Managing Drug Interactions in the Treatment of HIV-Related Tuberculosis

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Recommendations

Managing Drug Interactions with Antiretrovirals and Rifabutin

Until recently, rifampin was the only rifamycin available in many settings. Rifabutin, though, is now off-patent and available in many countries; access to this drug is rapidly expanding. ⁷⁴ Rifabutin taken at a dose of 300 mg once-daily might be as effective for tuberculosis treatment as rifampin. ^75-79 Compared to rifampin, though, rifabutin has significantly less effect on drugs metabolized by cytochrome p450 3a enzymes; ⁸⁰ this may reduce the magnitude of drug-drug interactions ^{(Table 3)}. However, several issues have negatively influenced its clinical utility. First, cost and/or access have historically precluded its use in most countries with high rates of HIV-related tuberculosis; ⁷⁴ this situation is now changing. Second, drugs that induce or inhibit CYP3A metabolizing enzymes can influence rifabutin concentrations leading to the need for rifabutin dose adjustment, which adds to the complexity of co-treatment. Finally, if a patient whose rifabutin dose was decreased to avoid drug interactions related to co-treatment with antiretroviral therapy subsequently stops taking the interacting antiretroviral drug (e.g., ritonavir), the resulting rifabutin concentrations can become sub-therapeutic, putting the patient at risk of tuberculosis treatment failure or emergence of rifamycin resistance.

Rifabutin and Protease Inhibitors
Rifabutin has little, if any, effect on the serum concentrations of ritonavir-boosted protease-inhibitors. However, rifabutin concentrations are increased when rifabutin is taken together with protease inhibitors. To mitigate the risk for rifabutin-related toxicity (such as uveitis or neutropenia), the previous edition of this guideline recommended giving rifabutin at a dose of 150 mg thrice-weekly to adults taking boosted protease inhibitors. While cohort studies have yielded favorable virological and immunological outcomes of protease-inhibitor-based antiretroviral therapy in the setting of rifabutin-based tuberculosis treatment ^{17, 81} clinical evaluation of the anti-tuberculosis efficacy of that combination remains limited. Some studies suggest that rifabutin concentrations among patients are too low with rifabutin 150 mg given thrice-weekly. ^{82, 83}

In a trial among adults co-infected with HIV and tuberculosis taking ritonavir-boosted lopinavir, a dose of rifabutin 150 mg once daily was relatively well-tolerated and was more likely to achieve target rifabutin concentrations than thrice-weekly dosing of 150 mg.⁸⁴ Given the risk of acquired rifamycin resistance with low rifabutin concentrations, ⁸⁵we recommend rifabutin at a dose of 150 mg daily when given with a boosted protease inhibitor in adults. ^{82, 84, 86} However, clinicians should recognize that there are limited safety data with this dose and combination, and it is unclear whether or not the increase in concentrations of rifabutin and its metabolite resulting from this dose will lead to higher risk of uveitis, neutropenia, or hepatotoxicity. Patients taking this combination should be monitored for rifabutin-related toxicities. ^{87 88}

In addition, therapeutic drug monitoring, if available, is one method for verifying that the desired rifabutin concentrations have been achieved. Since rifabutin 150 mg once daily would be sub-therapeutic if the patient stopped taking the protease inhibitor, 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 a once-daily protease-inhibitor at the same time as the directly observed dose of tuberculosis treatment.

Rifabutin and Other Antiretrovirals

Because efavirenz reduces the concentration of co-administered rifabutin, rifampin is the rifamycin of choice for patients taking efavirenz-based antiretroviral therapy. In a study that evaluated rifabutin concentrations among patients receiving rifabutin twice-weekly, increasing the rifabutin from 300 mg to 600 mg in patients taking efavirenz-based antiretroviral therapy resulted in concentrations that were similar to those achieved among patients taking rifabutin 300 mg without efavirenz. ⁸⁹ However, other rifabutin dosing frequencies, such as thrice-weekly or daily, have not been evaluated.

Given that nevirapine concentrations may be diminished among patients taking rifampin-containing tuberculosis treatment, rifabutin may be an option for patients taking nevirapine-based antiretroviral treatment. In a pharmacokinetic study among patients receiving nevirapine at standard doses and rifabutin at 300 mg daily, neither drug significantly impacted the concentrations of the other. ⁹⁰ Therefore, dose adjustment is unlikely to be necessary, although clinical evaluations of the safety and efficacy of this combination in larger numbers of patients are needed.

Trough concentrations of etravirine are reduced by 35% by rifabutin, and etravirine reduces rifabutin concentrations by 17%. These changes are unlikely to be clinically significant, so no dose adjustment is recommended.⁴⁷ There is, however, limited clinical experience with this combination. Although overall raltegravir concentrations are not significantly affected by rifabutin, trough raltegravir concentrations are diminished modestly (by about 20%) when the two drugs are co-administered. ⁹¹ Until additional data become available, we recommend using standard-dose raltegravir (400 mg twice daily) with rifabutin.Trough concentrations of elvitegravir are reduced by 67% when cobicistat-boosted elvitegravir is given together with rifabutin, so co-dosing of these drugs is not recommended.⁹²