Systematic Review of Clofazimine for the Treatment of Drug-Resistant Tuberculosis

Systematic review of clofazimine for the treatment of drug-resistant tuberculosis

M. Gopal,* N. Padayatchi,† J. Z. Metcalfe,‡ M. R. O’Donnell*† * Division of Pulmonary Medicine, Albert Einstein College of Medicine, Bronx, NY, USA; † Centre for AIDS Programme of Research in South Africa, Durban, South Africa; ‡ Division of Pulmonary and Critical Care Medicine, San Francisco General Hospital, and Francis J Curry International Tuberculosis Center, University of California, San Francisco, California, USA

SUMMARY The increased incidence of drug-resistant tuberculosis vational studies (6 MDR-TB and 3 XDR-TB) including has created an urgent necessity for the development of patients with drug-resistant TB treated with CFZ. Over- new and effective anti-tuberculosis drugs and for alter- all, 65% (95% confidence interval [95%CI] 54–76) of native therapeutic regimens. Clofazimine (CFZ) is a fat- the patients experienced favorable outcomes, defined as soluble riminophenazine dye used in the treatment of either cure or treatment completion. Using random leprosy worldwide. CFZ has also been used as a Group effects meta-analysis, 65% (95%CI 52–79) of those 5 drug in the treatment of tuberculosis (TB). A large co- with MDR-TB and 66% (95%CI 42–89) of those with hort study from Bangladesh published in 2010 described XDR-TB experienced favorable treatment outcomes. a treatment regimen for multidrug-resistant tuberculosis High-quality prospective cohort studies and clinical tri- (MDR-TB) including CFZ as being highly effective als examining the effect of CFZ as part of drug-resistant against MDR-TB. We searched multiple databases for TB treatment regimens are needed. studies published through February 2012 that reported KEY WORDS: clofazimine; MDR-TB; XDR-TB; treat- use of CFZ in MDR- and extensively drug-resistant TB ment outcome; systematic review (XDR-TB) treatment regimens. We identified nine obser-

CLOFAZIMINE (CFZ), initially known as B663, METHODS was fi rst synthesized in 1954 by Barry et al. as an anti-tuberculosis drug.1,2 In initial studies, the drug We searched PubMed, Embase and the Cochrane Li- was thought to be ineffective in the treatment of tu- brary to identify studies in all languages that reported berculosis (TB),3 and in 1955 Chang identifi ed its the use of CFZ for the treatment of MDR- or XDR-TB effectiveness against Mycobacterium leprae.4 In re- up to February 2012. The search terms used included cent years, as the global prevalence of drug-resistant ‘clofazimine,’ ‘tuberculosis’ and ‘treatment.’ Two re- TB has increased, researchers have sought to reviewers (MG and MRO) independently screened the evaluate the chemotherapeutic role of CFZ as an anti- accumulated citations for relevance, reviewed full text tuberculosis drug. The hypothesis is that if CFZ is of articles and extracted data using a standardized form. value in treating TB, its benefi cial effects would be In addition to database searches, we reviewed the most easily observed in drug-resistant TB, as the com- meeting abstracts of the American Thoracic Society panion drugs are likely to be less effective. The effi - and the American College of Chest Physicians from cacy of CFZ in the treatment of drug-resistant TB is 2010 to 2012, major pulmonary and textbooks on currently unclear. We performed this systematic re- TB, reference lists and completed trials not yet pub- view of the literature to review in vitro and animal lished. References and related articles from studies data for CFZ, to identify all human studies utilizing that fi t the study population were reviewed. Articles CFZ for the treatment of drug-resistant TB, and to were searched in the above resources with the follow- estimate treatment outcomes for multidrug-resistant ing search concepts with their synonyms; major search (MDR-TB) and extensively drug-resistant TB (XDR- concepts included clofazimine, tuberculosis, out- TB) of regimens that include CFZ. comes, drug-resistant, multidrug-resistant tuberculosis

Correspondence to: Max R O’Donnell, Division of Pulmonary Medicine, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461, USA. e-mail: [email protected] Article submitted 21 February 2012. Final version accepted 19 October 2012. 1002 The International Journal of Tuberculosis and Lung Disease

(MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB). These concepts were exploded to include all sub-headings of Medical Subject Headings (MeSH) as well as text searches for articles not yet indexed. No other search fi lters were used. We attempted to reduce publication bias by searching for abstracts of unpublished and non-English language studies. In addition to the literature on CFZ and TB, in vitro and animal studies were also comprehensively reviewed. The Preferred Reporting Items for Systematic Re- views and Meta-Analyses (PRISMA) guidelines were used for the reporting of this systematic review.5 The following defi nitions were used to standardize outcome measurement: MDR-TB was defi ned as resistance to at least isoniazid (INH) and rifampin (RMP); XDR-TB was defi ned as resistance to INH and RMP, as well as to two of the most effective second-line drugs—a fl uoroquinolone and at least one Figure 1 Flow diagram of included studies. of the second-line injectable agents (amikacin, capre- omycin or kanamycin); cure was defi ned as completion of treatment with fi ve or more negative cultures over at least 12 months after the last positive culture; on treatment protocol and outcomes. The results and completion was defi ned as completion of treat- from animal studies, case reports and small case series ment with documented bacteriological conversion were reviewed and are summarized in this article. persisting through the end of treatment, but fewer We summarized the proportion of patients who than fi ve negative cultures or <12 months of obser- experienced favorable outcomes stratifi ed by MDR- vation after the last positive culture. TB vs. XDR-TB status using a random effects model, Where available, we defi ned favorable outcomes which provides more conservative estimates than in accordance with the World Health Organization fixed effects modeling when heterogeneity is a con- (WHO) recommendations6 as patients who meet cri- cern.9 We visually assessed heterogeneity with use of teria either for cure or for treatment completion. forest plots, characterized the variation in study re- However, not all studies used these outcome defi ni- sults attributable to heterogeneity (c-value) and sta- tions and studies were not excluded on that basis. tistically tested for heterogeneity (χ2 test).10 To evalu- All relevant articles were retrieved and indepen- ate for potential publication bias, we examined funnel dently assessed by two reviewers (MG and MRO). plots and performed Egger’s regression test.11 Finally, All articles that met these criteria were then exposed to determine the infl uence of small studies on our ef- to a second stage of quality assessment. The US Pre- fect estimates, we performed a sensitivity analysis ventive Services Task Force guidelines7 for grading removing studies with fewer than 15 individuals the validity of individual studies for use in systematic (Figure 1). reviews were applied to all potential articles; the Cochrane Collaboration tool for assessing risk of RESULTS bias was also used.8 This is a scale that evaluated the generalizability, sample size, dropout rate, reproduc- Mechanism of action ibility and statistical methodology of each study. It was initially thought that CFZ works by binding to No studies were excluded due to quality concerns. the guanine bases of bacterial DNA, thereby inhibit- Data extracted for each study included age, sex, ing bacterial proliferation,12,13 but this theory has treatment regimen, treatment duration, dates treated, been replaced by the belief that it works through percentage of retreatment cases, proportion of pa- effects on intracellular redox cycling14 and membrane tients human immunodefi ciency virus (HIV) tested, destabilization.15 By increasing reactive oxidant spe- proportion of HIV-positive patients, adverse drug re- cies, CFZ may act to promote killing of antibiotic actions, deaths, default, failure, treatment completion tolerant M. tuberculosis persister organisms.16 In ad- and cure. dition to antimicrobial activity, the drug has other Duplicate publications from the same cohort were pharmacological activities such as anti-infl ammatory, excluded, and animal studies/case reports/case series pro-oxidative and immune-pharmacological proper- with fewer than three patients were also excluded, ties.17 Synergistic effects of interferon-gamma and from outcome analysis. If multiple published reports CFZ, as shown by Parak et al., may contribute to the from the same cohort were available, we included anti-tuberculosis effect of the drug.18 CFZ reverses only the report with the most detailed information the inhibitory effect of M. tuberculosis-derived factors Systematic review of CFZ 1003 on phagocyte intracellular killing mechanisms which being associated with clinical failure. Clinical M. tu- may also contribute to enhanced M. tuberculosis kill- berculosis isolates have been found to have an MIC ing.19 Newer data suggest a potential synergistic ef- of between 0.12 and 0.25 μg /l for CFZ;29 1 μg /ml fect of CFZ with pyrazinamide (PZA)20 and with was identifi ed as the breakpoint for CFZ resistance clarithromycin (CLM)21 in M. tuberculosis killing, al- using the MGIT™ 960 method (BD, Sparks, MD, though the mechanism is unclear. USA) for MDR-TB and XDR-TB isolates.30 Clinical resistance to CFZ is rare. Rastogi et al. noted that a Pharmacokinetics clinical M. tuberculosis isolate was susceptible to CFZ has a half-life of approximately 70 days in hu- CFZ even after the serial development of resistance mans,22 and average steady state concentrations are to INH, fl uoroquinolones, RMP, PZA and ethambu- achieved at about 1 month. Autopsies performed on tol during anti-tuberculosis treatment.31 Satana et al. patients treated with CFZ have found crystallized showed that all 35 MDR-TB isolates tested were sus- CFZ in the intestinal mucosa, liver, spleen and lymph ceptible to CFZ,32 and only 2.9% resistance to CFZ nodes.22 It has slow and variable (45–62%) absorp- was detected among 69 MDR-TB isolates in Russia.33 tion, and a substantial portion of the unchanged drug MIC cut-off points for susceptibility were determined is excreted in the feces.22 The adult dose in published using the epidemiological cut-off value based on the clinical literature varies from 50 to 300 mg daily,22 distribution of MICs in two different sets of clinical although the optimal dose for anti-tuberculosis treat- isolates rather than by using pharmacokinetic/phar- ment is unknown. Average peak serum concentra- macodynamic data, as clinical outcome data are lack- tions for a single dose of 100 mg and 300 mg are re- ing. CFZ resistance was rare in both series (1/45 and spectively 0.7 and 1.0 μg /ml (Lamprene, Food and 0/28 isolates),30,34 and therefore the validity of the Drug Administration label, Basel, Switzerland). There proposed cut-offs is uncertain. is high inter- and intra-subject variability in the bioavailability of CFZ, but highest bioavailability occurs Adverse effects when taken with fatty meals.23 No dose change is rec- In a retrospective review of 60 patients with MDR- ommended in renal disease, but dose adjustment may TB treated with second-line agents, which included be necessary in patients with severe hepatic impair- CFZ, there was a low rate of major adverse events ment. No specifi c laboratory monitoring is recom- and no discontinuation of treatment;35 40–50% of mended in patients taking CFZ. Newer analogues14 patients developed gastrointestinal intolerance.36 with improved pharmacokinetics and alternative for- CFZ produces orange to brownish skin pigmentation mulations24 (liposomal, nano-suspension, inhalational) in 75–100% of patients within a few weeks, as well of CFZ are being studied. as similar discoloration of most bodily fl uids and se- cretions.36 These discolorations are reversible but Animal studies may take months to years to disappear. Cases of Animal data for the effi cacy of CFZ have been incon- icthyosis and skin dryness have also been reported in sistent. CFZ has shown good anti-tuberculosis activ- response to CFZ (8–28%).36 ity in murine models of TB disease, less in guinea pig models and no activity in the rhesus monkey model, Cohort studies despite a CFZ dosage of 100 mg /kg and high serum The Table includes cohort studies utilizing CFZ. In levels.25 Recent studies in mice show substantial 1993, Goble et al. treated 17 patients with MDR-TB killing with CFZ, and recent murine studies have with CFZ in Denver, but outcomes in these patients shown that 3- and 4-drug combinations containing could not be discerned from the paper nor from per- CFZ, particularly the combination of CFZ, PZA and sonal correspondence with study authors.45 Geerligs TMC207, showed the greatest reduction in M. tuber- et al. reported the 15-year experience of their TB culosis colony-forming unit counts of all regimens treatment center in the Netherlands. In 39 MDR-TB tested.20,26 Guinea pigs infected by intracardiac injec- patients, the majority treated with CFZ-containing tion of M. tuberculosis did not show increased sur- TB regimens (mean treatment duration 608 days), the vival when treated with CFZ.27 Between-species dif- successful treatment percentage was 75%.37 In 2003, ferences in M. tuberculosis killing may be explained Mitnick et al. used CFZ in patients with 26 MDR- in part by differences in peak serum levels achieved; TB in Peru and reported a cure rate of 83%.38 In however, in the rhesus monkey model no signifi cant 2004, Senaratne et al. treated 14 MDR-TB patients killing was observed.28 in Sri Lanka with a combination of second-line anti- tuberculosis drugs that included CFZ; four patients Minimal inhibitory concentration studies were cured.39 In Spain, in 2005, Fortun et al. included Minimal inhibitory concentrations (MICs) for CFZ CFZ as part of a regimen that included linezolid for are low in clinical M. tuberculosis strains; as clinical 5 MDR-TB patients, with 100% culture conversion resistance is rare, the MIC breakpoint was derived at 6 weeks.40 Mitnick et al. (Peru, 2008, n = 46) from epidemiologic data rather than an MIC cut-off showed an 83% cure rate; the majority of these 1004 The International Journal of Tuberculosis and Lung Disease

patients were treated with CFZ.41 Condos et al. (New York City, 2010, n = 7) evaluated linezolid as a part of a treatment regimen that included other Group 5 drugs (amoxicillin-clavulanate, CLM, CFZ, imipenem and linezolid), and six were cured.42 Van Deun et al. Patients with no. treated (%) no. treated (2010, n = 427) used CFZ as a part of a 9-month favorable outcome/ 65% (95%CI 52–79) 66% (95%CI 42–89) 65% (95%CI 54–76) multidrug regimen in the treatment of MDR-TB in Bangladesh, with a favorable outcome of 75.6%.43 Xu et al. (China, 2011, n = 39) included CFZ to treat

mg MDR-TB and XDR-TB utilizing CFZ, and demon- Dose 44 50–100(75.6) 323/427 100(80) 4/5 knownNot (100) 3/3 strated a favorable outcome of 43.5%. The percentage of adverse events attributable to CFZ in these eight cohort studies was 11.4%, and resulted in discontinuation of the drug in <1% of pa-

extensively drug-resistant TB. extensively drug-resistant tients. The CFZ dose used in these eight studies var- = (range) 5 4 7 of drugs ∼ ∼ ∼ Median no. ied from 50 to 100 mg daily, but the majority of patients (84.1%) received 100 mg. A random effects meta-analysis demonstrated that % 25 5121.4 6 (5–9) 5–734.4known Not known Not (4–7) 6 21/26 (83) 34.4 100(28.5) 4/14 (4–7) 6 100(40) 8/20 (47.3) 9/19 35.4 5.3 (4–7) 200–300 28/46 (60.8) 20 85.7 65% (95% confi dence interval [95%CI] 54–76) of all Female patients treated with CFZ-containing regimens experienced favorable outcomes, defi ned as either cure or SD) 15) 1.1) 9.9) treatment completion (Figure 2). In stratifi ed analy- ± ± 26) 18) 16) ± ± confidence interval; XDR-TB = ± ± ± sis, 65% (95%CI 52–79) of those with MDR-TB and 33.8 ( 26.8 ( 50 ( 38 ( 32.0 ( 38 ( 26 31 Age, years 66% (95%CI 42–89) of those with XDR-TB experi- mean ( ∼ ∼ enced favorable treatment outcomes. The heterogeneity of this effect estimate (I2 value) was 76% of the variance (P < 0.001), indicating signifi cant heterogeneity. Egger’s regression test for publication bias was not statistically signifi cant (P = 0.18). Reassessment patients/ multidrug-resistant TB; CI multidrug-resistant HIV-positive HIV-positive = Not tested of favorable outcomes following removal of the total no. tested smaller studies (n < 15) from the analysis resulted in no change in the overall summary statistic, and an approximate 10% change in the stratifi ed analysis (from 65% [95%CI 52–79] to 68% [95%CI 50–86] for patients with MDR-TB, and from 66% [95%CI

with CFZ 42–89] to 57% [95%CI 44–69] for patients with Sample size/ patients treated patients treated and 244/427 in consolidative XDR-TB). This indicates that small study effects (i.e., standard deviation; MDR-TB standard

= systematically higher effect estimates for smaller relative to larger studies) may have infl uenced summary estimates for XDR- but not MDR-TB.

DISCUSSION CFZ is a major component of drug regimens used in the treatment of leprosy.46 Our systematic review is to our knowledge the fi rst review of the literature with Study human immunodeficiency virus; SD respect to CFZ in the treatment of drug-resistant TB. location Study years =

NetherlandsPeruSri Lanka 1985–1998SpainBangladesh 44/39 1997–2002 1996–1999 1997–2007China 1999–2004 14/14 75/26 427/427 in intensive 5/5USAPeru 2008–2011China 0/39 20/20 Not available 2000–2005 1999–2002 2008–2011 1/65 7/3 33 48/46 19/19 1/5 Althoughtested Not 29.5in vitrotested Not (4–9) 6 1/7 0 andknown animal Not studies 33/44 are not uniformly positive, the majority of those studies and most MIC studies suggest that CFZ has a measurable anti-

43 tuberculosis effect. CFZ may be useful in the treat- 37 42 38 41 tuberculosis; HIV tuberculosis;

40 ment of MDR-TB as an additional agent to prevent = 39

44 44 amplifi cation of resistance on treatment and improve outcome. Preliminary data suggest that CFZ may improve killing of persister M. tuberculosis and have synergy with existing antimycobacterial agents. TB Summary of cohort studies utilizing CFZ for drug-resistant clofazimine; TB

= A 2004 review of the treatment of drug-resistant Xu et al., 2011 Geerligs et al., 2000 Mitnick et al., 2003 Senaratne, 2003 Fortun et al., 2005 Deun et al., 2010 Van MDR-TB favorable outcome Condos et al., 2004 Mitnick et al., 2008 XDR-TB favorable outcome Xu et al., 2011 Proportion with favorable outcome in overall group, as outcome in CFZ strata was not available. with favorable outcome in overall group, Proportion

MDR-TB Table reference year, Author, * XDR-TB Overall favorable outcome CFZ TB and the 2008 guidelines from the WHO for the Systematic review of CFZ 1005

Figure 2 Proportion of patients with favorable outcomes among studies including clofazamine in MDR- or XDR-TB treatment regimens. CI = confidence interval; MDR-TB = multidrug-resistant tuberculosis; XDR-TB = extensively drug-resistant TB. treatment of drug-resistant TB lists CFZ as a Group outcomes in drug-resistant TB. Compared to a meta- 5 drug, defi ned as a potentially useful agent with con- analysis of MDR-TB treatment outcomes, our esti- fl icting animal or clinical evidence, or an agent with mate of successful outcome in MDR-TB treatment unclear effi cacy due to possible cross-resistance.6,47 A with CFZ is slightly higher (65%, 95%CI 52–79 vs. 2009 systematic review and meta-analysis of treat- 54%, 95%CI 43–68), but there is broad overlap of ment outcomes among patients with MDR-TB,48 and the CIs. a 2010 systematic review and meta-analysis of treat- The long half-life of CFZ is a pharmacokinetic ment outcomes in patients with XDR-TB did not ex- characteristic that may improve its effi cacy.22 The amine the effects of individual agents such as CFZ.49 low cost of CFZ is an additional advantage.52 The In the study from Bangladesh,43 CFZ was a prominent limited supply of CFZ presents a potential problem, part of a multidrug regimen and may have played a as the majority of the global supply is directed to- role in the successful shortening of the duration of wards the treatment of leprosy.53 Adverse effects of treatment of MDR-TB. Theoretically, CFZ may have CFZ are generally minor and rarely life-threatening. contributed to the elimination of persistent organ- Although the optimal dose of CFZ is unknown, based isms and thus have facilitated success of the 9-month on clinical experience and the published literature, regimen due to its extended half-life and lipophilicity. we would recommend a dose of 100 mg /day except The role of CFZ in the treatment of XDR-TB has not in patients with a weight < 33 kg, where 50 mg /day been well defi ned. should be used. In a study of M. leprae, the authors Our systematic review of 599 patients with drug- did note a correlation between CFZ dosage and ad- resistant TB who were treated with CFZ showed a verse events,44 and a decrease in dose was found to cumulative favorable outcome proportion of 65%. reduce the severity of the adverse drug event. This point estimate was unchanged in an analysis Limitations of our study include signifi cant het- stratifi ed by MDR- vs. XDR-TB, although we could erogeneity for our primary outcome measure. We locate only three studies in the literature where CFZ used empirical random effects weighting, performed was incorporated into treatment regimens for XDR- a sensitivity analysis excluding all studies contribut- TB. The high concentration of CFZ achieved in mac- ing <15 eligible individuals, and separately synthe- rophages,50,51 the ability of CFZ to reverse the in- sized data for MDR- and XDR-TB patients to mini- hibitory effect of M. tuberculosis-derived factors on mize heterogeneity. Our results are also limited by the phagocyte intracellular killing mechanisms19 and the observational nature of the studies included. There possible synergistic effects of CFZ with gamma inter- may have been selection bias in that patients who feron,18 PZA20 and CLM,21 may improve treatment received CFZ were systematically different from 1006 The International Journal of Tuberculosis and Lung Disease those who did not, in terms of disease severity, ac- 12 Morrison N E, Marley G M. Clofazimine binding studies with cess to expanded drug-susceptibility testing, and/or deoxyribonucleic acid. Int J Lepr Other Mycobact Dis 1976; accompanying agents in the treatment regimen. Treat- 44: 475– 481. 13 Arbiser J L, Moschella S L. Clofazimine: a review of its medical ment outcome defi nitions were not uniform through- uses and mechanisms of action. J Am Acad Dermatol 1995; 32: out the different clinical studies in our analysis, and 241–247. this limitation may have biased the results. Limita- 14 Yano T, Kassovska-Bratinova S, Teh J S, et al. 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RÉSUMÉ L’incidence croissante de la tuberculose à germes rési- CFZ dans les régimes de traitement de la TB-MDR et de stants a créé un besoin urgent de développement de nou- la tuberculose ultrarésistante (TB-XDR). Nous avons veaux médicaments antituberculeux efficients et celui de identifié neuf études observationnelles (6 TB-MDR et régimes thérapeutiques alternatifs. La clofazimine (CFZ) 3 TB-XDR) incluant des patients atteints d’une TB à est un colorant riminophénazine soluble dans les germes résistants et traités par la CFZ. Au total, les graisses, utilisée au niveau mondial pour le traitement de résultats du traitement ont été favorables chez 65% des la lèpre. La CFZ a également été utilisée comme médica- patients (IC95% 54–76), qu’il s’agisse de guérison ou ment de Group 5 pour le traitement de la tuberculose d’achèvement du traitement. Au moyen d’une méta- (TB). Une grande étude de cohorte provenant du Bengla- analyse des effets aléatoires, 65% (IC95% 52–79) de desh et datant de 2010 a décrit un régime de traitement ceux atteints de TB-MDR et 66% (IC95% 42–89) de de la TB à germes multirésistants (TB-MDR) incluant la ceux atteints de TB-XDR ont connu des résultats finaux CFZ comme médicament hautement efficace contre la favorables après traitement. Des études prospectives de TB-MDR. Nous avons fait des recherches dans de mul- cohorte de haute qualité et des essais cliniques exami- tiples bases de données concernant les études publiées nant l’effet de la CFZ au sein d’un régime de traitement jusqu’à février 2012 qui signalaient l’utilisation de la de la TB résistante aux médicaments s’imposent.

RESUMEN El aumento de la incidencia de tuberculosis (TB) farma- miento de la TB-MDR y la TB extremadamente dro- corresistente ha dado lugar a una necesidad apremiante gorresistente (TB-XDR). Se encontraron nueve estudios de desarrollar nuevos medicamentos antituberculosos de observación (seis sobre TB-MDR y tres sobre TB- eficaces y establecer otras opciones terapéuticas. La XDR) en los cuales participaron pacientes con TB clofazimina (CFZ) es un colorante liposoluble de la farmacorresistente que recibieron tratamiento con CFZ. riminofenazina que se utiliza en el tratamiento de la lepra En general, el 65% de los pacientes alcanzó un desen- en todo el mundo. Además, la CFZ se ha usado como me- lace favorable (IC95% 54–76) definido ya sea como la dicamento del Grupo 5 en el tratamiento de la TB. En curación o la compleción del tratamiento. Mediante un un amplio estudio de cohortes realizado en Bangladesh metanálisis de efectos aleatorios, se encontró que 65% de y publicado en el 2010 se describió un régimen terapéu- los pacientes con TB-MDR (IC95% 52–79) y 66% de los tico sumamente eficaz contra la TB multidrogorresistente pacientes con TB-XDR (IC95% 42–89) lograron un de- (TB-MDR), que comportaba la CFZ. En el presente senlace terapéutico favorable. Se precisan estudios pro- e studio se llevó a cabo una búsqueda en múltiples bases spectivos de cohortes y ensayos clínicos de gran calidad de datos de artículos publicados hasta febrero del 2012 que examinen el efecto de la CFZ como parte del régi- que comunicaran el uso de la CFZ en regímenes de trata- men de tratamiento de la TB farmacorresistente.