Managing Drug Interactions in the Treatment of HIV-Related Tuberculosis

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Recommendations

The Role of Rifamycins in Tuberculosis Treatment

Rifamycins are an Essential Part of Successful Tuberculosis Treatment
Rifamycins play a key role in the success of tuberculosis treatment. Therefore, despite the complexity of drug interactions between rifamycins and antiretrovirals, treatment of HIV-related tuberculosis requires their co-administration. This should not be avoided by using tuberculosis treatment regimens that do not include a rifamycin or by withholding antiretroviral therapy until completion of anti-tuberculosis therapy. In randomized trials, regimens without rifampin or in which rifampin was only used for the first two months of therapy resulted in higher rates of tuberculosis treatment failure and relapse.^{15, 16} Although efforts are underway to identify new sterilizing drugs that can prevent relapse as effectively as rifampin, there are currently no good substitutes for rifamycins. Therefore, patients with HIV-related tuberculosis should be treated with a regimen including a rifamycin for the full course of tuberculosis treatment, unless the isolate is resistant to the rifamycins or the patient has a severe side effect that is clearly due to the rifamycins (Table 1a and 1b).

Frequency of Rifamycin Dosing
Patients with advanced HIV disease (CD4 cell count < 100 cells/mm³) have an increased risk of acquired rifamycin resistance if treated with a rifamycin-containing regimen administered once-, twice-, or thrice-weekly, especially during the intensive phase (first 2 months) of therapy, when bacillary load is still quite high. ^17-19 Tuberculosis drugs, especially rifamycins, should be administered 5 to 7 days per week for at least the first 2 months of treatment to patients with advanced HIV disease. ^19a

Predicting Drug Interactions Involving Rifamycins
Rifamycins are notorious for causing drug interactions because they induce (or upregulate) multiple drug metabolizing enzymes and drug transporters. Rifampin, for example, is a potent inducer of cytochrome P450 enzyme 3A, the enzyme subfamily responsible for metabolizing a large proportion of drugs currently on the market, as well as other cytochrome P450 enzymes. The rifamycins vary in their potential to induce cytochrome P450 enzymes, with rifampin and rifapentine being much more potent inducers than rifabutin. Rifampin also induces Phase II metabolizing enzymes, which are responsible for biotransformations such as glucuronidation and sulfation, as well as the efflux pump p-glycoprotein and other drug transporters.

Induction of these enzymes can lead to reduced plasma concentrations of co-administered drugs that are substrates of these enzymes. For example, since most of the protease inhibitor and NNRTI classes of antiretrovirals as well as the CCR5 antagonist maraviroc are metabolized by CYP3A4, induction of CYP3A4 by rifampin can lead to reduced serum concentrations of these antiretroviral drugs with the attendant risks of HIV treatment failure and emergence of antiretroviral drug resistance. Similarly, rifampin upregulates the synthesis of UDP-glucuronosyltransferase 1A1, which is the enzyme that metabolizes integrase inhibitors, including raltegravir.²⁰ Knowledge of the metabolic pathway(s) of a drug can help the clinician predict the likelihood of a drug interaction with co-administered rifamycins. The magnitude and the clinical relevance of the interaction, however, usually must be determined experimentally in clinical studies.