ATHENA – Early results from first randomised study of clinical benefits of TDM

15 May 2000. Related: Conference reports, PK Workshop 1st 2000.

Simon Collins, HIV i-Base

18 months ago, two large randomised studies designed to look at the clinical benefit of TDM, were both being planned. While the UK’s MRC sponsored and long awaited OPIUM has yet to enrol, and indeed is still dependent on a last-minute reprieve, early results of the Dutch ATHENA study were presented at this meeting.

ATHENA will randomise 600 patients (50% treatment naive, 50% experienced) from 22 sites in Holland, to one of two study arms. The intervention arm involves drug concentrations being determined at regular intervals and the results reported to the treating physicians, together with advice from a pharmacologist; in the control arm the results of the tests are not reported. MIC levels for each PI were determined at 0.1mg/ml for indinavir, 0.4 mg/ml for nelfinavir. 2.1mg/ml for ritonavir and 0.05 mg/ml for saquinavir (SGC). Target values for the concentration ratio (CR) were between 0.75 – 2.0 population values (ie if CR < 0.75 a dose increase was recommended and if CR >2.0 it is thought safe to recommend dose reduction). It was stressed that individual patient treatment histories provided by clinicians are essential in order to be able to provide a recommendation. By refusing to run tests unless this history was provided, produced a 95% adherence by clinicians for these forms. Results and advice were available within four weeks.

Results to December 1999 include 391 patients (34% treatment naive), with 1828 sample levels, evenly split between the intervention and control arms (938 vs 890).

Table 1

* from both arms combined

Early results indicate that at least a quarter of patients on each of these PIs lead to a recommendation to prompt adherence support and/or increased dosing. Although a smaller number of samples showed levels more than double the target level, in practice recommendations to reduce doses were rarely followed unless high toxicity was reported. TDM is already routinely available for all patients in the Netherlands, and this was one of the difficulties for patients in the blinded arm. This study identified a disturbingly high percentage of patients failing outside a very broadly defined therapeutic range for each drug and further results of this and other studies and needed urgently. [1]

Reference:

1. Burger D, Hoetelmans R, Hugen P et al – ATHENA: A Randomised, Controlled Clinical Trial to Evaluate whether Therapeutic Drug Monitoring (TDM) Contributes to Reduced HIV-related Morbidity and  Mortality. Abstract 6.6 First International Workshop on Clinical Pharmacology, 30-31 March 2000. Noordwijk, Netherlands.