Bedaquiline significantly reduces XDR- and MDR-TB mortality

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JohnsonBedaquiline-based regimens are associated with ‘striking’ reductions in mortality in patients with drug-resistant tuberculosis, University of Cape Town and Department of Health research has found.

This is according to a study by researchers at the Health Economics Unit, School of Public Health and Family Medicine, faculty of health sciences, University of Cape Town and the National TB Programme, South African National Department of Health, Pretoria, South Africa. Compared to standard regimens, use of bedaquiline reduced the risk of all-cause mortality by 75% in patients with extensively drug-resistant tuberculosis (XDR-TB) and by 65% for patients with rifampicin resistant or multidrug- resistant tuberculosis (MDR-TB).

“The results are striking and suggest that under field conditions, use of bedaquiline within a rifampicin-resistant tuberculosis treatment regimen might be associated with a lower risk of death,” write the authors of an editorial comment, Anja Reuter at Médecins Sans Frontières, Khayelitsha, Cape Town and Jennifer Furin at Harvard Medical School. “The recent decision by the South African National Tuberculosis Programme to offer bedaquiline to most people diagnosed with rifampicin-resistant tuberculosis in place of injectable drugs rings as a call to action.”

Drug-resistant tuberculosis is a global health crisis. In 2016, an estimated 600,000 cases of rifampicin-resistant tuberculosis were diagnosed and there were 190,000 deaths due to multidrug-resistant tuberculosis. Treatment of MDR- and XDR-TB is successful in only 54% and 30% of cases, respectively, and the presence of resistance is associated with high mortality rates.

In 2012, the US Food and Drug Administration approved bedaquiline for the treatment of rifampicin-resistant tuberculosis. The drug showed high levels of efficacy in clinical trials. However, uptake has been sluggish because a phase 2 study suggested that its use was associated with an increased risk of mortality, possibly due to its side-effects. World Health Organisation (WHO) guidelines recommend the use of bedaquiline only when there is rifampicin resistance, the patient is not eligible for standard rifampicin-resistant tuberculosis therapy, or the patient has no other treatment options.

South Africa has a high burden of tuberculosis, with many cases categorised as MDR- or XDR-TB. Starting in 2013, access to bedaquiline was provided to patients with XDR-TB and in 2014 the drug was approved for the treatment of MDR-TB. In 2015, the South African National Tuberculosis Programme started rolling out bedaquiline as an additional drug to strengthen existing regimens for the therapy of rifampicin-resistant tuberculosis.

Investigators undertook a retrospective study comparing mortality rates and risk among patients with XDR- and rifampicin-resistant and MDR-TB, according to whether their regimens included bedaquiline.

They identified 19,617 adult patients treated for drug-resistant tuberculosis between mid-2014 and early 2016. The median age was 36 years. Approximately three-quarters were HIV-positive and 63% of the patients with HIV were taking ART. XDR-TB was diagnosed in 6% of patients and rifampicin-resistant or MDR-TB in 94% of individuals. Treatment outcomes were available for 87% of patients.

A cure or completion of treatment was reported for 42%. Sixteen percent were lost to follow-up, 4% were reported as failing treatment and 21% were reported to have died. Overall, 13% of patients treated with bedaquiline died compared to 25% of patients who did not receive this drug (p < 0.0001).

In patients with XDR-TB, the mortality rate was 15% among patients treated with bedaquiline, almost three times lower than the rate observed among patients who received standard regimens (40%).

For patients with rifampicin-resistant or MDR-TB the mortality rate was 12% among those who received bedaquiline and 24% for patients who received alternative therapies.

The authors calculated that for patients with XDR-TB, treatment with bedaquiline was associated with an almost four-fold reduction in mortality risk (HR = 0.26; 95% CI, 0.07-0.91), and use of the drug was also associated with a substantial reduction in mortality risk for patients with rifampicin-resistant and MDR-TB (HR = 0.35; 95% CI, 0.024-0.49). These reductions in mortality risk were little altered when HIV-infection status and degree of tuberculosis drug resistance were taken into account.

“Treatment with bedaquiline was associated with a 3 times reduction in mortality for patients with multidrug-resistant or rifampicin-resistant tuberculosis and an even larger reduction in mortality for patients with extensively drug-resistant tuberculosis,” conclude the authors. “Our results justify consideration of revised recommendations from WHO and wider use of bedaquiline in multidrug-resistant, and extensively drug-resistant tuberculosis treatment.”

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.

Authors
Kathryn Schnippel, Norbert Ndjeka, Gary Maartens, Graeme Meintjes, Iqbal Master, Nazir Ismail, Jennifer Hughes, Hannetjie Ferreira, Xavier Padanilam, Rodolfo Romero, Julian te Riele, Francesca Conradie

Aidsmap material
The Lancet Respiratory Medicine abstract summary
The Lancet Respiratory Medicine comment


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