Intracellular antiviral activity of low-dose ritonavir in boosted protease inhibitors regimens

Protease inhibitors are largely used for the treatment of HIV infection in combination with other antiretroviral drugs. Their improved pharmacokinetic profile is achieved through the concomitant administration of low doses of ritonavir, a protease inhibitor nowadays used as "booster", increasing the exposure of companion drugs. Since ritonavir-boosted regimens are associated with long-term adverse events, cobicistat, a CYP3A4 inhibitor without antiviral activity, has been developed.Recently, high intracellular concentrations of ritonavir in lymphocytes and monocytes have been reported even when administered at low dose, so we aimed to compare its theoretical antiviral activity with that of the associated protease inhibitors.Ritonavir and different protease inhibitors intracellular concentrations were determined through the same method. Inhibitory constants were literature-obtained.103 patients were enrolled, receiving different boosted protease inhibitors: darunavir/ritonavir 600/100mg twice-daily and 800/100 once-daily (22 and 4), atazanavir/ritonavir 300/100mg once-daily (n=40), lopinavir/ritonavir 400/100 twice-daily (n=21) and tipranavir/ritonavir 500/200 twice-daily (n=16).According to the observed concentrations, we calculated ratios between intracellular concentrations of ritonavir and that of the companion protease inhibitor and between the theoretical viral protease reaction speed with each drug, considering and not-considering ritonavir. Respectively, the median ratios were: 4.04 and 0.63 for darunavir/ritonavir twice-daily, 2.49 an 0.74 for darunavir/ritonavir once-daily, 0.42 and 0.74 for atazanavir/ritonavir, 0.57 and 0.95 for lopinavir/ritonavir, 0.19 and 0.84 for tipranavir/ritonavir. Therefore, the antiviral effect of RTV resulted lower than that of the concomitant protease inhibitors, but still important, mostly with DRV. So, further in-vitro and in-vivo studies about RTV antiviral effect are warranted.