Abstract No. 113: The Multiple Nucleoside Analogue Resistance Mutations Confer Cross-Resistance to Abacavir
In this collaborative European study the authors began with the observation that the mutation Q151M, together with other mutations that code on 62, 68, 75, 77 and 116 of the HIV I RT gene response for high level resistance against the NRTI's. Abacavir (ABC) is a guanosine deoxynucleoside analog and is a potent inhibitor of HIV I reverse transcriptase (RT). During in vitro passage, it can select for the permutations K65R, L74V, Y115F and M184V. Combinations of these mutations are necessary to confer resistance to ABC. The purpose of the study was to determine the susceptibility for ABC of HIV strains carrying mutations of a multi-drug resistant pattern. Fiber samples from 5 patients showing Q151M mutation were extracted and the RT coding region was amplified using PCR. Resistance to AZT, DDC, DDI, d4T, 3TC and ABC and Nevirapine were determined from recombinant virus stock in the laboratory. None of the five recombinant viruses were still sensitive to the ABC. Three recombinant viruses proved to be highly resistant to ABC. Two of these viruses carried, in addition to the multi-drug mutations, also one of the mutations associated with ABC resistance, namely K65R and M184V. All of the patients from whom serum was obtained had been on antiretroviral treatment. Some were on regimens as simple as ZDV and DDI, and others were on extremely complex regimens involving almost all available medications. All samples showed, in addition to the different sets of resistance related mutations, polymorphic amino acid substitutions and substitutions found to be resistance-related but showing a different amino acid such as T69I and K103R.
Conclusions: The authors observed none of the five recombinant viruses showed wild type sensitivity to Abacavir. Three recombinant viruses showed a resistance level above seven-fold toward Abacavir. Two of these strains were also phenotypically resistant to at least two additional NRTI's. Interestingly, on one strain, Q151M was noted, and a classical zidovudine mutation, T214Y, was found. This has not been seen from patient samples or in laboratory in vitro recombinants.
In conclusion, this data, although limited to a rather small number of patients and strains, shows that multi-nucleoside resistant strains have a reduced sensitivity toward Abacavir. As the mutations accumulate, significant resistance continues to develop.
Abacavir, or Zygen, is a recently approved reverse transcriptase inhibitor. Where precisely this drug fits into the armamentaria available to clinicians, remains to be determined. Initially this drug was being used as part of a salvage regimen by most physicians in patients. It is clear from this study, however, that in a salvage setting, significant resistance may have already developed. While there may be some value by using ABC in this setting in combination with a protease inhibitor, perhaps it should be used sooner. In a number of other presentations there was convincing data that ABC should perhaps be used as part of as initial therapy. It may also have a well-defined role as second line therapy in a patient not extensively treated. I think that by this time next year, we will have a much greater understanding of where precisely Abacavir fits.