Does lopinavir/ritonavir alter the primary gingival epithelium?

Abstract

Evaluation of: Israr M, Mitchell D, Alam S, Dinello D, Kishel JJ, Meyers C. The HIV protease inhibitor lopinavir/ritonavir (Kaletra) alters the growth, differentiation and proliferation of primary gingival epithelium. HIV Med. DOI: 10.1111/j.1468-1293.2010.00863.x (2010) (Epub ahead of print).In clinical practice, a significant proportion of HIV-infected patients receive lopinavir/ritonavir (LPV/r) as a component of highly active antiretroviral therapy (HAART). The study by Israr et al. was designed to evaluate the effects of the HIV protease inhibitor LPV/r on gingival epithelium growth and differentiation. The authors isolated gingival keratinocytes from human gingival tissue from patients undergoing dental surgery. Raft cultures of gingival keratinocytes were established and treated with a range of LPV/r concentrations. LPV/r inhibited the growth of gingival epithelium when the drug was present throughout the growth period of the tissue. When LPV/r was added on day 8 of tissue growth, it compromised tissue integrity and altered the proliferation and differentiation of gingival keratinocytes. The expression pattern of cytokeratin-5, -14, -10 and -6, proliferating cell nuclear antigen and cyclin A were altered in treated rafts. These findings suggest that LPV/r compromised tissue integrity and deregulated the cell cycle/proliferation and differentiation pathways, resulting in abnormal epithelial repair and proliferation. However, these findings do not correlate with those observed in clinical practice. In clinical trials, the adverse effects in the oral cavity have been uncommon in patients receiving HAART containing standard doses of LPV/r. This disparity may be due to a few limitations in the study design. The investigators assumed that the blood levels of LPV/r would be the same as in the saliva, and thus chose the peak concentration of LPV/r in blood serum as the baseline concentration in the study. However, the correlation between LPV/r levels in blood serum and in oral tissues has not been widely studied. Lopinavir and ritonavir are highly (98–99%) bound to serum proteins. Thus, the concentrations of these drugs in saliva would be expected to be 50–100-times lower than total plasma concentrations, rather than equivalent, as the authors assumed. Thus, the concentrations assessed in this in vitro study are very likely to be much higher than the actual concentrations of LPV/r encountered in the saliva of patients.