Abacavir (ABC), Ziagen, 1592U89; component of Trizivir
Guanosine analog reverse transcriptase inhibitor
Mutations associated with drug resistance:
M184V, L74V, K65R, and Y115F are responsible for ABC resistance during in vitro passage experiments and each of these mutations have also been reported to develop in patients receiving ABC [Tisdale M, et al. 1997; Staszewski S, et al. 1998]. Each of these mutations decreases ABC susceptibility 2- to 4-fold; two to three mutations are required to reduce susceptibility by greater than or equal to 10-fold. Q151M and its associated multinucleoside resistance mutations also confer ABC resistance (see AZT resistance summary) [Palmer S, et al. 1999].
Phenotypic resistance:
The dynamic range in susceptibility between wild-type isolates and the most highly drug-resistant isolates is only slightly greater than 10-fold [Tisdale M, et al. 1997].
Cross-resistance:
Until now, ABC has been used most often as salvage therapy. Of course, this may change with the introduction of Trizivir, a single tablet that contains AZT, 3TC and ABC. Data are gradually accumulating on the genotypic response to ABC therapy. The common RT mutation, M184V, which reduces ABC susceptibility 2-fold, has little or no effect by itself on virologic response to ABC [Miller V, et al. 1998; Lanier R, et al. 1999; Henry K, et al. 1999]. Although thymidine analog mutations (TAMs) and/or nucleotide excision mutations (NEMs) on their own may only cause low levels of ABC resistance [Lanier R, et al. 1999; Falloon J, et al. 2000; Khanna N, et al. 2000], the presence of greater than or equal to 2 AZT resistance mutations together with M184V ± noncanonical RT mutations may lead to high-level 10-fold ABC resistance that precludes the further use of the drug [Palmer S, et al. 1999; Shafer RW, et al. 1998]. Q151M also confers phenotypic resistance [Palmer S, et al. 1999]; data on the b3-b4 insertion are pending. Resistance to ABC can often be predicted based on viral genotyping.
Emergence of resistance in vivo:
There are few published data on mutations associated with ABC either as the sole NRTI or in combination with other NRTIs. There are no complete published sequences in GenBank [Shafer RW, et al. 1999]. As noted above, the data that are available suggest that M184V, L74V, K65R and Y115F can develop in patients receiving ABC together with AZT and 3TC [Staszewski S, et al. 1998].
Clinical correlates of drug resistance:
ABC resistance is probably clinically significant. In previously untreated patients, ABC is the most potent NRTI virologically. Unfortunately, patients whose virus isolates contain multiple TAMs and 184V will have little benefit from ABC salvage therapy.
Henry, K., Shaeffer, M., Ross, L., Johnson, M., Fisher, R., Liao, Q., and Graham, D.
Response to Combivir and abacavir given BID to nucleoside experienced patients is not affected by the M184V mutation.
6th Conference on Retroviruses and Opportunistic Infections. 31 Jan-4 Feb, 1999, Chicago, IL. Abstract 132.
Lanier R., Ait-Khaled M., Madison S., Hetherington B., Wang B., Dix L., and Lafon S.
Analysis of possible predictors of response to abacavir (ABC) in antiretroviral-experienced adults; Comparison of viral genotype, viral phenotype, and patient treatment history.
6th Conference on Retroviruses and Opportunistic Infections. 31 Jan-4 Feb, 1999, Chicago, IL. Abstract 134.
Lanier R, Scott J, Steel H, et al.
Multivariate analysis of predictors of response to abacavir: comparison of prior antiretroviral therapy, baseline HIV RNA, CD4 count and viral resistance [abstract 82].
Antivir Ther 1999; 4(Suppl. 1):56.
Staszewski, S., Harrigan, P.R., Stone, C., Griffin, P., Tortell S., and CNAA2002 International Project Group.
Efficacy and resistance profile of abacavir at 24 and 48 weeks therapy including monotherapy and following switch to combination therapy (abacavir/zidovudine/lamivudine).
Second International Workshop on HIV Drug Resistance and Treatment Strategies. 24-27 June 1998, Lake Maggiore, Italy, Abstract 99.
Abacavir (ABC), Ziagen, 1592U89; component of Trizivir
2 AZT resistance mutations together with M184V ± noncanonical RT mutations may lead to high-level 10-fold ABC resistance that precludes the further use of the drug [Palmer S, et al. 1999; Shafer RW, et al. 1998]. Q151M also confers phenotypic resistance [Palmer S, et al. 1999]; data on the b3-b4 insertion are pending. Resistance to ABC can often be predicted based on viral genotyping.