ATHENA TDM Study:
Follow-up conversation with David Burger, the study principal investigator
     - cost effectivess & lab quality control for TDM
     - intracellular tests being developed for NRTIs
      Reported by Jules Levin

In a follow-up telephone discussion with David Burger ((Univ. Med Ctr Nijmegen, the Netherlands), he explained to me more details about how the ATHENA study was conducted. You should have received an email summary report on the ATHENA study already, and that report and others are being posted to a Pharmacology Workshop Conference Report section on the NATAP web site. It should be posted today. Patients in the ATHENA study had an initial blood sample taken anywhere from 4 weeks to 3 months after entering the study and very importantly these patients were all treatment-naive. These study results do not necessarily apply to treatment-experienced individuals for a variety of reasons. After the initial blood sample was taken, the patient was called into a meeting with the doctor to discuss if the drug blood level was too low or too high. This is called an "intervention". This conversation consists of talking about issues relevant to drug levels being too high or low. The conversation includes --is patient being adherent, are they following the proper diet for the regimen they're taking, are they hydrating adequately (water hydration if indinavir). The purpose is to address any reasons why the patient may be having low or high drug blood levels, which may be fixed without changing dosing. Subsequently, the patient is called into the office for a second visit to draw a second blood sample. This visit could occur 2 months later. If the drug blood level is too low or high, at this point the doctor is advised to modify the protease inhibitor dosing. So, the dosing for the PI or NNRTI may not be changed for a few months. This raises the concern that increasing dosing after several months if drug blood levels are too low may be too late to improve viral outcome, as resistance could develop. Nonetheless, ATHENA was able to show that these "interventions" improved viral outcome for patients taking nelfinavir or indinavir in treatment-naive. The outcome might be different for patients taking NNRTIs because resistance can develop more quickly if low doses are being taken over a period of months. Burger is analyzing the data on patients in ATHENA taking NNRTIs and that data will be available in the near future.

Another question is how did the ATHENA researchers determine that blood levels are too low or high. They conducted a study of about 15-20 patients for each drug. Patients would come into the clinic and blood samples would be taken every 30 or 60 minutes during the dosing period. So for each patient they had a series of drug blood levels through the entire dosing period. This gave them a "population" reference for what drug levels should be for that particular drug. When a patient in ATHENA had their blood sample taken, they could compare it to their data on samples taken at that time point for the reference population. The ATHENA patient had one blood sample taken at each clinic visit. So, if an ATHENA patient drew their blood sample at 3 hours after taking nefinavir doses, Burger would look at blood levels in the reference population at 3 hours after pill ingestion. In Workshop abstract 6.6 Burger reports "the indinavir concentration ratio in samples drawn between 1 and 6 hours post ingestion can be used to estimate the AUC in patients using IDV 800 mg every 8 hours".

It's fair to say that using TDM to test a patient's drug blood levels is more than just changing their doses. It's an "intervention". It's an opportunity to present the findings to the patient and open a discussion about adherence and other factors related to the patient following proper procedure in taking their medications. As mentioned above, there is some concern that waiting several months to change dosing, if it's necessary, may be too long and resistance may develop. Although success in improving viral outcome was found in ATHENA despite this delay, my thinking is that it would certainly be advantageous to change dosing much sooner. For example, an initial meeting between doctor & patient could occur 3-4 weeks after starting therapy where an initial blood sample could be drawn. The second blood sample could be taken 3 weeks later to see if the patient improved drug blood levels after talking about adherence and other related issues. This might help to minimize the risk that resistance could develop due to low drug levels. If drug levels are too high this might help to prevent the patient from not adhering because of experiencing side effects & toxicities.

Burger and I also discussed his other study presented at the Workshop in which he found that 10%-20% of women had high indinavir levels and were experiencing toxicities and had their indinavir dosing changed. He feels that this is a real concern for women. Some women may be getting high drug levels. Although he doesn't know the reason for the high levels, he speculates that low weight is not the reason but that it may be a gender-specific metabolism issue or maybe some women-related drugs they are taking. I didn't ask him but I assume he may mean some contraceptive pill or other women-specific medication. I would speculate that it might also be related to such concerns as hormones or menstruation.

David Burger will be a guest on the NATAP radio show "Living Well With HIV & Hepatitis" which will air either this Sunday or next Sunday at our regular time--every Sunday on WOR 710 AM 11pm-12 midnight in NYC. If you are outside the WOR listening range, live streaming audio is available at www.wor710.com. Free recorded tapes and you can listen to downloads of all old shows available at NATAP web site: www.natap.org.

COST EFFECTIVENESS

An interesting aspect of TDM is that in France and the Netherlands clinics extensively use TDM in treating patients. But here in the US it is not used very widely. At the Workshop costs were reported for using TDM and they are not very much. In abstract 6.3 N.A. Risebrough from Toronto (Sunnybrook & Women's college Health Sciences Center in Toronto) reported hat the added cost would be $238 (CDN$) in physician visits & labs for the patient making a dose adjustment. She reported one TDM measure per PI costs $100 (CDN$). And she asumed 3 measures per PI and 2 physician visits were required. The dose adjustment, whether it be too raise or lower dose, would also have to e factored into the equation. She concluded that on average TDM would cost an extra $178 per patient. If adverse event drop-out was reduced 7.5% with TDM guided dose reduction for toxicity, TDM would cost an extra $109 (CDN$) and achieve undetectabl viral load in 8 additional patients per 100 by 6 months. Risebrough concluded that based on this preliminary data, TDM potentially provides an important improvement at a reasonable cost.

INTERLABORATORY QUALITY CONTROL

In abstract 8.3, M Legrand (Pharmacologie, Pitie-Salpetriere Hosp, Paris) reported on the quality control organized at 10 labs throughout France. All the labs used HPLC-UV to assay protease inhibitor concentration. Standards were provided by the drug manufacturers. Legrand reported that within the labs the coefficient of variability (CV) was less than 15% for day-to-day and within-day variabilities. The CV between labs was less than 20%. In a survey Legrand reported that drug concentrations for IDV and NFV were within 15% of the target concentrations for all concentration levels. 9/10 labs reported IDV measurements in the accepted range, 6/9 and 5/7 for NFV and M8, respectively. To further reduce variability, it was decided to share a single stock solution between all lab participants.

TESTING NRTI INTRACELLULAR LEVELS

NRTIs are processed inside the cell and so far testing blood levels has not been proven as a reliable way to evaluate if a patient is achieving adequate NRTI levels. Two abstracts (8.1,8.5) were presented at the Workshop on methods being developed that could evaluate intracellular NRTI levels. F Becher reported in abstract 8.1 that he has developed a method which allows for the first time the simultaneous determination of cellular concentrations of 3 NRTI anabolites and their ratios with their natural nucleotides. Becher said 40 samples per day could be processed using commercially available instruments. Becherr concluded this method could be useful in studying intracellular metabolism of NRTIs in large numbers of patients, thereby allowing relevant individual drug monitoring and enhanced understanding of drug efficacy and toxicity. In abstract 8.5, Becher reports that in vivo data on ddI intracellular metabolites have been lacking since methods used for phosphorylated metabolites of AZT, 3TC and d4T have not been applied or were not sensitive enough. Becher reported that they have developed a method (LC/MS/MS) which allows simultaneous determination of cellular levels of ddA-TP and the ratio of dda-TP/dA-TP. This was reported to be fully validated and meets recommendations for PK studies in humans. More than 30 samples can be run daily.