Managing Drug Interactions in the Treatment of HIV-Related Tuberculosis

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Rifabutin and Antiretroviral Drugs

Rifabutin is as effective for tuberculosis treatment as rifampin ^{38, 39}, but has much less effect on drugs metabolized through the CYP3A system ⁴⁰ (Table 3). However, rifabutin is either not available or is very expensive in countries with high rates of HIV-related tuberculosis. Furthermore, some antiretroviral drugs have a substantial effect on rifabutin concentrations, necessitating somewhat complex dosing guidelines for rifabutin in the setting of antiretroviral therapy (see Table 3). In addition to their complexity, there is another potential problem of using rifabutin for tuberculosis treatment. If a patient whose rifabutin dose was decreased in response to antiretroviral therapy then stops taking the interacting drug (e.g., ritonavir), the resulting rifabutin concentrations are likely to be sub-therapeutic. These factors, in addition to the limited availability of the drug, limit the use of rifabutin in the treatment of HIV-related tuberculosis.

Rifabutin and Protease Inhibitors

Rifabutin has little, if any effect on the serum concentrations of protease-inhibitors (other than unboosted saquinavir) ²². Cohort studies have shown favorable virological and immunological outcomes of protease-inhibitor-based antiretroviral therapy in the setting of rifabutin-based tuberculosis treatment ^{1, 41}. Though no comparative studies have been done, the combination of rifabutin (if available) with protease-inhibitor based antiretroviral therapy is the preferred form of therapy for patients unable to take NNRTI-based antiretroviral therapy (Table 1). As above, there are concerns about the safety of super-boosted protease-inhibitors and the efficacy of nucleoside-only regimens in the setting of rifampin-based tuberculosis treatment.

The protease-inhibitors, particularly if pharmacologically boosted with ritonavir, markedly increase serum concentrations and toxicity of rifabutin ⁴². Therefore, the dose of rifabutin should be decreased when used with protease-inhibitors (Table 3). As above, the decreased dose of rifabutin would be sub-therapeutic if the patient stopped taking the protease-inhibitor without adjusting the rifabutin dose. Therefore, adherence to the protease-inhibitor should be assessed with each dose of directly observed tuberculosis treatment; one convenient way to do so is to give a supervised dose of protease-inhibitor at the same time as the directly observed dose of tuberculosis treatment.