Efficacy and Safety of Bedaquiline and Delamanid in the Treatment of Tuberculosis: a Focus on Multidrug-resistant Tuberculosis

124 ISSN 0377-9556 (PRINT) ISSN 2383-9457 (ONLINE)

약학회지 제 61 권 제 2 호 124~134 (2017) Yakhak Hoeji Vol. 61, No. 2

DOI 10.17480/psk.2017.61.2.124

Efficacy and Safety of Bedaquiline and Delamanid in the Treatment of Tuberculosis: a Focus on Multidrug-resistant Tuberculosis

Young-Mo Yang and Eun Joo Choi

Department of Pharmacy, College of Pharmacy, Chosun University, Gwangju, Korea (Received March 17, 2017; Revised April 5, 2017; Accepted April 6, 2017)

Abstract — The emergence of multi-drug resistant tuberculosis (MDR-TB) poses a major difficulty in controlling TB worldwide. More potent TB drugs, higher cost, and longer duration of treatment are necessary for MDR-TB compared with drug-sensitive TB. However, currently available TB drugs have been used for more than 40 years. Therefore, a novel anti- TB drug is required for the treatment of MDR-TB. This study was aimed at assessing the efficacy and safety of bedaquiline and delamanid and determining the therapeutic validity of them in controlling MDR-TB. A literature search of original stud- ies published in PubMed, MEDLINE, and Scopus until August 2015 was conducted using the terms ‘bedaquiline OR dela- manid’ AND ‘efficacy OR safety’ AND ‘tuberculosis’ to identify the clinical trials regarding bedaquiline or delamanid in TB.

Six and four clinical studies regarding bedaquiline and delamanid, respectively, were examined in this review. The treatment durations of bedaquiline and delamanid in the selected studies were from 2 weeks to 32 weeks. The higher falls in log

colony forming units (CFU)/mL during the treatment period were observed in the regimens including bedaquiline than in the standard anti-TB regimen. The median time to sputum-culture conversion (TTC) of the bedaquiline group was shorter than that of the placebo group. The sputum-culture conversion rate of the delamanid group was higher than that of the pla- cebo group. In the included studies, serious adverse effects were not reported due to bedaquiline or delamanid. However, their uses were more highly associated with potential QT-interval prolongation. The clinical trials suggest that the uses of bedaquiline or delamanid with other anti-TB medications were at least efficacious and safe in the treatment of MDR-TB at this point.

Keywords multidrug-resistant tuberculosis, MDR-TB, bedaquiline, delamanid, efficacy, safety

With 9 million cases and 1.5 million deaths in 2013, tubercu- losis (TB), caused by infection with Mycobacterium tuberculo- sis, is second only to the human immunodeficiency virus (HIV) in its lethal impact on humans.

The emergence of multidrug- resistant TB (MDR-TB), defined as TB with resistance to at least two first-line anti-TB drugs isoniazid and rifampicin, poses a major difficulty in controlling TB worldwide.

In 2013, approximately 480,000 new cases of MDR-TB were reported, and nearly 210,000 MDR-TB patients died.

However, only about 97,000 MDR-TB patients received treatment in 2013.

Although MDR-TB incidence rate remained stable worldwide from 2008 to 2013, serious MDR-TB epidemics threaten prog- ress in some countries, including India and China.

Prolonged administration of a combination of TB drugs is required to cure TB. More potent and more expensive TB drugs and longer treatment duration are necessary to cure MDR-TB compared to drug-sensitive TB.

Previous studies reported that the success rate of MDR-TB treatment was nearly 65% world- wide.

Studies conducted in Korea demonstrated that the treatment success rate varied from 37.1% to 66.0%.

How- ever, currently available TB drugs have been used for over 40 years.

Therefore, novel anti-TB drugs are required for MDR- TB treatment and should have the following characteristics: new mechanism of action, good efficacy and safety, and a suitable pharmacokinetic profile and bioavailability.

In December 2012, the US Food and Drug Administration (FDA) approved bedaquiline, belonging to a new class of TB

#

Corresponding Author Eun Joo Choi

Department of Pharmacy, College of Pharmacy, Chosun Univer- sity, 309 Pilmun-daero, Dong-gu, Gwangju 61452, Korea

Tel.: 062-230-6382 Fax.: 062-222-5414 E-mail: [email protected]

Short Report

agents called diarylquinolines, for MDR-TB treatment.

Bedaquiline blocks mycobacterial ATP synthase, an enzyme needed for energy production in M. tuberculosis.

Together with at least 3 anti-TB drugs, 400 mg bedaquiline is initially administered orally once daily for 2 weeks followed by admin- istration of 200 mg 3 times a week for 22 weeks.

Another MDR-TB drug approved in both the European Union (EU) and Japan is delamanid, a dihydro-nitroimidazole.

Delamanid inhib- its the synthesis of methoxy-mycolic and keto-mycolic acids that constitute the mycobacterial cell wall.

In combination with an optimized MDR-TB regimen, 100 mg delamanid is adminis- tered orally twice daily for 24 weeks and then, the optimized regimen is continued after delamanid’s administration period.

This study was aimed at assessing the efficacy and safety of bedaquiline and delamanid in the treatment of MDR-TB patients by reviewing clinical studies. Additionally, we sought to determine the therapeutic validity of bedaquiline and dela- manid in controlling MDR-TB.

Methods

A literature search was performed to identify clinical trials in

which the efficacy and/or safety of bedaquiline and delamanid were evaluated in TB patients. PubMed, MEDLINE, and Sco- pus were utilized to select clinical trials written only in English with the following search terms: (bedaquiline OR delamanid) AND (efficacy OR safety) AND tuberculosis. The search was restricted to peer-reviewed journals published until August 2015. The reference lists of the selected articles and relevant reviews were also used to search for additional articles.

Two reviewers independently scanned article titles and abstracts and identified relevant articles that could satisfy the following inclusion criteria: 1) a prospective or retrospective trial; 2) inclusion of TB patients; and 3) bedaquiline or dela- manid used to treat TB. Consensus was achieved by discus- sion between the two reviewers when any disagreement occurred regarding the inclusion of an article for evaluation.

Abstracts, conference proceedings, and unpublished articles were not considered because their results may not have been finalized yet.

Results

Through the literature search (Fig. 1), 6 and 4 clinical trials

Fig. 1 − Flowchart of the study selection process.

126 Yo ung -Mo Ya ng a n d Eun Joo Choi

J. Pharm . Soc. K ore a

Table I − Study methods of the selected clinical trials of bedaquiline in the treatment for TB Trial Study

design Intervention No. of patients (n) Treatment

duration (wks) Mean or median age (yrs) Mean fall in log

CFU/mL/day (95% CI or SD) Diacon

et al.

(2015)

P BED+PRE+PYR+CLO: (BED 400 mg on day 1, 300 mg on day 2, 200 mg on day 3-14) + PRE 200 mg + PYR 1,500 mg + (CLO 300 mg on day 1- 3, 100 mg on day 4-14); BED+PRE+PYR: (BED 400 mg on day 1, 300 mg on day 2, 200 mg on day 3-14) + PRE 200 mg + PYR 1,500 mg;

BED+PRE+CLO: (BED 400 mg on day 1, 300 mg on day 2, 200 mg on day 3-14) + PRE 200 mg + (CLO 300 mg on day 1-3, 100 mg on day 4-14);

BED+PYR+CLO: (BED 400 mg on day 1, 300 mg on day 2, 200 mg on day 3-14) + PYR 1,500 mg + (CLO 300 mg on day 1-3, 100 mg on day 4-14);

PYR: PYR 1,500 mg; CLO: CLO 300 mg on day 1-3, 100 mg on day 4-14

BED+PRE+PYR +CLO: 15;

BED+PRE+PYR : 15;

BED+PRE+CL O: 15;

BED+PYR+CL O: 15; PYR: 15;

CLO: 15; Rifa- four: 15

2 BED+PRE+PYR+CLO: 35.5 (8.74); BED+PRE+PYR: 33.4 (14.22); BED+PRE+CLO: 33.3 (11.15); BED+PYR+CLO: 30.9 (13.12); PYR: 32.4 (11.44); CLO:

28.4 (8.77); Rifafour: 34.3 (10.25)

BED+PRE+PYR+CLO: 0.115 (0.039-0.189); BED+PRE+PYR: 0.167 (0.075 – 0.257); BED+PRE+CLO: 0.076 (0.005 – 0.145); BED+PYR+CLO: 0.124 (0.035 – 0.214); PYR: 0.036 (-0.026 – 0.099); CLO: -0.017 (-0.085 – 0.053);

Rifafour: 0.151 (0.071 – 0.232)

Diacon et al.

(2014)

P BED: (BED 400 mg QD for 2 wks followed by BED 200 mg TIW for 22 wks + BR for 24 wks) → ^BR only for 96 wks; Placebo: (placebo + BR) for 24 wks → BR only for 96 wks

BED: 79;

Placebo: 81

24 BED: 32 (18–63); Placebo: 34 (18–57)

BED: N/A; Placebo: N/A

Diacon et al.

(2013)

P BED 100 mg: 200 mg on day 1, 100 mg on day 2, 100 mg on day 3-14; BED 200 mg: 400 mg on day 1, 300 mg on day 2, 200 mg day 3-14; BED 300 mg:

500 mg on day 1, 400 mg on day 2, 300 mg on day 3- 14; BED 400 mg: 700 mg on day 1, 500 mg on day 2, 400 mg on day 3-14

BED 100 mg: 15;

BED 200 mg: 15;

BED 300 mg: 15;

BED 400 mg: 15;

Rifafour: 8

2 BED 100 mg: 29.5 (9.4); BED 200 mg: 34.7 (18.1); BED 300 mg: 31.4 (7.4); BED 400 mg:

31.8 (10.9); Rifafour: 26.1 (4.9)

BED 100 mg: 0.040 (0.068); BED 200 mg: 0.056 (0.051); BED 300 mg: 0.077 (0.064); BED 400 mg: 0.104 (0.077);

Rifafour: 0.112 (0.077)

Diacon et al.

(2012)

P BED: (BED 700 mg on day 1, 500 mg on day 2, 400 mg QD) + PYR placebo; BED+PA-824: (BED given in doses as in BED alone group) + PA-824 200 mg QD; BED+PYR: (BED given in doses as in BED alone group) + PYR 25 mg/kg QD; PA- 824+PYR: PA-824 200 mg QD + PYR 25 mg/kg QD; PA-824+MOX+PYR: PA-824 200 mg QD, MOX 400 mg QD, PYR 25 mg/kg QD

BED: 15;

BED+PA-824:

15; BED+PYR:

15; PA-824+PYR:

15; PA-

824+MOX+PYR:

15; Rifafour: 10

2 BED: 31.27 (11.60); BED+PA- 824: 33.33 (8.47); BED+PYR:

29.13 (8.67); PA-824+PYR:

29.73 (8.93); PA-

824+MOX+PYR: 28.33 (9.34);

Rifafour: 27.00 (6.63)

BED: 0.061 (0.068); BED+PA-824: 0.114 (0.050); BED+PYR: 0.131 (0.102);

PA-824+PYR: 0.154 (0.040); PA- 824+MOX+PYR: 0.233 (0.128);

Rifafour: 0.140 (0.094)

Diacon et al.

(2009)

P BED: BED 400 mg QD for 2 wks followed by BED 200 mg TIW for 6 wks + BR for 8 wks; Placebo:

(placebo + BR) for 8 wks

BED: 23;

Placebo: 24

8 BED: 33 (18–57), Placebo: 33 (19–57)

BED: N/A; Placebo: N/A

Diacon et al.

(2012)

P BED: (BED 400 mg QD for 2 wks followed by BED 200 mg TIW for 6 wks + BR for 8 wks) → ^{BR only} for 96 wks; Placebo: (placebo + BR) for 8 wks → BR only for 96 wks

BED: 23;

Placebo: 24

8 BED: 33 (18–57 ), Placebo: 33 (19–57)

BED: N/A; Placebo: N/A

Notes: Ages are mean (SD) or median (range); Rifafour is a fixed-dose combination of ISO (75 mg), RIF (150 mg), PYR (400 mg), and ETH (275 mg).

Abbreviations: BR, background regimen; P, prospective; QD, every day; TIW, three times a week; wk, week; yr, year; BED, bedaquiline; ISO, isoniazid; RIF, rifampicin; PRE,

pretomanid; PYR, pyrazinamide; ETH, ethambutol; MOX, moxifloxacin; N/A, not available.

investigating bedaquiline and delamanid, respectively and meeting the predefined criteria were identified. The methods of the selected trials are presented in Tables I and II.

Efficacy and safety of bedaquiline

A total of 105 pulmonary TB patients were enrolled in the two-centre, open-label, randomized clinical trial conducted by Diacon et al. (2015) in South Africa.

The patients received 7 different anti-tubercular drug regimens for 2 weeks (Table I).

The primary efficacy endpoint was the early bactericidal activ- ity (EBA) expressed as the rate of change in log

colony form- ing units (CFU)/mL during the 14-day treatment period. Its secondary endpoint was the EBA assessed as the change in time to a positive signal (TTP) in the liquid medium. The highest mean change in log

CFU/mL after 14 days (0.167;

95% confidence interval [CI], 0.075–0.257) was observed for the combination of bedaquiline, pretomanid, and pyrazinamide as compared to the values observed following the standard anti-TB treatment with Rifafour (0.151; 95% CI, 0.071–0.232).

The highest mean daily percentage TTP change after 14 days (7.0%; 95% CI, 5.1%–9.4%) was also observed for the same drug combination compared to the same parameter measured after the treatment with Rifafour (6.3%; 95% CI, 4.8%–7.6%).

Five patients were withdrawn from the trial (1, adverse event; 1, non-compliance; 1, patient request; and 2, consent with- drawal). Adverse events occurred in 65 patients (61.9%). How- ever, they were treatment-related only in 29 patients (27.6%).

More adverse events were observed in patients receiving a combination therapy involving bedaquiline than in those receiv- ing a single-drug therapy (diarrhoea, 3 vs. 1; first-degree AV block, 3 vs. 1; prolonged QT interval, 8 vs. 0).

Another randomized, double-blind, placebo-controlled trial conducted in multiple countries enrolled 160 MDR-TB patients.

The primary endpoint was the time to sputum cul- ture conversion (TTC). It was defined as ≥ 2 consecutive neg- ative sputum cultures; however, samples were obtained ≥ ²⁵ days apart. The secondary endpoint was the culture conver- sion rate after 24 and 120 weeks. The median TTC of the bedaquiline group (83 days) was shorter than that of the pla- cebo group (125 days) and the hazard ratio for the conversion in the bedaquiline group was 2.44 (95% CI 1.57 – 3.80; P <

0.001). Confirmed culture conversion occurred at a higher rate in the bedaquiline group than in the placebo group at 24 weeks (79% vs. 58%; P = 0.008) and at 120 weeks (62% vs. 44%; P

= 0.04). During 120 weeks, the rates of adverse events were similar in both groups. The most frequent adverse events were nausea, arthralgia, and vomiting. The majority of these had grade 1 or 2 severity. Ten patients out of 79 in the bedaquiline group died during the trial (13%) and there were 2 deaths among 81 patients (2%) in the placebo group. How- ever, the investigators concluded that none of these deaths was specifically associated with the used drug (bedaquiline).

The mean change of QTcF (QT interval corrected by Frideri- cia’s formula) values from baseline parameters at 24 weeks was higher in the bedaquiline group than in the placebo group (15.4 ms vs. 3.3 ms; P < 0.001); however, after bedaquiline was discontinued, the mean QTcF values of both groups were similar by 60 weeks. QTcF prolongation exceeding 500 ms at any time occurred in only 1 patient in the bedaquiline group.

In the prospective, double-blinded, randomized clinical trial enrolling 68 pulmonary TB patients in South Africa, EBA and safety of bedaquiline administered in different doses were eval- uated (100 mg, 200 mg, 300 mg, and 400 mg).

Mean changes (±SD) in log

CFU/mL values for 14 days were 0.040 (0.068), 0.056 (0.051), 0.077 (0.064), 0.104 (0.077), and 0.112 (0.077) in the 100-mg, 200-mg, 300-mg, 400-mg bedaquiline groups, and the Rifafour group, respectively. EBA

changes were posi- tively proportional to the bedaquiline dose (P = 0.001). During the 14-day treatment period, the EBA

in the 400-mg dose group of bedaquiline was significantly greater than that in the 100-mg dose group (P = 0.014). The mean EBA

(±SD) for 14 days was 4.0 h (5.1), 4.2 h (3.1), 4.9 h (5.1), 5.4 h (3.4), and 14.3 h (11.4) in the 100-mg, 200-mg, 300-mg, 400-mg bedaquiline groups and Rifafour group, respectively. However, we did not find statistically significant differences between groups ( P = 0.831).

Mild to moderate adverse events, such as skin abnormalities, headache, nausea, or vomiting occurred in 8 patients (13.3%) on bedaquiline and in 2 patients (25%) on Rifafour. Only one severe adverse event, namely the increase in aspartate amino- transferase (AST) from 78 U/L to 125 U/L, occurred in a patient who received 100-mg bedaquiline treatment. No patient had changes in the QTcF or QTcB (QT interval corrected by Bazett’s formula) values of more than 60 ms. In addition, pro- longation of QTcF and QTcB intervals never exceeded 500 ms at any time.

A total of 85 pulmonary TB patients with were enrolled in

the prospective, randomized clinical trial conducted in South

Africa.

The patients received various anti-TB drug regimens

128 Young-Mo Yang and Eun Joo Choi

Vol. 61, No. 2, 2017

presented in Table I. The mean changes (±SD) in log

CFU/

mL values after 14 days were 0.061 (0.068), 0.131 (0.102), 0.114 (0.050), 0.154 (0.040), 0.233 (0.128), and 0.140 (0.094) in the bedaquiline, bedaquiline-pyrazinamide, bedaquiline-PA-824, PA-824-pyrazinamide, PA-824-moxifloxacin-pyrazinamide, and Rifafour groups, respectively. The EBA

change after 14-day PA-824-moxifloxacin-pyrazinamide treatment was significantly higher than similar parameters in bedaquiline, bedaquiline-pyr- azinamide, and bedaquiline-PA-824 groups. The mean EBA

(±SD) values after 14 days were 5.414 h (3.523), 9.970 h (6.987), 5.855 h (2.785), 8.805 h (3.468), 18.482 h (22.582), and 11.841 h (3.932) in the bedaquiline, bedaquiline-pyrazinamide, bedaquiline-PA-824, PA-824-pyrazinamide, PA-824-moxifloxa- cin-pyrazinamide, and Rifafour groups, respectively. Most adverse events were mild and not directly associated with the drugs used during the study. The following adverse events occurred in the patients whose regimens included bedaquiline:

gastrointestinal (GI) disorders (2 cases), headache (2 cases), hyperthermia (1 case), lenticular opacity (1 case), increased lev- els of ALT, AST (3 cases), and serum amylase (1 case). One patient who received PA-824-moxifloxacin-pyrazinamide treat- ment was withdrawn due to the increase of QTcF and QTcB val- ues over 60 ms from baseline values on day 5.

Forty-seven MDR-TB patients were randomized to either a bedaquiline or a placebo group in the clinical trial.

The pri- mary efficacy endpoint was the conversion of sputum cultures from positive to negative, which was defined as ≥ 2 consecu- tive negative cultures at weekly intervals. The secondary end- point was the change from baseline in the log

CFU count.

Compared to placebo, adding bedaquiline to a standard regi- men for MDR-TB helped to achieve TTC more quickly (haz- ard ratio [HR], 11.8; 95% CI, 2.3 – 61.3; P = 0.003). During the 8-week treatment period, the median log

CFU count in the bedaquiline group decreased at a faster rate than that in the placebo group. The percentage of negative smears at 8 weeks was higher in the bedaquiline group than in the pla- cebo group (84% vs. 68%). Most adverse events (such as nau- sea, unilateral deafness, arthralgia, hemoptysis, hyperuricemia, pain in the extremities, rash, and chest pain) occurred in both groups and were mild or moderate. Significantly more patients in the bedaquiline group had nausea than those in the placebo group (26% vs. 4%; P = 0.04). Mean QTcF values after 8 weeks were nominally higher in patients from the bedaquiline group than in the placebo group, but the effect did not reach

statistical significance ( P > 0.05). Differences in this parame- ter between the two groups ranged from 1.0 ms to 10.8 ms.

QTcF values never exceeded 500 ms at any time.

This study was the 2-year follow-up of the results from a randomized, placebo-controlled clinical trial, which enrolled 47 MDR-TB patients.

The addition of bedaquiline to the stan- dard therapy for MDR-TB significantly reduced TTC over the first 24 weeks as compared with TTC values in the placebo group (HR, 2.253; 95% CI, 1.08 – 4.71; P = 0.031). The period to 50% sputum-culture conversion was shorter in the bedaquiline group than in the placebo group (78 days vs. 129 days) and the percentage of negative cultures at 24 weeks was higher in the bedaquiline group than in the placebo group (81.0% vs. 65.2%).

After 104 weeks, the treatment success rates in the bedaquiline and placebo groups were 52.4% and 47.8%, respectively. The adverse events described in that study were similar to those presented in the previous report.

Efficacy and safety of delamanid

A multicentre, double-blind, randomized, placebo-controlled trial was conducted in multiple countries.

During an 8-week treatment period, 481 MDR-TB patients were assigned to one of the three groups presented in Table II. The primary effi- cacy endpoint was the sputum-culture conversion defined as ≥ 5 consecutive negative weekly cultures followed by the absence of subsequently confirmed positive cultures. During the 8-week intervention period, the sputum-culture conver- sion rate in patients receiving 100 mg delamanid twice daily was significantly higher than that in the placebo group patients (45.4% vs. 29.6%; P = 0.008). The sputum-culture conversion rate in patients receiving 200 mg delamanid was similar to that of patients in the 100-mg delamanid group but significantly higher than the conversion rate in placebo-treated patients (41.9% vs. 29.6%; P = 0.04). Overall, more adverse events occurred in the 200-mg delamanid group than in the 100-mg delamanid group. However, the frequency was similar to that in the placebo group. Additionally, prolongation of the QT interval was observed more frequently in the 200-mg dela- manid group (13.1%) than in the 100-mg delamanid group (9.9%). The occurrence rate of prolonged QT interval was sig- nificantly higher in drug treatment groups than in the placebo group (13.1% vs. 3.8%, P = 0.005 for 200-mg delamanid; 9.9%

vs. 3.8%, P = 0.048 for 100-mg delamanid).

This study was the 2-year follow-up results from the previ-

ous randomized, placebo-controlled trial of delamanid.

The treatments presented in Table II were administered to patients who participated in the previous study.

Therapeutic out- comes were classified as favourable (patients who were “cured”

with “treatment completed”) or unfavourable (patients who met the criteria for “died,” “failed,” and “defaulted”) based on the evaluation of clinicians and definitions of the World Health Orga- nization (WHO).

Overall, 74.5% patients in the long-term ( ≥ 24 weeks) delamanid treatment group achieved favourable out- comes compared to 55.0% patients in the short-term ( ≤ ⁸ weeks) delamanid treatment or placebo group (Relative Risk [RR], 1.35; 95% CI, 1.17–1.56; P < 0.001). Specifically, 17.2%

patients completed the treatment in the long-term delamanid treatment group, whereas only 6.6% patients did so in the short-term delamanid treatment group (RR, 2.624; 95% CI, 1.47–4.68; P < 0.001). Nineteen patients (8.3%) died in the short-term delamanid treatment group, but only 2 patients (1.0%) died in the long-term delamanid group. There was a statistically significant difference between groups (RR, 0.13;

95% CI, 0.03 – 0.53; P < 0.001). A separate analysis of Chi- nese patients among those who participated in the previous studies

was published.

In that study, it was reported that elevated morning blood cortisol levels were observed more frequently in Chinese patients from the delamanid treatment group than in placebo-treated patients (34.6% vs. 16.7%).

In an open-label, actively controlled, randomized clinical trial conducted in South Africa, a total of 54 pulmonary TB patients were assigned to four study groups with different delamanid doses and to one control group as shown in Table II.

Dela- manid’s bactericidal efficacy was evaluated by the fall (±SD) in log

CFU/mL sputum values as EBA

. The mean fall val- ues (±SD) in log

CFU/mL after 14 days were 0.026 (0.042), 0.052 (0.045), 0.065 (0.089), 0.020 (0.027), and 0.147 (0.164) in the 100-mg, 200-mg, 300-mg, 400-mg delamanid groups, and the Rifafour group, respectively. Most adverse events were either mild or moderate, and no serious adverse events occurred during the treatment period. No patients died during this study, and the QTcF or QTcB values never exceeded 480 Table II − Study methods of the selected clinical trials of delamanid in the treatment for TB

Trial Study

design Intervention No. of patients (n) Treatment duration (wks)

Mean or median age (yrs)

Mean fall in log

CFU/mL/day (95% CI or SD) Gler et al.

(2012)

P DEL 100 mg: 100 mg BID with BR for 8 wks; DEL 200 mg: 200 mg BID with BR for 8 wks; Placebo:

placebo with BR for 8 wks

DEL 100 mg: 161;

DEL 200 mg: 160;

Placebo: 160

8 DEL 100 mg: 36 (19–63); DEL 200 mg:

33 (18–63); Placebo:

35 (18–63)

DEL 100 mg: N/A; DEL 200 mg: N/A; Placebo: N/A

Skripco- noka et al.

(2013)

P (DEL 200-400 mg QD or placebo) with BR for 8 wks → observation with BR only for 4 wks → ^DEL 200-400 mg QD with BR for 24 wks → observation with BR only up to 96 wks

DEL: 321; Placebo 160

8 + 24 Total: 35 (18–63) DEL: N/A; Placebo: N/A

Zhang et al. (2013)

P (DEL 200-400 mg QD or pla- cebo) with BR for 8 wks → observation with BR only for 4 wks → DEL 200-400 mg QD with BR for 24 wks

DEL: 26; Placebo:

12

8 + 24 Total: 34.8 (11.1) DEL: N/A; Placebo: N/A

Diacon et al. (2011)

P DEL 100 mg: 100 mg QD for 2 wks; DEL 200 mg:

200 mg QD for 2 wks, DEL 300 mg: 300 mg QD for 2 wks; DEL 400: 400 mg QD for 2 wks

DEL 100 mg: 12;

DEL 200 mg: 12;

DEL 300 mg: 12;

DEL 400 mg: 12;

Rifafour: 6

2 DEL 100 mg: 37.4 (14.5); DEL 200 mg;

27.2 (7.9); DEL 300 mg: 27.8 (9.3);

DEL 400 mg: 30.5 (8.1)

DEL 100 mg: 0.026 (0.042);

DEL 200 mg: 0.052 (0.045);

DEL 300 mg: 0.065 (0.089);

DEL 400 mg: 0.020 (0.027);

Rifafour: 0.147 (0.164)

Notes: Ages are mean (SD) or median (range); Rifafour is a fixed-dose combination of ISO (75 mg), RIF (150 mg), PYR (400 mg), and ETH (275 mg).

Abbreviations: P, prospective; wk, week; yr, year; BID, twice a day; QD, every day; BR, background regimen; DEL, delamanid; N/A,

not available.

130 Young-Mo Yang and Eun Joo Choi

Vol. 61, No. 2, 2017

ms at any time during the 14-day treatment period.

Discussion

TB is one of the most urgent public health priorities world- wide. The emergence of MDR-TB makes it difficult for the international community to control and eradicate TB.

Thus, it is important to detect TB and establish the fact of the drug resistance as early as possible. Furthermore, it is neces- sary to shorten the duration of TB treatment by using potent anti-TB medications to prevent early treatment discontinua- tion. In the present study, the efficacy and safety of bedaquiline and delamanid were determined using a literature search and subsequent analysis.

The clinical trials reviewed in this study demonstrated that bedaquiline has the potential to treat TB, particularly MDR- TB. As shown by previous studies, regimens including bedaquiline led to better clinical outcomes than those exclud- ing bedaquiline in terms of changes in mean log

CFU/mL val- ues.

When bedaquiline was the only drug administered, its effects on changes in mean log

CFU/mL were weaker than those of multi-drug regimens.

However, these changes became larger upon the increase in doses of singly adminis- tered bedaquiline.

In some studies included in this review, bedaquiline’s addition to the standard MDR-TB regimen resulted in a faster sputum culture conversion from positive to negative compared to conversion rates in placebo groups.

However, the difference in negative culture rates between the bedaquiline and placebo groups decreased after bedaquiline treatment was discontinued.

For example, this differ- ence was reduced from 15.8% at 24 weeks to 4.6% at 104 weeks.

Taken together, the data from clinical trials assessed in this review suggest that the use of bedaquiline together with other anti-TB medications may be beneficial in con- trolling MDR-TB. Nonetheless, based on our analysis of the available published data, bedaquiline’s long-term benefit is hardly conclusive.

Delamanid’s efficacy in the treatment of TB, including MDR- TB, was also evaluated in our review. Delamanid’s addition to the standard anti-TB regimen was overall beneficial for MDR- TB treatment. Compared with a placebo, statistically signifi- cant sputum-culture conversion rates were observed when delamanid was administered with other anti-TB medications.

However, the fraction of patients with persisting MDR-TB

receiving 100 mg delamanid twice a day was a little higher than that of MDR-TB patients under 200 mg delamanid twice a day.

In cases where long-term delamanid treatment was used, higher rates of cure and treatment completion may be expected although it is difficult to verify precisely the duration of drug administration at this point. In particular, delamanid’s long-term use was definitely shown to reduce the mortality rate of MDR-TB patients.

Consequently, it is likely that pro- tracted treatment with delamanid in combination with other anti-TB drugs may be effective against MDR-TB.

Bedaquiline does not usually cause significant adverse signs, but its use may be associated with potential cardiologic side effects, such as QT-interval prolongation.

In the reviewed studies, adverse GI manifestations, such as nausea, vomiting, and diarrhoea occurred in patients who received bedaquiline.

Although the severity of these signs was either mild or moder- ate, bedaquiline’s presence in administered treatments was asso- ciated with a significant increase in patients who experienced nausea, compared to patients who did not receive the drug. One severe adverse event, an increase in AST levels, occurred in a patient who received 100 mg bedaquiline. As expected, more pronounced increases in the mean QT interval duration were observed in patients who were administered bedaquiline. At the same time, except for one patient who received the combina- tion therapy of PA-824, moxifloxacin, and pyrazinamide, no patients were withdrawn from the studies due to adverse effects. As in the case with bedaquiline, delamanid’s use is also associated with QT-interval prolongation as the latter clinical sign was observed more frequently in patients who received delamanid than in patients administered with placebo.

The severity of delamanid’s other adverse effects was either mild or moderate.

The clinical trials evaluated in this review suggest that bedaquiline and delamanid can be fairly effective and safe medi- cations for the treatment of MDR-TB. However, it is necessary to address the following questions in order to reach a more definitive conclusion about the efficacy and safety of bedaquiline and delamanid in the treatment of MDR-TB: 1) What anti-TB medications should be combined with bedaquiline or delamanid?

2) How long should the regimens including bedaquiline or dela- manid be administered for? 3) Did clinical trials use appropriate study durations to adequately assess the potential of possible adverse effects of bedaquiline and delamanid?

Bedaquiline was approved for the treatment of MDR-TB by

FDA nearly 3 years ago and this drug is recommended to be administered together with more than 3 anti-TB medica- tions.

Delamanid was also approved as an anti-MDR-TB medication in the EU and Japan later.

This medication should be administered together with an optimized MDR-TB regimen.

However, sufficient information about optimized MDR-TB regimens including bedaquiline or delamanid were not mentioned in the clinical trials reviewed in this study.

Additionally, when an MDR-TB regimen is designed and administered, it is necessary to consider such factors as the infecting strain, patient’s history of previous TB treatments, and contact history.

Most clinical trials that involved bedaquiline were carried out only in South Africa except for one clinical trial conducted in multiple centres worldwide.

Potentially, this restriction to one region may have an effect on our conclusions about the clinical studies reviewed. Thus, to find out effective and safe combinations of bedaquiline or dela- manid with other anti-TB medications, it is necessary to con- duct additional well-designed, large-scale, multicentre clinical trials in the near future.

The total treatment duration of approximately 20 months is recommended for patients newly diagnosed with MDR-TB and this duration may be adjusted based on their responses to the therapy.

It is necessary to continue the therapy for at least 24 months in patients who previously received MDR-TB regi- men.

However, the treatment duration used in the reviewed clinical trials was much shorter than 20 months recommended in the WHO guidelines. In only one clinical trial, bedaquiline was administered for 24 weeks, while in the remaining trials patients took bedaquiline only for 2 or 8 weeks. In the reviewed clinical trials that involved administration of dela- manid, patients received the drug for 2, 8, or 32 weeks. In addi- tion, it is likely that if bedaquiline or delamanid is administered for the duration recommended in the WHO guidelines, the inci- dence of bedaquiline- or delamanid-associated adverse events, especially QT-interval prolongation, may be higher than that observed in the reviewed studies and their severity may also be worse than what has been observed so far. As a result, it may be difficult to adequately assess the efficacy and safety of bedaquiline or delamanid at this point. It should be noted that administration of verapamil, an efflux pump inhibitor, which was recently co-administered with other anti-TB drugs, may potentiate bedaquiline’s bactericidal activity and help inhibit

QT-interval prolongation.

Further clinical studies are required to assess synergistic effects of combined administra- tion of bedaquiline or delamanid with verapamil during MDR- TB treatment.

According to the WHO guidelines, which classified all anti- TB drugs into five groups, bedaquiline and delamanid belong to Group 5, which includes anti-TB drugs without sufficient data regarding efficacy and/or long-term safety in treating MDR- TB.

Group 5 anti-TB drugs are added to MDR-TB treat- ment regimens in cases when 4 second-line anti-TB agents from other groups are unlikely to be effective.

Unfortu- nately, it is hard to make definitive conclusions about the ther- apeutic validity of bedaquiline and delamanid in the treatment of MDR-TB on the basis of clinical trials reviewed in this study. There are very limited data regarding the efficacy and safety of bedaquiline or delamanid as compared to other anti- TB medications. Furthermore, it is hardly possible to directly compare the efficacy and safety parameters of bedaquiline and delamanid during MDR-TB treatment because there is not enough relevant data available about these drugs. Thus, it is necessary to follow the recommendations of the WHO guide- lines for the use of bedaquiline and delamanid in treating MDR-TB. Consequently, these drugs should be reserved only for patients with MDR-TB resistant to other anti-TB medica- tions until their therapeutic validity is fully elucidated.

Our study had several limitations that need to be addressed.

We should have utilized more electronic databases available in order to identify a potentially larger number of relevant stud- ies. In particular, it is regrettable that our institution could not access EMBASE. This limited search could have prevented us from finding additional relevant studies. Most of the selected studies were geographically restricted, particularly to South Africa, where 15,419 MDR-TB cases were reported in 2012 alone, although many MDR-TB cases were also reported in Europe and South-East Asia.

In addition, the majority of the included clinical trials did not last for 20 months recom- mended for MDR-TB treatment by the WHO guidelines.

Therefore, longer treatments with bedaquiline and delamanid

may further increase incidence of adverse events. Lastly, the

efficacy of bedaquiline and delamanid against MDR-TB was not

evaluated by the same criteria in the selected studies. This

discrepancy in endpoints may partially account for vague effi-

cacy results observed in the reviewed trials.

132 Young-Mo Yang and Eun Joo Choi

Vol. 61, No. 2, 2017

Conclusion

Clinical trials reviewed in this study suggest that a com- bined use of bedaquiline or delamanid with other anti-TB med- ications may provide a sufficiently effective and safe treatment of MDR-TB. However, due to relative scarcity of available evi- dence, it is difficult to appropriately determine the therapeutic validity of bedaquiline or delamanid in controlling MDR-TB.

Furthermore, it is necessary to monitor MDR-TB patients, which receive these medications together with other anti-TB drugs, since serious adverse events, such as QT-prolongation, may occur as a result of their long-term administration. In our opinion, additional well-designed, prospective, long-term, large- scale, multicentre, randomized clinical trials are required to conclusively determine the efficacy and safety of bedaquiline or delamanid in the treatment of MDR-TB patients.

Acknowledgement

This study was supported by research fund from Chosun University, 2016.

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