A narrative review of facilitators and barriers to smoking cessation and tobacco-dependence treatment in patients with tuberculosis in low- and middle-income countries

INTRODUCTION Smoking is a substantial cause of premature death in patients with tuberculosis (TB), particularly in low- and middle-income countries (LMICs) with high TB prevalence. The importance of incorporating smoking cessation and tobacco-dependence treatment (TDT) into TB care is highlighted in the most recent TB care guidelines. Our objective is to identify the likely key facilitators of and barriers to smoking cessation for patients with TB in LMICs. METHODS A systematic search of studies with English-language abstracts published between January 2000 and May 2019 was undertaken in the EMBASE, MEDLINE, EBSCO, ProQuest, Cochrane and Web of Science databases. Data extraction was followed by study-quality assessment and a descriptive and narrative synthesis of findings. RESULTS Out of 267 potentially eligible articles, 36 satisfied the inclusion criteria. Methodological quality of non-randomized studies was variable; low risk of bias was assessed in most randomized controlled studies. Identified facilitators included brief, repeated interventions, personalized behavioural counselling, offer of pharmacotherapy, smoke-free homes and a reasonable awareness of smoking-associated risks. Barriers included craving for a cigarette, low level of education, unemployment, easy access to tobacco in the hospital setting, lack of knowledge about quit strategies, and limited space and privacy at the clinics. Findings show that the risk of smoking relapse could be reduced through consistent follow-up upon completion of TB therapy and receiving a disease-specific smoking cessation message. CONCLUSIONS Raising awareness of smoking-related health risks in patients with TB and implementing guideline-recommended standardized TDT within national TB programmes could increase smoking cessation rates in this high-risk population.


INTRODUCTION
The 'dual epidemics' of pulmonary tuberculosis (TB) and tobacco smoking are major global public health challenges faced especially by low-and middleincome countries (LMICs) 1,2 . Tobacco smoking increases the risk of pulmonary TB infection, development of pulmonary TB and related mortality, and is closely associated with multi-drug resistant TB 3 . Smoking is positively associated with poor TB treatment outcomes, especially treatment failures and early deaths 4 .
Abstinence from smoking is essential for patients with TB. TB mortality rates drop substantially after quitting smoking 5 ; interestingly, however, Jeyashree et al. 6 did not find any randomized controlled trials to support the effect of smoking cessation on TB treatment outcomes. Two comprehensive practice and policy guidelines on tobacco cessation interventions within TB programmes were developed by the World Health Organization (WHO) and the International Union Against Tuberculosis and Lung Disease (IUATLD) 1,3 . These guidelines highlight the importance of incorporating professional tobaccodependence treatment (TDT) into TB care. While only about 4% of unassisted quit attempts in the general population are successful 7 , simple advice from a clinician to patients with TB who smoke has been shown to increase abstinence rates significantly (by 30%) compared to no advice 1 . Although in general populations, behavioural support combined with pharmacotherapy is the most effective strategy in helping people to quit, there is no evidence for the effectiveness of this strategy in TB patients who smoke. While medications are widely recommended, their costs prohibit their use in LMICs 8 .
A systematic review of the effectiveness of smoking cessation interventions among TB patients was already published, but little is known about the factors that affect smoking cessation and TDT in these patients. Thus, we conducted a narrative literature review with the main aim to identify facilitators and barriers that affect smoking cessation and TDT among people with TB in LMICs.

Search strategy
A systematic search was conducted by the Institute of Scientific Information of the First Faculty of Medicine, Charles University in Prague, Czech Republic. The search was carried out in May 2019 and was followed by manual literature searches in the reference lists from the retrieved articles and through MEDLINE database to identify referenced articles and additional articles on smoking cessation in the TB context in LMICs 9 . Records were identified through searches in: 1) Ovid-EMBASE and MEDLINE databases selected, 2) EBSCO databases -Academic Search Complete database selected, 3) ProQuest, 4) Cochrane, and 5) Web of Science databases; and included articles published between January 2000 and May 2019 according to the inclusion and exclusion criteria described below (see the search strategy in the Figure 1  to be subsequently discussed and checked by at least one other reviewer. Extracted data included the following items: author/year, country, study design, sample size, study purpose, findings, limitations, and quality assessment. Quality assessment was performed after data extraction and done independently by two reviewers (KZ, EK). Randomized controlled studies (RCS) were assessed using the Cochrane Risk of Bias tool for intervention studies 10 , non-randomized studies using the Newcastle-Ottawa Scale (NOS) and modified NOS adapted for cross-sectional studies 11 .

Data synthesis and reporting
We descriptively summarised data and undertook a narrative synthesis of findings. PRISMA was used to inform reporting.

RESULTS
The initial search generated 267 potentially eligible articles after duplication removal, plus 72 records identified additionally by manual search (n=339) (Figure 1, PRISMA flow diagram) 12 . Only 36 publications were deemed relevant for review after screening abstracts and full texts according to the prespecified inclusion and exclusion criteria. Of those papers excluded, 94.4% (286/303) reported only on tobacco or TB or LMICs separately, 11 (3.6%) were excluded for being prevention or prevalence studies, or for assessing smoking as a risk factor, with the remainder (2%) not being original research.

Characteristics of eligible studies
Regarding design, the selected studies were prospective (including randomized controlled and non-randomized studies), cross-sectional studies, and qualitative studies. All studies but one (in French) were published in English. Eight of the included studies were RCS [13][14][15][16][17][18][19][20] , 28 articles reported on non-randomized studies  . Characteristics of the studies and their main findings are presented in Tables 1 and 2. Only one study recruited patients aged ≥15 years, with the participants of the other studies aged ≥18 years. Studies were conducted mainly in TB clinics, centres or units, health centres registered as diagnostic by TB program or provided DOTS services, respiratory clinics and, less often, in primary healthcare services. One study intervention was provided at home. In addition to smoking of cigarettes followed in all studies, 1 study included also rolled tendu or temburni leaf (bidi) smoking, 2 studies a hookah session, and 7 studies the use of smokeless tobacco. Data extracted from the studies were reviewed to identify possible facilitators of and barriers to smoking cessation or TDT and relapse (Table 3). Table 4 shows factors associated with smoking relapse among TB patients.

Study quality
The inclusion criteria were met by 8 RCS, two of which were secondary analyses of data obtained from the selected studies (Table 1). Low risk of bias was assessed in 7 of 8 RCS (Table 5). The inclusion criteria were met by 28 non-randomized studies of variable methodological quality ( Table 2).

Facilitators of smoking cessation/TDT in patients with TB of LMICs
Facilitators of smoking cessation/TDT in patients with TB of LMICs are summarized in Table 3.
The most frequently described facilitators that foster smoking cessation/TDT in TB patients were repeated brief interventions (including motivation and brochures) [15][16][17]28,31 followed by personalized behavioural counselling incorporated into routine TB services 24,35,43,46 . The SCIDOT project showed that adding smoking cessation intervention (SCI) to conventional DOTS increased biochemically validated 6-month abstinence 24 . RCS assessing behavioural intervention considered it an effective part of treatment increasing the success rate in quitting: • The study of Louwagie et al. 17 16 , the quit rate in the intervention group (physicians' advice) was higher compared to the control group, but with no significant difference. However, the study evaluated only a 1-month abstinence period in a relatively small sample. Three RCS studies confirmed the efficacy of combined interventions (behavioural support plus pharmacotherapy) in achieving longer-term abstinence at six months: • The ASSIST study compared the success rates in a group treated by behavioural support (30-min consultation to encourage patients to plan smoking cessation 1 week later, and a 10-min session to review progress) combined with 7 weeks of bupropion therapy (75 mg/day during week 1, and 150 mg/day thereafter) to behavioural support only and usual care 20 . • A similarly combined intervention that included behavioural therapy plus medical treatment with bupropion 150 mg/day during week 1, increased to 300 mg/day through week 9 led to success rates of 71.7% vs 33.9% for the brief advice group vs 9.8% for a control group receiving only the short-course, directly-observed treatment (DOTS) regimen (p<0.001) 13 . • Biochemically verified quit rates were higher in the intervention arm (6 weeks of nicotine gum after which both arms received the same counselling) than in the control arm (47.8% vs 32.4%, p<0.001) 19 . Two studies showed efficacy of repeated tobacco use intervention follow-up at a minimum of 6 months after end of TB treatment 30,43 .
In a secondary analysis of the ASSIST study 20 , Elsey et al. 14 concluded that patients diagnosed with TB were more likely to be abstinent than those diagnosed with other respiratory conditions. Although intervention of nicotine replacement treatment (NRT) (nicotine gum 2 mg for smokers up to 25 bidis/cigarettes/day or 4 mg for those smoking more for 6 weeks) combined with counselling achieved higher quit rates (47.8% versus 32.4% for control group) and a greater reduction in TB score was seen in intervention arm, TB score did not meaningfully change at 8 and 24 weeks. Subsequent to treatment completion, most patients in both arms reported re-initiation of tobacco smoking (80.6% vs 79.7%).
The trial did not have a 'drug treatment only' arm without counselling. Also, the results of the study are ascribable to predominantly a single centre. The absent sputum production in a significant proportion of patients led to high loss to follow-up of the culture reports. Socioeconomic factors were not noted during the study.    The study compared persons motivated to quit smoking in an intervention group with those contemplating quitting smoking in a control group; therefore, the observed difference in smoking cessation between the groups would likely not have been so great.
Potential mis-classification of exposure due to self-report. The use of cotinine concentration has its own limitations, including the detection of tobacco chewers and patients using NRT, and failure to detect those who had not smoked for >48 h. *** ***

Review Paper
Tobacco Induced Diseases The relapse rate of SLT use was much higher than that of smoking because most tobacco messages provided by doctors to patients were general in nature and focused on smoking.
More tobacco and TB-specific cessation messages need to be given to these patients.    138 former smokers were reclassified as current smokers upon reporting smoking within 2 months before TB diagnosis, resulting in 26% of current smokers (184). By categorizing smoking status solely based on participants' self-reported status at the time of interview, the group of participants who were current smokers but quit at symptom onset were misclassified as former smokers, when in reality they were smoking at the onset of TB symptoms.
Not reported **** ***  Potential of recall bias when asking ex-TB patients about smoking levels. Our intention was to assess general levels of smoking at different points of time. Some of these former patients resumed smoking at the same levels as they did prior to illness, while others smoked at lower levels, mistakenly thinking that smoking at such levels is relatively safe.

Review Paper Tobacco Induced Diseases
** ***  Their self-rated ability to communicate the 5 As improved significantly between pretraining and post-training, and to provide smoking cessation support improved without statistical significance. There is a dose-response relation between the session length of person-toperson contact and successful treatment outcomes. However, even minimal interventions lasting less than 3 min increase overall tobacco abstinence rates. Person-to-person treatment delivered for four or more sessions appears to be especially effective in increasing abstinence rates.
The confirmation regarding quitting of tobacco use was subjective assessment based on the self-statement by the patients. It was not validated by performing tests such as urine cotinine or carbon monoxide analysis of breath. What are the barriers to smoking cessation among DR-TB inpatients in South Africa?
Using smoking as a coping mechanism was identified as an addiction-related barrier (for more details, see Table 3). Lack of access to smoking cessation interventions is a key structurallevel barrier highlighted in this study.
This study recruited participants who were inpatients and were being treated for drug-resistant tuberculosis; therefore, the generalizability of the results to outpatients is limited.
*** *** To determine whether a modified version of The Union's ABC guideline (5-10 min of brief advice to quit smoking) in Bangladesh was effective in promoting smoking cessation among TB patients and determinants associated with smoking cessation Overall, 82% (464/562) of smokers had quit and the quit rate increased progressively from the first follow-up to the end of TB treatment (usually at month 6 or 8). Patients were considered to have quit smoking if they reported that they had not smoked tobacco in the past 15 days.
This was a pilot study and may have generated an exceptionally high level of enthusiasm for counselling that led to higher quit rates. Such enthusiasm may not be sustained over the long term if introduced more widely. Self-reporting of quitting. *** ***   Table 3.
Use of multiple data sources (health workers, policymakers and patients), multiple methods (focus groups, interviews and questionnaire) and drawing on the theoretical framework of COM-B to guide data collection and analysis.
*** *** Living in urban areas, office jobs, being single significantly increased the intention to quit smoking 22 Combined interventions 13,19,20 Brief, but repeated interventions, motivation, brochures [15][16][17]28,31 Tobacco-free healthcare facilities 25 Time from waking to first cigarette of >30 min, routine screening for smoking, having a smoke-free home and display of 'no smoking' sign at home, regular reminders and encouragement of by family members to quit smoking 25 Willingness to quit -higher in those with previous attempt(s) in the past year 32 Incorporating of training in brief advice into existing training of DOTS providers 33 Personalized behavioural counselling incorporated into routine TB services 24,35,43,46 High level of awareness regarding smoking risk for health 36 Multiple risk behaviour interventions 37 Repeated tobacco use intervention follow-up at a minimum of 6 months after end of TB treatment 30,43 Providing intervention not only at a health facility but also on a daily basis at community level by health volunteers 46

Barriers
High nicotine dependence 18 Misclassification of current smokers as former smokers at the time of TB diagnosis (= quit smoking at the onset of TB symptoms 34 ) Limited space and privacy at the clinics 37 Male gender, lower education 38 Daily smoking of more than 15 cigarettes/bidis at the time of diagnosis 41 Patients' cards without the provision to include about brief advice on smoking cessation given which has been mentioned in the TB treatment guidelines; lack of coordination between the TB treatment programme and tobacco cessation 39,43 Identified in patients with drug-resistant TB: • Addiction-related personal barriers -initiating smoking as teenagers, craving for a cigarette, smoking as part of the daily routine, failed quit attempts (relapses when feeling better) • Structural (institutional) factors -lack of impact of health education sessions, lack of extramural activities when on hospital admission, lack of access to smoking cessation interventions (unaware of any available aids to stop smoking or NRT), easy access to cigarettes within a hospital setting (from staff, peers, visitors, shops close to hospital, hospital café) 44 • Non-addiction-related personal barriers -lack of knowledge about quit strategies, lack of willpower to quit, psychosocial stress, peer smokers' influence Barriers for HW to provide BSS: institutional lack of resources (insufficient space, high patient load, no reporting/recording of tobacco, overwork) and an absence of professional support through monitoring and evaluation 48 Possible barriers to smoking cessation/TDT -patients'/staff's knowledge, attitudes Lack of resources (human, financial), low level of education of health providers on smoking cessation 21 Beliefs that smoking is fun, calms nerves, relieves all life stresses 23 Stigma (especially in women to admit using tobacco) 26,48 Tolerance of smoking or snuff dipping at a health centre by medical assistants providing SCI, smoking staff 30 Not considering low-to-moderate level smokers to be real smokers, particularly those who have reduced their smoking from one to two packs a day to just a few sticks 41 Less knowledge that smoking increases risk of stroke and heart attack 36 Physicians' low levels of knowledge regarding the effect of smoking on TB -particularly physicians who smoked did not view smoking cessation as an integral part of TB treatment 45 Decrease of initial enthusiasm for counselling (seen in pilot studies) over the long-term if introduced more widely 46 Relying on the fact that the diagnosis of TB alone will lead to a more significant decrease in the prevalence of smoking among patient with TB 47 Some smokers' characteristics were found to be facilitators too: willingness to quit -higher in those with previous attempt(s) in the past year 32 , time from waking to the first cigarette of >30 min, having a smoke-free home, display of 'no smoking' sign at home 25 , and a high level of awareness regarding smoking risk for health 36 . Other identified facilitators were: living in urban areas, office jobs, and being single, which significantly increased the intention to quit smoking 22 .
Facilitators originating in the healthcare system were the following: incorporating training in brief advice into existing training of DOTS providers 33 , multiple risk behavior interventions 37 , and tobaccofree healthcare facilities 25 . Finally, providing intervention not only at a health facility but also on a daily basis at community level by health volunteers facilitated smoking cessation 46 .

Barriers to smoking cessation/TDT in patients with TB of LMICs
Barriers to smoking cessation/TDT in patients with TB of LMICs are presented in Table 3.
Male gender, lower education, high nicotine dependence and daily smoking of more than 15 cigarettes/bidis at the time of diagnosis, may be marked as non-influenceable risk factors that are negatively associated with success in smoking cessation/TDT 18,38,42 . Possible patients' barriers to quit smoking may be less knowledge that smoking increases risk of cardiovascular diseases 36 and their beliefs that smoking is fun and helps to deal with stress 23 .
The qualitative study of Shangase et al. 44 conducted in patients with drug-resistant TB in South Africa found 2 categories of barriers to smoking cessation in patients with drug-resistant TB: 1) personal factors including addiction-related barriers (initiating smoking as teenagers, craving for a cigarette, smoking as part of the daily routine, failed quit attempts -relapses when feeling better) and non-addiction-related barriers (lack of knowledge about quit strategies, lack of willpower to quit, psychosocial stress, peer smokers' influence); and 2) structural (institutional) factors (lack of impact of health education sessions, lack of extramural activities when on hospital admission, lack of access to smoking cessation interventions (unaware of any available aids to stop smoking or NRT), easy access to cigarettes within a hospital setting (from staff, peers, visitors, shops close to hospital, hospital café). Socio-cultural influences (i.e. family/friends smokers) 26 Brief advice focused only on smoking could lead to a higher rate of SLT relapse seen as a form of harm reduction 29 Receiving a disease-specific cessation message -associated with a lower likelihood of smoking relapse 40 Perception of low-moderate level smoking as harmless 41 Period of follow-up: increase in relapses within the 6 months of treatment and within the 3-6 months following treatment [40][41][42]  Several barriers were connected to the healthcare system itself: limited space and privacy at the clinics 37 , lack of coordination between the TB treatment programme and tobacco cessation 39,43 , lack of resources (human, financial), low level of education of health providers on smoking cessation 21 , tolerance of smoking or snuff dipping at a health centre by medical assistants providing SCI, and smoking staff 30 .
Regarding HW, barriers to provide BSS were as follows: institutional lack of resources (insufficient space, high patient load, no reporting/recording of tobacco, overwork), an absence of professional support through monitoring and evaluation 48 or misclassification of current smokers as former smokers at the time of TB diagnosis (= quit smoking at the onset of TB symptoms) 34 . Low level of education of health providers on smoking cessation 21 , e.g. relying on the fact that the diagnosis of TB alone will lead to a more significant decrease in the prevalence of smoking among patients with TB 47 , and decrease of initial enthusiasm for counselling over the longterm 46 , may be barriers to provide SCI.
Staff knowledge regarding the effect of smoking on TB, as well as attitudes to smoking cessation may have an impact in providing smoking cessation/TDT within TB care 45,48 . Shin et al. 45 in their qualitative study pointed out that mainly those physicians who smoked did not view smoking cessation as an integral part of TB treatment. Other barriers were not considering low-to-moderate level smokers to be real smokers, particularly those who have reduced their smoking from one to two packs a day to just a few sticks 41 , and less knowledge that smoking increases risk of stroke and heart attack 36 .
Another important barrier is mentioned in the Boeckmann et al. 26 and Warsi et al. 48 studies -asking about tobacco use was perceived a sensitive issue, especially among women who may not admit to tobacco use. Table 4 shows factors associated with smoking relapse among TB patients in LMICs. Ng et al. 40 conducted qualitative interviews with TB patients and concluded that the majority of daily smokers quit smoking when diagnosed with TB; however, over one in three of those patients relapsed within 6 months of TB treatment completion. Similarly, Pradeepkumar et al. 42 and Nichter et al. 41 found that most relapses occurred after completion of treatment.
Short duration of pharmacotherapy might influence the number of patients who quit smoking, according to the randomized controlled study of Sharma et al. 18 . Possessing a disease-specific cessation message and focusing on all forms of tobacco use may decrease the probability of tobacco-dependence relapse 29,40 .

Statement of principal findings
The studies included in this narrative literature review highlighted the feasibility and efficacy of incorporating brief advice as well as specialized treatment for smokers into TB care. Based on the findings from the selected studies and identification of factors affecting successful quitting, we propose a summary of implications for practice regarding smoking cessation or TDT in patients with lung TB in LMICs in the following paragraphs.
Tobacco-free TB centres and non-smoking staff are a condition sine qua non to support their patients in quitting. The centres' staff members should have an opportunity to treat their potential tobacco dependence or not to smoke during their working hours (e.g. to reduce withdrawal symptoms by nicotine replacement therapy) 25 .
The staff should understand the importance of quitting smoking for TB prognosis, of providing brief interventions, of their own non-smoking status; regular refresher training session should be arranged and made available.
In TB centres, a brief, repeated and empathic intervention should be provided to all patients with TB who smoke. It is possible that a majority can quit smoking when diagnosed with TB 40 or at the time of onset of TB symptoms 34 . Support for these patients should be part of routine care. They would benefit from regular monitoring of their withdrawal symptoms (WSs) and from an offer of pharmacotherapy in the case of intensive WSs, and brief support at each session within their respective TB centres. Motivational intervention should increase the number of patients quitting in the future. Empathic intervention increases the probability that the majority of patients will admit smoking. A potential gender barrier should also be taken into account 26 .
While it may seem unnecessary to measure CO levels in patients with suspected TB at the first consultation to verify their smoking status 27 , such a strategy could help as bio-feedback for patients who are quitting.
All patients in TB centres who smoke should be educated, through a brief intervention, about the risks of smoking associated with their disease and the importance of the 'not-even-one-puff' rule, because a higher level of awareness implies a higher probability of quitting and a lower one a tendency to relapse 36,40 . Likewise, patients should be told that use of smokeless tobacco is a potential factor for smoking relapse 29 . Screening for smoke-free homes and recommendations to create them should be part of routine brief advice in smoking cessation.
Health volunteers may play a most important role in daily provision of intervention outside of health facilities directly in patients' communities 46 .
Tobacco-dependence treatment ranges from brief advice to intensive behavioural support together with pharmacological treatment 7 . It has been proven by RTCs that behavioural support combined with first-line pharmacotherapy (bupropion and nicotine replacement therapy) is effective in achieving prolonged abstinence at six months in adult TB patients participating in TB programmes in LMICs 13,19,20 . One of the possible less expensive pharmacotherapy options is cytisine, whose efficacy compares to that of currently licensed products. A study from Bangladesh 8 may bring interesting findings; two face-to-face behavioural support sessions will be delivered and cytisine (active arm) or matching placebo (control arm) will be administered in a 25-day course. The success rate may depend on pharmacotherapy duration (at least 3 months) as well as on the type of intervention provided. A brief motivational session (15-20 min) and the ABC approach (A=ask, B=brief advice, C=cessation support) are more effective than only a smoking cessation message. The specialized TDT should be provided by a trained doctor, nurse, psychologist or another health care provider, with such a specialist ideally available in each TB centre 49 .
Several months' follow-up after TB treatment completion with brief behavioural support and offer of pharmacotherapy in the case of a lapse or early relapse should be available as prevention of relapse in abstaining patients. A high number of patients relapsed 3-6 months after completion of TB treatment 40,42 .
It is critical that national policymakers support effective tobacco control policies developed by the World Health Organization (WHO) Framework Convention of Tobacco Control (FCTC). According to the WHO MPOWER policy package, the main effective strategies designed to reduce the prevalence of tobacco use in the general population include those affecting the availability of tobacco products (taxes, advertising), minimizing exposure to tobacco smoke (smoke-free public indoor spaces without exception) and offering specialized help. Limiting bans on tobacco advertising and the ease of access to cheap tobacco, often in a single cigarette form, enhance barriers to quit 50 .

Limitations and strengths
Although we conducted quality assessment of eligible studies, this is not a systematic review. Heterogeneous study designs made it impossible to conduct a metaanalysis and to assess the importance of individual factors in the quit process. However, this review maps and summarizes the available data on the topic, so that the formulated barriers and suggested facilitators can be identified for clinicians and policymakers to use. This summarized evidence could facilitate implementation of TDT in patients with TB in LMICs as an underused opportunity to significantly improve TB treatment outcomes and overall health.

Implications for policy, practice and research
Effective TDT provided by trained healthcare professionals is based on the same pillars, regardless of country or socioeconomic status. These include: a brief intervention as a routine part of healthcare; appropriately adapted information materials about the harmfulness of smoking in relation to TB and about the options in a smoking cessation programme; trained non-smoking staff in specialized centres; availability of pharmacotherapy; and regular follow-up. All these should be incorporated as a new standard into care of TB patients who smoke.

CONCLUSIONS
Raising awareness of the health risks of smoking in patients with TB as well as health providers and routine offer of tobacco-dependence treatment in established system of TB treatment in tobacco-free healthcare facilities may significantly contribute to increasing the abstinence success rate in patients with TB. Due to its low current availability but high potential impact, it is crucial to consider TDT in patients with TB as a topic for future research.