DEVELOPMENT OF RESISTANCE TO ZIDOVUDINE (ZDV) AND DIDANOSINE (DDL) INHIV FROM PATIENTS IN ZDV, DDL AND ALTERNATING ZDV DDL THERAPY/

Objective: To study development of phenotypic and genotypic resistance against zidovudine (ZDV) and didanosine (ddl) during 24 months of mon o- and monthly alternating therapy. Patients: Forty-six patients, not previously treated with antiretroviral drugs, were included in the stu dy. Methods: ZDV and ddl sensitivity were determined in a biological a ssay based on production of HIV antigen in cultures of CD4+ lymphocyte s. The ZDV-associated mutations at codon 41 and 215, and the ddl-assoc iated mutation at codon 74 of the reverse transcriptase (RT) gene were analysed using selective polymerase chain reaction on DNA from periph eral blood mononuclear cells. The biological phenotype [syncytium-indu cing (SI)/non-SI (NSI)] of the viral isolates was assessed using a MT2 assay. Results: Of the patients, 82% in ZDV therapy and 73% in altern ating therapy developed phenotypic resistant HIV [median inhibitory co ncentration (IC50) > 0.1 mu M]. Patients treated for 1 year with ddl ( monotherapy or alternating) had significant higher ddl IC50 values tha n patients in ZDV monotherapy. During ZDV and alternating therapy, 67 and 75% of the patients, respectively, developed mutations in RT codon 41, whereas 83 and 75%, respectively, developed mutations in codon 21 5. In patients treated with ddl, 60% developed mutations in codon 74, whereas none of the patients in either alternating ZDV/ddl or ZDV ther apy developed this mutation. Forty-six per cent of the patients had SI HIV at start of therapy. Four patients switched from SI to NSI during either ZDV, ddl or alternating therapy. Faster development of resista nce was associated with the SI phenotype. Conclusions: No difference i n either phenotypic ZDV or ddl resistance, or genotypic ZDV resistance could be demonstrated during monotherapy or monthly alternating ZDV/d dl therapy, whereas genotypic ddl resistance (mutation in RT codon 74) only were detected in patients in ddl monotherapy. In addition, we fo und that development of phenotypic and genotypic resistance was faster in patients harbouring SI isolates, and that switches from SI to NSI during therapy was independent of the type of therapy.