Start Date
April 2024
Location
2nd floor - Library
Abstract
Sirolimus, a mammalian target of rapamycin (mTOR) inhibitor commonly used to prevent organ rejection in transplant recipients was evaluated for safety and efficacy to reduce latent HIV reservoirs in people with HIV (PWH) on chronic suppressive antiretroviral (ARV) therapy (ART). Despite the potential for ARVs to alter common metabolic pathways (e.g., CYP3A4, P-gp) shared by ARVs and sirolimus, there are no prospective PK drug interaction studies. This PK substudy aimed to assess the impact of ARVs on sirolimus PK, during the A5337 study. This single-arm open label study enrolled 32 PWH on suppressive ART for at least two years. Sirolimus was administered orally for up to 20 weeks following a 12-week lead-in period. Sirolimus was dose adjusted to attain target trough levels of 5-10 mcg/mL. The most common ARVs (i.e., tenofovir, TFV; emtricitabine, FTC; efavirenz, EFV; dolutegravir, DTG) were analyzed from samples collected every 4 weeks. Dose-corrected average sirolimus levels were compared across ARVs, and ARV trough levels were compared before, during, and after sirolimus therapy, by calculating geometric mean ratios. Using Wilcox rank-sum test, the impact of each ARV on time to achieve target sirolimus trough was also assessed. Participants enrolled were 28% female, 56% black, 52 years on average. No ARV had any impact on time to achieve target sirolimus trough (p>0.05). This analysis suggests EFV as a moderate inducer, and DTG as a weak inhibitor of sirolimus metabolism. There was no apparent difference in ARV exposure following sirolimus therapy.
Efavirenz and Dolutegravir May Alter Sirolimus Metabolism in People Living with HIV
2nd floor - Library
Sirolimus, a mammalian target of rapamycin (mTOR) inhibitor commonly used to prevent organ rejection in transplant recipients was evaluated for safety and efficacy to reduce latent HIV reservoirs in people with HIV (PWH) on chronic suppressive antiretroviral (ARV) therapy (ART). Despite the potential for ARVs to alter common metabolic pathways (e.g., CYP3A4, P-gp) shared by ARVs and sirolimus, there are no prospective PK drug interaction studies. This PK substudy aimed to assess the impact of ARVs on sirolimus PK, during the A5337 study. This single-arm open label study enrolled 32 PWH on suppressive ART for at least two years. Sirolimus was administered orally for up to 20 weeks following a 12-week lead-in period. Sirolimus was dose adjusted to attain target trough levels of 5-10 mcg/mL. The most common ARVs (i.e., tenofovir, TFV; emtricitabine, FTC; efavirenz, EFV; dolutegravir, DTG) were analyzed from samples collected every 4 weeks. Dose-corrected average sirolimus levels were compared across ARVs, and ARV trough levels were compared before, during, and after sirolimus therapy, by calculating geometric mean ratios. Using Wilcox rank-sum test, the impact of each ARV on time to achieve target sirolimus trough was also assessed. Participants enrolled were 28% female, 56% black, 52 years on average. No ARV had any impact on time to achieve target sirolimus trough (p>0.05). This analysis suggests EFV as a moderate inducer, and DTG as a weak inhibitor of sirolimus metabolism. There was no apparent difference in ARV exposure following sirolimus therapy.
