PK and TB Drug Interactions Substudy

Tuberculosis is one of the most common opportunistic infections in HIV-infected people taking antiretroviral therapy (ART). Concomitant use of the anti-TB drug rifampicin and many antiretroviral drugs is complicated by drug-drug interactions, which can result in sub-therapeutic antiretroviral drug concentrations. The alternative strategy followed in resource-rich settings is to replace rifampicin with rifabutin. Pharmacokinetic studies in healthy volunteers demonstrated a substantial increase in rifabutin levels when given in the standard dose of 300mg daily if taken with boosted protease inhibitor (bPI), and so the current dosing recommendations are 150mg rifabutin thrice weekly when administered with bPI. However, there is some concern that with the reduced dose, the resulting levels of rifabutin might be inadequate and that this, together with intermittent dosing of the companion anti-tuberculosis drugs, could lead to failure of anti-tuberculosis therapy or TB relapse. 

One barrier to using a higher dose of rifabutin with bPI is the potential for substantial increases in toxicity. A second potential concern is that a higher dose of rifabutin may also increase lopinavir levels. Studies on rifabutin-PI drug-drug interactions in healthy volunteers have been hampered by the occurrence of adverse events which are unacceptable in a healthy population, whereas in clinical management of patients with TB the need to optimise therapeutic efficacy may lead to a higher threshold for discontinuing therapy or reducing dose. 

This pilot randomised open-label pharmacokinetic substudy will therefore compare 150mg rifabutin daily versus thrice weekly, both in combination with lopinavir/ritonavir taken as part of second-line ART in the EARNEST trial of second-line antiretroviral therapy, in terms of (i) toxicity, (ii) pharmacokinetics of rifabutin, lopinavir/ritonavir, raltegravir and (iii) PK/PD (pharmacokinetic/pharmacodynamic) relationships.

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