THE M184V MUTATION IN HIV-1 REVERSE-TRANSCRIPTASE (RT) CONFERRING LAMIVUDINE RESISTANCE DOES NOT RESULT IN BROAD CROSS-RESISTANCE TO NUCLEOSIDE ANALOG RT INHIBITORS

Objective: To investigate the prevalence and magnitude of M184V-mediat ed changes in susceptibility to zalcitabine, didanosine, stavudine and abacavir (1592U89 succinate) in a cohort of lamivudine-treated patien ts. Design and methods: A total of 255 samples from patients treated w ith lamivudine and zidovudine with or without other nucleoside reverse transcriptase inhibitors (NRTI) were analysed for susceptibility to z idovudine, lamivudine, zalcitabine, didanosine and stavudine using a r ecombinant virus assay. Seventy-three samples originated from patients exposed to zidovudine and lamivudine only. A subset of 27 samples was investigated for cross-resistance to abacavir. Resistance was defined as a change in median inhibitory concentration more than fivefold com pared with wild-type (high-level resistance, > 10-fold). A genotypic a nalysis of plasma-derived reverse transcriptase coding regions was car ried out in samples with cross-resistance. Results: The majority of sa mples displayed wild-type or greater than wild-type sensitivity to zal citabine, didanosine and stavudine: resistance was seen in 17.2, 9 and 6.3% of the total sample population, respectively. Of these, 1.2, 2.7 and 2.4%, respectively, showed high-level resistance. The prevalence of resistance to a particular NRTI was lower in samples from patients not pretreated with that NRTI and in samples from patients exposed to zidovudine-lamivudine only. Cross-resistance was more prevalent in sam ples with high ZDV resistance. There was no obvious correlation betwee n cross-resistance and genotype; all but two samples were mutant at co don 184. There were no consistent changes at positions associated with zidovudine resistance. The majority of samples from a subset (n = 27) were four-to eightfold less sensitive to abacavir. There were no othe r genotypic changes in addition to M184V known to be associated with a bacavir resistance. Conclusions: Cross-resistance was not commonly obs erved in this lamivudine-treated cohort. M184V per se is not expected to compromise subsequent treatment with NRTI such as didanosine-stavud ine or combinations containing abacavir. (C) 1998 Lippincott-Raven Pub lishers.