Measuring the effectiveness of antiretroviral agents

Considerable progress has been made recently in developing effective antire troviral combination therapy that can suppress viral replication and delay disease progression in individuals infected with HIV. A range of up to 15 a pproved antiretroviral agents is now available, which target two different viral enzymes, while several agents are in clinical development. The rapid development and approval of antiretroviral agents, driven by the urgency of clinical need as well as the complexity of possible combinations, has prec luded the extensive comparative clinical testing of regimens, which is nece ssary to establish the relative efficacy of various different agents. The l ack of an appropriate animal model for HIV disease also increases reliance on in vitro measures. Several different in vitro and in vivo parameters hav e been defined in an attempt to quantify the effectiveness of antiretrovira l agents, most importantly the 50% inhibitory and effective concentrations (IC50 and EC50). However, the clinical relevance of these measures is uncer tain. Additionally, considerable variation exists in the usage of the terms 'IC50' and 'EC50' in recent publications in the literature. These issues p ose interpretation problems to clinicians seeking information on the relati ve clinical efficacy of the agents. In this brief review, we attempt to cla rify the different measures available and their potential utility for clini cal decision-making, focusing particularly on the example of HIV protease i nhibitors. There are many different quantifiable parameters that give infor mation regarding the effectiveness of an antiviral drug. These include: inh ibition of the viral target enzyme (inhibition constant, K-i); selectivity for viral versus host enzymes; inhibition of viral replication in cell cult ure (IC50); ratio of efficacy to cytotoxicity in vitro (therapeutic index); inhibition of viral replication or symptoms in an appropriate animal model of the disease (EC50); and the effect on surrogate markers, such as viral load or CD4 cell count, after administration to humans (in vivo EC50). Each of these different parameters gives valid information about the properties of an antiretroviral agent, which can help to build up a picture of its po tential clinical utility relative to other drugs. However, to gain meaningf ul results, it is important to apply this information intelligently, unders tanding the limitations of each parameter.