Intermittent therapy.

Current key issues in the drug therapy of HIV infection include the timing of treatment initiation, the use of multiple-drug therapy and the duration of treatment. Although most clinicians agree that symptomatic HIV disease should be treated, there is no consensus as to whether patients should be treated before symptoms develop; the results of the Concorde trial failed to demonstrate any long term improvement in disease progression or survival when antiretroviral therapy was initiated in asymptomatic individuals rather than deferring it until the development of AIDS or ARC. However, combination therapy may prove to be the most effective long term option. In the future, monitoring viral load or viral resistance may be a useful aid in determining whether antiretroviral therapy should be stopped or changed, particularly if any clinical benefits are transient or if adverse effects persist. New antiretroviral therapies must be evaluated in terms of both risks (associated adverse effects) and benefits (increase in survival, delay in disease progression or improvement in quality of life). There is an urgent need to identify the best surrogate markers to permit more rapid evaluation of therapeutic strategies.

Didanosine↗

PubMed1994

A direct, general approach based on isobolograms for assessing the joint action of drugs in pre-clinical experiments.

Pharmacologists and other biologists frequently use methods based on the interpretation of isobolograms to quantify the extent of synergy or antagonism between drugs used in combination in pre-clinical studies. Most methods have been unsatisfactory from a statistical viewpoint, many because they have relied solely on visual evaluation, others because the methods have not taken into account the variability of the measurements. We describe a direct approach for quantifying the joint potency of two drugs, a central feature being the use of simple isobole models that lead directly to response surface models for the expected experimental outcomes. The approach is general in the sense that one can use it for discrete or continuous responses, different underlying probability distributions, linear or non-linear dose-response functions of the drugs used singly, and a variety of experimental designs. Our approach extends the suggestions made by Hewlett for measuring the joint potency of drugs, and is similar in spirit to the approaches proposed by Greco et al. and Weinstein et al. We describe the analysis of data from an in vitro experiment conducted to evaluate the efficacy of the antiviral drugs AZT and ddI used in combination.

Didanosine↗