Bedaquiline safety, efficacy, utilization and emergence of resistance following treatment of multidrug-resistant tuberculosis patients in South Africa: a retrospective cohort analysis

Abstract

Background This retrospective cohort study assessed benefits and risks of bedaquiline treatment in multidrug-resistant-tuberculosis (MDR-TB) combination therapy by evaluating safety, effectiveness, drug utilization and emergence of resistance to bedaquiline. Methods Data were extracted from a register of South African drug-resistant-tuberculosis (DR-TB) patients (Electronic DR-TB Register [EDRWeb]) for newly diagnosed patients with MDR-TB (including pre-extensively drug-resistant [XDR]-TB and XDR-TB and excluding rifampicin-mono-resistant [RR]-TB, as these patients are by definition not multidrug-resistant), receiving either a bedaquiline-containing or non-bedaquiline-containing regimen, at 14 sites in South Africa. Total duration of treatment and follow-up was up to 30 months, including 6 months’ bedaquiline treatment. WHO treatment outcomes within 6 months after end-of-treatment were assessed in both patient groups. Longer term mortality (up to 30 months from treatment start) was evaluated through matching to the South African National Vital Statistics Register. Multivariable Cox proportional hazards analyses were used to predict association between receiving a bedaquiline-containing regimen and treatment outcome. Results Data were extracted from EDRWeb for 5981 MDR-TB patients (N = 3747 bedaquiline-treated; N = 2234 non-bedaquiline-treated) who initiated treatment between 2015 and 2017, of whom 40.7% versus 80.6% had MDR-TB. More bedaquiline-treated than non-bedaquiline-treated patients had pre-XDR-TB (27.7% versus 9.5%) and XDR-TB (31.5% versus 9.9%) per pre-2021 WHO definitions. Most patients with treatment duration data (94.3%) received bedaquiline for 6 months. Treatment success (per pre-2021 WHO definitions) was achieved in 66.9% of bedaquiline-treated and 49.4% of non-bedaquiline-treated patients. Death was reported in fewer bedaquiline-treated (15.4%) than non-bedaquiline-treated (25.6%) patients. Bedaquiline-treated patients had increased likelihood of treatment success and decreased risk of mortality versus non-bedaquiline-treated patients. In patients with evaluable drug susceptibility testing data, 3.5% of bedaquiline-susceptible isolates at baseline acquired phenotypic resistance. Few patients reported bedaquiline-related treatment-emergent adverse events (TEAEs) (1.8%), TEAE-related bedaquiline discontinuations (1.4%) and QTcF values > 500 ms (2.5%) during treatment. Conclusion Data from this large cohort of South African patients with MDR-TB showed treatment with bedaquiline-containing regimens was associated with survival and effectiveness benefit compared with non-bedaquiline-containing regimens. No new safety signals were detected. These data are consistent with the positive risk–benefit profile of bedaquiline and warrant continued implementation in combination therapy for MDR-TB treatment.

Bedaquiline resistance in patients with drug-resistant tuberculosis in Cape Town, South Africa: a retrospective longitudinal cohort study

“…Large national or subnational molecular epidemiology studies have quantified population-level bedaquiline resistance, 14 , 29 and one study found an overall baseline bedaquiline resistance rate of 5·0% (19 of 383) in people with drug-resistant tuberculosis in South Africa, with 3·5% (five of 142) of people gaining resistance in the longitudinal cohort. 30 This difference in the magnitude of resistance gain versus our study is possibly attributable to patient profiles (all patients starting bedaquiline in these other studies vs patients with complex treatment histories and sustained culture positivity in our study). We did not quantify bedaquiline minimal inhibitory concentrations, as our objective was to characterise the proportion of people whose minimal inhibitory concentrations exceeded the critical concentration for bedaquiline; however, our isolates will contribute to future efforts to accomplish this important goal.…”

A prospective patient registry to monitor safety, effectiveness, and utilisation of bedaquiline in patients with multidrug-resistant tuberculosis in South Korea

“…In addition, we note that the rate of loss to followup was higher in this registry than elsewhere [22]. Results from a much larger (> patients) retrospective South African registry [28] showed increased rates of treatment success and reduced mortality in patients receiving bedaquiline.…”

Update on drug treatments for multidrug resistant tuberculosis

“…Among the latter, 60% had an adverse treatment outcome. The majority of the cohort were HIV positive and all but one of those with emergent resistance had preexisting additional resistance to fluoroquinolones and/or aminoglycosides [13 ▪ ].…”