A new tuberculosis treatment regimen has been shown to be safe and effective in a clinical trial conducted in southern Africa. However, the high cost and a lack of clear support from producers mean that access to the drug in the South African public sector is unlikely for years to come.

The RIFAQUIN trial

Tuberculosis (TB) treatment consists of a combination of four medicines taken daily for two months, followed by two medicines taken daily for another four months – a total of six months of treatment. Researchers are exploring ways in which the duration of treatment and the number of pills that patients must take can be reduced.

The results of the RIFAQUIN trial were reported recently at the 2013 Conference on Retroviruses and Opportunistic Infections held in Atlanta in the USA.

In this trial researchers compared the current standard treatment against two experimental alternatives: one regimen that also lasted six months (but with fewer pills), and one that only lasted four months.

The researchers reported that the six-month experimental regimen was non-inferior to (i.e. it was at least as good as) the current standard treatment. 5% of the 163 patients who received the standard treatment had unfavourable outcomes compared to 4% of the 187 patients on the six-month experimental treatment. Those on the four-month treatment did much worse: 17% of patients had unfavourable outcomes. (These included treatment failure, relapse, and death.)

In other words, patients who took moxifloxacin and rifapentine only once a week for the last four months did as well as patients who took isoniazid and rifampicin every single day for the last four months. This means the experimental regimen is as effective as the current standard treatment, but with a much lower pill burden.

Taking treatment just once a week is likely to be more convenient for patients and may require fewer visits to the clinic, depending on how the treatment is be rolled out. Similarly, where treatment has to be directly observed by a health worker, it will require much less time to monitor treatment once a week instead of every day.

No rifapentine in South Africa

The RIFAQUIN trial was conducted from 2008 to 2012 in southern Africa and included sites in Cape Town and Johannesburg. Yet, despite the encouraging findings, it seems unlikely that the new regimen will be available here any time soon.

In order to implement the new regimen with its lower pill burden in the South African public health sector we will need access to both affordable moxifloxacin and rifapentine. In the South African private sector a supply of ten 400mg moxifloxacin pills costs over R250 per month. By comparison, a 4-in-1 fixed-dose combination of the current standard regimen costs R38.

The prospects for rifapentine are even worse. Even though the drug was registered with the Food and Drug Administration in the USA in 1998, it has not yet been registered with South Africa’s Medicines Control Council and can therefore not be sold in South Africa. According to the French pharmaceutical company Sanofi, “plans are underway to register rifapentine in South Africa”.

The price of rifapentine in the USA has varied recently between R450 and R660 per month. The drug was patented in the USA in 1970. The patent on rifapentine has expired and there is no barrier to another manufacturer producing a generic version of the medicine.

The trial was conducted in South Africa, and it’s therefore unacceptable that Sanofi has waited so long before trying to register rifapentine with the Medicines Control Council. Registration must be accelerated and rifapentine made available at a reduced price that would allow the state to buy it for use in the public sector TB programme.
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The outcomes of the trial per regimen

Control regimen (standard World Health Organization treatment regimen):

Two months of daily ethambutol, isoniazid, rifampicin and pyrazinamide followed by four months of daily isoniazid and rifampicin.

Unfavourable outcomes (Per-protocol analysis): 5% (8 in 163 participants)

Unfavourable outcomes (Modified intention-to-treat analysis): 14% (27 in 188 participants)

Six-month experimental regimen:

Two months of daily ethambutol, moxifloxacin, rifampicin and pyrazinamide followed by four months of once-weekly moxifloxacin (500mg) and rifapentine (1200mg)

Unfavourable outcomes (Per-protocol analysis): 4% (7 in 187 participants)

Unfavourable outcomes (Modified intention-to-treat analysis): 14% (30 in 213 participants)

Four-month experimental regimen:

Two months of daily ethambutol, moxifloxacin, rifampicin and pyrazinamide followed by two months of twice-weekly moxifloxacin (500mg) and rifapentine (900mg).

Unfavourable outcomes (Per-protocol analysis): 17% (28 in 163 participants)

Unfavourable outcomes (Modified intention-to-treat analysis): 26% (50 in 192 participants)

Per-protocol analysis: This analysis looks only at those study participants who completed the study as prescribed. It excludes people who dropped out of the trial or who stopped taking treatment.

Modified intention-to-treat (ITT) analysis: Normal ITT analysis includes all the study participants who were assigned to a treatment arm – even if they dropped out of the trial or had poor treatment compliance. Modified ITT analysis allows for some specified study participants to be excluded from the analysis.[/box]

This is a simplified and updated version of an article by Nathan Geffen first published in the journal HTB South. HTB South is published by HIV i-Base and can be found at http://i-base.info/htb-south/.