The potential role of resistance testing and therapeutic drug monitoring in the optimization of antiretroviral drug therapy

The two studies below (Resistance Workshop, June ’99) suggest that researchers may be able to figure out a way to use TDM (therapeutic drug monitoring) as a tool in predicting soon after a person starts therapy if they will achieve undetectable viral load. TDM is measuring the drug levels of a drug in your blood. One potential problem raised is that you can measure a drug level in plasma on a given day that may be different when measuring it a week later. The study reported by Philippe Clevenbergh, at the Resistance Workshop in June at San Diego, suggests that by taking two measures of trough levels at different times you may be able to overcome that obstacle. The other study reported by Scott Wegner also suggests that "serial measurements" may overcome that obstacle. Performing serial measurements will require multiple visits to draw blood and is obviously time consuming for both the patient and the personnel performing the tasks, but this may be required to research and implement this treatment strategy. This strategy will have to be tested and a protocol developed. For example, how many blood draws may be necessary to feel secure in overcoming the potential variability in drug levels from day to day as mentioned as a potential obstacle above. It would appear that measuring drug levels at trough (at the end of dosing period just before taking next dose) would be most important, but that may not be the case. It may be preferable to observe drug levels at various time points including the trough. Using drug level testing is a useful tool in clinical studies. The ACTG uses it in many studies but transitioning its use and utility to the setting of medical treatment in a doctor’s office may not be an easy task.

Scott Wegner, with the US Military HIV Research Program in Rockville MD, reported  on this study of therapeutic drug monitoring. The authors used an assay to assess whether plasma levels remain above the minimum effective concentration throughout therapy for each individual drug. NVP, DLV, EFV, IDV, RTV, SQV, and NFV concentrations in human plasma (100ul) were determined by protein precipitation with acetonitrile followed by HPLC with MS/MS detection.

Wegner presented an analysis of 150 random plasma samples along with drug regimen, time of administration of drugs, viral load, phenotypic and genotypic resistance information. A population pharmacokinetic (PK) model for 3 anti-HIV drugs (indinavir, nelfinavir and ritonavir) was built using measured plasma levels in 31, 41, and 10 patients, respectively.

Results.  In 10% (n=16) of the samples, particular components of the therapeutic regimen, mainly protease inhibitors and NNRTIs, were undetectable. In an additional 5% (n=7) of the samples, drug levels were below normal therapeutic values, while in another 30% (n=44), drug levels were far above expected therapeutic values. Resistance profiles correlated well with therapy regimens and high viral loads, with the prevalence of samples with a VL of >1000 copies/ml being 20% higher in the group with low or undetectable levels of specific inhibitors.

Wegner said that a clear relationship exists between drug resistance, plasma concentration of the drug and clinical result taking viral load as a marker. In a number of patients with absence of drug resistance, too low plasma concentrations were the probable reason for therapy failure. He said – having serial measurements and clinical data, an estimate of trough concentrations can be obtained using a population PK model. Wegner concluded that therapeutic drug monitoring in combination with resistance testing and viral load determination, will probably be a strong tool in optimizing drug therapy.

Philippe Clevenbergh reported at the Resistance Workshop on the relevance of protease inhibitor plasma levels in patients guiding their treatment decisions by using genotypic resistance testing. He concluded that 30% of the 85 patients in this study, called the VIRADAPT Study, had sub-optimal protease inhibitor levels, and that having low trough levels was predictive of a reduced viral load response to therapy.

The stated goal of the investigators was to assess in a prospective randomization the relevance of plasma protease inhibitor trough levels in patients failing combination therapy managed with genotypic assay (HIV-RNA >10,000 copies/ml, at least 6 months NRTI treatment, and at least 3 months PI treatment).

The study authors said—in contrast to reverse transcriptase inhibitors, significant correlations between antiviral activity and plasma drug concentrations have been demonstrated for HIV protease inhibitors and that PI drug levels are significantly related to the decline in viral load. Patients were randomized in VIRADAPT to make treatment decisions based on standard of care, in consultation with doctor, and without the benefit of genotypic resistance testing, or to making treatment decision according to genotypic resistance mutations.

Analysis was on an intent-to-treat basis with viral load as the primary endpoint. Monthly PI plasma levels were performed in patients for 6 months. The levels of the PIs were determined by HPLC. Sub-optimal concentration (SOC) was defined as at least two PI trough plasma levels below a threshold defined as 2X IC95 (10). Patients were categorized into 4 groups: G1 (SOC/no genotype); G2 ( OC/no genotype); G3 (SOC/genotyping); G4 (OC/genotyping).

Results. PI plasma trough concentration was an independent predictor of viral load reduction. The patients who had optimal drug levels and used genotypic testing to guide treatment decisions (G4) had the greatest log reduction in viral load. The patients without genotypic testing but with optimal drug concentrations (G2) had the second greatest log reduction. Using statistical analysis the authors found that drug concentration and the presence of primary PI mutations were independent predictors of viral load response.

The authors concluded that a minimum threshold of drug exposure may be required to provide optimum suppression of plasma viral load.