Rifabutin dose inadequate alongside Kaletra

The standard dose of the antibiotic rifabutin, used in the treatment of tuberculosis and other mycobacterial infections, is probably inadequate when used alongside the protease inhibitor Kaletra (lopinavir /ritonavir), US researchers report in the November 1^st edition of Clinical Infectious Diseases.

The study also found that half of HIV-positive patients with active TB had low peak levels of rifabutin even before they began taking Kaletra.

The findings underline the need for further research into interactions between rifabutin and antiretroviral drugs, especially those used frequently in first and second-line treatment in resource-limited settings. More research is also needed to understand the extent to which concentrations of TB drugs are reduced in people with HIV infection when compared to adults or children without HIV.

Rifabutin is used in the United States as an alternative to rifampicin in people taking antiretroviral drugs because it has a lower theoretical risk of drug interactions with protease inhibitors or non-nucleoside reverse transcriptase inhibitors (NNRTIs).

Nevertheless, rifabutin levels are affected by protease inhibitors, and a pharmacokinetic study in healthy volunteers has led to a recommendation that the dose of rifabutin can be reduced from 300mg daily to 150mg three times a week when it is dosed alongside lopinavir/ritonavir.

However, this recommendation has never been validated in people with HIV infection.

In this study, ten patients with active tuberculosis and HIV infection received open-label treatment for two weeks with rifabutin (300mg three times a week), isoniazid, ethambutol and pyrazinamide before initiating antiretroviral treatment containing lopinavir/ritonavir (Kaletra, tenofovir (Viread) and FTC (emtricitabine, Emtriva). At this point, the rifabutin dose was reduced to 150mg three times a week.

Eight out of ten participants were male, eight were African-American, they had a median age of 33.5 years and a median body mass index of 23.1 (neither wasted nor obese). (Research published earlier this year showed that, for another TB drug pyrazinamide, those with higher body weights had inadequate concentrations, leading the researchers to note that current dosing of some TB drugs is likely to be optimal only in people with subnormal body weight.)

Rifabutin levels (C_max, Tmax, AUC_0-24 and AUC_0-48) were measured at three visits: at week 2 to 4 (rifabutin steady state without lopinavir/ritonavir); at week 4 to 5 (rifabutin steady state after dose reduction and addition of lopinavir/ritonavir); and at week 6 to 7, at which point the rifabutin dose was increased if concentrations were below 0.30 ug/ml.

At visit 1, half of patients had below-normal rifabutin peak levels (<0.30ug) and at visit 2, after switching to a lower dose and initiating Kaletra, seven out of ten had a decrease in peak levels, leading to a doubling of the rifabutin dose to 300mg three times a week.

Before the rifabutin dose was doubled, only three of the ten patients had rifabutin peak levels above 0.45ug/ml, the drug level previously associated with a successful treatment outcome in a Tuberculosis Trials Consortium study of rifabutin and isoniazid as TB treatment in HIV-positive people (study 23A). Peak levels below this threshold were associated with an increased risk of relapse or the development of resistance to rifabutin in that study.

The researchers also found that at visits 1 and 2 the AUC_0-24 values were below the levels associated with an increased risk of acquired rifamycin resistance in study 23A. (In this ten-patient study, one patient experienced tuberculosis relapse and the development of rifamycin resistance.)

They concluded that standard dosing of rifabutin in HIV-positive patients (300mg three times a week) is potentially inadequate, and that a dose of 150mg three times a week with Kaletra is also potentially inadequate.

Using data from the study and pharmacokinetic modelling, the researchers estimate that in HIV-positive patients dosing with 450mg of rifabutin five times a week may be necessary to reliably achieve the peak levels and total drug exposure associated with successful treatment outcomes in study 23A.

The study also showed that lopinavir concentrations were low in the majority of patients at visits 2 and 3, and may need to be increased.

The researchers recommend monitoring levels of both rifabutin and lopinavir if they are used together, and adjusting doses accordingly, but this may not be practical in resource-limited settings where rifabutin will become more affordable following an agreement between manufacturer Pfizer and the Clinton HIV/AIDS Initiative. Further research is needed in order to determine the optimal use of rifabutin in resource-limited settings, Professor Gary Maartens of the University of Cape Town told a recent international meeting on TB/HIV research.