From The Podium - Resistance to Nucleoside Analogs: Update From the 8th CROI

Most of the data presented at the 8^th CROI regarding resistance to NRTI were merely of confirmatory data concerning trends observed in previous meetings last year. For example, a biochemical study evaluated the effect of AZT resistant mutations on the sensitivity of RT for d4t (Abstract 442) [1]. The study showed that on the enzyme level, AZT mutations also cause resistance to d4T, confirming an earlier finding showing that AZT mutations make the virus less sensitive to d4T in the test tube.

These findings have led to new terminology namely, the so-called thymidine analog mutations (or TAMs). This term refers to the fact that both AZT and d4T are analogs of thymidine. Some of us feel this terminology is confusing, because it becomes more and more obvious that the classical AZT mutations can confer varying levels of resistance to most NRTI. Therefore, some people favor the terminology nucleoside-associated mutations (or NAMs). Indeed, in a subanalysis of the French NARVAL study, the presence of at least three TAMs (215Y/F with at least two of the following: 41L,67N,70R,210W,K219Q/E) was shown to significantly diminish antiviral responses to both ddI and d4T (Abstract 450) [2].These data were confirmed in a smaller study which also showed that AZT resistance patterns limited the antiviral activity of d4T (Abstract 437) [3].

In the NARVAL study, however, the response to abacavir was not influenced by the presence of three TAMs. In a large study evaluating HIV's susceptibility to abacavir in four large trials where abacavir was added to an existing regimen, it was shown that the antiviral response was much greater for patients with HIV having an abacavir IC50 < 4.5 fold greater than wild-type (Abstract 254) [4].

Finally, in vitro selection data regarding a novel compound, BCH-10618, were presented. This drug was shown to select for V75I or K65R. Both changes gave rise to low levels of resistance, have been observed before with other compounds, and are located in the area of RT where most NRTI have been shown select for mutations (Abstract 472) [5].

Duan CY, Poticha D, Stoeckli TC, Lu J, Petropoulos C, Whitcomb J, McHenry1 CS Kuritzkes DR.Biochemical Evidence of Cross-Resistance to Stavudine (d4T) Triphosphate in Purified HIV-1 Reverse Transcriptase (RT) Derived from a Zidovudine (AZT) Resistant Isolate. 8^th Conference on Retroviruses and Opportunistic Infections. 2-4 Feb 2001, Chicago, IL. Abstract 442.
Costagliola D, Descamps D, Calvez V, et al. Presence of Thymidine- Associated Mutations and Response to d4T, Abacavir and ddI in the Control Arm of the Narval ANRS 088 Trial. 8^th Conference on Retroviruses and Opportunistic Infections. 2-4 Feb 2001, Chicago, IL. Abstract 450.
Shulman N, Shafer R, Winters M, and others. Genotypic predictors of virologic response to stavudine after zidovudine monotherapy (ACTG 302). 8^th Conference on Retroviruses and Opportunistic Infections. 2-4 Feb 2001, Chicago, IL. Abstract 437.
Lanier ER, Hellmann N, Scott J, et al. Determination of a Clinically Relevant Phenotypic Resistance "Cutoff" for Abacavir Using the PhenoSense Assay. 8^th Conference on Retroviruses and Opportunistic Infections. 2-4 Feb 2001, Chicago, IL. Abstract 254.
Gu Z, Nguyen-Ba N, Mellors J, Fortier C, M. Wainberg M. In Vitro Selection and Characterisation of HIV-1 Resistance to BCH-10618. 8^th Conference on Retroviruses and Opportunistic Infections. 2-4 Feb 2001, Chicago, IL. Abstract 472.