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Rifampicin dose can be increased safely in TB treatment, may shorten duration
Mara Kardas-Nelson, 2013-11-13 13:10:00
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.
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.
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.
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.
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.
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.
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.”
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