High-dose rifampicin may shorten time to TB clearance

Martin Boeree presenting at CROI 2015. Photo by Liz Highleyman, hivandhepatitis.com

A combination regimen containing high-dose rifampicin (also known as rifampin) was associated with faster tuberculosis (TB) bacteria culture conversion in people with drug-sensitive TB, but moxifloxacin and the experimental drug SQ109 showed no benefit compared to standard therapy, according to results from a study presented at the recent Conference on Retroviruses and Opportunistic Infections (CROI 2015) in Seattle, USA.

An estimated 9 million people develop active TB disease each year and it remains a major cause of death for people with HIV worldwide. Current standard treatment for TB requires multiple drugs taken for six months or longer, which presents difficulties with adherence and toxicity; shorter, well-tolerated regimens are urgently needed.

Martin Boeree from Radboud University Medical Centre in the Netherlands and colleagues conducted the PanACEA MAMS TB 01 trial to evaluate whether high-dose rifampicin, moxifloxacin and/or the experimental drug SQ109 could reduce the time to Mycobacterium tuberculosis culture conversion from positive to negative. The evaluation programme started in 2007 looking at high-dose rifampicin, moxifloxacin and SQ109 separately, and the MAMS TB 01 trial brought the three products together.

Glossary

culture

In a bacteria culture test, a sample of urine, blood, sputum or another substance is taken from the patient. The cells are put in a specific environment in a laboratory to encourage cell growth and to allow the specific type of bacteria to be identified. Culture can be used to identify the TB bacteria, but is a more complex, slow and expensive method than others.

isoniazid

An antibiotic that works by stopping the growth of bacteria. It is used with other medications to treat active tuberculosis (TB) infections, and on its own to prevent active TB in people who may be infected with the bacteria without showing any symptoms (latent TB). 

control group

A group of participants in a trial who receive standard treatment, or no treatment at all, rather than the experimental treatment which is being tested. Also known as a control arm.

hazard ratio

Comparing one group with another, expresses differences in the risk of something happening. A hazard ratio above 1 means the risk is higher in the group of interest; a hazard ratio below 1 means the risk is lower. Similar to ‘relative risk’.

hazard

Expresses the risk that, during one very short moment in time, a person will experience an event, given that they have not already done so.

This open-label trial enrolled adults with drug-sensitive, smear-positive TB at seven sites in South Africa and Tanzania. About 70% were men, the median age was approximately 33 years and 7% were HIV-positive. A total of 368 participants were randomised and five were excluded due to errors, leaving 363 in the modified intention-to-treat analysis.

Participants were randomly allocated to receive one of the following initial regimens, followed by standard doses of rifampicin and isoniazid for a total of 26 weeks of treatment:

  • SQ109, 10mg/kg standard-dose rifampicin, isoniazid and pyrazinamide for 12 weeks
  • SQ109, 20mg/kg rifampicin, isoniazid and pyrazinamide for 12 weeks
  • 20mg/kg rifampicin, moxifloxacin, isoniazid and pyrazinamide for 12 weeks
  • 35mg/kg high-dose rifampicin, ethambutol, isoniazid and pyrazinamide for 12 weeks
  • Standard therapy using 10mg/kg rifampicin, ethambutol, isoniazid and pyrazinamide for 8 weeks (control arm).

The trial had a multi-arm, multi-stage design with one interim analysis, after which recruitment to specific arms could be halted due to lack of efficacy based on pre-specified stopping rules. Recruitment to both SQ109 arms was terminated in March 2014 after the interim analysis. The primary endpoint was stable culture conversion in liquid media over 12 weeks.

In the final analysis at 12 weeks, 63% and 57% of participants in the two SQ109 arms, 79% in the moxifloxacin arm and 80% in the 35mg/kg rifampicin arm experienced stable culture conversion in liquid media, compared to 70% in the standard therapy arm.

The researchers also analysed data at 8 weeks so it could be directly compared to previous phase 2 TB trials using shorter initial therapy. In this analysis, the proportions with stable culture conversion were 41% and 32% in the SQ109 arms, 60% in the moxifloxacin arm and 56% in the 35mg/kg rifampicin arm, compared with 42% in the standard therapy arm.

At 12 weeks, the SQ109 arms showed no reduction in time to culture conversion (63 and 66 days) compared to standard therapy (62 days), while the moxifloxacin arm reduced clearance time somewhat (to 55 days) and the 35mg/kg rifampicin arm produced the greatest reduction (48 days).

In the 12-week analysis, the adjusted hazard ratios for the four investigational arms compared to the control arm were 0.82, 0.73, 1.42 and 1.75, respectively, with the last being a statistically significant improvement. In the 8-week analysis, the adjusted hazard ratios were 1.05, 0.91, 1.69 and 1.99, respectively, with the latter two being statistically significant.

When looking at solid media, culture conversion rates were higher overall and more similar across regimens. At 12 weeks, the culture conversion rates were 94% in both SQ109 arms, 98% in the moxifloxacin arm, 100% in the 35mg/kg rifampicin arm and 97% in the control arm.

Treatment with all regimens was generally safe and well-tolerated. Grade 3 or worse adverse events were reported by 12% of participants in both SQ109 arms and 14% of participants in both the moxifloxacin and 35mg/kg rifampicin arms, compared to 10% in the standard therapy arm. Overall frequency of serious adverse events was also similar across arms (7%, 9%, 6%, 6% and 5%, respectively). A total of ten people (three in the SQ109-20mg/kg rifampicin arm, five in the 35mg/kg rifampicin arm and 2 in the control arm) experienced liver-related adverse events leading to a change in treatment.

"35 mg/kg of rifampicin resulted in an increased likelihood of, and shorter time to culture conversion in liquid media, not in solid media," the researchers concluded. "The SQ109 and moxifloxacin arms were not different from [the control arm]."

References

Boeree MJ et al. (on behalf of the PanACEA Consortium) High-dose rifampin, SQ109 and moxifloxacin for treating TB: the PanACEA MAMS-TB trial. 2015 Conference on Retroviruses and Opportunistic Infections (CROI), Seattle, USA, abstract 95LB, 2015.

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