Improving treatment outcomes of tuberculosis
Pradipta, Ivan
DOI:
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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6
INTERVENTIONS TO IMPROVE
MEDICATION ADHERENCE
IN PATIENTS WITH LATENT
AND ACTIVE TUBERCULOSIS
INFECTION: A SYSTEMATIC
REVIEW OF RANDOMIZED
CONTROLLED STUDIES
Ivan S. Pradipta
Daphne Houtsma
Job F.M. van Boven
Jan-Willem C. Alffenaar
Eelko Hak
Submitted
ABSTRACT
Introduction: Tuberculosis (TB) treatment is long and takes up to 24 months.
Non-adherence to medication is a major risk factor for poor treatment outcome. A contemporary comprehensive overview of potential interventions to improve treatment and their effectiveness is needed. We therefore systematically reviewed studies on the effectiveness of various interventions for optimization of medication adherence in TB patients.
Methods: We performed a systematic review using the Medline/PubMed and Cochrane
literature databases and included randomized controlled studies. Studies with patients of all ages with either latent tuberculosis infection (LTBI) or active TB were eligible for inclusion in this review. We included studies that analysed single and/or multifactorial interventions to improve medication adherence. We defined adherence rate, completed and defaulted treatment as the primary outcomes, while negative sputum conversion, cured and poor treatment outcomes were secondary outcomes. The quality of the included studies was assessed using the JADAD score. Data were narratively described for LTBI and active TB groups separately.
Results: We identified four and eleven eligible studies with LTBI and active TB patients,
respectively. The interventions targeted several aspects, including socio-economic, health-care, patient, and treatment aspects. Not all interventions appeared to significantly improve medication adherence. 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 counselling 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 improved treatment completion effectively. Interestingly, intervention using DOT showed heterogeneous effects on the study outcomes.
Conclusions: Our study showed that interventions to increase TB drug adherence can be
effective with varying impact across studies and settings. Since non-adherence factors are patient-specific, personalized interventions that take into account such factors are required to enhance the impact of a program to improve medication adherence in TB patients.
INTRODUCTION
Tuberculosis (TB) remains an important worldwide health issue. The World Health Organization (WHO) reported that TB is the cause of illness for around 10 million people every year and has been ranked among the top ten causes of death globally.(1) TB, caused by Mycobacterium tuberculosis (M.tb), can be spread easily from patients suffering from pulmonary TB to healthy people by air transmission.(1) Consequently, anti-tuberculosis drug treatment is required for TB patients to cure the disease and prevent disease transmission. Like in other complex diseases, TB patients have to be treated with several drugs for a long period. According to the WHO guideline, active pulmonary TB patients should take drugs for at least six months,(2) while latent tuberculosis infection (LTBI) patients should take drugs for at least three months.(3) The treatment duration can be extended if TB patients are diagnosed as multi-drug resistant tuberculosis (MDR-TB), a resistance of the pathogen to the most potent anti-tuberculosis medicines (isoniazid and rifampicin). The MDR-TB treatment can be up to 24 months using multiple drugs.(4)
Poor adherence to medication is widely known as a causal factor for increased risk of morbidity, mortality and cost burden.(5,6) A global meta-analysis revealed that non-adherence to treatment is a risk factor for MDR-TB.(7) Furthermore, MDR-TB patients, as compared to drug-susceptible patients, have more frequently poor treatment outcomes. (8,9) Treatment adherence is affected by multiple factors. These factors are divided into five different interacting dimensions, including socio-economic, health care system, condition, therapy, and patient factors.(10) Although studies on adherence in other diseases than TB showed that interventions targeting these factors can significantly improve adherence rates,(11–13) a better understanding of the effects of possible interventions in TB is required. We therefore systematically reviewed the effectiveness of various interventions to improve medication adherence in LTBI and active TB patients.
METHODS
Literature review
We performed a systematic review of the randomized controlled trials that were published between January 1, 2003 and April 24, 2018, and reported in the English language. The search period was restricted from 2003 because in that year the influential WHO Adherence report was published and created wide-scale awareness on the issue of non-adherence ever since.(10) Given their increased risk for bias, quasi-experimental, cohort, cross-sectional, case-control, case reports, case series, review articles, and abstract conference were not eligible for inclusion. This systematic review was reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidance.(14)
Study population and interventions
To be able to better distinguish between the potential impact of experienced symptoms on extent of adherence, the study population was divided into two different groups, i.e. patients with latent tuberculosis infection (LTBI) and active TB. The status of TB disease should be confirmed by clinical or laboratory examination (e.g., TB symptoms, Mantoux, IGRA, chest radiograph, or other TB examination) and/ or microbiological verification (e.g. smear sputum test, phenotyping drug susceptibility test or polymerase chain reaction). We excluded studies restricted to specific high-risk treatment non-adherence groups, such as TB patients with Human Immunodeficiency Virus (HIV), drug resistant TB, alcoholism and illicit drug use. Studies that analysed interventions related to improving medication adherence and treatment outcomes were included in this review. The intervention was allowed to target one or multiple factors of adherence such as socio-economic, health care team and system, health condition, therapy, or patient factors. The intervention should have a comparison group to analyse the effect of the intervention.
Study outcomes
In terms of the study outcomes, we followed the global definition published by the WHO in 2014. (15) We defined medication adherence as the primary outcome. Of note, adherence consists of three phases: initiation, implementation and persistence.(16) In our assessment, persistence was deemed a synonym terms for “completed treatment” and “defaulted treatment”, respectively. Implementation was deemed similar to “adherence rate”. Treatment completion is defined as successful treatment by the WHO, because it is a combination of cured and completed treatment. Defaulted treatment was defined as an interruption of TB treatment for two or more consecutive months, while adherence rate was identified by the proportion of missing anti-TB dose during treatment period defined. In case of limited data on adherence, cured treatment, negative sputum conversion and poor treatment outcomes were used as the secondary outcomes. Cured treatment was defined as smear- or culture-negative in the last month of treatment and on at least one previous occasion, while completed treatment was defined as a TB patient who completed treatment without evidence of failure, but with no record to show that sputum smear or culture results were positive in the last month of treatment. Negative sputum conversion was defined as the conversion sputum to a negative result, while poor treatment outcome is a combination of defaulted, failed treatment and death outcome. Failed treatment was defined as a positive sputum smear or culture at fifth months after treatment initiation.
Data collection
The relevant articles were obtained from the Medline/PubMed and Cochrane databases with specific key-terms. To obtain the relevant articles effectively, we used restriction to the following filters in the Medline/PubMed database, such as clinical trial, comparative study, controlled clinical trial, observational study, randomized controlled trial and humans.
Applying observational study in the Medline/PubMed filter was intended to anticipate potential RCT studies in the group labelled as observational studies. Key terms for obtaining the articles can be found in the Appendix.
Data extraction and quality assessment
Title and abstract of the articles were screened by ISP and DH, then the full-text of the articles were assessed for the eligibility and quality by ISP. Duplicated articles from two databases were removed using Refwork® software. The eligible articles were then reviewed for the relevant information. Information related to year publication, population, type of intervention, comparator group, and study outcome were extracted by ISP. Any disagreement between the reviewers during the screening phase were solved by discussion. Regarding the quality assessment, we used the JADAD score for assessing the quality of the randomized studies.(17) Three main domains were appraised in the JADAD score system, i.e. randomization, blinding method, and subject withdrawal. The domains were assessed by five questions. For each question, a study could earn 1 point, with a total score of 5 points. The five questions were described as follows: Was the study described as randomized ?; Was the method used to generate sequence of randomization described and appropriate ?; Was the study described as double-blind ?; Was the method of double-blinding appropriately described ?; and was there a description of withdrawals and dropouts?.
Summary measures and synthesis of results
The total number and group of patients with any specific outcome for both primary and secondary outcomes were extracted by ISP from studies and summarized in the tables. For the point estimate of the intervention, we used relative risk (RR) for dichotomous outcome data and mean ratio (MR) for continuous outcome data with a 95% confidence interval (95%CI).
RESULTS
Study selection
During the search, we found 200 records from the Medline/PubMed database and 186 records from the Cochrane database. We identified 72 duplicate records from the Refwork® software. A total of 314 articles were screened for the title and abstract. This initial screening excluded 268 irrelevant records, then the full-text screening process was continued for 46 records. In the full-text screening, 31 articles were excluded due to different populations (3 articles), different study outcomes (11 articles), and non-randomized study design (17 articles). We finally analysed 15 studies for qualitative synthesis. The flow diagram, literature search, and screening process are presented in Figure 1.
Figure 1. Flow diagram of the included articles
Study characteristics and interventions
In total, 16,029 subjects were included in the analysis. In all, 1,991 LTBI patients and 14,038 active TB patients participated. The minimum number of subjects in the included studies was 89, while the maximum number was 4,154 subjects. The included studies were conducted in both low and high burden TB countries, i.e. Pakistan,(18,19) Australia,(20) Iraq,(21) China,(22,23) Senegal,(24) South Africa,(25–27) Tanzania,(28) Timor Leste,(29) Canada,(30) United States, (27,31) Spain,(27) Hong Kong,(27) and Mexico.(32)
The 15 randomized controlled trials assessed a broad range of adherence management interventions. These included Short Message Service (SMS) intervention,(18,19,21,23,27) DOT administered by a family member,(20) DOT with supervision by a community,(21,27,28) a reinforced counselling method,(24) a trained lay health workers intervention to manage TB case,(25) monthly TB vouchers,(33) a drugs box reminder,(23) a combination text messaging and drugs box reminder,(23) a nutritious intervention,(29) shorter regimen,(30) a
peer-based intervention(31) and a behavioural intervention.(32) The characteristics of the included studies are shown in Table 1.
Outcomes
In the active TB patients, the primary outcomes were treatment completion,(18–20,22,25,26) interrupted rate(18,19,21,24,26) and adherence rate,(23,29) while the secondary outcomes were negative sputum conversion,(21,22,28) cured(21,24,28) and poor treatment outcomes.(23) In the LTBI studies, we observed that treatment completion was the only outcome. Regarding the intervention effect, not all interventions significantly improved drug adherence and treatment outcomes. Several interventions were found effective in improving medication adherence and outcomes of active TB patients, i.e. DOT by trained community members, SMS combined with TB education, a reinforced counselling method, monthly TB voucher, drugs box reminder, a combination drugs box reminder and text messaging. However, only two studies reported adherence rate as the study outcome. (23,29) We identified that a drugs box reminder (MR 0.58; 95%CI 0.42- 0.79) and its combination with text messaging (MR 0.49; 95%CI 0.27-0.88) significantly reduced missing a drug dose among active TB patients,(23) while food incentives were not significantly different from the comparator for the intensive (MR -4.7; 95%CI-0.8 - -8.6) and continuation phase (MR 0; 95%CI -1.7- 1.7) in the active TB patients,(29) see Table 2.
In the LTBI patients, shorter regimens and DOT interventions significantly improved treatment completion. We identified that 4 months of daily rifampicin 10 mg/kg was more effective to improve treatment completion than 9 months of daily isoniazid 5 mg/ kg (RR 1.2; 95%CI 1.02-1.4),(30) while DOT intervention was more effective to improve treatment completion than self-administration therapy with monthly monitoring (RR 1.18; 95%CI;1.09-1.27).(27) In contrast, several interventions, such as self-administration therapy with weekly text message reminders plus monthly monitoring (RR 1.03;95%CI 0.95-1.13),(27) a peer-based intervention (RR 1.06; 95%CI 0.86-1.31),(31) adherence coaching intervention (RR 1.36; 95%CI 0.98-1.88) (32) and self-esteem counselling (RR 1.12; 95%CI 0.78-1.58)(32) did not significantly improve treatment completion in the LTBI patients, see Table 3.
Ta b le 1 . C h ar ac te ri sti cs o f t h e in cl u d ed a rti cl es Au th o rs St u d y d esi gn St u d y p eri o d Ty p e p ar ti ci p ant Se tt in g Int er ve nti o n C o nt ro l O u tco m es M o ha m m ed S , e t a l., 2 0 1 6 (1 8 ) RC T 2 0 11-2 0 14 A d ul t n ew ly T B p ati en ts T B c lin ic s a n d h o sp it als in K ara chi , Pa ki st an Z in d ag i S M S , a t w o -w ay S M S re m in d er sy st em , s en t d ai ly S M S re m in d er s a n d m oti va ti o n al m es sa ge s t o p ar ti cip an ts a n d as ke d t h em t o re sp o n d t h ro u gh S M S o r m is s ca lls a ft er t ak in g t h eir m ed ic ati o n St an d ard o f ca re Tre at m en t c o m p le ti o n (s u m o f c o m p le te d tre at m en t a n d c u re d tre at m en t) a n d d ef aul te d t re at m en t M ac In ty re C R , e t a l., 20 0 3 (20) RC T 1998 -2 000 A d ul t n ew ly T B p ati en ts Tw o c lin ic s in t h e No rt h -W est er n H ea lt h c are n et w o rk , V ic to ri a, A u str al ia D O T a d m in is te re d b y a f am ily m em b er (F D OT ) St an d ard su p er vi se d b u t n o n -d ire ctl y o bse rv ed th era py Tre at m en t c o m p le ti o n (s u m o f c o m p le te d tre at m en t a n d c u re d tr eat m ent ) M oh an A , e t a l., 2 0 0 3 (2 1 ) RC T 2 0 0 1 A d ul t n ew ly T B p ati en ts 1 5 T B c en te rs in B ag hd ad , I raq D O T a n d h o m e v is it s f ro m t ra in ed m em b er s o f t h e I ra q i W o m en ’s F ed er ati o n ( IW F ) D O T w it h o u t h o m e v isi ts C u re d a n d d ef aul te d tr ea tm en t; s p u tum co n ve rs io n : a n eg ati ve sp u tu m s m ea r a t t h e fi ft h m o n th a ft er tr eat m ent Fa n g X H , et a l., 2 0 17 (2 2 ) RC T 2 0 14 -2 0 1 5 A d ul t p ulm o n ar y T B p ati en ts Si x d is tr ic ts in A n h u i P ro vin ce , C hi na R eg ul ar S M S t o re m in d t ak in g m ed ic in e a n d ed u ca te c o re k n o w le d ge a b o u t p ulm o n ar y T B . T h e S M S c o n te n ts : a ). F o llo w in g t h e d o ct o r’ s in st ru cti o n s a n d t ak in g m ed ic in e tim el y, b ). R ee xa m in in g s p u tu m a n d c h es t X -r ay p er io d ic al ly , c ). C o ve rin g n o se a n d m o u th w h en s n ee zin g o r c o u gh in g, a n d d o in g n ot s p it e ve ry w h ere d ). P ay in g a tt en ti o n t o w as h in g h an d s, o p en in g a w in d o w V en ti la te d re gul ar ly , d o in g s p o rt s m o re , a n d im p ro vin g re si sti b ili ty , e ). ad h er in g to re gul ar tre at m en t, an d m o st o f T B p ati en ts c an b e c u re d D OT Tre at m en t c o m p le ti o n (s u m o f c o m p le te d tre at m en t a n d c u re d tre at m en t) a n d s p u tu m co n ve rs io n : a n eg ati ve sp u tu m s m ea r a t t h e si xt h m o n th a ft er tr eat m ent
Au th o rs St u d y d esi gn St u d y p eri o d Ty p e p ar ti ci p ant Se tt in g Int er ve nti o n C o nt ro l O u tco m es T h ia m S , e t a l., 2 0 0 7 (24 ) C lu ste r RC T 2 0 0 3 - 2 0 05 N ew ly d ia gn os ed T B p ati en ts G o ver n m en t d is tr ic t h eal th ce n te rs in S en eg al R ein fo rc ed c o u n se llin g t h ro u gh im p ro ve d co m m u n ic ati o n b et w ee n h ea lt h p er so n n el an d p ati en ts , d ec en tr al iz ati o n o f t re at m en t, ch o ic e o f D O T s u p p o rt er b y t h e p ati en t, a n d re in fo rc em en t o f s u p er vi si o n a cti vi ti es T h e u sua l st an d ard c are o f T B C u re d a n d d ef aul te d tr eat m ent C la rke M , e t a l., 2 0 0 5( 2 5) C lu ste r RC T 20 0 -2 0 0 1 A d ul t n ew ly T B p ati en ts Fa rm s in t h e B o la n d h ea lt h dis tr ic t, W es te rn C ap e, S o u th Afr ic a Tr ain ed l ay h ea lt h w o rk er s t o s cre en , re fe r, re p o rt , m o n it o r, e d u ca te a n d m oti va te T B p at ie nt s N o in te rv en ti o n o f l ay h ea lt h w o rke rs Tre at m en t c o m p le ti o n (s u m o f c o m p le te d tre at m en t a n d c u re d tr eat m ent ) Fa ro o qi R A , e t a l., 2 0 1 6 (1 9 ) RC T 2 0 14 -2 0 1 5 A d ul t n ew ly p ulm o n ar y an d e xt ra -p ulm o n ar y T B p ati en ts K h yb er T ea ch in g H o sp it al P es h aw ar a n d E m er gen cy Sa te lli te H o sp it al N ah aqi , P ak is ta n D O T a n d d ai ly m o b ile S M S re m in d er s D OT Tre at m en t c o m p le ti o n (s u m o f c o m p le te d tre at m en t a n d c u re d tre at m en t) a n d d ef aul te d t re at m en t Lu tg e E , e t a l., 2 0 1 3 (2 6) C lu ste r RC T 2 0 0 9-2 0 10 A d ul t n ew ly T B p ati en ts P rim ar y p u b lic h ea lt h c are a t K wa zu lu -Na ta l, S o u th o f A fr ic a M o n th ly v o u ch er U S D 1 5 p er m o n th N o m o n th ly vo u ch er Tre at m en t c o m p le ti o n (s u m o f c o m p le te d tre at m en t a n d c u re d tre at m en t) a n d d ef aul te d t re at m en t Ta b le 1 ( C o n ti n u ed ). C h ar ac te ri sti cs o f t h e in cl u d ed a rti cl es
6
Au th o rs St u d y d esi gn St u d y p eri o d Ty p e p ar ti ci p ant Se tt in g Int er ve nti o n C o nt ro l O u tco m es Li u X , e t a l., 2 0 1 5 (2 6) C lu ste r RC T 2 0 09 A d ul t n ew ly p ulm o n ar y T B p ati en ts P ro vin ce s o f H ei long jiang , Ji ang su , H u n an , a n d C h o n gq in g, C h in a, Te xt m es sa gin g re m in d er T h e u sua l c are : tre at m en t m on it or ing ca n b e s el f-ad m in is te re d tre at m en t o r tre at m en t su p er vis ed b y f am ily m emb er s o r tre at m en t su p er vi se d b y h ea lt h c are w o rke rs . T h e l o ca l do ct or m on it or th e tr ea tm en t P o o r a d h ere n ce : w as t h e p er ce n ta ge of p at ie nt -m o nt h s w h ere a t l ea st 2 0 % o f d o se s ( 1 5 d o se s) w ere m is se d ; p o o r t re at m en t o u tc o m e D ru g b o x re m in d er C o m b in ed ( te xt m es sa gin g a n d d ru g b o x re m in d er ) Lw ill a F, e t a l., 2 0 0 3 (2 6) C lu ste r RC T 1999 -2 000 A d ul t n ew ly p ulm o n ar y T B p ati en ts K ilo mb er o D is tr ic t, M o ro go ro , S o ut h ern Tan zan ia C o m m u n it y-b as ed D O T ( C B D O T ): d ai ly o b se rv ed p ati en t b y a v o lu n te er f o r t h e fi rs t tw o m o n th s a n d t h e p ati en ts h av e a m o n th ly vi si t t o h ea lt h f ac ili ty In sti tu ti o n -b as ed D O T (I B D OT ): P ati en ts v is it h ea lt h f ac ili ty d ai ly f o r t h e fi rs t t w o m o nt h s Sp u tu m c o n ve rs io n : A F B n eg ati ve s p u tu m af te r t w o m o n th s o f tre at m en t; C u re r at e at s ev en m o n th s: A F B -n eg ati ve s p u tu m a t tw o m o n th s, re m ain in g n eg ati ve a t m o n th fi ve a n d /o r a t m o n th se ve n a ft er t h e s ta rt o f tr eat m ent Ta b le 1 ( C o n ti n u ed ). C h ar ac te ri sti cs o f t h e in cl u d ed a rti cl es
Au th o rs St u d y d esi gn St u d y p eri o d Ty p e p ar ti ci p ant Se tt in g Int er ve nti o n C o nt ro l O u tco m es M ar tin s N , e t a l., 2 0 0 9 (2 9 ) RC T 2 0 05 -20 0 6 A d ul t n ew ly p ulm o n ar y T B p ati en ts T h re e p rim ar y ca re c lin ic s in D ili , T im o r-Le st e N u tr iti o u s, c ul tu ra lly a p p ro p ri at e d ai ly m ea l (w ee ks 1 -8 ) a n d f o o d p ac ka ge ( w ee ks 9 -3 2) N u tr iti o n al ad vice Tre at m en t c o m p le ti o n : cl ea ra n ce o f a ci d -f as t b ac ill i f ro m t h e s p u tu m af te r t re at m en t o r t h e co m p le ti o n o f e ig h t m o n th s o f t re at m en t, o r b ot h ; a d h ere n ce to t re at m en t: c lin ic at te n d an ce , D O T, in te rv ie w a n d p ill c o u n t M en zi es D , e t a l., 20 0 4 (3 0) RC T 2 0 02 A d ul t L T B I A u n iv er si ty -af fi lia te d re sp ir at o ry h o sp it al , C ana d a 4 m o n th o f d ai ly r if am p ic in 1 0 m g / k g 9 m o n th o f da ily is o n ia zi d 5 m g / k g C o m p le te d t re at m en t d efi n ed a s t o o k 8 0 % o r m o re o f d o se s w it h in 2 0 w ee ks f o r 4 R IF o r w it h in 4 3 w ee ks f o r 9I N H B elk n ap R e t a l., 2 0 17 (2 7 ) N on -in fe ri o rit y RC T 20 12 -2 0 14 A d ul t L T B I p at ie nt s O u tp ati en t tu b er cul o si s cl in ic s in t h e U n it ed S ta te s ( 9 si te s) , S p ain ( 1 si te ), H ong K ong (1 s it e) , a n d S o u th A fr ic a ( 1 s it e) D ire ct o b se rv ati o n t re at m en t SA T w it h m o n thl y m on it or ing Tre at m en t c o m p le ti o n (s u m o f c o m p le te d tre at m en t a n d c u re d tr eat m ent ) SA T w it h m o n th ly m o n it o rin g a n d t ex t m es sa ge re m in d er s Ta b le 1 ( C o n ti n u ed ). C h ar ac te ri sti cs o f t h e in cl u d ed a rti cl es
6
Au th o rs St u d y d esi gn St u d y p eri o d Ty p e p ar ti ci p ant Se tt in g Int er ve nti o n C o nt ro l O u tco m es H irsc h-M ove rm an Y , e t a l., 2 0 1 3 (3 1 ) RC T 2 0 0 2-2 0 05 A d ul t L T B I p at ie nt s T h e H ar le m H o sp it al C h es t C lin ic in N ew Y o rk , N Y , U SA P ee r-b as ed in te rv en ti o n : p ee rs e d u ca te d a n d co ac h ed p ati en ts o n a d h ere n ce ; g av e s o ci al an d e m oti o n al s u p p o rt a n d p ro vi d ed h ea lt h ca re a n d s o ci al s er vi ce s ys te m n av ig ati o n , to ge th er w it h p ati en ts a n d h ea lt h w o rk er s, to e n h an ce p ati en t-p ro vi d er c o m m u n ic ati o n . T h e p ee rs w ere p eo p le w h o h ad c o m p le te d LT B I o r a n ti -T B t re at m en ts a n d h ad a tt en d ed a 4 -w ee k t ra in in g p ro gr am t h at in cl u d es ro le -p la yin g e xe rc is e, in fo rm ati o n al s es si o n s, an d o b se rv ati o n . P ee rs m et p ar ti cip an ts b y o n e-o n -o n e a t l ea st o n ce a w ee k S elf -ad m in is te re d 9 -m o n th is o n ia zid tr eat m ent Tre at m en t c o m p le ti o n (s u m o f c o m p le te d tre at m en t a n d c u re d tr eat m ent ) H o ve ll M F, e t a l., 2 0 0 3 (3 2 ) RC T 19 9 6 -2 000 A d ol es ce nt s LT B I p at ie nt s Sa n Di eg o -T iju ana , M ex ico - U n ite d S ta te s U sua l c are p lu s a d h ere n ce c o ac h in g: m o n th ly ca se re vi ew a n d d is cu ss io n a b o u t a d h ere n ce p robl ems a n d a d vi ce T h e u sua l m ed ic al c are : 3 0 0 m g I N H p er d ay w as p re sc ri b ed fo r 6 -9 m o n th w ith m o n thl y ev al u at io n Tre at m en t c o m p le ti o n : co m p le ti o n o f L T B I tre at m en t a s t ak in g 1 8 0 p ills w it h in 2 7 0 d ay s U sua l c are p lu s s el f-es te em c o u n se llin g: m o n th ly m ee tin g a b o u t re la ti o n sh ip a n d co m m u n ic ati o n w it h f am ily , f ri en d s a n d cul tu ra l i d en ti ty t o e n h an ce s el f-es te em In fo rm ati o n : R C T, R an d o m iz ed c o n tr o l t ri al ; L T B I, l at en t t u b er cul o si s in fe cti o n ; D O T, d ire ctl y o b se rv ed t h er ap y; S A T, S el f-ad m in is tr ati o n t h er ap y; S M S , s h o rt m es sa ge s er vice s, A FB , a ci d -f as t b aci lli Ta b le 1 ( C o n ti n u ed ). C h ar ac te ri sti cs o f t h e in cl u d ed a rti cl es
Ta b le 2 . E ff ec t o f t h e in te rv en ti o n o n t h e t re at m en t o u tc o m es in a cti ve t u b er cul o si s p ati en ts N o Au th o rs Int er ve nti o n Int er ve nti o n ta rg et N um b er o f pa rt ic ipa n ts Tr ea tm en t o u tc o m es Int er ve nti o n gro u p C o m p ar at o r gro u p Tr ea tm en t co m p le ti o n In te rr u p te d ra te A d h er en ce ra te C u re d tr ea tm en t Sp u tu m con ve rs ion Po o r tr ea tm en t 1 M o ha m m ed S , e t a l, 2 0 1 6 (1 8 ) Tw o -w ay S M S re m in d er sy st em w it h m oti va ti o n al wo rds P ati en t a n d h ea lt h c are 1 ,1 0 4 1 ,0 93 R R 1 .0 0 ; (0 .9 6 -1 .0 4 ) R R 0 .9 2 ; (0 .6 8 -1 .2 4 ) -2 M ac In ty re C R , e t a l., 20 0 3 (20) Fa m ily D O T H ea lt h c are 87 86 R R 1 .9 6 ; (0 .9 8 -1 .1 5 ) -3 M oh an A , e t a l., 2 0 0 3 (2 1 ) D O T a n d h o m e vi si ts b y t ra in ed m em b er s o f t h e Ir aq i W o m en ’s F ed era tio n P ati en t a n d h ea lt h c are 24 0 24 0 -R R 0 .8 3 ; (0 .0 2 -0 .3 4 ) -R R 1 .2 ; (1 .1 4 -1 .3 3) R R 1 .2 6 ; (1 .1 5 -1. 3 7) * -4 Fa n g X H , et a l., 2 0 17 (2 2 ) S M S a n d re gul ar ed u ca ti o n o f co re k n o w le d ge ab o u t p ulm o n ar y T B P ati en t a n d h ea lt h c are 1 6 0 19 0 R R 1 .1 1 ; (1. 0 4 -1. 1 8 ) -R R 1 .26 ; (1 .1 4 -1 .42 ) ¥ -5 T h ia m S , e t a l., 2 0 0 7 (24 ) R ein fo rc ed co u n se lli n g m eth o d P ati en t a n d h ea lt h c are 7 7 8 74 4 -RR 0 .4 3 ; (0 .2 1-0 .8 9 ) -R R 1 .1 8 ; (1 .0 3-1 .3 4) -6 C la rke M , e t a l., 2 0 0 5( 2 5) Tr ain ed L H W s in te rv en ti o n P ati en t a n d h ea lt h c are 47 42 R R 1 .0 8 ; (0 .9 2 -1. 2 7) -7 Fa ro o qi R A , e t a l., 2 0 1 6 (1 9 ) M o b ile S M S re m in d er s P ati en t a n d h ea lt h c are 74 74 R R 1 .0 1 ; (0 .9 5 -1 .1 0 ) R R 0 .75 ; (0 .1 7-3 .2 4 )
-6
N o Au th o rs Int er ve nti o n Int er ve nti o n ta rg et N um b er o f pa rt ic ipa n ts Tr ea tm en t o u tc o m es Int er ve nti o n gro u p C o m p ar at o r gro u p Tr ea tm en t co m p le ti o n In te rr u p te d ra te A d h er en ce ra te C u re d tr ea tm en t Sp u tu m con ve rs ion Po o r tr ea tm en t 8 Lu tg e E , e t a l., 2 0 1 3 (2 6) M o n thl y vo u ch er U S D 1 5 p er m o n th S o ci o -ec on om y 2 ,1 7 0 1 ,9 8 4 R R 1 .0 7; (1. 0 4 -1. 11 ) 0 .0 6 (0 .0 4 -0 .1 1 ) -9 Li u X , e t a l., 2 0 1 5 (2 3 ) Te xt m es sa gin g re m in d er P ati en t a n d h eal th ca re 9 96 1 ,0 91 -M R 0 .9 4 (0 .7 1-1 .2 4 ) -M R 0 .4 4 (0 .1 7, 1 .1 3 ) D ru g b o x re m in d er 99 2 -M R 0 .5 8 (0 .4 2 , 0 .7 9 ) -M R 0 .7 1 (0 .3 3 , 1 .51 ) C o m b in ati o n o f te xt m es sa gin g an d d ru g b o x re m in d er 1 ,0 59 -M R 0 .4 9 (0 .2 7, 0 .8 8 ) -M R 1 .0 0 (0 .45 , 2 .20) 10 Lw ill a F, e t a l., 2 0 0 3 (2 8 ) C omm u n it y b as ed D OT P ati en t a n d h ea lt h c are 2 2 1 3 0 1 -O R 1 .5 8 (0 .3 2-7. 8 8 ) 0 .6 2 (0 .2 3-1 .71 ) -11 M ar tin s N , e t a l., 2 0 0 9 (2 9 ) F o o d in ce n ti ve P at ie nt 13 6 1 29 R R 0 .9 8 (0 .8 6 - 1 .1 1 ) -M R -4 .7 (-0 .8 - -8 .6) * M R 0 (-1. 1. 7) ** -In fo rm ati o n : T re at m en t c o m p le ti o n i s c o m p le tin g t h e p re sc ri b ed d o se s o f d ru gs ( co m p le te d a n d c u re d t re at m en t) ; I n te rr u p te d t re at m en t i s a d ef aul te d o r/ an d in te rr u p te d t re at m en t g ro u p s t h at w ere c o m p are d w it h n o n -in te rr u p te d p ati en t g ro u p; P o o r t re at m en t is a c o m b in ati o n o f d ef aul te d , f ai le d t re at m en t a n d d ea th o u tc o m e; A d h ere n ce r at e i s a p ro p o rti o n o f m is sin g a n ti -T B d o se ; S p u tu m c o n ve rs io n i s a c o n ve rs io n s p u tu m t o a n eg ati ve re sul t; M R , m ea n r ati o ; R R , R el ati ve R is k; O R , O d d s R ati o ; * in te n si ve p h as e; * *C o n tin u ati o n p h as e; T B , t u b er cul o si s; L T B I, l at en t t u b er cul o si s in fe cti o n ; D O T, d ire ctl y o b se rv ed t h er ap y; S A T, S el f-ad m in is tr ati o n t h er ap y; S M S , s h o rt m es sa ge s er vi ce s; A F B , a ci d -f as t b ac ill i; U S D , U n it ed S ta te s d o lla r; L H W s, l ay h ea lt h w o rk er s. Ta b le 2 ( C o n ti n u ed ). E ff ec t o f t h e in te rv en ti o n o n t h e t re at m en t o u tc o m es in a cti ve t u b er cul o si s p ati en ts
Table 3. Effect of the interventions on the treatment outcomes in latent tuberculosis infection (LTBI)
patients
No Authors Intervention Intervention target
Number of participants Study outcome Intervention group Comparator group Treatment completion (RR; 95%CI) 1 Menzies D, et al., 2004(30) 4 month of daily rifampicin 10 mg/ kg Treatment 58 58 1.2; (1.02-1.4) 2 Belknap R, et al., 2017(27)
DOT Patient and health care
337 337 1.18; (1.09-1.27) Self-administration
therapy with weekly text message reminders and monthly monitoring Patient and health care 328 337 1.03; (0.95-1.13) 3 Hirsch-Moverman Y, et al., 2013(27) Peer-based intervention Patient and health care 128 122 1.06; (0.86-1.31) 4 Hovell MF, et al., 2003(27)
Usual care plus adherence coaching
Patient and health care
92 96 1.36; (0.98-1.88) Usual care plus
self-esteem counselling
Patient and health care
98 1.12; (0.78-1.58) Information: Treatment completion is completing the prescribed doses of drugs (completed and cured treatment); DOT, directly observed therapy; RR, relative risk; 95%CI, 95% confidence interval.
Quality assessment of the included studies
A double-blinding method was either not possible or not applied for most of the included studies. This is due to the fact that intervention activities were impossible to blind, such as SMS reminders, DOT, counselling, monthly vouchers, drugs box reminders, food incentive and peer-based intervention. Often, an open-label design was applied. Therefore, none of the included had a maximum JADAD score (5 points). Three points of the JADAD score was the maximum score among the included studies because none of the studies applied the blinding method. Six of the 15 studies had the lowest JADAD score (2 points) due to absence of a description of randomization procedure.(20–22,28,31,32) The other studies had a higher score (3 points) given they appropriately described the randomization method and clearly illustrated the withdrawals of participants.(18,19,23–27,29,30) The risk of bias assessment is presented in Table 4.
Table 4. The risk of bias assessment for randomized studies using JADAD score No Author Randomization Description of
randomization Double-blind method Description of the blinding method Description of participants withdrawal/ drop-out Total score 1 Mohammed S, et al, 2016(18) 1 1 0 0 1 3 2 MacIntyre CR et al., 2003(20) 1 0 0 0 1 2 3 Mohan A, et al., 2003(21) 1 0 0 0 1 2 4 Belknap R, et al., 2017(27) 1 1 0 0 1 3 5 Fang XH, et al., 2017(22) 1 0 0 0 1 2 6 Hirsch-Moverman Y, et al., 2013(31) 1 0 0 0 1 2 7 Thiam S, et al., 2007(24) 1 1 0 0 1 3 8 Clarke M, et al., 2005(25) 1 1 0 0 1 3 9 Farooqi RA, et al., 2016(19) 1 1 0 0 1 3 10 Hovell MF, et al., 2003(32) 1 0 0 0 1 2 11 Lutge E, et al., 2013(26) 1 1 0 0 1 3 12 Menzies D, et al., 2004(30) 1 1 0 0 1 3 13 Liu X, et al., 2015(23) 1 1 0 0 1 3 14 Lwilla F, et al., 2003(28) 1 0 0 0 1 2 15 Martins N, et al., 2009(29) 1 1 0 0 1 3
Information: JADAD questions: (1) Was the study described as randomized?; (2) Was the method used
to generate sequence of randomization described and appropriate?; (3) Was the study described as double-blind?; (4) Was the method of double-blinding described and appropriate?; (5) Was there a description of withdrawals and dropouts?
DISCUSSION
We observed various interventions that were successful in improving medication adherence and outcomes in TB patients. The interventions targeted several factors of adherence, such as socio-economic, patient, healthcare, and treatment aspects. The effective interventions to improve treatment completion in active TB patients were DOT with daily home visits by community-trained members, SMS reminders combined with TB education, a reinforced counselling method, and a monthly voucher intervention. In the LTBI patients, DOT and a shorter regimen significantly improved treatment completion. We identified that the drugs box reminder or its combination with text messaging reminder significantly improved the medication adherence rate among active TB patients, while no studies were found showing an effective intervention to improve medication adherence rate in LTBI patients. In contrast, we found that some interventions, such as SMS reminders or its combination with motivational messages, family DOT, community-based DOT, involving trained lay health workers in TB management, and food incentives were not significantly different compared with the comparator groups for improving treatment completion and outcomes in active TB patients. Similarly, we identified SMS reminders combined with monthly monitoring, peer-based intervention, coaching adherence and self-esteem counselling were not effective in improving treatment completion in LTBI patients.
Interestingly, interventions using DOT showed various effects on the study outcomes. Studies that used community-based DOT interventions showed opposite effect in Iraq(21) and Tanzania.(28) Family DOT(20) and community DOT(28) were not superior in the improvement of treatment outcomes among active TB patients, while institutional DOT significantly improved treatment completion in the LTBI patients. Unfortunately, a meta-analysis of the crude data was impossible because heterogeneities were identified across the included studies with regard to population, intervention and study outcomes. However, a previous meta-analysis stated that the understanding of resources and situations in which DOT can be beneficial is an essential part of successful implementation of DOT.(34) Furthermore, the interaction between DOT providers and TB patients may also influence the effect on medication adherence and outcome. Therefore, the differences of resources, situation and interaction between DOT providers and TB patients may indicate that the effects of interventions can vary across studies and settings.
Generally, the differences in observed effect sizes of the interventions in this review can be explained by several aspects: 1) characteristics of the subjects, 2) measurement method of the adherence (outcome), 3) characteristics of the comparator group, and 4) the quality of the study design and intervention. According to the WHO,(10) adherence is a multidimensional phenomenon that can be determined by the interaction of the five essential factors, i.e., socio-economic, provider-patient/healthcare system,
related, therapy-related, and patient-related. Since the essential causal factors for poor adherence can be individual, assessing the individual non-adherence factors is a critical approach to have effective personalized interventions to increase medication adherence. The most optimal intervention to improve medication adherence should not be “one-size-fits-all”. As an example, an intervention using SMS reminders for taking medicine may not be effective if the individual problem of medication adherence is mainly caused by inaccessibility of the patient to have a qualified medicine.
In terms of outcome measurement, heterogeneity was shown in the included studies. Most of the studies used a treatment completion parameter measured by temporary patient visits or self-reported/medical documentation as the outcome parameter for medication adherence. An implication of this is the possibility of misclassification for the status of medication adherence. The measurement did not represent the daily consumption of the medicines during the treatment phase. Hence, potential information bias is high in the studies that used temporary patient visits or self-reported/medical documentation to assess medication adherence. The accuracy of adherence measurement in TB patients was reported in a systematic review.(35) Methods to measure adherence can be categorized as direct (e.g. DOT, ingestible sensors, drug or metabolites measurements) and indirect (e.g. patient self-report, pill counts, health information system, electronic pill bottles, and SMS). Currently, digital adherence technologies have been developed that offer large potential to measure and improve medication adherence in TB patients.(36) The technology potentially facilitates drug monitoring adherence that provides a more patient-centric approach than the existing DOT.(37) The digital technology for monitoring medication adherence of TB patients was reported in the form of video observed therapy (VOT) and electronic medication monitoring. (33) Considering the accuracy, direct measurement should be preferably used for measuring medication adherence in an interventional study to enhance the validity of the results. There were some variations in the comparator group in the included studies, which may also have affected the validity of the findings. We noted that self-administration of treatment without supervision and DOT were the comparator groups in the included studies. Theoretically, the effect of the studied intervention will be higher in the studies that used self-administration without supervision as the comparator group instead of DOT. A previous study showed that DOT was more effective than self-administration treatment (SAT) in the improvement of treatment adherence(38) and DOT intervention was also recommended by WHO for improving treatment adherence in TB patients.(38) It is possible, therefore, that using different comparators to compare two or more intervention studies will lead to an under- or over-estimation.
Another aspect, which may explain the variations in the results of studied interventions, is the quality of the included studies. Among the randomized studies, in six studies the
randomization method was unclear.(20–22,28,31,32) The investigators did not describe how the random allocation was conducted. In most of the included studies, blinding was impossible. Since the intervention involved direct activities with the research subjects such as reminders, counselling, education, and incentives, performing a blinding procedure was impossible. In addition, the quality of intervention is also essential. For instance in DOT studies, ability treatment observer to improve medication adherence of TB patients will affect the successful intervention. As previously described, the interaction between treatment observer and TB patients should also be considered to have an improvement in medication adherence.
Several limitations to our review should be acknowledged. First, the review was based on the two databases with restriction to English publications and searching period, hence not all the intervention studies may be covered in this study. However, to the best of our knowledge most studies are published in the English language and recent trials incorporated knowledge from the potential trials before 2003. Second, only a few studies used adherence rate as the study outcome. Most of the study mentioned treatment outcomes (i.e. sputum conversion, completed, cured, defaulted and poor treatment outcome), but did not include sufficient detail on adherence to correlate them. Therefore, the effectiveness of the interventions to improve medication adherence, as reported in the studies, should be carefully interpreted, and clearly high-quality intervention studies should be developed in the future.
CONCLUSIONS
Our review highlighted various interventions that have the potential to improve medication adherence among LTBI and active TB patients. Characteristics of the research subjects, accurate measurement of the adherence, type of the comparator group, robustness of study design and intervention should be considered to develop an effective and unbiased intervention for medication adherence in TB patients. Since non-adherence factors can be individual, interventions that takes into account the individual factors are required to have an effective medication adherence program. Therefore, further intervention studies that consider patient’s problems and develop a personalized approach are required for future development of effective programs on improving medication adherence among TB patients.
Funding
This work was supported by the Indonesia Endowment Fund for Education or LPDP in the form of a Ph.D. scholarship to ISP; this funding source had no role in the concept development, study design, data analysis or article preparation.
Conflict of interests
All authors have no competing financial or non-financial interests in this work.
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APPENDIX.
Search strategies
Medline/ PubMed database:
((Tuberculosis[tiab] or TB[tiab] OR tuberculosis infection[tiab] OR active tuberculosis[tiab] OR latent tuberculosis[tiab] OR pulmonary tuberculosis[tiab] OR extrapulmonary tuberculosis[tiab] OR anti-tuberculosis treatment*[tiab] OR anti-tb treatment*[tiab] OR “Tuberculosis”[Mesh]) AND (Adherence[tiab] OR compliance[tiab] OR nonadherence[tiab] OR non-adherence[tiab] OR concordance[tiab] OR medication adherence[tiab] OR patient adherence[tiab] OR patient compliance[tiab] OR “Medication Adherence”[Mesh]) AND (self-administration[tiab] OR self-administered[tiab] OR DOT*[tiab] OR directly observed*[tiab] OR directly observed therapy[tiab] OR directly observed treatment[tiab] OR incentive*[tiab] OR social support*[tiab] OR patient organization*[tiab] OR education[tiab] OR adherence education[tiab] OR dose frequency[tiab] OR memory aid*[tiab] OR reminder*[tiab] OR reinforcement*[tiab] OR reminder system*[tiab] OR motivation[tiab] OR motivational tool*[tiab] OR home visit*[tiab] OR patient education[tiab] OR counseling[tiab])).
Cochrane database: #1. Tuberculosis[Mesh]
#2. ‘tuberculosis’ OR ‘tb’ OR ‘tuberculosis infection’ OR ‘active tuberculosis’ OR ‘latent tuberculosis’ OR ‘pulmonary tuberculosis’ OR ‘extra pulmonary tuberculosis’ OR ‘anti-tuberculosis treatment’ OR ‘anti-tb treatment*’
#3. #1 AND #2
#4. Medication Adherence [Mesh}
#5. ‘adherence’ OR ‘compliance’ OR ‘non adherence OR ‘non-adherence’ OR ‘concordance’ OR ‘medication adherence’ OR ‘patient adherence’ OR ‘patient compliance’
#6. #4 AND #5
#7. ‘self-administration’ OR ‘self-administered’ OR ‘DOT*’ OR ‘directly observed*’ OR ‘directly observed therapy’ OR ‘directly observed treatment’ OR ‘incentive*’ OR ‘social support*’ OR ‘patient organization*’ OR ‘education’ OR ‘adherence education’ OR ‘dose frequency’ OR ‘memory aid*’ OR ‘reminder*’ OR ‘reinforcement*’ OR ‘reminder system*’ OR ‘motivation’ OR ‘motivational tool*’ OR ‘home visit*’ OR ‘patient education’ OR ‘counseling’ #8. #3 AND #6 AND #7
