Early access to bedaquiline for extensively drug-resistant (XDR) and pre-XDR tuberculosis

To the Editor:

Globally in 2016, 19% of previously treated tuberculosis (TB) cases and 4.1% of newly diagnosed cases were reported to be resistant to isoniazid and rifampicin (multidrug-resistant (MDR)-TB) or rifampicin alone (rifampicin-resistant TB) [1]. In 2017, 8.5% of MDR-TB cases were caused by extensively drug-resistant (XDR)-TB [1], defined as MDR-TB with additional resistance to a fluoroquinolone (FQ) and a second-line injectable drug (SLI) (amikacin, kanamycin or capreomycin). TB drug resistance, especially XDR-TB, is associated with poorer treatment outcomes [1–3].

Based on phase 2 clinical data, bedaquiline (TMC207), a diarylquinoline antimycobacterial, was granted accelerated or conditional approval in various countries for MDR-TB [4, 5]. Compassionate-use and expanded-access programmes have made bedaquiline available in 95 countries worldwide [6, 7]. “Real-world” data have shown bedaquiline achieves high culture conversion and treatment success rates in patients with MDR-TB and XDR-TB, with a low proportion of adverse events (AEs) [8–13]. In a large-scale study, all-cause mortality was lower in patients treated with bedaquiline (12.6%) than in those who received alternative treatments (24.8%) [14].

The primary objective of study TMC207TBC3001 (www.clinicaltrials.gov identifier number NCT01464762) was to provide early access to bedaquiline for adult patients (≥18 years of age) with confirmed sputum smear- or culture-positive TB and drug susceptibility testing results, performed locally as per the local standard of care, demonstrating pulmonary pre-XDR-TB (MDR-TB with additional FQ or SLI resistance) or XDR-TB. The secondary objective was to evaluate safety, tolerability and microbiological status. Enrolled patients had limited to no treatment options and were unable/ineligible to participate in any other bedaquiline study. Results of the 120-week final analysis are presented here.

Patients received bedaquiline for 24 weeks (400 mg orally once daily for 2 weeks and 200 mg orally three times weekly for 22 weeks) with an investigator-selected background regimen (BR) in accordance with national TB programme guidelines. The BR was chosen using three or more drugs to which the TB isolate was known (based on drug-susceptibility testing from within the previous 6 months) or likely (based on known treatment history) to be susceptible, and administered under supervision using the directly observed treatment short-course for MDR-TB (DOTS-Plus). After completing the 24-week bedaquiline plus BR treatment, participants continued to receive BR only for ≤96 weeks. Clinic visits were at 2, 4, 12, 24, 28, 48, 72, 96 and 120 weeks. Safety, tolerability and microbiological status were assessed throughout. Patients who prematurely withdrew from the study were rigorously followed up to verify survival, unless consent was withdrawn.

The study protocol was reviewed by an independent ethics committee or institutional review board. The study was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. All patients provided written informed consent.

Sample size calculation was not performed and no statistical hypotheses were tested. Unless stated otherwise, safety and efficacy analyses were performed on the intent-to-treat (ITT) population, which included all patients who had one or more intake of bedaquiline, regardless of their protocol compliance.

Of 61 screened patients, 57 were recruited and received bedaquiline plus BR (ITT population) at three sites in Russia (n=54) and one site in Lithuania (n=3). All patients were Caucasian and HIV negative, with a median (range) age of 28 (18–61) years (table 1); 57.9% were female. Most patients (93%) had previously used second-line TB drugs. Pre-treatment, 47.4% had pre-XDR-TB (24.6% FQ resistant and 22.8% SLI resistant) and 52.6% had XDR-TB.

The most frequently used TB drugs in the BR (>40%) during the 120-week study were FQs (100%; levofloxacin 82.5% (47 out of 57) and moxifloxacin 57.9% (33 out of 57), with some patients switching from levofloxacin to moxifloxacin or vice versa), para-aminosalicylic acid (PAS) (89.5%, 51 out of 57), pyrazinamide (87.8%, 50 out of 57), capreomycin (84.2%, 48 out of 57), linezolid (66.7%, 38 out of 57), terizidone (61.4%, 35 out of 57) and cycloserine (54.4%, 31 out of 57). Prothionamide, ethambutol, amikacin sulfate, kanamycin, gatifloxacin, ofloxacin and amoxicillin/clavulanate were used by <40% of patients.

By 120 weeks, 43 patients had completed the study (75.4%) and 14 discontinued (24.6%) (table 1). During 120 weeks, most AEs were grade 1 or 2 in severity and 10.5% were considered by the investigator to be related to bedaquiline. Observed grade 3–4 (26.3%) and serious AEs (14%) were not considered to be related to bedaquiline. The most frequent AEs, regardless of cause or severity, were increased aspartate aminotransferase (AST) and alanine aminotransaminase (ALT), and eosinophilia (table 1). Acknowledging the small study size and limitations of comparing across studies, no new clinically relevant safety findings were noted, and the pattern and severity of AEs was generally similar to that reported in the phase 2b bedaquiline studies [4, 5]. While elevated AST and ALT, and eosinophilia occurred more frequently than in the phase 2b studies [4, 5], grade 3 ALT/AST increases were of similar incidences and no grade 4 increases were reported. None of the eosinophilia AEs or grade 3 increases in ALT or AST were considered by the investigator to be related to bedaquiline, and none led to bedaquiline discontinuation. Furthermore, most patients with ALT/AST increases were using PAS, which may be associated with hepatotoxicity and drug-induced hepatitis [16], and two of these patients had a medical history of hepatitis C.

None of the three deaths were considered to be bedaquiline or BR related by the investigator (table 1), or associated with a QT interval corrected for heart rate using Fridericia's method (QTcF) >450 ms. Two deaths occurred during the post-investigational phase (441–442 days after last bedaquiline intake); both were due to pulmonary haemorrhage and considered to be TB related by the investigator. Neither patient had culture converted (table 1). The third death occurred after week 120 (411 days after bedaquiline) and was due to an acute myocardial infarction (table 1). Overall mortality was 5%, compared with 7% in C209 [5], 12% in C208 stage 2 [4] and 15% in a large meta-analysis of patients with MDR-TB [17].

Bedaquiline was associated with a small QTcF prolongation at week 24 (mean change from baseline +1.4 ms) that gradually declined after bedaquiline treatment ended. AEs related to QTcF prolongation considered possibly related to bedaquiline by the investigator were reported in only two patients, starting 15 and 94 days, respectively, after bedaquiline treatment. Neither event was grade 3 or 4, or considered serious. Both events resolved with no action required (mean change in QTcF at 24 weeks was −15 ms and +123 ms, respectively). No events of ventricular arrhythmia or torsades de pointes were reported. None of the patients received clofazimine with bedaquiline, or had a clinically significant QTcF prolongation >500 ms or other ECG abnormalities.

In the 45 patients (ITT) who had a positive baseline TB culture and available post-baseline results, sputum culture conversion at 24 weeks was 68.9% (31 out of 45) overall, 72.7% (16 out of 22) in pre-XDR-TB and 65.2% (15 out of 23) in XDR-TB patients. Only 16 patients had sputum culture data reported at 120 weeks; six were negative and 10 were reported as “not done”. Table 1 shows the analysis censoring for assessments that were not done and “unknown”. The efficacy results support observations from the phase 2b and real-world bedaquiline studies [4, 5, 8–10].

A strength of the trial was its design, which reflected routine clinical practice and included a high proportion of difficult-to-treat patients. Most patients had previously received second-line TB drugs (93% versus 86% in C209 [5]) and >50% had XDR-TB (versus 16% in C209). However, the study did not have strictly defined data collection goals, so a large amount of microbiological data were missing, especially towards the end of treatment, as is expected during MDR-TB therapy in the real-world setting. Aside from the small study size, other limitations were the lack of a comparator arm or inclusion of HIV-positive patients.

In conclusion, bedaquiline added to a BR was generally well tolerated and efficacious over 120 weeks, as measured by traditional endpoints in patients infected with pre-XDR-TB and XDR-TB. These findings support the inclusion of bedaquiline in an individualised BR for the treatment of MDR-TB, including XDR-TB, across a broad spectrum of patients.

• Received June 26, 2018.
• Accepted April 5, 2019.

• Copyright ©ERS 2019