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written by Robert W. Shafer, M.D.
published on HIVresistanceWeb: May 12, 1999
Abacavir (Ziagen, ABC, 1592U89; Glaxo-Wellcome) is the most recently approved nucleoside RT inhibitors (NRTI). It is the first guanine analogue and is probably the most potent of the available NRTI. In phase I/II dose-escalation studies, ABC monotherapy reduced plasma HIV-1 levels by a median of 1.5-2.0 logs (70- to 100-fold) over 12 weeks [1]. In an open-label study of about 50 patients receiving ABC followed by ABC + AZT + 3TC, plasma HIV-1 levels were reduced by a median of 2.8 logs (600-fold) after 48 weeks of therapy [2].
M184V, L74V, K65R, and Y115F are the RT mutations responsible for ABC resistance when HIV-1 is passed in vitro [3]. These mutations have also been reported in clinical isolates from patients receiving ABC [4]. Each mutation decreases ABC susceptibility 2- to 4-fold; 2-3 of these mutations are required to decrease ABC susceptibility 10-fold. ABC is similar to ddI and d4T in that the dynamic range of drug susceptibility (or maximum possible drug resistance) is only about 10-fold. (In contrast, the dynamic range of drug susceptibility for AZT and 3TC is several-hundred fold.) It is therefore likely that even small changes in ABC susceptibility are clinically significant.
ABC is most often used as salvage therapy and data are gradually accumulating on the genotypic predictors of response to ABC therapy. Fortunately, the common RT mutation M184V, which reduces ABC susceptibility 2-fold, does not by itself block the antiviral response to ABC [5-7]. Unfortunately, there are multiple mechanisms of drug resistance, in addition to those identified during in vitro passage experiments.
Although AZT resistance mutations by themselves do not cause ABC resistance, the presence of two or more AZT resistance mutations is correlated with a poor response to ABC therapy [7,8]. It appears that a complex comprising AZT resistance mutations and additional, as yet unidentified, RT mutations may be responsible for ABC resistance in many clinical situations [7,9]. Q151M also confers phenotypic resistance [9], while data on the effect of RT insertion between codons 68-70 are pending.
Although extremely potent, ABC's antiretroviral activity is diminished in patients who have received previous NRTI and have ABC-resistant HIV-1 isolates. The benefit of ABC as salvage therapy depends on the mechanisms of cross-resistance between ABC and the other NRTI. Since these mechanisms of cross-resistance are not completely known it is not yet possible to accurately predict the antiviral response to ABC in previously treated patients.
References
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- Antiretroviral effect and safety of abacavir alone and in combination with zidovudine in HIV-infected adults.
Saag MS; Sonnerborg A; Torres RA; Lancaster D; Gazzard BG; Schooley RT; Romero C; Kelleher D; Spreen W; LaFon S. Abacavir Phase 2 Clinical Team ; AIDS. 1998 Nov 12;12(16):F203-9.
- A dose-ranging study to evaluate the safety and efficacy of abacavir alone or in combination with zidovudine and lamivudine in antiretroviral treatment-naïve subjects.
Staszewski S; Katlama C; Harrer T; Massip P; Yeni P; Cutrell A; Tortell SM; Harrigan RP; Steel H; Lanier RE; Pearce G.; AIDS. 1998 Nov 12;12(16):F197-202.
- Combination of mutations in human immunodeficiency virus type 1 reverse transcriptase required for resistance to the carbocyclic nucleoside 1592U89.
Tisdale M; Alnadaf T; Cousens D. ; Antimicrob Agents Chemother. 1997 May;41(5):1094-8.
- Efficacy and resistance profile of abacavir at 24 and 48 weeks therapy including monotherapy and following switch to combination therapy (abacavir/zidovudine /lamivudine).
Staszewski S, Harrigan PR, Stone C, Griffin P, Tortell S, Tisdale M, and the CNAA2002 International Project Group. ; Second International Workshop on HIV Drug Resistance and Treatment Strategies. 24-27 June 1998, Lake Maggiore, Italy. Abstract 99. - ABSTRACT NOT AVAILABLE
- Analysis of possible predictors of response to abacavir (ABC) in antiretroviral-experienced adults; comparison of viral genotype, viral phenotype, and patient treatment history
Lanier R, Ait-Khaled M, Madison S, et al. ; 6th Conference on Retroviruses and Opportunistic Infections. 31 Jan-4 Feb, 1999, Chicago, IL. Abstract 134.
- Response to Combivir and abacavir given BID to nucleoside experienced patients is not affected by the presence of the M184V mutation.
Henry K, Shaeffer M, Ross L, et al.; 6th Conference on Retroviruses and Opportunistic Infections. 31 Jan-4 Feb, 1999, Chicago, IL. Abstract 132.
- 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).
Ait-Khaled M, Stone C, Mesogit D, Purdon S, Vernazza P, for the CNA3002 International Study Group. ; 6th Conference on Retroviruses and Opportunistic Infections. 31 Jan-4 Feb, 1999, Chicago, IL. Abstract 114.
- Genotypic and phenotypic correlates of response to abacavir (ABC, 1592).
Lanier R, Danehower S, Daluge S, et al. ; Second International Workshop on HIV Drug Resistance and Treatment Strategies. 24-27 June 1998, Lake Maggiore, Italy. Abstract 52. - ABSTRACT NOT AVAILABLE
- Highly drug-resistant HIV-1 isolates are cross-resistant to many of the current anti-HIV compounds in clinical development.
Palmer S, Shafer RW, Merigan TC. ; AIDS. In press. - ABSTRACT NOT YET AVAILABLE
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