Treatment with bedaquiline significantly reduces mortality among South African people with XDR- and MDR-TB

Bedaquiline-based regimens are associated with large reductions in mortality in people with drug-resistant tuberculosis, according to research conducted in South Africa and published in The Lancet Respiratory Medicine.

Compared to standard regimens, use of bedaquiline reduced the risk of all cause mortality by 75% in people with extensively drug-resistant tuberculosis (XDR-TB) and by 65% for people 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. “The recent decision by the South African National Tuberculosis Program to offer bedaquiline to most people diagnosed with rifampicin-resistant tuberculosis in place of injectable drugs rings as a call to action.”

Glossary

multidrug-resistant tuberculosis (MDR-TB)

A specific form of drug-resistant TB, due to bacilli resistant to at least isoniazid and rifampicin, the two most powerful anti-TB drugs. MDR-TB usually occurs when treatment is interrupted, thus allowing organisms in which mutations for drug resistance have occurred to proliferate.

extensively drug-resistant TB (XDR-TB)

A form of drug-resistant tuberculosis in which bacteria are resistant to isoniazid and rifampicin, the two most powerful anti-TB drugs, plus any fluoroquinolone and at least one injectable second-line drug. 

retrospective study

A type of longitudinal study in which information is collected on what has previously happened to people - for example, by reviewing their medical notes or by interviewing them about past events. 

drug resistance

A drug-resistant HIV strain is one which is less susceptible to the effects of one or more anti-HIV drugs because of an accumulation of HIV mutations in its genotype. Resistance can be the result of a poor adherence to treatment or of transmission of an already resistant virus.

cure

To eliminate a disease or a condition in an individual, or to fully restore health. A cure for HIV infection is one of the ultimate long-term goals of research today. It refers to a strategy or strategies that would eliminate HIV from a person’s body, or permanently control the virus and render it unable to cause disease. A ‘sterilising’ cure would completely eliminate the virus. A ‘functional’ cure would suppress HIV viral load, keeping it below the level of detection without the use of ART. The virus would not be eliminated from the body but would be effectively controlled and prevented from causing any illness. 

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 Food and Drug Administration in the United States 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 Organization (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 people 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 people with XDR- and rifampicin-resistant and MDR-TB, according to whether their regimens included bedaquiline.

They identified 19,617 adults 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 people with HIV were taking antiretroviral therapy. XDR-TB was diagnosed in 6% of people and rifampicin-resistant or MDR-TB in 94% of individuals.

Treatment outcomes were available for 87% of people.

A cure or completion of treatment was reported for 42%. Sixteen per cent were lost to follow-up, 4% were reported as failing treatment and 21% were reported to have died.

Overall, 13% of people treated with bedaquiline died compared to 25% of those who did not receive this drug (p < 0.0001).

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

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

The authors calculated that for people with XDR-TB, treatment with bedaquiline was associated with an almost fourfold 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 people 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.”

References

Schnippel K et al. Effect of bedaquiline on mortality in South African patients with drug-resistant tuberculosis: a retrospective cohort study. The Lancet Respir Med, https://doi.org/10.1016/S2213-2600(18)30235-2 (2018).

Reuter A et al. Bedaquiline use in South Africa reveals a lifesaving policy in action. The Lancet Respir Med, https://doi.org/10.1016/S2213-2600(18)30280-7 (2018).

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