In vivo administration of ritonavir worsens intestinal damage caused by cyclooxygease inhibitors

The protease inhibitor ritonavir is part of the highly active anti-retroviral therapy (HAART) successfully used in the treatment of human immunodeficiency virus (HIV)-1 infection. There is evidence that ritonavir alters intestinal permeability and induces damage to the small intestine. Because HIV infected patients taking HAART are at high risk for developing cardiovascular complications, there might be a need for the use of low dose of aspirin (ASA) to prevent ischemic events. Similarly, long term survival exposes HIV infected persons to detrimental interactions of ritonavir with non-steroidal anti-inflammatory drugs (NSAIDs). In the present work we tested whether ritonavir worsens intestinal injury caused by NSAIDs and ASA. C57BL6 mice were treated for 25 days with ritonavir and for a further 5 days with the combination of ritonavir plus ASA or ritonavir plus naproxen. In a second set of experiments C57BL6 mice were cotreated with ritonavir plus misoprostol, a PGE1 analog. We found that ritonavir administration caused intestinal damage and its co-administration with naproxen or ASA exacerbated the severity of injury and intestinal inflammation, as assessed by measuring haematocrit, MPO, mucosal levels of PGE2 and mRNA levels of iNOS, MCP-1 and VLA-1. Co-administration of misoprostol protected against intestinal damage induced by naproxen and ritonavir. In conclusion we demonstrated that ritonavir causes intestinal damage and that its association with NSAIDs or ASA worsens the damage caused by COX-inhibitors. Misoprostol rescues from intestinal damage caused by ritonavir. Further studies are need to clarify whether this observation has a clinical readout.