title: Evolution patterns of raltegravir-resistant mutations after integrase inhibitor interruption.
abstract: The objective of this study was to address the evolution of human immunodeficiency virus type 1 (HIV-1) mutations resistant to the integrase inhibitor raltegravir after drug interruption. Thirteen HIV-1 infected patients undergoing virological failure due to the selection of raltegravir-resistant variants, who had interrupted raltegravir treatment, were enrolled. For all patients, the virological failure was associated with the selection of variants, with mutations conferring resistance to all of the drugs present in their regimens. Patients were prospectively monitored at baseline (raltegravir interruption) and every 4-24 weeks for clinical, virological and immunological parameters, including HIV-1 viraemia, CD4(+) T-cell counts, and sequence analysis of the HIV-1 integrase sequence. Reversion to the wild-type HIV-1 integrase sequence genotype was observed between 4 and 36 weeks after raltegravir withdrawal in eight out of the 13 patients. Reversion was not observed in three patients. In two patients, reversion was partial at week 24 from raltegravir interruption. These results highlight that in eight out of 13 patients under treatment with raltegravir and experiencing a virological failure, HIV-1 variants harbouring mutations associated with raltegravir resistance become undetectable after drug interruption within a few weeks (in some cases, very rapidly). This occurs under different therapy regimens and in patients receiving 3TC mono-therapy. In the other patients, complete reversion of the integrase sequence is not observed, and either primary or secondary resistance mutations are fixed in the replication competent viral population in vivo also for long time, suggesting that other factors may influence this dynamic process.
authors.affiliation: Laboratorio di Microbiologia e Virologia, Università Vita-Salute San Raffaele, Milano, Italy. Canducci.filippo@hsr.it
authors.forename: F
authors.initials: F
authors.lastname: Canducci
authors.forename: B
authors.initials: B
authors.lastname: Barda
authors.forename: E
authors.initials: E
authors.lastname: Ceresola
authors.forename: V
authors.initials: V
authors.lastname: Spagnuolo
authors.forename: M
authors.initials: M
authors.lastname: Sampaolo
authors.forename: E
authors.initials: E
authors.lastname: Boeri
authors.forename: S
authors.initials: S
authors.lastname: Nozza
authors.forename: F
authors.initials: F
authors.lastname: Cossarin
authors.forename: A
authors.initials: A
authors.lastname: Galli
authors.forename: N
authors.initials: N
authors.lastname: Gianotti
authors.forename: A
authors.initials: A
authors.lastname: Castagna
authors.forename: A
authors.initials: A
authors.lastname: Lazzarin
authors.forename: M
authors.initials: M
authors.lastname: Clementi
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000494:pharmacology*; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods; D018791:CD4 Lymphocyte Count; D024882:Drug Resistance, Viral; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D019427:HIV Integrase / Q000235:genetics*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics* / Q000302:isolation & purification; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D011446:Prospective Studies; D011760:Pyrrolidinones / Q000008:administration & dosage / Q000494:pharmacology*; D000068898:Raltegravir Potassium; D017211:Treatment Failure; D019562:Viral Load
chemical_list: D019380:Anti-HIV Agents; D011760:Pyrrolidinones; D000068898:Raltegravir Potassium; D019427:HIV Integrase