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Treatment outcomes of standardized injectable shorter regimen for multi-drugs resistant tuberculosis in Ethiopia: a retrospective cohort study

BMC Infectious Diseases volume 24, Article number: 837 (2024) Cite this article

Abstract

Background

The injectable shorter multi-drug resistant tuberculosis (MDR-TB) regimen, has been reported to be less costly and more effective in the treatment of MDR-TB compared to the longer regimen. Ethiopia introduced the injectable shorter regimen (SR) in April 2018 following official recommendation by the World Health Organization (WHO) in 2016. While the WHO recommendation was based on evidence coming from extensive programmatic studies in some Asian and African countries, there is paucity of information on patient outcomes in the Ethiopian context. Thus, we aimed to assess the treatment outcomes and identify factors associated with the outcomes of MDR-TB patients on injectable SR.

Methods

A multi-center facility-based retrospective cohort study was conducted in Ethiopia on 245 MDR-TB patients who were treated between April 2018 and March 2020. Data were collected from patients’ medical records and analyzed using SPSS version 25. Descriptive statistics was used to summarize the results while inferential analysis was employed to investigate predictors of treatment outcomes and survival status.

Results

A total of 245 patients were included in the study, with 129 (52.7%) of them being female. Median age of the patients was 27 (IQR: 21–33). The overall treatment success rate was 87.8%, with 156 (63.7%) cured and 59 (24.1%) patients who completed treatment. The unfavorable outcomes accounted for 12.2%, with 16 (6.5%) treatment failure, 8 (3.3%) death and 6 (2.4%) lost to follow up. Majority of the unfavorable outcomes occurred during the early phase of therapy, with median time to event of 1.8 months (95% CI: 0.99—2.69). The use of khat (a green leafy shrub abused for its stimulant like effect) and being diagnosed with MDR-TB than rifampicin resistant only, were identified as independent factors associated with unfavorable outcomes.

Conclusion

The injectable SR for MDR-TB was found to have positive treatment outcomes in the context of programmatic management in Ethiopia.

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Introduction

The emergence of drug resistant tuberculosis (TB) significantly impacted the effective control of the disease [1]. While resistance can develop to specific agents, such as rifampicin, resistance to multiple anti-TB medications is frequently observed. [2]. Multidrug-resistant TB (MDR-TB) occurs when the mycobacterium becomes resistant to isoniazid and rifampicin [3]. With an estimated 400,000 new cases of MDR-TB/ rifampicin resistant tuberculosis (RR-TB) diagnosed in 2022 alone, the issue continues to pose a growing global public health threat [4].

Management of MDR-TB was entirely based on longer regimens (LR) of at least 20 months duration until the World Health Organization (WHO) guidelines included options for treating MDR/RR-TB with injectable shorter regimen (SR) in 2016 [5]. The injectable SR lasts 9–12 months, where the intensive phase lasts for four months and can be extended up to a maximum of six months in case of lack of sputum smear conversion and followed by a continuation phase of five months [6]. Gatifloxacin/moxifloxacin, clofazimine, pyrazinamide and ethambutol are given throughout the treatment period, while kanamycin/amikacin, prothionamide, and high-dose isoniazid are used during the intensive phase only [7].

The LR was largely associated with higher non-adherence rate, significant adverse events and poor clinical outcomes [8]. In contrast, the injectable SR has been proven in many settings to be less costly and more effective [9, 10]. When used appropriately, it is estimated that over 85% of patients on the injectable SR can be cured [11]. In contrast, treatment success with the LR was relatively low, ranging from 54%-56% [12].

The injectable SR was implemented by countries following recommendations by the WHO [11]. Despite reports on the better effectiveness of the injectable SR in treating MDR-TB from some African and Asian countries, there was uncertainty about its generalizability to all settings [11, 13]. Moreover, evidence on outcomes of the injectable SR in young patients and those with HIV co-infection was inadequate and some studies reported, slightly lower success rate in children and lower treatment success with higher mortaliy in HIV patients on the SR compared to those on the LR [14, 15]. Furthermore, time to unfavorable outcomes remains largely unstudied [6].

Generally, MDR-TB treatment success is affected by a variety of factors. Among these, medication associated adverse events [16, 17], co-infection with HIV and body mass index (BMI) [18], malnutrition [17], absence of culture conversion at month 2 [13], male gender and substance abuse [19], negatively affected the treatment outcome.

Ethiopia has transitioned out of the 30 high MDR/RR-TB burden countries list in 2021 [20]. However, the condition still remains to be of great public health importance in the country. Until the introduction of the injectable SR in April 2018, management of MDR-TB in Ethiopia was based on the LR. A meta-analysis of six studies from 2014 to 2018 showed that LR was associated with low cured rate of 46.1% [21]. However, the patterns of treatment outcomes with the SR in Ethiopian patients remains unknown and since treatment success can vary across several countries and settings, we aimed to assess the success rate and factors affecting treatment outcome with shorter injectable regimen among MDR-TB patients in Ethiopia.

Methods

Study area

The study was conducted in drug resistant TB treatment initiation centers (TICs) across Ethiopia. Ethiopia has a three-tier healthcare system providing services at primary-, secondary- and tertiary-level health facilities. TICs are established in secondary and tertiary care levels while treatment follow up centers (TFCs) are available at all care levels. Ethiopia began implementing the ‘standardized injectable SR for MDR-TB treatment in April 2018, transitioning to the full oral regimen by mid-2020. From the 62 TICs (as of January, 2020) in Ethiopia, eight TICs with high patient load (i.e., Africa Leprosy, Tuberculosis, Rehabilitation and Training (ALERT) Hospital, Gondar University Hospital, Borumeda Hospital, Adama Hospital Medical College, Yirgalem Hospital, Shanen Gibe Hospital, Hossana Hospital and Tulu Bollo Hospital) were purposively selected for the study.

Study design

A multi-center hospital-based retrospective cohort study was conducted to evaluate the treatment outcomes of standardized injectable SR for MDR-TB treatment. The records of all MDR-TB patients who have been on injectable SR at the selected sites from April 2018 to March 2020 were reviewed.

Study participants selection

The study included all bacteriologically confirmed DR-TB positive patients who were on the injectable SR between April 1, 2018 and March 31, 2020 having complete record of treatment outcomes. In Ethiopia, drug susceptibility testing (DST) is required to confirm drug resistance status. Patients were eligible for treatment with injectable SR, only if they had no resistance to fluoroquinolones (FQ) and second line injectable (SLI) agents. The facilities use Gene expert (Xpert) for detection of MDR- and RR-TB directly from the sputum and Line Probe Assay (LPA) as a rapid DST technique to test resistance to other first line TB drugs as well as resistance to fluoroquinolone and injectable core second line TB drugs [22]. Therefore, patients whose MDR-TB positive status was confirmed by Xpert and those who were declared as non-resistant to FQ and SLI agents with confirmed LPA test were included. In addition, diagnosis during follow up was also used for eligibility criteria. Sputum smear microscopy and culture test was commonly used for detection of TB and monitoring treatment response in follow up period [22]. Accordingly, patients whose treatment follow ups were monitored by one or both of the methods to declare outcome were included in the study. However, all MDR-TB patients who were clinically diagnosed, with incomplete record of treatment outcome and other important variables, who were transferred to other hospitals were excluded from the study.

Data collection and management

Patients’ socio-demographic characteristics, medical history, and treatment outcomes were collected from the medical chart, using data abstraction format adopted from the national registration log-book. Data collection was carried out by trained nurses working in MDR-TB units and facilitated by MDR-TB coordinators under supervision of the first author (DLA). A pretest was conducted on 10 patients’ medical charts prior to data collection in order to check the applicability of the data collection format. The patient registration number was used to uniquely identify individual patient and to avoid duplication of records.

Data analysis

SPSS version 25 was used for data entry and analysis. Descriptive statistics was computed to present summary results. Binary and multi-variable logistic regression analysis were employed to effect of independent variables (age, sex, patients’ BMI, nutritional status, previous history of TB, Co-morbidity, audiometry status, smear result status, smear conversion period, resistance type (RR or MDR), chest X-ray results, prior use of first and/ or second line anti-TB medicines on the treatment outcomes of injectable SR. Listwise deletion method was employed in handling missing data in analysis. Multi-variable analysis was computed by stepwise method to test the model fitness. Significance of association were determined using unadjusted (crude) and adjusted odds ratios (OR) at corresponding 95% confidence intervals (CI) with p. value ≤ 0.05.

For the purpose of binomial analysis cured and treatment completed cases were categorized as favorable outcomes and the outcomes of death, treatment failure and lost to follow-up were classified under unfavorable outcomes. Regarding survival analysis, Kaplan Meier survival method was used to examine time to events (unfavorable treatment outcomes), as well as to plot and describe survival experience among the different categories. Survival data were analyzed by survival probability and hazards ratio.

Normality was tested for continuous variable using Shapiro wilk test and through examining the histogram and line plot. Accordingly, age and time to events were not normally distributed whereas BMI was found to be approximately normally distributed. Accordingly, median and inter-quartile range (IQR) were used to describe the non-normally distributed data while the mean and standard deviation were used for describing the normally distributed data..

Operational definition

World Health Organization has defined MDR-TB treatment outcomes as listed below [23]:

  • MDR-TB treatment outcomes – includes: cured, treatment completed, treatment success, death, treatment failure and loss to follow up.

  • Cured: treatment completed as recommended by the national policy without evidence of failure AND three or more consecutive cultures taken at least 30 days apart are negative after the intensive phase.

  • Treatment completed: treatment completed as recommended by the national policy without evidence of failure BUT no record that three or more consecutive cultures taken at least 30 days apart are negative after the intensive phase.

  • Treatment success: means the sum of cured and treatment completed

  • Death: refers to a patient who dies for any reason during the course of treatment.

  • Treatment Failure: treatment terminated or need for permanent regimen change of at least two anti-TB drugs because of: lack of conversion by the end of the intensive phase, or bacteriological reversion in the continuation phase after conversion to negative, or evidence of additional acquired resistance to fluoroquinolones or second-line injectable drugs, or adverse drug reactions (ADRs).

  • Lost to follow up: refers to a patient whose treatment was interrupted for two or more consecutive months.

Results

Baseline characteristics

All MDR-TB patients in the selected TICs who met the eligibility criteria were included. From the total of 256 patients who started treatment at selected TICs, 245 fulfilled inclusion criteria and thus, were included in the study. The remaining 11 patients were not eligible because they had been transferred to other facilities (n = 5), their records were unavailable (n = 4) and their outcomes were unknown (n = 2). The median age of the patients was 27(IQR 21–33) years. More than half (129, 52.7%) of the patients were female. Mean BMI of patients was 17.5 ± 3.2 kg/m2, with 156 (63.7%) being underweight (< 18.5 kg/m2) at baseline. Thirty-seven (15.1%) patients had history of substance use; 25 (10.2%) chewed khat (a green leafy shrub abused for its stimulant like effect) 18 (7.3%) used alcohol and 5 (2.0%) smoked cigarettes (Table 1).

Table 1 Socio-demographic characteristics of MDR-TB patients treated with injectable SR, Ethiopia, April 2018—March 2020
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Regarding patient’s medical data, the majority of patients (155, 63.3%) had malnutrition at baseline. According to previous history, relatively larger number of patients were new (91, 37.1%) and followed by those previously treated by first line drug (FLD) (81, 33.1%). More than 16% of the patients had comorbid conditions. The majority of the patients (183, 74.7%) had smear conversion within 4 months of treatment while 34 (13.9%) patients had intensive phase of the treatment extended to 5 or 6 months. Almost all of the participants had RR-TB (237, 96.7%) and 107 (43.7%) experienced at least one therapy related adverse events in the duration of the treatment (Table 2).

Table 2 Clinical information of MDR-TB patients treated with injectable SR, Ethiopia, April 2018—March 2020
Full size table

Treatment outcomes

The overall MDR-TB treatment success rate was 87.8% (cured plus treatment completed) and 12.2% had unsuccessful treatment outcomes. From 245 patients, 156 (63.7%) were cured, 59 (24.1%) completed treatment, 16 (6.5%) treatment failure, 8 (3.3%) died and 6 (2.4%) were lost to follow up (Table 3).

Table 3 Treatment outcomes of MDR-TB patients with respect to TIC Ethiopia
Full size table

Sub-group descriptive analysis of treatment outcomes was done with respect to study sites and selected independent variables. Accordingly, 100% of patients from Boru Meda TIC were cured implying 100% success rate. Additionally, all patients were either cured or completed treatment in in Shenen Gibe and Adama TICs. Relatively lesser success rates (72.6%) were observed among patients from Hossaina TIC (Table 3).

Factors associated with MDR-TB treatment outcomes

The bivariate logistic regression analysis showed that drinking alcohol, chewing khat and having MDR-TB were strongly associated with unfavorable outcomes (Table 4). Having MDR-TB and chewing khat were independent factors for unfavorable treatment outcome as per the multi-variable logistic regression. Patients with MDR-TB were six times more likely to have poor outcomes (AOR = 6.136; 95%CI: 1.358 – 27. 729) compared to those with RR. The likelihood of unfavorable outcomes among khat chewers was three times higher as compared to non-chewers (AOR = 3.012; 95%CI: 1.056 – 8.590). However, alcohol drinking was not significantly associated with unfavorable treatment outcomes (Table 4).

Table 4 Bivariate and multivariable analysis of factors associated with unfavorable treatment outcomes
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As observed from patients’ medical records, the most common reason cited by physicians for treatment failure was adverse drug event (ADE). Out of the 16 treatment failure cases, 10 (62.5%) were directly related to ADE while 5 (31.3%) were as a result of bacteriological failure (non-conversion or reversion after conversion). The cause of treatment failure was not reported for one (6.2%) patient.

Survival analysis

Median and cumulative proportion of MDR-TB patients who survived from unfavorable outcomes during the treatment period was analyzed by Kaplan Meier survival method. Survival analysis was done for the period of9 months from start of the treatment to assess whether the patients survived from experiencing any unfavorable outcomes or not. Time to events was calculated as difference, in months between the treatment start date and the date the events occurred. In the treatment period, for patients with event, median time to overall unfavorable outcomes (combination of death, failure and lost to follow-up) was 1.8 months (Table 5).

Table 5 Median time to events for unfavorable outcomes
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The probability of survival from events was evaluated using Kaplan Meier survival method. Plot of survival function showed that at the end of the 2nd, 4th and 8th months of follow up, cumulative survival from unfavorable events were 0.992, 0.984 and 0.880, respectively. The last event occurred at month 8.25 and the proportion that survived from month 8.25 to 9 was 0.878 (Fig. 1a, b).

Fig. 1
figure 1

Kaplan–Meier curve showing: (A) Cumulative survival of patients from unfavorable treatment outcomes, and (B) hazards to the events

Full size image

Time to unfavorable outcomes was compared among patients with adverse effects and without adverse effects. Median survival for patients with and without adverse effects was 8.067 and 8.422 respectively. In general, probability of survival was lower for patients with adverse effects (Fig. 2a). Again, the cumulative hazard was higher for patients with adverse effects (Fig. 2b).

Fig. 2
figure 2

Plot of Kaplan–Meier: (A) percentage of survival of patients from and (B) hazards to unfavorable treatment outcomes with respect to their adverse events status

Full size image

Discussion

This study evaluated outcomes and associated predictors of treatment with injectable SR of MDR-TB under programmatic management. We identified that 87.8% of patients were successfully treated (i.e. cured or completed treatment).The study also established that having MDR-TB and chewing khat were significant predictors of unfavorable outcomes and the median of time to unfavorable outcome was1.8 months.

The treatment success rate we identified was comparable to the outcome of gatifloxacin based injectable SR treatment success rate (88%) in Niger [14]. However, it was higher than finding of multi-site STREAM stage 1 clinical trial (78.8%) [15]; slightly higher than that reported in a meta-analysis of studies from various African countries (83.0%), [13] and a prospective study from Bangladesh (84.5%), [9]. This observed difference may be due to variations in patients’ baseline characteristics, differences in programmatic management styles, sample size and study design. Compared to the LR, our result was greatly higher than findings of studies in Ethiopia (78.6%, 59.2%, and 73.2%), [21, 24, 25], China (52%) [16], India (60%) [26] and the global average as per the results of a meta-analysis (64.6%), [13]. This larger variance is attributable to better ADE profiles of the SR and the improved treatment compliance due to the shorter duration [8].

The multivariable analysis indicated the association between poor outcome and substance abuse and resistance type. Khat chewing (3.01, 1.056–8.590) was identified as an independent predictor of unfavorable outcomes. This aligns with findings of previous studies that evaluated the association between substance abuse and poor outcomes [19, 27, 28]. This highlights the critical role of counseling patients to modify their substance abuse behaviors during their treatment period.

In addition, we found that being resistant to both rifampicin and isoniazid (MDR) than mono-resistant only (RR) were strongly linked with poor outcomes (6.136, 1.358–27.729) which is in agreement with previously explored evidence indicating the existence of association between resistance to certain anti-TB medicines and poor treatment outcomes [29]. MDR was caused by a series of genetic mutations in MTB strains than RR, which negatively affect outcomes [30, 31].

Status of time to poor outcomes of treatment with injectable SR were not well studied in previous research [6]. In this regard, our findings indicated, for cohorts with events, the median time to unfavorable outcomes was 1.8 months. This indicates that majority of poor outcomes occurred in early intensive phase of treatment possibly due to high disease progress, pill burden, prior patients’ adaptation to treatment and intolerance to ADEs. Therefore, this warrants the need of intensive and close patient follow up and treatment monitoring during early phase of the therapy.

Similar to other retrospective studies, the current study is not without limitations. Given the retrospective nature of the study, it’s possible that certain significant associations were obscured due to incomplete data. Moreover, the fact that the current study did not have post treatment follow-up data limits the applicability of the results. Despite these limitations, the study involved multi-sites that can generate robust results at the national level and support the decision making process at various levels of the health system.

Conclusion

Our study revealed a higher treatment success rate with the injectable SR for MDR-TB treatment in Ethiopia under programmatic management. MDR-TB and chewing khat were found as independent factors that affect treatment outcome. Overall, the injectable SR has demonstrated strong effectiveness in the treatment of MDR-TB in Ethiopia. We recommend further studies to compare the injectable SR with current MDR-TB treatment regimens to indentify better treatment options for eligible patients.

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

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Acknowledgements

We sincerely thank the management and ethics committees of all participating hospitals for granting us data access for this study.

Funding

The data collection for the study was funded by Armauer Hansen research Institute (AHRI) and the graduate student research fund of Addis Ababa University (AAU).

Author information

Authors and Affiliations

  1. Armauer Hansen Research Institute (AHRI), Addis Ababa, Ethiopia

    Daniel Legese Achalu, Adamu Bayissa Kiltu, Mekonnen Teferi & Foziya Getachew Mohammed

  2. Department of Social and Administrative Pharmacy, Wollo University, Dessie, Ethiopia

    Birhanu Demeke Workneh

  3. Department of Pharmaceutical and Administrative Sciences, University of Health Sciences and Pharmacy in St. Louis, St. Louis, MO, USA

    Kebede Abera Beyene

  4. Canada’s Drug and Health Technology Agency, Toronto, ON, Canada

    Gebremedhin Beedemariam Gebretekle

  5. Department of Pharmaceutics and Social Pharmacy, Addis Ababa University, Addis Ababa, Ethiopia

    Eskinder Eshetu Ali

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Contributions

DLA, GBG, KAB and EEA conceived the study and were in charge of the overall direction and planning. All authors contributed to the study design. ABK, MT, FGM, GBG, KAB and BDW were engaged in the preparation of tools and data collection. DLA, GBG and EEA analyzed the data and drafted the manuscript while ABK, MT, KAB and GBG reviewed the manuscript critically for essential intellectual content. All authors read, commented and approved the final manuscript.

Corresponding author

Correspondence to Eskinder Eshetu Ali.

Ethics declarations

Ethics approval and consent to participate

Ethical approval was obtained from Addis Ababa University, College of Health Science, School of Pharmacy Ethical committee. Permission to data access and waiver of informed consent for patients’ medical records was obtained from each facility. The information obtained from individual patient chart was kept secret. All potential identifiers were removed from data collection forms and analysis.

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Not applicable.

Competing interests

The authors declare no competing interests.

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Achalu, D.L., Kiltu, A.B., Teferi, M. et al. Treatment outcomes of standardized injectable shorter regimen for multi-drugs resistant tuberculosis in Ethiopia: a retrospective cohort study. BMC Infect Dis 24, 837 (2024). https://doi.org/10.1186/s12879-024-09745-8

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  • DOI: https://doi.org/10.1186/s12879-024-09745-8

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BMC Infectious Diseases

ISSN: 1471-2334

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