Drug interactions between sirolimus (rapamycin) and ARVs

This study aimed to i) evaluate the safety and toxicity of rapamycin (sirolimus) in HIV-infected individuals with KS receiving antiretroviral therapy, ii) investigate rapamycin interactions with both PI-containing and NNRTI-containing regimens, and iii) assess clinical and biological endpoints.

Seven participants, 4 on ritonavir-boosted PIs (2 lopinavir, 2 atazanavir) and 3 on NNRTI-based regimens (2 efavirenz, 1 nevirapine), had rapamycin titrated to achieve trough concentrations of 5-10 ng/mL. Patients were monitored for safety and KS response. Despite pharmacokinetic interactions resulting in >200-fold differences in cumulative weekly rapamycin doses between participants on PI-containing and NNRTI-containing regimens, treatment was well tolerated. Maintenance rapamycin doses in the PI subjects were 0.1 mg and 0.2 mg twice weekly with lopinavir and 0.2 mg twice weekly and 0.3 mg three times weekly for atazanavir; doses in the NNRTI subjects were 2.3 mg and 6.7 mg daily for efavirenz and 2.8 mg daily for nevirapine. There were no significant changes in viral loads or cytokine levels; modest initial decreases in CD4 counts occurred in some patients. Three participants, all on PI-containing regimens and with higher rapamycin exposure, showed partial KS responses.

Rapamycin appears safe in HIV-positive individuals with KS and can, in some cases, induce tumour regression and affect its molecular targets. Significant pharmacokinetic interactions require careful titration to achieve target drug trough concentrations, but may be exploited to achieve therapeutic benefit.

Krown SE et al. Rapamycin with antiretroviral therapy in AIDS-associated Kaposi sarcoma: an AIDS Malignancy Consortium Study. J Acquir Immune Defic Syndr, 2011, epub ahead of print.