Biomedical subjects
Publications and source records attributed to Ottavia Viganò.
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BACKGROUND: Despite the increasing number of antiretroviral compounds, the number of useful drug regimens is limited owing to the high frequency of cross-resistance. PATIENTS AND METHODS: We studied in vitro two-drug combinations using three protease inhibitors (PIs), tipranavir, amprenavir and lopinavir, on isolates (003 and 004) derived from patients with resistance to multiple PIs compared with the drug-susceptible isolate 14aPre in peripheral blood mononuclear cells. Drug interactions were determined by median dose-effect analysis, with the combination index calculated at several inhibitory concentrations (IC). RESULTS: In 14aPre experiments, the combination tipranavir + lopinavir demonstrated synergy at low concentrations (IC(50)), an additive effect at IC(75) and antagonism at IC(90)-IC(95); tipranavir + amprenavir were antagonistic at all concentrations except IC(95), where they were synergic; and the lopinavir + amprenavir combination was always antagonistic. In 003 and 004 infections, tipranavir + lopinavir and tipranavir + amprenavir combinations were antagonistic, and lopinavir + amprenavir were synergic, at all concentrations, with the exception of being additive at IC(95). CONCLUSIONS: Our in vitro experiments did not show any advantage in combining second generation PIs as a therapeutic strategy in naive or multi-treatment failure subjects, with the exception of tipranavir + amprenavir at IC(95) in infections by a wild-type isolate.
INTRODUCTION: Multiple amino acid changes in the reverse transcriptase (RT) enzyme of the human immunodeficiency virus 1 (HIV-1) confer simultaneous resistance to most nucleoside RT inhibitors (NRTI). It may take place through different pathways: one of these is the codon 69 insertion, which can involve several 2-amino acid patterns. MATERIALS AND METHODS: We are reporting the case of three patients treated with various antiretroviral compounds. For these subjects we have conducted both a genotypical and a phenotypical analysis in order to understand what kind of influence these insertions may have on HIV-1 RT drug susceptibility. Plasma samples from these patients have been extracted and the RT region has been amplified, cloned and sequenced; meanwhile their PBMCs have been separated, cultivated and then tested for drug susceptibility. RESULTS: Data obtained from the cloning assay showed that the patients had different mutational patterns but constant multiple resistance to NRTI. In particular, they harbored mutations related to Zidovudine (ZDV), 3TC and various NRTIs. Moreover, all three samples had a T69S substitution followed by three different dual amino acid insertions: SG, TG and VG. Several phenotypic experiments revealed that the viruses were resistant to 3TC as well as to ZDV and ABC. Different results were obtained using d4T and ddI. DISCUSSION: In our three patients, all mutation inserts impaired the use of NRTI, particularly ZDV and 3TC. Patient 001 presented a pattern that should not cause a high phenotypic resistance to 3TC per se, and so we can argue that the concomitant presence of the insertion T69S (SG) makes this isolate moderately resistant to this drug. We observed a similar phenomenon in subject 003. d4T was less involved in the resistance generation caused by the RT insertion (in one out of three cases). Moreover, we identified a new 2aa insertion (TG) that has, to the best of our knowledge, never been reported before. A careful survey of novel RT genotypic insertion is thus warranted.
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