Tuberculosis

AIDS 2014: Novel PaMZ Tuberculosis Regimen Could Reduce Treatment Duration

A novel tuberculosis (TB) drug regimen could treat drug-sensitive and some forms of drug-resistant TB far more quickly than current standard therapy, according to findings from a Phase 2b trial presented today at the 20th International AIDS Conference (AIDS 2104) in Melbourne, Australia.

[Produced in collaboration with Aidsmap]

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 4 months.

A regimen consisting of the new nitroimidazole antibiotic PA-824 (Pa), the fluoroquinolone antibiotic moxifloxacin (M), and pyrazinamide (Z) -- called PaMZ -- was given to 181 people with drug-sensitive TB and 26 people with multidrug-resistant (MDR) TB.

PaMZ demonstrated excellent bactericidal activity in people with drug-sensitive TB over 14 days in a previous study and can be used for MDR-TB because it minimizes the risk of cross-resistance with drugs used in standard regimens for drug-sensitive TB.

Phase 2b trials evaluate the efficacy and safety of a novel therapy and determine which dosage is most effective. This study was conducted at 8 sites in Tanzania and South Africa. 

A total of 181 smear-positive people with drug-sensitive TB were randomized to receive a daily regimen of 400 mg moxifloxacin, 100 mg PA-824, and 1500 mg pyrazinamide (M-Pa100-Z), or the same regimen with 200 mg PA-824 (M-Pa200-Z), or standard treatment using weight-adjusted isoniazid, rifampicin, pyrazinamide, and ethambutol (called HRZE) for 8 weeks. All participants with MDR-TB received M-Pa200-Z.

In the study, 19.5% of participants (n=35) had HIV coinfection. People living with HIV continued on the same antiretroviral therapy (ART) regimen they were already receiving or, if newly diagnosed, started ART within a few weeks after starting TB treatment.

The primary endpoint was the rate of change in Mycobacterium tuberculosis colony-forming units (CFU) from sputum on solid culture over 8 weeks. This gives an early indication of the speed at which an experimental TB treatment regimen is preventing bacteria from replicating.

There were 5 secondary endpoints including 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 8 weeks. These measures provide more sensitive measures of the regimens' effects on bacterial activity.

The experimental treatment arms produced greater average reductions in CFU counts than HRZE over 8 weeks, which was statistically significant for the M-Pa200-Z arm.

For drug-sensitive patients, the log CFU daily decrease over 56 days for the M-Pa200-Z treatment arm (n=56) was 0.155. For the M-Pa100-Z treatment arm, the log CFU daily decrease was found to be 0.133, and for the standard HRZE treatment regimen it was 0.112. 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 2 months, so less drug-resistance will develop in the future," said Daniel Everitt of the TB Alliance, who presented the study. "The cost of TB treatment could also be reduced by 90% in some parts of world if PaMZ is used." 

Almost twice as many drug-sensitive TB patients treated with PaMZ produced TB-negative sputum cultures during the 8-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 2 months, when evaluated with liquid culture, the most sensitive diagnostic method available. Only 38% of those treated with HRZE were clear at 8 weeks. 

In the MDR-TB arm, the log daily CFU decrease using M-Pa200-Z was 0.117. Although only 9 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 on 3 of the 5 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 M-Pa100-M-Z, M-Pa200-Z, and M-Pa200-Z MDR groups, respectively, experienced at least 1 Grade 3 adverse event, and only 5%, 15%, and 8%, respectively, experienced a grade 4 adverse events.

On the basis of these data, TB Alliance will advance PaMZ to a global Phase 3 clinical trial named STAND (Shortening Treatment by Advancing Novel Regimens) by the end of 2014, provided adequate funding is secured.

The study will consist of 5 treatment arms of 300 participants each. The first 2 arms will receive M-Pa100-Z and M-Pa200-Z for 4 months. The third arm will receive M-Pa200-Z for 6 months, and the fourth arm will receive HZRE for 6 months. These 4 treatment arms for people with drug-sensitive TB will be randomized. The drug-resistant TB arm will also receive M-Pa200-Z for 6 months. Participants in the study will be followed up at 12 and 24 months after randomization.

If it proves effective in a Phase 3 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%.

7/21/14

Reference

D Everitt, R Dawson, A Diacon, 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 (AIDS 2014). Melbourne, July 20-25, 2014. Abstract MOAB0202.