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Initiation and completion rates for latent tuberculosis infection treatment: a systematic review

Initiation and completion rates for latent tuberculosis infection treatment: a systematic review Background: Control of latent tuberculosis infection (LTBI) is an important step towards tuberculosis elimination. Preventive treatment will prevent the development of disease in most cases diagnosed with LTBI. However, low initiation and completion rates affect the effectiveness of preventive treatment. The objective was to systematically review data on initiation rates and completion rates for LTBI treatment regimens in the general population and specific populations with LTBI. Methods: A systematic review of the literature (PubMed, Embase) published up to February 2014 was performed. Results: Forty-five studies on initiation rates and 83 studies on completion rates of LTBI treatment were found. These studies provided initiation rates (IR) and completion rates (CR) in people with LTBI among the general population (IR 26–99 %, CR 39–96 %), case contacts (IR 40–95 %, CR 48–82 %), healthcare workers (IR 47–98 %, CR 17–79 %), the homeless (IR 34–90 %, CR 23–71 %), people who inject drugs (IR 52–91 %, CR 38–89 %), HIV-infected individuals (IR 67–92 %, CR 55–95 %), inmates (IR 7–90 %, CR 4–100 %), immigrants (IR 23–97 %, CR 7–86 %), and patients with comorbidities (IR 82–93 %, CR 75–92 %). Generally, completion rates were higher for short than for long LTBI treatment regimens. Conclusion: Initiation and completion rates for LTBI treatment regimens were frequently suboptimal and varied greatly within and across different populations. Keywords: Tuberculosis, Latent tuberculosis, Treatment initiation, Treatment completion, Risk groups Background the world population is estimated to be latently infected In the European Union and European Economic Area with TB, there is a huge reservoir for the development of (EU/EEA) 65 thousand cases of tuberculosis (TB) were future TB disease [6]. reported in 2013, of which 77 % had pulmonary TB [1]. As long as a M. tuberculosis reservoir exists in individuals Cases with pulmonary TB produce microscopic droplets with LTBI, elimination of TB will not be feasible. Thus, the when coughing, sneezing, or spitting which can infect control of LTBI is an important step towards TB elimin- other individuals [2]. Exposure to Mycobacterium tuber- ation. In addition to TB case detection and treatment, TB is culosis may result in latent TB infection (LTBI), a state controlled by identifying individuals who are latently in- in which the host immune system controls the replica- fected with M. tuberculosis and offering them treatment tion of the bacillus to the extent that the progression to that will prevent the development of TB disease, especially TB disease is prevented [3, 4]. In a later phase, LTBI in high-income countries [7–9]. may progress to TB disease, especially if the immune Several LTBI treatment regimens have shown effective- system is compromised [3, 5]. Given that one-third of nesss [10]. However, adherence to these treatment regi- mens was sometimes low and differed between treatment regimens and populations [8, 11–18]. Numerous reasons * Correspondence: marieke.vanderwerf@ecdc.europa.eu Tomtebodavägen 11a, 171 65 Solna, Sweden for low adherence have been reported, such as (fear of) Full list of author information is available at the end of the article © 2016 Sandgren et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Sandgren et al. BMC Infectious Diseases (2016) 16:204 Page 2 of 12 side effects of the treatment, lack of symptomatic disease were considered relevant. Eligibility for LTBI treatment and thus lack of motivation for taking preventive treat- was defined as “being diagnosed with LTBI”. There was no ment, or low risk perception of progression to active TB required minimum study duration or number of subjects, [11, 17, 19]. except for studies in the general population diagnosed Incorporating programmatic LTBI control into the na- with LTBI that also presented data stratified for specific tional and EU/EEA strategies to fight TB is likely to be populations (e.g. case contacts, immigrants etc.). Since of value for all EU/EEA Member States. Therefore, the these studies were primarily aimed at the total population, European Centre for Disease Prevention and Control and sampling strategies were applied accordingly, data for (ECDC) aims to provide EU/EEA Member States and the specific populations were only extracted when such a candidate countries with scientific advice and guidance population consisted of at least 30 subjects. Studies were on programmatic LTBI control. In order to collect the evi- considered to be conducted in the general population dence base for developing the ECDC guidance a series of when they did not specifically focus on certain risk groups. systematic reviews have been performed. This was done in For an article to be included in the review, baseline data collaboration with World Health Organization (WHO) (e.g. population characteristics) must be presented, LTBI who used the same evidence base for the development of had to be defined in the study (e.g. as “positive tuberculin the WHO guidelines on LTBI control [20] launched in skin tests (greater of equal 10 mm) and negative chest ra- early 2015. One important aspect for LTBI control is to diographs”) and the LTBI treatment regimen had to be ensure adherence to and completeness of the preventive specified, and for studies presenting completion rates, a treatment. Therefore, a systematic literature review was definition for “completion” had to be provided. Studies performed to assess initiation and completion rates of did not have to apply a specific definition for LTBI or LTBI treatment and to identify determinants and inter- completion to be included. Adherence rates that met the ventions for adherence and completion, in the general and definition of “completion” (e.g. “full adherence” or “ad- in specific populations with LTBI. In this article we herence for nine months”) were interpreted as comple- present the results of the initiation and completion rates tion rates. If individuals whose completion status was for recommended preventive treatments. pendingbythe endofa studywere includedin the completion rate, the rate was recalculated to exclude Methods these individuals. Studies that included only case con- A systematic literature review was performed according tacts who received chemoprophylaxis irrespective of to a review protocol and following the Cochrane guide- whether or not LTBI was diagnosed were excluded lines. The aim of the systematic review was to provide from this review. answers to the following research questions: 1) What is the LTBI treatment initiation rate and the completion Information sources and search strategy rate for each recommended LTBI treatment regimen; 2) We searched the databases PubMed and Embase. Search What are determinants of LTBI treatment initiation, ad- strings were composed for 1) LTBI, 2) LTBI treatment, herence, and completion; 3) What are the interventions and 3) initiation, adherence, completion and implemen- with demonstrated efficacy or effectiveness to improve tation. A fourth search string was composed to exclude LTBI treatment initiation, adherence and completion in animal studies (see Additional file 2: Search strings). No individuals who are eligible for LTBI treatment. Due to geographical, time, or language limits were applied, how- the extensive results, the results for review question 1 ever only full-text articles in English, French, Spanish, are presented in this article and the results for review German, and Dutch were reviewed. The search was car- questions 2 and 3 will be presented separately. rd ried out on February 3 , 2014 for all literature published up to that date. Output from the searched databases was Eligibility criteria exported to Endnote version X4.0.2. PICO (Population-Intervention-Comparator-Outcome) questions were formulated based on the review questions (see Additional file 1: PICO questions). Only primary Study selection articles describing randomised controlled trials (RCTs), Articles were selected by a three-step selection procedure non-randomised prospective comparative studies of inter- based on 1) screening of title and abstract, 2) screening of ventions, prospective longitudinal observational studies, full-text article, and 3) final screening during the data- and retrospective studies were included in this review. extraction phase. One-hundred percent of the title and ab- Systematic reviews were not included; however the refer- stract selection and critical appraisal of the full-text articles ence lists of relevant systematic reviews were screened to was done in duplicate by two independent researchers; the find primary articles that were not found via our literature results were compared and discussed and any doubts were search. Studies in individuals eligible for LTBI treatment resolved by a third researcher. Sandgren et al. BMC Infectious Diseases (2016) 16:204 Page 3 of 12 Risk of bias assessment Results The risk of bias of each included full-text article was Results of the review process assessed with standardised, study-design specific, quality The search resulted in 2536 unique hits; 115 relevant ar- appraisal forms following the risk of bias assessment ticles were included for all review questions (see Fig. 1). proposed by the Cochrane Collaboration [21]. A few For review question 1, a total of 95 unique articles were additional aspects, not mentioned in the Cochrane Col- found, including 43 prospective studies and 52 retrospect- laboration, were considered when evaluating the quality ive studies. Of these articles, 45 provided information on of the articles, i.e. the adequacy of recall assessment and initiation rates of LTBI treatment regimens and 83 on reporting, whether confidence intervals were provided, completion rates. An overview of the study characteristics, and for retrospective studies, the adequacy of the initiation and/or completion rates, and the quality aspects method of retrospective selection of the population. of the risk of bias assessment of the included studies are Each aspect was evaluated as high risk of bias, moderate presented in Additional file 3: Study characteristics, out- or unclear risk of bias, or low risk of bias. Because of comes, and quality aspects. the descriptive nature of the review question, risk of bias was only assessed for aspects of the individual studies, Initiation and completion rates without providing an overall level of quality for each in- Most study populations in the included articles consisted dividual study. As review question 1 does not deal with of individuals from the general population diagnosed with the effects of health interventions and treatment and LTBI, case contacts or immigrants with LTBI (Table 1; populations vary widely between studies, risk of bias was Additional file 3: Study characteristics, outcomes, and also not assessed across the evidence base per outcome. quality aspects). In prospective studies, initiation and completion rates were most often presented for long treat- Data extraction ment regimens and in retrospective studies rates were Evidence tables were compiled by two researchers and most frequently reported for either long treatment regi- reviewed by a third researcher. The data extraction was mens or for short and long treatment regimens combined. done in duplicate for 15 % of the included articles, no major differences were found. Evidence tables were cre- Initiation rates ated for different populations with LTBI: 1) general Overall, twenty prospective studies [18, 19, 23–40] that population (primarily unselected individuals with LTBI reported initiation rates were found (Table 1; Additional at clinics), 2) case contacts, 3) healthcare workers, 4) the file 3: Study characteristics, outcomes, and quality as- homeless, 5) people who inject drugs (PWID), 6) human pects). Initiation rates varied considerably among popula- immunodeficiency virus (HIV)-infected individuals, 7) tions with LTBI, ranging from 26 to 99 % in the general inmates, 8) immigrants, and 9) patients with comorbidi- population (four studies [18, 23–25]) (Fig. 2), from 40 to ties, e.g. patients with rheumatoid arthritis or patients 85 % in case contacts (four studies [25–28]), from 34 to with hematologic malignancies. The definitions of com- 90 % in the homeless (three studies [25, 29, 30]), from 52 pletion were those used in the individual studies; there to 91 % in PWID (three studies [31–33]), from 90 to 92 % were differences in definitions between studies. Study re- in HIV-infected individuals (three studies [34–36]), and sults were sorted by study design and split by duration from 23 to 97 % in immigrants (four studies [25, 38–40]) of the LTBI treatment regimen, i.e. short (≤four months), (Additional file 3: Study characteristics, outcomes, and long (>four months), or short and long combined when quality aspects). Only one prospective study each reported no data were presented for short and long LTBI treat- an initiation rate in healthcare workers or inmates, the ini- ment separately. tiation rates for these groups were 98 % [19] and 65 % [37], respectively. No prospective studies that reported ini- Synthesis of results tiation rates were found for patients with comorbidities. Meta-analysis is performed in accordance with GRADE Twenty-five retrospective studies that reported initi- methodology and results are reported in accordance with ation rates, mostly based on medical records, were found the Preferred Reporting Items for Systematic Reviews and (Table 1; Additional file 3: Study characteristics, outcomes, Meta-Analyses (PRISMA) statement. For data visualisa- and quality aspects). There was considerable overlap in the tion, forest plots of initiation and completion rates were ranges of initiation rates reported in prospective studies created for the identified populations in Excel 2010 [22]. and retrospective studies. The MetaXL 2.1 add-in in Excel was used to calculate 95 % confidence intervals around initiation and comple- Completion rates tion rates. We planned to calculate pooled rates, however In total, 39 prospective studies reporting completion this was not done for the first review question, because of rates were identified [12, 18, 23–27, 30–32, 34–62]. the large heterogeneity of the included articles. Completion rates ranged from 46 to 95 % in the general Sandgren et al. BMC Infectious Diseases (2016) 16:204 Page 4 of 12 Fig. 1 Flow chart of selection process. RQ: review question. LTBI: latent tuberculosis infection; TB: tuberculosis. Review question 1a: What is the initiation rate for each recommended LTBI treatment regimen?; Review question 1b: What is the completion rate for each recommended LTBI treatment regimen?; Review question 2a: What are the determinants of LTBI treatment initiation?; Review question 2b: What are the determinants of LTBI treatment adherence?; Review question 2c: What are the determinants of LTBI treatment completion?; Review question 3: In individuals who are eligible for LTBI treatment, what are the interventions with demonstrated efficacy or effectiveness to improve LTBI treatment initiation, adherence and completion? population (thirteen studies [12, 18, 23–25, 41, 42, As for initiation rates, considerable overlap in the ranges of 46, 47, 49, 50, 57, 60]), from 53 to 82 % in case con- completion rates reported in prospective studies and retro- tacts (six studies [12, 25–27, 51, 52]), from 25 to spective studies appears to exist. 71 % in the homeless (four studies [18, 25, 30, 60]), from 38 to 89 % in PWID (four studies [31, 32, 56, 58]), Short versus long treatment regimens from 55 to 95 % in HIV-infected individuals (eight studies In most of the 27 studies that presented separate com- [18, 34–36, 44, 48, 54, 55]), from 4 to 48 % in inmates pletion rates for patients that received short treatment (three studies [37, 53, 63]), and from 7 to 83 % in immi- regimens and for patients that received long treatment grants (nine studies [12, 25, 38–40, 43, 45, 57, 59]). Only regimens, completion rates appear to be higher for the one study reported a completion rate in healthcare short treatment group (Fig. 3; Additional file 4: Forest workers and patients with comorbidities, the completion plots). However, an exception to this observation was rates for these groups were 44 % [18] and 87 % [61], re- Clerk et al., who showed higher completion rates for spectively. In addition, 44 retrospective studies reporting long treatment regimens than shorter regimens (67 % completion rates were found (Table 1; Additional file 3: vs 79 %) [65], and a small number of other studies that Study characteristics, outcomes, and quality aspects). showed very similar completion rates between the two Within-study comparisons show that the homeless had treatment groups [48, 52, 66, 67] in various populations lower completion rates than other populations [18, 25, 64]. with LTBI. Due to large heterogeneity across studies Sandgren et al. BMC Infectious Diseases (2016) 16:204 Page 5 of 12 Table 1 Number of included studies and ranges of initiation and completion rates per study population Study population Short treatment regimens Long treatment regimens Short/long treatment regimens combined n Range rates (%) n Range rates (%) n Range rates (%) N Initiation rates Prospective studies (n = 20 unique articles; some present data for more than one population and more than one treatment regimen) General 1 [23]86 2[18, 24]44–99 1 [25]26 4 Case contacts 0 – 3[26–28]40–85 1 [25]53 4 Healthcare workers 1 [19]98 0 – 0 – 1 Homeless 0 – 2[29, 30]76–90 1 [25]34 3 PWID 0 – 3[31–33]52–91 0 – 3 HIV infected 0 – 2[34, 35]90–92 1 [36]91 3 Inmates 0 – 1[37]65 0 – 1 Immigrants 0 – 3[38–40]77–97 1 [25]23 4 Patients with 0 – 0 – 0 – 0 comorbidities Retrospective studies (n = 25 unique articles; some present data for more than one population and more than one treatment regimen) General 0 – 4[89–92]82–98 5 [16, 78, 93–95]53–83 9 Case contacts 0 – 1[96]81 5[13, 78, 97–99]74–95 6 Healthcare workers 0 – 1[100]92 4 47–89 5 [78, 94, 101, 102] Homeless 0 – 0 – 0 – 0 PWID 0 – 1[103]56 0 – 1 HIV infected 0 – 1[104]67 0 – 1 Inmates 0 – 0 – 2[80, 105]7–90 2 Immigrants 0 – 2[106, 107]78–84 3 [16, 93, 94]57–82 5 Patients with 1[108]93 1[109]82 0 – 2 comorbidities Completion rates Prospective studies (n = 39 unique articles; some present data for more than one population and more than one treatment regimen) General 10 [12, 23, 25, 41, 42, 61–95 10 [12, 18, 24, 25, 41, 46–76 0 – 13 46, 47, 49, 50, 60] 42, 46, 47, 50, 57] Case contacts 2 [51, 52]71–82 4 [26, 27, 51, 52]53–73 2 [12, 25]60–64 6 Healthcare workers 0 – 1[18]44 0 – 1 Homeless 1 [60]71 2[18, 30]25–33 1 [25]44 4 PWID 0 – 4[31, 32, 56, 58]38–89 0 – 4 HIV infected 6 [36, 44, 48]62–95 8 [18, 34–36, 44, 48, 54, 55–89 0 – 8 55] Inmates 1 [53]48 3[37, 53, 62]4–38 0 – 3 Immigrants 2 [43, 59]72–80 8 [38–40, 43, 45, 57]7–83 2 [12, 25]61–79 9 Patients with 1[61]87 0 – 0 – 1 comorbidities Retrospective studies (n = 44 unique articles; some present data for more than one population and more than one treatment regimen) General 14 [14–17, 65–67, 78, 56–93 23 [14–16, 64–67, 78, 39–96 1 [93]54 27 79, 81–83, 110, 111] 79, 81–83, 89–92, 112–118] Case contacts 3 [13, 14, 17]63–69 4 [13, 14, 113, 116]56–78 5 [78, 82, 97, 48–81 10 98, 119] Healthcare workers 0 – 2[100, 113]17–75 3 [15, 78, 101]40–79 5 Sandgren et al. BMC Infectious Diseases (2016) 16:204 Page 6 of 12 Table 1 Number of included studies and ranges of initiation and completion rates per study population (Continued) Homeless 1 [120]44 1[64]23 0 – 2 PWID 0 – 1[103]55 0 – 1 HIV infected 0 – 2[14, 104]55–66 0 – 2 Inmates 4 [80, 120]48–100 2 [80, 121]23–68 0 – 3 Immigrants 4 [14, 16, 17, 122]60–85 11 [14, 16, 64, 89, 91, 92, 38–86 5 [15, 65, 53–69 18 106, 113, 116, 123, 124] 79, 82, 93] Patients with 1[108]92 1[125]75 0 – 2 comorbidities HIV human immunodeficiency virus, n number of included studies, N total number of included studies, PWID people who inject drugs and the fact that most studies were not designed to Risk groups specifically assess the effect of treatment duration on The population for which most studies were identified was completion, no pooled analysis was performed to deter- the general population diagnosed with LTBI. Though this mine if there was a statistically significant association population consisted primarily of unselected individuals between treatment duration and completion rates. with LTBI at clinics, it was very diverse, mainly due to the varying proportion of specific populations, such as immi- Discussion grants, across clinics. Generally, two types of risk groups This is, to our knowledge, the first systematic review to could be distinguished: groups with higher risk of TB comprehensively explore both initiation and completion infection, but without an increased risk of progression rates of LTBI treatment worldwide. In total, evidence from to TB (e.g. health care workers, inmates, and the home- 95 studies has been reviewed. Forty-five studies reported less) [68–70] and groups with LTBI who are at higher on initiation rates and 83 on completion rates, covering risk of progression to active TB (e.g. HIV-infected indi- nine different population types with LTBI. There was wide viduals, patients with comorbidities) [71–74]. Case con- variation in initiation and completion rates; the initiation tacts appear to have both a higher risk of TB infection rates ranged from 7 to 99 % and the completion rates and a higher risk of progression to active TB due to re- ranged from 4 to 100 % across the different population cent infection [68, 75]. The initiation rates and comple- groups. These rates should be interpreted taking into ac- tion rates of LTBI treatment appeared slightly higher in count the variety of treatment options (i.e. choice of regi- the groups with higher risk of progression of LTBI to men, duration, self-administered or observed). active TB than in the groups with higher risk of TB Duration Initiation rates – General population with LTBI Study % (95%CI) Design regimen Goswami et al., 2012 Combined 26 (22-30) Lee et al., 2011 Short 86 (79-92) Prospective Morano et al., 2013 Long 44 (38-50) Pettit et al., 2013 Long 99 (98-99) Goswami et al., 2012 Combined 53 (52-54) Cruz et al., 2012 Long 98 (95-99) Gershon et al., 2004 Combined 58 (53-64) Gilroy et al., 2000 Long 98 (97-99) Retro- Horsburgh et al., 2010 Combined 83 (80-86) spective Kwara et al., 2008 Long 82 (79-84) Nuzzo et al., 2013 Combined 78 (75-80) Parsyan et al., 2007 Long 91 (90-93) Shah et al., 2012 Combined 77 (74-80) 0 102030405060708090 100 Fig. 2 Forest plots with ranges of initiation rates in the general population diagnosed with LTBI. LTBI: latent tuberculosis infection; Circle: combined, square: long, triangle: short Sandgren et al. BMC Infectious Diseases (2016) 16:204 Page 7 of 12 Completion rates – General population with LTBI Duration Design Study % (95%CI) regimen Bastos et al., 2013 Short 82 (73-90) Bastos et al., 2013 Long 62 (51-72) Jasmer et al., 2002 Short 61 (55-66) Jasmer et al., 2002 Long 57 (51-62) Menzies et al., 2008 Short 78 (74-82) Menzies et al., 2008 Long 60 (55-64) Menzies et al., 2004 Short 91 (83-97) RCT Menzies et al., 2004 Long 76 (64-86) Schechter et al., 2006 (1) Short 93 (89-96) Schechter et al., 2006 (2) Short 94 (90-97) Spyridis et al., 2007 (1) Short 95 (92-98) Spyridis et al., 2007 (2) Short 93 (91-95) Spyridis et al., 2007 Long 86 (81-90) Trajman et al., 2010 Short 81 (77-85) Trajman et al., 2010 Long 64 (59-69) Goswami et al., 2012 Short 68 (50-83) Goswami et al., 2012 Long 52 (42-61) Lee et al., 2011 Short 93 (87-98) Prospective Morano et al., 2013 Long 60 (49-69) Morisky et al., 2003 Long 69 (65-73) Pettit et al., 2013 Long 47 (45-50) Stout et al., 2003 Short 68 (59-76) Cain et al., 2012 Combined 54 (53-56) Chang SH et al., 2013 Long 78 (76-80) Clerk et al., 2011 Short 67 (53-81) Clerk et al., 2011 Long 79 (53-97) Codecasa et al., 2013 Long 74 (73-75) Cruz et al., 2012 Long 75 (69-80) Cruz et al., 2013 Long 96 (94-97) Duarte et al., 2012 Short 93 (90-95) Duarte et al., 2012 Long 90 (85-94) Fresard et al., 2011 Short 83 (77-88) Fresard et al., 2011 Long 74 (70-78) Gilroy et al., 2000 Long 51 (46-55) Haley et al., 2008 Short 76 (73-79) Hirsch-Moverman et al., 2010 Long 45 (39-50) Horsburgh et al., 2010 Short 64 (55-73) Horsburgh et al., 2010 Long 46 (44-48) Retro- Kan et al., 2013 Long 76 (71-80) spective Kwara et al., 2008 Long 62 (58-65) Lardizabal et al., 2006 Short 80 (75-85) Lardizabal et al., 2006 Long 53 (46-60) Li et al., 2010 Short 60 (57-63) Li et al., 2010 Long 44 (43-45) LoBue et al., 2003 Long 64 (62-65) Nuzzo et al., 2013 Short 80 (75-84) Nuzzo et al., 2013 Long 72 (67-78) Page et al., 2006 Long 53 (49-56) Parsyan et al., 2007 Long 39 (36-41) Rennie et al., 2007 Short 60 (55-66) Rennie et al., 2007 Long 46 (40-52) Smith et al., 2011 Short 56 (52-61) Smith et al., 2011 Long 54 (53-55) Vinnard et al., 2013 Long 46 (39-52) Young et al., 2009 Short 91 (85-95) Young et al., 2009 Long 65 (61-69) 0 102030405060708090 100 Fig. 3 Forest plot with completion rates in the general population diagnosed with LTBI. LTBI: latent tuberculosis infection; Circle: combined, square: long, triangle: short infection. Care has to be taken when comparing find- of the sixteen studies they included were also included ings between studies, due to differences within popula- in our review. Both the presented completion rate of iso- tions, in setting and in methodology. niazid treatment during incarceration and after release Hirsch-Moverman et al. [11] reviewed studies in the from jail appeared slightly higher than the completion United States and Canada published between 1997 and rates of long LTBI treatment regimens in inmates found 2007 and presented completion rates of LTBI treatment in our review. that are in line with the results found in our review. Overall, 20 of the 60 studies that were included in their Short and long treatment regimens review were also included in ours; differences are due to Short LTBI treatment most frequently consisted of four the fact that we did not include studies that did not pro- months of rifampicin or two months of rifampicin and vide a definition for completion, did not specify the type pyrazinamide, though other combinations of rifampicin, of treatment or did not define LTBI. isoniazid, rifabutin and pyrazinamide were also adminis- Al-Darraji et al. [76] reviewed completion rates of tered for two to four months. Currently, the combin- treatment with isoniazid in inmates with LTBI, from ation of rifampicin with pyrazinamide is not generally studies published between 1966 and January 2011. Four offered to persons with LTBI as it has been associated Sandgren et al. BMC Infectious Diseases (2016) 16:204 Page 8 of 12 with hepatotoxicity [77]. Long LTBI treatment consisted Stagg et al. [10] and was part of the same evidence base of isoniazid regimens, usually for six or nine months and collection as our systematic review. often for twelve months in the case of concurrent HIV- infection. Only three studies presented initiation rates Limitations for short treatment regimens, therefore initiation rates Studies without a definition for “completion” were ex- between short and long treatment regimens could not cluded from this review. Still, the definition of completion be compared. varied considerably between studies, and this hetero- A considerable number of prospective articles pre- geneity complicated comparison of completion rates sented completion rates for both short and long treat- between studies. Definitions used varied from “com- ment regimens, especially in the general population pleted four months of rifampicin” [81] to “picked up diagnosed with LTBI and in HIV-infected individuals nine months of isoniazid within twelve months” [25] with LTBI. Most results of within-study comparisons of and “took at least 80 % of the prescribed medication short and long treatments [13–16, 78–83] indicated within twenty weeks” [15]. Also, the quality of the defi- higher completion rates for shorter regimens, although nitions of “completion” varied throughout the included in two studies rates were comparable for short and long studies and the distinction between definitions for adher- treatment regimens [66, 67]. In one study lower comple- ence and completion was not always obvious. Besides, the tion rates were reported for short treatment than for quality of the definition of “completion” is closely linked longer treatments [65] due to adverse effects. It should to the way treatment adherence is assessed, which varied be kept in mind that the type of drugs used in short and from self-reported adherence (least reliable) [35], dispense long LTBI treatment regimens varied considerably between of medication [58], pill counts [52], urine tests [43], to studies and within populations. Directly Observed Treatment (DOT; most reliable) [62]. Hirsch-Moverman et al. [11] also reviewed data on Furthermore, it was not always clear whether and to what completion rates of short (rifampicin or rifampicin in extent the classification of a patient as having completed combination with pyrazinamide) and long (isoniazid) treatment was influenced by the time that a patient treatment regimens within studies and found a higher per- needed to take all the doses. Finally, some patients may centage of completion among short treatments in all in- have discontinued treatment due to toxicity. In our ana- cluded studies, although the difference was not always lysis, this is included in non completion. Discontinuation significant. Ziakas et al. [84] systematically reviewed the because of side effects will influence the effectiveness of literature for studies that compared four months of rifam- latent TB infection treatment but it will need other efforts picin with nine months of isoniazid, published up to July than voluntary discontinuation of treatment. 2009, and included four studies in a meta-analysis. These In addition, rate calculations varied across included four studies were also included in this review. They con- studies; different rules were applied for in- and exclusion cluded that four months of rifampicin was associated with into the denominator to calculate the initiation and/or a significant reduction in the risk of non-completion [84]. completion rates. All these differences between studies Sharma et al. [85] conducted a systematic review on RCTs and unclarities hampered the analysis. worldwide among HIV-negative people at risk of active Within our review, no distinction was made between TB that compared rifampicin monotherapy or rifamycin- studies that looked at a priori defined risk groups versus combination therapy with isoniazid monotherapy. Their studies that identified risk factors in a non-selected group meta-analysis of five trials, of which two were included in of individuals with LTBI. Also, population characteristic our review, compared rifampicin (three or four months) or settings of risk groups may vary between studies, for with isoniazid (six months) and showed that significantly example immigrants in the United States might differ more people completed the shorter course. Two more of from immigrants in Europe with respect to their origin their meta-analyses compared isoniazid in combination [86, 87]. In addition, it should be noted that individuals with rifampicin (three months; two trials) or rifampicin in with LTBI might belong to multiple risk groups, as overlap combination with pyrazinamide (two months; three trials, between the groups exists; however, most studies did not one of which was included in our review) with isoniazid specify if there was any overlap between risk groups. (six months) and found that there was no difference in completion rates [85]. Conclusions By comparing completion rates between short and long The goal of LTBI treatment is to eradicate M. tuberculosis LTBI treatment we do not take into account any effect of from the body and to reduce the risk of progression to ac- the treatment regimen on completion rate, e.g. due to dif- tive TB disease [88]. Only treatment can clear the bacteria ferent side effect patterns. The effect of different treatment from the body, and therefore individuals with LTBI who regimens for preventing active TB, and thus indirectly do not initiate treatment contribute to the persistence of taking into account completion, has been compared by the TB reservoir. Clinical benefit to the individual with Sandgren et al. BMC Infectious Diseases (2016) 16:204 Page 9 of 12 LTBI and the success of control programs is subject to Acknowledgements Not applicable. completion of LTBI treatment. This systematic review found that initiation and com- Funding pletion rates for LTBI treatment regimens were fre- This work was performed under the ECDC Framework Contract FWC/ECDC/ quently suboptimal and varied greatly within and across 2013/005 Specific Contract No. 1 ECD.4065 awarded to the consortium consisting of Pallas, health research and consultancy and the Department of Public Health, different populations. Population groups with a higher risk Erasmus MC, and Service contract ECD.5000 of OJ/02/05/2014-PROC/2014/015 of TB infection, but without an increased risk of progres- awarded to Pallas, health research and consultancy. sion to TB (e.g. health care workers, inmates, and the Author details homeless) seemed at slightly higher risk of low initiation Former Surveillance and Response Section, European Centre for Disease and completion rates. However, the limited number of 2 Prevention and Control (ECDC), Stockholm 171 65, Sweden. Pallas, Health studies found for certain LTBI treatment regimens and Research and Consultancy B.V., Rotterdam 3001, The Netherlands. Tomtebodavägen 11a, 171 65 Solna, Sweden. study populations, and the variation in types of risk popu- lations, settings, treatment regimens and study methodolo- Received: 16 February 2016 Accepted: 7 May 2016 gies in the included studies make it difficult to draw firm conclusions. 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Initiation and completion rates for latent tuberculosis infection treatment: a systematic review

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References (136)

Publisher
Springer Journals
Copyright
Copyright © 2016 by Sandgren et al.
Subject
Medicine & Public Health; Infectious Diseases; Parasitology; Medical Microbiology; Tropical Medicine; Internal Medicine
eISSN
1471-2334
DOI
10.1186/s12879-016-1550-y
pmid
27184748
Publisher site
See Article on Publisher Site

Abstract

Background: Control of latent tuberculosis infection (LTBI) is an important step towards tuberculosis elimination. Preventive treatment will prevent the development of disease in most cases diagnosed with LTBI. However, low initiation and completion rates affect the effectiveness of preventive treatment. The objective was to systematically review data on initiation rates and completion rates for LTBI treatment regimens in the general population and specific populations with LTBI. Methods: A systematic review of the literature (PubMed, Embase) published up to February 2014 was performed. Results: Forty-five studies on initiation rates and 83 studies on completion rates of LTBI treatment were found. These studies provided initiation rates (IR) and completion rates (CR) in people with LTBI among the general population (IR 26–99 %, CR 39–96 %), case contacts (IR 40–95 %, CR 48–82 %), healthcare workers (IR 47–98 %, CR 17–79 %), the homeless (IR 34–90 %, CR 23–71 %), people who inject drugs (IR 52–91 %, CR 38–89 %), HIV-infected individuals (IR 67–92 %, CR 55–95 %), inmates (IR 7–90 %, CR 4–100 %), immigrants (IR 23–97 %, CR 7–86 %), and patients with comorbidities (IR 82–93 %, CR 75–92 %). Generally, completion rates were higher for short than for long LTBI treatment regimens. Conclusion: Initiation and completion rates for LTBI treatment regimens were frequently suboptimal and varied greatly within and across different populations. Keywords: Tuberculosis, Latent tuberculosis, Treatment initiation, Treatment completion, Risk groups Background the world population is estimated to be latently infected In the European Union and European Economic Area with TB, there is a huge reservoir for the development of (EU/EEA) 65 thousand cases of tuberculosis (TB) were future TB disease [6]. reported in 2013, of which 77 % had pulmonary TB [1]. As long as a M. tuberculosis reservoir exists in individuals Cases with pulmonary TB produce microscopic droplets with LTBI, elimination of TB will not be feasible. Thus, the when coughing, sneezing, or spitting which can infect control of LTBI is an important step towards TB elimin- other individuals [2]. Exposure to Mycobacterium tuber- ation. In addition to TB case detection and treatment, TB is culosis may result in latent TB infection (LTBI), a state controlled by identifying individuals who are latently in- in which the host immune system controls the replica- fected with M. tuberculosis and offering them treatment tion of the bacillus to the extent that the progression to that will prevent the development of TB disease, especially TB disease is prevented [3, 4]. In a later phase, LTBI in high-income countries [7–9]. may progress to TB disease, especially if the immune Several LTBI treatment regimens have shown effective- system is compromised [3, 5]. Given that one-third of nesss [10]. However, adherence to these treatment regi- mens was sometimes low and differed between treatment regimens and populations [8, 11–18]. Numerous reasons * Correspondence: marieke.vanderwerf@ecdc.europa.eu Tomtebodavägen 11a, 171 65 Solna, Sweden for low adherence have been reported, such as (fear of) Full list of author information is available at the end of the article © 2016 Sandgren et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Sandgren et al. BMC Infectious Diseases (2016) 16:204 Page 2 of 12 side effects of the treatment, lack of symptomatic disease were considered relevant. Eligibility for LTBI treatment and thus lack of motivation for taking preventive treat- was defined as “being diagnosed with LTBI”. There was no ment, or low risk perception of progression to active TB required minimum study duration or number of subjects, [11, 17, 19]. except for studies in the general population diagnosed Incorporating programmatic LTBI control into the na- with LTBI that also presented data stratified for specific tional and EU/EEA strategies to fight TB is likely to be populations (e.g. case contacts, immigrants etc.). Since of value for all EU/EEA Member States. Therefore, the these studies were primarily aimed at the total population, European Centre for Disease Prevention and Control and sampling strategies were applied accordingly, data for (ECDC) aims to provide EU/EEA Member States and the specific populations were only extracted when such a candidate countries with scientific advice and guidance population consisted of at least 30 subjects. Studies were on programmatic LTBI control. In order to collect the evi- considered to be conducted in the general population dence base for developing the ECDC guidance a series of when they did not specifically focus on certain risk groups. systematic reviews have been performed. This was done in For an article to be included in the review, baseline data collaboration with World Health Organization (WHO) (e.g. population characteristics) must be presented, LTBI who used the same evidence base for the development of had to be defined in the study (e.g. as “positive tuberculin the WHO guidelines on LTBI control [20] launched in skin tests (greater of equal 10 mm) and negative chest ra- early 2015. One important aspect for LTBI control is to diographs”) and the LTBI treatment regimen had to be ensure adherence to and completeness of the preventive specified, and for studies presenting completion rates, a treatment. Therefore, a systematic literature review was definition for “completion” had to be provided. Studies performed to assess initiation and completion rates of did not have to apply a specific definition for LTBI or LTBI treatment and to identify determinants and inter- completion to be included. Adherence rates that met the ventions for adherence and completion, in the general and definition of “completion” (e.g. “full adherence” or “ad- in specific populations with LTBI. In this article we herence for nine months”) were interpreted as comple- present the results of the initiation and completion rates tion rates. If individuals whose completion status was for recommended preventive treatments. pendingbythe endofa studywere includedin the completion rate, the rate was recalculated to exclude Methods these individuals. Studies that included only case con- A systematic literature review was performed according tacts who received chemoprophylaxis irrespective of to a review protocol and following the Cochrane guide- whether or not LTBI was diagnosed were excluded lines. The aim of the systematic review was to provide from this review. answers to the following research questions: 1) What is the LTBI treatment initiation rate and the completion Information sources and search strategy rate for each recommended LTBI treatment regimen; 2) We searched the databases PubMed and Embase. Search What are determinants of LTBI treatment initiation, ad- strings were composed for 1) LTBI, 2) LTBI treatment, herence, and completion; 3) What are the interventions and 3) initiation, adherence, completion and implemen- with demonstrated efficacy or effectiveness to improve tation. A fourth search string was composed to exclude LTBI treatment initiation, adherence and completion in animal studies (see Additional file 2: Search strings). No individuals who are eligible for LTBI treatment. Due to geographical, time, or language limits were applied, how- the extensive results, the results for review question 1 ever only full-text articles in English, French, Spanish, are presented in this article and the results for review German, and Dutch were reviewed. The search was car- questions 2 and 3 will be presented separately. rd ried out on February 3 , 2014 for all literature published up to that date. Output from the searched databases was Eligibility criteria exported to Endnote version X4.0.2. PICO (Population-Intervention-Comparator-Outcome) questions were formulated based on the review questions (see Additional file 1: PICO questions). Only primary Study selection articles describing randomised controlled trials (RCTs), Articles were selected by a three-step selection procedure non-randomised prospective comparative studies of inter- based on 1) screening of title and abstract, 2) screening of ventions, prospective longitudinal observational studies, full-text article, and 3) final screening during the data- and retrospective studies were included in this review. extraction phase. One-hundred percent of the title and ab- Systematic reviews were not included; however the refer- stract selection and critical appraisal of the full-text articles ence lists of relevant systematic reviews were screened to was done in duplicate by two independent researchers; the find primary articles that were not found via our literature results were compared and discussed and any doubts were search. Studies in individuals eligible for LTBI treatment resolved by a third researcher. Sandgren et al. BMC Infectious Diseases (2016) 16:204 Page 3 of 12 Risk of bias assessment Results The risk of bias of each included full-text article was Results of the review process assessed with standardised, study-design specific, quality The search resulted in 2536 unique hits; 115 relevant ar- appraisal forms following the risk of bias assessment ticles were included for all review questions (see Fig. 1). proposed by the Cochrane Collaboration [21]. A few For review question 1, a total of 95 unique articles were additional aspects, not mentioned in the Cochrane Col- found, including 43 prospective studies and 52 retrospect- laboration, were considered when evaluating the quality ive studies. Of these articles, 45 provided information on of the articles, i.e. the adequacy of recall assessment and initiation rates of LTBI treatment regimens and 83 on reporting, whether confidence intervals were provided, completion rates. An overview of the study characteristics, and for retrospective studies, the adequacy of the initiation and/or completion rates, and the quality aspects method of retrospective selection of the population. of the risk of bias assessment of the included studies are Each aspect was evaluated as high risk of bias, moderate presented in Additional file 3: Study characteristics, out- or unclear risk of bias, or low risk of bias. Because of comes, and quality aspects. the descriptive nature of the review question, risk of bias was only assessed for aspects of the individual studies, Initiation and completion rates without providing an overall level of quality for each in- Most study populations in the included articles consisted dividual study. As review question 1 does not deal with of individuals from the general population diagnosed with the effects of health interventions and treatment and LTBI, case contacts or immigrants with LTBI (Table 1; populations vary widely between studies, risk of bias was Additional file 3: Study characteristics, outcomes, and also not assessed across the evidence base per outcome. quality aspects). In prospective studies, initiation and completion rates were most often presented for long treat- Data extraction ment regimens and in retrospective studies rates were Evidence tables were compiled by two researchers and most frequently reported for either long treatment regi- reviewed by a third researcher. The data extraction was mens or for short and long treatment regimens combined. done in duplicate for 15 % of the included articles, no major differences were found. Evidence tables were cre- Initiation rates ated for different populations with LTBI: 1) general Overall, twenty prospective studies [18, 19, 23–40] that population (primarily unselected individuals with LTBI reported initiation rates were found (Table 1; Additional at clinics), 2) case contacts, 3) healthcare workers, 4) the file 3: Study characteristics, outcomes, and quality as- homeless, 5) people who inject drugs (PWID), 6) human pects). Initiation rates varied considerably among popula- immunodeficiency virus (HIV)-infected individuals, 7) tions with LTBI, ranging from 26 to 99 % in the general inmates, 8) immigrants, and 9) patients with comorbidi- population (four studies [18, 23–25]) (Fig. 2), from 40 to ties, e.g. patients with rheumatoid arthritis or patients 85 % in case contacts (four studies [25–28]), from 34 to with hematologic malignancies. The definitions of com- 90 % in the homeless (three studies [25, 29, 30]), from 52 pletion were those used in the individual studies; there to 91 % in PWID (three studies [31–33]), from 90 to 92 % were differences in definitions between studies. Study re- in HIV-infected individuals (three studies [34–36]), and sults were sorted by study design and split by duration from 23 to 97 % in immigrants (four studies [25, 38–40]) of the LTBI treatment regimen, i.e. short (≤four months), (Additional file 3: Study characteristics, outcomes, and long (>four months), or short and long combined when quality aspects). Only one prospective study each reported no data were presented for short and long LTBI treat- an initiation rate in healthcare workers or inmates, the ini- ment separately. tiation rates for these groups were 98 % [19] and 65 % [37], respectively. No prospective studies that reported ini- Synthesis of results tiation rates were found for patients with comorbidities. Meta-analysis is performed in accordance with GRADE Twenty-five retrospective studies that reported initi- methodology and results are reported in accordance with ation rates, mostly based on medical records, were found the Preferred Reporting Items for Systematic Reviews and (Table 1; Additional file 3: Study characteristics, outcomes, Meta-Analyses (PRISMA) statement. For data visualisa- and quality aspects). There was considerable overlap in the tion, forest plots of initiation and completion rates were ranges of initiation rates reported in prospective studies created for the identified populations in Excel 2010 [22]. and retrospective studies. The MetaXL 2.1 add-in in Excel was used to calculate 95 % confidence intervals around initiation and comple- Completion rates tion rates. We planned to calculate pooled rates, however In total, 39 prospective studies reporting completion this was not done for the first review question, because of rates were identified [12, 18, 23–27, 30–32, 34–62]. the large heterogeneity of the included articles. Completion rates ranged from 46 to 95 % in the general Sandgren et al. BMC Infectious Diseases (2016) 16:204 Page 4 of 12 Fig. 1 Flow chart of selection process. RQ: review question. LTBI: latent tuberculosis infection; TB: tuberculosis. Review question 1a: What is the initiation rate for each recommended LTBI treatment regimen?; Review question 1b: What is the completion rate for each recommended LTBI treatment regimen?; Review question 2a: What are the determinants of LTBI treatment initiation?; Review question 2b: What are the determinants of LTBI treatment adherence?; Review question 2c: What are the determinants of LTBI treatment completion?; Review question 3: In individuals who are eligible for LTBI treatment, what are the interventions with demonstrated efficacy or effectiveness to improve LTBI treatment initiation, adherence and completion? population (thirteen studies [12, 18, 23–25, 41, 42, As for initiation rates, considerable overlap in the ranges of 46, 47, 49, 50, 57, 60]), from 53 to 82 % in case con- completion rates reported in prospective studies and retro- tacts (six studies [12, 25–27, 51, 52]), from 25 to spective studies appears to exist. 71 % in the homeless (four studies [18, 25, 30, 60]), from 38 to 89 % in PWID (four studies [31, 32, 56, 58]), Short versus long treatment regimens from 55 to 95 % in HIV-infected individuals (eight studies In most of the 27 studies that presented separate com- [18, 34–36, 44, 48, 54, 55]), from 4 to 48 % in inmates pletion rates for patients that received short treatment (three studies [37, 53, 63]), and from 7 to 83 % in immi- regimens and for patients that received long treatment grants (nine studies [12, 25, 38–40, 43, 45, 57, 59]). Only regimens, completion rates appear to be higher for the one study reported a completion rate in healthcare short treatment group (Fig. 3; Additional file 4: Forest workers and patients with comorbidities, the completion plots). However, an exception to this observation was rates for these groups were 44 % [18] and 87 % [61], re- Clerk et al., who showed higher completion rates for spectively. In addition, 44 retrospective studies reporting long treatment regimens than shorter regimens (67 % completion rates were found (Table 1; Additional file 3: vs 79 %) [65], and a small number of other studies that Study characteristics, outcomes, and quality aspects). showed very similar completion rates between the two Within-study comparisons show that the homeless had treatment groups [48, 52, 66, 67] in various populations lower completion rates than other populations [18, 25, 64]. with LTBI. Due to large heterogeneity across studies Sandgren et al. BMC Infectious Diseases (2016) 16:204 Page 5 of 12 Table 1 Number of included studies and ranges of initiation and completion rates per study population Study population Short treatment regimens Long treatment regimens Short/long treatment regimens combined n Range rates (%) n Range rates (%) n Range rates (%) N Initiation rates Prospective studies (n = 20 unique articles; some present data for more than one population and more than one treatment regimen) General 1 [23]86 2[18, 24]44–99 1 [25]26 4 Case contacts 0 – 3[26–28]40–85 1 [25]53 4 Healthcare workers 1 [19]98 0 – 0 – 1 Homeless 0 – 2[29, 30]76–90 1 [25]34 3 PWID 0 – 3[31–33]52–91 0 – 3 HIV infected 0 – 2[34, 35]90–92 1 [36]91 3 Inmates 0 – 1[37]65 0 – 1 Immigrants 0 – 3[38–40]77–97 1 [25]23 4 Patients with 0 – 0 – 0 – 0 comorbidities Retrospective studies (n = 25 unique articles; some present data for more than one population and more than one treatment regimen) General 0 – 4[89–92]82–98 5 [16, 78, 93–95]53–83 9 Case contacts 0 – 1[96]81 5[13, 78, 97–99]74–95 6 Healthcare workers 0 – 1[100]92 4 47–89 5 [78, 94, 101, 102] Homeless 0 – 0 – 0 – 0 PWID 0 – 1[103]56 0 – 1 HIV infected 0 – 1[104]67 0 – 1 Inmates 0 – 0 – 2[80, 105]7–90 2 Immigrants 0 – 2[106, 107]78–84 3 [16, 93, 94]57–82 5 Patients with 1[108]93 1[109]82 0 – 2 comorbidities Completion rates Prospective studies (n = 39 unique articles; some present data for more than one population and more than one treatment regimen) General 10 [12, 23, 25, 41, 42, 61–95 10 [12, 18, 24, 25, 41, 46–76 0 – 13 46, 47, 49, 50, 60] 42, 46, 47, 50, 57] Case contacts 2 [51, 52]71–82 4 [26, 27, 51, 52]53–73 2 [12, 25]60–64 6 Healthcare workers 0 – 1[18]44 0 – 1 Homeless 1 [60]71 2[18, 30]25–33 1 [25]44 4 PWID 0 – 4[31, 32, 56, 58]38–89 0 – 4 HIV infected 6 [36, 44, 48]62–95 8 [18, 34–36, 44, 48, 54, 55–89 0 – 8 55] Inmates 1 [53]48 3[37, 53, 62]4–38 0 – 3 Immigrants 2 [43, 59]72–80 8 [38–40, 43, 45, 57]7–83 2 [12, 25]61–79 9 Patients with 1[61]87 0 – 0 – 1 comorbidities Retrospective studies (n = 44 unique articles; some present data for more than one population and more than one treatment regimen) General 14 [14–17, 65–67, 78, 56–93 23 [14–16, 64–67, 78, 39–96 1 [93]54 27 79, 81–83, 110, 111] 79, 81–83, 89–92, 112–118] Case contacts 3 [13, 14, 17]63–69 4 [13, 14, 113, 116]56–78 5 [78, 82, 97, 48–81 10 98, 119] Healthcare workers 0 – 2[100, 113]17–75 3 [15, 78, 101]40–79 5 Sandgren et al. BMC Infectious Diseases (2016) 16:204 Page 6 of 12 Table 1 Number of included studies and ranges of initiation and completion rates per study population (Continued) Homeless 1 [120]44 1[64]23 0 – 2 PWID 0 – 1[103]55 0 – 1 HIV infected 0 – 2[14, 104]55–66 0 – 2 Inmates 4 [80, 120]48–100 2 [80, 121]23–68 0 – 3 Immigrants 4 [14, 16, 17, 122]60–85 11 [14, 16, 64, 89, 91, 92, 38–86 5 [15, 65, 53–69 18 106, 113, 116, 123, 124] 79, 82, 93] Patients with 1[108]92 1[125]75 0 – 2 comorbidities HIV human immunodeficiency virus, n number of included studies, N total number of included studies, PWID people who inject drugs and the fact that most studies were not designed to Risk groups specifically assess the effect of treatment duration on The population for which most studies were identified was completion, no pooled analysis was performed to deter- the general population diagnosed with LTBI. Though this mine if there was a statistically significant association population consisted primarily of unselected individuals between treatment duration and completion rates. with LTBI at clinics, it was very diverse, mainly due to the varying proportion of specific populations, such as immi- Discussion grants, across clinics. Generally, two types of risk groups This is, to our knowledge, the first systematic review to could be distinguished: groups with higher risk of TB comprehensively explore both initiation and completion infection, but without an increased risk of progression rates of LTBI treatment worldwide. In total, evidence from to TB (e.g. health care workers, inmates, and the home- 95 studies has been reviewed. Forty-five studies reported less) [68–70] and groups with LTBI who are at higher on initiation rates and 83 on completion rates, covering risk of progression to active TB (e.g. HIV-infected indi- nine different population types with LTBI. There was wide viduals, patients with comorbidities) [71–74]. Case con- variation in initiation and completion rates; the initiation tacts appear to have both a higher risk of TB infection rates ranged from 7 to 99 % and the completion rates and a higher risk of progression to active TB due to re- ranged from 4 to 100 % across the different population cent infection [68, 75]. The initiation rates and comple- groups. These rates should be interpreted taking into ac- tion rates of LTBI treatment appeared slightly higher in count the variety of treatment options (i.e. choice of regi- the groups with higher risk of progression of LTBI to men, duration, self-administered or observed). active TB than in the groups with higher risk of TB Duration Initiation rates – General population with LTBI Study % (95%CI) Design regimen Goswami et al., 2012 Combined 26 (22-30) Lee et al., 2011 Short 86 (79-92) Prospective Morano et al., 2013 Long 44 (38-50) Pettit et al., 2013 Long 99 (98-99) Goswami et al., 2012 Combined 53 (52-54) Cruz et al., 2012 Long 98 (95-99) Gershon et al., 2004 Combined 58 (53-64) Gilroy et al., 2000 Long 98 (97-99) Retro- Horsburgh et al., 2010 Combined 83 (80-86) spective Kwara et al., 2008 Long 82 (79-84) Nuzzo et al., 2013 Combined 78 (75-80) Parsyan et al., 2007 Long 91 (90-93) Shah et al., 2012 Combined 77 (74-80) 0 102030405060708090 100 Fig. 2 Forest plots with ranges of initiation rates in the general population diagnosed with LTBI. LTBI: latent tuberculosis infection; Circle: combined, square: long, triangle: short Sandgren et al. BMC Infectious Diseases (2016) 16:204 Page 7 of 12 Completion rates – General population with LTBI Duration Design Study % (95%CI) regimen Bastos et al., 2013 Short 82 (73-90) Bastos et al., 2013 Long 62 (51-72) Jasmer et al., 2002 Short 61 (55-66) Jasmer et al., 2002 Long 57 (51-62) Menzies et al., 2008 Short 78 (74-82) Menzies et al., 2008 Long 60 (55-64) Menzies et al., 2004 Short 91 (83-97) RCT Menzies et al., 2004 Long 76 (64-86) Schechter et al., 2006 (1) Short 93 (89-96) Schechter et al., 2006 (2) Short 94 (90-97) Spyridis et al., 2007 (1) Short 95 (92-98) Spyridis et al., 2007 (2) Short 93 (91-95) Spyridis et al., 2007 Long 86 (81-90) Trajman et al., 2010 Short 81 (77-85) Trajman et al., 2010 Long 64 (59-69) Goswami et al., 2012 Short 68 (50-83) Goswami et al., 2012 Long 52 (42-61) Lee et al., 2011 Short 93 (87-98) Prospective Morano et al., 2013 Long 60 (49-69) Morisky et al., 2003 Long 69 (65-73) Pettit et al., 2013 Long 47 (45-50) Stout et al., 2003 Short 68 (59-76) Cain et al., 2012 Combined 54 (53-56) Chang SH et al., 2013 Long 78 (76-80) Clerk et al., 2011 Short 67 (53-81) Clerk et al., 2011 Long 79 (53-97) Codecasa et al., 2013 Long 74 (73-75) Cruz et al., 2012 Long 75 (69-80) Cruz et al., 2013 Long 96 (94-97) Duarte et al., 2012 Short 93 (90-95) Duarte et al., 2012 Long 90 (85-94) Fresard et al., 2011 Short 83 (77-88) Fresard et al., 2011 Long 74 (70-78) Gilroy et al., 2000 Long 51 (46-55) Haley et al., 2008 Short 76 (73-79) Hirsch-Moverman et al., 2010 Long 45 (39-50) Horsburgh et al., 2010 Short 64 (55-73) Horsburgh et al., 2010 Long 46 (44-48) Retro- Kan et al., 2013 Long 76 (71-80) spective Kwara et al., 2008 Long 62 (58-65) Lardizabal et al., 2006 Short 80 (75-85) Lardizabal et al., 2006 Long 53 (46-60) Li et al., 2010 Short 60 (57-63) Li et al., 2010 Long 44 (43-45) LoBue et al., 2003 Long 64 (62-65) Nuzzo et al., 2013 Short 80 (75-84) Nuzzo et al., 2013 Long 72 (67-78) Page et al., 2006 Long 53 (49-56) Parsyan et al., 2007 Long 39 (36-41) Rennie et al., 2007 Short 60 (55-66) Rennie et al., 2007 Long 46 (40-52) Smith et al., 2011 Short 56 (52-61) Smith et al., 2011 Long 54 (53-55) Vinnard et al., 2013 Long 46 (39-52) Young et al., 2009 Short 91 (85-95) Young et al., 2009 Long 65 (61-69) 0 102030405060708090 100 Fig. 3 Forest plot with completion rates in the general population diagnosed with LTBI. LTBI: latent tuberculosis infection; Circle: combined, square: long, triangle: short infection. Care has to be taken when comparing find- of the sixteen studies they included were also included ings between studies, due to differences within popula- in our review. Both the presented completion rate of iso- tions, in setting and in methodology. niazid treatment during incarceration and after release Hirsch-Moverman et al. [11] reviewed studies in the from jail appeared slightly higher than the completion United States and Canada published between 1997 and rates of long LTBI treatment regimens in inmates found 2007 and presented completion rates of LTBI treatment in our review. that are in line with the results found in our review. Overall, 20 of the 60 studies that were included in their Short and long treatment regimens review were also included in ours; differences are due to Short LTBI treatment most frequently consisted of four the fact that we did not include studies that did not pro- months of rifampicin or two months of rifampicin and vide a definition for completion, did not specify the type pyrazinamide, though other combinations of rifampicin, of treatment or did not define LTBI. isoniazid, rifabutin and pyrazinamide were also adminis- Al-Darraji et al. [76] reviewed completion rates of tered for two to four months. Currently, the combin- treatment with isoniazid in inmates with LTBI, from ation of rifampicin with pyrazinamide is not generally studies published between 1966 and January 2011. Four offered to persons with LTBI as it has been associated Sandgren et al. BMC Infectious Diseases (2016) 16:204 Page 8 of 12 with hepatotoxicity [77]. Long LTBI treatment consisted Stagg et al. [10] and was part of the same evidence base of isoniazid regimens, usually for six or nine months and collection as our systematic review. often for twelve months in the case of concurrent HIV- infection. Only three studies presented initiation rates Limitations for short treatment regimens, therefore initiation rates Studies without a definition for “completion” were ex- between short and long treatment regimens could not cluded from this review. Still, the definition of completion be compared. varied considerably between studies, and this hetero- A considerable number of prospective articles pre- geneity complicated comparison of completion rates sented completion rates for both short and long treat- between studies. Definitions used varied from “com- ment regimens, especially in the general population pleted four months of rifampicin” [81] to “picked up diagnosed with LTBI and in HIV-infected individuals nine months of isoniazid within twelve months” [25] with LTBI. Most results of within-study comparisons of and “took at least 80 % of the prescribed medication short and long treatments [13–16, 78–83] indicated within twenty weeks” [15]. Also, the quality of the defi- higher completion rates for shorter regimens, although nitions of “completion” varied throughout the included in two studies rates were comparable for short and long studies and the distinction between definitions for adher- treatment regimens [66, 67]. In one study lower comple- ence and completion was not always obvious. Besides, the tion rates were reported for short treatment than for quality of the definition of “completion” is closely linked longer treatments [65] due to adverse effects. It should to the way treatment adherence is assessed, which varied be kept in mind that the type of drugs used in short and from self-reported adherence (least reliable) [35], dispense long LTBI treatment regimens varied considerably between of medication [58], pill counts [52], urine tests [43], to studies and within populations. Directly Observed Treatment (DOT; most reliable) [62]. Hirsch-Moverman et al. [11] also reviewed data on Furthermore, it was not always clear whether and to what completion rates of short (rifampicin or rifampicin in extent the classification of a patient as having completed combination with pyrazinamide) and long (isoniazid) treatment was influenced by the time that a patient treatment regimens within studies and found a higher per- needed to take all the doses. Finally, some patients may centage of completion among short treatments in all in- have discontinued treatment due to toxicity. In our ana- cluded studies, although the difference was not always lysis, this is included in non completion. Discontinuation significant. Ziakas et al. [84] systematically reviewed the because of side effects will influence the effectiveness of literature for studies that compared four months of rifam- latent TB infection treatment but it will need other efforts picin with nine months of isoniazid, published up to July than voluntary discontinuation of treatment. 2009, and included four studies in a meta-analysis. These In addition, rate calculations varied across included four studies were also included in this review. They con- studies; different rules were applied for in- and exclusion cluded that four months of rifampicin was associated with into the denominator to calculate the initiation and/or a significant reduction in the risk of non-completion [84]. completion rates. All these differences between studies Sharma et al. [85] conducted a systematic review on RCTs and unclarities hampered the analysis. worldwide among HIV-negative people at risk of active Within our review, no distinction was made between TB that compared rifampicin monotherapy or rifamycin- studies that looked at a priori defined risk groups versus combination therapy with isoniazid monotherapy. Their studies that identified risk factors in a non-selected group meta-analysis of five trials, of which two were included in of individuals with LTBI. Also, population characteristic our review, compared rifampicin (three or four months) or settings of risk groups may vary between studies, for with isoniazid (six months) and showed that significantly example immigrants in the United States might differ more people completed the shorter course. Two more of from immigrants in Europe with respect to their origin their meta-analyses compared isoniazid in combination [86, 87]. In addition, it should be noted that individuals with rifampicin (three months; two trials) or rifampicin in with LTBI might belong to multiple risk groups, as overlap combination with pyrazinamide (two months; three trials, between the groups exists; however, most studies did not one of which was included in our review) with isoniazid specify if there was any overlap between risk groups. (six months) and found that there was no difference in completion rates [85]. Conclusions By comparing completion rates between short and long The goal of LTBI treatment is to eradicate M. tuberculosis LTBI treatment we do not take into account any effect of from the body and to reduce the risk of progression to ac- the treatment regimen on completion rate, e.g. due to dif- tive TB disease [88]. Only treatment can clear the bacteria ferent side effect patterns. The effect of different treatment from the body, and therefore individuals with LTBI who regimens for preventing active TB, and thus indirectly do not initiate treatment contribute to the persistence of taking into account completion, has been compared by the TB reservoir. Clinical benefit to the individual with Sandgren et al. BMC Infectious Diseases (2016) 16:204 Page 9 of 12 LTBI and the success of control programs is subject to Acknowledgements Not applicable. completion of LTBI treatment. This systematic review found that initiation and com- Funding pletion rates for LTBI treatment regimens were fre- This work was performed under the ECDC Framework Contract FWC/ECDC/ quently suboptimal and varied greatly within and across 2013/005 Specific Contract No. 1 ECD.4065 awarded to the consortium consisting of Pallas, health research and consultancy and the Department of Public Health, different populations. Population groups with a higher risk Erasmus MC, and Service contract ECD.5000 of OJ/02/05/2014-PROC/2014/015 of TB infection, but without an increased risk of progres- awarded to Pallas, health research and consultancy. sion to TB (e.g. health care workers, inmates, and the Author details homeless) seemed at slightly higher risk of low initiation Former Surveillance and Response Section, European Centre for Disease and completion rates. However, the limited number of 2 Prevention and Control (ECDC), Stockholm 171 65, Sweden. Pallas, Health studies found for certain LTBI treatment regimens and Research and Consultancy B.V., Rotterdam 3001, The Netherlands. Tomtebodavägen 11a, 171 65 Solna, Sweden. study populations, and the variation in types of risk popu- lations, settings, treatment regimens and study methodolo- Received: 16 February 2016 Accepted: 7 May 2016 gies in the included studies make it difficult to draw firm conclusions. 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