title: HIV-1 DNA dynamics and variations in HIV-1 DNA protease and reverse transcriptase sequences in multidrug-resistant patients during successful raltegravir-based therapy.
abstract: There is limited information on the variations of HIV-1 DNA mutation profile in reverse transcriptase (RT) and protease (PR) genes during suppressive antiretroviral treatment (plasma HIV-1 RNA continuously <50 copies/ml) with raltegravir (RAL)-based regimens in patients with baseline RT/PR resistant HIV. Twelve multidrug resistant (RT: 12/12, PR: 8/12) HIV-infected patients were followed during effectively suppressive RAL-based therapy. Total and integrated HIV-1 DNA were assessed by real time PCR at baseline and every 6 months. Ultrasensitive (threshold: 2.5 copies/ml) plasma HIV-1 RNA and genotypic analysis of RT and PR in proviral DNA were performed at baseline and at 24 months. Half of the patients had full viral suppression (plasma HIV-RNA < 2.5 copies/ml) at month 12. Total HIV-1 DNA declined significantly after 12 months of therapy (from 249.2 to 145.7 copies/106cells, P = 0.023), and remained stable until 24 months, when total HIV-1 DNA levels raised, concomitantly with a less stringent suppression of HIV-1 RNA (81.8% of patients with >2.5 copies/ml). Integrated HIV-1 DNA did not show fluctuations during the study period. Sequencing of the PR and RT regions from HIV-1 DNA revealed changes in the resistance mutation profile in five patients. Total HIV-1 DNA declined after the introduction of RAL-based therapy, with a rebound after 2 years. No changes were observed in levels of integrated DNA, suggesting limited effect on archived HIV. The RT and PR sequence changes in archived HIV-1 DNA suggest that variation of the mutation profile can occur even in the absence of detectable HIV-1 RNA. J. Med. Virol. 88:2115-2124, 2016. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Zuleika
authors.initials: Z
authors.lastname: Michelini
authors.affiliation: Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Clementina Maria
authors.initials: CM
authors.lastname: Galluzzo
authors.affiliation: Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Maria Franca
authors.initials: MF
authors.lastname: Pirillo
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University of Perugia, Perugia, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Francisci
authors.affiliation: Department of Infectious Diseases and Hepatology, Azienda Ospedaliera di Parma, Parma, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Degli Antoni
authors.affiliation: Infectious Diseases Unit, Ospedale Civile, Pistoia, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Vivarelli
authors.affiliation: Division of Infectious Disease, University of Bari, Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Ladisa
authors.affiliation: Clinic of Infectious Diseases, Ospedali Riuniti, Marche Polytechnic University, Ancona, Italy.
authors.forename: Oscar
authors.initials: O
authors.lastname: Cirioni
authors.affiliation: Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Liliana Elena
authors.initials: LE
authors.lastname: Weimer
authors.affiliation: Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Fragola
authors.affiliation: Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cara
authors.affiliation: Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Floridia
authors.affiliation: Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Rome, Italy. silvia.baroncelli@iss.it.
authors.forename: Silvia
authors.initials: S
authors.lastname: Baroncelli
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active; D004279:DNA, Viral / Q000235:genetics*; D024921:Drug Resistance, Multiple, Viral; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D016333:HIV Protease / Q000235:genetics*; D054303:HIV Reverse Transcriptase / Q000235:genetics*; D015497:HIV-1 / Q000201:enzymology* / Q000235:genetics* / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D012367:RNA, Viral / Q000097:blood / Q000235:genetics; D000068898:Raltegravir Potassium / Q000009:adverse effects / Q000627:therapeutic use*; D019562:Viral Load
chemical_list: D019380:Anti-HIV Agents; D004279:DNA, Viral; D012367:RNA, Viral; D000068898:Raltegravir Potassium; D054303:HIV Reverse Transcriptase; D016333:HIV Protease
keywords: HIV genetic variations; multidrug resistance; raltegravir