Mutations at positions 219, 215, 210, 75, 69, 67, 41 (low level resistance), 118, 116, 77, 70, 62 and 44 (contributes to resistance), may all contribute, to some degree, to stavudine resistance. The spectrum of mutations responsible for d4T resistance is not well characterized, but increasing evidence points to a role for the same mutations associated with resistance to AZT, i.e., thymidine-associated mutations (TAMs; aka nucleotide excision mutations or NEMs) [Shulman NS, et al. 2001]. This lack of precision is partly due to the relative insensitivity of most phenotypic assays to d4T resistance and because there have been relatively few studies correlating published RT sequences from patients receiving d4T with carefully performed drug susceptibility testing. Although mutations such as V75T and the multinucleoside-resistance mutations are associated with about 5-fold resistance [Lacey SF, et al. 1994; Shafer RW, et al. 1994; Iversen AK, et al. 1996], these are seen relatively infrequently in the clinic. Other mutations at codon 75, including V75M, V75S and V75A, may also contribute to drug resistance [Bloor S, et al. 1998]. I50T has been reported during in vitro passage experiments but has not been reported in vivo [Gu Z, et al. 1994]. Most important, intermediate levels of d4T resistance (about 5-fold) have been reported in patients with multiple classical AZT resistance mutations in combination or not with the b3-b4 insertion [Winters MA, et al. 1998], mutations at codon 69 (T69D or T69N) [Shafer RW, et al. 1998], or multiple noncanonical RT mutations (see AZT resistance summary) [Katlama C, et al. 1998].
Phenotypic resistance:
Phenotypic resistance to d4T can be difficult to detect with current assays and requires establishment of sensitive cut-off values in comparison with wild-type clinical isolates. In this respect, detection of d4T resistance is similar to that for ddI; however, the explanation for the difficulty in detecting phenotypic d4T resistance is probably different than that of ddI because d4T does undergo triphosphorylation to its active form (d4T-TP) in activated lymphocytes. Recent work has shown that a 2-fold decrease in susceptibility to d4T can indicate a clinically significant level of drug resistance.
Cross-resistance:
Most cross-resistance data describe the extent to which isolates from patients receiving other treatments are resistant to d4T. Most of these data show that patients who have received prior AZT therapy have a markedly diminished response to treatment with d4T either alone or in combination with other drugs [Ross LL, et al. 1998; Izopet J, et al. 1998; Katzenstein DA, et al. 1998; Havlir DV, et al. 1998; Coakley E, et al. 1999]. There are few data available on patients who have switched from d4T to AZT.
The notion that AZT and d4T are cross-resistant is strengthened by the observation that the most common mutations in patients receiving d4T include the AZT-resistance mutations M41L and T215Y [Lin PF, et al. 1994; Shafer RW, et al. 1999]. Other potential mechanisms of cross-resistance between d4T and other drugs include multinucleoside resistance mediated by Q151M and the b3-b4 insertion (see AZT resistance summary).
Emergence of resistance in vivo:
There is currently not a single published sequence in GenBank from a patient receiving d4T monotherapy or d4T + ddI combination therapy [Shafer RW, et al. 1999]. The data described above on the spectrum of mutations occurring with d4T are based on reports in which only specific mutations were reported. Based on these reports, the most commonly occurring mutations during d4T therapy are the classical AZT-resistance mutations.
Clinical correlates of drug resistance:
There are gaps in our knowledge of the clinical correlates of drug resistance because phenotypic resistance is difficult to detect and because the genetic mechanisms of d4T resistance are still poorly defined. Nonetheless, heavily treated patients and patients with AZT-resistant isolates have diminished virologic responses to d4T-containing regimens.
Bloor S, Hertogs K, Larder B, Pauwels R, Larder BA. Virological basis for HIV-1 resistance to stavudine investigated by analysis of clinical samples.
Second International Workshop on HIV Drug Resistance and Treatment Strategies. 24-27 June 1998, Lake Maggiore, Italy, Abstract 15.
Coakley E, Gillis J, Hammer S.
. Mutations in the Reverse Transcriptase Genome of HIV-1 Isolates Derived from Subjects Treated with Didanosine and Stavudine in Combination.
6th Conference on Retroviruses and Opportunistic Infections. 31 Jan-4 Feb, 1999, Chicago, IL. Abstract 116.
Katzenstein DA, Shafer RW, Bosch RJ, Albrecht MA, Hammer SM. Reverse transcriptase and protease genotypes of nucleoside-experienced subjects with virological failure of nelfinavir or efavirenz.
Second International Workshop on HIV Drug Resistance and Treatment Strategies. 24-27 June 1998, Lake Maggiore, Italy, Abstract 84.
Ross LL, Johnson M, Graham N, St.Clair M.
Efficacy of stavudine therapy after prior zidovudine therapy is inversely correlated with the frequency of reverse transcriptase inhibitor resistance mutations and initial viral load.
Second International Workshop on HIV Drug Resistance and Treatment Strategies. 24-27 June 1998, Lake Maggiore, Italy, Abstract 94.
Stavudine (d4T), Zerit
