A novel TB drug regimen that could treat drug-sensitive and some forms of drug-resistant TB far more quickly than current standard TB therapy, according to findings from a phase IIb trial were presented today at the 20th International AIDS Conference (AIDS 2104) in Melbourne, Australia.
The new regimen has the potential to reduce the treatment time for multidrug-resistant TB from 24 months to 6 months, as well as eliminating the need for the use of injectable antibiotics. It also has the potential to cure drug-sensitive TB within four months.
A regimen of the fluoroquinolone antibiotic moxifloxacin (M), with the nitroimidazole antibiotic Pa-824 (PA), and pyrazinamide (Z), called PaMZ, was given to 181 people with drug-sensitive TB and 26 people with multidrug-resistant (MDR) TB. PaMZ had excellent bactericidal activity in people with drug-sensitive TB over 14 days in a previous study and can be used for multidrug-resistant TB because it minimises the risk of cross-resistance with drugs used in standard regimens for drug-sensitive TB.
Phase IIb trials evaluate the efficacy and safety of a novel therapy and determine which dosage is most efficacious. This study was conducted over eight sites in Tanzania and South Africa.
A total of 181 smear-positive people with drug-sensitive TB were randomised to receive a daily regimen of 400mg moxifloxacin, 100 mg Pa-824 and 1500mg pyrazinamide (M-PA100-Z), or the same regimen with 200mg Pa-824 (M-PA200-Z) or standard treatment of weight-adjusted isoniazid (H), rifampicin (R), pyrazinamide (Z), and ethambutol (E) (HRZE) for eight weeks of treatment. People with MDR-TB received M-PA200-Z. In the study, 19.5% of the participants (n = 35) had HIV co-infection. Participants living with HIV continued on the same ART regimen they were receiving or, if newly infected, started ART within a few weeks after starting TB treatment.
The primary endpoint was the rate of change in colony forming units (CFU) from sputum on solid culture over eight weeks. This gives an early indication of the speed at which an experimental TB treatment regimen is preventing TB bacteria from replicating.
Five secondary endpoints included the change in the time to sputum negativity in liquid culture and median time to conversion to negative growth and percentage negative growth in solid and liquid culture at eight weeks. These measures provide more sensitive tests of the regimens’ effects on bacterial activity.
All three experimental treatment arms had greater average reductions in CFU counts than HRZE over eight weeks, which was statistically significant for the M-PA200-Z arm (p< 0.05).
The log CFU daily decreases over 56 days for the M-PA200-Z treatment arm (n = 56) was 0.155 (95% CI: 0.133-0.178, p ≤ 0.05). For the M-PA100-Z treatment arm, the log CFU daily decreases was found to be 0.133 (95% CI: 0.109-0.155) and for the standard treatment regimen of HRZE it was 0.112 (95% CI: 0.093-0.131). The rate of decline in CFU over days 7-14 correlated highly with that over days 7-56, with correlation coefficients ranging from 0.90-0.98.
“Hopefully more people will comply with a shorter regimen of two months, so less drug-resistance will develop in the future. The cost of TB treatment could also be reduced by 90% in some parts of world if PaMZ is used”, said Dr Daniel Everitt of the TB Alliance, who was presenting the study.
Almost twice as many TB patients treated with PaMZ produced TB-negative sputum cultures in the eight-week course of the trial, compared to people treated with standard therapy: 71% of people treated with PaMZ were found to be clear of bacteria in their sputum at the end of two months, when evaluated with liquid culture, the most sensitive diagnostic method available. Only 38% of those treated with the standard therapy (HRZE) were clear at eight weeks.
In the MDR-TB arm, the log daily CFU decrease using M-PA200-Z was 0.117 (95% CI: 0.070-0.174). Although only nine people with MDR-TB could be included in the statistical analysis due to late exclusions for pyrazinamide resistance, the results are promising for PaMZ to be a 6-month treatment for MDR-TB compared to the current 2-year treatment regimen. This will result in a reduction in pill burden, economic cost and less time out of work for people with MDR-TB.
M-PA200-Z was also significantly more efficacious than HRZE in three of the five secondary outcome measures. There were no differences from the above when adjusted for site, HIV status or baseline CFU as baseline co-variates.
30%, 32% and 23% of participants in the Pa100-M-Z, PA200-M-Z and Pa200-M-Z MDR groups, respectively, experienced at least one Grade 3 adverse event and only 5%, 15% and 8% respectively experienced a Grade 4 adverse event.
On the basis of these data, TB Alliance will advance PaMZ to a global phase III clinical trial named STAND (Shortening Treatment by Advancing Novel Regimens) by the end of 2014, provided adequate funding is secured.
The study will comprise of five treatment arms of 300 participants each. The first two arms will receive Pa(100mg)-M-Z and Pa(200mg)-M-Z for four months. The third arm will receive Pa(200mg)-M-Z for six months and the fourth arm will receive HZRE for six months. These four treatment arms for drug-sensitive TB will be randomised. The drug-resistant TB arm will also receive Pa(200mg)-M-Z for six months. Participants in the study will be followed up at 12 and 24 months after randomisation.
If it proves effective in a phase III trial, the new regimen would reduce the pill burden associated with MDR-TB treatment by 97% and reduce its cost dramatically. Both moxifloxacin and pyrazinamide are generic antibiotics, and the TB Alliance estimates that the new regimen might reduce the cost of MDR-TB treatment by 90%.
Everitt D et al. Randomized trial of the bactericidal activity of 8-weeks treatment with moxifloxacin, Pa-824, and pyrazinamide in drug sensitive and multi-drug resistant tuberculosis. 20th International AIDS Conference, abstract MOAB0202, Melbourne, 2014.