Rifampicin dose can be increased safely in TB treatment, may shorten duration

Mara Kardas-Nelson
Published: 13 November 2013

Increasing the daily dose of rifampicin within the current TB treatment regimen from 10mg/kg to 15mg/kg and 20mg/kg did not result in an increased incidence of adverse events, according to findings from the RIFATOX trial presented at the 44th World Conference on Lung Health in Paris earlier this month.

The antibiotic rifampicin is a mainstay of the regimen for TB treatment recommended by the World Health Organization (WHO). There is some evidence to suggest that using a higher dose of rifampicin in both the induction and continuation phases of TB treatment might have the potential to shorten the duration of treatment. By promoting higher drug levels it might be possible to speed up the clearance of mycobacterium tuberculosis (m.TB).

Rifampicin dosing was determined in the 1960s, with one eye on the high cost of the drug. Trials determined that a dose of 600mg per day was adequate to treat TB, but did not define the highest tolerable dose.

Researchers in the Netherlands and South Africa have subsequently shown in a small study that the rifampicin dose can be safely increased to 35mg/kg, which increased total drug exposure sevenfold. This dose also reduced total colony-forming units of m.TB detectable after two weeks of treatment more rapidly than lower doses. The study results were presented at the 20th Conference on Retroviruses and Opportunistic Infections (CROI) in March 2013.

A separate research group, the International Consortium for Trials of Chemotherapeutic Agents in Tuberculosis (INTERTB), was already exploring the potential for reducing the duration of TB treatment by increasing the rifampicin dose when these results were presented.

The phase II RIFATOX trial was designed to evaluate whether increasing the daily dose of rifampicin would increase adverse events, given that rifampicin can have a negative impact on the liver, and furthermore whether it would increase culture conversion rates after eight weeks of treatment when compared with current dosing.

The randomised control trial included 300 HIV-negative people with newly diagnosed, microscopy positive pulmonary TB in Nepal, Bolivia, and Uganda. Study participants had to be over 18 years of age, never have received anti-tuberculosis chemotherapy, and give two positive sputum specimens before taking treatment. Women of childbearing age could not be pregnant or breastfeeding, and had to agree to use a form of contraception throughout the duration of treatment. Those with a weight below 35kg, with an AST or ALT level – measures of liver function – more than five times above the upper normal limit were excluded, as were people with severe anaemia (haemoglobin below 7g/l), and those with any disease likely to be negatively associated with rifampicin response, such as insulin-dependent diabetes or liver or kidney disease.  The majority of participants (150) were from the Bolivia site.

All enrolled patients received the standard six-month TB treatment regimen. They were randomly assigned to receive either standard WHO-recommended treatment that consists of ethambutol, isoniazid, pyrazinamide, and 10 mg/kg of rifampicin (called the control regimen); or the same regimen but with a higher rifampicin dose of either 15mg/kg (regimen 1) or 20mg/kg (regimen 2) for the first four months of treatment (all participants received 10mg/kg for the last two months of treatment). There were 84 people in the control group, 84 people received regimen 1, and 82 people received regimen 2.

Sixty-eight per cent of all participants were male, with a median age of 29 years. Liver function tests were carried out at 2, 4, 8, 12, and 16 weeks. Patients were tested for TB after 8 weeks of treatment. The primary outcome of the study was to consider the occurrence of grade 3 and 4 adverse events – that is, those that are severe or potentially life-threatening – for the first four months of treatment. The secondary outcome was the rate of culture conversion at two months.

Of the 32 reported adverse events, only one, from the regimen 1 arm, was hepatic – that is, liver-related, and therefore considered severe. As such, the researchers concluded that rifampicin at both 15mg/kg and 20mg/kg did not result in an increase in adverse events. However, a linear regression analysis done by the researchers showed a trend for higher ALT levels with increasing dosages. As such, the researchers suggest caution with further dose increases going forward.

Of the 300 people enrolled, culture conversion results were presented from 250 people who had completed four months of treatment. Given that there were 38 late screening failures and withdrawals, there were only pre-treatment and 8-week culture results for 220 people. Of these, 80.5% of patients receiving the control regimen had a culture conversion at eight weeks, versus 85% taking regimen 1, and 85.5% taking regimen 2. Clinical investigator Amina Jindani says that these differences in conversion rates are not statistically significant.

Given the results of the RIFATOX trial, Jindani says, “there is a very strong case for pursuing the high rifampicin angle for treatment shortening fairly rapidly. The latest vaccine trial failed to confer protection to the participants. The OFLOTUB trial showed that fluoroquinolones – at least, gatifloxacin, as well as moxifloxacin in [the] RIFAQUIN [trial]) – have not reduced treatment duration. That leaves rifampicin. Now that we have some reassurance about the safety of 1200mg [per day], the logical next step is to follow this with an efficacy trial… Our consortium (INTERTB) has applied for funding to carry out just such a trial and are waiting to hear the outcome.”