Selected Questions and Controversies About Bedaquiline: a View from the Field

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INT J TUBERC LUNG DIS 20(12):S24–S32 MDR-TB TRIALS LANDSCAPE SUPPLEMENT Q 2016 The Union http://dx.doi.org/10.5588/ijtld.16.0065

Selected questions and controversies about bedaquiline: a view from the field

K. Dheda,* A. Esmail,* J. Limberis,* G. Maartens† *Lung Infection and Immunity Unit, Division of Pulmonology and University of Cape Town Lung Institute, Department of Medicine, University of Cape Town, Cape Town, †Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa

SUMMARY Although there has been a slow decline in tuberculosis years. BDQ has sterilising activity and also shows (TB) incidence worldwide, the prevalence of drug- promise as a component of new treatment-shortening resistant TB in most high-burden countries has regimens for drug-susceptible TB. Here we review increased. Drug-resistant TB is associated with high insights from the field into the use of BDQ, issues mortality, is a threat to health care workers in TB- relevant to the practising clinician, implications for endemic countries and is prohibitively costly, which the selection for antiretroviral therapy, pharmacoki- diverts resources away from drug-susceptible cases. netic issues relevant to clinical practice and implica- Amplification of resistance means that there is an tions for combination therapy. Given the increasing increasing proportion of patients with multidrug- prevalence of resistance beyond XDR-TB, we also resistant TB who have extensively drug-resistant TB discuss how the development of resistance to BDQ (XDR-TB) or are programmatically untreatable. can be minimised. Thus, new treatment options are urgently needed. KEY WORDS: tuberculosis; MDR-TB; drugs; contro- Bedaquiline (BDQ) is the first new drug specifically versies; QT interval developed for TB to be licensed for use in almost 40

ALTHOUGH THE GLOBAL INCIDENCE of tuber- forTBtobelicensedforuseinalmost40years.2 culosis (TB) is slowly declining, the detection of BDQ may also benefit drug-susceptible TB, where drug-resistant TB (DR-TB) over the last several years the objective is to reduce the rate of relapse and has been going up in most of the 22 high-burden minimise treatment duration, thus improving TB countries (Figure 1).1,2 The temporal incidence of control. BDQ is a diarylquinoline, which depletes DR-TB is also increasing in certain countries and mycobacterial intracellular energy levels. Its mech- several parts of the world.1 Multidrug-resistant anism of action and development of resistance is (MDR-TB, defined as TB resistant to at least outlined in Figure 2. Here we review insights from isoniazid [INH] and rifampicin [RMP]), extensively the field into BDQ use, with a focus on issues drug-resistant TB (XDR-TB, defined as MDR-TB relevant to the practising clinician. plus resistance to a fluoroquinolone and one of the three second-line injectables) and resistance beyond POTENTIAL COMPANION DRUGS THAT MAY BE XDR-TB is associated with substantial mortality COMBINED WITH BEDAQUILINE: INSIGHTS (30–60%), is a major threat to the recruitment and FROM ANIMAL AND HUMAN STUDIES retention of health care workers,3 and treatment is associated with prohibitive costs.4 For example, in Combination with first-line drugs countries such as South Africa, almost 40% of the With regard to combination with first-line drugs, national TB budget is consumed by DR-TB, murine and human data indicate that BDQ can although it comprises less than 5% of the total TB safely be administered with isoniazid,10,11 is syner- burden.4 There is also a worrying and burgeoning gistic with pyrazinamide (PZA),9 but cannot be used problem of programmatically incurable TB,5–7 and with RMP or rifapentine (RPT), which increase new drugs are thus urgently needed. Bedaquiline BDQ clearance by about four-fold due to induction (BDQ; Sirturo, Janssen Pharmaceuticals, Beerse, of CYP3A4 isoenzyme, which metabolises BDQ Belgium) is the first new drug specifically developed (Table, A).12,13

Correspondence to: Keertan Dheda, Department of Medicine, Lung Infection and Immunity Unit, Division of Pulmonology and University of Cape Town Lung Institute, University of Cape Town, South Africa. e-mail: [email protected] Article submitted 25 January 2016. Final version accepted 1 June 2016. Questions and controversies about BDQ S25

Figure 1 Global trend of increasing detection of MDR-TB in the 27 high MDR-TB burden countries, 2009–2014; MDR-TB cases and additional rifampicin-resistant TB cases detected are compared with TB cases enrolled on MDR-TB treatment. Reproduced with permission from the WHO.1 MDR-TB¼multidrug-resistant tuberculosis; WHO¼World Health Organization. This image can be viewed online in colour at http://www.ingentaconnect.com/content/iuatld/ijtld/2016/00000020/00000012/A00112s1/art000....

Potential to shorten multidrug-resistant tuberculosis line TB drugs apart from RMP and RPT, or with treatment second-line TB drugs.17,18 Two Phase II studies (early Murine studies have suggested that BDQ may be used bactericidal activity [EBA] and a randomised con- to shorten the duration of MDR-TB treatment to 12 trolled trial [RCT]) demonstrated faster sputum months,15 and have shown an additive effect with culture conversion with BDQ in patients with clofazimine (CFZ).16 Human studies have not shown MDR-TB when combined with an optimised back- clinically significant drug-drug interactions with first- ground regimen (OBR) (Table, A).19,20 S26 The International Journal of Tuberculosis and Lung Disease

Figure 2 BDQ transverses the mycobacterial cell wall and enters the cytoplasm via an unknown mechanism. It then binds to subunit c of mycobacterial F-ATP synthase, encoded by atpE, at the essential Asp or Glu amino acids that allow ion transfer to occur during the production on ATP. This leads to the inhibition of ATP synthesis. Resistance to BDQ arises when there is a relevant mutation in the atpE gene or when the negative regulation of the mmpL5-mmpS5 RND-like efflux pump subunit is interrupted due to a mutation(s) in the Rv0678 regulatory protein. This protein normally prevents binding (or makes binding occur at a diminished rate) to the operator/ promoter region of the mmpL5-mmpS5 operon.8 BDQ remains active against any mycobacteria that have residual ATP synthase activity. The figure is partly adapted from Wells et al., with the permission of PLOS ONE.9 BDQ ¼ bedaquiline; RND ¼ resistance- nodulation-cell division; ATP¼adenosine triphosphate. This image can be viewed online in colour at http://www.ingentaconnect.com/ content/iuatld/ijtld/2016/00000020/00000012/A00112s1/art000...

Combination of bedaquiline with newer or repurposed nodeficiency virus (HIV) co-infection rates and strain drugs heterogeneity, high rates of culture conversion were Studies of the combination of bedaquiline with newer seen in patients with pre-XDR (defined as MDR-TB or repurposed drugs have shown encouraging results. with resistance to either a fluoroquinolone or a Combination with oxazolidinones has shown treat- second-line injectable agent) and XDR-TB in South ment shortening potential in murine models21 and African25 and French cohorts,22 and a case series human studies22,25 (Table, A). Similarly, a combina- from India (Table A).32 In the South African cohort, tion of BDQ with nitroimidazoles (pretomanid 33 of 39 (85%) pre-XDR and XDR-TB patients who [PMD] or TBA-354) had favourable outcomes in were initially culture-positive culture converted after murine studies.24 Two EBA studies indicated that a treatment initiation. By contrast, conversion rates combination of BDQ, PMD and PZA appeared to be were ~20% in XDR-TB patients using a non- promising26,31 for a new treatment regimen. Howev- linezolid/non-BDQ-based regimen.6,33 er, combination with delamanid could cause cardio- toxicity, as both drugs prolong the QT interval. In Adverse events vitro SQ109, a 1,2 ethylenediamine, showed encour- BDQ may be associated with several adverse events. aging results when used in combination with BDQ.27 Mortality was higher in the BDQ than in the placebo Collectively, these data have facilitated the initiation arm in the Phase II(b) RCT, but almost all of these or planning of several studies evaluating a number of deaths occurred after the 6 months of BDQ BDQ-containing regimens for MDR-TB (Table, B). administration, and most deaths were ascribed to TB. However, it should be noted that there is ongoing exposure for several years after stopping INSIGHTS AND EXPERIENCE FROM FIELD USE, BDQ, due to its very long terminal elimination half- INCLUDING USE IN HIV-INFECTED PERSONS life.20 BDQ is associated with a modestly prolonged Efficacy QT interval. In the Phase II(b) RCT, the mean QTcF In clinical practice BDQ is used in patients with DR- increase from baseline was 15.4 ms in the BDQ TB when toxicity (not uncommonly ototoxicity groupvs.3.3msintheplacebogroup,and associated with aminoglycosides) or the degree of normalised by week 60; only 1/79 patients had a mycobacterial drug resistance precludes the construc- QTcF . 500 ms at one time-point.20 In the French tion of an effective regimen. Although performed in cohort, 7/35 (20%) had a .60 mS increase in the QT different contexts and settings, with human immu- interval; however, BDQ was stopped in only 2/35 Table A) Murine and Phase I and II human studies that clarify the potential role of BDQ in treatment regimens

Drug combination co-evaluated with Companion drugs evaluated BDQ or regimen details Study design Results of studies or clinical trials Comments

BDQ with first-line anti- INH and PZA10,11 Pre-clinical murine curative/PK study No clinically relevant reduction in drug BDQ can safely be administered with INH tuberculosis agents (curative model of murine TB levels despite in vitro reports of INH and PZA evaluating combinations containing being a potent inhibitor of CYP BDQ/INH/RMP and PZA or MFX*10 isoenzymes Phase I open-label cross-over study of Combination of BDQþPZA was more BDQþPZA are synergistic INH/PZA for 5 days, followed by effective compared to BDQ with other introduction of BDQ after washout11 agents (BDQþINHþRMP or BDQþMFXþRMP) after 2 months of treatment; PZA may have an indirect inhibition of ATP synthase13 Rifamycins12,14 Phase I. Co-administration of RMP and Co-administration increased BDQ Co-administration of these rifamycins RPT with BDQ12,14 clearance by 4.78 fold (RMP) and 3.96 with BDQ is not recommended; fold (RPT); BDQ levels are thus reduced rifabutin is unlikely to cause significant by ~50% reductions in BDQ concentrations, but there are no data yet on this interaction BDQ with conventionally used Conventionally used MDR-TB agents as Preclinical murine model: mice inoculated Similar relapse rates for the WHO Potential to shorten MDR-TB treatment to MDR-TB agents part of optimised background regimen with TB (H37Rv) and treated with and recommended regimen (12 months 12 months when BDQ is added to OBR (OBR; including kanamycin, MFX, EMB, without BDQ*15 duration) vs. BDQ þ WHO CS, ETH and PZA in various recommended regimen (6 months combinations)15–20 duration) Preclinical murine model: BDQþPZA in CFZ was the best additional drug when Combination of BDQþPZAþCFZ has combination with a third agent combined with a BDQþPZA excellent sterilising activity compared to a first-line regimen*16 combination Phase II PK study: MDR-TB drugs co- BDQþPZA with either RPT or MFX BDQþPZAþMFX achieved better cure administered with BDQ or placebo for superior to RMPþPZAþINH than first-line anti-tuberculosis drug 14 days17,18 combination Phase IIa 14 day EBA; BDQ or placebo No clinically relevant effects of BDQ were No clinically significant interactions with added to a 5-drug standard MDR-TB seen on the PK of MDR-TB drugs. AUC drugs in the WHO-recommended regimen in 47 patients19 of kanamycin was increased by 1.5 fold MDR-TB regimen usin n otoese bu BDQ about controversies and Questions but due to lower creatinine clearance in the BDQ group (91 vs. 112 ml/min) Phase IIb RCT of 160 patients with smear- 8 week proportion and time to culture Combination of BDQ with standard MDR- positive MDR-TB who received BDQ or conversion was significantly shorter in TB regimen accelerated culture placebo þ OBR20 the BDQ arm (hazard ratio 11.8, P ¼ conversion 0.0034; 48% vs. 9% for proportion) The BDQ arm had reduced time to culture BDQ when added to preferred OBR MDR- conversion (125 days vs. 83 days) and TB regimen resulted in faster culture increased rate of culture conversion at conversion 24 weeks (79% vs. 58%). Adverse There were concerns about unexplained event rates were similar except for deaths, QTc prolongation and hepatitis unexplained death, which occurred in the BDQ arm significantly more frequently in the BDQ group (10 vs. 2). There was a trend towards increased hepatic events, and prevention of the acquisition of resistance to accompanying drugs S27 S28 Table (continued)

Drug combination co-evaluated with Disease Lung and Tuberculosis of Journal International The Companion drugs evaluated BDQ or regimen details Study design Results of studies or clinical trials Comments BDQ with new and Oxizolidinone21–23 Preclinical murine model. 3–4 drug BDQ with SZD was the most effective BDQ when used in combination with SZD repurposed drugs combination involving BDQ, PMD, SZD drug pair compared to BDQ combined has treatment-shortening potential and/or CFZ compared to a first-line with PMD or CFZ anti-tuberculosis regimen*21 Preclinical murine model. BDQ-PMD with/ BDQþPMDþLZD had sterilising activity Sterilising activity of LZD approaches that without PZA combined with SZD or approaching that of BDQþPMDþSZD. of SZD when combined with BDQ LZD24 Halving the dose of LZD modestly reduced sterilising activity over the first month but not after 2 months. TZD had bactericidal activity against M. tuberculosis but less than other oxazolidinones Retrospective human cohort study. 35 At 24 weeks, culture conversion was BDQ when combined with other drugs, patients with XDR- (54%) and pre- achieved in 97% (28/29) with median including LZD, has a potential to XDR-TB (40%) had BDQ together with time to culture conversion of 85 days. achieve high 6-month culture a median of 4 other drugs (range 2–5) BDQ-related adverse events were mild conversion rates. Adverse events including LZD in most patients (94%)22 or moderate and regressed included hepatitis and prolonged QTc spontaneously. 2 patients (6%) had BDQ stopped due to prolonged QTc (20% had 7 60 ms increase in QTc). Liver enzymes were elevated in 14% with severe elevation (7 5 fold) in 6% of patients Interim cohort analysis of 91 patients 63 patients from the cohort had at least 6 BDQ is safe and efficacious in the receiving BDQ for XDR and pre-XDR-TB month follow up, of these 76% (48/63) treatment of XDR- and pre-XDR-TB in an HIV-prevalent setting (56% of the achieved culture conversion or patients, including HIV-infected patients in this cohort were HIV- remained culture-negative after patients receiving ART infected) receiving BDQ. QTcF exceeded 500 ms OBR including LVX (83.5%), LZD (70%), in 3 patients necessitating temporary CFZ (74%) high-dose INH, PZA, MFX, withdrawal in 1 patient while 1 patient EMB, ETH or TZD in various developed atrial fibrillation combinations as per the South African necessitating BDQ discontinuation National Tuberculosis Control Program Guidelines25 Nitroimidazoles24,26 *Preclinical murine model: TBA-354 is 5–10 times more potent than The addition of either nitoimidazole nitroimidazoles (PMD and TBA-354) PMD when used as monotherapy and significantly improved the sterilising used as monotherapy and in 2–4 times more effective when used in activity of BDQ and SZD combination with BDQ, PZA, SZD and/ combination with BDQ or CFZ24 Phase II EBA. BDQ, PMD and CFZ were BDQ in combination with PMD and PZA Combination of BDQþPMDþPZA is a used in dual or triple combinations had comparable EBA to a standard potentially effective treatment regimen compared to a standard first-line first-line regimen with no significant with no significant drug-drug regimen (NC003)26 drug-drug interaction. CFZ did not interaction have any measurable 14-day EBA Diamine (SQ 109)27 In vitro study. Interaction of SQ109 and Combination of BDQ with SQ109 Combination of BDQ with SQ109 may BDQ with each other, and RMP24 27 improved MIC for H37Rv by 4–8 fold have additive benefit without any with no antagonistic activity drug-drug interaction Table (continued)

Drug combination co-evaluated with Companion drugs evaluated BDQ or regimen details Study design Results of studies or clinical trials Comments BDQ with ART Lopinavir/ritonavir28,29 PK study: healthy non-HIV-infected Co-administration of LPV/r with BDQ The clinical significance of elevated BDQ volunteers and HIV-infected individuals increases BDQ exposure by ~ 3 fold and M2 levels is uncertain and careful who were ART-na¨ıve were included in and M2 (N-monodesmethyl) by 2 fold monitoring is recommended the study28 Nevirapine28 As above No clinically significant effects on either NVP can safely be co-administered with drug BDQ28 EFV30 Sequential PK study in healthy adults BDQ and M2 concentrations during Co-administration of BDQ with EFV is not steady state are reduced by 52% recommended

B) Clinical trials currently underway or in planning stages that include BDQ with other companion agents for the treatment of DR-TB

Companion agents Study design Phase Reference Comments

BDQ þ WHO-recommended BR for the Multicentre, open label, single-arm study to evaluate PK, Phase II NCT02354014 Planned treatment of MDR-TB in children and safety, tolerability and antimycobactericidal activity of adolescents BDQ when used in combination with BR in children and adolescents with MDR-TB BDQ þ WHO-recommended BR for the Safety, efficacy and PK study of BDQ when used in Phase II NCT02365623 Recruiting treatment of MDR-TB combination with BR in Japanese patients BDQ in combination with MFX, PMD and PZA Partially randomised trial to evaluate safety, efficacy and Phase II NCT02193776 Recruiting (GATB NC-005) tolerability of various combinations of BDQ during 8 weeks of treatment in smear positive adults with DS- or MDR-TB BDQ in combination with DLM Trial to assess safety, tolerability and PK of BDQ and DLM Phase II NCT02583048 Planned alone and in combination for treatment of DR-TB BDQ in combination with LZD, LVX, PZA and RCT comparing a 6-month injection-free BDQ-containing Phase III NCT02454205 Recruiting ETH/INH (NExT) regimen to standard WHO MDR-TB regimen BDQ in combination with PMD and LZD (NiX- Use of BDQ with PMD and LZD in XDR-TB or treatment Phase III NCT02333799 Recruiting BDQ about controversies and Questions TB) intolerant/non-treatment responsive MDR-TB BDQþLZDþPZA6CFZ in combinations with RCT comparing various regimens for the treatment of Phase III Planned LVX/MFX (endTB) MDR-TB. This study is also comparing DLM-based regimens to standard WHO MDR-TB regimen BDQþLVXþCFZþPZAþINH6PTH6EMB6KM RCT comparing 3 regimens, i.e., Bangladesh regimen Phase III NCT02409290 Funded but not yet (STREAM II) and two BDQ-containing regimens to standard WHO recruiting at the MDR-TB regimen time of writing BDQþPMDþLZD6MFX/CFZ (TB Practecal) RCT comparing various regimens for the treatment of Phase III NCT02589782 Planned MDR/XDR-TB to standard WHO regimen for MDR/ XDR-TB

* Animal studies. All Phase I and II studies involve humans. BDQ¼ bedaquiline; INH¼isoniazid; PZA ¼pyrazinamide; PK¼pharmacokinetic; TB¼tuberculosis; RMP¼rifampicin; MFX¼moxifloxacin; ATP¼ adenosine triphosphate; RPT¼rifapentine; MDR-TB ¼multidrug-resistant TB; WHO ¼World Health Organization; OBR ¼ optimised background regimen; EMB ¼ ethambutol; CS ¼ cycloserine; ETH ¼ ethionamide; CFZ ¼ clofazimine; EBA ¼ early bactericidal activity; AUC ¼ area under the curve; RCT ¼randomised controlled trial; PMD ¼ pretomanid; SZD ¼ sutezolid; LZD ¼ linezolid; XDR-TB ¼ extensively drug-resistant TB; TZD ¼ terizidone; HIV ¼ human immunodeficiency virus; ART ¼ antiretroviral therapy; LVF ¼ levofloxacin; MIC ¼ minimum inhibitory concentration; LPV/r ¼ lopinavir/ritonavir; NVP ¼ nevirapine; EFV ¼ efavirenz; DR-TB ¼ drug-resistant TB; BR ¼ balanced randomisation; DS-TB ¼ drug-susceptible TB; DLM ¼ delamanid; KM ¼ kanamycin. S29 S30 The International Journal of Tuberculosis and Lung Disease

(6%) patients.22 By contrast, only 1/91 (1%) South monitoring for toxicity. Other potential ART op- African patients had BDQ withdrawn due to atrial tions for co-administration with BDQ are the fibrillation; a prolonged QTc (.500 ms) occurred in integrase strand transfer inhibitors raltegravir or three patients, but this resolved spontaneously.25 dolutegravir, together with dual nucleoside reverse Over time there was no sustained or significant transcriptase inhibitors (NRTIs), or triple NRTIs, increase in QTc even when stratified by HIV status, which should only be used after virological suppres- age or sex; although CFZ was associated with a 18.4 sion has been achieved.36 ms increase in QTc, it was not associated with an absolute increase of .50 ms compared to those not on CFZ.25 Thus, from our personal experience, QT PHARMACOKINETIC AND prolongation does not seem to be a major problem in PHARMACODYNAMIC ISSUES clinical practice. However, more data are required As the relative bioavailability of BDQ is doubled and caution should be exercised when BDQ is used when taken with a high-fat meal, BDQ should be with other QT-prolonging drugs, such as moxiflox- taken with a meal (SirturoTM prescribing informa- acin and CFZ, with regular electrocardiography tion. Beerse, Belgium: Janssen Pharmaceutical Co, monitoring, and rapid treatment of aminoglycoside- 2015). Peak concentrations are reached at 4–6 h. induced hypokalaemia and hypomagnesaemia. Oth- BDQ is highly protein bound in plasma, and is er potential serious adverse events include hepato- toxicity, which was reported in 7.7% of BDQ- primarily metabolised in the liver by the cytochrome treated patients (alanine aminotransferase . 5times P450 isoenzyme CYP 3A4 to its main metabolite, the upper limit of normal) vs. 2.5% in the placebo M2, which is less active but more toxic. BDQ is 37 group,20 andin6%ofpatientsintheFrench primarily eliminated in the faeces. The plasma half- cohort.22 Although other adverse events such as life is 24–30 h, but the terminal elimination half-life is nausea, vomiting and arthralgia have been de- much longer (see below).37 BDQ is dosed at 400 mg scribed, in our experience BDQ is fairly well daily for 2 weeks as a loading dose, followed by 200 tolerated in clinical practice. BDQ is not teratogenic mg three times a week. in rats and rabbits, but there is no experience with BDQ distributes extensively into tissues. Like many human pregnancy. BDQ should be used with other cationic amphiphilic drugs, BDQ, and especial- caution, and there should be appropriate monitoring ly its M2 metabolite, induces phospholipidosis in the of patients with renal dysfunction. cells it penetrates.37 Drug-induced phospholidosis is an acquired lysosomal storage disease that causes Use in human immunodeficiency virus-infected ultrastructural changes in cells, characterised by patients lamellar bodies.38 The polar phospholipids generated Data on drug-drug interactions between BDQ and by the cell bind the inducing drug, resulting in drug antiretrovirals are limited. The World Health Orga- accumulation. It remains unclear whether drug- nization-recommended first-line antiretroviral ther- induced phospholipidosis causes toxicity.38 The apy (ART) regimens include nevirapine (NVP) and phospholidosis gradually resolves after stopping the efavirenz (EFV), both of which induce CYP3A4, inducing drug. while second-line regimens include ritonavir-boost- The phospholipidosis induced by BDQ has impor- ed protease inhibitors, which inhibit CYP3A4. tant consequences. First, BDQ accumulates intracel- Drug-drug interaction studies of HIV-infected pa- lularly, which is beneficial, as Mycobacterium tients at steady state on ART given single doses of tuberculosis is primarily an intracellular pathogen. BDQ found the following effects on the area under The bactericidal activity of BDQ is higher in the curve of BDQ: NVP, no effect; lopinavir- macrophages than extracellularly.39 Second, the ritonavir (LPV/r), modest increase; EFV, modest terminal elimination half-life is extremely long, about decrease.28–30,34 However, single doses of BDQ may underestimate the magnitude of interactions when 6 months. This results in several years of low plasma 40 BDQ reaches steady state. Population pharmacoki- concentrations after stopping treatment, which netic (PK) studies modelling data from single-dose could select for resistance if re-infection occurs. BDQ and ART drug-drug interaction studies esti- However, the high concentrations of BDQ inside mated the following changes in BDQ exposure at alveolar macrophages will likely protect against steady state: LPV/r, marked increase; EFV, marked reinfection. Of greater concern is the development decrease; NVP, no significant effect (Table, A). A of acquired resistance in patients defaulting from study of patients on ART being treated with BDQ treatment, who will effectively be on monotherapy for DR-TB confirmed the findings of the population with BDQ for a prolonged period after defaulting. PK studies on interactions with NVP and LPV/r.35 Finally, the extremely long tissue half-life of BDQ EFV should be avoided in patients on BDQ, and could be useful in treatment-shortening regimens by caution exercised when using LPV/r, with close effectively prolonging the duration of treatment. Questions and controversies about BDQ S31

INFORMING THE CURRENT AND FUTURE USE suboptimal concentrations of BDQ for many months OF BEDAQUILINE: THE EQUIPOISE OF in environments where the force of infection is high OBSERVATIONAL VS. RANDOMISED remains unclear. In addition to using robust and CONTROLLED TRIALS comprehensive regimens with at least 3–4 effective agents and additional investment in a limited drug How BDQ should be used in clinical practice and pipeline, alternative novel approaches will thus need what evidence base should guide this process remains to be investigated, including those such as therapeutic contentious. A one-regimen approach, irrespective of drug monitoring, use of efflux pump inhibitors the degree of drug resistance, raises several concerns, (raising intracellular BDQ concentrations) and the including the lack of alternatives in treatment failures use of inhaled antibiotics for adequate drug penetra- (likely to incorporate several classes of drugs), cost tion to diseased areas of the lung (reviewed in Dheda and toxicity, given the existence of an effective, low- et al.5). Alternative immunotherapeutic approaches, cost RMP-based first-line regimen. The impact of such as host-related therapies, will require further treatment-shortening on disease control also remains and more intensive investigation. unclear. By contrast, use in highly drug-resistant populations (those with XDR-TB and resistance Conflicts of interest: none declared. beyond XDR-TB), where mortality is considerable and existing regimens ineffective, is where the drug is References most likely to fail and amplification of resistance is likely to develop. In South Africa, where BDQ is 1 World Health Organization. Global tuberculosis report, 2015. available on a limited access basis, it is being used WHO/HTM/TB/2015.22. Geneva, Switzerland: WHO, 2015. 2 Dheda K, Barry C E, 3rd, Maartens G. Tuberculosis. Lancet with companion drugs, including linezolid and 2016; 387: 1211–1226. levofloxacin, in patients with XDR-TB, pre-XDR- 3 O’Donnell M R, Jarand J, Loveday M, et al. High incidence of TB or in patients with MDR-TB, where toxicity, most hospital admissions with multidrug-resistant and extensively commonly to aminoglycosides, precludes the creation drug-resistant tuberculosis among South African health care of an effective regimen. workers. Ann Intern Med 2010; 153: 516–522. 4 Pooran A, Pieterson E, Davids M, Theron G, Dheda K. What is Awaiting guidance from RCTs has the advantage of the cost of diagnosis and management of drug resistant clarifying toxicity concerns and accurately measuring tuberculosis in South Africa? PLOS ONE 2013; 8: e54587. efficacy and the rate of adverse events. By contrast, 5 Dheda K, Gumbo T, Gandhi N R, et al. Global control of operational research through immediate roll-out of tuberculosis: from extensively drug-resistant to untreatable BDQ will gather data on toxicity and save lives. tuberculosis. Lancet Respir Med 2014; 2: 321–338. 6 Pietersen E, Ignatius E, Streicher E M, et al. Long-term However, the lack of a control group makes it outcomes of patients with extensively drug-resistant difficult to accurately gauge efficacy and clarify tuberculosis in South Africa: a cohort study. Lancet 2014; concerns about drug-related unexplained death. 383: 1230–1239. 7 Dheda K, Migliori G B. The global rise of extensively drug- resistant tuberculosis: is the time to bring back sanatoria now MINIMISING RESISTANCE TO BEDAQUILINE overdue? Lancet 2012; 379: 773–775. AND CONCLUSIONS 8 Andries K, Villellas C, Coeck N, et al. Acquired resistance of Mycobacterium tuberculosis to bedaquiline. PLOS ONE 2014; Resistance to BDQ41 and acquired resistance to both 9: e102135. delamanid and BDQ in the same patient were recently 9 Wells R M, Jones C M, Xi Z, et al. Discovery of a siderophore export system essential for virulence of Mycobacterium described;42 several treatment failures have emerged tuberculosis. PLoS Pathog 2013; 9: e1003120. from the BDQ access programme in South Africa. 10 Ibrahim M, Andries K, Lounis N, et al. Synergistic activity of Thus, despite perfect adherence, and due to several R207910 combined with pyrazinamide against murine factors, it is inevitable that acquired resistance to tuberculosis. Antimicrob Agents Chemother 2007; 51: 1011– BDQ will develop. Over time widespread resistance 1015. 11 van Heeswijk R. The pharmacokinetic (PK) interaction may develop, as to the fluoroquinolones. The key is to between isoniazid/pyrazinamide and TMC207, an minimise and reduce the rate at which this occurs. investigational antimycobacterial agent. 47th Interscience Strengthening national TB programmes by appropri- Conference on Antimicrobial Agents and Chemotherapy. ate training of health care workers, ensuring access to Chicago, IL, USA, 17–20 September 2007. Washington, DC, care, preventing drug stock-outs and promoting USA: American Society of Microbiology, 2007: A-780. 12 Svensson E M, Murray S, Karlsson M O, Dooley K E. treatment adherence via intensive support and Rifampicin and rifapentine significantly reduce concentrations counselling, and using other measures, is crucial. of bedaquiline, a new anti-TB drug. J Antimicrob Chemother However, several other factors will drive the ampli- 2015; 70: 1106–1114. fication of resistance. These include suboptimal 13 Zhang Y, Wade M M, Scorpio A, Zhang H, Sun Z. Mode of penetration of drug into fibrocaseous lung foci, action of pyrazinamide: disruption of Mycobacterium tuberculosis membrane transport and energetics by pyrazinoic population-based PK variability and cross-resistance acid. J Antimicrob Chemother 2003; 52: 790–795. to CFZ, which is widespread in many parts of the 14 Winter H, Egizi E, Murray S, et al. Evaluation of the world (Figure 1).5 The significance of the lingering pharmacokinetic interaction between repeated doses of S32 The International Journal of Tuberculosis and Lung Disease

rifapentine or rifampin and a single dose of bedaquiline in 28 Svensson E M, Dooley K E, Karlsson M O. Impact of lopinavir- healthy adult subjects. Antimicrob Agents Chemother 2015; ritonavir or nevirapine on bedaquiline exposures and potential 59: 1219–1224. implications for patients with tuberculosis-HIV coinfection. 15 Veziris N, Ibrahim M, Lounis N, Andries K, Jarlier V. Sterilizing Antimicrob Agents Chemother 2014; 58: 6406–6412. activity of second-line regimens containing TMC207 in a 29 van Heeswijk V A, Meyvisch P, et al. The effect of lopinavir/ murine model of tuberculosis. PLOS ONE 2011; 6: e17556. ritonavir on the pharmacokinetics of TMC207, an 16 Tasneen R, Li S Y, Peloquin C A, et al. Sterilizing activity of investigational antimycobacterial agent. 18th International novel TMC207- and PA-824-containing regimens in a murine AIDS Conference, Vienna, Austria, 18–23 July 2010. model of tuberculosis. Antimicrob Agents Chemother 2011; 55: [Abstract WEPE0097] 5485–5492. 30 Svensson E M, Aweeka F, Park J G, Marzan F, Dooley K E, 17 Centers for Disease Control and Prevention. Provisional CDC Karlsson M O. Model-based estimates of the effects of efavirenz guidelines for the use and safety monitoring of bedaquiline on bedaquiline pharmacokinetics and suggested dose fumarate (Sirturo) for the treatment of multidrug-resistant adjustments for patients coinfected with HIV and tuberculosis. tuberculosis. MMWR Recomm Rep 2013; 62(RR-09): 1–12. Antimicrob Agents Chemother 2013; 57: 2780–2787. 18 van Heeswijk R. The pharmacokinetics (PK) of second line 31 Diacon A H, Dawson R, von Groote-Bidlingmaier F, et al. 14- antituberculosis agents with and without TMC207, an day bactericidal activity of PA-824, bedaquiline, pyrazinamide, investigational antimycobacterial agent in patients with and moxifloxacin combinations: a randomised trial. Lancet MDR-TB. 52nd Interscience Conference on Antimicrobial 2012; 380: 986–993. Agents and Chemotherapy, San Francisco, CA, USA, 9–12 32 Udwadia Z F, Amale R A, Mullerpattan J B. Initial experience September 2012. [Abstract A-1260] of bedaquiline use in a series of drug-resistant tuberculosis 19 Janssen Briefing Document. TMC207 (bedaquiline): treatment patients from India. Int J Tuberc Lung Dis 2014; 18: 1315– of patients with MDR-TB. NDA 204-384. Beerse, Belgium: 1318. Janssen Pharmaceutical Co, 2012. http://www.fda.gov/ 33 Dheda K, Shean K, Zumla A, et al. Early treatment outcomes and HIV status of patients with extensively drug-resistant downloads/AdvisoryCommittees/CommitteesMeetingMaterials/ tuberculosis in South Africa: a retrospective cohort study. Drugs/Anti-InfectiveDrugsAdvisoryCommittee/UCM329260. Lancet 2010; 375: 1798–1807. pdf Accessed August 2016. 34 van Heeswijk R P, Dannemann B, Hoetelmans R M. 20 Diacon A H, Pym A, Grobusch M P, et al. Multidrug-resistant Bedaquiline: a review of human pharmacokinetics and drug- tuberculosis and culture conversion with bedaquiline. N Engl J drug interactions. J Antimicrob Chemother 2014; 69: 2310– Med 2014; 371: 723–732. 2318. 21 Williams K, Minkowski A, Amoabeng O, et al. Sterilizing 35 Pandie M, Wiesner L, McIlleron H, et al. Drug-drug activities of novel combinations lacking first- and second-line interactions between bedaquiline and the antiretrovirals drugs in a murine model of tuberculosis. Antimicrob Agents lopinavir/ritonavir and nevirapine in HIV-infected patients Chemother 2012; 56: 3114–3120. with drug-resistant TB. J Antimicrob Chemother 2016; 71: 22 Guglielmetti L, Le Du D, Jachym M, et al. Compassionate use 1037–1040. of bedaquiline for the treatment of multidrug-resistant and 36 World Health Organization. Consolidated guidelines on the use extensively drug-resistant tuberculosis: interim analysis of a of antiretroviral drugs for treating and preventing HIV French cohort. Clin Infect Dis 2015; 60: 188–194. infection: recommendations for a public health approach. 23 Tasneen R, Betoudji F, Tyagi S, et al. Contribution of Geneva, Switzerland: WHO, 2013. oxazolidinones to the efficacy of novel regimens containing 37 Worley M V, Estrada S J. Bedaquiline: a novel antitubercular bedaquiline and pretomanid in a mouse model of tuberculosis. agent for the treatment of multidrug-resistant tuberculosis. Antimicrob Agents Chemother 2015; 60: 270–277. Pharmacotherapy 2014; 34: 1187–1197. 24 Tasneen R, Williams K, Amoabeng O, et al. Contribution of the 38 Anderson N, Borlak J. Drug-induced phospholipidosis. FEBS nitroimidazoles PA-824 and TBA-354 to the activity of novel Lett 2006; 580: 5533–5340. regimens in murine models of tuberculosis. Antimicrob Agents 39 Dhillon J, Andries K, Phillips P P, Mitchison D A. Bactericidal Chemother 2015; 59: 129–135. activity of the diarylquinoline TMC207 against 25 Ndjeka N, Conradie F, Schnippel K, et al. Treatment of drug- Mycobacterium tuberculosis outside and within cells. resistant tuberculosis with bedaquiline in a high HIV Tuberculosis (Edinb) 2010; 90: 301–305. prevalence setting: an interim cohort analysis. Int J Tuberc 40 McLeay S C, Vis P, van Heeswijk R P, Green B. Population Lung Dis 2015; 19: 979–985. pharmacokinetics of bedaquiline (TMC207), a novel 26 Diacon A H, Dawson R, von Groote-Bidlingmaier F, et al. antituberculosis drug. Antimicrob Agents Chemother 2014; Bactericidal activity of pyrazinamide and clofazimine alone and 58: 5315–5324. in combinations with pretomanid and bedaquiline. Am J Respir 41 Andries K, Verhasselt P, Guillemont J, et al. A diarylquinoline Crit Care Med 2015; 191: 943–953. drug active on the ATP synthase of Mycobacterium 27 Reddy V M, Einck L, Andries K, Nacy C A. In vitro interactions tuberculosis. Science 2005; 307: 223–227. between new antitubercular drug candidates SQ109 and 42 Bloemberg G V, Keller P M, Stucki D, et al. Acquired resistance TMC207. Antimicrob Agents Chemother 2010; 54: 2840– to bedaquiline and delamanid in therapy for tuberculosis. N 2846. Engl J Med 2015; 373: 1986–1988. Questions and controversies about BDQ i

RESUME Bien qu’il y ait eu un lent déclin de l’incidence de la spécifiquementelabor´ ´ e pour la TB dont l’utilisation a tuberculose (TB) dans le monde, la prévalence de la TB et´´ e autorisée après près de 40 ans. La BDQ a une activité pharmacorésistante dans la majorité des pays durement stérilisatrice et se montreegalement ´ prometteuse en tant frappés a augmenté. La TB pharmacorésistante est qu’élément de nouveaux protocoles de traitement de associéea ` une mortalitéélevée, menace le personnel de courte durée pour la TB pharmacosensible. Nous santé dans les pays d’endémie de TB et le cout ˆ de sa prise revoyons ici les informationsemanant ´ du terrain en charge est prohibitif, ce qui détourne les ressources concernant l’utilisation de la BDQ, les problèmes posés des cas pharmacosensibles. L’amplification de la aux cliniciens, les implications relativesalas´ ` election du résistance signifie qu’il y a une proportion croissante traitement antirétroviral, les questions de de patients atteints de TB multirésistante qui ont en fait pharmacocinétique relativesa ` la pratique clinique et une TB ultrarésistante (TB-XDR) ou ne peuvent pasetre ˆ les implications en matière de traitement combiné. Etant pris en charge dans le cadre des programmes. Il est donc donnélaprévalence croissante de la résistance, au-delà urgent de disposer de nouvelles options de traitement. La de la TB-XDR, nous discutons de la manière dont on bédaquiline (BDQ) est le premier médicament nouveau peut minimiser la survenue de résistancesa ` la BDQ.

RESUMEN Pese a que ha ocurrido una lenta disminución de la manera espec´ıfica contra la TB en cerca de 40 anos˜ y que incidencia de tuberculosis (TB) en el mundo, se observa cuenta con la autorización de utilización. La BDQ tiene un aumento de la prevalencia de farmacorresistencia en la actividad esterilizante y adema´s aparece prometedora mayor´ıa de los pa´ıses con alta carga de morbilidad. La TB como componente de los nuevos esquemas breves de farmacorresistente se asocia con alta mortalidad, tratamiento de la TB normosensible. En el presente representa un peligro para los profesionales de salud en art´ıculo se analizan perspectivas del terreno sobre la los pa´ıses donde la enfermedad es endémica y acarrea utilización de la BDQ, aspectos que interesan al médico costos extremadamente altos que desv´ıan los recursos tratante, las consecuencias de su uso en la elección del destinados al tratamiento de los casos farmacosensibles. tratamiento antirretrov´ırico, las caracter´ısticas La amplificación de la resistencia significa que en el farmacocinéticas de interés en la praćtica cl´ınica y sus marco del programa una proporción cada vez mayor de consecuencias en la polifarmacoterapia. Al considerar la pacientes con TB multirresistente alberga tipos de TB prevalencia cada vez mayor de espectros de resistencia extremadamente resistente (TB-XDR) o intratables. Por que superan la TB-XDR, se examinan adema´s los esta razon ´ existe una necesidad urgente de nuevas mecanismos que puedan contribuir a disminuir al opciones terapéuticas. La bedaquilina (BDQ) es el m´ınimo la aparición de resistencia a la BDQ. primer medicamento nuevo que se ha desarrollado de