In a study that could have an impact on the treatment of drug-resistant tuberculosis (TB), a team of South African researchers report that the novel TB drug bedaquiline was associated with a significant reduction in mortality for patients with multidrug-resistant (MDR), rifampicin-resistant, and extensively drug-resistant (XDR) strains of the infection.
In the retrospective cohort study published in The Lancet Respiratory Medicine, the researchers analyzed patient data from the South African rifampicin-resistant tuberculosis case register (EDRweb) and additional mortality data from a national vital statistics registry to compare all-cause mortality between patients who received bedaquiline in treatment regimens and those who did not. South Africa has a high burden of drug-resistant TB, with 19,073 laboratory-confirmed cases of MDR-TB or rifampicin-resistant TB and 967 XDR-TB cases diagnosed in 2016.
Of the 24,014 TB cases registered in the EDRweb from July 2014 through March 2016, 19,617 initiated treatment and met eligibility criteria. A bedaquiline-containing regimen was given to 743 (4.0%) of 18,542 patients with MDR or rifampicin-resistant TB and 273 (25.4%) of 1,075 patients with XDR-TB. Among 1,016 patients who received bedaquiline, 128 deaths (12.6%) were reported, while 4,612 deaths (24.8%) were reported among 18,601 patients on the standard regimens.
Further statistical analysis showed that bedaquiline was associated with a reduction in the risk of all-cause mortality for patients with MDR-TB or rifampicin-resistant TB (hazard ratio [HR], 0.35) and XDR-TB (HR, 0.26) compared with standard regimens.
Mortality concerns lead to limited use
The results are significant, because bedaquiline, approved by the US Food and Drug Administration in 2012, can considerably shorten treatment for drug-resistant TB, and is less toxic than the drugs used in standard treatment regimens, which can last up to 2 years. In addition, success rates for standard treatment of drug-resistant TB in South Africa are only around 54%.
But while bedaquiline is currently used in at least 89 countries, the World Health Organization (WHO) recommends that the drug be used only for rifampicin-resistant TB when there is also resistance to second-line drugs, when the patient is not eligible for standard treatment, or when no other options are available. That's because a phase 2b clinical trial that showed improved outcomes in people treated with bedaquiline compared with placebo also showed an increase risk of mortality in those patients. Even though none of the deaths in the bedaquiline arm of that study were attributed to the drug, concerns about increased mortality have remained.
But since 2015, South Africa's National Tuberculosis Program has allowed for wider use of bedaquiline in all patients with rifampicin-resistant, MDR, and XDR-TB, and use of the drug has risen in hospitals and clinics throughout the country. Earlier studies have indicated that widening access has produced encouraging outcomes. The authors of the current study say the finding of reduced mortality associated with bedaquiline suggest that the WHO should reconsider its position.
"Our results justify consideration for revised recommendations from WHO and wider use of bedaquiline in multidrug-resistant, rifampicin-resistant, and extensively drug-resistant tuberculosis treatment," the authors write.
In an accompanying commentary, Jennifer Furin, MD, PhD, of Harvard Medical School and Anja Reuters, MD, of the nonprofit Medecins Sans Frontieres write that there are limitations to the study, including the fact that patients on bedaquiline may have been more closely monitored, and that the results need to be confirmed in phase 3 trials. Nonetheless, they believe South Africa's approach to bedaquiline use should be emulated in other countries.
"The decreased mortality observed among people receiving bedaquiline through South Africa's National Tuberculosis Program provides hope that it is possible not only to talk about a tuberculosis-free world, but to actually create one," they write.
Jul 9 Lancet Respir Med full text
Jul 9 Lancet Respir Med commentary landing page