RESUMO
The drug sensitivities of human immunodeficiency virus type 1 (HIV-1) isolates from a group of four untreated and seven TIBO R82913-treated patients were determined in a reverse transcriptase (RT) assay. Five of the treated patients harbored HIV-1 isolates with R82913 sensitivity comparable to that of the isolates of untreated patients, ranging from almost 2-fold higher sensitivity to 13-fold lower sensitivity than that of recombinant p66 RT. From one of the seven treated patients, an HIV-1 strain with a 20-fold reduced sensitivity to R82913 could be isolated; and from another patient, a strain with 100-fold reduced sensitivity (resistance) was isolated. The drug-resistant strain in this patient emerged after 3 weeks of treatment and was due to the Y188L mutation in its RT. On passaging the virus in cord blood lymphocytes, but not in CEM cells, the resistant virus was lost in favor of a different HIV-1 strain harboring the wild-type Y188 with a sensitivity to R82913 comparable to that of wild-type p66 RT. In several HIV-1 isolates (from treated and untreated patients), some HIV-2- and CIVgab-specific amino acids were found. One of these substitutions, that is, I/V179D (from an untreated patient), conferred a sevenfold reduced RT sensitivity to R82913.
Assuntos
Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Benzodiazepinas/uso terapêutico , HIV-1/efeitos dos fármacos , Imidazóis/uso terapêutico , Síndrome da Imunodeficiência Adquirida/microbiologia , Sequência de Aminoácidos , Sequência de Bases , Células Cultivadas , Primers do DNA , Resistência Microbiana a Medicamentos , Variação Genética , Transcriptase Reversa do HIV , HIV-1/classificação , HIV-1/isolamento & purificação , Humanos , Dados de Sequência Molecular , DNA Polimerase Dirigida por RNA/genética , Inibidores da Transcriptase Reversa , Alinhamento de SequênciaRESUMO
R 82913, a tetrahydroimidazobenzodiazepinthione (TIBO) derivative with potent activity against human immunodeficiency virus 1 (HIV-1) in vitro, was given to 22 patients with AIDS or AIDS-related complex in a dose-escalating pilot study. Doses of 10 to 300 mg administered daily by intravenous infusion were well tolerated for up to 50 weeks, with no haematological or biochemical evidence of toxicity. Mean OKT4 cell count rose slightly during the second month of treatment when higher steady-state plasma concentrations of the drug were achieved. Median p24 antigen concentration fell by 41% during the first month of therapy. When the rise in p24 antigen before therapy was compared to the fall during treatment, end-point analysis showed a significant difference (p less than 0.03). The combination of potent antiretroviral activity in vitro and the observed effect on HIV p24 antigen and absence of toxicity in vivo indicate that R 82913 and related TIBO derivatives merit further study in the treatment of retroviral infections.