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Efficacy, safety and economic impact of shortened MDR-TB treatment

Final results from Stage 1 of the STREAM randomised clinical trial show that a 9-11-month treatment regimen is as effective in treating multidrug-resistant tuberculosis (MDR-TB), when given under trial conditions, as the 20-24-month treatment regimen recommended in the 2011 World Health Organisation (WHO) guidelines.

The STREAM trial is the world’s first multi-country randomised phase III clinical trial to test the efficacy, safety and economic impact of shortened MDR-TB treatment regimens. STREAM – funded by the US Agency for International Development (USAID), initiated by The Union and sponsored by Vital Strategies – is being implemented with key global partners, including the Medical Research Council Clinical Trials Unit at University College London (UCL), Liverpool School of Tropical Medicine and Institute of Tropical Medicine Antwerp.

Stage 1 of the STREAM trial looked to determine whether a 9-11-month treatment regimen that demonstrated cure rates exceeding 85 percent during a pilot programme in Bangladesh is as effective as the longer regimen under clinical trial conditions. Seven sites in Vietnam, Mongolia, South Africa, and Ethiopia participated in Stage 1. In June 2015, Stage 1 of the trial enrolled its 424th and final patient. As the 9-11-month regimen provides potential cost savings to patients and health systems compared to the 20-month regimen, an assessment of the costs under each regimen faced by participants and health systems was included in Ethiopia and South Africa.

Worldwide in 2017, an estimated 558,000 people developed TB that was resistant to rifampicin, the most effective first-line drug, and of these, 82% had MDR-TB (defined as resistant to at least the two first-line antibiotics isoniazid and rifampicin) (source WHO 2018 Global Tuberculosis Report). MDR-TB has been declared a public health crisis by WHO. The 20-24-month regimen used in many countries globally is costly, has significant side effects and the length of the regimen makes it hard for both patients and the health system. The regimen has an average treatment success rate of approximately 50% when used in many real-world treatment settings.

Because of these widely-acknowledged challenges, in 2016 the WHO guidelines were updated to recommend a shorter, 9-12-month regimen for most people with MDR-TB under specific conditions. The guidelines acknowledge that this recommendation is based on very low certainty in the evidence.

The results showed that the 9-11-month regimen was statistically non-inferior to the 20-24-month regimen, in terms of efficacy (78.8% of assessable participants had a favourable outcome, compared to 79.8% in the longer regimen). There was no evidence that efficacy results were worse in HIV-infected participants compared to HIV-negative participants.

ID Rusen, project director for the STREAM trial said: “Until now there has been a lack of strong supporting evidence to underpin MDR-TB treatment guidelines. The results from STREAM Stage 1 help to fill that gap. The final results show that the trial setting meant more patients successfully completed treatment on the 20-24-month regimen than we know is often the case in real life settings. In routine programmes unable to achieve the high STREAM retention rates, the 9-11-month regimen may actually perform better in comparison to the longer regimen.”

Andrew Nunn, STREAM co-chief investigator from the MRC Clinical Trials Unit at UCL, said: “We know from programmatic data that the 20-24-month regimen has a number of major drawbacks, including the difficulty of completing such a long treatment, the significant side-effects of the drugs used and poor treatment outcomes. Shorter, more effective and safer regimens are urgently needed. The outcomes in patients coinfected with HIV are particularly important as they suggest that the 9-11-month regimen is no less effective in this patient group than the longer regimen.”

The final results show that electrocardiogram (ECG) monitoring was very useful, and required throughout treatment. This was done effectively during the trial, and close monitoring would also be necessary with regimen use in routine programme settings.

Sarah Meredith, clinical co-chief investigator for STREAM and professor of clinical trials at the MRC Clinical Trials Unit at UCL, said: “We know that ECG monitoring throughout treatment is likely to be challenging in most routine programme settings, where access to ECG monitoring is limited. We have the opportunity to try to improve the regimen during the remainder of STREAM Stage 2 to see if we can reduce the need for ECG monitoring throughout treatment. This is just one reason why dynamic clinical trials of this nature are so important.”

The analysis of the economic burden of MDR-TB, led by the Liverpool School of Tropical Medicine in collaboration with University of Warwick and investigators in South Africa and Ethiopia, will be published in due course. For South Africa and Ethiopia, this analysis presents a breakdown of health system data for each regimen from including costs of in-patient stay, laboratory tests, cardiac safety monitoring, medication, staff time, social support, and consumables. More detailed data are presented from Ethiopia on costs of management of serious adverse events (SAEs) and costs incurred by trial participants, which also give an insight into the financial and social well-being of participants on each regimen.

Bertie Squire, co-investigator for STREAM and lead for the Health Economic Analysis said: “This is the first phase III trial of TB treatment that includes a within-trial economic evaluation. The results will be useful for countries and programmes as they decide on whether and how to introduce shorter regimens for treatment of MDR-TB”.

Stage 1 of the Standardised Treatment Regimen of Anti-TB Drugs for Patients with MDR-TB (STREAM) trial was funded through the TREAT TB cooperative agreement with USAID with additional funding from the UK Medical Research Council and the UK Department for International Development (DFID).

Irene Koek, deputy assistant administrator in USAID's Global Health Bureau, said: “USAID is proud to have supported the STREAM study, the first randomised clinical trial for MDR-TB. This study has already served as a benchmark for other MDR-TB clinical trials and as a result, there are now more MDR-TB treatment regimens being studied than ever. In addition, data from this study, combined with data from observational studies, have demonstrated that shorter, less toxic, effective, and well-tolerated treatment regimens are now feasible.”

Dr Paula I Fujiwara, scientific director, The Union, said: “The results from STREAM Stage 1 support the programmatic evidence that the STREAM Stage 1 9-11 month shorter regimen is as good as the longer 20-24-month regimen, recommended in the 2011 WHO guidelines, in terms of efficacy. Observational studies and individual patient data show that the regimen performs similarly in the randomised clinical trial as in programmatic conditions. This cannot be said for the previous longer regimen. The shorter duration of the shorter regimen is a clear advantage to the patient and increases the likelihood that the treatment is completed, with an earlier return of the patient to work and social activity. The STREAM Stage 1 results come at a time when TB science is progressing quickly; we are very keen to keep this momentum going. There is still a very real and urgent need to improve the efficacy and safety of MDR-TB treatment and trials like STREAM and STREAM Stage 2, as well as other ongoing trials are a vital part of this work.”

Background: Cohort studies in Bangladesh showed promising cure rates among patients with multidrug-resistant tuberculosis who received existing drugs in regimens shorter than that recommended by the World Health Organization (WHO) in 2011.
Methods: We conducted a phase 3 noninferiority trial in participants with rifampin-resistant tuberculosis that was susceptible to fluoroquinolones and aminoglycosides. Participants were randomly assigned, in a 2:1 ratio, to receive a short regimen (9 to 11 months) that included high-dose moxifloxacin or a long regimen (20 months) that followed the 2011 WHO guidelines. The primary efficacy outcome was a favorable status at 132 weeks, defined by cultures negative for Mycobacterium tuberculosis at 132 weeks and at a previous occasion, with no intervening positive culture or previous unfavorable outcome. An upper 95% confidence limit for the between-group difference in favorable status that was 10 percentage points or less was used to determine noninferiority.
Results: Of 424 participants who underwent randomization, 383 were included in the modified intention-to-treat population. Favorable status was reported in 79.8% of participants in the long-regimen group and in 78.8% of those in the short-regimen group — a difference, with adjustment for human immunodeficiency virus status, of 1.0 percentage point (95% confidence interval [CI], −7.5 to 9.5) (P=0.02 for noninferiority). The results with respect to noninferiority were consistent among the 321 participants in the per-protocol population (adjusted difference, –0.7 percentage points; 95% CI, −10.5 to 9.1). An adverse event of grade 3 or higher occurred in 45.4% of participants in the long-regimen group and in 48.2% in the short-regimen group. Prolongation of either the QT interval or the corrected QT interval (calculated with Fridericia’s formula) to 500 msec occurred in 11.0% of participants in the short-regimen group, as compared with 6.4% in the long-regimen group (P=0.14); because of the greater incidence in the short-regimen group, participants were closely monitored and some received medication adjustments. Death occurred in 8.5% of participants in the short-regimen group and in 6.4% in the long-regimen group, and acquired resistance to fluoroquinolones or aminoglycosides occurred in 3.3% and 2.3%, respectively.
Conclusions: In persons with rifampin-resistant tuberculosis that was susceptible to fluoroquinolones and aminoglycosides, a short regimen was noninferior to a long regimen with respect to the primary efficacy outcome and was similar to the long regimen in terms of safety

Andrew J Nunn, Patrick PJ Phillips, Sarah K. Meredith, Chen-Yuan Chiang, Francesca Conradie, Doljinsuren Dalai, Armand van Deun, Phan-Thuong Dat, Ngoc Lan, Iqbal Master, Tesfamarium Mebrahtu, Daniel Meressa, Ronelle Moodliar, Nosipho Ngubane, Karen Sanders, Stephen Bertel Squire, Gabriela Torrea, Bazarragchaa Tsogt, ID Rusen

[link url=""]New England Journal of Medicine abstract[/link]

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