Genotypic and penotypic resistance patterns of human immunodeficiency virus type 1 variants with insertions or deletions in the reverse transcriptase(RT): Multicenter study of patients treated with RT inhibitors

Genomic rearrangements in the 5' part of the human immunodeficiency virus t ype 1 (HN-I) reverse transcriptase (RT) have been involved in multidrug res istance to nucleoside RT inhibitors (NRTI). We carried out a retrospective, multicenter study to investigate the prevalence, variability, and phenotyp ic consequences of such rearrangements. Data concerning the HIV-I RT genoty pe and the biologic al and clinical characteristics of NRTI-freated patient s were collected from 10 virology Laboratories. Sensitivities of the differ ent HIV-I variants to RT inhibitors were analyzed in a single-cycle recombi nant virus assay. Fifty-two of 2,152 (2.4%) RT sequences had a rearrangemen t in the 5' part of the RT, with an extensive molecular variation. The numb er of codons inserted between positions 68 and 69 ranged from 1 (3 samples) or 2 (41 samples) to 5 and 11 in one case each. In four cases, codon 67 wa s deleted. High levels of phenotypic resistance to zidovudine (AZT), lamivu dine (3TC), stavudine (d4T), abacavir (ABC), and didanosine (ddI) were foun d in 95, 92, 72, 62, and 15% of the 40 samples analyzed, respectively. Resi stance to AZT, d4T, and ABC could be found in the absence of the T215Y/F mu tations. Resistance to 3TC could develop in the absence of specific mutatio ns. Low-level resistance to ddI was noticed in 40% of the patients. The del etions of codon 67 seemed to have little effect on NRTI sensitivity. Most o f the rearrangements were shown to contribute to cross-resistance to NRTI. The results regarding susceptibility to ddI raise the question of the inter pretation of the phenotypic data concerning this drug.