New Pilot Study: Therapeutic Drug Monitoring + Genotypic Resistance Testing

This article is about The GREAT Study which explores making treatment decisions using genotypic resistance testing plus theraprutic drug level testing (TDM) for individuals failing HAART (viral load >2000 copies/ml). What is TDM? Therapeutic Drug Monitoring is testing the levels of a drug in a person's blood to see if the level is lower than it needs to be to adequately suppress HIV. For protease inhibitors and NNRTIs it appears that their levels in blood are key to viral suppression. For NRTIs the intra-cellular levels may be more important.

The goal of HAART therapy is to suppress HIV replication to below detection so resistance doesn't develop to such a degree that viral load increases above detection causing resistance to drug's in a person's regimen resulting in virologic failure. A minimal certain level of drug concentration is key to viral suppression. If a person is non-adherent drug levels in blood will likely be low. If a person has very high metabolism drug levels may be too low. If it's recommended to eat a certain type of meal when taking a drug, drug levels may be low if those recommendations are not followed.

For several years there has been a sense that drug levels could be measured and drug dosing could be adjusted up in the hopes this would optimize response to therapy. Drug level testing is available through some commercial labs. But studies have yet been unable to establish that changing doses in response to drug level testing improves outcome to therapy. Nonetheless, some doctors use drug level testing to adjust dosing. Some of these doctors and researchers feel it makes a difference in impoving a person's response to therapy. A study in the Netherlands called ATHENA, conducted by David Burger and others, was unable to show that dose adjustment based on drug level testing made a difference in response to therapy. However, Burger and others felt that the reason was that the study was not well designed. Allegiance remains by Burger and others to the notion that drug level testing based dosing adjustment can improve response to therapy. However, other researchers say it needs to be proven.

A new pilot study called The GREAT Study is starting. The principal investigators are Charles Boucher and an Amsterdam based research group. The study will randomize individuals failing a HAART regimen to use of genotypic testing in making a therapy change or to making that therapy change based on genotypic testing + testing drug levels. At baseline for the study, individuals will select a regimen after receiving Retrogram results. Retrogram is a genotype software program (algorithm) designed by Johnathan Schapiro and Charles Boucher. They've designed a computer software program to analyze and interpret the resistance mutations obtained by genotypic testing. It's a rules designed process in interpreting genotypic test results and making a ranking of recommendations on drugs a doctor could use for the patient.  But there is no obligation to follow the advice.

One arm in the study will select a regimen solely based on Retrogram. The second study arm will select a regimen based on Retrogram, but after 4 weeks on drug PI or NNRTI drug levels will be tested and dose adjustments will be made if it appears needed. Four weeks following dose changes a second drug level test will be performed to see if the person's drug level is the within expected or desired level. Study doctors are expected to receive drug level test results within 5 days of drawing blood (real-time). Following these first 2 tests, blood levels will continue to be tested but not in real time (batched). In order to set the desired drug levels, the study investigators studied 10-20 individuals taking each drug who had undetectable HIV RNA. In addition they factored in the recommended drug levels by a drug's manufacturer. If a study participant's drug level is 25% or more off from the desired levels, their dose is recommended to be changed.

A study participant's doctor will consider Retrogram results or Retrogram+TDM in making treatment decisions. This study is a pilot randomized open-label study with 180 individuals in each of the 2 arms at 25 sites in Western Europe. As far as I can see, this is the first study of TDM+resistance testing. The study has already started recruitment and about 20 patients are enrolled.

Certainly it would be very helpful if we could use drug level testing to optimize response to therapy. One benefit of drug level testing is that it may identify to a doctor if their patient is non-adherent. But, there are some real questions about whether drug levl based dose changing can effect therapy response. Is a single measure adequate or do you need a series of measures? When do you take that measure--a few hours after taking the dose, at the end of the dosing period (trough), or at some other point during dosing? Other uncontrollable factors may be crucial--non-adherence, improper diet, and a person's individual drug metabolism or drug clearance.