Study reveals new reverse transcriptase mutations

Many clinicians recognise that resistance testing remains a work in progress. Significant progress is being made, however, in understanding resistance and the complex interactions that different viral mutations have on drug sensitivity as well as replication capacity.

In a recent report from the Stanford group studying these issues, new reverse transcriptase (RT) mutations and three complex series of patterns of nucleoside analogue (NA) resistance were reported.

The study, published in AIDS, was designed to characterise RT mutations by their association with the extent of past NA therapy and to identify mutational clusters in RT sequences from persons receiving multiple NAs. To accomplish this objective, the investigators analysed a total of 1,210 RT sequences from persons whose history of antiretroviral therapy was known, 641 of which were performed at Stanford University Hospital and 569 were from previously published data.

The investigators found that mutations at 26 positions were significantly associated with NA usage. These included 17 known resistance mutations (positions 41, 44, 62, 65, 67, 69, 70, 74, 75, 77, 116, 118, 151, 184, 210, 215, 219) and nine previously unreported mutations (positions 20, 39, 43, 203, 208, 218, 221, 223, 228). The nine new mutations correlated linearly with number of NAs used and 777 out of 817 (95%) instances occurred with resistance mutations known to be associated with the NAs.

Importantly, the investigators found that mutations at positions 203, 208, 218, 221, 223, and 228 were conserved in untreated persons and those at positions 20, 39, and 43 were polymorphisms. Finally, the investigators expanded on the knowledge regarding the NA resistance mutation clustering, with most NA-associated mutations clustered into one of three groups: (A) 62, 65, 75, 77, 115, 116, 151; (B) 41, 43, 44, 118, 208, 210, 215, 223; of (C) 67, 69, 70, 218, 219, 228.

The authors conclude, “Mutations at nine previously unreported positions are associated with [NA] therapy. These mutations are probably accessory because they occur almost exclusively with known drug resistance mutations. Most [NA] mutations group into one of three clusters, although several (e.g., M184V) occur in multiple mutational contexts.”

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