Comparative effectiveness of shorter regimen with oral bedaquiline or injectable on treatment outcomes and mortality among patients with multidrug-resistant tuberculosis in Guinea: A retrospective cohort study

INTRODUCTION

Tuberculosis (TB) is the foremost infectious disease globally, and almost a billion people have died due to TB over the past two centuries.^[1] In 2022, TB was the world’s second leading cause of death from a single infectious agent after COVID-19 and caused almost twice as many deaths as human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome.^[2] More than 10 million people continue to fall ill with TB every year,^[2] and around half a million cases of multidrug-resistant TB (MDR-TB) are diagnosed worldwide.^[3] Despite numerous efforts to improve the management of these patients, cure rates remain below the thresholds set by the World Health Organization (WHO).^[2] This rate is close to 70% in Guinea, while the incidence of MDR-TB continues to rise.^[4] Under the impetus of the WHO, health authorities are modifying national guidelines as new data emerges. In 2022, the WHO recommended the use of the 6 months all-oral treatment regimen composed of bedaquiline, pretonamid, linezolid (600 mg), and moxifloxacin (BPaLM) rather than 9 months or longer (18 months) regimens in MDR/rifampicin (RIF)-resistant tuberculosis patients.^[5] However, the availability and implementation of this new strategy could take time, depending on the responsiveness of healthcare systems in many countries. This is one of the reasons why the classic oral regimen, including bedaquiline, continues to be used in many developing countries. The real-life efficacy of this short all-oral regimen containing bedaquiline compared with a short injectable regimen containing kanamycin or amikacin was demonstrated in a large cohort of patients in South Africa.^[6,7] In Guinea, this short oral regimen, including bedaquiline, was introduced in 2021.^[8] In the present study, we aimed to compare the shorter oral bedaquiline-containing versus injectable regimens on treatment success and mortality in patients treated for MDR-TB in Guinea.

MATERIALS AND METHODS

RESULTS

A total of 1193 patients were retrieved from the national MDR-TB registry in June 2022. Among these patients, we excluded 81 (6.8%) who had previously received treatment with second-line drugs, making them ineligible for short regimens and 64 (5.3%) who had missing value outcomes. Of the remaining 1048 patients who were analyzed, 225 (21.5%) were in the bedaquiline group and 823 (78.5%) in the injectable group [Figure 1].

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Figure 1:

Study population selection.

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Patients in the bedaquiline group were older, with a mean age of 36.3 years (SD: 14.0) versus 33.1 years (SD: 12.5; P = 0.002) in the injectable group. Patients in the injectable group were more likely to have a 3+ positive smear (32.2% vs. 28.9%; P < 0.001). There were similar proportions of women and HIV status [Table 1].

At the end of treatment, 161 (71.6%) patients in the bedaquiline group and 602 (73.1%) in the injectable group were considered as treatment success. Among patients included in the bedaquiline group, 35 (15.6%) died, 16 (7.1%) had treatment failure or recurrence, and 13 (5.8%) were lost to follow-up. The corresponding end-treatment outcomes in patients included in the injectable group were 146 (17.7%), 20 (2.4%), and 55 (6.7%), respectively. In the adjusted analyses, the bedaquiline-containing regimen was associated with a reduction of all-cause mortality by 38% (HR = 0.62, 95% confidence interval [CI], 0.42–0.91), with a higher probability of treatment success (OR = 1.08, 1.00–1.17) and a similar risk of loss to follow-up (HR = 0.62, 0.32–1.22), compared with the injectable group. In subgroup analyses, we found that women included in the bedaquiline group had a 56% reduction in mortality (HR = 0.46, 0.24–0.89) and a higher probability of treatment success (OR = 1.15, 1.00–1.32) compared with women in the injectable group [Figure 2].

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Figure 2:

Kaplan–Meier survival curves up to 12 months after TB treatment initiation. CI: Confidence interval.

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A similar effect between bedaquiline and the injectable groups in terms of reducing mortality and the number of patients lost to follow-up, and an increased probability of successful treatment was observed for men regardless of HIV status [Table 2].

DISCUSSION

In this large cohort of patients treated for MDR-TB in Guinea, we found that the bedaquiline-containing regimen was associated with lower risks of mortality and loss of follow-up and a higher probability of treatment success. Importantly, women treated with the bedaquiline-containing regimen had more benefits than those from the injectable group. Although women were younger and more frequently HIV-infected than men, this observed benefit appeared to be independent of HIV status. However, it should be pointed out that many authors reported more unfavorable treatment outcomes in cases of MDR-TB and HIV co-infection.^[3,10,11] Depending on the year, the therapeutic success rate for MDR-TB in Guinea varies between 70% and 75%.^[12,13] The loss to follow-up rate was almost identical in the two groups.

Our results are consistent with those reported in a South African cohort.^[7] Nevertheless, in our study, the success rate in the bedaquiline arm was 71.6%, slightly lower than what was reported in the South African cohort (74%) and a large meta-analysis (74.7%).

Our study has a number of strengths. First, it analyzed a large sample of patients from three referral centers for MDR-TB management in Guinea, which reduced selection bias and increased the validity of the extrapolation of our findings to the entire population of Guinean patients with MDR-TB. Second, our results are consistent with those reported in a South African cohort. The statistical methods used to analyze the data were similar in both cohorts. These two cohorts were very comparable in terms of participant profiles and statistical methods used to analyze the data. However, the limits of our study were its retrospective design and small sample size, which had an impact on the internal validity of the study, and some missing information on antiretroviral treatment (ART) initiation, which could possibly serve as a proxy for MDRTB assessment. Further prospective cohort studies are needed to confirm our findings.

Our results are consistent with the work carried out in Africa, which justified the WHO recommendations on the use of bedaquiline in the treatment of MDR TB. Treatment regimens with bedaquiline have a better therapeutic outcome, are better tolerated, and easier to administer. Treatment regimens for MDR TB using injectable drugs are no longer justified in our context, regardless of the adverse effects, which were not analyzed in our study.

Even more effective and shorter antituberculosis treatments (BPal and BPal M) have been developed in recent years and have been recommended by the WHO.^[14] These treatments can be used for both MDR TB and extensively drug-resistant TB and are already in use in many countries. Guinea, like other countries, has updated its national guidelines to switch to BPAL and BPAL M as MDR-TB treatment for all eligible patients. However, due to the high toxicity of these treatments, it is more than necessary to find treatments with better safety.

CONCLUSION

Pending the availability of the 6-month BPaLM regimen in Guinea, the bedaquiline-containing regimen was associated with a significant improvement in TB treatment outcomes and should replace the injectable-containing regimen in the management of MDR-TB.