Development of Lys to Arg Mutation at Codon 70 of the Reverse Transcriptase Gene of HIV-1 during Zidovudine Monotherapy and Alternating Zidovudine/Didanosine Therapy

Abstract

Objective

To study the association between the Lys to Arg mutation at codon 70 of the reverse transcriptase (RT) gene and resistance development during zidovudine monotherapy and alternating zidovudine/didanosine therapy.

Methods

Blood samples from 33 antiretroviral-naive patients were drawn prior to therapy and after 6, 12, 18 and 24 months (18 patients received zidovudine monotherapy and 15 patients alternating zidovudine/didanosine). Results: After 6 months of zidovudine monotherapy, 72% of the patients had provirus encoding Lys to Arg at codon 70. This decreased to 53% and 38% after 12 and 18 months, respectively, but increased to 60% after 24 months. During alternating zidovudine/didanosine therapy, the percentages with the mutation were 6%, 7%, 11% and 20% after 6, 12, 18 and 24 months of therapy, respectively. During both therapy regimens provirus showed the same progression of mutations in RT codons 41 and 215, increasing from 10% after 6 months to 80–100% after 24 months. Codon 70 and 215 mutations together were only found with the codon 67 mutation. No significant difference in IC₅₀ or viral load was shown between patients on either therapy.

Conclusions

The codon 70 mutation was present in a low proportion of the patients during alternating zidovudine/didanosine therapy compared with patients on zidovudine monotherapy (P<0.01). Mutations associated with zidovudine resistance appeared in an ordered manner. Based on the phenotypic susceptibility of the virus isolated, the appearance of the different combinations of mutations could be explained by outgrowth of virus with an increased level of phenotypic resistance.