Predictors of mortality and loss to follow-up among drug resistant tuberculosis patients in Oromia Hospitals, Ethiopia: A retrospective follow-up study.

BACKGROUND: Drug resistance tuberculosis (DR-TB) patients' mortality and loss to follow-up (LTF) from treatment and care is a growing worry in Ethiopia. However, little is known about predictors of mortality and LTF among drug-resistant tuberculosis patients in Oromia region, Ethiopia. The current study aimed to identify predictors of mortality and loss to follow-up among drug resistance tuberculosis patients in Oromia Hospitals, Ethiopia.
METHODS: A retrospective follow up study was carried out from 01 November 2012 to 31 December 2017 among DR-TB patients after calculating sample size using single proportion population formula. Mean, median, Frequency tables and bar charts were used to describe patients' characteristics in the cohort. The Kaplan-Meier curve was used to estimate the probability of death and LTF after the treatment was initiated. The log-rank test was used to compare time to death and time to LTF. The Cox proportional hazard model was used to determine predictors of mortality and LTF after DR-TB diagnosis. The Crude and adjusted Cox proportional hazard ratio was used to measure the strength of association whereas p-value less than 0.05 were used to declare statistically significant predictors. RESULT: A total of 406 DR-TB patients were followed for 7084 person-months observations. Among the patients, 71 (17.5%) died and 32 (7.9%) were lost to follow up (LTF). The incidence density of death and LTF in the cohort was 9.8 and 4.5 per 1000 person-months, respectively. The median age of the study participants was 28 years (IQR: 27.1, 29.1). The overall cumulative survival probability of patients at the end of 24 months was 77.5% and 84.5% for the mortality and LTF, respectively. The independent predictors of death was chest radiographic findings (AHR = 0.37, 95% CI: 0.17-0.79) and HIV serostatus 2.98 (95% CI: 1.72-5.19). Drug adverse effect (AHR = 6.1; 95% CI: 2.5, 14.34) and culture test result (AHR = 0.1; 95% CI: 0.1, 0.3) were independent predictors of LTF.
CONCLUSION: This study concluded that drug-resistant tuberculosis mortality and LTF remains high in the study area. Continual support of the integration of TB/HIV service with emphasis and work to identified predictors may help in reducing drug-resistant tuberculosis mortality and LTF.

Background

Drug resistant tuberculosis (DR-TB) is defined as resistance to any anti-TB drugs. Extensively drug-resistant tuberculosis (XDR-TB) is a subset of DR-TB with additional resistance to a fluoroquinolone and a second-line injectable agent [1].

According to the WHO, there were an estimated 484000 incident cases of DR/RR-TB in the year 2018 worldwide. Globally in 2018, an estimated 3.4% of new cases and 18% of previously treated cases had DR/RR-TB. A global total of 206,030 people with drug- or rifampicin-resistant TB (DR/RR-TB) were detected and notified in 2019, a 10% increase from 186,883 in 2018 [2,3].

The WHO estimates that about 5% of all TB cases progress to DR-TB, from which more than 40% died in 2013. Treating DR- TB and XDR-TB is particularly difficult even in resource-rich countries because the required long term treatment, a minimum of 18–24 months with second-line TB drugs, has significant adverse effects [4].

Drug resistant tuberculosis surveys in 2005 and 2014 and the 2018 WHO TB report in Ethiopia showed that the prevalence of DR-TB respectively, was 1.6%, 2.3%, and 2.7% among new and 11.8%, 17.8%, and 14% among previously treated TB cases [5-7].

Tuberculosis programmes have reported the LTF of two or more consecutive months to contribute to the poor levels of treatment success in DR-TB [5]. Although DR-TB treatment lasting for 20–24 months has shown to achieve a success rate of 50% of patients worldwide, recent advances show that a short course treatment regimen achieves high treatment success [3].

The 2020 WHO report [3] showed 0.71% and 12% respectively, as proportions of new cases and previously treated cases with DR/RR-TB in Ethiopia, making Ethiopia one among the countries with poorest treatment success rate when compared to other member states. Factors including LTF and poor adherence to treatment were reported to contributing to poor treatment outcome in some countries [3].

The Ethiopian Federal Ministry of Health adopted a two armed standardized regimen consisting of an 8-month intensive phase and a 12-month continuation phase. However, few observational studies have been conducted and reveal poor treatment outcomes including loss to follow-up among DR-TB patients [6]. Both patient- and regimen-related factors were associated with loss to follow-up, important information which may guide interventions to improve treatment adherence, particularly in the first 11 months [8]. Studies have also shown that, similar to what happens with drug-susceptible TB patients, the LTF is one of the main problems in the treatment of DR-TB. In a study conducted in Brazil, identified number of determinants to loss to follow-up such as drug toxicity, long duration of treatment, and other social determinants [9].

Previous studies have shown that predictors of DR-TB mortality are: immune-suppression, tuberculosis related complications, malnutrition, HIV/AIDS, smoking cigarette, LTF, tuberculosis treatment history, and diabetes mellitus, for which, some are determined by patients’ social-demographic, behavioural and lifestyle factors [10-12]. As far as is known to us, only one report has been published in Ethiopia to assess risks for mortality among DR-TB patients [13,14].

Limited studies conducted in Ethiopia showed lost to follow-up among DR-TB registered patients for treatment was high in the first 6 months compared to later follow-up months [12], and the incidence of mortality was 7.42/100 person-years follow-up during treatment and most patients died early on the initiation of treatment [15].

Therefore, the current study aimed to assess predictors, time to mortality and loss to follow-up among patients infected with drug resistance tuberculosis in Ethiopia.

Methods

Study design and study area

A retrospective follow up study was carried out from 01 November 2012 to 31 December 2017 among DR-TB patients in hospitals of Oromia regional state, Ethiopia where high prevalence of TB has been reported to be as high as 21.3%. Included hospitals were Metu Karl, Shanen Gibe, Bishoftu, Shashemene, Adama, Chiro, Deder and Nekemt. The 2016 WHO global report puts Ethiopia among countries with high burden of DR-TB, with more than 3,300 cases estimated annually. In 2016, it was estimated that 2.7% (1.5–4.0 of newly notified and 14% (3.6–25) of previously treated TB patients had DR-TB [16].

Study population and inclusion criteria

The study population involved all DR-TB patients with complete chart, aged 18 years and above enrolled into the adult Tuberculosis clinics in the Oromia Hospitals from 01 November 2012 to 31 December 2017. The period was selected in order to have the nearest five year follow up study period and it was also the period when hospitals in Oromia started the full implementation of standardized formats, documentation and recording systems in a regular manner.

Sample size determination

The sample size was calculated using single population proportion formula after considering the following assumptions: 50% proportion, 95% confidence level (Zα/2 = 1.96), 5% margin of error (d). The final sample size was 423 but the registered DR-TB patients at the study period was 497 and 91 patient charts were incomplete. Hence, we have included 406 patient charts.

Data collection tools and procedures

Data were extracted by using a structured format that was developed from the standard treatment protocol for DR-TB treatment. The checklist sought from individual records, information on patient-related data (Socio demographic characteristics), clinical characteristic, comorbidities, treatment and others.

Selected nurses who worked in TB clinics extracted all DR-TB patients’ data retrospectively (including date of death and LTF) from the hospitals’ registration log books during January 1–30, 2018. Trained data collectors assessed the data quality using a pre-tested data collection tool, and two public health professionals provided continuous supervision and monitoring. Supervisors, data clerks and investigators checked the completeness and consistency of data before and after data entry.

Data analysis

Data were entered into EPI data (version 4.6.0.0) and the analysis was conducted using Statistical package for Social Science (SPSS version 20.0) and Stata (version 14.0). Data were cleaned to remove irrelevant observations before analyses were performed. Median, mean and frequencies (as percentages) were used to describe patients’ characteristics in each cohort. The response variable was survival time, defined as “time in months transpired from the date of initial DR-TB treatment to death/LTF” or, in the case of individuals who did not die/not LTF (censored), “the time in months transpired to LTF. The Kaplan-Meier curve was used to estimate the probability of death and LTF and the median time to death and LTF after the initiation of the DR-TB treatment. The log-rank test was used to compare time to death and LTF between the two groups. The Cox proportional hazard model was used to determine predictors of death and LTF after DR-TB diagnosis. All statistically significant (p < 0.05) variables in the multivariate proportional hazard cox regression model were considered as predictors for mortality and LTF. The crude and adjusted hazard ratio (HR) and its 95% confidence interval (CI) were estimated.

Ethical issues

Ethical approval was obtained from the Review Ethics Committee of the School of Health Science at Madda Walabu University. The data were fully anonymized and name and identifications were not extracted. To preserve patient confidentiality, the identified patients’ data were extracted from medical charts by nurses working in the respective TB clinic.

Result

Socio demographic characteristics

A total of 497 DR-TB patients were registered during the study period. Ninety one (91) patients were excluded due to missing charts, incomplete baseline and follow-up data. The median age of the included participants (406), the median age was 28 (IQR: 27.1, 29) years, and 147 (36.2%) individuals aged between 25–30 years old, made the largest group of participants. Two hundred and thirty nine (58.9%) were males and 41.1% were females. Among males, 41 died and 20 were LTF and individual aged 41 and above years old, recorded the highest death rate (Table 1).

Table 1

Socio-demographic characteristics of drug resistance tuberculosis infected patents in Oromia region, Ethiopia, 2020.

Variables		Number (406)	Mortality		LTF
			Event (n = 71)	Censored (n = 335)	Event (n = 32)	Censored(n = 374)
Gender	Male	239 (58.9)	41	198	20	219
	Female	167 (41.1)	30	137	12	155
Address	Urban	261 (64.3)	52	209	18	243
	Rural	145 (35.7)	19	126	14	131
Age	19–24	117 (28.8)	15	102	14	103
	25–30	147 (36.2)	19	128	7	140
	31–40	79 (19.2)	55	55	7	72
	≥41	63 (15.5)	50	50	4	59

Clinical characteristics of the study participants

Almost all study participants had a diagnosis of pulmonary TBs 397 (97.8%), of which 71 died and 31 were LTF. About 2/3 of DR-TB patients had only rifampicin resistance 260 (64%), of whom 46 died and 23 were LTF. Almost all patients (99.8%), had treatment initiated after the confirmation of TB. Among HIV tested patents, 77 (19.1%) were positive for HIV of which 31 died and 4 were LTF. One tenth 41 (10.1%) of DR-TB patents had comorbidity, of whom 25 died and 7 were LTF. Forty nine (12.1%) DR-TB had unilateral lung cavity, of whom 12 died and 3 were LTF. About 11 (2.7%) patients had any type of addiction, of which 2.8% and 3.1% patients died and LTF respectively. At the beginning of treatment, the majority of patents had BMI ≤ 18 and after treatment a similar number of patients had BMI ≥ 18 (359 (88.4%) and 362 (89.2%) respectively) (Table 2).

Table 2

Clinical characteristics of drug resistance tuberculosis infected patents in Oromia region, Ethiopia, 2020.

Variables		Number (406)	Mortality		LTF
			Event (n = 71)	Censored (n = 335)	Event (n = 32)	Censored (n = 374)
Site of TB infection	Pulmonary	397 (97.8%)	71	326	31	366
	Extra pulmonary	9 (2.2%)	0	9	1	8
Type of resistance	RR-Rifampicin	260 (64%)	46	214	23	237
	M-MDR	143(35.2%)	24	119	135	8
	X-XDR	3 (0.7%)	1	2	2	1
Smear result at zero month	Positive	276 (68%)	46	230	16	260
	Negative	62 (15.3%)	6	56	10	52
	Not done/result not available	68 (16.7%)	19	49	6	62
Culture result at start	Positive	252 (62.1%)	34	218	19	233
	Negative	40 (9.9%)	2	38	3	37
	Not done/result not available	114 (28.1%)	35	79	10	104
Culture result at the end of treatment	Positive	18 (4.4%)	7	11	3	15
	Negative	322 (79.3%)	30	292	15	307
	Not done/result not available	66 (16.3%)	34	32	14	52
Smear result at the end of treatment	Positive	14 (3.4%)	7	7	2	12
	Negative	339(83%)	35	304	20	319
	Not done/result not available	53 (13.1%)	29	24	10	43
Diagnostic method	Xpert/MTB/TB/RIF	316 (77.8%)	61	255	20	296
	LPA	68 (16.7%)	9	59	8	60
	Culture	3 (0.7%)	0	3	0	3
	Others	19 (4.7%)	1	18	4	15
Reason for entering MDR treatment	Bacteriological confirmed	405 (99.8%)	71	334	32	373
	Clinically diagnosed	1 (0.2%)	0	1	0	1
HIV tested	Yes	402(99%)	70	332	32	370
	No	2(4%)	1	3	0	4
HIV test result	Reactive	77 (19.1%)	31	46	4	73
	None reactive	326 (80.9%)	39	287	28	298
ART started	Yes	30(98.8%)	30	45	3	72
	No	1(3.2%)	1	1	1	1
Co-infections	Yes	41 (10.1%)	16	25	7	34
	No	365 (89.9%)	55	310	25	340
Chronic diseases	Yes	12 (3%)	4	8	2	10
	No	394 (97%)	67	327	30	364
Drug Adverse effect	Yes	40 (9.9%)	5	35	9	31
	No	366 (90.1%)	66	300	23	343
Treatment regimen	Standard	401 (98.9%)	70	331	31	370
	Individualized	5 (1.2%)	1	4	1	4
Steroid use	Yes	8 (2%)	2	6	0	8
	No	140 (34.5%)	24	116	6	134
	Unknown	258 (63.5%)	45	213	26	232
Chest radiographic finding	Unilateral Cavity	49 (12.1%)	12	37	3	46
	Bilateral Cavity	28 (6.9%)	9	19	4	24
	Abnormality without cavity	128 (31.5%)	11	117	7	121
	Massive effusion	24 (5.9%)	6	18	3	21
	Others	177 (43.6%)	33	144	15	162
Any type of addiction	Yes	11 (2.7%)	2	9	1	10
	No	395 (97.3%)	69	326	31	364
BMI at start of treatment	18	359 (88.4%)	67	292	30	329
	>18	47 (11.6%)	4	43	2	45
BMI at end of treatment	= <18	44 (10.8%)	10	34	4	40
	>18	362 (89.2%)	61	301	28	334

Magnitude and time to mortality and loss to follow up

Of the 406 study participants, 275 (67.7%) were cured, 71(17.5%) died, 32 (7.9%) LTF and the treatment failed in 13 (3.2%). (Fig 1) The incidence density of death in the cohort was 9.8 per 1000 person-months. The incidence density of loss to follow up in the cohort was 4.5 per 1000 person-months.

Fig 1

Treatment outcomes of drug resistance tuberculosis infected patents in Oromia region, Ethiopia, 2020.

Survival probability of DR-TB patients for mortality

A total of 406 DR-TB patients were followed for a minimum of 1 month and for a maximum of 24 months with mean follow up period of 21 months (CI: 20.4, 21.7) and contributed 7084 person months observations. The cumulative survival probability of patients at the end of 9 months was 87.4%, at the end of 19 months was 83.3%, and at the end of 24 months was 77.5% (Fig 2). For loss to follow-up, they had follow up for a minimum of one months and maximum of 23 months on follow up with mean follow up period of 22 months. The cumulative survival probability of patients at the end of 8 months was 96.5%, at the end of 19 months was 94.3%, and at the end of 24 months was 84.5% (Fig 3). Kaplan-Meier analysis revealed that LTF was higher in patients who were HIV-infected compared to non-infected (Fig 4). Additionally, patients with co infection had lower survival probability than their counterparts (Fig 5).

Fig 2

Kaplan–Meier survival estimate for mortality of drug resistance tuberculosis infected patents in Oromia region, Ethiopia, 2020.

Fig 3

Kaplan–Meier survival estimate for loss to follow up of drug resistance tuberculosis infected patents in Oromia region, Ethiopia, 2020.

Fig 4

Kaplan–Meier survival estimate for LTF of drug resistance tuberculosis infected patents for HIV reactive and non-reactive patients in Oromia region, Ethiopia, 2020.

Fig 5

Kaplan–Meier survival estimate for mortality of drug resistance tuberculosis infected patents for patients with co morbidity and without co morbidity in Oromia region, Ethiopia, 2020.

Predictors of time to mortality and loss to follow up

According to multivariate Cox proportional hazard regression analysis model, two variables were found to be independent predictors for the mortality during the DR-TB patients’ treatment, include chest radiographic finding and HIV sero status. The risk of death decreased by 63% in patients with normal chest radiographic finding compared to chest radiographic with massive effusion (AHR = 0.37, 95% CI: 0.17–0.79). With regards to HIV sero status, HIV positive DR-TB patients had three times higher risk of death compared to their counterpart, 2.98 (95% CI: 1.72–5.19) (Table 3). Patients who had drug adverse effect were six times at higher risk of LTF compared to patients who had no adverse drug effect (AHR = 6.1; 95% CI = 2.5, 14.34). Moreover, those who had negative culture result were 90% less likely to record LTF compared to patients had no culture done [AHR = 0.1; 95% CI: 0.1, 0.3] (Table 4).

Table 3

Predictors of mortality among drug resistance tuberculosis infected patents in Oromia region, Ethiopia, 2020.

Variables		No. at risk	No. of death	CHR (95% CI)	AHR (95% CI)
Address	Urban	261	52	1.5(0.1, 2.6)	1.06(0.62, 1.83)
	Rural	145	19	1	1
HIV sero status	Positive	2	1	3.9(2.4, 6.2)	2.98(1.72, 5.19)*
	Negative	402	70	1	1
Confection	Yes	41	16	2.9(1.7, 5.2)	1.616(0.82, 3.20)
	No	365	55	1	1
Chronic diseases	Yes	12	4	1.9 (0.7, 5.3)	2.57(0.88, 7.51)
	No	394	67	1	1
Drug adverse effect	Yes	40	5	0.7(0.3, 1.7)	0.65(0.26, 1.65)
	No	366	66	1	1
Chest radiographic finding	Massive effusion	49	12	1	1
	Bilateral Cavity	28	9	1.3(0.7, 2.5)	1.60(0.79, 3.24)
	Abnormality without cavity	128	11	1.9(0.9, 3.9)	2.09(0.95, 4.66)
	Normal	24	6	0.4(0.2, 0.8)	0.37(0.17, 0.79)*
	Unilateral Cavity	177	33	1.3(0.6, 3.2)	1.10 (0.44, 2.76)
BMI at start of treatment	= <18	44	10	2.5(0.9, 6.9)	1.7(0.83, 3.51)
	>18	362	61	1	1
BMI at end of treatment	= <18	359	67	1.3(0.7, 2.6)	1.88(0.65, 5.49)
	>18	47	4	1	1

Notes:

*Significant at p<0.05.

Table 4

Predictors of LTF among drug resistance tuberculosis infected patents in Oromia region, Ethiopia, 2020.

Variable		No. at risk	No. of LTF	CHR (95% CI)	AHR (95% CI)
Address	Urban	261	18	0.6 (0.3, 1.2)	0.5 (0.3, 1.2)
	Rural	145	14	1	1
Confection	Yes	41	7	3.1(1.3, 7.1)	1.6 (0.6, 3.8)
	No	365	25	1	1
Drug A/E	Yes	40	9	4.1(1.9, 8.8)	6.1 (2.5, 14.34)*
	No	366	23	1	1
Steroid use	Yes	8	0
	No	140	6
	Unknown	258	26
BMI at start	= <18	44	30	2.8(0.7, 11.8)	1.5 (0.3, 6.7)
	>18	362	2	1	1
Sex	Male	239	20	1.2(0.6, 2.5)	1.5 (0.6, 3.2)
	Female	167	12	1	1
Culture at end	Positive	18	3	0.6(0.2, 1.9)	1.0 (0.3, 3.9)
	Negative	322	15	0.13(0.06, 0.28)	0.1 (0.1, 0.3)
	Not done/result not available	66	14	1	1

Notes:

*Significant at p<0.05.

Discussion

This study was designed to assess the incidence rate and to identify the predictors of mortality and lost to follow-up among DR-TB patients attending their treatment at the Oromia Hospitals, Ethiopia. A total of 406 DR-TB patients were followed and produced 7084 person-months observations and 71 (17.5%) died. This finding was higher than a study conducted in Dangila and agreed with a systematic review and meta-analysis conducted in Ethiopia [17,18].

The patients who were LTF would have not completed their treatment regime, resulting in serious public health problems because these patients are at higher risk of extra DR-TB and transmission to the community [19]. In this study, 32 (7.9%) for DR-TB treatment enrolled patents were LTF. Similar high rate of LTF among DR-TB patients has been demonstrated in a systematic review and other studies conducted in China, Pakistan, and Brazil [20-23], together illustrating the immense challenges in achieving completion of currently recommended treatment regimens for DR-TB. In this study LTF rate was also substantially higher than the WHO recommended target of 5% [24], which implies the need to demand for more comprehensive approaches to reduce LTF among DR-TB patients by targeting those risk factors for treatment interruptions.

The incidence density of LTF in the current study cohort was 4.5 per 1000 person-months. This finding was lower than a study conducted in Northern part of Ethiopia and higher than a study conducted in St. Peter’s specialized Tuberculosis treatment hospital in Ethiopia [13,25]. We hypothesise that this variation could possibly be due to differences, including in the sample size, study population, treatment guideline, and regimens.

The incidence density of death in the cohort was 9.8 per 1000 person-months. This finding was higher than a study conducted in Amhara region as well as a study conducted in nationwide in Ethiopia [12,26]. The possible explanation for this might be due to the difference in the follow-up periods, because the longer follow up periods have the probability of decreasing the occurrence of events.

The risk of death decreased by 63% in patients with normal chest radiographic findings compered to chest radiographic finding with massive effusion. This finding was consistent with previous studies conducted in Tanzania and central Ethiopia [15,27]. The lower respiratory tract infections are known to have consequences including the accumulation of inflammatory exudate in the alveoli, resulting in reduced oxygen exchange and respiratory insufficiency, and the DR-TB patients with clinical complications experience longer recovery times and poor response to anti TB-medications [28,29].

In this study, HIV positive DR-TB patients had 2.98 times higher risk of death compared to the HIV negative DR-TB, findings which are consistent with studies conducted in other sites including: Amhara region, Dangila, St. Peter’s specialized Tuberculosis hospital in Ethiopia, eastern and central Africa, and in Ethiopia, Eastern Europe, Brazil, Peru, Nigeria [12,17,25,26,30-34]. The high mortality rate of DR-TB patients among HIV positive participants might be due to the synergistic effects of the two co-infections, i.e. HIV and DR-TB. Because DR-TB patients receive treatment for a minimum of two years, they might experience serious drug adverse effects and toxicities due to the high burden of pills, which may result in poor adherence to treatment and poorer overall patients’ poor outcome. Coupled with the known higher rate of smear negative in HIV positive patients, the diagnosis of DR-TB in HIV positive patients is said to difficult as may be confused with other pulmonary or systemic infections. These interactions, can result in misdiagnosis or delays in a diagnosis and leading to higher morbidity and mortality [35,36].

Patients who had drug adverse effect were six times higher risk of LTF compared to patients who had no adverse drug effect. This finding was consistent with studies that were conducted in the Philippines, Pakistan, Tajikistan, Georgia, and a systematic review and Meta-analysis [8,21,37-39]. These findings support the knowledge that an association exists between LTF and individuals taking DR-TB drugs since second line drugs are more toxic and more likely to cause severe side effects.

Drug resistance Tuberculosis patients who had negative culture result at the end of initiation phase were 90% less likely to be LTF compared to patients who had no culture undertaken. This seems to be promising result as at the end of initiation phase could motivate patients to finish treatment, and thus a possibility of positive outcome.

Limitations of the study

As a limitation, this study did not considered some predictors such as viral load, liver function and renal function tests because it was conducted using secondary data that have missing records. Additionally, there could also be underestimation of the mortality incidence rate and LTF due to record problems.

Conclusion and recommendation

Our findings point to some risk factors related to mortality and loss to follow-up, which are public health problems that contribute to worsening DR-TB treatment. It is important for TB control programs and health professionals to identify predictors in patients with increased risk of loss to follow-up and to adopt specific strategies to address this problem and prevent death. Continual support of the integration of TB/HIV service with emphasis and further work on identified predictors may help in reducing DR-TB mortality and LTF.

Available data for predictors of mortality and loss to follow-up among drug resistant tuberculosis patients in Oromia Hospitals, Ethiopia.

(SAV)

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17 Mar 2021

PONE-D-21-04578

Predictors of Mortality and Loss to Follow-up among Drug Resistant Tuberculosis Patients in Ethiopia: A Retrospective Follow-up Study

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4. In the ethics statement in the manuscript and in the online submission form, please provide additional information about the patient records used in your retrospective study, including: a) whether all data were fully anonymized before you accessed them; b) the date range (month and year) during which patients' medical records were accessed; c) the date range (month and year) during which patients whose medical records were selected for this study sought treatment. If the ethics committee waived the need for informed consent, or patients provided informed written consent to have data from their medical records used in research, please include this information.

5. You indicated that you had ethical approval for your study. In your Methods section, please ensure you have also stated whether you obtained consent from parents or guardians of the minors included in the study or whether the research ethics committee or IRB specifically waived the need for their consent.

6.Thank you for submitting the above manuscript to PLOS ONE. During our internal evaluation of the manuscript, we found some minor occurrences of overlapping text with the following previous publication(s), some of which you are an author, which needs to be addressed:

- https://doi.org/10.1590/0102-311X00048217

- https://doi.org/10.1186/1471-2334-13-297

We would like to make you aware that copying extracts from previous publications word-for-word, especially outside the methods section, is unacceptable. In addition, the reproduction of text from published reports has implications for the copyright that may apply to the publications.

Please revise the manuscript to quote or rephrase the duplicated text and cite your sources for text outside the methods section. Please note that further consideration is dependent on the submission of a manuscript that addresses these concerns about the overlap in text with published work.

Additional Editor Comments:

dear Auhtors follow reviewer suggestions to improve your paper

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This paper evaluated the incidence and predictors of mortality and lost to follow-up among Rifampin resistant TB patients in a state of Ethiopia. RR/MDR-TB is a major public health problem all over the world. The authors presented us the severity and poor outcome of RR/MDR-TB in Oromia regional state of Ethiopia which is common in many high burden countries. The article could help the readers to update the factors for the treatment outcome in this country. However, there some questions need to be addressed for this paper.

1. The definition for DR-TB was not correctly described in the background. Drug resistant tuberculosis (DR-TB) was referred to resistance to any anti-TB drugs, and resistance to at least Isoniazid (H) and rifampin(R) was defined as MDR-TB according to WHO. The definition needs to be clear for the entire study.

2. The study was only conducted in in a state of Ethiopia, thus cannot represent the whole country of Ethiopia. The title and conclusion of the article should be more precisely set and described.

3. Although the study had been approved by the ethics committee, it had used the patient retrospective data which the patient consent exempt is also needed for the study. Was it also approved by the committee?

4. According to the study, 91 patients were excluded due to missing charts, incomplete baseline and follow-up data. How many patients among these excluded group died or LTF? Because the poor outcome could also cause the missing of data.

5. Page 8, line 5, there was a mistake of “of which 7 died…”. It should be 71 died.

Reviewer #2: I read with great interest this paper.Demelash Woldeyohannes and colleague wrote on important global health problem: Predictors of Mortality and Loss to Follow-up among Drug Resistant Tuberculosis in high burden setting.

Below my suggestions:

1. Introduction: well that article show data on TB global burden data of TB Report 2020. Add the role of social determinants of health in worst outcome of TB, therapy failure and onset on TB MDR (see and cite Social determinants of therapy failure and multi drug resistance among people with tuberculosis: A review. Tuberculosis (Edinb). 2017 Mar;103:44-51. doi: 10.1016/j.tube.2017.01.002.2. Methods: clear. Correct tuberculosis in TB or Tuberculosis.

3. Results: no suggestions

4. Discussion: discuss better the role of age (Active Pulmonary Tuberculosis in Elderly Patients: A 2016-2019 Retrospective Analysis from an Italian Referral Hospital. Antibiotics (Basel) in worse outcome and onset adverse events and how they need more medical attention and the role of comorbidity exspecially diabetes (Diabetes in active tuberculosis in low-income countries: to test or to take care? Lancet Glob Health. 2019 Jun;7(6):e707. doi: 10.1016/S2214-109X(19)30173-1. PMID: 31097272.). In fact, Many factors contribute to the lack of efficacy in contain- ing TB, as social determinants of health (SDH) and con- comitance of other co-morbidities, such as co-infections (in particular with HIV) and non-communicable diseases, such as diabetes mellitus (DM). Furthermore, TB and DM remain serious public health problems particularly in low‐ and middle‐income countries. The coexistence of these two conditions is an example of a bidirectional association between a communicable and non‐communicable disease that increases the dual burden of DM and TB(see and cite Pizzol D, et al. Prevalence of diabetes mellitus in newly diagnosed pulmonary tuberculosis in Beira, Mozambique. Afr Health Sci. 2017 Sep;17(3):773-779. )

Compare better your data with other data from low income country anger high burden of Tb (es Mozambique) (Predictors of therapy failure in newly diagnosed pulmonary tuberculosis cases in Beira, Mozambique. BMC Res Notes. 2018 Feb 5;11(1):99. doi: 10.1186/s13104-018-3209-9. PMID: 29402317; PMCID: PMC5800087)

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: Yes: Francesco Di Gennaro

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

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12 Apr 2021

Responses for the comments from reviewers

We are very grateful to the editor and reviewers for their valuable comments and we believe that the revised manuscript is much stronger as a result of their feedback.

Dear Editor and reviewers:

Thank you for the opportunity to revise our manuscript “Predictors of Mortality and Loss to Follow-up among Drug Resistant Tuberculosis Patients in Ethiopia: A Retrospective Follow-up Study” (PONE-D-21-04578) for publication by PLOS ONE.

We have addressed the Editors’ and reviewers’ comments in our responses and incorporated related changes into the manuscript. For convenience, the reviewers’ comments are in black and our responses are in blue.

The primary changes made to the study include: Editing of the manuscript to improve clarity and consistency

Additional requirements

1. Please ensure that your manuscript meets PLOS ONE's style requirements

Response: Thank you very much for reminding us to stick on the guideline, the revised manuscript meets PLOS ONE's style requirements

2. Regarding data availability

Response: Thank you very much for flagging this point, all data are fully available without restriction

3. Regarding financial disclosure

Response: “The authors received no specific funding for this work.”

4. Regarding ethics statement

Response: We have addressed the revised point regarding the ethics statement in the revised manuscript and cover letter.

5. Please ensure you have also stated whether you obtained consent from parents or guardians of the minors included in the study or whether the research ethics committee or IRB specifically waived the need for their consent.

Response: This study didn’t included the minors

6. Minor occurrences of overlapping text with the following previous publication:

Response: We are grateful to the editor comments; we have paraphrased the overlapping statements

Reviewer #1:

1.1. The definition for DR-TB was not correctly described in the background. Drug resistant tuberculosis (DR-TB) was referred to resistance to any anti-TB drugs, and resistance to at least Isoniazid (H) and rifampin(R) was defined as MDR-TB according to WHO. The definition needs to be clear for the entire study.

Response: We are grateful to the reviewer comments; we made a correction in background of the study

1.2. The study was only conducted in in a state of Ethiopia, thus cannot represent the whole country of Ethiopia. The title and conclusion of the article should be more precisely set and described.

Response: We thank the reviewer for catching this. We made correction on the title of the study

1.3. Although the study had been approved by the ethics committee, it had used the patient retrospective data which the patient consent exempt is also needed for the study. Was it also approved by the committee?

Response: Yes, the ethical approval was received after the considering these issues

1.4. According to the study, 91 patients were excluded due to missing charts, incomplete baseline and follow-up data. How many patients among these excluded group died or LTF? Because the poor outcome could also cause the missing of data.

Response: Thank you very much, 91 patent (missing) charts not included outcomes

1.5. Page 8, line 5, there was a mistake of “of which 7 died…”. It should be 71 died.

Response: Thank you for flagging this, we effected in the manuscript (Result section, line 5, page 8)

Reviewer #2

2.1. Introduction: well that article show data on TB global burden data of TB Report 2020. Add the role of social determinants of health in worst outcome of TB, therapy failure and onset on TB MDR (see and cite Social determinants of therapy failure and multi drug resistance among people with tuberculosis: A review. Tuberculosis (Edinb). 2017 Mar;103:44-51. doi: 10.1016/j.tube.2017.01.002.2.

Response: We are grateful to the Reviewer for this comments, we have considered the factors and cited manuscript

2.2. Methods: clear. Correct tuberculosis in TB or Tuberculosis.

Response: We thank the reviewer for catching this. We made correction in the whole document

2.3. Results: no suggestions

2.4. Discussion: discuss better the role of age (Active Pulmonary Tuberculosis in Elderly Patients: A 2016-2019 Retrospective Analysis from an Italian Referral Hospital. Antibiotics (Basel) in worse outcome and onset adverse events and how they need more medical attention and the role of comorbidity exspecially diabetes (Diabetes in active tuberculosis in low-income countries: to test or to take care? Lancet Glob Health. 2019 Jun;7(6):e707. doi: 10.1016/S2214-109X(19)30173-1. PMID: 31097272.). In fact, Many factors contribute to the lack of efficacy in contain- ing TB, as social determinants of health (SDH) and con- comitance of other co-morbidities, such as co-infections (in particular with HIV) and non-communicable diseases, such as diabetes mellitus (DM). Furthermore, TB and DM remain serious public health problems particularly in low‐ and middle‐income countries. The coexistence of these two conditions is an example of a bidirectional association between a communicable and non‐communicable disease that increases the dual burden of DM and TB (see and cite Pizzol D, et al. Prevalence of diabetes mellitus in newly diagnosed pulmonary tuberculosis in Beira, Mozambique. Afr Health Sci. 2017 Sep;17(3):773-779.)

Response: We are grateful to the reviewer comments; our study included co infection such as HIV but it didn’t included non-communicable disease specifically diabetes mellitus and role of age. We take these concerns as the limitations of the study.

2.5. Compare better your data with other data from low income country anger high burden of Tb (es Mozambique) (Predictors of therapy failure in newly diagnosed pulmonary tuberculosis cases in Beira, Mozambique. BMC Res Notes. 2018 Feb 5;11(1):99. doi: 10.1186/s13104-018-3209-9. PMID: 29402317; PMCID: PMC5800087)

Response: Thank you very much for flagging this. The outcome variable for the study conducted in Zimbabwe was therapy failure our study outcome variable were mortality and Loss to follow up, hence we unable to compare and contrast with our study findings.

Please contact me again if additional information and editing required

Kind regards,

Demelash Woldeyohannes

The second Responses for the comments from editor and reviewers

We are very grateful to the editor and reviewers for their valuable comments and we believe that the revised manuscript is much stronger as a result of their feedback.

Dear Editor and reviewers:

Thank you for the opportunity to revise our manuscript “Predictors of Mortality and Loss to Follow-up among Drug Resistant Tuberculosis Patients in Oromia Hospitals, Ethiopia: A Retrospective Follow-up Study” (PONE-D-21-04578R1) for publication by PLOS ONE.

We have addressed the Editors’ and reviewers’ comments in our responses and incorporated related changes into the manuscript. For convenience, the reviewers’ comments are in black and our responses are in blue.

The primary changes made to the study include: Editing of the manuscript to improve clarity and consistency

1. According to Table 1, the study included data from minors (age <18). In your Methods section, please ensure you have also stated whether you obtained consent from parents or guardians of the minors included in the study or whether the research ethics committee or IRB specifically waived the need for parental consent.

Responses: Thank very much for flagging this: Under age 18 study participants were included due to editorial problem. They are under age category of 19 to 24.

2. Please amend the title either on the online submission form or in your manuscript so that they are identical.

Responses: We made correction

3. Please ensure that you refer to Figure 2 and Figure 3 in your text as, if accepted, production will need this reference to link the reader to the figures.

Responses: We made correction

4. Please upload a copy of Supporting Information Table S1 - S4 which you refer to in your text.

Responses: We made correction

5. Thank you for updating your data availability statement. You note that your data are available within the Supporting Information files, but no such files have been included with your submission. At this time we ask that you please upload your minimal data set as a Supporting Information file, or to a public repository such as Figshare or Dryad. Please also ensure that when you upload your file you include separate captions for your supplementary files at the end of your manuscript.

Responses: We have uploaded as supplementary file

Submitted filename: Responses to reviewers 2.docx

Click here for additional data file.

14 Apr 2021

Predictors of Mortality and Loss to Follow-up among Drug Resistant Tuberculosis Patients in Oromia Hospitals, Ethiopia: A Retrospective Follow-up Study

PONE-D-21-04578R1

Dear Dr. Demelash Woldeyohannes,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Claudia Marotta

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

congratulations

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

Reviewer #2: (No Response)

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

19 Apr 2021

PONE-D-21-04578R1

Predictors of Mortality and Loss to Follow-up among Drug Resistant Tuberculosis Patients in Oromia Hospitals, Ethiopia: A Retrospective Follow-up Study

Dear Dr. Woldeyohannes:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

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on behalf of

Dr. Claudia Marotta

Academic Editor

PLOS ONE