[Mechanisms of resistance and failure of treatment with maraviroc].
Maraviroc (MVC) is a new antagonist of the CCR5 coreceptor and is the first antiviral compound available that has a cell factor essential for HIV entry as a target. The information available from clinical studies with MVC suggests that the main cause of therapeutic failure is, more than the tropism change, the rapid selection of pre-existing strains with an affinity for CXCR4, not detected by the reference test. A recently developed tropism test with an improved sensitivity will help to detect the minority, but clinically significant, presence of strains that use CXCR4. Evidence of resistance to MVC has been shown in vivo in some patients. The mechanism of this resistance appears to be related to changes in gp120 and mainly in the V3 region which enables the virus to recognise the CCR5-co-receptor bound to the MVC molecule. From a practical point of view, standardised tests are currently unavailable to assess susceptibility to MVC, although in dose-response phenotype tests a maximum percentage inhibition (MPI) < 95% would be indicative of resistance to the compound. Similarly, although some mutations associated with resistance in V3, and other zones of gp120, have been described, this preliminary information suggests different resistance patterns and at the moment, we do not know the canonical mutations to be able to establish genotyping algorithms.
Delgado
Rafael
R
Laboratorio de Microbiología Molecular, Servicio de Microbiología, Hospital Universitario 12 de Octubre, Madrid, España. rdelgado.hdoc@salud.madrid.org
D000595:Amino Acid Sequence; D065100:CCR5 Receptor Antagonists; D002986:Clinical Trials as Topic / Q000706:statistics & numerical data; D003510:Cyclohexanes / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D024882:Drug Resistance, Viral / Q000235:genetics; D015752:Genes, env; D006678:HIV / Q000235:genetics / Q000502:physiology*; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D023581:HIV Fusion Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D000077592:Maraviroc; D008561:Membrane Fusion / Q000187:drug effects*; D008969:Molecular Sequence Data; D015337:Multicenter Studies as Topic; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D019718:Receptors, CXCR4 / Q000502:physiology; D012641:Selection, Genetic; D017211:Treatment Failure; D014230:Triazoles / Q000494:pharmacology* / Q000627:therapeutic use; D053585:Virus Attachment / Q000187:drug effects*; D053586:Virus Internalization / Q000187:drug effects*; D054299:env Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000502:physiology
D065100:CCR5 Receptor Antagonists; C527276:CXCR4 protein, human; D003510:Cyclohexanes; D015699:HIV Envelope Protein gp120; D023581:HIV Fusion Inhibitors; C059762:HIV envelope protein gp120 (305-321); D010446:Peptide Fragments; D019718:Receptors, CXCR4; D014230:Triazoles; D054299:env Gene Products, Human Immunodeficiency Virus; C514793:gp120 protein, Human immunodeficiency virus 1; D000077592:Maraviroc