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Treatment of Latent Tuberculosis Infection: A Network Meta-analysisTreatment of Latent Tuberculosis Infection FREE

Helen R. Stagg, PhD*; Dominik Zenner, MD*; Ross J. Harris, MSc; Laura Muñoz, MD; Marc C. Lipman, MD; and Ibrahim Abubakar, MBBS, PhD
[+] Article and Author Information

* Drs. Stagg and Zenner contributed equally to this work.

This article was published online first at www.annals.org on 12 August 2014.


From University College London, Public Health England, and Royal Free London National Health Service Foundation Trust, London, United Kingdom, and Bellvitge University Hospital-IDIBELL, Barcelona, Spain.

Financial Support: From the United Kingdom National Institute for Health Research (Drs. Abubakar, Stagg, and Lipman).

Disclosures: Dr. Stagg reports other financial support from the World Health Organization and grants from the United Kingdom National Institute for Health Research (Department of Health) during the conduct of the study and personal fees and other financial support from Otsuka Pharmaceutical's public health group and nonfinancial support from Sanofi outside the submitted work. Dr. Harris reports other financial support from the World Health Organization during the conduct of the study and personal fees from the World Health Organization outside the submitted work. Dr. Abubakar reports being a member of the World Health Organization Latent Tuberculosis Guideline Development Group, chair of the United Kingdom National Institute for Health and Care Excellence Tuberculosis Guideline Development Group, and head of the Tuberculosis Section at Public Health England. Authors not named here disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M14-1019.

Requests for Single Reprints: Helen R. Stagg, PhD, Research Department of Infection and Population Health, University College London, London WC1E 6JB, United Kingdom; e-mail, h.stagg@ucl.ac.uk.

Current Author Addresses: Drs. Stagg and Abubakar: Research Department of Infection and Population Health, University College London, Mortimer Market Centre, London WC1E 6JB, United Kingdom.

Dr. Zenner: Tuberculosis Section, Respiratory Diseases Department, Public Health England, 61 Colindale Avenue, London NW9 5EQ, United Kingdom.

Mr. Harris: Statistics, Modelling and Bioinformatics Department, Public Health England, 61 Colindale Avenue, London NW9 5EQ, United Kingdom.

Dr. Muñoz: Tuberculosis Unit, Infectious Diseases Department, Bellvitge University Hospital-IDIBELL, Av/Feixa Llarga s/n, 08907 Barcelona, Spain.

Dr. Lipman: Centre for Respiratory Medicine and Department of Medicine, Royal Free London National Health Service Foundation Trust, London NW3 2QG, United Kingdom.

Author Contributions: Conception and design: H.R. Stagg, D. Zenner, I. Abubakar.

Analysis and interpretation of the data: H.R. Stagg, D. Zenner, R.J. Harris, L. Muñoz, M.C. Lipman, I. Abubakar.

Drafting of the article: H.R. Stagg, D. Zenner, M.C. Lipman, I. Abubakar.

Critical revision of the article for important intellectual content: H.R. Stagg, D. Zenner, R.J. Harris, L. Muñoz, M.C. Lipman, I. Abubakar.

Final approval of the article: H.R. Stagg, D. Zenner, R.J. Harris, L. Muñoz, M.C. Lipman, I. Abubakar.

Statistical expertise: R.J. Harris.

Administrative, technical, or logistic support: D. Zenner.

Collection and assembly of data: H.R. Stagg, D. Zenner, L. Muñoz.


Ann Intern Med. 2014;161(6):419-428. doi:10.7326/M14-1019
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Background: Effective treatment of latent tuberculosis infection (LTBI) is an important component of TB elimination programs. Promising new regimens that may be more effective are being introduced. Because few regimens can be directly compared, network meta-analyses, which allow indirect comparisons to be made, strengthen conclusions.

Purpose: To determine the most efficacious regimen for preventing active TB with the lowest likelihood of adverse events to inform LTBI treatment policies.

Data Sources: PubMed, EMBASE, and Web of Science up to 29 January 2014; clinical trial registries; and conference abstracts.

Study Selection: Randomized, controlled trials that evaluated LTBI treatment in humans and recorded at least 1 of 2 prespecified end points (preventing active TB or hepatotoxicity), without language or date restrictions.

Data Extraction: Data from eligible studies were independently extracted by 2 investigators according to a standard protocol.

Data Synthesis: Of the 1516 articles identified, 53 studies met the inclusion criteria. Data on 15 regimens were available; of 105 possible comparisons, 42 (40%) were compared directly. Compared with placebo, isoniazid for 6 months (odds ratio [OR], 0.64 [95% credible interval {CrI}, 0.48 to 0.83]) or 12 months or longer (OR, 0.52 [CrI, 0.41 to 0.66]), rifampicin for 3 to 4 months (OR, 0.41 [CrI, 0.18 to 0.86]), and rifampicin–isoniazid regimens for 3 to 4 months (OR, 0.52 [CrI, 0.34 to 0.79]) were efficacious within the network.

Limitations: The risk of bias was unclear for many studies across various domains. Evidence was sparse for some comparisons, particularly hepatotoxicity.

Conclusion: Comparison of different LTBI treatment regimens showed that various therapies containing rifamycins for 3 months or more were efficacious at preventing active TB, potentially more so than isoniazid alone. Regimens containing rifamycins may be effective alternatives to isoniazid monotherapy.

Primary Funding Source: None.


In many countries with a low incidence of tuberculosis (TB), many new cases emerge as a result of reactivation of latent TB infection (LTBI), which is often acquired in high-incidence areas or from recent exposure in occasional outbreaks. Therefore, such countries have had a renewed interest in LTBI screening and treatment, generally for groups at particularly high risk for reactivation, such as contacts of patients with pulmonary TB, persons who are immunocompromised, and migrants from high-incidence areas.

Although efficient and safe, LTBI treatment regimens are lengthy. It is thus essential to offer the least toxic and shortest possible effective regimen to ensure high completion rates. Globally, it is most common to use 6 to 9 months of isoniazid (INH) monotherapy; in the United States, 9 months is recommended (1). Three months of INH plus rifampicin (RMP) and 3 to 4 months of RMP alone may be equally as efficacious as INH regimens (23). Twelve weeks of INH plus rifapentine (RPT) has been shown to be noninferior to 9 months of INH alone (4) and is now included in Centers for Disease Control and Prevention guidelines (1).

To date, all reviews of LTBI treatment have used conventional meta-analyses. By allowing only direct comparisons between regimens, such analyses were severely limited in the inferences they could make about relative efficacy and toxicity. Bayesian hierarchical models use a network approach that also enables the indirect comparison of regimens and thus produces inferences of relative efficacy that would not otherwise be possible (56). We therefore undertook a systematic review using such an analytic approach to provide an up-to-date summary of the randomized, controlled trials (RCTs) that have evaluated LTBI treatment and an informative comparison of the relative efficacies and adverse event (AE) profiles of different regimens.

Data Sources and Searches

PubMed, EMBASE, and the Web of Science were mined by using the preestablished search terms “chemoprevention,” “preventive therapy,” “chemoprophylaxis,” or “treatment” AND “latent tuberculosis,” “tuberculous infection,” or “latent TB infection,” and filters to select RCTs and human studies applied wherever possible. Reference lists of included papers and review articles were also searched, as well as the Cochrane Central Register of Controlled Trials; World Health Organization International Clinical Trials Registry Platform; International Standardized Randomized Controlled Trial Number Register; ClinicalTrials.gov; and abstracts from international conferences of the International Union Against Tuberculosis and Lung Disease, American Thoracic Society, and European Respiratory Society from 2010 to 2013. This review was registered in the PROSPERO database (CRD42014008851).

Study Selection

We included all RCTs, regardless of language, that treated participants for LTBI and were indexed until 29 January 2014. Studies that were done in animals, were not RCTs, or did not record at least 1 of our 2 end points (hepatotoxicity or development of active TB) were excluded. Title, abstract, and full-text screening was completed in duplicate by 2 reviewers.

Data Extraction and Quality Assessment

The reviewers independently extracted data from the selected studies into a standardized spreadsheet. Discrepancies were resolved by discussion until consensus was reached; the other reviewers were consulted when required. When a publication was not written in a language fluently spoken by 1 of the 2 main reviewers a translator did the extraction and their work was validated with an English-language extraction. The following variables were recorded: details of participants (age, sex ratio, selection criteria, immune status, and HIV status); country of study; year that study was undertaken; if or how LTBI was diagnosed; regimens (drugs, dose, timing of administration, length of treatment, number treated, and treatment adherence); number of patients subsequently developing active TB; how active TB was diagnosed; length of follow-up; number of patients developing AEs; and the type or severity of AEs.

Two authors independently assessed study quality using the Cochrane Collaboration's tool for evaluating study bias (7). A high risk of bias across 4 or more categories resulted in exclusion. Methodological aspects of study quality were analyzed as per the study by Savovic and colleagues (8).

Data Synthesis

The following treatments, which were considered to be clinically similar, were grouped for analysis purposes: all RMP regimens, INH regimens 3 to 4 months in duration, INH regimens 12 months or more in duration, INH-RMP regimens 3 to 4 months in duration, all RMP plus pyrazinamide (PZA) regimens, and all RMP-INH-PZA regimens. When the dosing schedule was not stated, it was assumed to be daily.

Predefined stratification was conducted by the age of participants (children, adults or children, and adults), immunosuppression status (at least some participants known to be HIV-positive, patients with end-stage renal disease, and those receiving immunomodulatory drugs), and TB incidence when and where the RCT took place (cutoff of 40/100 000). We also considered the year of publication (before 1992, 1992 to 2004, and 2005 onward, yielding 3 groups of roughly equal size); HIV status; treatment adherence (overall percentage of doses received); study quality indicators; and the potential effect of pyridoxine on hepatotoxicity. If a study spanned 1 or more strata of a category, data were extracted separately for each, when possible.

Our main AE of interest was hepatotoxicity; we analyzed events of grade 3 or above as defined by standard criteria (9). Classifications were translated to the standard when possible. Studies also varied in the way a case of active TB was defined. To quantify this limitation, we assessed study quality by calculating the ratio of odds ratios (RORs) between studies with robust versus less robust outcome definitions.

Statistical Analysis

In standard meta-analysis, only direct comparisons (regimens compared within RCTs) are assessed. Mixed-treatment comparisons (MTCs) allow the inference of indirect comparisons (regimen comparisons without RCTs) by creating a network of evidence. We used a random-effects model that allowed the effect of treatments to vary across trials, and we accounted for the correlation structure of multigroup trials. The correlation coefficient was assigned a value of 0.5, which allowed identification of the covariance parameters (10).

We extended the model to include covariates, akin to meta-regression, and stratified the analysis by the groups previously described using the approach detailed by Cooper and coworkers (11).

All models were implemented in a fully Bayesian framework by using the WinBUGS software (12), with posterior distributions based on 20 000 samples after a burn-in period of 10 000 iterations (Supplement 1). Convergence was assessed by visual examination of parameter chains and the Gelman–Rubin diagnostic (13). Models were compared via the deviance information criteria (14). Summary statistics and 95% credible intervals (CrIs) were obtained from the posterior distributions produced. Rankings (1 [best] and n [worst], where n is the number of regimens) should not be seen as a quantification of efficacy, but as an ordering of the regimens assessed.

Inconsistency

Inconsistency may arise in a network meta-analysis if indirect evidence conflicts with direct evidence. Dias and colleagues have proposed various methods to examine inconsistency within “loops” of evidence (15). In this study, the evidence structure was complex and we therefore used the omnibus test of inconsistency (15). This model was compared against the standard model; if it provided a better fit (assessed via the deviance information criteria), then the network exhibited inconsistency.

Publication Bias

Publication bias is more complex to assess in a network meta-analysis than in a standard meta-analysis because multiple treatment comparisons are considered concomitantly. In each case, we assumed that the reference category was either placebo or no treatment, standard treatment (INH), or the least new treatment if only non-INH treatments were compared, as per the study by Savovic and colleagues (8). We examined potential small-study effects by including study SE as a covariate in the model (the average SE is taken for multigroup trials), similar to the approach of Trinquart and colleagues (16), but we assumed a fixed effect across all comparisons. For studies that include counts of 0 and theoretically have infinite SEs, the covariate was truncated at 2 (counts of 1 produce SEs of around 1.4).

Role of the Funding Source

This study received no funding.

Of the 1516 articles identified, 1214 were left after deduplication (Figure 1). Two studies were excluded because some, but not all, persons who were randomly assigned to the RMP plus PZA group were switched to rifabutin (RFB) plus PZA (1718). One study was excluded because randomization was broken, and results could not be interpreted on an intention-to-treat basis (19). A total of 53 studies met our inclusion criteria (Supplement 2). Articles that provided data from the same study were merged ((20) and (21);(22) and (23)). Some demographic and study setup information for the study by Quigley and colleagues (24) was taken from the work of Mwinga and coworkers (25). Four studies (5 articles) were randomized on a stratified basis by HIV status (2627), time frames of recruitment (28), or tuberculin reactivity; each group was extracted and analyzed separately (2223).

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Figure 1.

Summary of evidence search and selection.

TB = tuberculosis; RCT = randomized, controlled trial.

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Twenty-five studies contained extractable data on hepatotoxicity, and 45 had extractable data on progression to active TB. Supplement 2 describes study characteristics. Nineteen of the studies were published in the past 10 years, starting in 1962. Many studies were conducted in Europe, Canada, and the United States. One specifically targeted health care workers, and 12 included close or household contacts of patients with active TB (4, 2939). Six studied fewer than 100 persons. Five studied only children (26, 28, 34, 41). Twenty-five contained at least some immunosuppressed persons (4, 21, 23, 2527, 35, 4158), and 18 of these were HIV studies (21, 23, 2527, 41, 4346, 4851, 5356). Five studies had only male participants (39, 5962). All studies included INH in at least 1 group; 23 included RMP and 3 RPT regimens. Eight had a no-treatment group, 6 of which were written in the 1990s and the 2000s. One study's 6-month regimen had a 3-month medication break for participants in the center (63). Thirteen studies contained pyridoxine as part of the regimen (21, 4245, 49, 5153, 5557, 64).

Fifteen regimens were included in the network (Supplements 3 and 4). Within-study comparisons with no TB and/or hepatotoxicity events were excluded (2728). Our analysis of the study by Comstock and colleagues excluded 211 persons because their original regimen was not stated (65).

Connectivity within the MTC network for active TB was high for INH regimens, but for almost all other treatment comparisons, only 1 study yielded data (Supplements 3 and 4). Of the possible 105 comparisons, 42 (40%) had data available. For hepatotoxicity, the number of connections was sparser still and even INH versus placebo comparisons were limited (Supplement 4).

Study Quality

Of the 53 studies, many were deemed to be of unclear or high risk of bias in the following domains: randomization (n = 33 [62%]); allocation concealment (n = 37 [70%]); blinding (n = 34 [64%]); blinding of outcome assessment (n = 39 [74%]); incomplete outcome reporting (n = 30 [57%]); and selective reporting (n =10 [19%]) (Supplement 5). A strong correlation existed between many of these domains.

All study quality indicators for high risk of bias were associated with only very weak evidence for modification of treatment efficacy; for example, inadequate or unclear allocation concealment had an ROR of 0.75 (95% CrI, 0.37 to 1.27). Similar results were observed for high or unclear risk of bias due to inadequate randomization and blinding; this was consistent with other studies (8). The ROR for incomplete or unclear versus adequate outcome reporting was 1.03 (CrI, 0.50 to 1.65) and also crossed the null for selective reporting.

Results for hepatotoxicity indicated a possible reduction for treatment versus no treatment or placebo in studies with high or unclear risk of bias, although results were highly uncertain. The ROR for incomplete outcome reporting was 0.61 (CrI, 0.12 to 2.93); RORs for other domains ranged from 0.25 to 4.22 and had a similar level of uncertainty.

Prevention of Active TB

Fifteen regimens were available for comparison, including INH-only regimens of 3 to 4, 6, 9, and 12 to 72 months. Odds ratios with 95% CrIs were calculated for all regimens versus placebo from the MTC (Table 1). Isoniazid for 6 months (OR, 0.64 [CrI, 0.48 to 0.83]) or 12 months or longer (OR, 0.52 [CrI, 0.41 to 0.66]), RMP alone for 3 to 4 months (OR, 0.41 [CrI, 0.18 to 0.86]), and RMP-INH for 3 to 4 months (OR, 0.52 [CrI, 0.34 to 0.79]) were efficacious versus placebo, as well as PZA-containing regimens. The RFB-INH regimen estimates had wide CrIs that crossed 1 (OR for RFB-INH, 0.28 [CrI, 0.05 to 1.49]; OR for RFB-INH [high], 0.31 [CrI, 0.06 to 1.59]).

Table Jump PlaceholderTable 1. Odds Ratios for the Prevention of Active Tuberculosis, Derived From the Network Meta-analysis 

Stratifying the results on the basis of immunosuppression, HIV status, and TB incidence did not markedly affect our conclusions. The inclusion of high versus low incidence as a covariate reduced between-study variability; treatment was generally less efficacious in high-incidence populations. Subgroup analysis by year, adherence (efficacy only), and age also resulted in little change to treatment rankings. By using covariate models, treatment effects were attenuated slightly in more recent years, although the evidence for this was fairly weak (ROR, 1.67 [CrI, 0.84 to 3.05] for 1992 to 2004 and 2005 onward versus 1.67 [CrI, 0.79 to 3.48] for before 1992). No evidence of a relationship between adherence and efficacy was found. Restricting to only culture-confirmed TB cases did not alter our conclusions.

We found differences in OR estimates when comparing the results derived from a random-effects pairwise meta-analysis with the corresponding estimate from the MTC model (Table 2, Figure 2; Supplement 6). Many treatment comparisons showed a stronger beneficial effect in a standard pairwise meta-analysis, which was attenuated in the MTC or otherwise usually moved toward the null.

Table Jump PlaceholderTable 2. Standard Random-Effects Meta-analysis for Preventive Effect Against Tuberculosis 
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Figure 2.

Comparison of odds ratios for active tuberculosis obtained from random-effects pairwise meta-analysis, with a corresponding estimate from the mixed treatment comparison model.

When data on direct comparisons of treatment pairs are available for active tuberculosis, they may be pooled via standard meta-analysis for each pair of treatments in turn. The resulting estimates are then compared with those obtained from the mixed-treatment comparison analysis, which incorporates indirect evidence and the overall network structure in addition to the direct evidence. EMB = ethambutol; INH = isoniazid; PZA = pyrazinamide; RFB = rifabutin; RMP = rifampicin; RPT = rifapentine.

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We ranked regimens according to their efficacy using the MTC model (Supplements 7 and 8). Acknowledging that the relative ranking among treatments does not provide quantified values for treatment differences, the RFB-INH regimens, which used different doses of RFB, ranked highest (both with a median rank of 2). However, the CrIs were wide and contained the second-to-worst rank (14). The RMP-INH-PZA regimens ranked third, with narrower, but still rather wide, CrIs (18). In addition, using either RMP for 3 to 4 months or RMP-INH for 3 to 4 months seemed to be particularly efficacious, although these results are based on limited data. The ranks for all lengths of INH therapy had overlapping CrIs, with INH regimens of 12 months or more ranking the highest (OR, 6 [CrI, 3 to 9]).

Inconsistency

Comparing inconsistency models with consistency models found no evidence that the additional complexity of the former was required (Supplement 9). However, because this study used a full random-effects model and the data exhibited a moderate level of between-study heterogeneity, the power to detect inconsistency was low and this result cannot be interpreted as conclusive evidence of network consistency.

Hepatotoxicity

Because of the limited data on hepatotoxicity, results from the direct comparison are presented here. (Data on hepatotoxicity from the network meta-analysis were largely consistent with the direct comparisons and can be found in Supplements 7, 8, and 10) Twenty pairwise comparisons were available. Results from the standard meta-analysis suggest that RMP-only and RPT-INH regimens had lower rates of hepatotoxicity than an INH-only regimen of 6 or 9 months, or 9 or 12 to 72 months, respectively (Table 3 and Supplement 6). RMP-INH regimens also potentially had lower hepatotoxicity versus INH-only regimens, although good evidence for this was found only when it was compared with the INH regimen of 12 to 72 months. There was good evidence that regimens containing PZA had higher hepatotoxicity than 6 months of INH or 12 weeks of RPT-INH. Data about the hepatotoxicity of the RFB-INH regimens were not available. Stratifying the results on the basis of immunosuppression, HIV status, and TB incidence did not markedly affect our conclusions.

Table Jump PlaceholderTable 3. Standard Random-Effects Meta-analysis for Hepatotoxicity 
Other AEs

Aside from toxic hepatitis, AEs included death as well as major and milder symptoms (Supplement 11). The definitions of such AEs were often highly variable across studies, and AEs were frequently not detailed. The RMP-PZA regimens had the highest risk for gastrointestinal AEs, and RMP regimens had the highest risk for central nervous system AEs. Serious AEs were rare across all studies.

A total of 5 toxicity-attributable deaths were reported, mostly from a single trial (66). All were due to severe hepatitis in INH treatment groups, and at least 4 occurred in patients who were receiving INH for 12 to 72 months. In many studies, the cause of death was not always clear; there is a possibility of underascertainment for toxicity-related deaths.

Publication Bias

The effect of study size was modest aside from when very large to very small studies were being compared in terms of outcome counts; however, the result was statistically significant and gave an improved model fit, with a deviance information criteria score of 609.8 versus 613.4 (Supplement 12). The covariate effect for study SE was found to have an ROR of 0.89 (CrI, 0.79 to 0.99) per 0.2 increase in SE. To interpret this result, the 25th and 75th percentiles of study SEs (0.30 and 0.78, respectively) are used to calculate an ROR of 0.89(0.78 − 0.30) = 0.76 (that is, a 24% reduction in the effect estimate for a study with an above-average vs. a below-average SE).

Despite many systematic reviews and meta-analyses of trials investigating the treatment of LTBI (3, 6770), to our knowledge this is the first study that, using an MTC methodology, indirectly infers the relative efficacy and AE profiles of LTBI treatment regimens that would otherwise not be comparable. Our analysis suggests that currently recommended regimens are efficacious when studied in various settings and patient populations, which therefore shifts the focus of clinical decision making to potential AEs and interactions for each patient.

Previous RCTs and meta-analyses have shown the safety and efficacy of INH monotherapy for HIV-negative and HIV-positive adults and children (6870). These regimens are recommended by the World Health Organization in resource-constrained settings for a minimum duration of 6 months. The Centers for Disease Control and Prevention also advises that INH be administered for 6 or 9 months (1, 69) on the basis of a pragmatic compromise between efficacy and toxicity (7173). In comparison with INH monotherapy, the evidence base in our analysis for all other drug treatments was relatively small. Although the ranks derived from this analysis cannot be considered as quantified values for treatment differences and are therefore of limited statistical or clinical value, 3 to 4 months of RMP monotherapy, a commonly used LTBI regimen, ranked highly for both efficacy and a low hepatotoxicity profile in comparison with other treatments. This short duration of RMP monotherapy has been reported to be at least as effective as INH and has possibly higher rates of acceptance and completion (3). Regimens containing PZA were found to be efficacious but generally had unacceptable toxicity.

On the basis of a trial showing noninferiority in efficacy and fewer AEs than 9 months of daily self-administered INH monotherapy (4), a weekly combination of INH-RPT for 12 weeks under direct observation was recently recommended in the United States (1). Our network meta-analysis highlights the improved efficacy and lower toxicity of the therapies containing rifamycin over INH. This extends the work of Sharma and colleagues (3) and allows for more robust conclusions. Well-planned and targeted RCTs to fill the knowledge gaps shown by our analysis are vital—for example, to resolve the issue surrounding the extent to which direct observation contributes to better outcomes in LTBI trials. Our ongoing trial (HALT [Hepatitis and Latent Tuberculosis]: LTBI, ISRCTN04379941) and Centers for Disease Control and Prevention study 33 (NCT01582711) are investigating RPT-INH adherence without direct observation.

The long half-life of RPT is a key factor in making weekly RPT-INH noninferior to the current standard of care. Even shorter regimens may be feasible with other anti-TB drugs that also have a long half-life, such as bedaquiline, assuming its AE profile is similar to existing TB drugs.

The RFB-INH regimens seem promising (50), although no data on AEs are available. We might infer from previous meta-analyses and studies using RFB to treat active TB that the AE profile will be similar to that of RMP (74), but this needs to be formally tested. It is reassuring that various regimens seem effective, especially given the recent reports of INH unavailability in the United States (and elsewhere), which leads to changes in clinical practice (75).

Bayesian methodologies have their own limitations when using sparse data. For example, the low ranking of INH monotherapy was unexpected, although this does not necessarily indicate ineffectiveness per se. The uncertainty of estimates also needs to be acknowledged. It is vital to interpret hepatotoxicity results in the context of the likelihood of such effects arising during treatment and to note that many trials are not powered to detect AEs because of their rarity. Furthermore, some comparisons were limited by the paucity of data. A modest relationship was seen between the effect estimates and study size, which is usually considered to be a measure of potential publication bias; however, our inconsistency assessment found no evidence of a potential exaggeration of published results.

We show that regimens containing rifamycins may be just as, if not more, effective than INH monotherapy for treating LTBI. In light of their efficacy and taking contraindications and cost considerations into account, such regimens should be considered by clinicians and global policymakers. We also identify 2 major areas of work for future RCTs: RFB-INH regimens and shorter regimens (including RMP monotherapy). The post-2015 World Health Organization strategy, with its emphasis on global elimination of TB in our lifetime, depends on shorter, effective, and well-tolerated LTBI regimens.

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Figures

Grahic Jump Location
Figure 1.

Summary of evidence search and selection.

TB = tuberculosis; RCT = randomized, controlled trial.

Grahic Jump Location
Grahic Jump Location
Figure 2.

Comparison of odds ratios for active tuberculosis obtained from random-effects pairwise meta-analysis, with a corresponding estimate from the mixed treatment comparison model.

When data on direct comparisons of treatment pairs are available for active tuberculosis, they may be pooled via standard meta-analysis for each pair of treatments in turn. The resulting estimates are then compared with those obtained from the mixed-treatment comparison analysis, which incorporates indirect evidence and the overall network structure in addition to the direct evidence. EMB = ethambutol; INH = isoniazid; PZA = pyrazinamide; RFB = rifabutin; RMP = rifampicin; RPT = rifapentine.

Grahic Jump Location

Tables

Table Jump PlaceholderTable 1. Odds Ratios for the Prevention of Active Tuberculosis, Derived From the Network Meta-analysis 
Table Jump PlaceholderTable 2. Standard Random-Effects Meta-analysis for Preventive Effect Against Tuberculosis 
Table Jump PlaceholderTable 3. Standard Random-Effects Meta-analysis for Hepatotoxicity 

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Letters

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Comments

Submit a Comment
Availibility of isoniazide
Posted on August 12, 2014
Gauranga Dhar
Bangladesh Institute of Family medicine and Research
Conflict of Interest: None Declared
As far as I know that production of isolated isoniazide preparation has been discontinued but due to high prevalence of latent tuberculosis in many countries we need this preparation again in the market because INH only regimen for the management of latent tuberculosis is highly effective as well as cost effective.
Submit a Comment

Supplements

Supplemental Content
Supplement 1. Statistical code
Supplemental Content
Supplement 2. Extracted studies
Supplemental Content
Supplement 3. Summary of extracted data
Supplemental Content
Supplement 4. Treatment network for a) all studies, b) those with active tuberculosis data, and c) those with hepatotoxicity data*
Supplemental Content
Supplement 5. Study quality
Supplemental Content
Supplement 6. Standard meta-analysis forest plot for a) active tuberculosis and b) hepatotoxicity
Supplemental Content
Supplement 7. Posterior distributions of rankings for preventive effect against tuberculosis for each treatment and hepatotoxicity*
Supplemental Content
Supplement 8. Treatment rankings for a) active tuberculosis and b) hepatotoxicity, with 95% credible intervals (CrI)*
Supplemental Content
Supplement 9. Inconsistency plot for prevention of active tuberculosis
Supplemental Content
Supplement 10. Odds ratios for hepatotoxicity, derived from the network meta-analysis
Supplemental Content
Supplement 11. Other adverse events by regimen- a) all-cause mortality, b) tuberculosis mortality, c) other adverse events
Supplemental Content
Supplement 12. Funnel plots for publication bias

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