|Year : 2022 | Volume
| Issue : 3 | Page : 261-267
Treatment Outcomes of Multidrug-Resistant Tuberculosis Patients in East Java, Indonesia: A Retrospective Cohort Analysis
Hardini Tri Indarti1, Erna Kristin2, Soedarsono Soedarsono3, Dwi Endarti4
1 Doctorate Program of Medical and Health Science, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia
2 Department of Pharmacology and Therapy, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia
3 Department of Pulmonology and Respiratory Medicine, Faculty of Medicine, Universitas Airlangga, Dr Soetomo Hospital, Surabaya, Indonesia
4 Department of Pharmaceutics, Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta, Indonesia
|Date of Submission||01-Jun-2022|
|Date of Decision||23-Jul-2022|
|Date of Acceptance||08-Aug-2022|
|Date of Web Publication||12-Sep-2022|
Hardini Tri Indarti
Faculty of Medicine, Public Health and Nursing Universitas Gadjah Mada Jl. Farmako Sekip Utara, Sinduadi, Mlati, Sinduadi, Mlati, Kabupaten Sleman, Daerah Istimewa Yogyakarta 55281
Source of Support: None, Conflict of Interest: None
Background: The drug regimen for the treatment of multidrug-resistant tuberculosis (MDR-TB) has lower potency, is more costly, and has a greater risk of adverse effects than first-line anti-TB drugs. We aimed to compare the treatment outcomes of patients using standard shorter regimen (STR regimen) versus bedaquiline (BDQ)-containing individual regimen in a high TB-burden setting. Methods: This was a retrospective cohort study using secondary data from the medical records in the hospital. The study population were patients with MDR-TB who started treatment in 2016–2018. Treatment outcomes were classified as successful (cured/completed treatment) or unsuccessful (failure/death/loss to follow-up/not evaluated). Categorical data were presented as frequencies and percentage, whereas continuous data were presented as mean± standard deviations. Risk ratio (RR) was obtained by using the Chi-square statistical test with 95% confidence interval (CI) and P < 0.05 set as a significant result. Results: We included 99 patients out of 444 registered patients in 2016–2018. The overall success proportion was 41.4%. Success was more likely in patients who received BDQ regimen than those receiving STR regimen (52.9% vs. 35.4%, RR: 1.496, 95% CI: 0.948–2.362). Factors that influenced the treatment outcomes were smear status and sputum culture status. Conclusions: The success rate of the STR regimen and the BDQ regimen in this study is still below the national and global figures due to the high rate of lost to follow-up. The success was higher in the BDQ regimen, although not statistically significant. Further research is needed on adverse effects, quality of life, and costs during treatment.
Keywords: Bedaquiline, multidrug-resistant tuberculosis, shorter regimen, treatment outcome
|How to cite this article:|
Indarti HT, Kristin E, Soedarsono S, Endarti D. Treatment Outcomes of Multidrug-Resistant Tuberculosis Patients in East Java, Indonesia: A Retrospective Cohort Analysis. Int J Mycobacteriol 2022;11:261-7
|How to cite this URL:|
Indarti HT, Kristin E, Soedarsono S, Endarti D. Treatment Outcomes of Multidrug-Resistant Tuberculosis Patients in East Java, Indonesia: A Retrospective Cohort Analysis. Int J Mycobacteriol [serial online] 2022 [cited 2022 Sep 29];11:261-7. Available from: https://www.ijmyco.org/text.asp?2022/11/3/261/355930
| Introduction|| |
Tuberculosis (TB) is still a leading cause of death globally. In 2019, the World Health Organization (WHO) estimated a total of 10 million TB cases and 1.4 million deaths. Multidrug-resistant TB (MDR-TB), defined as resistance to rifampicin and isoniazid, is the cause of 25% of TB deaths in the world. Worldwide in 2019, close to half a million people developed rifampicin-resistant TB (RR-TB), of which 78% had MDR-TB. The WHO established MDR-TB as one of the ten threats to global health, while Indonesia is one of the thirty high-burden countries of TB. The incidence of MDR-TB cases in Indonesia in 2017 was 23,000 with an estimated 2.4% of cases occurring in new patients and 13% of patients who had previously received TB treatment.
Treatment of MDR-TB is longer, more expensive, more toxic, and less effective, thus reducing quality of life. MDR-TB treatment outcomes are poor, and globally, the therapeutic success rate is only about 55%. A significant factor contributing to treatment failure in many settings is the lack of effective drugs to manage MDR-TB. Several new drugs for TB treatment have been evaluated.
A prospective observational study conducted over 12 years in Bangladesh succeeded in finding a shorter duration of MDR-TB treatment regimen. A cohort of 206 patients was treated for 9–12 months with kanamycin, gatifloxacin, prothionamide, clofazimine, pyrazinamide, ethambutol, and high-dose isoniazid. The success of therapy was 87.9% (95% confidence interval [CI]: 82.7–91.6). The same drug regimen was subsequently studied in Nigeria with a success rate of 89.2% (95% CI: 81.7–96.7), and in Cameroon with a success rate of 89.3% (95% CI: 84.5–94.4).
In 2016, the WHO published a revised guideline for controlling MDR-TB with the addition of the Bangladesh therapy regimen as a standard shorter regimen and the addition of bedaquiline (BDQ) as one of the compositions of the individual regimen. BDQ, a diarylquinoline that inhibits mycobacterial adenosine triphosphate synthase, is the first anti-TB drug in 40 years to be approved for MDR-TB patients. Over the last few years, several studies have assessed the efficacy of BDQ.,,
In this study, we aimed to analyze treatment outcomes of patients with MDR-TB using standard shorter regimen (STR regimen) versus BDQ-containing individual regimen in East Java, Indonesia, a high TB-burden setting.
| Methods|| |
This study was approved by the Medical and Health Research Ethics Committee, Faculty of Medicine, Public Health, and Nursing Universitas Gadjah Mada with the Approval Number KE/134/01/2020 January 2, 2020.
Study design and patient population
This was a retrospective study using data from the medical records of patients with MDR-TB in hospital. This hospital is the largest DR-TB treatment center in East Java. The study population were patients with MDR-TB who started treatment in 2016–2018. We used total sampling technique to collect the data. Subjects were divided into two groups based on the drug regimen, with a group of patients who received a STR regimen and a group that received a BDQ regimen. Research subjects must meet the criteria for a diagnosis of pulmonary TB MDR through a molecular rapid test and phenotypic drug susceptibility test, aged above 18 years old; have finished receiving MDR-TB drug regimen therapy; and have clear and complete medical records. Patients with additional resistance to fluoroquinolones and/or aminoglycoside injection drugs were excluded from the study.
STR regimen defined as standardized regimens consists of two phases: the intensive and continuation phases. The intensive phase includes 4–6 months of kanamycin, moxifloxacin, ethionamide, high-dose isoniazid, clofazimine, pyrazinamide, and ethambutol, which is then followed by a continuation phase of 5 months of moxifloxacin, clofazimine, pyrazinamide, and ethambutol. The BDQ individual regimen is a MDR-TB treatment using a combination of anti-TB agents BDQ, cycloserine, pyrazinamide, isoniazid, and para-aminosalicylic acid for 20–24 months based on the 2016 WHO guidelines.
Treatment outcomes were classified into cured, completed treatment, died, failed, lost to follow-up (LTFU), and not evaluated., The successful outcome was defined as the combined proportion of cured patients (complete treatment with negative culture result for at least three consecutives with an examination interval of at least 30 days during follow-up) and had complete treatment. The unsuccessful outcome was defined as the combined proportion of patients who died, failed, LTFU (defined as patients whose treatment was interrupted for two consecutive months or more), and not evaluated.
Data were analyzed by using SPSS version 20. (IBM SPSS Statistics, IBM, New York, US). Categorical data were presented as frequencies and percentages, whereas continuous data were presented as mean ± standard deviations. Risk ratio (RR) was obtained by using the Chi-square statistical test with 95% CI and P < 0.05 set as a significant result.
| Results|| |
Out of the 444 patients with MDR-TB who were recorded to have started treatment in 2016–2018, 122 patients received the STR regimen and 86 patients received the BDQ regimen. Another 236 patients received conventional longer regimen and individual regimen which did not contain BDQ. A total of 99 patients met the inclusion criteria and were included in this study [Figure 1].
|Figure 1: Study flowchart. STR regimen: Standard shorter regimen, BDQ regimen: Bedaquiline regimen, RR-TB: Rifampicin-resistant TB|
Click here to view
The characteristics of the patients are described in [Table 1]. Most patients were 46–55 years old (31.3%), male (69.7%), and work as private employees (25.3%).
Most of the patients had negative HIV status (55.6%), were former smokers (33.3%), did not consume alcohol (58.6%), did not consume drugs (63.6%), and had normal body mass index (39.4%). In terms of disease conditions, most of the patients with MDR-TB had a positive smear status (69.7%), positive culture (89.9%), and no history of diabetes mellitus (36.4%). As many as 49.5% of patients were relapsed patients, who had recovered from a previous TB case. There were differences in the distribution of patient types between the STR regimen and the BDQ regimen. Most of the patients on the BDQ regimen consisted of relapsed and LTFU from previous TB treatments, while patients on the STR regimen were mostly relapsed and had failed first-line therapy.
Regarding outcomes, as shown in [Table 2], many patients in both the regimen groups experienced a LTFU treatment outcome. LTFU was more common in the STR regimen group (49.2%) compared to the BDQ regimen (29.4%). In contrast, the clinical outcome of death was higher in the BDQ regimen (11.8%) compared to the STR regimen (9.2%). The overall treatment success rate was 41.4%, with a greater proportion in the BDQ regimen group (52.9%) than in the STR regimen (35.4%). The smear conversion time of 1–3 months was more common in the BDQ regimen group compared to the STR regimen (58.3% vs. 52.2%).
[Table 3] displays the bivariate analyses of factors associated with treatment outcome. For the analyses, we further classified outcomes and compared success versus: (i) failure or death (considered equivalent to an efficacy analysis) and (ii) failure or death or LTFU or not evaluated (considered equivalent to an effectiveness analysis).
|Table 3: Factors associated with multidrug-resistant tuberculosis treatment outcomes|
Click here to view
Compared to failure/death, factors that influence the success of therapy (P < 0.05) were smear status (RR: 0.629, 95% CI: 0.487–0.811). Furthermore, an analysis was conducted comparing the success outcomes with failure, death, LTFU, and not evaluated. In this analysis, factors that influence the success of therapy were smear status (RR: 0.503, 95% CI: 0.324–0.781) and sputum culture status (RR: 0.024 95% CI: 0.273–0.688).
The analysis of the relationship between drug regimens and therapeutic success is described in [Table 4]. In the analysis that did not include LTFU and not evaluated patients, the success of therapy was more common in the BDQ regimen group (RR: 1.055, 95% CI: 0.782–1.423). After being analyzed using all treatment outcome data, the BDQ regimen group was still superior with an increase in the RR value to 1.496 (95% CI: 0.948–2.362).
| Discussion|| |
This study found that the overall success rate of MDR-TB therapy in East Java was 41.4%. This was comparatively lower than treatment success rates reported by studies conducted in other cities in the country. According to the 2019 WHO report, the national success rate of MDR and RR-TB therapy in Indonesia was 48%, which is still below the global treatment success rate of 56%, and far from the target of 75%. The WHO reported that the reasons for lower success rates in Indonesia were high rates of death and LTFU. This study also found high rates of LTFU (42.4%) and deaths (10.1%). Research in Indonesia and South Africa stated that a high LFTU rate was associated with the age and sex of the patient, as well as being related to physical conditions and job demands.,, Patients aged > 45 years are more at risk for discontinuing treatment. In this study, 64% of patients were > 45 years old. LTFU is also associated with previous treatment history. Psychological conditions in the form of stress, lack of social support, and stigma are more common in patients who have received previous TB therapy which results in a tendency to drop out of treatment. Most of the patients in this study (94%) were relapsed and had failed previous TB therapy.
The treatment outcome of LTFU was more prevalent in the STR regimen group (49.2%) compared to the BDQ regimen (29.4%). Whereas, the duration of treatment with STR was 9–11 months, much shorter than the 18–24-month duration of BDQ treatment. This result contradicts the LTFU of the STR regimen found in observational studies in Bangladesh, South Africa, and Nigeria which were 1.5%–7.8%. Low LTFU rates were also found in the randomized controlled trial of the STR regimen versus a long-term regimen (STREAM trial) of 0.4%. However, this study is consistent with a study in Afghanistan which stated that the LTFU in the STR group was higher than the individual regimen group (18.2% vs. 13.6%). The cause of the high LTFU in MDR-TB therapy is due to drug adverse effects.,,, The adverse effects of STR compared with long-term individualized regimens (not limited to the BDQ regimen) were not statistically significant (48.2% and 45.4% for the STR and individualized regimens, respectively). Studies comparing the adverse effects of the STR regimen and the BDQ regimen have not been published.
A previous study in East Java reported that negative attitudes toward treatment, limitation of social support, dissatisfaction with health services, and limitation of economic status are factors correlated with increased LTFU in DR-TB patients. Patients who seek treatment at Dr. Soetomo Hospital came from all areas of East Java, where patients are required to come to the hospital every day to receive treatment. Economic and time constraints, including conflicting times between work and treatment, financial constraints, and the late payment of enablers from the government are found to be the causes of LTFU in this study.
Further analysis conducted in this study is divided into two analyzes. The first analysis compared the success outcomes with failure and death. This analysis was performed to assess the efficacy of the drug regimen. It was found that the BDQ regimen increased the probability of success outcomes by 1.055 times (95% CI: 0.782–1.423), but was not statistically significant. The influencing factor is smear status (positive vs. negative, RR: 0.629, 95% CI: 0.487–0.811). The second analysis compared success outcomes with failure, death, LTFU, and not evaluated. The BDQ regimen increased the probability of success outcomes by 1.496 times (95% CI: 0.948–2.362). Factors affecting success were smear status (RR: 0.503, 95% CI: 0.324–0.781) and sputum culture status (RR: 0.434, 95% CI: 0.273–0.688).
This result is consistent with another study in West Java, Indonesia, which stated that culture status and smear status were associated with treatment outcomes related to the bacterial load that infected patients. The clinical condition of the patient is closely related to the patient's recovery rate. Early detection of MDR-TB disease could increase the patient's recovery rate.
The difference in the results of the first and second analyses showed the important influence of LTFU cases on the achievement of MDR-TB therapy. Further research is needed on the causes of the high LTFU rate in Indonesia. The results of this study still need to be confirmed with other studies, especially studies on adverse effects, quality of life, and costs during treatment.
The strength of this study is the use of a specific individualized regimen, the BDQ regimen as a comparison to the STR regimen. The selection of this regimen was based on the regimen recommended by the WHO in the latest 2019 guidelines. BDQ is also a potential new drug as MDR-TB therapy. Another strength is the use of treatment outcome criteria in this study referring to the WHO guidelines to minimize outcome bias.
| Conclusions|| |
The success of MDR-TB therapy using the STR regimen and the BDQ regimen in East Java, Indonesia, is still below national and global figures due to the high rate of treatment dropouts (LTFU). The patient success rate was higher in the BDQ regimen group, although not statistically significant. Further research is needed on adverse effects, quality of life, and costs during treatment in both regimens.
Limitation of the study
This study has several limitations, one being the retrospective cohort observational study design caused some data to be incomplete. To increase research power, samples were taken using a total sampling technique among a population of all patients with MDR-TB who started treatment within a period of 3 years (2016–2018). Although total sampling was used, the number of samples included was not large because the MDR-TB diagnosis used as the basis for selecting samples was taken based on the two examinations of rapid molecular tests and phenotypic drug susceptibility tests to prevent selection bias.
This study was approved by the Medical and Health Research Ethics Committee, Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada with the Approval Number KE/134/01/2020 January 2, 2020.
Financial support and sponsorship
This study was financially supported by Lembaga Pengelola Dana Pendidikan (LPDP), Ministry of Finance of Indonesia, Contract Number PRO-88/LPDP. 4/2020.
Conflicts of interest
There are no conflicts of interest.
| References|| |
Dheda K, Gumbo T, Maartens G, Dooley KE, McNerney R, Murray M, et al
. The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis. Lancet Respir Med 2017;5:291-360.
World Health Organization. WHO Consolidated Guidelines on Tuberculosis: Module 4: Treatment-Drug-Resistant Tuberculosis Treatment. Geneva: World Health Organization; 2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK558570/
. [Last accessed on 2022 Feb 16].
Van Deun A, Maug AK, Salim MA, Das PK, Sarker MR, Daru P, et al.
Short, highly effective, and inexpensive standardized treatment of multidrug-resistant tuberculosis. Am J Respir Crit Care Med 2010;182:684-92.
Piubello A, Harouna SH, Souleymane MB, Boukary I, Morou S, Daouda M, et al.
High cure rate with standardised short-course multidrug-resistant tuberculosis treatment in Niger: No relapses. Int J Tuberc Lung Dis 2014;18:1188-94.
Kuaban C, Noeske J, Rieder HL, Aït-Khaled N, Abena Foe JL, Trébucq A. High effectiveness of a 12-month regimen for MDR-TB patients in Cameroon. Int J Tuberc Lung Dis 2015;19:517-24.
World Health Organization. WHO Treatment Guidelines for Drug-Resistant Tuberculosis, 2016 Update. Geneva: World Health Organization; 2016. Available from: https://www.ncbi.nlm.nih.gov/books/NBK390455/
. [Last accessed on 2022 Mar 20].
Hatami H, Sotgiu G, Bostanghadiri N, Abadi SSD, Mesgarpour B, Goudarzi H, et al.
Bedaquiline-containing regimens and multidrug-resistant tuberculosis: A systematic review and meta-analysis. J Bras Pneumol 2022;48:e20210384.
Borisov SE, Dheda K, Enwerem M, Romero Leyet R, D'Ambrosio L, Centis R, et al.
Effectiveness and safety of bedaquiline-containing regimens in the treatment of MDR- and XDR-TB: A multicentre study. Eur Respir J 2017;49:1700387.
Borisov SE, D'Ambrosio L, Centis R, Tiberi S, Dheda K, Alffenaar JW, et al
. Outcomes of patients with drug-resistant-tuberculosis treated with bedaquiline-containing regimens and undergoing adjunctive surgery. J Infect 2019;78:35-9.
Koirala S, Borisov S, Danila E, Mariandyshev A, Shrestha B, Lukhele N, et al
. Outcome of treatment of MDR-TB or drug-resistant patients treated with bedaquiline and delamanid: Results from a large global cohort. Pulmonology 2021;27:403-12.
Samuels JP, Sood A, Campbell JR, Ahmad Khan F, Johnston JC. Comorbidities and treatment outcomes in multidrug resistant tuberculosis: A systematic review and meta-analysis. Sci Rep 2018;8:4980.
Soeroto AY, Pratiwi C, Santoso P, Lestari BW. Factors affecting outcome of longer regimen multidrug-resistant tuberculosis treatment in West Java Indonesia: A retrospective cohort study. PLoS One 2021;16:e0246284.
Noerfitri N, Sutiawan R, Wahyono TY, Hartono PA. Influence of decentralization and type of patient on loss to follow-up among multidrug-resistant tuberculosis patients in Indonesia from 2014 to 2015. Natl Public Health J 2019;13:105-11.
Akessa GM, Tadesse M, Abebe, G. Survival analysis of loss to follow-up treatment among tuberculosis patients at Jimma University Specialized Hospital, Jimma, Southwest Ethiopia. Int J Stat Mech 2015;923025 [doi.org/10.1155/2015/923025]. Available from: https://www.hindawi.com/journals/ijsm/2015/923025
. [Last accessed on 2022 Mar 19].
Moyo S, Cox HS, Hughes J, Daniels J, Synman L, De Azevedo V, et al.
Loss from treatment for drug resistant tuberculosis: Risk factors and patient outcomes in a community-based program in Khayelitsha, South Africa. PLoS One 2015;10:e0118919.
Ndambuki J, Nzomo J, Muregi L, Mutuku C, Makokha F, Nthusi J, et al.
Comparison of first-line tuberculosis treatment outcomes between previously treated and new patients: A retrospective study in Machakos subcounty, Kenya. Int Health 2021;13:272-80.
Trébucq A, Decroo T, Van Deun A, Piubello A, Chiang CY, Koura KG, et al.
Short-course regimen for multidrug-resistant tuberculosis: A decade of evidence. J Clin Med 2019;9:E55.
Nunn AJ, Phillips PP, Meredith SK, Chiang CY, Conradie F, Dalai D, et al.
A trial of a shorter regimen for rifampin-resistant tuberculosis. N Engl J Med 2019;380:1201-13.
Mesic A, Khan WH, Lenglet A, Lynen L, Ishaq S, Phyu EH, et al.
Translating drug resistant tuberculosis treatment guidelines to reality in war-torn Kandahar, Afghanistan: A retrospective cohort study. PLoS One 2020;15:e0237787.
Gualano G, Mencarini P, Musso M, Mosti S, Santangelo L, Murachelli S, et al
. Putting in harm to cure: Drug related adverse events do not affect outcome of patients receiving treatment for multidrug-resistant Tuberculosis. Experience from a tertiary hospital in Italy. PLoS One 2019;14:e0212948.
Ajema D, Shibru T, Endalew T, Gebeyehu S. Level of and associated factors for non-adherence to anti-tuberculosis treatment among tuberculosis patients in Gamo Gofa zone, southern Ethiopia: Cross-sectional study. BMC Public Health 2020;20:1705.
Xing W, Zhang R, Jiang W, Zhang T, Pender M, Zhou J, et al.
Adherence to multidrug resistant tuberculosis treatment and case management in Chongqing, China-A mixed method research study. Infect Drug Resist 2021;14:999-1012.
Deshmukh RD, Dhande DJ, Sachdeva KS, Sreenivas A, Kumar AM, Satyanarayana S, et al.
Patient and provider reported reasons for lost to follow up in MDRTB treatment: A qualitative study from a drug resistant TB centre in India. PLoS One 2015;10:e0135802.
Soedarsono S, Mertaniasih NM, Kusmiati T, Permatasari A, Juliasih NN, Hadi C, et al
. Determinant factors for loss to follow-up in drug-resistant tuberculosis patients: The importance of psycho-social and economic aspects. BMC Pulm Med 2021;21:360.
Bastos ML, Lan Z, Menzies D. An updated systematic review and meta-analysis for treatment of multidrug-resistant tuberculosis. Eur Respir J 2017;49:1600803.
[Table 1], [Table 2], [Table 3], [Table 4]