Multi-resistant tuberculosis: studies are taking too long

With only a few studies available, the current WHO recommendations are mainly based on observations. Jennifer Furin, Harvard Medical School, USA, presented current developments in MDR-TB treatments.

The current state of multidrug-resistant tuberculosis (MDR-TB) treatment is alarming

With only a few studies available, the current WHO recommendations are mainly based on observations. Jennifer Furin, Harvard Medical School, Boston, MA, USA, presented current developments at the CROI 2019 in March 2019 in Seattle, Washington.

Tuberculosis is the leading infectious killer worldwide and the number one cause of death among HIV-infected people. "This is a disease that we must take very seriously," Furin stressed. The situation is made even more complicated by the increasing spread of MDR-TB. 580,000 new cases of rifampicin-resistant tuberculosis occur every year. "We are really in the middle of a crisis here." But, Furin continues, "we are in an exciting time in the treatment of MDR-TB. For the first time in 50 years, Delamanid and Bedaquilin are two new drugs that are approved for the treatment of MDR-TB, based on randomized and controlled data." There are many other substances in clinical development, while numerous studies are ongoing in all phases.

Phase III trials

Until recently, there were no phase III trials with MDR-TB, now there are two studies, the 123 study on Delamanid and the Stream study.

Delamanid was approved by the EU Commission in May 2014 as part of combination therapy for the treatment of adults with pulmonary tuberculosis who do not tolerate or respond to other therapies. Delamanide inhibits the synthesis of the cell wall components methoxy- and keto-mycolic acid. In the Phase III 123 study, published in January 2019, 511 patients with multiple-resistant pulmonary tuberculosis received delamanide orally (100mg twice daily) for 2 months in addition to an optimized background regimen, followed by 200mg daily for 4 months or placebo. The primary endpoint was the time to conversion of the sputum culture and the difference in time distribution until the conversion of the sputum culture over 6 months. The median time to sputum culture conversion did not differ significantly between the delamanide group with 51 days and the placebo group with 57 days (hazard ratio 1.17, p = 0.2157). The standard therapy arm was much better than expected in this group. The Phase II study had yielded a significant result for delamanide. However, the Phase III study clearly showed that delamanide is a safe drug.

The Stream study is the first large-scale two-stage study to investigate shortened treatment regimes for MDR tuberculosis. It is also the first Phase III study to investigate the efficacy and tolerability of bedaquiline in a shortened regimen. Stage I was a randomized, controlled study with a non-inferiority design. 424 patients were randomly treated 2:1. The standard regime recommended by the WHO in 2011 was used as a control. The study regime consisted of moxifloxacin, clofazimine, ethambutol, and pyrazinamide. This was supplemented in the first four months by isoniazid, kanamycin, and prothionamide. In the final analysis, the short regime proved not to be inferior to the standard regime.

Observational studies as a main basis for recommendations

Observational studies are the main basis for recommendations for the treatment of MDR tuberculosis. In a meta-analysis of such observational studies using individual patient data, data from 50 studies with 12,030 patients from 25 countries were considered. Treatment success was particularly evident when patients were treated with linezolid, levofloxacin, carbapenem, moxifloxacin, bedaquiline and clofazimine. Mortality was significantly reduced with linezolid, levofloxacin, moxifloxacin or bedaquiline. Amikacin had only a limited benefit, kanamycin and capreomycin worsened the condition of the patients. Most substances were more likely to cause harm if they had been used despite evidence of in vitro resistance.

WHO 2018 recommendation

For the first time in history, the WHO now recommends all oral therapy regimes for MDR tuberculosis, although in many cases data from randomized clinical trials are missing. Furin described it as astonishing that modified short oral therapies can also be used, although there is no data on this. Although the WHO recommends that parameters such as feasibility or acceptance be taken into account when considering therapy, these are not measured.

Current studies

Furin described as "exciting" the fact that a large number of studies are currently being conducted with multiple regimens; she cited NixTB, ZeNix, Tb-Practecal or endTB as examples.

A major problem with all studies is that it takes 8 to 10 years from the planning stage to the final result. Therefore, there are frequent changes in standard therapy during the course of the study. For example, Arm 2 of the Stream study had to be discontinued in some countries because the therapy regime investigated was introduced as the new therapy standard.

Although multiple potentially effective regimes are being investigated, there are no head-to-head comparisons and some studies do not include a comparison group at all. The drugs are often only given for 24 weeks.

New substances only slowly accepted

Furin also complained that the new substances such as bedaquiline and delamanide are only slowly absorbed into the therapy regime. Bedaquilin, which was introduced into therapy in 2015, has treated just under 29,000 patients, and delamanide, which was introduced in 2014, has treated just under 2,300 patients. According to conservative estimates, less than 15% of people who need a new substance are treated with it - according to conservative estimates.

As a "desperate MDR doctor", Furin lamented above all the excessively long duration of studies. "The standard of therapy is so bad, you can't wait for studies to improve it." New study designs and better predictive interim outcome tests are needed, corresponding to the viral load in HIV infection. It is necessary to derive more benefit from the increased number of clinical trials and to make them feasible. It is important to overcome the paradigm of trials scarcity.

Furin J. Treating multidrug-resistant tuberculosis in the real world: new drugs and regimens. CROI 2019, Seattle, Washington, March 6, 209, Abstract 115.