Improving treatment outcomes of tuberculosis
Pradipta, Ivan
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10.33612/diss.113506043
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2020
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Pradipta, I. (2020). Improving treatment outcomes of tuberculosis: towards an antimicrobial stewardship
program. University of Groningen. https://doi.org/10.33612/diss.113506043
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8
DISCUSSION AND FUTURE
PERSPECTIVES
MAIN FINDINGS
Our meta-analytic study (chapter 2) showed that previous TB disease and prior drug treatment are the most influential risk factors for the development of multi-drug resistant tuberculosis (MDR-TB).(1) The study confirmed that drug resistance might occur because of treatment issues in an earlier episode of the disease. Another finding from this meta-analysis supported the essential role of drug treatment because non-adherence to drug regimens was highly associated with the development of MDR-TB. Importantly, the effects of several other risk factors for MDR-TB, such as male gender, being married, urban domicile, homelessness and having a history of imprisonment vary by geographical area. This so-called effect modification highlighted that prognostic studies for MDR-TB should be conducted locally to enable the development of the most effective strategy to control drug-resistant TB (DR-TB).
The Netherlands, as an example of a low burden TB country, showed a high success rate in TB treatment from 2005 to 2015.(2,3) Our database study confirmed that approximately 92% of patients with a diagnosis of drug-susceptible tuberculosis (DS-TB) were successfully treated, while the remainder experienced either defaulted or failed treatment or died due to TB (chapter 3). Multivariable regression analysis revealed that having an age between 18 to 24 years, being homeless or prisoner, and having diabetes predicted unsuccessful treatments, while several other factors, such as older age, combined pulmonary and extra-pulmonary TB, central nervous system or miliary TB, drug addiction and renal insufficiency/ dialysis predicted the severe outcome mortality among adult DS-TB patients. Furthermore, in the Netherlands, the treatment success slightly increased over time and 95% of patients with the diagnosis of DR-TB were cured (chapter 4). The highest proportion of DR-TB cases existed of patients with isoniazid mono- or poly-resistance (68%), followed by patients with MDR-TB (18.9%), pyrazinamide mono-resistance (8.3%), rifampicin mono- or poly-resistance (3.1%), extensively drug-poly-resistance (0.7%), and ethambutol mono-poly-resistance (0.1%). Among all DR-TB cases, patients with MDR-TB, substance abuse and homelessness were more likely to experience unsuccessful treatment, while miliary and central nervous system TB predicted TB mortality. In addition, male gender and substance abuse were more likely to predict poor outcome after MDR-TB treatment. Our study highlighted that the majority of DS-TB and DR-TB cases in the Netherlands were foreign-born and most of the DR-TB patients were diagnosed with primary drug-resistant TB. This situation is substantially different from a high TB burden country such as Indonesia.(4–6)
In a qualitative study, we identified several barriers to successful TB treatment in a high burden TB setting in Indonesia (chapter 7). We identified three central themes from the patient perspective: 1) socio-demography and economy; 2) knowledge and perception; 3) TB treatment. The socio-demography and economy theme comprised barriers such as
stigmatization, lack of family support, long-distance to public health service, transportation difficulties, costs of the private and public health service, cost of transportation and loss of household income. The knowledge and perception theme consisted of barriers such as lack of knowledge about TB (i.e., TB program, diseases and treatment), negative perception of the own patient condition, and negative viewpoint of public health service, while barriers related to adverse drug reaction and long duration of treatment were classified within the TB treatment theme. The results of data analysis demonstrated that all different barriers could be interrelated. In all, the most important barriers that should be prioritized for intervention are part of the following five main barriers: lack of TB knowledge, stigmatization, long-distance to the health facility, loss of household income and adverse drug reaction that can lead to non-adherence.
Medication adherence and persistence are still one of the main concerns for treatment success in chronic diseases, such as tuberculosis. The drug adherence assessments are therefore crucial to improve treatment outcomes. In a systematic review, we included studies on multiple cardio-metabolic medications since such studies that used prescription databases were lacking in the scientific TB area (chapter 5).(7) We demonstrated that adherence to multiple medications is currently measured using several different approaches, namely: 1) “all medication” which is adherence to at least 80% utilization of each medicine; 2) “both medication”, adherence to two medication by calculating the number days when both of medicine were available; 3) “any medication”, adherence to at least 80% utilization of one of the medication; 4) “average medication”, adherence assessed by calculating adherence at the individual level and then calculate the overall average; 5) “highest/lowest medication”, adherence determined by calculating adherence for each medication class and presented by both the “highest” and the “lowest” level as measure of adherence. Regarding persistence to medication, two main approaches were applied: 1) persistence to “all medication”, and 2) “both medication”. In the TB context, the “all medication” approach with an interval-based measurement can be used to measure treatment adherence of anti-TB drugs, because the regimen should be strictly taken by patients within a defined period. However, the prescription system and quality of the database should be considered when measuring drug adherence and persistence in TB patients using a prescription database.
We reviewed available randomized controlled studies on intervention to improve medication adherence in chapter 6. In contrast with methodologies of measurement of drug adherence used with prescription databases (chapter 5), we identified several other different measures in the various interventional studies, such as directly observed therapy, patient self-report (e.g. interview and questionnaire), pill counts, patient attendance and electronic medication monitor (e.g. short message service). We identified that the interventions targeted several aspects, including socio-economic, health-care, patient, and treatment aspects. However, not all interventions appeared to improve medication adherence significantly. Several
interventions were found effective in improving adherence and outcomes of active TB patients, i.e. DOT by trained community members, SMS combined with TB education, a reinforced counseling method, monthly TB voucher, drug box reminder, and a combination drug box reminder with text messaging. In the LTBI patients, shorter regimens and DOT interventions effectively improved treatment completion. Interestingly, intervention using DOT showed different effects on the study outcomes, which indicates that the impact of interventions can vary across studies and settings.
IMPLICATIONS AND FUTURE PERSPECTIVES
Our work demonstrated the important role of the management of TB drug treatment, which may substantially vary across countries and modify the impact on TB care. Therefore, strategies to develop an effective anti-microbial stewardship program for TB disease should consider local issues.
The implication for the Netherlands as a low burden TB country
In the Netherlands with relatively high treatment success rates for TB disease (92-95%), management of TB drug treatment is not a major issue, though further small improvement is still possible.(2,3) The current screening strategy to find and treat latent tuberculosis infections (LTBI) and active TB patients should even more focus on migrants since the majority of TB cases are foreign-born, while drug resistant TB cases are dominated by primary drug resistance. Strategies in TB screening among migrants in low TB countries may include pre-entry screening,(8,9) one point-of-entry screening,(10) post-entry screening(9,11–13) and screening at all three points.(14) Pre- or post-entry screening were reviewed as a favorable strategy compared with no-screening in low TB incidence countries.(15) Although entry screening for asylum seekers and people from high endemic TB countries were efficiently implemented in the Netherlands,(16,17) the effectiveness and cost-effectiveness of entry screening strategy are still under debate.(18–20) Such studies are needed to support screening strategies as part of an antimicrobial stewardship program in low TB countries, such as the Netherlands.
We confirmed that hard-to-reach populations (i.e., migrants, homeless people, drug or alcohol abusers, and prisoners) are in most studies identified as the major driver for continuing TB disease in low incidence countries.(2,3) Hence, screening and treatment programs should be focused on this population to be able to achieve the national target. Health care-seeking behavior in these hard-to-reach populations has been reported to be suboptimal in low TB-incidence countries.(21) It is therefore essential to find and treat these high-risk groups to avoid therapeutic failure, further disease transmission and development of MDR-TB.
Furthermore, our work suggests that increasing awareness among patients that acknowledges and addresses local perceptions can be used to improve the outcome of TB treatment in the hard-to-reach populations.(22,23) Intervention programs, such as family and community education, treatment-supporters, counseling and incentive policy, considering individual culture and belief can be developed as part of an antimicrobial stewardship program that specifically focuses on these hard-to-reach populations in the Netherlands. Moreover, screening and possible chemoprophylaxis for latent TB in dialyzed patients may prevent the activation of TB that can potentially lead to a poor outcome of TB treatment (24,25). The activation of TB is due to the alteration of immune response associated with uremia and dialysis exacerbation that can be a predisposing factor for active TB in dialysis patients (24). Potential drug toxicity due to drug accumulation in patients with insufficient renal function (26) may be tackled by the implementation of therapeutic drug monitoring (TDM). TDM can reduce the incidence of adverse drug reactions and optimize the treatment,(27,28) especially in diabetics and impaired renal patients.(29) To have a more designed care program and treatment, admission of the hard-to-reach populations to modern sanatoria hospitals (TB center) for the first treatment period may further improve the treatment outcome in those groups. Although a recent study showed that LTBI screening among an Eritrean group of asylum seekers is feasible to be implemented in the Netherlands,(30) further study on the cost-effectiveness of screening programs in populations of immigrants (e.g. asylum seekers, legal and illegal immigrants) in the Netherlands is needed. Moreover, since population migration from high endemic TB countries has been an essential factor for developing TB in the Netherlands, cooperation to solve TB problems in the origin countries can be beneficial to further reduce the incidence of TB in the Netherlands.
The implication for Indonesia as a high burden TB country
In Indonesia, TB care is managed both by the public and private health sectors, from primary to tertiary healthcare facilities. The Community Health Centre (CHC), designated as ‘Puskesmas’, is a backbone TB care facility established as the primary public health sector at the sub-district level. Managed by the local government at the district level, CHCs have the responsibility to identify, notify and monitor TB patients within their specific area. TB care is also supported by referral hospitals, although not all referral hospitals have the facilities to support MDR-TB care. MDR-TB is therefore managed in several centralized and specialized hospitals in Indonesia.
An extremely high economic burden due to TB was reported in Indonesia and an antimicrobial stewardship program may reduce these costs.(31) Our qualitative study suggests that such programs should cover several activities, such as promoting TB knowledge and government’s programs, reducing TB stigma in the society and health facility, providing better access to a qualified TB diagnostic facility and treatment as well
as facilitating social protection for TB patients, notably for those with the lowest income groups. Several strategies are required to develop an optimal program, including engaging leadership commitment, strengthening CHC for TB case detection and treatment, increasing public-private mix (PPM), and re-defining the pharmacist’s role in TB management.
Engaging leadership commitment as part of an Antimicrobial Stewardship Program
The governmental system of Indonesia has been shifting from a centralized government to a decentralized government since 1999.(32) The local governments at the district level have more authority to manage their area than earlier in the decentralized era. It enables the authority of local governments at the district level to operationalize national policies, such as TB policies. We identified several problems concerning such policies, such as lack of health care staff working in a TB team and the absence of efficient facilities for TB diagnosis and treatment at the district level. We also observed that collaborations between CHC and private sectors (e.g., private clinics, hospitals and pharmacies) are not optimal and an MDR-TB center is not always available at the district level which hampers access of patients to such qualified TB care. From the patient perspective, we identified that defaulted treatment occurred in the low socio-economic groups due to the loss of household income. The principal of the local government at the district level, who is supervised by the mayor (regent), has an essential role in the TB management at the district level. Accordingly, leadership commitment and awareness for TB elimination should not only be part of the central government but also by local governments to be able to achieve the national and global target of TB elimination. The leaders should be committed to providing proper facilities, human resources, finance, information technology and regulation to establish qualified TB care. Decentralized MDR-TB treatment at the district level may improve the accessibility of MDR-TB patients to have qualified TB care.(33) Considering sub-standard TB management(34) and incompliant TB guidelines in the private health facilities,(35) implementation of strong regulations and cooperation between local government and the private sectors at the district level should be performed to fight TB together in the same framework. Social protection schemes, reaching beyond direct medical costs, such as loss of household income, should be a concern for the government. This might tackle issues related to defaulted treatment due to the patient’s decreasing household income, especially for patients with the lowest income. As a large democratic country, the role of non-governmental TB actors (such as non-governmental organizations, academics, and TB communities) will be important to advocate leadership commitment for TB elimination in Indonesia. Therefore, synergism programs involving local government, private health sectors and TB actors should be developed to explore and solve the existing problems.
Strengthening the capacity of the community health center for TB case detection and treatment
Strengthening public health facilities is essential. According to our qualitative study, human resources and facilities at the CHC level should be improved. According to the national TB guideline, the TB program at the CHC level should be operated by at least three TB officers, i.e., one general practitioner, one nurse and one laboratory analyst.(36) However, we observed that the workload of the TB officer is high. The TB officers should manage all TB programs, such as case detection, diagnosis, drug services, TB coordination for Public-Private partnership, and reporting. The tasks of TB officers are burdened with operating other non-TB programs at CHC level.
We identified a lack of laboratory facilities for sputum tests as well as limited room for TB examination, counseling and treatment in some CHCs. An analyst for sputum tests is not always available in the CHC. This might lead to diagnostic problems at the CHC level. Regarding a TB room, we observed that rooms for TB diagnosis and treatment showed a lack of space and inadequate protective equipment as well as ventilation in some CHCs. To avoid disease transmission in the health facility and provide an optimal TB care, TB officers should be supported with proper equipment and environment, such as protective equipment and examination for TB officers (e.g., special mask, routine TB test), patient environment (e.g., privacy and isolation room), and staff environment (space for both clinical and administrative work).
Increasing public-private partnership programs
The global framework for TB elimination emphasizes the need for collaboration between public and private parties, also called public-private mix (PPM). Developing networks between public and private sectors in TB management should be continuously developed as an effort to manage TB cases in Indonesia. Although a PPM initiative has been implemented within some sectors, our observation is that the engagement should be strengthened especially within private clinics. The observed unwillingness of some private clinics to refer or report TB patients to the TB officer at CHC/district level leads to loss to follow up of TB patients. Deviations in diagnosis and treatment procedures in some private sectors from the national guideline procedures were also identified in our interview with TB officers. Potential lost to follow up commonly occurs in patients who use private services because few private sectors have adequate resources to follow up defaulted patients. Consequently, many TB patients are under-reported and defaulted treatment occurs due to high medical costs.
As previously described, a strong local government regulation followed by adequate socialization and implementation of the regulation as well as strict law enforcement is required to engage private sectors in TB management. Punishment schemes in the form
of deregistering private practitioners or revoking the license may be effective in engaging private sectors for working together under national guidance. Such regulation option was proposed by Healy and Brathwaite (2006) and Moke et al. (2010), who suggested that deregistration or revoking a license can be used as a policy when noncompliance to the standard TB diagnostic and treatment guidelines persist in the private sectors.(37,38) To improve treatment outcomes, broadening the public-private partnership can be performed with community pharmacists to support TB case detection and treatment.
Re-defining the pharmacist’s role in the TB management
Pharmacists are health care professionals who are responsible for the rational use of medicines. Nowadays, the new paradigm of pharmacy not only focusses on the drugs but also on the patient outcome, preferably in a personalized way. Consequently, drug-related issues in TB can be explored and targeted by pharmacists as part of their activities to ensure the rational use of medicine. However, the current regulation states that there is no direct service to the TB patients provided by pharmacists. The pharmacist is only involved in the non-direct service, such as management of TB logistics and medicine.(36) On the other hand, a massive program to involve pharmacists in the society has been launched by the Ministry of Health, Indonesia, in close collaboration with the Indonesian Pharmacist Association. There is a national program called “GEMA CERMAT” that attempts to encourage and support pharmacists in the conduct of direct services to patients or society to improve the rational use of medicine. Selected pharmacists are appointed as “agents of change” who should be a role model for direct involvement of pharmacists into the society or patients for improving the rational use of medicine. Within the TB context, it is now an opportunity to develop a national TB stewardship program that involves pharmacists in TB areas. Referral activities of community pharmacists may be implemented as a function to refer suspected TB patients from private pharmacies to the CHC. Currently, the referral function of the community pharmacist does not work effectively because of the lack of TB awareness among pharmacists and the absence of pharmacist guidelines for the referral function. Our field notes made during focus group discussions with pharmacists (chapter 7) demonstrated a lack of awareness about TB disease from private pharmacists due to only few diagnosed TB patients who visit their pharmacies. TB patients do not visit the pharmacy because a TB diagnosis via CHCs results in receiving free medications. The community pharmacists in our study felt that TB is a low prevalence disease and nothing to be worried about. This is in contrast with the fact that the pharmacy is the typical facility for the initial health care seeking of suspected TB patients in Indonesia. (39) Therefore, the involvement of community pharmacists in stewardship programs has the potential to increase TB case detection in Indonesia.
Regarding the referral concept, a pharmacist should be able to screen suspected TB patients when disease symptoms are presented in the private pharmacies and to refer the suspected TB patient to CHC for further examination. The referral of suspected TB patients will be more effective if there is excellent communication between community pharmacists and TB officers at the CHC. The pharmacist may schedule for the medical examination at the nearest CHC of the suspected TB patient. In case the suspected patient does not attend for the medical examination at the CHC, a TB officer will follow up the patient using contact details registered by the pharmacist. Hence, an active role of pharmacists and TB officers is needed to increase case detection and improve treatment in Indonesia. This concept may also raise awareness of the pharmacists for not dispensing anti-TB drugs directly without a medical prescription. The flow diagram of the pharmacist’s referral activity is further depicted in Figure 1.
Figure 1. Flow diagram of the referral function of the suspected TB patient from a pharmacy to a
community health center.
As mentioned earlier, drug-related problems are one of the major issues in TB treatment. Adverse drug reactions and inappropriate drugs are among the main factors of defaulted treatment. Community pharmacists at the private pharmacy can act as a treatment supporter. As a treatment supporter, community pharmacists can provide drug consultations and information as well as contribute to directly observed treatment (DOT) for TB patients. Furthermore, community pharmacists can be involved in promoting the rational use of anti-tuberculosis drugs in society. A drug promotion program, a stewardship program for medication and health education in the TB area, can be performed by community pharmacies coordinated by CHC’s pharmacist at the sub-district level. The program can be developed to improve awareness and knowledge about TB disease, treatment and program. The educational program can also include a topic about how people can support TB patients
for successful treatment that may be beneficial in reducing TB stigma in society, improving treatment outcome and controlling DR-TB.
A pre-condition is required to engage community pharmacists in TB management. A structured training program to increase awareness and knowledge about TB disease, treatment and program should be delivered to the community pharmacists. A pharmacist’s guideline in TB management will support their involvement in TB management. An incentive strategy may be needed as a complementary program to attract and motivate community pharmacists participating in TB management. The incentive can be the credit points from professional organizations for continuing pharmacist licenses or the combination with financial compensation. Importantly, involving pharmacists as a part of the TB team at CHC level is necessarily required. The CHC’s pharmacist will coordinate activities of TB management that are related to community pharmacists at the sub-district level. Therefore, the availability of a trained pharmacist in a CHC is crucial to have a successful stewardship program. An explorative intervention study should be performed to analyze the process and possible impact of the implementation.
The role of pharmacists in the management of TB disease was studied in another setting. A study in India showed that involving community pharmacists in referring suspected TB patients to health facilities improves an earlier detection/case finding of TB patients. (40,41) Moreover, educational programs and drug monitoring provided by a pharmacist demonstrated a significant improvement of adherence to TB treatment among TB and MDR-TB patients.(42,43) Other pharmacist’s activities in TB program could be employed, such as drug assessment for the appropriateness of TB treatment and comorbidity treatment, drug monitoring (proposal to monitor parameters and therapeutic drug monitoring for drug adjustment), promotion of treatment adherence (assessment knowledge and beliefs from patients, patient education, monitoring adherence by pill count, urine check or therapeutic drug monitoring/TDM), medication review, and participation in direct observed treatment (DOT) programs.(40,42,44,45) Such activities may all be developed as part of an antimicrobial stewardship program for TB in Indonesia.
Improving treatment adherence in TB disease
Treatment adherence is one of the critical factors for successful TB treatment. Our systematic review described several approaches to monitor adherence and persistence of multiple medications in cardiometabolic disease using prescription databases (chapter 5). Monitoring TB treatment adherence using a prescription database can be applied and may include large numbers of patients. The so-called “all medication” measurement with an interval-based approach may be used to measure treatment adherence to anti-tuberculosis drugs. The “all medication” measurement is selected because all TB drugs are equally important and must be taken by the patients to avoid drug resistance and poor
treatment outcome. The interval-based approach is more accurate than the prescription-based approach because the period of TB medication treatment has been standardized in guidelines. For instance, active DS-TB cases should take anti-TB drugs for a 6-month treatment period. However, the assessment of treatment persistence can be challenging because the duration of anti-TB drug treatment periods is shorter than most cardio-metabolic treatments. Difficulty in assessing treatment persistence of anti TB drugs will be faced in an area that can prescribe medicines for a maximum 3-month treatment in one time of dispensing. As an example, the persistent gap is only one gap and it cannot be interpreted for the persistence of medication use for 6 month TB treatment regimen. In the case of MDR-TB, measurement of treatment adherence may be more effective using daily records of patient visits in TB facility, since the patients use injections.
Our study suggests that the prescription system and quality of prescription databases in particular areas should be considered to measure adherence. Quality of prescription databases should be assessed in terms of volume, variety, velocity, veracity and validity. We analyzed that direct monitoring is more accurate than non-direct monitoring (e.g., using a prescription database) for measuring adherence in daily practice. Furthermore, interventional strategies for improving treatment adherence should be developed incorporating local issues. We identified at least four essential factors to have a successful intervention for improvement of medication adherence in patients with TB disease and assessment: 1) characteristics of the research subject, 2) accurate measurement of treatment adherence as the study outcome, 3) type of the comparator group, 4) robustness of study design for minimizing potential bias. Since non-adherence factors can be individual, a personalized intervention that takes into account the individual factors are required to have an effective medication adherence program.
To sum up, strategies to control DR-TB by developing an antimicrobial stewardship program should consider local issues. An effective screening strategy and treatment program for immigrants and hard-to-reach populations in low burden countries as the Netherlands should be developed to achieve the national and global targets for TB elimination. In high burden countries such as Indonesia, TB treatment outcomes can only be improved by the development and implementation of an integrated antimicrobial stewardship program. Since delayed treatment has been found as a factor for unsuccessful TB treatment in Indonesia, TB case detection should be part of such a program. Several strategies are required to have an optimal antimicrobial stewardship program in Indonesia, including engaging leadership commitment, strengthening CHC as a health facility for case detection and TB treatment, increasing public-private partnership, and re-defining the pharmacist’s role in TB management.
REFERENCES
1. Pradipta IS, Forsman LD, Bruchfeld J, Hak E, Alffenaar JW. Risk factors of multidrug-resistant tuberculosis: A global systematic review and meta-analysis. J Infect. 2018;77(6):469–78. 2. Pradipta IS, Van’T Boveneind-Vrubleuskaya N,
Akkerman OW, Alffenaar JWC, Hak E. Treatment outcomes of drug-resistant tuberculosis in the Netherlands, 2005-2015. Antimicrob Resist Infect Control. 2019;8(1):1–12.
3. Pradipta IS, van’t Boveneind-Vrubleuskaya N, Akkerman OW, Alffenaar JWC, Hak E. Predictors for treatment outcomes among patients with drug-susceptible tuberculosis in the Netherlands: a retrospective cohort study. Clin Microbiol Infect. 2019;25(6):761.e1-761.e7. 4. Chaidir L, Sengstake S, De Beer J, Krismawati
H, Lestari FD, Ayawaila S, et al. Mycobacterium tuberculosis genotypic drug resistance patterns and clustering in Jayapura, Papua, Indonesia. Int J Tuberc Lung Dis. 2015;19(4):428–33. 5. Kelly PM, Ardian M, Waramori G, Anstey NM,
Syahrial H, Tjitra E, et al. A community-based TB drug susceptibility study in Mimika District, Papua Province, Indonesia. Int J Tuberc Lung Dis. 2006;10(2):167–71.
6. Parwati I, Van Crevel R, Sudiro M, Alisjahbana B, Pakasi T, Kremer K, et al. Mycobacterium tuberculosis population structures differ significantly on two Indonesian islands. J Clin Microbiol. 2008;46(11):3639–45.
7. Alfian SD, Pradipta IS, Hak E, Denig P. A systematic review of measures estimates adherence and persistence to multiple medications. J Clin Epidemiol. 2019;108:44–53. 8. Aldridge RW, Yates TA, Zenner D, White PJ,
Abubakar I, Hayward AC. Pre-entry screening programmes for tuberculosis in migrants to low-incidence countries: A systematic review and meta-analysis. Lancet Infect Dis. 2014;14(12):1240–9.
9. Campbell JR, Krot J, Elwood K, Cook V, Marra F. A Systematic Review on TST and IGRA Tests Used for Diagnosis of LTBI in Immigrants. Mol Diagnosis Ther. 2015;19(1):9–24.
10. Abdoulie S, Mohammed A. Effectiveness and costeffectiveness of screening immigrants schemes for tuberculosis (TB) on arrival from high TB endemic countries to low TB prevalent countries. Afr Health Sci. 2014;14(3):663–71. 11. Arshad S, Bavan L, Gajari K, Paget SNJ, Baussano
I. Active screening at entry for tuberculosis among new immigrants: A systematic review and meta-analysis. Eur Respir J. 2010;35(6):1336–45.
12. Bozorgmehr K, Razum O, Saure D, Joggerst B, Szecsenyi J, Stock C. Yield of active screening for tuberculosis among asylum seekers in Germany: A systematic review and meta-analysis. Eurosurveillance. 2017;22(12):1–12.
13. Campbell JR, Chen W, Johnston J, Cook V, Elwood K, Krot J, et al. Latent Tuberculosis Infection Screening in Immigrants to Low-Incidence Countries: A Meta-Analysis. Mol Diagnosis Ther. 2015;19(2):107–17.
14. Zenner D, Hafezi H, Potter J, Capone S, Matteelli A. Effectiveness and cost-effectiveness of screening migrants for active tuberculosis and latent tuberculous infection. Int J Tuberc Lung Dis. 2017;21(9):965–76.
15. Collin SM, Wurie F, Muzyamba MC, de Vries G, Lönnroth K, Migliori GB, et al. Effectiveness of interventions for reducing TB incidence in countries with low TB incidence: a systematic review of reviews. Eur Respir Rev. 2019;28(152):1–18.
16. Akkerman OW, De Lange WCM, Schölvinck EH, Wolters B, Aartsma Y, Van Der Werf TS, et al. Implementing tuberculosis entry screening for asylum seekers: The Groningen experience. European Respiratory Journal. 2016.
17. de Boer A, de Vries G. National Tuberculosis Control Plan 2011-2015. Bilthoven: National Institute for Public Health and the Environment; 2011. 119 p.
18. Schwartzman K, Menzies D. Tuberculosis screening of immigrants to low-prevalence countries: A cost-effectiveness analysis. Am J Respir Crit Care Med. 2000;
19. Dasgupta K, Menzies D. Cost-effectiveness of tuberculosis control strategies among immigrants and refugees. Eur Respir J. 2005; 20. Mandalakas AM, Menzies D. Is screening
immigrants for latent tuberculosis cost-effective? The Lancet Infectious Diseases. 2011. 21. Heuvelings CC, de Vries SG, Grobusch MP.
Tackling TB in low-incidence countries: improving diagnosis and management in vulnerable populations. Int J Infect Dis. 2017;56(S2017):77–80.
22. de Vries SG, Cremers AL, Heuvelings CC, Greve PF, Visser BJ, Bélard S, et al. Barriers and facilitators to the uptake of tuberculosis diagnostic and treatment services by hard-to-reach populations in countries of low and medium tuberculosis incidence: a systematic review of qualitative literature. Vol. 17, The Lancet Infectious Diseases. 2017. p. e128–43.
23. Waisbord S. Beyond the medical-informational model: Recasting the role of communication in tuberculosis control. Soc Sci Med. 2007;65(10):2130–4.
24. Christopoulos AI, Diamantopoulos A A , Dimopoulos PA, Goumenos DS, Barbalias GA. Risk factors for tuberculosis in dialysis patients: A prospective multi-center clinical trial. BMC Nephrol. 2009;10(1).
25. Getahun H, Matteelli A, Abubakar I, Abdel Aziz M, Baddeley A, Barreira D, et al. Management of latent Mycobacterium tuberculosis infection: WHO guidelines for low tuberculosis burden countries. European Respiratory Journal. 2015. 26. Eastwood JB, Corbishley CM, Grange JM.
Tuberculosis and the kidney. J Am Soc Nephrol. 2001;12(6):1307–14.
27. Ghimire S, Bolhuis MS, Sturkenboom MGG, Akkerman OW, De Lange WCM, Van Der Werf TS, et al. Incorporating therapeutic drug monitoring into the World Health Organization hierarchy of tuberculosis diagnostics. Eur Respir J. 2016;47(6):1867–9.
28. Van Der Burgt EPM, Sturkenboom MGG, Bolhuis MS, Akkerman OW, Kosterink JGW, De Lange WCM, et al. End TB with precision treatment! Eur Respir J [Internet]. 2016;47(2):680–2. Available from: http://dx.doi. org/10.1183/13993003.01285-2015 29. Sturkenboom MGG, Akkerman OW, Van Altena
R, De Lange WCM, Kosterink JGW, Van Der Werf TS, et al. Dosage of isoniazid and rifampicin poorly predicts drug exposure in tuberculosis patients. European Respiratory Journal. 2016. 30. Spruijt I, Tesfay Haile D, Suurmond J, van
den Hof S, Koenders M, Kouw P, et al. Latent tuberculosis screening and treatment among asylum seekers: a mixed methods study. Eur Respir J. 2019;1900861.
31. Collins D, Hafidz F, Mustikawati D. The economic burden of tuberculosis in Indonesia. Int J Tuberc Lung Dis. 2017;
32. House of representative RI. The local government act of Indonesia No.22 1999. Ministry of law, Republic of Indonesia 1999.
33. Ho J, Byrne AL, Linh NN, Jaramillo E, Fox GJ. Decentralized care for multidrug-resistant tuberculosis: A systematic review and meta-analysis. Bull World Health Organ. 2017;95(8):584–93.
34. Mahendradhata Y, Lestari T, Probandari A, Indriarini LE, Burhan E, Mustikawati D, et al. How do private general practitioners manage tuberculosis cases? A survey in eight cities in Indonesia Public Health. BMC Res Notes. 2015;8(1):564.
35. Mahendradhata Y. The case for stronger regulation of private practitioners to control tuberculosis in low- and middle-income countries Infectious Diseases. BMC Res Notes. 2015;8(1):600.
36. Kementerian Kesehatan Republik Indonesia. Peraturan menteri kesehatan Republik Indonesia no 67 tahun 2016 tentang penanggulangan tuberkulosis. Kementerian Kesehatan Republik Indonesia; 2010.
37. Healy J, Braithwaite J. Designing safer health care through responsive regulation. Med J Aust. 2006;184(S10):S56–9.
38. Mok EA, Gostin LO, Gupta M Das, Levin M. Implementing public health regulations in developing countries: Lessons from the OECD countries. J Law, Med Ethics. 2010;38(3):508–19. 39. Surya A, Setyaningsih B, Suryani Nasution
H, Gita Parwati C, Yuzwar YE, Osberg M, et al. Quality Tuberculosis Care in Indonesia: Using Patient Pathway Analysis to Optimize Public-Private Collaboration. J Infect Dis. 2017;216(Suppl_7):S724–32.
40. Gharat MS, Bell CA, Ambe GT, Bell JS. Engaging community pharmacists as partners in tuberculosis control: A case study from Mumbai, India. Res Soc Adm Pharm. 2007;
41. Daftary A, Satyanarayana S, Jha N, Singh M, Mondal S, Vadnais C, et al. Can community pharmacists improve tuberculosis case finding? A mixed methods intervention study in India. BMJ Glob Heal. 2019;4(3):e001417.
42. Clark PM, Karagoz T, Apikoglu-Rabus S, Izzettin FV. Effect of pharmacist-led patient education on adherence to tuberculosis treatment. Am J Heal Pharm. 2007;64(5):497–506.
43. Karuniawati H, Putra ON, Wikantyasning ER. Impact of pharmacist counseling and leaflet on the adherence of pulmonary tuberculosis patients in lungs hospital in Indonesia. Indian J Tuberc. 2019;66(3):364–9.
44. Abrogoua DP, Kamenan BAT, Ahui BJM, Doffou E. Pharmaceutical interventions in the management of tuberculosis in a pneumophtisiology department, ivory coast. Ther Clin Risk Manag. 2016;12:1749–56. 45. Mitrzyk BM. Treatment of extensively
drug-resistant tuberculosis and role of the pharmacist. Pharmacotherapy. 2008;28(10):1243–54.
