Zidovudine (ZDV, AZT), Retrovir; component of Combivir and Trizivir
Thymidine analog reverse transcriptase inhibitor.
Mutations associated with drug resistance:
The most common mutations associated with drug resistance include M41L, D67N, K70R, L210W, T215Y/F, and K219 Q/E ("classical pathway") [Larder BA, et al. 1989; Larder BA, et al. 1989a; Kellam P, et al. 1992; Hooker DJ, et al.1996]. Less common mutations associated with AZT resistance include the mutations V75I, F77L, F116Y, and Q151M ("multinucleoside resistance pathway") [Shafer RW, et al.1994; Shirasaka T, et al.1995; Schmit JC, et al. 1996]. A third genetic mechanism associated with drug resistance is a double amino acid insertion between codons 69 and 70 in the b3-b4 hairpin loop of the RT "fingers" subdomain ("b3-b4 insertion") [Winters MA, et al.1998]. Also, deletions in this region of RT may contribute to resistance [Hirsch MS, et al. 2000].
Phenotypic resistance:
Drug resistance to AZT is readily detectable in vitro by a variety of phenotypic assays. In most assays, the dynamic range in susceptibility between susceptible wild-type isolates and the most highly drug-resistant isolates is about several hundred fold.
In the classical pathway, K70R and T215Y/F are generally the first mutations to develop. K70R causes 4- to 8-fold AZT resistance; T215Y/F causes 10- to 16-fold resistance. The most common cluster of classical mutations includes M41L and T215Y/F, which together cause ˜ 64-fold resistance. More than 100-fold AZT resistance develops with certain combinations of 3 mutations. In the multinucleoside resistance pathway, Q151M is the first mutation to develop and causes about 10- to 20-fold AZT resistance. With the accumulation of V75I, F77L and F116Y, resistance can become several hundred-fold.
T215S is not associated with decreased AZT susceptibility, but represents a transition mutation on the way towards either T215F or Y. T215C and T215D occur rarely and probably are associated with some degree of AZT resistance. K219N occurs commonly in heavily treated patients and is probably associated with resistance.
Cross-resistance:
Because AZT is the oldest NRTI, most cross-resistance data describe the extent to which AZT-resistant isolates are resistant to other NRTIs. HIV-1 laboratory constructs with classical AZT-resistance mutations are not cross-resistant to other NRTIs in most phenotypic assays. However, clinical isolates with AZT-resistance mutations together with additional RT mutations often demonstrate low-to-intermediate levels of resistance to ddI, ddC, d4T, abacavir, and PMEA [Shafer RW, et al. 1998;Palmer S, et al. 1999; Bloor S, et al. 1998; Lanier R, et al. 1998]. Furthermore, clinical studies have shown that AZT resistance compromises the subsequent efficacy of ddI, d4T and abacavir [D'Aquila RT, et al. 1995; Katlama C, et al. 1998; Ross LL, et al. 1998; Izopet J, et al. 1998]. Notably, AZT resistance mutations are the most common mutations occurring in patients receiving d4T and also develop in about 10% of patients receiving ddI [Demeter LM, et al. 1995; Winters MA, et al. 1997]. Recently, mutations associated with resistance to either AZT or d4T have become known as thymidine-analog mutations (TAMs), nucleoside analog mutations (NAMs) and/or nucleotide excision mutations (NEMs) [Kozal MJ, et al. 1993; Rey D, et al. 1998], since it is increasingly evident that both thymidine analogs can select for the same resistance-conferring mutations in RT and that these same mutations can confer a degree of resistance to either drug [Shulman NS, et al. 2001].
Emergence of resistance in vivo:
About 90% of clinical AZT-resistant HIV-1 isolates have classical pathway mutations. The remaining 10% of AZT-resistant isolates have multinucleoside resistance mutations or the b3-b4 insertion. The multinucleoside resistance pathway and the b3-b4 insertion have only been reported in patients receiving AZT in combination with other NRTIs. The multinucleoside resistance mutations usually occur by themselves; in contrast, the b3-b4 insertion is nearly always accompanied by classical pathway mutations.
Clinical correlates of drug resistance:
During AZT monotherapy, the development of AZT resistance mutations is correlated with subsequent CD4 decline and increases in plasma HIV-1 RNA [Winters MA, et al. 1997; Shulman NS, et al. 2001]. Patients with AZT-resistant isolates also experience diminished virologic responses to subsequent therapy with other NRTIs, including ddI [D'Aquila RT, et al. 1995;Ross LL, et al. 1998; Izopet J, et al. 1998; Japour AJ, et al. 1995; Katzenstein DA, et al. 1998]. The presence of AZT mutations together with the 3TC mutation M184V also compromises the efficacy of abacavir [Palmer S, et al. 1999; Lanier R, et al. 1998; Ait-Khaled M, et al. 1999]. Among AZT-experienced patients treated with six months of induction therapy with AZT/3TC/indinavir followed by maintenance therapy with AZT/3TC, those having baseline isolates with mutations at codon 215 experienced significantly higher rates of virologic relapse [Havlir DV, et al. 1998].
The development of multiple AZT mutations may not be required to abrogate the clinical efficacy of AZT monotherapy [de Jong MD, et al. 1996]. However, in patients receiving AZT in combination with a second NRTI, multiple mutations appear to be required for the development of clinically significant drug resistance.
Comment: Mutation interactions:
At least two NRTI mutations (L74V and M184V) and two NNRTI mutations (L100I and Y181C) partially reverse AZT resistance mediated by classical pathway mutations [Larder BA, et al. 1994]. These interactions are almost certainly clinically relevant and probably play a role in the prolonged duration of activity of certain dual and triple NRTI combinations. It is possible that other clinically significant antagonistic mutation interactions exist, but none have been identified with the same certainty or exploited to the same extent clinically. The mechanism through which the 184V mutation can resensitize viruses to AZT has been partially elucidated, and is attributable to the finding that 184V-containing enzymes have diminished rates of the reverse step in a reverse transcriptase reaction, i.e., nucleotide primer unblocking and/or pyrophosphorolysis [Gotte M, Wainberg MA. 2000; Gotte M, et al. 2000].
Ait-Khaled M, Stone C, Mesogit D, Purdon S, Vernazza P, for the CNA3002 International Study Group.
Genotype and phenotype of HIV-1 in ART experienced adults prior and following therapy with Ziagen (abacavir, ABC) added to stable background therapy (ABC + SBG).
6th Conference on Retroviruses and Opportunistic Infections. 31 Jan-4 Feb, 1999, Chicago, IL. Abstract 114.
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.
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.
Lanier, R., Danehower, S., Daluge, S., Cutrell, A., Tisdale, M., Pearce, G., Spreen, B., Lafon, S., Kemp, S. D., Bloor, S., and Larder, B. A.
Genotypic and phenotypic correlates of response to abacavir (ABC, 1592).
Second International Workshop on HIV Drug Resistance and Treatment Strategies. 24-27 June 1998, Lake Maggiore, Italy, Abstract 52.
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.
Zidovudine (ZDV, AZT), Retrovir; component of Combivir and Trizivir
3 mutations. In the multinucleoside resistance pathway, Q151M is the first mutation to develop and causes about 10- to 20-fold AZT resistance. With the accumulation of V75I, F77L and F116Y, resistance can become several hundred-fold.
