July 9, 2002
There is plenty of new information on the development of genotypic resistance to antiretroviral agents at this year's International AIDS Conference. It seems that the more we learn about genotypic resistance, the more complicated the topic becomes. Consequently, we can never fully understand or characterize a single mutation when new ones become relevant -- even mutations that we originally thought to be simple and straightforward. For example, mutation M184V, which confers resistance to 3TC, now appears to reveal itself as an important mutation potentially affecting pathways of resistance for other drugs.
We have learned that HIV tends to develop resistance first to the agent with the lowest resistance barrier. Thus, virologic resistance to 3TC by the development of mutation M184V is common in patients rebounding from an original regimen, including, for example, AZT/3TC and a protease inhibitor. This mutation M184V not only confers resistance to 3TC, but also increases susceptibility to the thymidine analogues and to tenofovir. On the other hand, development of resistance to thymidine analogues and to most protease inhibitors appears to be more complicated, requiring for the most part multiple mutations before clinically significant resistance to these drugs is reached.
This study is trying to answer what is the prevalence of baseline mutations associated with phenotypic resistance to the NNRTI class in an experienced population, and what is the role of mutation M184V in that development.
The study data was collected using the information from 180 experienced patients who participated in the ZORRO trial. The ZORRO trial is a prospective cohort in which the tolerability and safety of abacavir in combination with other drugs is being followed both in naive and experienced patients. Genotypic and phenotypic resistance were conducted at baseline and at different intervals during the length of the trial.
Interestingly, the prevalence of NNRTI mutations (K103N, Y181C/I, G190A and Y188V) in the absence of mutation M184V was similar to the prevalence for having mutation M184V alone (without NNRTI-associated mutations) or having both mutations M184V and NNRTI-associated mutations simultaneously. When this data is matched to the duration of 3TC use (931 days) and NNRTI use (501 days), it appears that NNRTI-associated mutations may emerge before the M184V mutations develops.
The significance of this hypothesis, if true, is not clear. Certainly, it may be related to a higher prevalence of NNRTI mutations in the community than previously reported. If mutations to the NNRTI class, such as class-resistance mutation K103N is developed first, prior mutation M184V, that would explain why duration of therapy for subjects receiving NNRTI and 3TC therapy with isolates carrying the M184V and NNRTI mutations is longer than for subjects carrying only NNRTI-associated mutations.
Because this study is just trying to establish a potential explanation for the sequence in development of M184V and NNRTI-associated mutations, it has little immediate clinical relevance. However, perhaps in the future -- when we better understand the different resistance pathways -- we can intervene and influence or favor one mutation over others.