High dose pills can be tested on HIV patients with TB meningitis
Researchers have confirmed that it is worthwhile to begin testing whether high doses of the drug rifampicin can save HIV patients with tuberculosis meningitis.
Up to 3 in every 5 HIV patients who also get tuberculosis meningitis die because of this disease, which attacks the nervous system. Survivors are commonly left with permanent damage to their central nervous system and important nerves that run from the brain. This can affect their emotions and movement. Some patients have seizures or strokes, or parts of their face or body become paralysed.
Rifampicin, a strong antibiotic drug used against tuberculosis, is normally given as capsules to try and kill the bacteria that causes tuberculosis meningitis. Very sick patients often find the pills difficult to swallow.
Rifampicin can also be given intravenously (in veins) in liquid form. A needle is then inserted into a patient’s vein so that the fluid can be released into the body.
No tests have yet been done to find out how a patient’s body takes up the medicine when this method is used.
Intravenous treatment requires more equipment, hospitalisation and a trained health worker who knows how to insert an intravenous needle correctly. It is therefore not necessarily an option in under-resourced areas of the world.
Doctors already know that rifampicin is not taken up well by the fluid in the brain, spine and skull, which is where the bacteria can hide. That is why high doses (amounts) are needed to effectively kill all bacteria in a patient’s body.
But researchers were unsure how high a dose could be both effective and safe.
South African and United Kingdom researchers thus wanted to find out, using a small number of patients, if it is safe to give high doses of rifampicin either as capsules or intravenously, and how their bodies will take up each version.
It is important to know this before other researchers start with larger trials, or tests, in which they plan to give many more patients high doses of rifampicin.
One of three types of rifampicin treatment was given to 46 HIV-positive South African patients with tuberculous meningitis. The first was the standard treatment of capsules currently given to patients, totalling 10mg of rifampicin for each kilogram that the patient weighs. Another group received high dose capsules of 35 milligrams per kilogram of a patient’s weight. A third group intravenously received 20 milligrams per kilogram of a person’s weight.
Blood samples were taken from the patients after three days. The researchers then measured how much rifampicin was present in their blood plasma (the liquid part of blood).
More rifampicin was found in the bodies of patients who received high dose capsules than of those who received intravenous treatment or the standard dose.
The concentration of the drug in the blood plasma was the same for the high dose and intravenous treatment. These concentrations were higher than when patients only received the standard dose.
According to the researchers, this shows that the health of patients suffering from tuberculosis meningitis can be improved if they receive higher doses of rifampicin. It doesn’t matter if they receive it as pills or intravenously - what matters is that they receive higher doses, because their bodies are then able to store higher concentrations of it.
The results support the findings of trials done in Uganda and Indonesia. Two small trials in Indonesia for instance suggested that the lives of many more patients can be saved if they are given higher doses of rifampicin either orally or intravenously.
Unfortunately though, researchers caution that fewer participants took part in this study than they initially had hoped for, which might compromise their results.
The study was done in South Africa. It supports the plan to run trials to test whether it is worthwhile to give HIV patients with tuberculosis meningitis high doses of rifampicin. It is hoped that such treatment will save more lives of people in Africa and in other areas of the world where tuberculosis meningitis is a major problem.
Higher doses of intravenous rifampicin may improve outcomes in tuberculous meningitis but are impractical in high-burden settings. We hypothesized that plasma rifampicin exposures would be similar between oral dosing of 35 mg/kg of body weight and intravenous dosing of 20 mg/kg, which has been proposed for efficacy trials in tuberculous meningitis. We performed a randomized parallel-group pharmacokinetic study nested within a clinical trial of intensified antimicrobial therapy for tuberculous meningitis. HIV-positive participants with tuberculous meningitis were recruited from South African hospitals and randomized to one of three rifampicin dosing groups: standard (oral 10 mg/kg), high dose (oral 35 mg/kg), and intravenous
(20 mg/kg). Intensive pharmacokinetic sampling was done on day 3. Data were described using noncompartmental analysis, and exposures were compared by geometric mean ratios (GMRs). Forty-six participants underwent pharmacokinetic sampling (standard dose, n = 17; high-dose oral, n = 15; intravenous, n = 14). The median CD4 count was 130 cells/mm3 (interquartile range [IQR], 66 to 253 cells/mm3). The rifampicin geometric mean area under the concentration-time curve from 0 to 24 h (AUC0–24) values were 42.9mg · h/ml (95% confidence interval [CI], 24.5 to 75.0mg ·h/ml) for the standard dose, 295.2mg · h/ml (95% CI, 189.9 to 458.8mg · h/ml) for the high oral dose, and 206.5mg · h/ml (95% CI, 154.6 to 275.8mg · h/ml) for intravenous administration. The rifampicin AUC0–24 GMR was 1.44 (90% CI, 0.84 to 2.21) and the maximal concentration of drug in serum (Cmax) GMR was 0.89 (90% CI, 0.63 to 1.23) for high-dose oral administration with respect to intravenous dosing. The plasma rifampicin AUC0–24 was higher after an oral 35-mg/kg dose than with intravenous administration at a 20-mg/kg dose over the first few days of tuberculosis (TB) treatment. The findings support oral rifampicin dosing in future tuberculous meningitis trials.
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