These landmark results are from a field study assessing the safety and efficacy of combination therapy with delamanid and bedaquiline in the treatment of drug-resistant tuberculosis.
Tuberculosis (TB) may not be a “priority pathogen” for the World Health Organization (WHO)—again—but it certainly remains top of mind for Médecins Sans Frontières (MSF), or Doctors Without Borders.
In fact, researchers working under the auspices of the international nongovernmental organization (NGO), which provides health care services in regions in crisis, have published landmark results of a field study assessing the safety and efficacy of combination therapy with delamanid and bedaquiline (Sirturo, Janssen) in the treatment of drug-resistant (DR) TB. Their findings were published February 13, 2018, in The Lancet Infectious Diseases.
“This was not drug research in the traditional sense, [but] rather pragmatic operational data compiled retrospectively to assess safety and early signs of effectiveness,” MSF Operational Research Coordinator Petros Isaakidis, MD, PhD, told Contagion®. “Our clinicians [were] in despair at dealing with DR-TB patients with very limited therapeutic options due to resistance and/or toxicity or intolerability to other drugs. Results from clinical trials using this combination are years away, but our patients can’t wait that long. We will continue to follow these patients for the remainder of their treatment in the same way, as well as all new patients started on these drugs, individually and in combination. We are trying to produce more robust, randomized evidence on the use of the new drugs under pragmatic trial conditions.”
Indeed, this isn’t MSF’s first foray into drug “research” in the field, as it strives to fulfill what Dr. Isaakidis calls its “core mandate” of providing care to patients who otherwise would not have access to it. At present, he said, the NGO is engaged in 2 active formal clinical trials: the ongoing PRACTECAL (or Pragmatic Clinical Trial for a More Effective Concise and Less Toxic treatment regimen for DR-TB) study, working in conjunction with the Stop TB Partnership, and the EndTB project, in partnership with Partners in Health and other organizations. In the past, MSF has also taken an active role in studies of treatments for malaria and other neglected diseases.
However, Dr. Isaakidis described their findings as “programmatic data.” He emphasized that the combination assessed was provided within a “compassionate access” framework and that “patients were closely monitored and managed, with detailed clinical records were kept.” The data, of course, was peer-reviewed prior to publication.
In all, 28 patients (23 with positive baseline cultures) receiving treatment for DR-TB via MSF initiatives in Armenia, India, and South Africa were administered combination therapy with bedaquiline and delamanid (400 mg bedaquiline qd for 2 weeks followed by 200 mg bedaquiline 3 times per week and 100 mg delamanid bid) and monitored for a 6- to 12-month period in 2016. Notably, 11 of the subjects included in the analysis were HIV-positive and 24 had isolates resistant to fluoroquinolones; 14 had what the authors describe as “extensively drug-resistant tuberculosis.”
Of the 23 patients with positive baseline cultures, 17 (74%) tested negative for TB after 6 months of therapy. Of the 5 who were culture negative at the onset of treatment, 4 remained culture negative at 6 months. Overall, 7 of the patients had at least 1 serious adverse event, and a total of 16 serious adverse events were reported, including gastrointestinal disorders (n = 4), nervous system disorders (n = 4), and psychiatric disorders (n = 2). One of the 7 patients died; this patient had disseminated TB and advanced HIV and was not receiving antiretroviral therapy at the beginning of the study.
“The TB community, including MSF, is still trying to understand the benefits and advantages of the combination,” Dr. Isaakidis explained. “Currently, we can only say that from the limited programmatic data we have, the combination seems promising in terms of efficacy and relatively safe in terms of toxicity, but more high-quality evidence is needed.”
Both delamanid and bedaquiline have been available for years, and both have approved indications from multiple regulatory bodies as monotherapy for DR-TB. According to Dr. Isaakidis, both are also very expensive.
“No new TB drugs have been developed for half a century,” he noted. “We know that TB, like all infectious organisms, becomes more and more resistant to more and more of the existing drugs, but we haven’t invested in research and development. This is a collective responsibility. MSF is calling for sustained global research and development efforts to get new drugs and more revolutionary ways of treating all forms of TB. Treating HIV showed us that if you put the political will, the money, and the brains together you can do fantastic things and amazingly fast. TB has not reached that level of commitment, innovation, and/or funding yet.”
Which is remarkable, when you consider that, per MSF, some 10 million individuals worldwide were diagnosed with the disease in 2016, and more than 500,000 of them had drug-resistant strains.
Sounds like a priority to us.
Brian P. Dunleavy is a medical writer and editor based in New York. His work has appeared in numerous health care-related publications. He is the former editor of Infectious Disease Special Edition.