RIFAQUIN study demonstrates once-weekly dosing during follow-up phase of TB treatment
Nathan Geffen, CSSR
The results of the much-anticipated RIFAQUIN trial were announced at CROI 2013 by Amina Jindani of St Georges Hospital, University of London. Jindani has been involved in TB trials since the 1960s and her work has informed WHO guidelines.
The RIFAQUIN trial found that a regimen using moxifloxacin and rifapentine was non-inferior to using isoniazid and rifampicin. Moreover, in the continuation phase, moxifloxacin and rifapentine were taken once-weekly compared to the daily dosing required for the standard regimen. 
In mice, a rifapentine, moxifloxacin and pyrazinamide regimen sterilised TB at two months. However, Jindani explained that in clinical studies of rifapentine at 600mg, relapse rates have been unacceptably high and patients with HIV developed resistance to the rifamycin group (rifampicin, rifabutin and rifapentine). The RIFAQUIN trial sought regimens to address this by randomising patients to one of three arms.
- Control regimen (standard WHO): Two months of daily ethambutol, isoniazid, rifampicin and pyrazinamide followed by four months of daily isoniazid and rifampicin.
- Four-month study regimen: Two months of daily ethambutol, moxifloxacin, rifampicin and pyrazinamide followed by two months of twice weekly moxifloxacin (500mg) and rifapentine (900mg)
- Six-month study regimen: Two months of daily ethambutol, moxifloxacin, rifampicin and pyrazinamide followed by four months of once weekly moxifloxacin (500mg) and rifapentine (1200mg)
This trial was designed to detect non-inferiority within a six percent margin. Patients were followed up for 18 months after randomisation. The primary endpoint was the absolute difference in the proportion of unfavourable outcomes, calculated using modified intention-to-treat and per-protocol analyses. The planned sample size was 1,100.
Recruitment began in August 2008 and was completed in August 2011 at which point 827 patients had been enrolled from Johannesburg (n=255), Cape Town (209), Macha (15), Harare (203), Marondera (89) and Botswana (56). After exclusions, withdrawals, loss-to-follow-up and after accounting for missing or contaminated cultures, there were 592 patients included in the modified intention-to-treat (ITT) analysis, of whom 188 were on the control arm, 191 on the four-month regimen and 213 in the six-month regimen.
Baseline characteristics were similar across the three groups. Men comprised 64% of participants. Median (range) age and weight were 32 years (18 – 75) and 53 kg (35 – 82), respectively. Only 28% of the participants were HIV positive, with a median CD4 count of 312 cells/mm3 (IQR: 253-441).
The primary outcomes in the per-protocol analysis of the control and six-month arms were almost identical. In the control arm, of whom 163 patients were assessable, there were two culture-confirmed treatment failures, one death during treatment, four culture-confirmed relapses and one clinical relapse for a total of eight unfavourable outcomes (5%). In the six-month regimen, of whom 187 patients were assessable, there was one death during treatment, five culture-confirmed relapses and one clinical relapse for a total of seven unfavourable outcomes (4%).
Likewise, in the modified ITT analysis, outcomes were almost identical between these two arms. In the control arm, in addition to the unfavourable outcomes listed above, eleven patients changed their regimens, five were lost to follow-up and two were inadequately treated. There was also one further clinical relapse not included in the per-protocol analysis, for a total of 27 unfavourable outcomes out of 188 patients (14%). For the six-month regimen, there were also eleven regimen changes, ten lost to follow-up and one inadequately treated patient for a total of 30 unfavourable outcomes out of 213 patients (14%).
The four-month regimen had significantly worse outcomes on both analyses. In the per-protocol analysis of 163 patients there were 28 unfavourable outcomes (17%) including two culture-confirmed failures, 18 culture-confirmed relapses, six clinically assessed relapses and two patients who were culture-positive when last seen. In the modified intention-to-treat analysis there were 50 unfavourable outcomes (26%). A Kaplan-Meier graph showed that most of the unfavourable outcomes in the four-month regimen were due to relapses in months five to nine.
After the two-month intensive phase, 90% of the six-month intervention arm were culture-negative versus 85% of the control arm. This was on the border of significance (p=0.058).
There were 39 grade three and four adverse events, 13 in the control arm, 11 in the four-month study regimen and 15 in the six-month study regimen.
Adherence was high on all regimens. There were no differences across arms according to HIV status. No rifamycin mono-resistance occurred in any of the arms.
Jindani concluded that the six-month study regimen was non-inferior, safe and well-tolerated. The four-month study regimen was safe and well-tolerated but its efficacy was inferior to the control.
This trial has exciting implications for TB treatment. The 6-month study regimen appears more convenient than the current standard of care. In settings were treatment is directly observed it will require less health worker time to administer, at least from the third month of treatment, and patients will have lower transport to clinic costs and interruptions to their normal schedule.
The cost of these drugs is a barrier to wider use. In the South African private sector, 10 x 400 mg moxifloxacin pills costs over R250 per month.  Rifapentine is not available in South Africa, but according to TB Online the price of 100 x 150 mg pills is $363 (as of 2011).  By comparison, a 4-in-1 fixed dose combination of the standard regimen costs R38.  Unless the cost of rifapentine is dramatically reduced, there is no prospect of this regimen being used at scale in poor countries and this should be an activist priority.
Perhaps the four-month study regimen should not be discarded if a patient-profile can be developed that predicts risk of relapse, though at twice-weekly dosing the four-month regimen is not necessarily more convenient to patients and health-workers than the six-month study regimen.
This trial was funded 5.4 million Euros (5.1m Euros from the European & Developing Countries Clinical Trials Partnership and 270,000 Euros from the Wellcome Trust), excluding drug costs which were donated by Sanofi, Genus and Sandoz. This had considerably lower per patient costs compared to industry-run phase 3 studies. 
- Jindani A et al. 2013. A multicentre randomized clinical trial to evaluate high-dose rifapentine with a quinolone for treatment of pulmonary TB: the RIFAQUIN trial. 20th Conference on Retroviruses and Opportunistic Infections, 3-6 March 2013, Atlanta. Oral late breaker abstract 147LB.
- TAC. 2013. Private sector single exit medicine prices (on 11 March 2013).
- TB Online. Moxifloxacin.
- Silverman E. 2011. Clinical trial costs are rising rapidly. Pharmalot, 26 July.