Drug Interactions between atazanavir / cobicistat and Rifadin

CONTRAINDICATED: Coadministration with rifampin may significantly decrease the plasma concentrations of most protease inhibitors (PIs) except ritonavir. The mechanism is rifampin induction of CYP450 3A4, the isoenzyme responsible for the metabolic clearance of PIs. In pharmacokinetic studies, the interaction has been associated with a 75% to 95% reduction in plasma PI concentrations and systemic exposure (AUC).

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiretroviral drug levels, alternative antimycobacterial agents should be considered in patients already receiving effective PI-containing antiretroviral therapy. For treatment of latent tuberculosis (TB) infection, a nine-month regimen of isoniazid may be considered if feasible. For treatment of HIV-related TB, a regimen that includes rifabutin is generally preferred, as rifabutin appears to be as effective as rifampin but is a much less potent inducer of CYP450 3A4. Nonrifamycin-containing regimens may be suboptimal (higher mortality rates; higher rates of treatment failure and relapse; increased adverse effects; longer treatment duration) and are usually not recommended for HIV-related TB except in patients who are intolerant of rifamycins or infected with a rifamycin-resistant isolate. Alternatively, rifampin may be used at usual dosages in patients receiving an antiretroviral regimen that includes ritonavir 600 mg or 400 mg twice a day in combination with another PI at a reduced dosage. In patients who have not begun antiretroviral therapy at the time TB treatment is initiated, clinicians may also consider using rifampin and postponing antiretroviral therapy. With early HIV disease, it may be reasonable to monitor CD4 cell count and postpone antiretroviral therapy until TB treatment is complete, since there is low risk of HIV disease progression or death during this period. However, the optimal time for starting antiretroviral therapy should be individualized based on initial response to TB treatment and occurrence of side effects. In patients with low CD4 cell counts, clinicians may consider delaying antiretroviral therapy until after the first one or two months of TB therapy, as side effects are common during this multi-drug phase of TB treatment and may overlap with those of antiretroviral medications. Moreover, delaying antiretroviral therapy may ameliorate adherence issues and decrease the frequency and severity of paradoxical reactions (i.e., immune restoration syndromes resembling exacerbation of TB that sometimes occur after initiation of antituberculosis treatment in patients receiving potent antiretroviral therapy). Rifabutin can be substituted approximately 2 weeks before the planned initiation of antiretroviral therapy to allow time for rifampin's enzyme induction effects to wane. In general, treatment of TB in the context of antiretroviral therapy is complex and requires an individualized approach. Experts in the treatment of HIV-related tuberculosis should be consulted, and TB and HIV care providers should work in close coordination throughout treatment.

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CONTRAINDICATED: Coadministration with potent inducers of CYP450 3A4 may significantly decrease the plasma concentrations of cobicistat, which is primarily metabolized by the isoenzyme. In a study of 12 healthy volunteers, coadministration of the potent CYP450 3A4 inducer carbamazepine (200 mg twice daily) with cobicistat-elvitegravir (150 mg-150 mg once a day) reduced the cobicistat systemic exposure (AUC) and peak plasma concentration (Cmax) by 84% and 72%, respectively, and the elvitegravir AUC and Cmax by 69% and 45%, respectively. In addition, the AUC and Cmax of carbamazepine increased by 43% and 40%, respectively, due to inhibition of the CYP450 3A4-mediated metabolism by cobicistat.

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic drug levels, concomitant use of antiretroviral regimens containing cobicistat with potent CYP450 3A4 inducers is considered contraindicated.

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