Individualized Antiretroviral Therapy: Impact of pharmacogenetic and therapeutic drug monitoring in the safety and efficacy of first line antirretroviral therapy in patients with HIV infection. Preliminary report

Abstract

Background: Combination antiretroviral therapy has modified the natural history of HIV infection in an unprecedent manner in medical history. But up to 20% of patients discontinue first-line antiretroviral therapy at currently standard doses.Methods & Materials: We explored the utility of prior phar- macogenetic (PG) analysis and ongoing drug monitoring (TDM) to individualize the dose of efavirenz or atazanavir in naive HIV patients.We developed a multiplex approach including main polymor- phisms of CYP2B6, CYP2A6, CYP3A4 and ABCB1 for efavirenz; and UGT1A1, ABCB1 and CYP3A4 for atazanavir. Drug plasma levels were analyzed with UPLC. Mean turnaround time for TDM was 30 days and median 23 days. For multiplex the mean turnaround time was 25 days and 23 days its median.First 60 patients included in the protocol -coming from 4 clin- ical sites in Buenos Aires- were randomized to standard of care -SC-(34 patients) or pharmacological adaptation -PA:PG + TDM-(26 patients).Results: The first TDM determination took place two weeks after starting antiretroviral therapy. All seven determinations of efavirenz resulted in serum concentration within regular limits. Following, three of four atazanavir determinations were above the maximum serum level. One of these patients had a genotype clas- sified as high impact.One patient in the PA arm received decreased individualized doses of Atazanavir with proper tolerance and mantaining treat- ment efficacy in 112 patients/months of follow up.Two patients from SC arm had adverse events, and both of them had to discontinue therapy.Conclusion: Pharmacological adaptation of initial and ongoing doses of first line antiretrovirals appears feasible and useful for the individualized therapeutic approach of patients with HIV infection starting treatment.