Last week a number of important study findings with implications for the treatment of multi-drug resistant tuberculosis (MDR-TB) were reported at the Union World Lung Conference in Guadalajara, Mexico.
Delamanid phase III findings
Early findings from the phase III trial of delamanid for the treatment of MDR-TB were announced last week – making delamanid the first of the new TB drugs to have phase III data. The trial compared a background regimen plus delamanid to the same background regimen plus a placebo.
Culture conversion at six months in the delamanid arm was 87.6% vs 86.1% in the control arm. Maybe most importantly, 24-month outcomes and all-cause mortality in the two arms were very similar. There were no serious safety issues with delamanid and one promising benefit associated with delamanid was a reduced risk of developing further drug resistance.
Given the high hopes many people had, and some still have, for delamanid, these findings are very disappointing. They suggest that delamanid is not the breakthrough blockbuster we had hoped it would be, or at least that the standard of care is better than most thought, especially now that many people are receiving powerful drugs repurposed for TB, like linezolid.
That said, the endTB consortium also last week reported some promising findings on the use of delamanid and bedaquiline in people with XDR-TB. 46 patients received delamanid and bedaquiline in combination, nearly half (48%) of whom started the two drugs within seven days of each other. Patients tolerated the combination well and there did not appear to be any additional increase in the side effect of concern (QT prolongation, a potentially dangerous disturbance of the heart’s electrical activity, which each drug causes independently).
Making sense of all the new evidence on delamanid will take time and will become easier once findings are reported in more detail in medical journals.
Standard of care on trial
In another critical study called STREAM stage I, the old 20/24-month World health Organisation (WHO) recommended standard of care for the treatment of MDR-TB was pitted against the still relatively new nine-month WHO recommended standard of care. While both arms in the study fared relatively well compared to abysmal treatment success rates of about 50% seen in routine care, the study findings reported so far failed to show that the nine-month regimen is non-inferior to the 24-month regimen. 78.1% of patients in the nine-month arm achieved a favourable outcome compared to 80.6% of patients in the 20/24-month arm. Surprisingly, the shorter regimen also did not appear to have an advantage in terms of side effects over the longer regimen.
These results (as well as the delamanid findings described above) are somewhat complicated by the fact that the 20/24-month regimen did much better in these studies than observed historically and in many healthcare programmes. There is some speculation that this effect is due to broader access to linezolid and clofazimine (which essentially means that the background regimen has been improved). It could also be due to earlier diagnosis of MDR-TB given much increased access to faster TB testing in the form of Xpert MTB/RIF, or the exclusion of patients with more complicated drug-resistant TB from these trials.
Despite the failure so far to show non-inferiority, the cure rates in the 9-month arm may well be good enough to justify its continued use – especially given the cost-savings and likely improved treatment adherence associated with this shorter regimen in real-world settings. That said, it is hard to come to any firm conclusions based on early and incomplete data. It will, for example, be critical for the South African context to see how the 9-month regimen did in people living with HIV. Earlier this year South Africa’s Minister of Health Dr Aaron Motsoaledi announced that South Africa will be switching to the nine-month regimen.
Prior to these early results from STREAM stage I, the case for the nine-month regimen was built on mostly observational data. In recommending the nine-month regimen last year, the WHO recognised that the evidence-base for the recommendation was weak. The STREAM stage I findings once again shows that observational data can sometimes overstate comparative efficacy and that questions of which regimen is better is best answered by large randomised controlled trials.
The findings of STREAM stage I also vindicates earlier decisions taken about the design of STREAM stage II (the trial serving as the bedaquiline phase III trial). In STREAM stage II, two bedaquiline-containing regimens are pitted against both the nine-month regimen and the old 20/24-month regimen. Earlier thinking was that STREAM stage II would only contain the nine-month regimen as a control – it having been assumed that the nine-month regimen would be non-inferior to the 20/24-month regimen. Since this non-inferiority has not been shown, the insurance option of maintaining the 20/24-month arm as a control has been vindicated.