ABSTRACT:
Despite most HIV-infected patients being treated with a series of three or four antiviral drugs, combination therapy often leads to treatment failure. The reasons for treatment failure include (i) the development of resistant virus; and/or (ii) the antiretroviral agent does not reach plasma concentrations high enough for long-term suppression of virus replication. An assay method for simultaneous determination of plasma levels of all antiretroviral drugs was developed. The objective was to assess whether plasma levels remain above the minimum effective concentration (MEC) throughout therapy for each individual drug; nucleoside analogue reverse transcriptase inhibitors (NRTI), non-nucleoside analogue reverse transcriptase inhibitors (NNRTI) and protease inhibitors (PI). We present an analysis of 150 random plasma samples with complete documentation of drug regimen, time of administration of drugs, viral load, phenotypic and genotypic resistance information. In 10% (n=16) of the samples, particular components of the therapeutic regimen, mainly PIs and NNRTIs, were undetectable. In an additional 5% (n=7) of the samples, drugs levels were below normal therapeutic values while in another 30% (n=44), drug levels were far above expected therapeutic values. Resistance profiles correlated well with therapy regimens and high viral load (VL), with the prevalence of samples with a VL of >1000 copies/ml being 20% higher in the group with low or undetectable levels of specific inhibitors. A population pharmacokinetic model makes it possible to forecast an optimum drug dosage via Bayesian feedback.
