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Conference
"Interactions among HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors" Dr. Keith Gallicano (biography) English - 2003-03-29 - 30 minutes
Summary : Drugs interactions occurring among protease inhibitors (PI) and non-nucleoside reverse transcriptase inhibitos (NNRTI) are complex, time-dependent and multi-directional. Co-administration of dual PI with NNRTI or triple PI without NNRTI have necessitated management strategies to ensure a balance between maximizing efficacy, tolerance and convenience and minimizing toxicity. All HIV PI are metabolized by and inhibit cytochrome P450 (CYP) 3A4. Ritonavir, lopinavit, nelfinavir and amprenavir also simultaneously induce this enzyme leading to time-dependant interactions that vary in magnitude of effect. In addition, ritonavir and nelfinavir induce a host of other CYP isoforms. The NNRTI delavirdine potently inhibits CYP3A4, whereas nevirapine and efavirenz are inducers of CYP3A4. Antiretroviral regimens that include low-dose ritonavir (100mg BID) have been successfully implemented to elevate plasma exposure of other PI, improve tolerability, and maintain suppression of HIV replication. However, this dose does not appear to offset inductive effects by NNRTI, leading to potentially sub-optimal levels. Ritonavir 200 mg BID or 400 mg BID can be used with efavirenz or nevirapine to prevent decreases in amprenavir or saquinavir levels but 200 mg QD may not be effective. The use of low-dose delavirdine (100 or 200 mg BID) to boost PI exposure may be an alternative to low-dose ritonavir as a PI booster, but the potential inductive effect of PI such as amprenavir and nelfinavir on delavirdine needs to be considered. Regimens of delavirdine (600 mg BID) and amprenavir (600 mg BID) show a strong bi-directional interaction whereby amprenavir reduces delavirdine exposure by 30% to 50% and delavirdine increases amprenavir exposure by about 4-fold. Several triple regimens that include ritonavir/lopinavir (400/100 mg BID) and another PI are currently being investigated, particularly for treating PI-experienced HIV-infected patients or those requiring salvage therapy. Combining nelfinavir or amprenavir with ritonavir/lopinavir significantly reduces both ritonavir and lopinavir plasma exposures. In addition, adding lopinavir/ritonavir to amprenavir/ritonavir regimens lowers amprenavir levels by about 50%. No significant negative interactions between ritonavir/lopinavir and either saquinavir or indinavir have been reported. This presentation reviews clinically important beneficial and detrimental interactions in HIV therapy that occur among PI and NNRTI agents.
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