Magnitude and predictors of khat use among patients with tuberculosis in Southwest Ethiopia: A longitudinal study.

INTRODUCTION: Tuberculosis (TB) is a leading cause of morbidity and mortality in low and middle-income countries. Substance use negatively affects TB treatment outcomes. Our recent study has found that khat use predicted poorer adherence to anti-TB medications. However, there is scarce longitudinal study on predictors of khat use among outpatients with TB, and this study aimed at addressing this research gap.
METHODS: From October 2017 to October 2018, 268 outpatients with tuberculosis on DOTs were enrolled in a longitudinal study from 26 health institutions in Southwest Ethiopia. Structured questionnaires translated into local languages (Afaan Oromoo and Amharic) were used to assess khat use. Patients were followed for six months, and data were collected on three occasions during the follow-up. A generalized linear mixed model was used to identify the relation between khat use and predictors. Model fitness was checked using the Bayesian Information Criterion (BIC). Odds ratio (OR) and 95% CI were used to describe the strength of association between the outcome variable and predictors.
RESULTS: The overall prevalence of khat use at baseline and first follow up was 39.2% while it was 37.3% at second follow up. Of this, 77.1% and 96.2% of them believed that khat use reduces the side effects of anti-TB medications and symptoms of tuberculosis respectively. In the final model, being male (aOR = 7.0, p-value = 0.001), being government employee (aOR = 0.03, p-value≤0.001) and presence of alcohol use disorders (AUD) (aOR = 2.0, p-value≤0.001) predicted khat use among outpatients with tuberculosis.
CONCLUSION: A considerable proportion of patients with TB used khat throughout DOTs and wrongly perceived that it had health benefits. The finding implies that all patients diagnosed with TB should be screened for khat use, and a particular emphasis should be given to males and individuals with a history of alcohol use. Moreover, further studies are needed to assess patients' beliefs regarding the benefits of khat use so that interventions can be developed.

Introduction

Globally, despite the availability of effective anti-TB drugs, tuberculosis (TB) remains a major public health problem and one of the top ten causes of death from a single agent [1]. According to the 2018 World Health Organization (WHO) report, 10 million people were infected by TB across the world, while an estimated 1.6 million of people died because of the disease in 2017 [1]. The burden of TB is exceptionally high in middle and low-income countries because of poverty, malnutrition, overcrowded living condition, poor ventilation, HIV, and other chronic diseases. Similarly, substance use disorders, remain the major contributing factors for TB in these countries [1-5]. Almost 90% of all patients with TB living in these countries face elevated TB-related mortality rates [1, 4]. Out of the total deaths attributed to TB in 2017, over 80% of the deaths were from Africa and Southeast Asia [1]. Ethiopia is one of the 22 countries with the highest burden of tuberculosis with an incidence rate of 164 and a mortality rate of 24 per 100,000 [1, 4]. Moreover, TB was the second most frequent cause of death in Ethiopia next to Malaria [4]. Non-adherence to the medication has been earmarked as one of the major issues contributing to excess mortality in Ethiopia [6-8]. Besides, non-adherence increases the risk of multi-resistant TB strains. While any substance use disorder among patients with TB might decrease adherence, it has been shown that excessive use of khat and alcohol may be one major reason for non-adherence to treatment regimens in Ethiopia [9-11].

Khat is an amphetamine-like natural stimulant that has legally been used for many years in East Africa and the Southern Arabian Peninsula [12-14]. Khat use belongs to stimulant use disorder [15]. Fresh leaves of khat contain more than 40 types of compounds, among these, cathinone and cathine are known stimulants [12–14, 16, 17].

Studies showed that people use khat to be alert while praying, to reduce the feeling of hunger, to enhance productivity at work, and to elevate their mood and to be physically strong [18-22]. Also, factors such as common mental disorder, being male, and other sociodemographic characteristics were found to determine khat use in the general population [21, 23]. However, using khat for a long period leads to khat use disorder which could have a potential impact on the mental and physical health of the users [24, 25]. Likewise, cathinone which is found in khat has been linked to a decreased immune response that might increase the risk of developing TB [26]. Besides, TB seems to be more frequently underdiagnosed in khat users [27-29]. Khat users with TB were found to have higher bacillary load and were more likely to develop drug resistance [30]. Also, they were more likely to be stigmatized [31], had longer treatment regimens [32], poor adherence [7, 19], poor appetite [33], and increased levels of anxiety [10]. Even though khat use is known to affect treatment outcomes and mental health of patients with tuberculosis, there is only limited longitudinal study on the magnitude and predictors of khat use among patients with TB in Ethiopia and other African countries. Knowing the predictors and magnitude of khat use would help to tailor interventions and to intensify the efforts to improve treatment outcomes of TB. Moreover, early identification of predictors of khat use is important to take preventive measures to mitigate complications such as comorbid mental illness and MDR-TB. Therefore, our study aimed at assessing longitudinally the magnitude and predictors of khat use among patients with TB in Southwest Ethiopia.

Methods

Study area and design

A longitudinal study was conducted among patients with tuberculosis in Jimma Zone, Southwest Ethiopia. Jimma Zone has more than three million inhabitants; about 3% of the total population of Ethiopia. In Ethiopia, TB care is mainly provided by local decentralized health centers to increase take-up of therapy and to monitor Directly Observed Treatment (DOT). There were 112 health centers in Jimma Zone. Out of these, 91 were providing services for patients with TB at the time of data collection. Likewise, there were dedicated TB treatment services at all hospitals. Patients were recruited from four hospitals and 22 randomly selected health centers of Jimma Zone. Twenty health centers and three hospitals were situated in rural areas whereas one hospital and two health centers are found in Jimma town. The study was conducted over a year from October 2017 to October 2018.

Study population and sampling procedure

This study included all patients who had recently been diagnosed with TB and started DOT in the selected health centers and hospitals. Patients who had started TB treatment within less than four weeks and not planning to transfer to other health institutions were included in the study. There are two reasons for including new patients who started treatment within four weeks. The first one is to see if there will be any change over time and the second is to see whether the patients increase or decrease their Khat use. Patients whose age is less than 18 years, patients infected with multidrug-resistant TB strains, polysubstance users (using three or more substances), and patients who were hospitalized during data collection were excluded from the study. The data for this study was drawn from a cohort registered as ጤ/ኢ/ም/ድ/ም/ዳ/476/2011 (Institute of health, research, and postgraduate director 476/2011) which aimed to assess substance use disorder, quality of life, mental health and adherence to anti-TB medication. The sample was calculated considering power = 80%, 95% confidence interval, 62.4% prevalence of non-adherence to anti-TB medications among khat users, 43.6% prevalence of non-adherence among non-khat user TB patients, and 20% of drop out. The total sample size was 268, and patients who fulfilled the inclusion criteria and consented to participate in the study during the data collection period were consecutively recruited then baseline data were collected. Patients were followed on two occasions: at the end of two and six months.

Patients who were using khat (105) and free of khat use (163) were followed for six months. Detail information regarding the study was given by trained data collectors to each patient before the written informed consent was obtained.

Data collection procedure

Before data collection, the questionnaires were pretested on a sample (5% of the total sample) of patients with TB outpatients who had been on treatment at one health center in Agaro (a town found in Jimma zone at a distance of about 45 kilometers from Jimma city) to check whether the questions work as intended or understood by patients. Fourteen patients from the pretest were not included in the final analysis of the data. Patients were interviewed on three occasions, namely, baseline (starting treatment), first follow up (after 2 months), and second follow up (at the end of six months). The follow up was made at the end of two and six months of treatment because it is the end of intensive as well as the continuous phase of the treatment. Also, at the end of the six-month, patients received another test for tuberculosis so that the status of the patients would be known. Recruitment of patients and data collection were carried out by health professionals who were working in the tuberculosis clinic and specifically trained on the questionnaires, supervised by trained district focal persons. Interviews were conducted within the respective health institutions when the participants came for their TB clinic visits. All questionnaires including the pretest were translated into Afaan Oromoo and Amharic languages because the participants speak either of the two languages.

Data collection tools

Outcome variable. A questionnaire used to assess khat use was developed after reviewing different kinds of literature because there is no specific standard tool to assess khat use in any population. In this study, khat use was defined as using khat in the past 30 days before the interview [34]. The questionnaire includes ever use of khat, current khat use, frequency, amount, and patients’ beliefs regarding khat use.

Explanatory variables. Socio-demographic characteristics. Structured questionnaires were used to assess the socio-demographic characteristics (age, sex, marital status, level of education, religion, ethnicity, annual income, household size, occupation, place of residence) of the participants. Income was categorized considering the minimum monthly wage for employees of a governmental organization in Ethiopia which is 1,214 Ethiopian birr (36.67 Euros) [35]. Then, the monthly income of each patient was multiplied by 12 months to obtain the annual income, and we used a cutoff 14,568‬ Ethiopian birr (439.98 Euros).

Alcohol use disorders (AUDs). Alcohol use disorder identification test (AUDIT) was used to assess alcohol use disorders. The AUDIT has been evaluated over two decades and provides an accurate measure of the risk of AUDs across gender, age, and cultures. A multi-country validation of AUDIT among people attending primary health care in Norway, Australia, Kenya, Bulgaria, Mexico and the United States of America showed that at a cut-off score of eight or more, the sensitivity and specificity of AUDIT for AUDs were 0.90 and 0.80, respectively [36]. The AUDIT has been translated and adapted for studies in the Ethiopian setting [37].

Disease-related factors. Type of TB diagnoses (smear-positive, smear-negative, and extrapulmonary TB) were collected from the patients’ charts.

Comorbidities. Any comorbidity such as HIV, previous mental illness, hypertension, and diabetes mellitus were collected from patients’ charts.

Mental distress. Self-reporting questionnaire-20 (SRQ-20) which was developed by WHO was used to assess mental distress. This questionnaire assesses depressive, anxiety, and somatic symptoms that patients have experienced in the past four weeks. SRQ-20 has been adapted and validated in the Ethiopian setting, but the cut-off point varies from study to study [38, 39]. In this study, a total score of below 7 indicates the absence of mental distress whereas values of 7 and above indicate mental distress. At a cut-off point 7/8 the sensitivity and specificity was 89.7% and 95.2% respectively [40, 41].

Data analysis

Participants’ characteristics and study variables were described using descriptive statistics. A generalized linear mixed model was used to examine the predictors of khat use over six months. The model was built based on the theoretical importance and the adequate number of participants in each cell for each category. The missing value was excluded from the analysis. The findings have been adjusted for potential confounders. An intercept only model was used to investigate khat use over time (model 0) without adding other variables; model 1 investigated the longitudinal association of khat use and socio-demographic characteristics variables. Model 2 investigated the association between socio-demographic variables, mental distress, and the outcome variable (khat use). Model 3 was adjusted for the full set of predictors and examined covariates related to the khat use. Model fit was examined with the Bayesian Information Criterion (BIC). Lower BIC indicates a better model fit. Data were analyzed using R studio (1.2.1335). The study findings are reported in line with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement.

Ethical considerations

Ethical clearance was obtained from Jimma University and LMU Ethical Review Boards. After the participants were given detail information about the importance of the study, written informed consent was obtained from each patient. The anonymity of the study participants was kept in all stages of data processing and write-up of the manuscript. Patients who were using khat more than once weekly were advised to contact a mental health professional.

Results

Socio-demographic and clinical characteristic

In this longitudinal study, a total of 268 patients (age range of 18 to 80 years, mean age 32.4, SD = 14.4, 60.1% male) were recruited. The majority of the study participants were married (58.6%) and Muslim (61.6%). Two-third (63.1%, n = 169) of all participants did not attend formal education (see Table 1). A total of 40.3% (n = 108), 32.5% (n = 87), and 27.2% (n = 73) were diagnosed as smear-positive, smear-negative and extrapulmonary TB, respectively. At baseline, 3.7% (n = 10) patients were diagnosed with HIV, and 7.1% (n = 19) with other comorbidities (see Table 1). There were 22 missing data of annual income which we excluded from the analysis.

Table 1

Characteristics of patients with tuberculosis in Southwest Ethiopia 2017/18 (n = 268).

Variables		Frequency N (%)	Khat use
			Baseline	First follow-up (end 2nd month)	Second follow-up (end of six months)
			N (%)	N (%)	N (%)
Gender	Male	161(60.1)	75(46.6)	75(46.6)	67(41.6)
	Female	107(39.9)	30(28.0)	30(28.0)	33(30.8)
Age	18–24	93(34.7)	33(35.5)	30(32.3)	28(30.1)
	25–34	87(32.5)	32(36.8)	30(34.5)	32(36.8)
	35–44	36(13.4)	18(50.0)	20(55.6)	15(41.7)
	45–54	27(10.1)	13(48.1)	13(48.1)	13(48.1)
	55–64	25(9.3)	9(36.0)	12(48.0)	12(48.0)
Annual income in Eth Birr	<14,568‬	206(76.9)	86(41.7)	85(41.3)	83(40.3)
	≥14,568‬	40(14.9)	11(27.5)	15(37.5)	13(32.5)
Marital status	Single	97(36.2)	33(34.0)	30(30.9)	26(26.8)
	Married	157(58.6)	66(42.0)	70(44.6)	68(43.3)
	Divorced/widow	14(5.2)	6(42.9)	5(35.7)	6(42.9)
Religion	Orthodox	82(30.6)	21(25.6)	19(23.2)	20(24.4)
	Muslim	165(61.6)	83(50.3)	84(50.9)	78(47.3)
	Protestant and others	21(7.8)	1(4.8%)	2(9.5)	2(9.5)
Ethnicity	Amhara	59(22.0)	13(22.0)	12(20.3)	12(20.3)
	Oromo	165(61.6)	79(47.9)	79(47.9)	74(44.8)
	Tigre/Gurage	44(16.4)	13(29.5)	14(31.8)	14(31.8)
Occupation	Merchant	29(10.8)	21(72.4)	7(58.6)	17(58.6)
	Farmer	92(34.3)	47(51.1)	47(51.1)	49(53.3)
	Government Employee	105(39.2)	24(22.9)	26(24.8)	21(20.0)
	Daily laborer	42(15.7)	13(31.0)	15(35.7)	13(31.0)
Education	No formal education	169(63.1)	15(32.5)	56(33.1)	46(27.2)
	Primary/secondary	71(26.5)	35(49.3)	34(47.9)	36(50.7)
	Tertiary	28(10.4)	15(53.6)	15(53.6)	18(64.3)
Family size	Less than 5	181(67.5)	70(38.7)	37(42.5)	66(36.5)
	5 and more	87(32.5)	35(40.2)	8(37.6)	34(39.1)
Residence	Rural	127(47.4)	59(46.5)	57(44.9)	55(43.3)
	Urban	141(52.6)	46(32.6)	48(34.0)	45(31.9)
HIV	Positive	10(3.7)	6(60.0%)	7(58.3)	8(42.1)
	Negative	258(96.3)	99(38.4)	98(38.3)	92(36.9)
Mental distress	No		36(34.6)	55(33.1)	77(36.8)
	Yes		69(42.1)	50(49.0)	23(39.0)

*There were 22 missing data of annual income.

Prevalence of khat use

The prevalence of khat use was 39.2% (n = 105) at baseline and after two months, and 37.3% (n = 100) at the end of six months. Of the total khat users, 24.8% (n = 26), 46.7% (n = 49), and 37.0% (n = 37) chewed khat daily at baseline, first follow up and second follow up respectively, while 55.2% (n = 58), 46.7% (n = 49) and 32.0% (n = 32) chewed it 2–3 times per week.

Those patients who were using khat were compared against patients free of khat use during the follow-up. Males were found to use khat more than women at baseline (46.6% versus 28.0%, p<0.05), at second month (46.6% versus 28.0%, p<0.001), and sixth month (41.6% versus 30.8%). The majority of khat users were merchants (72.4%, n = 21), followed by farmers (51.1%, n = 47), and being educated till the tertiary level (53.6%, n = 15) at baseline (see Table 1). The majority of khat users (77.1%, n = 81) believed that khat can reduce medication side effects or reduce symptoms of tuberculosis (96.2%, n = 101).

The prevalence of mental distress among patients with khat users was 42.1% (n = 69), 49.0% (n = 50) and 39.0% (n = 23) at baseline (T0), first (T1) and second (T2) follow up respectively. At the end of the second month, the majority (76.7%, n = 33), of khat users were found to have alcohol use disorder).

Predictors of khat use

The results of multivariable modeling are shown in Table 2. The prevalence of khat use did not change significantly over time (p = 0.48 in the final fully adjusted model). The strength of association was improved over time as witnessed by further improvement of model fit (BIC = 815.7). Being male and having AUDs were indicators for khat use after multivariable adjustment. Merchants still had a higher probability of khat use than government employees or day laborers. The odds of khat use among government employees was 97% lower when compared to that of merchants (aOR = 0.03, p-value = 0.001). Age, income, and mental distress were not associated with khat use.

Table 2

Predictors of khat use among patients with tuberculosis in Southwest Ethiopia (n = 268) in 2017/18).

Variables		Intercept only (empty model)			Model1 (Socio-demography)			Model2 (Model 1 including mental distress)			Model3 (Full model)
		OR	P-Value	95%CI(upper, lower)	aOR	P-Value	95%CI(upper, lower)	aOR	P-Value	95%CI(upper, lower)	aOR	P-Value	95%CI(upper, lower)
Gender	Female	Reference
	Male	-	-		5.9	0.01	2.0,17.7	5.9	0.01	2.0,17.7	7.0	0.001	2.2,22.2
Age	18–24	Reference
	25–34	-	-		0.9	0.83	0.2,3.2	0.9	0.83	0.2,3.2	0.9	0.83	0.2.3.4
	35–44	-	-		1.8	0.50	0.3,10.1	1.8	0.49	0.3,10.1	2.0	0.47	0.3,12
	45–54	-	-		1.1	0.91	0.2,7.4	1.1	0.92	0.2,7.4	1.3	0.82	0.2,9.2
	55–64	-	-		0.5	0.41	0.1,3.0	0.5	0.42	0.1,3.0	0.5	0.47	0.1.3.5
Annual Income in Ethiopian birr	<14,568‬	Reference
	>14,568‬	-	-		0.4	0.19	0.1,1.6	0.4	0.19	0.1,1.6	0.3	0.16	0.8,1.5
Occupation	Merchant	Reference
	Farmer	-	-		0.2	0.08	0.04,1.2	0.2	0.08	0.04,1.2	0.2	0.05	0.02,1.0
	Government Employee	-	-		0.04	0.001	0.01,0.3	0.04	0.001	0.01,0.3	0.03	0.001	0.01,0.2
	Day laborer	-	-		0.1	0.03	0.01,0.8	0.1	0.02	0.02,0.8	0.1	0.01	0.01,0.6
Religion	Orthodox	Reference
	Muslim		-		3.3	0.04	1.0,10.6	3.3	0.04	1.0,10.6	2.6	0.3	0.8,8.6
	Protestant		-		0.03	0.01	0.01,0.5	0.03	0.01	0.01,0.5	0.01	0.01	0.01,0.3
AUD	No	Reference
	Yes		-								2.0	0.001	6.0,38.1
Mental distress	No	Reference
	Yes				-	-	-	1.0	0.96	0.5,2.0	1.0	0.94	0.7,5.2
Time		0.9	0.48	0.7,1.2	0.8	0.2	0.6,1.1	0.8	0.25	0.6,1.2	0.9	0.47	0.6,1.3
BIC		819.0			815.2			821.9			815.7

Discussion

To our knowledge, this study is the first longitudinal study investigating predictors of khat use among patients with tuberculosis in Africa. Alarmingly, TB-patients believed that the use of khat is beneficial during treatment. Alcohol use disorder and male gender were predictors of continued khat use among TB patients in Southwest Ethiopia.

In this study, the prevalence of khat use was slightly declined over time from 39.2% at baseline to 37.3% at the end of six months. The reason might be patients use more khat at baseline as a self-treatment for tuberculosis related symptoms and medication side effects. Because we identified that most patients believe khat can reduce symptoms of tuberculosis and medication side- effects. So, when they get improvement from the disease, they might reduce their khat use but further study is needed.

The prevalence of khat use observed in this study at baseline (39.2%), during the first (39.2%) and second follow up (37.3%) was far higher than another study conducted in South Ethiopia which found moderate and high khat use to be 14.3% and 1.7% respectively [9]. The difference might be due to the fact that the setting for the present study is known with a higher level of khat consumption than other regions and zones in Ethiopia except for the Diredawa town and Harari region [42]. In these regions, khat is considered as part of the culture for the lubrication of social cohesion. Arguably, it is also seen as a help to stay alert during the praying time which patients would not like to miss [18, 22, 43]. This is generally worrisome as khat use has been shown to be associated with poor treatment outcomes among patients with tuberculosis [44].

The prevalence of khat use found in the current study is lower than the finding from a prospective nest case-control study done in Yemen (46.7%) [19]. The difference might be due to the definition of current khat use which is 30 days in our study, while this was not specified in the Yemenite study. Likewise, socio-cultural differences might contribute to the discrepancy between the two studies. We found that the proportion of khat use among male participants (46.6%) was far higher than among female participants (28.0%), which is consistent with the findings of previous studies [45, 46]. This might be due to cultural restriction on females regarding substance use including khat [45, 46]. Even though khat consumption among women is substantially lower than men, they are at higher risk of mental and physical effects of substance use disorder than men which is associated with hormonal factors [45, 47]. In this study, more than 2/5th of khat users reported that they were suffering from mental distress. Previous studies found that substance use (khat, alcohol, and tobacco) is associated with mental distress [10, 48], and specifically, khat was reported to increase emotional disturbance [49]. However, we could not show a clear association of mental distress and khat use in the adjusted models. Patients might be tempted to use khat as a self-treatment for their mental distress, but this observation needs to be supported by further investigations.

During the first follow up, a majority (76.7%) of patients who were using khat reported that they have alcohol use disorder. This could be due to the fact that patients might resume drinking alcohol after they begin to feel better within two to three weeks because bacterial load then usually starts to decline [4]. In addition, since alcohol counteracts the stimulant effect of khat such as sleep disturbance and restlessness, patients might be inclined to use both substances together [43, 50, 51]. Likewise, in this study, khat use was associated with alcohol use which is in agreement with previous studies [43, 48]. Combining alcohol and khat would affect patients' treatment outcomes and lead to physical and mental health problems. Because, both khat and alcohol were found to have a potential impact on the immunity of the user and associated with mental distress so that patients may develop severe medical and mental health complications or die earlier than non-users [26, 52, 53]. Furthermore, these two substances have an association with treatment-resistant tuberculosis [30, 32, 54, 55].

This study found that the majority (77.1%) of khat users believe that using khat can reduce anti-TB medication side effects which is consistent with a cross-sectional study conducted in the Butajira, Ethiopian [18]. This may be due to misinterpreting the euphoric mood from khat as a decrease in medication side effects. However, health professionals should create awareness regarding the effect of khat on mental and physical health so that patients may consider reducing their khat use. In this study, almost all khat users (96.2%) believe that khat use reduces TB symptoms, however, this is in clear contrast to the study indicating that patients with khat use had a higher bacterial load [30].

Moreover, we have found that merchants were using khat more than a farmers, government employees, and daily laborers which is in line with studies conducted in the general population [42, 56, 57]. This might be due to the fact that merchants use khat to be alert and energetic at the workplace [58]. Also, some of the merchants may be khat sellers and, as a result, they chew khat to attract customers but further study assessing this situation is needed.

To our knowledge, our study was unique in exploring predictors of continued khat use among patients with tuberculosis using a longitudinal study with multiple assessments and with no attrition. However, the following limitations need to be acknowledged. Because of social desirability, patients might minimize or deny their khat use and this could underestimate the magnitude of khat use. It could also affect the association of predictors with the outcome variables. Also, health professionals who were working in a TB clinic collected the data that might contribute to this bias; because patients may be inclined to not report about their khat use or minimize its amount. However, the prevalence of khat use was still higher than in other studies so our estimates might be rather conservative. There is no standardized instrument for the assessment of khat use. However, we are confident that we were able to capture khat use with sufficient precision. Moreover, patients with MDR-TB and who were attending their treatment at health posts, i.e. in more remote areas, were excluded from the study; hence the findings of the study may not be generalized to all patients with TB in Southwest Ethiopia. The findings of this study cannot be generalized to those patients who are getting treatment at the inpatient department who have limited access to psychoactive substances including khat. Moreover, since our sample size is not adequate, it might be difficult to draw a strong conclusion, but we can make an estimation based on the sample size without having a critical problem that could affect our findings. Also, we did not cover all possible predictors, and as a result, we recommend a qualitative study to explore other predictors of khat use among TB patients.

Conclusions

In conclusion, a significant proportion of patients on anti-TB continue to use khat throughout their course of treatment. Predictors of khat use were being male and concomitant alcohol use disorder. These findings underscore the need to integrate the screening and treatment for substance use, specifically for khat, into the tuberculosis services. All patients diagnosed with TB should be screened for khat use and a particular emphasis should be given to males and individuals with a history of alcohol use. Furthermore, patients’ beliefs about the beneficial effects of khat on tuberculosis outcomes need to be investigated so that these beliefs can be counteracted effectively.

11 Mar 2020

PONE-D-20-01650

Factors associated with khat use among patients with tuberculosis in Southwest Ethiopia: A longitudinal  study

PLOS ONE

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Reviewer #1: No

Reviewer #2: Partly

Reviewer #3: Partly

**********

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

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

**********

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Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: 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: Factors associated with Khat use among patients with tuberculosis in Southwest

Ethiopia: A longitudinal study by Motiwas Soboka et. al

This paper tries to explore the factors associated with Khat use among tuberculosis patients. However the paper has serious flaws of research design and rationale. It lacks coherency in terms of objectives of research. What factors authors are trying to associate??

Following are the specific comments.

1. The stated objective of the research is “there is limited information on factors associated with Khat use among patients with TB and this study aimed at addressing this research gap.” But data and conclusion doesn’t support it

2. Study design: The study design doesn’t support the curation of factors associated with Khat use.

3. Sample size: the sample size is not adequate enough to draw such broad conclusion.

4. The title and the subsequent research methodology adopted do not match at all.

5. There are language issues but they are of minor nature.

Reviewer #2: Study title: Factors associated with khat use among patients with tuberculosis in Southwest Ethiopia: A longitudinal study

General comment:

The paper is generally well-written and adds to the broader literature on substance use and TB in Africa. The findings may help readers better understand common factors that contribute to Khat use in this sub group; these insights may contribute to interventions. Although the paper may address a gap, there are several major weaknesses and the paper could be improved with a stronger background section, further elaboration of the methods, and a stronger and more well-organized discussion of the results. Specific comments follow:

Title & Introduction

The title is overly promising and yet the study mainly focuses on TB outpatients on DOTs. The authors should clarify the title further.

The burden of TB is fairly well described but the introduction is scanty of known risk factors for TB and khat use separately. In the discussion section, it might be worth highlighting if these risk factors are ant different from those found in this study, and why? This should be addressed.

Methods

Why was use of other illicit drug used a s an exclusion criteria?

The sources of selection of participants are clear but the and methods of both participant selection and follow up remain vague.

The authors need to clearly define khat use and to indicate sources of data and details of methods of assessment (measurement) and the rationale for the choice assessment. Indicate elsewhere in the paper that you refer to self-reported khat use not simply Khat use.

Your paper has many sources of selection bias from how participants were selected to how assessments of outcomes and exposures were done. Describe any efforts to address potential sources of bias.

Explain how the sample size was arrived at and the rationale underlying the models that were built during the analysis.

It remains unclear to me what conceptual framework underpinned the analysis, which confounders were known from before and how these were controlled for and why they were included.

Results

Would appreciate a note of missing data and how this was handled. At a minimum, Indicate the number of participants with missing data for each variable of interest

You need to show how the associations changed overtime-from baseline to endline and give plausible reasons.

Discussion

‘To our knowledge, this study is the first longitudinal study conducted among patients with tuberculosis investigating predictors of khat use in Africa’. Vague statement consider rephrasing.

Authors should discuss limitations of the study further, taking into account sources of potential bias or imprecision. Discuss both direction and magnitude of any potential bias.

Conclusion: ‘The findings imply that male patients and patients with alcohol use disorders should be focused on while screening for khat use among TB patients.’ I would argue that the goals of screening for khat use need to be much broader than male gender and AUD. Consider re phrasing this seemingly misleading statement.

Reviewer #3: Thank you for giving the opportunity to review this manuscript titled “Factors associated with khat use among patients with tuberculosis in Southwest Ethiopia: A longitudinal study” [PONE-D-20-01650]

Dear authors, Good study surely based on the needs of your area! Please consider the followings

1- Overall, this is an interesting study exploring the use of plants (khat) for stimulation purpose among patients with tuberculosis. However, it is unclear whether the use among the local population is mainly recreational, or due to its medicinal properties. Does Khat chewing has any scientific explanation to causes addiction?

2- Dear authors, I am great full for your efforts. But, your main massage is to demonstrate khat use by focusing on epidemiological data and factors associated with it among tuberculosis patients. However, as it is explained in your background information, chewing khat is not uncommon including tuberculosis patients. If so, I believe that the big deal is not reporting the magnitude or level of khat use, rather, since your study is longitudinal, the better was to give important intervention and to see its effect. This might helpful to recommend for policy makers and other stakeholders at national level. –

otherwise, you should write more about the gap in your context and the real problem which motives you to do such a study. Problem statement is not convincing! The clear gap to see the prevalence of khat use and factors affecting it at different stages is not well explained.

3- say the evidences that emphasize on the importance of to take preventive measures and reduces medical complications related tuberculosis that might be caused by Khat consumption during medication follow-up apart from non-adherence (found in your study)?

4- In your study, there is nothing intervention or education is given for participants i.e. not indicated in your writing, however, varied findings are documented regarding the prevalence of khat use at baseline and last data collection time. What sort of things can be reasons to decrease the prevalence (in percentile)? And writ more about this

5- This study reported that the use of Khat among patients with tuberculosis & alcohol problem is higher. Please discuss further whether this something good or bad, because it may divert the individuals from using other more harmful substances.

6- In your exclusion criteria………polysubstance users (using two or more substances) and patients were excluded from the study. However, alcohol use problem (disorder) is a predictor to use khat. It is unclear and ambiguous idea. Could you say more about this please? (Since the participants in your study were using both khat and alcohol)

7- Also in your sampling procedure regarding to exclusion and inclusion criteria, it is stated as…..We included all patients who had recently been diagnosed with TB who had started DOT in the selected health centers and hospitals. Patients were included only if they had started TB treatment within less than four weeks before inclusion and were not planning to transfer to other health institutions. Patients aged less than 18 years, patients infected with multidrug-resistant TB strains ,………..were excluded from the study. Reason behind to include recently diagnosed (4 weeks) only?? Does it have any significance difference to chew khat with people living with TB for long?????

8- In your data collection procedure part, It is first time Agaro is mentioned. No context provided as to why pre-testing was done in Agaro (which reader outside Ethiopia may not know why it is important for a study). Write more about Agaro where it is located??

9- Doe the pretest was done using both version of the questionnaires (Afan oromo and Amharic). ???

10- Self-Reporting Questionnaire (SRQ-20) to assess mental distress, -WHO's structured questionnaire of Alcohol Use Disorder Identification Test (AUDIT) to asses Alcohol Use Disorders and questions used to assess the frequency and patterns of Khat use- Operational definitions should be about measures items, dimensions, rating scales, theoretical basis, validity, reliability and so on...

I thought it seems to write it again deeply to increase the quality.

11- Prevalence of khat use at baseline and last assessment examined different (39.2% Vs 37.3%). What it its implication?? Clearly not explained specifically among tuberculosis patients? I suggest to discuss it more including thee pattern of khat chewing.

12- To show factors associated with khat chewing I suggest to include confidence interval also so that it will be clear more.

13- Try to discuss your findings detail……….. About merchants (why they chew more….. the prevalence of khat use if there is study findings done longitudinally…..)??? discussion is limited.

14- Lastly …I thought it looks scientifically sound. If your title re written as “Magnitude and factors associated with khat use among patients with tuberculosis in Southwest Ethiopia: A longitudinal study”

**********

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

[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 to be viewed.]

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Submitted filename: Factors associated with khat use among patients with tuberculosis in Southwest Ethiopia_Reviewer2_comments.docx

Click here for additional data file.

Submitted filename: Review comments.docx

Click here for additional data file.

23 Apr 2020

Response to reviewers

Reviewer #1

This paper tries to explore the factors associated with Khat use among tuberculosis patients. However the paper has serious flaws of research design and rationale. It lacks coherency in terms of objectives of research. What factors authors are trying to associate??

Following are the specific comments.

1. The stated objective of the research is “there is limited information on factors associated with Khat use among patients with TB and this study aimed at addressing this research gap.” But data and conclusion doesn’t support it

Response: Indeed we wanted to examine predictors of Khat use longitudinally, and we apologize if this was not completely clear. Our results showed that being male, being a government employee and the presence of alcohol use disorders were associated with khat use among TB patients. To our knowledge, this is one of the few studies that investigated a broad range of potential predictors.

2. Study design: The study design doesn’t support the curation of factors associated with Khat use.

Response: Data originates from a comprehensive cohort study, so the longitudinal aspect was incorporated. Cohort studies are generally state-of-the-art for investigating risk factors.

3. Sample size: the sample size is not adequate enough to draw such broad conclusion.

Response: This is a valuable comment. We now mention this as a limitation of the study. The sample size was calculated based on previous studies with a prevalence of almost 50%. We found a prevalence of about 40%, a difference which is acceptable. For regression models, 10 cases (here: patients using khat) per predictor to be included is generally sufficient. Thus, our sample size allows models with up to 10 predictors which is well in line with our specifications.

4. The title and the subsequent research methodology adopted do not match at all.

Response: We are grateful for this comment and amended the title.

5. There are language issues but they are of minor nature.

Response: We edited the manuscript.

Reviewer #2

General comment:

The paper is generally well-written and adds to the broader literature on substance use and TB in Africa. The findings may help readers better understand common factors that contribute to Khat use in this sub group; these insights may contribute to interventions. Although the paper may address a gap, there are several major weaknesses and the paper could be improved with a stronger background section, further elaboration of the methods, and a stronger and more well-organized discussion of the results.

Specific comments follow:

Title & Introduction

1. The title is overly promising and yet the study mainly focuses on TB outpatients on DOTs. The authors should clarify the title further.

Response: We agree and have amended the title. However, the reason why we have included only DOTs patients is that there is no chance that patients who are getting treatment at the inpatient department would access substance including khat. Also, we have included this issue in limitation of the study stating that the findings of this study will not be generalized to those patients who are getting treatment at the inpatients department.

2. The burden of TB is fairly well described but the introduction is scanty of known risk factors for TB and khat use separately. In the discussion section, it might be worth highlighting if these risk factors are ant different from those found in this study, and why? This should be addressed.

Response: We have accepted the reviewer’s comment and amended the introduction and discussion.

##Methods

3. Why was use of other illicit drug used a s an exclusion criteria?

Response: We did not exclude the use of illicit drugs but unfortunately we could not find a patient who uses illicit drug and this could be related to availability or fear of legal consequences. So, we consider this as social desirability and include it in the limitation of the study.

4. The sources of selection of participants are clear but the and methods of both participant selection and follow up remain vague.

Response: We have accepted the comment and amend the manuscript.

4. The authors need to clearly define khat use and to indicate sources of data and details of methods of assessment (measurement) and the rationale for the choice assessment. Indicate elsewhere in the paper that you refer to self-reported khat use not simply Khat use.

Response: We have accepted the comment and amend the manuscript.

5. Your paper has many sources of selection bias from how participants were selected to how assessments of outcomes and exposures were done. Describe any efforts to address potential sources of bias.

Response: We are grateful for the reviewer's comment. Since we have selected the participants consecutively participants who have fulfilled the inclusion criteria had an equal chance to be involved in the study. So, there was a limited selection and assessment of outcomes and exposures bias.

6.Explain how the sample size was arrived at and the rationale underlying the models that were built during the analysis.

Response: We have accepted the comment and amended the manuscript.

7.It remains unclear to me what conceptual framework underpinned the analysis, which confounders were known from before and how these were controlled for and why they were included.

Response: The variables with potential confounders were controlled using multivariable modeling in which we have included potential variables that could affect khat use. We used risk factors that were known from the literature. Therefore, the findings have been adjusted for potential confounders. For example, gender and age and others.

##Results

8.Would appreciate a note of missing data and how this was handled. At a minimum, indicate the number of participants with missing data for each variable of interest

Response: We have accepted the comment and amended the manuscript. We have used the case-wise deletion of participants with missing data. Hence, 22 participants have been omitted from the analysis because of missing data on one or more variables.

9. You need to show how the associations changed overtime-from baseline to endline and give plausible reasons.

Response: We have amended the manuscript based on the reviewer's comment. As it is indicated in table 2 the strength of the association was improved over time as witnessed by further improvement of the model fit (BIC=815.7).

##Discussion

10.‘To our knowledge, this study is the first longitudinal study conducted among patients with tuberculosis investigating predictors of khat use in Africa’. Vague statement consider rephrasing.

Response: We have accepted the comment.

Authors should discuss limitations of the study further, taking into account sources of potential bias or imprecision. Discuss both direction and magnitude of any potential bias.

Response: We are grateful for the reviewer's comment and added some additional potential limitations. Also, we want to inform the reviewer as we have reported the following bias: social desirability bias, data collection by health professionals working in the clinic, tools used to assess reported khat use etc.

Conclusion: ‘The findings imply that male patients and patients with alcohol use disorders should be focused on while screening for khat use among TB patients.’ I would argue that the goals of screening for khat use need to be much broader than male gender and AUD. Consider re phrasing this seemingly misleading statement.

Response: We agree with the reviewer's comment that screening of patients for khat use has to be comprehensive, but our conclusion is only based on the findings of the study. We rephrased the sentence with caution. The conclusion now reads as ”The findings indicate screening for khat use among TB patients needs to prioritize males and those with alcohol use disorders.”

Reviewer #3

Thank you for giving the opportunity to review this manuscript titled “Factors associated with khat use among patients with tuberculosis in Southwest Ethiopia: A longitudinal study” [PONE-D-20-01650]

Dear authors, Good study surely based on the needs of your area! Please consider the followings

1. Overall, this is an interesting study exploring the use of plants (khat) for stimulation purpose among patients with tuberculosis. However, it is unclear whether the use among the local population is mainly recreational, or due to its medicinal properties. Does Khat chewing has any scientific explanation to causes addiction?

Response: Thank you for the constructive comment. Khat can cause psychological dependence among long time users and we have included this in the introduction. Also, local people use khat for recreational, social lubrication, to reduce the feeling of hunger, as self-medication and to stay alert while praying. We have included some of these factors while we were discussing our results.

2. Dear authors, I am great full for your efforts. But, your main massage is to demonstrate khat use by focusing on epidemiological data and factors associated with it among tuberculosis patients. However, as it is explained in your background information, chewing khat is not uncommon including tuberculosis patients. If so, I believe that the big deal is not reporting the magnitude or level of khat use, rather, since your study is longitudinal, the better was to give important intervention and to see its effect. This might helpful to recommend for policy makers and other stakeholders at national level. –otherwise, you should write more about the gap in your context and the real problem which motives you to do such a study. Problem statement is not convincing! The clear gap to see the prevalence of khat use and factors affecting it at different stages is not well explained.

Response: We have accepted about explaining the statement of the problem further and amended the manuscript. But, arguably, there are not many studies targeting khat use among patients with tuberculosis. There is also a scarcity of information regarding the magnitude of khat use from longitudinal studies as many of the studies are cross-sectional. Also, those studies did not assess khat use primarily considering it as the main outcome variable but they report khat use on their way to assess other problems among TB patients. Our data provide evidence for continued use of khat among TB outpatients despite regular contact with health professionals so that we make the case for more structured and effective interventions to be developed and tested. Regrettably, our study was not designed as an intervention study, but the reviewer is correct to state that this should be the aim of further research, and this study is most likely to inform future trials in this regard.

3. Say the evidences that emphasize on the importance of to take preventive measures and reduces medical complications related tuberculosis that might be caused by Khat consumption during medication follow-up apart from non-adherence (found in your study)?

Response: We have studied the effect of khat use among tuberculosis including non-adherence but we have prepared a separate manuscript which gives detail of this information.

4. In your study, there is nothing intervention or education is given for participants i.e. not indicated in your writing, however, varied findings are documented regarding the prevalence of khat use at baseline and last data collection time. What sort of things can be reasons to decrease the prevalence (in percentile)? And writ more about this

Response: We have accepted the comment partly and amend the manuscript accordingly. Our study is not an interventional study so we did not primarily focus on intervention, but we have trained our data collectors to give education regarding problematic khat use and its effect at the end of data collection. During data collection, we have advised those who use khat more frequently to talk to a mental health professional and we have included this under the topic of “ethical consideration”. We added the probable reason why khat use was declined over time to the discussion part.

5. This study reported that the use of Khat among patients with tuberculosis & alcohol problem is higher. Please discuss further whether this something good or bad, because it may divert the individuals from using other more harmful substances.

Response: We have accepted the comment and made discussion as follows: Combining alcohol and khat would affect patients' treatment outcomes, and lead to physical and mental health problems. Because both khat and alcohol were found to have a potential impact on the immunity of the user and associated with mental distress so that patients may develop severe medical and mental health complications or die earlier than non-users. Furthermore, these two substances have an association with treatment-resistant tuberculosis

6. In your exclusion criteria………polysubstance users (using two or more substances) and patients were excluded from the study. However, alcohol use problem (disorder) is a predictor to use khat. It is unclear and ambiguous idea. Could you say more about this please? (Since the participants in your study were using both khat and alcohol)

Response: We are grateful for the comment. We have excluded patients who were using three or more substances (polysubstance users) and amended the manuscript accordingly. We are sorry for the typing error.

7. Also in your sampling procedure regarding to exclusion and inclusion criteria, it is stated as…..We included all patients who had recently been diagnosed with TB who had started DOT in the selected health centers and hospitals. Patients were included only if they had started TB treatment within less than four weeks before inclusion and were not planning to transfer to other health institutions. Patients aged less than 18 years, patients infected with multidrug-resistant TB strains ,………..were excluded from the study. Reason behind to include recently diagnosed (4 weeks) only?? Does it have any significance difference to chew khat with people living with TB for long?????

Response: Since we were also following other outcomes such as adherence, mental health and quality of life, we have decided to include only new patients because it allows us to see any change over time. Also, the phase of treatment is important because in the first few weeks since patients have serious symptoms of tuberculosis we want to see whether patients increase or decrease their khat consumption. Furthermore, it is difficult to include other patients such as those who are on retreatment and MDR-TB because the duration of treatment is quite different and we have included this in the limitation of the study.

8. In your data collection procedure part, It is first time Agaro is mentioned. No context provided as to why pre-testing was done in Agaro (which reader outside Ethiopia may not know why it is important for a study). Write more about Agaro where it is located??

Response: We have accepted the comment.

9. Doe the pretest was done using both version of the questionnaires (Afan oromo and Amharic). ???

Response: Yes we have done the pretest and data collection in both languages because our participants speak either of the two languages.

10. Self-Reporting Questionnaire (SRQ-20) to assess mental distress, -WHO's structured questionnaire of Alcohol Use Disorder Identification Test (AUDIT) to asses Alcohol Use Disorders and questions used to assess the frequency and patterns of Khat use- Operational definitions should be about measures items, dimensions, rating scales, theoretical basis, validity, reliability and so on...

I thought it seems to write it again deeply to increase the quality.

Response: We have accepted the comment and added detail information about the tools into the manuscript.

11. Prevalence of khat use at baseline and last assessment examined different (39.2% Vs 37.3%). What it its implication?? Clearly not explained specifically among tuberculosis patients? I suggest to discuss it more including thee pattern of khat chewing.

Response: We have accepted the comment and amended the manuscript.

12. To show factors associated with khat chewing I suggest to include confidence interval also so that it will be clear more.

Response: We have accepted the comment and included confidence intervals.

13. Try to discuss your findings detail……….. About merchants (why they chew more….. the prevalence of khat use if there is study findings done longitudinally…..)??? discussion is limited.

Response: We have accepted the comment and added the explanation why merchant chew khat more.

14. Lastly …I thought it looks scientifically sound. If your title re written as “Magnitude and factors associated with khat use among patients with tuberculosis in Southwest Ethiopia: A longitudinal study”

Response: We have accepted the comment and amended the title.

Submitted filename: Response to Reviewers_MT.docx

Click here for additional data file.

26 May 2020

PONE-D-20-01650R1

Magnitude and predictors of khat use among patients with tuberculosis in Southwest Ethiopia: A longitudinal  study

PLOS ONE

Dear Dr. Soboka,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Before we can accept the paper, English language editing is necessary.

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We look forward to receiving your revised manuscript.

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Academic Editor

PLOS ONE

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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: (No Response)

**********

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: (No Response)

Reviewer #2: Partly

**********

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: No

**********

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: No

**********

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: In view of the comments raised by the reviewer and it's subsequent clarification and modification in the manuscript draft the reviewer suggest that the manuscript may be accepted in its revised form . However reviewer still believes that authors may further look for broader range of predictors ranging from social norms , anxiety and economical distress , changing cultural practices , and off course the medical model offering TB care , also if the whole of Ethiopia can be targetted with modifications in design and methodology so that broader meaning full conclusions can be drawn which ultimately can be useful for the policy makers , stakeholders and government institutions to better understand predictors for khat use among TB patients in whole of Ethiopia.

Reviewer #2: Dear author,

Thanks for sharing the revised paper and rebuttal.

I have further comments on the response attached.

Of concern is that there are major comments that remian unadrressed. In addition, the paper would use a review from a native English speaker.

As is, this paper is not suitable for publication untill these issuse are clearly addresed. I now leave the final decision on this paper to the editor.

**********

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Reviewer #1: No

Reviewer #2: No

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Submitted filename: Response to Reviewers-Plos_Khat.docx

Click here for additional data file.

27 Jun 2020

Language: This manuscript is edited by a professional English language editor.

Response to reviewer

Comment [A1]: Could shorten title further:

“Magnitude and predictors of khat use among tuberculosis patients in Southwest Ethiopia: A longitudinal study”

Response: Thank you for the comment. We would like to keep the current title because we are concerned that further shortening of the title may make it less informative about the objectives, the area and design of the study.

Comment [A2]: Limited chance perhaps?

Response: We agree with the reviewer's comment because there is limited chance for TB inpatients access to substances including khat. We have included this issue in the discussion section on page 18, line 12 to 14 .

Comment [A3]: This change doesn’t show in the limitations section. Please revise.

Response: Thank you for your comment. This information was stated on page 18, lines 4 to 7 on the previous version of the manuscript. Now we have separately reported it on page 18, line 9 to 10 as “The findings of this study can not be generalized to those patients who are getting treatment at the inpatient facilities”

Comment [A4]: This response is unsatisfactory.

Response: On the top of theoretical importance and the adequate number of participants in each cell for each category, we have also used literature, clinical knowledge, and experience to build the model. The reason why we have included confounders is that they have the potential to distort the association between dependent and independent variables. Also, it is difficult to identify variables that independently predict khat use without controlling for confounders. Therefore, we have controlled them using multivariable analysis. We have made additional clarification to the analysis on page 9 lines 3 to 4.

Comment [A5]: Please show this missing data as a footnote to the table

Response: we have accepted and made changes on page 11.

Comment [A6]: Consider: “To our knowledge, this study is the first longitudinal study investigating predictors of khat use conducted among patients with tuberculosis in Africa.”

Response: We have accepted the comment and made changes on page 15, lines 1 and 2.

Comment [A7]: The author does not address issues of the direction of potential biases listed. This is a major omission in my view.

Response: We have reported the direction of bias on 18, lines 2 to 4 and now read as “Due to social desirability, patients may minimize or deny their khat consumption, which could have a negative impact on the extent of khat use. It could also affect the association of predictors with the outcome variables. In addition, health professionals working in a TB clinic might have contribute to this bias, as patients may be inclined not to report their khat use or to minimize its amount.

Comment [A8]: From your findings, it seems that screening for Khat is a major conclusion itself. Paying attention wo men and people with AUD is secondary right?

Response: We have rephrased the conclusion as “All patients diagnosed with TB should be screened for khat use and a particular emphasis should be given to males and individuals with a history of alcohol use” The changes are available on page 2, lines 2 and 3 and on page 18, lines 4 and 5.”

Submitted filename: V5. Response Reviewers.docx

Click here for additional data file.

1 Jul 2020

Magnitude and predictors of khat use among patients with tuberculosis in Southwest Ethiopia: A longitudinal  study

PONE-D-20-01650R2

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Reviewers' comments:

20 Jul 2020

PONE-D-20-01650R2

Magnitude and predictors of khat use among patients with tuberculosis in Southwest Ethiopia: A longitudinal study

Dear Dr. Soboka:

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.

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