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Case 2: Discussion

Concurrent treatment of HIV infection and tuberculosis is complex because of the numerous potential drug-drug interactions. Among the drugs used to treat tuberculosis, the 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 and uridine diphosphate glucuronosyltransferase (UGT) 1A1 enzymes and thus can potentially lower blood levels of other drugs that utilize this pathway of metabolism, including many antiretroviral medications[1]. Rifampin is a potent enzyme inducer whereas rifabutin acts as a more moderate enzyme inducer. Clinicians should avoid using rifapentine in HIV-infected individuals because of insufficient data related to its safety, drug interactions, and efficacy. 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 usually exist, particularly with the use rifabutin. Recomendations 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[2,3,4].

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 cytochrome P450 enzymes. One exception occurs with concomitant use of zidovudine (Retrovir) and rifampin, since both zidovudine and rifampin are cleared by glucuronidation. The interaction between zidovudine and rifampin results in a 47% decrease in the AUC concentration of zidovudine[9]. Nevertheless, no dose adjustment is recommended[4], presumably because the correlation of serum levels and intracellular levels of zidovudine remains poorly defined.

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 and some experts recommend increasing the efavirenz dose to 800 mg once daily in patients who weigh more than 60 kg[4]. Of note, however, one randomized trial showed no benefit of efavirenz 800 mg daily when compared with 600 mg daily[7] and one small observational trial showed high efavirenz levels and increased central nervous system toxicity in seven of nine patients treated rifampin plus efavirenz 800 mg daily[8]. Rifampin lowers nevirapine (Viramune) levels by 20 to 58% and most experts do not recommend using this combination[4]. Although limited data exist with the combinations of rifampin and etravirine (Intelence) or rifampin and rilpivirine (Edurant), the coadministration of these drugs should be avoided because of the potential significant decrease in plasma etravirine and rilpivirine concentrations. Rifampin causes a dramatic decrease (approximately 95%) in delavirdine blood levels. When using rifabutin and efavirenz together, the rifabutin dose should be increased from the standard dose of 300 mg once daily to 450 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[4]. If etravirine is used with a ritonavir-boosted protease inhibitor, then rifabutin should not be administered; otherwise. The use of rifabutin with either rilpivirine or delavirdine is not recommended.

Rifamycins and Protease Inhibitors

The protease inhibitors (PIs) have major interactions with the rifamycins: rifampin can dramatically lower the levels of all protease inhibitorsand levels of rifabutin can increase significantly when combined with protease inhibitors (Figure 2). Earlier recommendations suggested rifampin could be used in combination with selected protease inhibitors if the protease inhibitor was "super-boosted" with high dose-ritonavir; the recommendedation pertained to saquinavir (Invirase) plus ritonavir (Norvir), both dosed 400 mg twice daily, and lopinavir-ritonavir (Kaletra) if 300 mg twice daily of ritonavir was added to the standard lopinavir-ritonavir dose. Recent guidelines, however, recommend avoiding concomitant use of rifampin with all protease inhibitors, even if high dose ritonavir is used to boost the protease inhibitor[4]. The use of rifabutin with a protease inhibitor typically causes a minor decreases in the protease inhibitor level. More importantly, rifabutin levels significantly increase as a result of protease inhibitor inhibition of cytochrome P450 enzymes. Accordingly, rifabutin doses need decreasing when combined with protease inhibitors (typically reduced to 150 mg every other day or three times per week)[4]. In this setting, some experts recommend using rifabutin 150 mg daily or 300 mg three times per week.

Rifamycins and Integrase Strand Transfer Inhibitors

The integrase strand transfer inhibitor (INSTI) raltegravir (Isentress) undergoes metabolism by the glucuronidation pathway via UGT1A1 enzymes and thus has potential interactions with the rifamycins. Rifampin, and to a lesser extent rifabutin, can induce UGT1A1 enzymes and thus impact raltegravir levels (Figure 3). Specifically, rifampin coadministered with raltegravir lowers the AUC of raltegravir by 40% and the Cmin by 61%[5]. Accordingly, it is recommended that the dose of raltegravir is increased from 400 mg twice daily to 800 mg twice daily, but even with this increased dose the raltegravir trough levels are still reduced[5]. Thus, rifampin use concomitantly with raltegravir should be used cautiously. Although rifabutin can alter raltegravir levels, investigators have shown this alteration does not alter raltegravir to a clinically meaningful degree[6]. Raltegravir does not significantly alter the levels of the rifamycins.

Rifamycins and CCR5 Antagonists

The CCR5 antagonist maraviroc (Selzentry) is metabolized by the CYP3A pathway and thus can interact with the rifamycins. The dose adjustment of the maraviroc when used with either rifampin or rifabutin depends on whether an additional strong inducer or inhibitor is used (Figure 4).

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    Figure 1. Managing Drug Interactions with Non-Nucleoside Reverse Transcriptase Inhibitors and Rifamycins
    This figure is adapted from information contained in Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. January 10, 2011; 1–166.

    Figure 1
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    Figure 2. Managing Drug Interactions with Protease Inhibitors and Rifamycins
    This figure is adapted from information contained in Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. January 10, 2011; 1–166.

    Figure 2
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    Figure 3. Managing Drug Interactions with Integrase Strand Transfer Inhibitors and Rifamycins
    This figure is adapted from information contained in Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. January 10, 2011; 1–166.

    Figure 3
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    Figure 4. Managing Drug Interactions with CCR5 Antagonists and Rifamycins
    This figure is adapted from information contained in Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. January 10, 2011; 1–166.

    Figure 4