Research by the international medical humanitarian organisation Doctors Without Borders/Médecins Sans Frontières (MSF) provides strong evidence that a combination of two new drugs for tuberculosis (TB) – the world’s leading infectious disease killer – could be used to treat drug-resistant (DR-TB) forms of the disease. These findings encourage the wider use of these medicines in combination for DR-TB patients worldwide.
The drugs, delamanid and bedaquiline, have been registered for use for several years, but little evidence or guidance exists for using both in combination. The results – from early data from patients with drug-resistant TB treated with a combination of bedaquiline and delamanid in MSF-supported projects in Armenia, India, and South Africa – offer promising evidence that the treatment may be safe and effective. Of the 23 patients, 17 (74%) tested negative for TB after six months of treatment, an early indicator that the treatment will ultimately be successful. Additionally, no significant side effects were observed despite concerns about the effects both drugs could have on heart rhythm.
“With data coming from three TB epidemic hotspots around the world, the study offers concrete and practical insights into the potential of this drug combination,” said Dr Petros Isaakidis, operational research coordinator at the MSF Southern Africa Medical Unit, Cape Town. “We were excited to find such promising results under real field conditions. Even more reassuring was that safety concerns about how both drugs would affect the electrical activity of the heart weren’t justified, with no cases of cardiac arrhythmias or unexplained deaths reported.”
Of the 10m people who had TB in 2016 alone, more than 500,000 are estimated to have resistance to the most effective drugs used to treat TB. For those with highly resistant strains of TB, very few treatment options exist, and the tools to diagnose and treat patients with these strains remain limited and often ineffective. In fact, until recently, only one in five people treated for the most extensive form of resistance were cured, and often only after years of painful and toxic treatment with drug regimens containing up to seven different drugs.
This peer-reviewed MSF study helps contribute to building evidence and informs much-needed guidance for national health departments and clinicians in using this combination of drugs. While two clinical trials using both drugs have started enrolling participants, results aren’t expected to be released for several years.
“Our patients simply can’t wait for clinical trials,” said MSF TB advisor Dr Gabriella Ferlazzo. “These small but highly reassuring results from field conditions suggest that these drugs are safe and effective for use in combination among DR-TB patients with high levels of resistance. We believe it’s a clinical and public health responsibility to provide the best treatment available, and currently these drugs offer the best hope we have.”
Although bedaquiline and delamanid have been registered for use for several years, MSF estimates that globally in 2016 fewer than 5% of people who could benefit from these drugs had access to them.
Summary
Background: Bedaquiline and delamanid have been approved for treatment of multidrug-resistant (MDR) tuberculosis in the past 5 years. Because of theoretical safety concerns, patients have been unable to access the two drugs in combination. Médecins Sans Frontières has supported the use of combination bedaquiline and delamanid for people with few treatment options since 2016. We describe early safety and efficacy of regimens containing the bedaquiline and delamanid combination in patients with drug-resistant tuberculosis in Yerevan, Armenia; Mumbai, India; and Khayelitsha, South Africa.
Methods: We retrospectively analysed a cohort of all patients who received 6–12 months of oral bedaquiline and delamanid in combination (400 mg bedaquiline once per day for 2 weeks, then 200 mg bedaquiline three times per week and 100 mg delamanid twice per day) in MSF-supported projects. We report serious adverse events, QTc corrected using the Fridericia formula (QTcF) interval data, and culture conversion data during the first 6 months of treatment.
Findings: Between Jan 1, 2016, and Aug 31, 2016, 28 patients (median age 32·5 years [IQR 28·5–40·5], 17 men) were included in the analysis. 11 (39%) of 28 patients were HIV-positive. 24 patients (86%) had isolates resistant to fluoroquinolones; 14 patients (50%) had extensively drug-resistant tuberculosis. No patient had an increase of more than 500 ms in their QTcF interval. Four patients (14%) had six instances of QTcF increase of more than 60 ms from baseline but none permanently discontinued the drugs. 16 serious adverse events were reported in seven patients. Of 23 individuals with positive baseline cultures, 17 (74%) converted to negative by month 6 of treatment.
Interpretation: Use of the bedaquiline and delamanid combination appears to reveal no additive or synergistic QTcF-prolonging effects. Access to bedaquiline and delamanid in combination should be expanded for people with few treatment options while awaiting the results of formal clinical trials.
Authors
Gabriella Ferlazzo, Erika Mohr, Chinmay Laxmeshwar, Catherine Hewison, Jennifer Hughes, Sylvie Jonckheere, Naira Khachatryan, Virginia De Avezedo, Lusine Egazaryan, Amir Shroufi, Stobdan Kalon, Helen Cox, Jennifer Furin, Petros Isaakidis
[link url="http://www.doctorswithoutborders.org/article/promising-msf-research-highlights-immense-benefits-need-expanded-use-dr-tb-drug-combination"]MSF material[/link]
[link url="http://www.thelancet.com/journals/laninf/article/PIIS1473-3099(18)30100-2/fulltext"]The Lancet Infectious Diseases article summary[/link]