Therapeutic drug monitoring with resistance testing

The next step in the refinement of resistance testing will be to marry the results of genotypic resistance tests which can establish a virtual phenotype with the results of therapeutic drug monitoring (TDM), which can establish whether adequate drug levels are being achieved when supposedly 'active' drugs are added to a new regimen.

An analysis of plasma drug levels in the GART or CPCRA 046 study was carried out. This study did not sample plasma drug levels at standardised times after dosing. The study sought to correlate plasma drug levels at week twelve with viral load responses, and classified individuals as having drug levels above or below the median. Each drug in the regimen which had a plasma level above the median was associated with a viral load reduction of 0.40 log10 (the same level as seen for each genotypically active agent), and the viral load reduction increased with each genotypically active agent used which had a plasma level above the median. 1 When four or five drugs were used which achieved above-average concentrations, the median viral load reduction was 1.44 log10.

The way in which this study was designed makes it difficult to determine whether the very small additional benefit of having above average drug levels is worth pursuing. Because this was a short study, we do not know whether people with above average drug levels would be more likely to discontinue or switch therapy due to side-effects related to high drug levels. Also, the method used to sample drug levels makes it difficult to interpret.

The GENOPHAR study, in which 137 people with treatment failure were randomised to change treatment on the basis of either genotypic resistance testing or genotypic resistance testing coupled with the results of therapeutic drug monitoring for protease inhibitors and NNRTIs at weeks 4 and 8. After 24 weeks, 58% of the genotypic group and 66% of the TDM group had viral load below 200 copies/ml, and the authors concluded that TDM did not add anything to the selection of a new regimen on the basis of genotypic resistance testing. 2

A study of the genotypic inhibitory quotient in 49 people commencing ritonavir (Norvir)-boosted amprenavir treatment found that the ratio of amprenavir Cmin at week eight to the number of protease mutations was a better predictor of virological response at week twelve than either genotype or plasma drug level. 3

Finally, a Spanish study of 139 PI-experienced patients who commenced saquinavir/ritonavir found that genotypic inhibitory quotient was most strongly predictive of virological response after 48 weeks, when compared with either genotype or drug levels alone. 4

References

  1. Baxter JD et al. Both baseline HIV-1 drug resistance and antiretroviral drug levels are associated with short-term virologic responses to salvage therapy. AIDS 16: 1131-1138, 2002
  2. Bossi P et al. GENOPHAR: a randomised study of plasmatic drug measurements associated with genotypic resistance testing in patients failing antiretroviral therapy. Ninth Conference on Retroviruses and Opportunistic Infections, Seattle, abstract 585, 2002
  3. Marcelin AG et al. Genotypic inhibitory quotient as predictor of virological response to ritonavir-amprenavir in human immunodeficiency virus type 1 protease inhibitor-experienced patients. Antimicrob Agents Chemother 47: 594-600, 2003
  4. Soriano V et al. Predictive value of drug levels, HIV genotyping and genotypic inhibitory quotient (GIQ) at different time points along 48 weeks using a saquinavir/ritonavir salvage therapy. 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, abstract H-1999, 2003
Community Consensus Statement on Access to HIV Treatment and its Use for Prevention

Together, we can make it happen

We can end HIV soon if people have equal access to HIV drugs as treatment and as PrEP, and have free choice over whether to take them.

Launched today, the Community Consensus Statement is a basic set of principles aimed at making sure that happens.

The Community Consensus Statement is a joint initiative of AVAC, EATG, MSMGF, GNP+, HIV i-Base, the International HIV/AIDS Alliance, ITPC and NAM/aidsmap
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