Preliminary results from Stage 1 of the STREAM trial show that the nine-month treatment regimen being tested achieved favourable outcomes in almost 80 percent of those treated. These results were announced yesterday at The Union World Conference on Lung Health in Guadalajara, Mexico.
The results suggest the nine-month regimen is very close to the effectiveness of the 20-24 month regimen recommended in the 2011 WHO guidelines, when both regimens are given under trial conditions.
The STREAM trial is the world's first multi-country randomised clinical trial to test the efficacy, safety and economic impact of shortened multidrug-resistant tuberculosis (MDR-TB) treatment regimens.
MDR-TB, defined as forms of TB that are resistant to at least the two first-line antibiotics isoniazid and rifampicin, affected an estimated 480,000 people in 2015 and has been declared a public health crisis by the World Health Organization (WHO). The 20-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 global treatment success rate of only around 50 percent when used in real-world treatment settings.
Because of these widely-acknowledged challenges, in 2016 the WHO guidelines were updated to recommend a shorter, nine-12 month regimen for most people with MDR-TB. The guidelines acknowledge that this recommendation is based on very low certainty in the evidence.
In STREAM Stage 1, 424 patients from Ethiopia, Mongolia, South Africa and Vietnam were randomly allocated to receive either:
- The standard 20-month regimen recommended by the 2011 WHO guidelines
- A 9-month regimen consisting of moxifloxacin, clofazimine, ethambutol and pyrazinamide given for nine months, supplemented by kanamycin, isoniazid and prothionamide in the first four months
Nine-month and 20-month regimen very close in terms of efficacy
The results suggest the efficacy of the nine-month regimen in the trial will be very close to the longer regimen recommended in the 2011 WHO guidelines, but, statistically, we are not currently able to say the nine-month regimen is non-inferior to the longer regimen. 78.1 percent of patients receiving the nine-month regimen achieved a favourable outcome, compared to 80.6 percent of patients receiving the 20-24 month regimen.
I.D. Rusen, Union lead for the STREAM trial said: "The nine-month regimen did as well or even better than we expected given the rigorous standards of the clinical trial, but the 20-24 month regimen did much better than routinely reported outcomes from programme settings.
"The trial setting meant that more patients completed treatment successfully on the 20-24 month regimen than we know is often the case in most real life settings. In routine programmes unable to achieve the high STREAM retention rates, the nine-month regimen may actually perform better in comparison to the 20-24 month regimen."
Andrew Nunn, statistician at the MRC Clinical Trials Unit at UCL and STREAM co-chief investigator, said: "The outcomes in patients coinfected with HIV are particularly important as they suggest that the nine-month regimen is no less effective in this patient group that the 20-24 month regimen."
The preliminary 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 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, and why we felt it important to release these preliminary results as soon as they became available."
In terms of the economic burden of MDR-TB, the results show the nine-month regimen reduces costs to both the health system and patients, compared to the 20-month regimen. In South Africa the nine-month regimen reduced the cost to the health system for each patient by USD4,900 (around a third). Patients' direct costs were also reduced due to fewer visits to health facilities, reduced spending on supplementary food and the fact that the patient was able to return to work sooner than if on the 20-month regimen.
Follow-up of Stage 1 is ongoing, and full results will be published next year, which will include data from the final follow-up visits. These additional data are unlikely to materially change the results.
The Union and its global partners - Vital Strategies, the Medical Research Council Clinical Trials Unit at UCL, Institute of Tropical Medicine and Liverpool School of Tropical Medicine - launched the Standardised Treatment Regimen of Anti-TB Drugs for Patients with MDR-TB (STREAM) Trial in 2012. Stage 1 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).