Harrigan R, Stone C, Griffin P, Bloor S, Tisdale M, Larder B; Glaxo Wellcome, UK.
A recent 12 week dose ranging clinical trial (CNAA2001) of the safety and pharmacokinetics of 1592U89 has demonstrated that it has considerable in vivo antiretroviral activity alone and in combination with zidovudine (AZT). Decreases in HIV RNA greater than 1.4 logs were observed after 4 weeks of 1592 monotherapy at all doses examined. After 4 weeks, half the patients were randomised to receive 1592/AZT, while half remained on 1592 monotherapy for a further 8 weeks. The continued suppression of viral load indicated that significant resistance to 1592 had not generally occurred after twelve weeks of therapy in either the combination or the monotherapy arms. The considerable reductions in viral load made it difficult to determine the HIV RT nucleic acid sequence in all patient samples. Mutations in the HIV-1 RT at codons 65, 74, or 184 were observed in some patients after twelve weeks of 1592 monotherapy. The combination of AZT with 1592 appeared to prevent the selection of these mutations over the course of this trial. These data are consistent with in vitro observations which indicate that multiple mutations in the HIV-1 RT are required to confer modest (10-fold) reductions in 1592 susceptibility. In vitro passage in the presence of the combination of AZT and 1592 resulted in selection of the 65 mutation, but appeared to prevent or delay selection of the 184V substitution. Phenotypic characterisation of recombinant viruses cross-resistant to a number of nucleoside RT inhibitors indicates that the genetic basis for 1592 resistance in clinical isolates would most likely reside in the 5' region of the HIV RT. Phenotypic characterisation of recombinant viruses derived from trial CNAA2001 and replication competition experiments are currently under way.
Keywords: AEGIS, Reverse Transcriptase Inhibitors, Dideoxynucleosides, Zidovudine, Nucleosides, HIV-1 Reverse Transcriptase, HIV-1, Anti-HIV Agents, Viral Load, Codon, Virus Replication, Mutation, abacavir, In Vitro, Human, genetics, virology, AIDS
