INT J TUBERC LUNG DIS 18(11):1315–1318 Q 2014 The Union http://dx.doi.org/10.5588/ijtld.14.0284

Initial experience of bedaquiline use in a series of drug-resistant tuberculosis patients from India Z. F. Udwadia, R. A. Amale, J. B. Mullerpattan Department of Respiratory Medicine, Medical Research Centre, P D Hinduja National Hospital, Mumbai, India SUMMARY

Drug-resistant tuberculosis (DR-TB) is a major problem both in India and worldwide. Newer drugs such as TMC-207 (bedaquiline) may have an important role to play in making up an effective drug regimen in such cases. There have been a few reports of bedaquiline use in a non-trial setting from Europe. Our series of five patients is the first series of DR-TB patients from India

to receive bedaquiline. All five patients showed striking improvement, with microbiological conversion and an absence of notable adverse effects (e.g., prolonged QTcF), indicating the potential impact of this drug in such a population. K E Y W O R D S : XDR-TB; TMC-207; outcomes

DRUG-RESISTANT TUBERCULOSIS (DR-TB) is a major problem worldwide, and India is the epicentre. An increasing incidence of multidrug-resistant (MDR-TB, defined as TB resistant to at least isoniazid and rifampicin [RMP]) and extensively drug-resistant TB (XDR-TB, defined as MDR-TB plus resistance to any fluoroquinolone and at least one of three injectable second-line drugs, i.e., amikacin, kanamycin [KM] or capreomycin [CPM]) limits the options of effective drugs available to make up an optimal regimen.1 The rate of successful treatment of MDR-TB is approximately 50–60% and that of XDR-TB even lower, at about 40%.2 The low treatment success rates are partly attributable to the lengthy, toxic and expensive treatment for DRTB. For DR-TB, and especially XDR-TB, it is essential to find more drug options to create an effective regimen. Newer drugs such as TMC-207 (bedaquiline) could have an important role to play in this. Bedaquiline is the first new anti-tuberculosis drug to receive US Food & Drug Administration approval in almost 40 years, since RMP.3 Bedaquiline belongs to the diarylquinoline class of drugs and acts by inhibiting mycobacterial adenosine diphosphate synthase.4 Its unique mechanism of action results in no cross-resistance with any of the other classes of drugs. Phase 1, 2 and 2b trials have demonstrated the efficacy and safety of bedaquiline in MDR-TB, with Phase 3 results still awaited.5 In its interim policy document on bedaquiline,6 the World Health Orga-

nization (WHO) has recommended that the drug not be used for more than 24 weeks at a dose of 400 mg daily for 2 weeks, followed by 200 mg thrice weekly for the remaining 22 weeks. According to the interim US Centers for Disease Control and Prevention (CDC) guidelines, bedaquiline may be used with caution in children and in persons living with human immunodeficiency virus (HIV) infection, and extended beyond 24 weeks provided the benefit of using the drug outweighs the risk.7

METHODS There have been some reports from Europe on the compassionate use of bedaquiline outside the setting of a clinical trial.8,9 However, there have been no such reports from India, and we present the first series of five patients who received bedaquiline on a compassionate basis (Table 1) from Hinduja Hospital, a tertiary referral institute in Mumbai, India, with an accredited Level II mycobacteriology laboratory. Bedaquiline was procured from Janssen Therapeutics (Beerse, Belgium) if the patient satisfied the following criteria: 1) an optimum background regimen; 2) age .18 years; 3) normal baseline Fridericia-corrected QT interval (QTcF); c) normal liver and renal parameters, amylase, lipase; and 5) known HIV status. QTcF intervals were monitored weekly for 1 month and then monthly for the next 5 months (Table 1). Written informed consent was provided by all of the patients before initiating treatment with bedaqui-

Correspondence to: Jai Mullerpattan, Department of Respiratory Medicine, Medical Research Centre, P D Hinduja National Hospital, Veer Savarkar Marg, Mahim, Mumbai 400 016, India. Tel: (þ91) 22 2444 7353. Fax: (þ91) 22 2445 9151. e-mail: [email protected] Article submitted 8 April 2014. Final version accepted 19 June 2014.

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Table 1

The International Journal of Tuberculosis and Lung Disease

Serial QTcF intervals of patients Patient No.

QTcF interval, msec Baseline 1 week 2 weeks 3 weeks 4 weeks 2 months 3 months 4 months 5 months 6 months

1

2

3

4

5

400 410 404 390 396 390 400 410 404 410

410 414 420 414 416 410 420 414 420 418

380 360 376 390 400 404 390 386 400 410

360 380 400 420 400 412 390 380 400 410

380 400 420 410 420 416 420 410 400 390

QTcF ¼ Fridericia-corrected QT interval.

line. Ethics committee approval was not required, as this was not a prospective study but data collection among patients on salvage treatment.

CASE REPORT Our first patient was a 40-year-old HIV-positive patient on antiretroviral treatment with XDR-TB along with resistance to ethionamide (ETH), paraaminosalicylic acid (PAS) and all second-line injectables. He had undergone left pneumonectomy for TB, and while on second-line salvage regimen had developed a new cavity in the right upper lobe. Bedaquiline was requested and procured on a compassionate basis and given for 24 weeks, along with a background regimen of CPM, clofazimine (CFZ), cycloserine (CS), linezolid, rifabutin, thioridazine and amoxicillin-clavulanate. He showed marked radiological and clinical improvement, with microbiological conversion. The second patient was a 25-year-old male MDRTB patient with resistance to ethambutol (EMB), pyrazinamide (PZA), ETH and fluoroquinolones. His sputum grew Mycobacterium tuberculosis complex despite a year of second-line treatment. Bedaquiline was requested and added to a background regimen of CPM, CFZ, CS, PAS, linezolid and moxifloxacin (MFX). At 6 months, there was considerable radiological regression and clinical improvement, along with weight gain as well as sputum culture conversion. The third patient was a 22-year-old male who was not responding to 2 years of anti-tuberculosis treatment. Drug susceptibility testing (DST) showed an XDR-TB pattern with additional resistance to ETH and all second-line injectables. He was started on a background regimen of CPM, CFZ, CS, PAS, linezolid and MFX in addition to bedaquiline. At the end of 6 months, there was clinical improvement, with a weight gain of 6 kg and sputum culture conversion. The fourth patient was an 18-year-old female with an XDR-TB strain on treatment with second-line drugs for 4 months with poor response. She was put on bedaquiline along with a background regimen of KM,

ETH, CFZ, CS, linezolid and thioridazine. At 6 months, there was a weight gain of 8 kg, with radiological clearance and microbiological conversion. The fifth patient was a 29-year-old diabetic who had failed treatment despite 8 months of first-line treatment. Sputum TB culture showed an MDR-TB strain with additional resistance to EMB, ETH, PZA, SM and fluoroquinolones. He underwent a right upper lobectomy, followed by a left upper lobectomy a year later due to the development of a new cavity in the left upper lobe. He was put on bedaquiline accompanying an optimised salvage regimen comprising CPM, linezolid, PAS, amoxicillin-clavulanate, CS and CFZ. The patient showed excellent response to this combination and gained 13 kg, with negative sputum culture at 6 months. All five patients were on individualised optimal background regimens based on their DST results, with bedaquiline added to these regimens upon procurement. Drugs in the background regimen were prescribed in standard doses. The dose of bedaquiline was 400 mg daily for 2 weeks, followed by 200 mg thrice weekly for 22 weeks. Every patient received 180 doses of bedaquiline. There was no intolerance attributable to bedaquiline. Our patients showed sputum culture conversion at about 3 months, which was sustained even after stopping bedaquiline. All five patients showed good clinical, radiological and microbiological response to bedaquiline when prescribed in addition to a background MDR/XDR-TB regimen. All five patients are doing well at follow-up and remain culture-negative 3 months after stopping bedaquiline. Their background regimens continued unchanged. Despite concomitant use of CFZ in the background regimen in all five patients and MFX in two patients, no QTc prolongation was observed (Table 2).

DISCUSSION This series shows that bedaquiline is a useful addition to a multidrug anti-tuberculosis regimen, particularly for patients who have run out of all other drug options. Our series is limited in not having a control

180 None

CPM, CFZ, CS, PAS, LZD, MFX

AFB smear and M. tuberculosis culturepositive No

Susceptible to: MFX, KM, AMK, CPM, PAS, CFZ

180 None

CPM, LZD, MFX, CFZ, CS, PAS

AFB smear and M. tuberculosis culturepositive No

Resistance to: INH, RMP, EMB, PZA, SM, OFX, ETH, KM, AMK Susceptible to: MFX, PAS, CFZ, CPM

4 drugs (INH, RMP, PZA, EMB)

180 None

KM, CFZ, ETH, LZD, CS, thioridazine

AFB smear and M. tuberculosis culturepositive No

9 drugs (INH, RMP, PZA, EMB, KM, CFZ, ETH, CS, LZD, MFX) Resistance to: INH, RMP, EMB, PZA, SM, PAS, AMK, OFX, MFX Susceptible to: KM, CPM, ETH, CFZ

18/female None 4

4

All patients showed significant improvement in symptoms such as cough, fever and loss of appetite Increased by 3 Increased by 4 Increased by 6 Increased by 8 Sputum smear and culture Sputum smear and culture Sputum smear and culture Sputum smear and culture conversion at month 3 conversion at month 3 conversion at month 3 conversion at month 3 Significant improvement Significant improvement Significant improvement Significant improvement

CPM, RBT, CFZ, CS, AMXþCLV, LZD, thioridazine 180 None

AFB smear and M. tuberculosis culturepositive Left lung resection

Resistance to: INH, RMP, EMB, PZA, SM, OFX, MFX, KM, AMK, ETH, PAS Susceptible to: CPM, CFZ

13 drugs (INH, RMP, PZA, EMB, SM, PAS, LVX, KM, CFZ, CS, MFX, CLM, LZD) Resistance to: INH, RMP, EMB, PZA, SM, ETH, OFX

5 drugs (INH, RMP, PZA, EMB, KM)

22/male None 27

3

Increased by 13 Sputum smear and culture conversion at month 3 No new lesions

180 None

AFB smear and M. tuberculosis culturepositive Right upper, middle and left upper lobectomy CPM, LZD, CS, CFZ, PAS, AMXþCLV

11 (INH, RMP, PZA, EMB, CPM, LZD, CS, CFZ, PAS, CLM, AMXþCLV Resistance to: INH, RMP, EMB, PZA, SM, ETH, OFX, MFX Susceptible to: KM, AMK, CPM, PAS, CFZ

29/male Diabetes 8

5

DR-TB ¼ drug-resistant tuberculosis; HIV ¼ human immunodeficiency virus; INH ¼ isoniazid; RMP ¼ rifampicin; PZA ¼ pyrazinamide; EMB ¼ ethambutol; KM ¼ kanamycin; SM ¼ streptomycin; PAS ¼ para-aminosalicylic acid; LVX ¼ levofloxacin; CFZ ¼ clofazimine; CS ¼ cycloserine; MFX ¼ moxifloxacin; CLM ¼ clarithromycin; LZD ¼ linezolid; AMXþCLV ¼ amoxicillin þ clavulanate; OFX ¼ ofloxacin; AMK ¼ amikacin; CPM ¼ capreomycin; ETH ¼ ethionamide; BAL ¼ broncheoalveolar lavage; AFB ¼ acid-fast bacilli; RBT ¼ rifabutin; TB ¼ tuberculosis; CXR ¼ chest X-ray.

CXR

Response to bedaquiline Symptoms Change in weight (kg) Sputum

Bedaquiline exposure, days Adverse events due to bedaquiline use

Background regimen used along with bedaquiline

Surgery for DR-TB

All patients tested for susceptibility to INH, RMP, EMB, PZA, SM, OFX, MFX, KM, AMK, CPM, ETH, PAS and CFZ before applying for bedaquiline Sputum/BAL status before starting bedaquiline

Type of drug resistance

25/male None 12

2

38/male HIV-positive 40

1

Details and outcomes of patients with DR-TB who received bedaquiline

Age/sex Associated comorbidity Duration of treatment before diagnosis of DR-TB, months Drugs used before introduction of bedaquiline

Patient No.

Table 2

Bedaquiline in Indian DR-TB patients

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arm; however, historical controls with profiles similar to those of our patients have fared poorly, suggesting that the addition of an effective drug such as bedaquiline contributes to positive outcomes because it strengthens the MDR-TB regimen, allowing an optimal number of drugs to be used.10 Our initial encouraging results support the current WHO and CDC recommendations to use bedaquiline in XDR-TB patients with limited drug options. We would, however, like to point out that it is essential to have an optimal background drug regimen in place to enhance the success of the regimen. Bedaquiline should be prescribed only in centres with experience and expertise in managing complex DR-TB cases so as to prevent indiscriminate use and potential development of bedaquiline resistance. We found the drug to be well tolerated when carefully monitored despite co-administration of CFZ (all five patients) and MFX (patients 2 and 3). Whilst QTc was carefully and serially monitored, no patient showed QTc prolongation. Overall, this series highlights that this new drug has the potential to improve outcomes in Indian patients with XDR-TB and that it is safe and well tolerated. Conflict of interest: none declared.

References 1 Udwadia Z F, Amale R A, Ajbani K K, Rodrigues C S. Totally drug-resistant tuberculosis in India. Clin Infect Dis 2012; 54: 579–581.

2 Migliori G B, Sotgiu G, Gandhi N R, et al. Drug resistance beyond extensively drug-resistant tuberculosis: individual patient data meta-analysis. Eur Respir J 2013; 42: 169–179. 3 Food and Drug Administration. FDA approves first drug to treat multidrug-resistant tuberculosis [Press release]. Silver Spring, MD, USA: FDA, 31 December 2012. 4 Matteelli A, Carvalho A C C, Dooley K E, Kritski A. TMC207: the first compound of a new class of potent anti-tuberculosis drugs. Future Microbiol 2010; 5: 849–858. 5 Janssen Pharmaceuticals. TMC207 (bedaquiline) treatment of patients with MDR-TB (NDA 204–384). Briefing document to the Anti-Infective Drugs Advisory Committee Meeting, 28 November 2012. Beerse, Belgium: Janssen Pharmaceuticals, 2012. 6 World Health Organization. The use of bedaquiline in the treatment of multidrug-resistant tuberculosis. Interim policy guidance. WHO/HTM/TB/2013.6. Geneva, Switzerland: WHO, 2013. 7 Division of Tuberculosis Elimination, National Center for HIV/ AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention. Provisional CDC Guidelines for the use and safety monitoring of bedaquiline fumarate (Sirturo) for the treatment of multidrug-resistant tuberculosis. MMWR 2013; 62 (RR-09): 1–12. 8 Tiberi S, de Lorenzo S, Centis R, Viggiani P, D’Ambrosio L, Migliori G B. Bedaquiline in MDR/XDR-TB cases: first experience on compassionate use. Eur Respir J 2014; 43: 289–292. 9 van Halsema C, Humphreys S, Bonington A. Extensively drugresistant tuberculosis: early access to bedaquiline for a UK patient. Eur Respir J 2014; 43: 292–294. 10 Ahuja S D, Ashkin D, Avendano M, et al. Multidrug-resistant pulmonary tuberculosis treatment regimens and patient outcomes: an individual patient data meta-analysis of 9153 patients. PLOS MED 2012; 9: e1001300.

Bedaquiline in Indian DR-TB patients

i

RESUME

La tuberculose pharmacor´esistante (TB-DR) est un probl`eme majeur dans le monde et notamment en Inde. Des m´edicaments plus r´ecents comme la TMC-207 (bedaquiline) pourraient jouer un role ˆ important dans la constitution d’un protocole th´erapeutique efficace dans de tels cas. Il y a eu quelques rapports de l’utilisation de la bedaquiline hors du cadre d’un essai clinique en Europe. Notre s´erie de cinq patients est la premi`ere s´erie

de patients indiens atteints de TB-DR a` recevoir de la bedaquiline. Tous les cinq patients ont eu une am e´ lioration impressionnante couple´ e a` une conversion microbiologique ainsi qu’une absence d’effets secondaires notables (par exemple un allongement de QTcF), ce qui de´ montre l’impact potentiel de ce m´edicament dans une telle population.

RESUMEN

La tuberculosis farmacorresistente (TB-DR) representa un grave problema en todo el mundo y tambi´en en la India. Los nuevos medicamentos como la TMC-207 (bedaquilina) pueden desempe nar una funci on ´ ˜ importante en la formulaci on ´ de un re´ gimen terape´ utico eficaz en estos casos. Existen pocos informes sobre el uso de la bedaquilina en contextos diferentes de los estudios cl´ınicos en Europa. La presente

serie de cinco pacientes constituye la primera serie de pacientes con TB-DR que reciben bedaquilina en la India. Todos los pacientes presentaron una mejor´ıa cl´ınica considerable, adema´ s de la conversi on ´ bacteriologica ´ y la ausencia de reacciones adversas notables (por ejemplo, la prolongacion ´ del intervalo QTcF), con lo cual se destaca el posible efecto de este medicamento en poblaciones semejantes a la del estudio.

Initial experience of bedaquiline use in a series of drug-resistant tuberculosis patients from India.

Drug-resistant tuberculosis (DR-TB) is a major problem both in India and worldwide. Newer drugs such as TMC-207 (bedaquiline) may have an important ro...
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