July 11, 2002
Dr. Margot from Gilead Sciences presented data from two tenofovir (Viread) clinical trials representing over 300 patients that demonstrate which mutations at baseline are important in predicting viral load responses to tenofovir containing regimens in patients who failed prior NRTI-containing regimens. The current terminology around naming mutations is complex. A mutation is usually expressed as the amino acid number and the wild type and mutant amino acid letter code at that position (e.g., M184V, which stands for the wild type amino acid methionine at codon number 184 in the reverse transcriptase gene that is changed to a valine conferring 3TC resistance).
The results show that those patients without thymidine analogue mutations (TAMs) or 3TC resistance (M184V) had the greatest viral load reductions at 24 weeks. Those with TAMs and 3TC resistance (M184V) had only half the viral load reduction. However, the specific TAMs are also important. Patients who had viruses with a 41L or 210W TAM, had even less viral load reductions than those patients with TAMs that were not at codon 41or 210. Patients who had viruses with a K65R mutation had essentially no viral load reduction. Thus a patient, who had three to four TAM mutations without mutations at 41, 210 or 65, still had very good viral load response after adding tenofovir. To add further complexity, there may be different pathways the virus can take to evolve different sets of TAMs, which can have very different viral load outcomes with respect to tenofovir.
This study, as well as ThOrB1388, again emphasize the complexity of HIV drug resistance development in people, the difficulty in interpretation of resistance testing, and the need for continual updating of databases to understand the complex interplay between various mutations which confer resistance to one drug, or class of drugs, but may rescue activity or make other drugs hypersusceptible. Practitioners will need to keep up to date on these emerging findings in order to utilize information from resistance testing effectively.
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