A nine to 11-month treatment regimen is as effective in treating multi-drug resistant tuberculosis (MDR-TB) as the 20 to 24-month regimen recommended in the 2011 WHO guidelines, according to the final results from Stage 1 of the STREAM randomised clinical trial. The study was conducted by a team of researchers, including LSTM's Professor Bertie Squire - and was published this week in the New England Journal of Medicine (NEJM)
The STREAM trial – sponsored by The Union and Vital Strategies with key global partners, including the Medical Research Council Clinical Trials Unit at UCL, Liverpool School of Tropical Medicine (LSTM), Institute of Tropical Medicine (ITM) in Antwerp and others, 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.
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 percent 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 the World Health Organization (WHO).
The 20 to 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 percent 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.
- 9-11-month regimen is as effective as the 20-24-month regimen in terms of efficacy
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 percent of assessable participants had a favourable outcome, compared to 79.8 percent in the longer regimen.)
There was no evidence that efficacy results were worse in HIV-infected participants compared to HIV-negative participants.
I.D. 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.”
- ECG monitoring
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 Medical Research Council 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.”
- Health economics
The analysis of the economic burden of MDR-TB led by the Liverpool School of Tropical Medicine (LSTM) 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 (SAE’s) and costs incurred by trial participants, which also give an insight into the financial and social well-being of participants on each regimen.
LSTM Professor 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 MDRTB”.
Stage 1 of the Standardised Treatment Regimen of Ati-TB Drugs for Patients with MDR-TB (STREAM) trial was funded through the TREAT TB cooperative agreement with the U.S. Agency for International Development (USAID) with additional funding from the UK Medical Research Council and the UK Department for International Development (DFID).