Drug Interactions between rifampin and saquinavir

CONTRAINDICATED: Coadministration with rifampin may significantly decrease the plasma concentrations of protease inhibitors (PIs) including saquinavir. 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).

CONTRAINDICATED: Drug-induced hepatitis with marked transaminase elevations has been observed in healthy volunteers receiving rifampin 600 mg once daily in combination with ritonavir 100 mg and saquinavir 1000 mg twice daily (i.e., ritonavir-boosted saquinavir). The mechanism has not been described. In one clinical study, 11 of 28 (39.3%) subjects exposed to the regimen developed significant hepatocellular toxicity during the 28-day study period. Transaminase elevations up to or even exceeding 20 times the upper limit of normal were noted in some cases and one subject was hospitalized. Liver function tests returned to normal and clinical symptoms abated following prompt discontinuation of all study medications. No deaths were reported in the study.

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiretroviral drug levels, rifampin should not be administered to patients receiving unboosted saquinavir. Rifampin should also not be administered to patients receiving ritonavir-boosted saquinavir because of the risk of hepatotoxicity. Alternative antimycobacterial agents should be considered in such patients. 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. 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.