Background: Pharmacokinetics of antiretrovirals has been increasingly investigated in the first decade of HAART and the use of therapeutic drug monitoring (TDM) in some clinical circumstances is today recommended or at least considered. Although with variable strength of recommendation, TDM is advised in case of drug–drug interactions, liver or renal alterations, pregnancy, pediatric patients, as well as when reduced viral susceptibility or toxicity are concerned. Clinical pharmacology of antiretrovirals, however, has determined significant improvements in the therapeutic management of HIV infection that go beyond the boundaries of the currently approved indications for TDM. Concerning efficacy, the passage from the initial use of single protease inhibitors (PI) to the adoption of ritonavir-boosted PI is a story entirely based on the appraisal of the different immunovirological outcomes that are achievable depending on the magnitude of pharmacokinetic exposure. The introduction of drug concentration as a critical and modifiable variable in ART permitted some successful inferences from antibacterial chemotherapy, which led to the definition of viral inhibitory concentration (IC_50–90) or minimal effective concentration (MEC) and their incorporation in a ratio, the inhibitory quotient (IQ), which also includes drug concentration. Although difficult to be measured in several circumstances, the IQ nevertheless represents our progress in understanding the interplay between pharmacologic and virologic variables as well as a tool for interpreting or predicting the outcome of ART.

Conclusions: The next steps required for the further development of TDM include both old and new issues. Among the old issues, adherence of physicians to the indications resulting from TDM is one that deserves particular attention, together with an improvement of our average pharmacological knowledge. Studies on the long-term side-effects of antiretroviral drugs and their relationship with the magnitude of drug exposure are also required, as well as carefully planned clinical studies on the relevance of drug penetration in compartments and on old and new drug–drug interactions. Among the new issues, further to the clinico-pharmacological study of new drugs and drug classes, growing relevance is attributable to pharmacogenomics, whose clinical application is still in its infancy, but predictably significant in perspective.