1st International Workshop on HIV Drug Resistance & Treatment Strategies 25-28 June 1997, St. Petersburg, Florida, USA

DEVELOPMENT OF GENOTYPIC ZIDOVUDINE RESISTANCE DURING ZIDOVUDINE MONOTHERAPY AND ALTERNATING ZIDOVUDINE-DIDANOSINE THERAPY

Antiviral Therapy 1997;2 (Suppl 5):22 (abstract no. 35)

Louise Bruun¹, Terese Katzenstein², Jan Gerstoft², Court Pedersen^2,3, Lars R Mathiesen³ and C Nielsen^1
1Statens Serum Institut; ²Rigshospitalet; and ³Hvidovre Hospital, Copenhagen, Denmark

OBJECTIVE: To study development of genotypic zidovudine resistance during zidovudine monotherapy and alternating zidovudine-didanosine therapy.

METHODS: Blood samples from 33 antiretroviral-naive patients were drawn before initiation of therapy and after 6, 12, 18 and 24 months of therapy (18 patients were in zidovudine monotherapy and 15 patients were in alternating zidovudine-didanosine therapy). Zidovudine-associated mutations at codons 41, 70 and 215 of the RT gene were analysed using selective PCR on DNA from peripheral blood mononuclear cells (PBMC). The presence of other mutations were analysed by direct sequencing on selected samples.

RESULTS: After 6 months of zidovudine monotherapy 72% of the patients had proviral DNA with the Lys®Arg mutation in codon 70. The proportion of patients with the 70 mutation decreased to 53% and 38%, respectively, after 12 and 18 months of therapy. After 24 months the amount of patients with the mutation increased to 60%. However, during alternating zidovudine-didanosine therapy the percentage of patients with the 70 mutation were 6%, 7%, 11% and 20%, respectively, after 6, 12, 18 and 24 months of therapy. During both zidovudine monotherapy and alternating therapy, proviral DNA from the patients showed the same progressive development of mutations in both RT codon 41 and 215, increasing from 10% after 6 months to 80-100% after 24 months of therapy. Combination of the 70 and 215 mutation was only found in the presence of the 67 mutation. No significant difference in phenotypic resistance (IC₅₀) and viral load was shown between patients in zidovudine mono- and alternating therapy.

CONCLUSIONS: (1) As previously shown, the 70 mutation appeared as the first zidovudine-associated mutation during zidovudine therapy. During therapy the 70 mutation was replaced by mutations in codon 41 and 215. After 24 months of therapy the 70 mutation reappeared together with a mutation in codon 67. (2) Compared to zidovudine therapy, the 70 mutation was only present in a low proportion of the patients during alternating zidovudine-didanosine therapy. (3) Based on the phenotypic susceptibility of the isolated virus from PBMC, the appearance of the different combinations of mutations could be explained by outgrowth of virus with an increased level of phenotypic resistance. (4) The fact that no difference in phenotypic resistance and in viral load could be shown between zidovudine monotherapy and alternating therapy indicates that the presence of the 70 mutation in proviral DNA has a minor role after 6 months of zidovudine therapy.

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1997-06-25
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