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Effect of bedaquiline on mortality in South African patients with drug-resistant tuberculosis: a retrospective cohort study

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Summary

Background

Addition of bedaquiline to treatment for multidrug-resistant tuberculosis was associated with an increased risk of death in a phase 2b clinical trial, resulting in caution from WHO. Following a compassionate access programme and local regulatory approval, the South African National Tuberculosis Programme began widespread use of bedaquiline in March, 2015, especially among patients with extensively drug resistant tuberculosis for whom no other effective treatment options were available. We aimed to compare mortality in patients on standard regimens with that of patients on regimens including bedaquiline.

Methods

In this retrospective cohort study, we analysed patient data from the South African rifampicin-resistant tuberculosis case register (EDRweb), and identified additional mortality using the national vital statistics register. We excluded patients who started treatment before July 1, 2014, or after March 31, 2016; patients younger than 15 years or older than 75 years; patients without documented rifampicin resistance, and patients with pre-extensively drug-resistant tuberculosis (multidrug-resistant tuberculosis with further resistance to a second-line injectable or fluoroquinolone). We compared all-cause mortality between patients who received bedaquiline in treatment regimens and those who did not. Patients who did not receive bedaquiline had kanamycin or capreomycin and moxifloxacin as core medicines in their regimen. We estimated hazard ratios for mortality separately for multidrug-resistant or rifampicin-resistant tuberculosis and extensively drug-resistant tuberculosis and adjusted using propensity score quintile strata for the potential confounders of sex, age, HIV and antiretroviral therapy status, history of prior tuberculosis, valid identification number, and year and province of treatment.

Findings

24 014 tuberculosis cases were registered in the EDRweb between July 1, 2014, and March 31, 2016. Of these, 19 617 patients initiated treatment and met our analysis eligibility criteria. A bedaquiline-containing regimen was given to 743 (4·0%) of 18 542 patients with multidrug-resistant or rifampicin-resistant tuberculosis and 273 (25·4%) of 1075 patients with extensively drug-resistant tuberculosis. Among 1016 patients who received bedaquiline, 128 deaths (12·6%) were reported, and there were 4612 deaths (24·8%) among 18 601 patients on the standard regimens. Bedaquiline was associated with a reduction in the risk of all-cause mortality for patients with multidrug-resistant or rifampicin-resistant tuberculosis (hazard ratio [HR] 0·35, 95% CI 0·28–0·46) and extensively drug-resistant tuberculosis (0·26, 0·18–0·38) compared with standard regimens.

Interpretation

Our retrospective cohort analysis of routinely reported data in the context of high HIV and extensively drug-resistant tuberculosis prevalence showed that bedaquiline-based treatment regimens were associated with a large reduction in mortality in patients with drug-resistant tuberculosis, compared with the standard regimen.

Funding

None.

Introduction

In 2016, there were 600 000 cases of rifampicin-resistant tuberculosis globally, and an estimated 190 000 people died from multidrug-resistant tuberculosis.1 Rifampicin-resistant tuberculosis can be rifampicin mono-resistant, multidrug-resistant (that is, resistant to both rifampicin and isoniazid), extensively drug-resistant (that is, multidrug-resistant plus at least resistance to fluoroquinolones and second-line injectable drugs), or pre-extensively drug-resistant (that is, multidrug-resistant plus resistance to either a fluoroquinolone or a second-line injectable drug).2 Rifampicin-resistant tuberculosis requires 9–24 months of treatment using second-line antituberculosis drugs and is associated with high mortality.3, 4 Across all countries reporting to WHO, among patients initiating tuberculosis treatment only 54% of patients with multidrug-resistant or rifampicin-resistant tuberculosis and 30% of patients with extensively drug-resistant tuberculosis (2014 cohort) were successfully treated.1

Bedaquiline is a diarylquinoline that inhibits mycobacterial ATP synthase.5 As of June, 2017, at least 89 countries reported using bedaquiline for treatment of rifampicin-resistant tuberculosis.1 Stage 1 phase 2b clinical trial results showed an increase, from 9 to 48%, in the proportion of patients with multidrug-resistant tuberculosis who converted to a negative sputum culture at 8 weeks when bedaquiline was added to a standard multidrug-resistant tuberculosis regimen, with no significant increase in the frequency or severity of adverse drug reactions.6 However, the final outcomes at 120 weeks for stage 2 of the same phase 2b trial showed a statistically significant imbalance in mortality in the two treatment arms, with ten deaths occurring in the 79 patients exposed to bedaquiline (12·7%) and two deaths (2·5%) in the 79 patients in the placebo arm (p=0·02).7 None of the deaths in the bedaquiline arm were attributed to bedaquiline by the investigators. Nonetheless, interim WHO guidelines recommended use of bedaquiline in rifampicin-resistant tuberculosis only when there is second-line drug resistance, the patient is not eligible for the standard treatment for rifampicin-resistant tuberculosis, or when there are no other treatment options.8, 9 Similarly, because of the reported increased risk of mortality,7 regulatory approval in the USA included a black box warning10 to only use bedaquiline when an effective treatment regimen cannot otherwise be provided.11

Research in context

Evidence before this study

In 2014, only 54% of patients initiating treatment for multidrug-resistant or rifampicin-resistant tuberculosis had successful outcomes. In South Africa, about 20% of such patients die during the standard long-course 18–24 months of second-line treatment. Patients with multidrug-resistant or rifampicin-resistant tuberculosis who are co-infected with HIV and those with resistance to second-line injectable drugs and fluoroquinolones, including those with extensively drug-resistant tuberculosis, are 2–3 times more likely to die compared with people who are HIV-negative and those without second-line injectible or fluoroquinolone resistance. Results from phase 2b clinical trials of bedaquiline (TMC207-C208) showed significant benefit in terms of the proportion of patients who culture converted, time to culture conversion, and proportion of patients achieving cure when bedaquiline was added to the standard multidrug-resistant tuberculosis treatment. However, more deaths occurred in the bedaquiline plus background regimen arm compared with the standard multidrug-resistant tuberculosis treatment arm (10 of 79 patients vs 2 of 81 patients). The deaths in the bedaquiline arm were not attributed to bedaquiline by the investigators, but the significant increased risk of mortality led to a black box warning attached to the 2012 US Food and Drug Administration bedaquiline approval. WHO bedaquiline guidelines (2013 and 2017 revision) were also cautious, recommending bedaquiline only when an effective treatment regimen could not be constructed with other WHO-recommended drugs.

Added value of this study

Since March 2015, bedaquiline has been used within the South African National Tuberculosis Programme for all patients for whom an effective regimen could not be constructed (ie, those with second-line drug resistance or toxicity to the standard regimen). In our study, we analysed the South African drug-resistant tuberculosis case register from July 1, 2014, and March 31, 2016, and 18 601 patients who initiated drug-resistant tuberculosis regimens without bedaquiline were compared to 1016 patients who initiated bedaquiline-containing regimens. We used propensity score strata to adjust for potential confounders. In this cohort, bedaquiline was associated with a 3 times reduction in the adjusted hazard ratio for mortality. Results from our large cohort treated under the state tuberculosis programme and in a population with high prevalence of HIV and second-line drug resistance provided evidence that bedaquiline is associated with reduced rather than increased mortality in drug-resistant tuberculosis.

Implications of all the available evidence

Initial recommendations for bedaquiline weighed the benefits of the increased rate of culture conversion and cure against the unexplained higher risk of mortality observed in randomised controlled trials. However, given the evidence from our study that patients receiving bedaquiline are not at increased mortality risk, this risk evaluation could change. As bedaquiline was associated with increased culture conversion and cure in clinical trials and with decreased mortality in our large observational cohort, clinicians and policy makers should re-evaluate the practice and guidance of only using bedaquiline in drug-resistant tuberculosis treatment when there are no other options.

WHO categorised South Africa as a country with a high burden of tuberculosis, HIV tuberculosis, and multidrug-resistant tuberculosis in its 2017 global report.1 19 073 laboratory-confirmed multidrug-resistant or rifampicin-resistant tuberculosis cases were diagnosed and 967 extensively drug-resistant cases were diagnosed in 2016. Similar to global reporting, 54% (n=11 111) of the 2014 multidrug-resistant or rifampicin-resistant tuberculosis cohort in South Africa were successfully treated. Short-term mortality is highest in patients with extensively drug-resistant tuberculosis, compared with other forms of tuberculosis—42% of the 2014 South African cohort died during extensively drug-resistant tuberculosis treatment.1 Long-term survival for extensively drug-resistant tuberculosis is even poorer—in one South African cohort study, 73% had died within 5 years of initiating treatment.12

In January, 2013, the South African National Tuberculosis Programme, with the support of non-governmental and academic partners, established the Bedaquiline Clinical Access Programme so that patients with pre-extensively drug-resistant tuberculosis and extensively drug-resistant tuberculosis at specialised public health facilities in South Africa could receive bedaquiline.13 Early results of the South African Bedaquiline Clinical Access Programme cohort showed high amounts of culture conversion and encouraging outcomes, including survival.14 In October, 2014, the South African Medicines Control Council regulatory authority approved the use of bedaquiline for treatment of multidrug-resistant and rifampicin-resistant tuberculosis. Starting in March, 2015, the South African National Tuberculosis Programme began the process of rolling out bedaquiline as an additional drug to strengthen the existing regimens for rifampicin-resistant tuberculosis.

In our study, we analysed survival from routinely reported data from the South African National Tuberculosis Programme to establish the hazard ratio (HR) for mortality for patients who received bedaquiline compared with patients who received regimens that did not include bedaquiline in public sector health-care facilities in South Africa.

Section snippets

Setting and standard of care

In line with WHO 2011 treatment guidelines,15 in mid-2016 the standard of care for newly diagnosed multidrug-resistant or rifampicin-resistant tuberculosis treatment in South Africa was to use a standard long-course regimen, unless documented resistance or intolerance to the drugs in the regimen required an individualised regimen.16, 17 Standard multidrug-resistant and rifampicin-resistant tuberculosis treatment is divided into two phases—6 months (intensive phase) of five drugs (kanamycin,

Results

24 014 tuberculosis cases were registered in EDRweb between July 1, 2014 and March 31, 2016 (figure 1). 19 617 patients with multidrug-resistant, rifampicin-resistant, or extensively drug-resistant tuberculosis registered in EDRweb met eligibility criteria and were included in our analyses.

The median age of patients at case registration was 36 years (IQR 29–44). Just over half of patients were male. Most patients were HIV-infected, of whom 12 430 were on ART. 18 542 (94·5%) patients had either

Discussion

In our retrospective survival analysis, inclusion of bedaquiline in a drug-resistant tuberculosis treatment regimen was associated with a 3 times reduction in the adjusted HR for mortality in patients with extensively drug-resistant tuberculosis and multidrug-resistant or rifampicin-resistant tuberculosis compared with regimens not containing bedaquiline. Patients with extensively drug-resistant tuberculosis who received bedaquiline had similar mortality to patients with multidrug-resistant or

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