Concurrent treatment of HIV infection and tuberculosis remains complex due to the increased potential for drug-drug interactions. The commonly used rifamycins—rifampin (Rifadin, Rimactane), rifabutin (Mycabutin), and rifapentine (Priftin)—have the greatest potential to cause significant interactions with antiretroviral medications. The rifamycins induce the hepatic cytochrome P450 (CYP450), including CYP3A4 and uridine diphosphate glucuronosyltransferase (UGT) 1A1 enzymes, which may lead to decreased blood levels of other drugs dependent on CYP450 for metabolism. This includes many of the antiretroviral medications. Rifampin is a potent enzyme inducer and has the greatest capacity for reduction in blood levels of comcomitantly administered medications. Administration of rifapentine should be avoided, as there are insufficient data related to its safety and clinical efficacy when used in combination with antiretroviral medications. Other commonly used drugs to treat tuberculosis, such as isoniazid, ethambutol, and pyrazinamide, generally do not have significant interactions with antiretroviral drugs. Although problematic drug-drug interactions occur between rifamycins and many antiretroviral medications, options are available, particularly with the use rifabutin. Compared with rifampin, rifabutin has less extensive drug interactions and dose adjustments can be made. Recommendations regarding the use of rifamycins and antiretroviral medications have evolved with significant modifications in recommendations resulting from the introduction of new antiretroviral medications and new information generated with established antiretroviral medications.[,]
Rifamycins and Nucleoside Reverse Transcriptase Inhibitors
The nucleoside reverse transcriptase inhibitors (NRTIs) are not metabolized by the liver and are therefore levels are not significantly impacted by medications that induce or inhibit hepatic CYP450 enzymes. One exception occurs with concomitant use of zidovudine (Retrovir) and rifampin, since both zidovudine and rifampin undergo glucuronidation. The interaction between zidovudine and rifampin results in a 47% decrease in the area under the curve (AUC) of zidovudine. Nevertheless, no dose adjustment is recommended, presumably because the correlation of plasma levels and intracellular levels of zidovudine remains poorly defined. Use of NRTIs with rifamycins does not require dose adjustments.
Rifamycins and Non-Nucleoside Reverse Transcriptase Inhibitors
Among the non-nucleoside reverse transcriptase inhibitors (NNRTIs), significant interactions occur when these medications are combined with either rifampin or rifabutin (Figure 1). Efavirenz (Sustiva) can be used with rifampin, but some experts recommend increasing the efavirenz dose to 800 mg once daily in patients who weigh more than 60 kg. Of note, however, one randomized trial showed no benefit of efavirenz 800 mg daily when compared with 600 mg daily. In addition, one small observational trial showed elevated efavirenz levels and increased central nervous system toxicity in seven of nine patients treated rifampin plus efavirenz 800 mg daily. Rifampin decreases nevirapine (Viramune) levels by 20 to 58% and this combination should be avoided. In addition, the combination of rifampin with either etravirine (Intelence) or rilpivirine (Edurant) should be avoided because of the potential significant decrease in plasma etravirine and rilpivirine plasma levels. When using rifabutin and efavirenz together, the rifabutin dose should be increased from the standard dose of 300 mg once daily to 450 to 600 mg once daily, or 600 mg three times per week; efavirenz induces cytochrome P450 enzymes lowers rifabutin levels by 38%. Although nevirapine can be combined with rifabutin at standard doses of both drugs, this combination should be used cautiously. Rifabutin 300 mg daily may be administered with etravirine, unless a ritonavir-boosted protease inhibitor is concomitantly administered. The use of rifabutin with rilpivirine requires a dose increase in the rilpivirine from 25 mg once daily to 50 mg once daily.
Rifamycins and Protease Inhibitors
The protease inhibitors (PIs) have major interactions with the rifamycins. Rifampin can dramatically lower the levels of all protease inhibitors and levels of rifabutin may increase significantly when combined with protease inhibitors (Figure 2). Current guidelines recommend avoiding concomitant use of rifampin with all protease inhibitors, even if additional ritonavir is used to further boost the protease inhibitor. The use of rifabutin with a protease inhibitor typically causes a minor decreases in the protease inhibitor level. More importantly, rifabutin plasma levels increase significantly as a result of protease inhibitor inhibition of CYP450 enzymes. Accordingly, it is recommneded to decrease the rifabutin dose when combined with protease inhibitors. decreasing when combined with protease inhibitors. Typical reductions of 150 mg once daily or 300 three times per week may be required.
Rifamycins and Integrase Strand Transfer Inhibitors
The integrase strand transfer inhibitors (INSTI) dolutegravir (Tivicay) and raltegravir (Isentress) undergo glucuronidation via the UGT1A1 enzyme, which has the potential for interaction with the rifamycins. Rifampin, and to a lesser extent rifabutin, can induce UGT1A1 enzymes and thus impact raltegravir and dolutegravir levels (Figure 3). Specifically, rifampin coadministered with raltegravir decreases the AUC of raltegravir by 40% and the minimum concentration (Cmin) by 61%.[,] Similarly, rifampin decreases the AUC of dolutegravir by about 50%. The recommended dose increase for raltegravir is 800 mg twice daily and for dolutegravir it is 50 mg twice daily when coadministered with rifampin.[,] Although concomitant use of rifabutin may alter raltegravir and dolutegravir plasma levels,these alterations are not clinically significant and no dose adjustments are recommended. Raltegravir does not significantly alter the levels of the rifamycins. The use of elvitegravir as part of the fixed dose combination of elvitegravir-cobicistat-tenofovir-emtricitabine (Stribild) is not recommended with rifabutin, rifampin, or rifapentine.
Rifamycins and CCR5 Antagonists
The C-C chemokine receptor type 5 (CCR5) antagonist maraviroc (Selzentry) is metabolized by the CYP3A pathway, which may result in interactions with the rifamycins. The dose adjustments of maraviroc depend on the potency of the coadministered CYP3A inducer or inhibitor (Figure 4).