The face of tuberculosis treatment is changing for the first time in 40 years, particularly when it comes to the drug-resistant forms of the disease.
Approved in 2012 by the U.S. Food and Drug Administration (FDA), bedaquiline is an antimycobacterial drug that inhibits mycobacterial ATP synthetase and drains cellular energy stores. Based on how it works, bedaquiline maintains its effectiveness against certain forms of tuberculosis that are already resisting other, existing drugs.
But, despite its benefits, initial studies revealed more patients receiving bedaquiline died than those taking a placebo therapy regimen. The question has been whether adding bedaquiline into the tuberculosis treatment regimen is worth the risk.
The Infection Problem
According to the World Health Organization (WHO), there were 8.6 million new tuberculosis cases in 2012. Incidence rates of drug-resistant tuberculosis have also been rising in the 27 most affected countries, leading the WHO to estimate there were 450,000 new drug-resistant cases globally in 2012, as well.
Overall, based on data cited in a New England Journal of Medicine editorial, tuberculosis infection carries substantial morbidity and mortality risks – among sputum-smear positive, HIV-negative patients, the 10-year fatality rate is 70%. New treatments are needed to combat this continued problem, but their use must be weighed against the likelihood they will lead to avoidable deaths.
Despite bedaquiline presenting more deaths, the FDA made a rare move. It approved the drug for use despite the risks based on the results of a two-stage, Phase 2 trial that included sputum-positive participants who were sensitive to at least three of the five drugs used in the antimycobacterial drug regimen for multi-drug resistant pulmonary tuberculosis. The preferred background regimen included: kanamycin, ofloxacin, ethambutol, pyrazinamide, and cycloserine or terizidone.
During the first stage, 47 patients were blindly assigned to receive 8 weeks of placebo or bedaquiline, in addition to the background regimen. After 8 weeks, sputum-culture conversion was much better for bedaquiline patients (48%) than placebo (9%). In the second phase, 79 patients received bedaquiline, and 81 received placebo care. Sputum conversion, again, was much shorter for the bedaquiline group – 83 days versus 125 days.
However, the study also revealed more deaths occurred with bedaquiline. Only two placebo patients died, but 5 of 10 deaths in the bedaquiline group were attributed to disease progression. The drug’s benefit was significant enough, however, to win FDA approval.
Introducing Bedaquiline Treatment
Based on the FDA’s decision, a new study, published in PLOS, investigated different strategies for introducing bedaquiline to patients who could benefit from it. Each method was based on a patient’s resistance pattern and was designed to maximize efficacy and minimizing negative impacts. Effectively implementing antibiotic introduction strategies is important because it can affect the development of acquired resistance to new drugs, existing drugs, or both.
The new study used previously-published aggregate data to create a Markov decision model, based on a group of hypothetical patients who were beginning multi-drug resistant tuberculosis treatment. To test the various treatment methods, investigators assumed the population was mostly 30-year-old men who were susceptible to bedaquiline. They had either multi-drug resistant tuberculosis without additional resistance (67.1%), multi-drug resistant tuberculosis with resistance to at least one fluoroquinolone or at least one second-line injectable (26.2%), or multi-drug resistant tuberculosis with resistance to at least one fluoroquinolone and at least one second-line injectable (6.7%).
Investigators sampled 5,000 random parameter sets to create their decision model. They included estimating life expectancy, resistance acquisition patterns, and the number of – and outcomes – of secondary tuberculosis cases.
Given the questions around bedaquiline’s impact, researchers concentrated on mortality, resistance, and transmission outcomes.
To test effectiveness, researchers designed four treatment strategies:
- Withholding bedaquiline from all patients
- Providing bedaquiline to patients with extensively drug-resistant tuberculosis
- Providing bedaquiline to patients with pre-extensively drug-resistant tuberculosis or extensively drug-resistant tuberculosis
- Providing bedaquiline to all patients with multi-drug resistant tuberculosis
Researchers assured all multi-drug resistant tuberculosis patients received bedaquiline from baseline. For all other strategies, they assumed a 13-week lag time after treatment launch.
The decision model results supported the FDA’s decision to approve bedaquiline for patients who don’t have other treatment options.
Among multi-drug resistant tuberculosis patients, using bedaquiline maximized life expectancy in 76.8% of the 5,000 parameter simulations. For all other patients, the optimal strategy seemed to be withholding bedaquiline, indicating – for this group – the bedaquiline benefit of reducing culture conversion time doesn’t outweigh the mortality risk.
When most parameters remained at fixed midpoints, the “all multi-drug resistant tuberculosis” strategy is preferred when it can reduce the median culture conversion time by at least 35 percent over what the background drug regimen only is able to produce. It’s also best when the added bedaquiline mortality risk is less than 0.00025 per week – roughly 1.3 deaths per 100 patient years.
Overall, researchers said, making bedaquiline available to all patient with multi-drug resistant tuberculosis minimizes the actual number of and expected number of lives lost to secondary tuberculosis infections. After using the best strategies for each patient, life expectancy for the hypothetical 30-year-old participants reached 36.12 years compared to 34.67 years when suboptimal therapies were used.
Data analysis also showed, based on drug-susceptibility testing, the “all multi-drug resistant tuberculosis” method provides optimal life expectancy in 69.3% of cases. Pre-extensively drug resistant tuberculosis and extensively-drug resistant tuberculosis do so in 16.9% of situations, and no bedaquiline optimizes life expectancy in only 13.7% of instances.
The study did have limitations, however, other than presenting all participants as 30-year-old men. Investigators didn’t explore all potential bedaquiline use strategies, such as early drug substitution methods. They also held parameters unrelated to bedaquiline constant throughout the study even though reproducing those circumstances with actual study participants isn’t possible. They also assumed the background drug regimen effect would be the same for all patients even though those conditions are not reproducible in the real world.
Additionally, researchers did not consider the impact of introducing bedaquiline to HIV-positive participants.
As with all drugs, acquired resistance is a concern with bedaquiline, especially because the medication is a new treatment for tuberculosis. On average, in the simulation, 5.88% of patients developed bedaquiline resistance when the drug was made available to all multi-drug resistant tuberculosis patients. When bedaquiline was only given to extensively-drug resistant tuberculosis patients, drug resistance developed in only 3.5% of cases.
There’s a hope, though, researchers said, that expanding bedaquiline use could help protect the efficacy of the existing drug regimen. By offering an additional drug to fight infection, bedaquiline could potentially limit resistance to medications already in use. So far, based on the study’s findings, that benefit does materialize. Only 2.56% of patients developed extensively-resistant tuberculosis when all patients received bedaquiline compared to the 9.82% that do so when the drug is only given to extensively-drug resistant patients.
Ultimately, researchers said, their study highlights the need to investigate bedaquiline’s impact and benefit in real-world circumstances. Continued analysis of the drug’s safety and efficacy is paramount. If the results can be duplicated, a strong case could be made – even if it leads to future bedaquiline resistance – to extend the drug’s use beyond compassionate use situations, particularly where rapid second-line drug susceptibility testing isn’t an option.
Cox, Edward, Laessing, Katherine. FDA Approval of Bedaquiline – The Benefit-Risk Balance for Drug-Resistant Tuberculosis. N Engl J Med. 371;8: 689-691.
Diacon, Andreas, Pym, Alexander, et. al. Multidrug-Resistant Tuberculosis and Culture Conversion with Bedaquiline. N Engl J Med. 371: 723-732.
Kunkel, Amber, Cobelens Frank G., et. al. Tradeoffs in Introduction Policies for the Anti-Tuberculosis Drug Bedaquiline: A Model-Based Analysis, PLOS, 2016.