Inter-individual variability in pharmacokinetics and response to protease inhibitor-based antiretroviral therapy

Treatment for HIV clearly improves survival. However, some patients fail therapy either because of toxicity or because the virus mutates, allowing it to multiply even in the presence of the drug. Both of these factors are strongly influenced by the amount of drug that enters a patient?s bloodstream. For example, too much drug and the patient will experience some types of toxicity and too little drug and the virus is able to try out different mutations, eventually finding those which allow it to survive. Our knowledge of the factors that influence drug concentrations in the blood is rapidly developing. Our recent work has shown that SLCO transporters, which are molecular pumps that transfer anti-HIV drugs into gut and liver cells can influence the absorption and clearance of some drugs from the body. These transporters are encoded by the human genome and there are differences in these genes meaning that in some individuals they have different activity than in others. Therefore, the reason for this research is to assess whether differences in SLCO transporter genes are able to explain some of the differences in drug concentrations and susceptibility to toxicity and failure of anti-HIV drugs. Ultimately, if this project is successful it will aid the development of tests that help HIV doctors to give the right drug, at the right dose to the right patient.

The DOH acknowledges that ?pharmacogenomics should help make medicine use more effective?. Drug treatment (costing the NHS #220 million/year) becomes more expensive with each successive failure and Protease inhibitors (PIs) are associated with long term toxicities (e.g. fat redistribution), which are stigmatising but, like acquisition of resistance, are also difficult to reverse. Strategies to improve drug use are therefore needed and Pharmacogenetics offers a way of selecting drugs (by avoiding use in those with highest risk of toxicity) and individualising dosage. Using Xenopus laevis oocyte expression systems we have shown that PIs are substrates for SLCO (OATP) influx transporters. Moreover, in a proof of concept preliminary analysis we have shown a significant association between one common variant of SLCO1B1 (OATP1B1*1b; 521C T) and LPV concentrations in patients. We now propose to utilise high throughput genotyping (Sequenom) of single nucleotide polymorphisms to study associations with drug concentrations (through a therapeutic drug monitoring registry) and clinical response (through the UK CHIC cohort). We will also mine and assess copy number polymorphisms. For polymorphisms associated with response to therapy, we will determine the mechanism in intestinal biopsies (expression) and oocytes (function). Replication of pharmacogenetics studies is paramount and we will also confirm pharmacological phenotype by assessing full pharmacokinetic profiles in patients selected based on their genotype. We plan to gather substantive information on genetic influences associated with response and to assess how this information could be used in clinical practice, by using it to predict durability of LPV, DRV and ATV based regimens.