.

The Clo-Fast study was conducted concurrently, attempting to explore new treatment regimens by adding Clofazimine to the standard regimen and replacing Rifampicin with high-dose Rifapentine. Clofazimine, originally used for leprosy treatment, has recently gained prominence in tuberculosis treatment by disrupting the cell membrane and electron transport chain of Mycobacterium tuberculosis, proving effective against multidrug-resistant and extensively drug-resistant strains, and is one of the WHO-recommended drugs for treating multidrug-resistant tuberculosis; its main side effects include skin discoloration, gastrointestinal discomfort, and QT interval prolongation. In recent years, the anti-tuberculosis effects of Rifapentine have also been emphasized, with most studies recommending higher doses. Higher doses of Rifapentine may be more effective in shorter treatment regimens.

However, the Clo-Fast study did not achieve success, possibly due to: (1) Insufficient efficacy of the drug regimen: The 3-month regimen (including high-dose Rifapentine and Clofazimine) failed to achieve the same treatment effect as the 6-month standard regimen, despite similar stable culture conversion rates at week 12, the efficacy of shorter regimens for treating DS-TB was inadequate. (2) Higher incidence of adverse events: The proportion of adverse events (especially those related to changes in creatinine clearance) in the experimental group was higher than in the standard treatment group, possibly indicating that the safety of the shorter regimen was inferior to that of standard treatment, impacting overall treatment outcomes. Clofazimine is primarily excreted through feces, with only a small portion excreted through urine, and its excretion may not be significantly affected in patients with renal dysfunction, typically not requiring dose adjustments. The reasons for renal adverse events in the experimental group still require further analysis, with a need to be cautious of the renal toxicity brought by high-dose Rifapentine or drug interactions in the regimen leading to renal toxicity. (3) Higher probability of adverse outcomes: The cumulative probability of adverse outcomes (clinical/bacteriological) in the experimental group was higher than in the standard treatment group, possibly indicating that the shorter regimen did not effectively eliminate the infection or prevent relapse. Compared to the TRUNCATE-TB study, the treatment regimen in the Clo-Fast study may have been less effective; the former used two WHO Group A recommended drugs (Bedaquiline and Linezolid) and did not use Rifamycins, while the latter only used one WHO Group B recommended drug (Clofazimine) and employed high-dose Rifapentine. (4) Insufficient sample size and early termination: The study was terminated early due to not meeting expected outcomes, with participant numbers not reaching the planned sample size, potentially limiting the statistical power of the study results and reliability of conclusions. (5) Diversity of population and disease: The study spanned different countries, with participants having various demographic characteristics and disease statuses (such as HIV infection and severity of tuberculosis), this diversity may affect treatment response and the occurrence of adverse events.

In summary, the Clo-Fast study was innovative in attempting to shorten the treatment duration for DS-TB, but ultimately failed to meet expected efficacy and safety targets. The results of this study emphasize the need to consider both efficacy and safety, as well as individual patient differences when developing new short-course treatment regimens. Additionally, the Clo-Fast study also highlighted the challenges faced in conducting such trials, including selecting appropriate drug combinations and ensuring sufficient sample sizes to achieve statistically meaningful results.

Despite the study’s lack of success, its experiences and lessons are crucial for future tuberculosis treatment research. It prompts us to reflect on current treatment strategies, explore more innovative approaches, and adopt more comprehensive study designs in future clinical trials. For the future of tuberculosis treatment, ongoing research, innovation, and adaptive adjustments will be key.