hby-097 and HIV-Infections

HIV type-1 (HIV-1) non-nucleoside reverse transcriptase inhibitors (NNRTIs) are key drugs of highly active antiretroviral therapy (HAART) in the clinical management of AIDS/HIV infection. NNRTI-based HAART regimes effectively suppress viral reproduction, are not cytotoxic and show favourable pharmacokinetic properties. First-generation NNRTIs suffer the rapid selection of viral variants, hampering the binding of inhibitors into the reverse transcriptase (RT) non-nucleoside binding site (NNBS). Efforts to improve these first inhibitors led to the discovery of second-generation NNRTIs that proved to be effective against the drug-resistant mutant HIV-1 strains. The success of such agents launched a new season of NNRTI design and synthesis. This paper reviews the characteristics of second-generation NNRTIs, including etravirine, rilpivirine, RDEA-806, UK-453061, BIRL 355 BS, IDX 899, MK-4965 and HBY 097. In particular, the binding modes of these inhibitors into the NNBS of the HIV-1 RT and the most clinically relevant mutant RTs are analysed and discussed.

Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Binding Sites; Cell Line; Drug Design; Drug Resistance, Viral; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Indoles; Models, Molecular; Molecular Conformation; Nitriles; Phosphinic Acids; Pyrazoles; Pyridazines; Pyridines; Pyrimidines; Quinoxalines; Reverse Transcriptase Inhibitors; Rilpivirine

The safety and antiviral activity of the second-generation nonnucleoside inhibitor HBY 097 was investigated in asymptomatic or mildly symptomatic human immunodeficiency virus (HIV)-1-infected patients in a randomized, double-blinded, dose-escalation study. Mean maximum virus load decreases ranged from -1.31 log10 copies/mL of plasma at week 1 in the group receiving HBY 097 monotherapy (250 mg three times daily) to -2.19 log10 copies/mL at week 4 in the group receiving zidovudine plus HBY 097 (750 mg three times daily). After 12 weeks, these patients had viral RNA copy numbers 1.05 log10 below baseline. Genotypic analysis of resistance development revealed reverse transcriptase K103N variants in most patients, which was associated with less durable efficacy of HBY 097 treatment. Fewer patients receiving combination therapy with high-dose HBY 097 developed the K103N variant (P<.01). HBY 097 caused pronounced acute suppression of HIV-1 replication both in combination with zidovudine and alone. Therefore, sustained antiviral activity can be expected from multiple combination therapy regimens including a quinoxaline derivative.

Topics: Adult; Anti-HIV Agents; Antiviral Agents; CD4 Lymphocyte Count; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Male; Quinoxalines; Reverse Transcriptase Inhibitors; RNA, Viral; Time Factors; Viral Load; Zidovudine

The quinoxaline derivative HBY 097, an orally active nonnucleoside inhibitor of HIV-1 reverse transcriptase (NNRTI), showed an efficient suppression of viral load in a dose-escalating phase I study with mean trough concentrations increasing from 137-1299 ug/l [Rübsamen-Waigmann et al., Lancet 349:1517]. Half-maximal inhibitory concentrations (IC50) for viruses grown from the patients at entry of the study were 0.1-3 nM, except for one patient who had a virus with reduced susceptibility to HBY 097 at entry (IC50: 160 nM). During therapy, only two patients developed a virus with a moderately increased IC50 (2.2 and 15 nM). This reduced susceptibility was associated with the known NNRTI-resistance mutation K ==> N at position 103, in contrast to resistance selection in vitro, which had yielded predominant mutations at positions 179 and 190. The Tyr mutation at position 181, inducing high resistance for other NNRTIs, was never observed. The resistant virus at study entry (IC50 = 160 nM) had a mutation at position 103 as well, combined with an AZT resistance mutation (K ==> R) at position 70, suggesting that nucleoside-resistance mutations may help increasing resistance to HBY 097. This is in line with our in vitro selection studies, where resistance mutations at the 'nucleoside sites' 74 and 75 increased the resistance phenotype of NNRTI mutations. Our findings highlight the crucial importance of IC50 determinations from cultured virus for determination of phenotypic resistance development during therapy and demonstrate that in vivo resistance development cannot be predicted from in vitro selection.

Topics: Antiviral Agents; Dose-Response Relationship, Drug; Drug Resistance, Microbial; Genotype; HIV Infections; HIV-1; Humans; Mutation; Phenotype; Quinoxalines; Reverse Transcriptase Inhibitors; Viral Load

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Antiviral Agents; Cohort Studies; Double-Blind Method; Drug Combinations; Drug Resistance, Microbial; HIV Infections; HIV-1; Humans; Mutation; Placebos; Quinoxalines; Reverse Transcriptase Inhibitors; Viral Load; Viremia; Virus Replication

To investigate the genotypic and phenotypic effects of in vitro resistance selection with lamivudine and/or the second generation non-nucleoside reverse transcriptase inhibitor (NNRTI) quinoxaline HBY097 using HIV-1 isolates carrying the multi-nucleoside resistance pattern linked to the Q151M mutation.. Virus strains were selected in C8166 cells in the presence of increasing concentrations of lamivudine or HBY097. In parallel control experiments, the virus was cultured in C8166 cells in the absence of drugs. The entire reverse transcriptase encoding region was amplified using polymerase chain reaction and was subsequently sequenced. Antiviral activities of drugs were evaluated in C8166 cells.. High-level resistant viruses were selected rapidly in the presence of lamivudine and quinoxaline (less than 10 passages). The multi-nucleoside resistance mutations were stable during in vitro resistance selection. Lamivudine elicited the acquisition of the M184I mutation. Phenotypic resistance to all nucleoside-analog reverse transcriptase inhibitors (NRTIs) was increased when M184I was added to the multi-nucleoside resistance background in the absence of NNRTI-resistance mutations. In most cases of HBY097 resistance selection, at least two mutations associated with NNRTI resistance resulted in high-level NNRTI resistance. The NNRTI resistance-related mutations partially reversed the phenotypic resistance to most NRTIs, except to abacavir. The addition of the M184I mutation to the NNRTI-multi-nucleoside resistance set abolished this antagonizing effect for didanosine, zalcitabine and lamivudine, but further potentiated the phenotypic reversal for zidovudine and stavudine.. Changes in the non-nucleoside binding pocket must affect the conformation of residues at the dNTP binding site, and can result in a partial phenotypic reversal of the multi-nucleoside resistance phenotype.

Topics: Anti-HIV Agents; Antiviral Agents; Binding Sites; Drug Resistance, Microbial; Drug Resistance, Multiple; Genotype; HIV Infections; HIV Reverse Transcriptase; HIV-1; Humans; Lamivudine; Mutation; Nucleosides; Phenotype; Quinoxalines; Reverse Transcriptase Inhibitors

A non-nucleoside reverse transcriptase inhibitor, HBY 097, is being tested in a 12-week study. The new drug may weaken resistant HIV so that it is not as harmful to the body. Participants must have T cell counts between 200 and 500, and cannot have taken any anti-HIV drugs.

Topics: Antiviral Agents; Drug Resistance, Microbial; HIV Infections; HIV Reverse Transcriptase; HIV-1; Quinoxalines; Reverse Transcriptase Inhibitors; RNA-Directed DNA Polymerase