International Journal of Antimicrobial Agents 43 (2014) 287–291 Contents lists available at ScienceDirect International Journal of Antimicrobial Agents j o ur nal ho me pag e: http://www.elsevier.com/locate/ijantimicag Short Communication HIV-1-infected patients with advanced disease failing a raltegravir-containing salvage regimen in São Paulo, Brazil Jaqueline de Souza Cavalcanti a , Joao Leandro de Paula Ferreira a , Jose Ernesto Vidal b , Paula Morena de Souza Guimarães a , Denise Helena Moreira a , Luis Fernando de Macedo Brigido a,∗ , São Paulo Salvage Workgroup a Laboratório de Retrovirus, Instituto Adolfo Lutz, Av. Dr Arnaldo 355, Virology Service, São Paulo, SP, 01246-902, Brazil b Instituto de Infectologia Emílio Ribas, São Paulo, Brazil a r t i c l e i n f o Article history: Received 13 July 2013 Accepted 22 October 2013 Keywords: HIV-1 Brazil Integrase Raltegravir Genotype Resistance a b s t r a c t Raltegravir (RAL) is the first licensed antiretroviral integrase inhibitor that may be used both for treatment-naïve human immunodeficiency virus type 1 (HIV-1) patients and for salvage therapy. The Brazilian public free access programme limits its use for salvage therapy, with scarce information regarding RAL resistance from patients failing a RAL-containing salvage regimen. This study evalu- ated RAL resistance mutations detected by population sequencing in 69 HIV-infected patients with advanced disease failing a RAL-containing regimen in a real-world setting. RAL resistance mutations were identified in 47/69 patients (68%). The most common salvage regimen, used by 56/69 patients (81%), included lamivudine, tenofovir, darunavir/ritonavir and RAL. At failure, major RAL resistance mutations included Q148H/R/K (21/47; 45%), N155H (14/47; 30%), Y143R/H/C (3/47; 6%) and E92Q (1/47; 2%). Most samples with Q148H/R/K also showed G140S/A/C (21/47; 45%). RAL resistance was significantly associated with less than two active drugs in the optimised background therapy regi- men at failure [39/39 (100%) vs. 9/17 (53%); P < 0.001] and with a longer cumulative duration with detectable viraemia (viral load >50 copies/mL) (86 weeks vs. 32 weeks; P = 0.001). A high frequency of RAL mutations was observed in this study. In addition, these results reinforce the importance of close monitoring of RAL-containing regimens to reduce the time of failure and consequent resistance accumulation. © 2013 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. 1. Introduction Integration of the retrotranscribed human immunodeficiency virus type 1 (HIV-1) DNA into the human genome is a funda- mental step in retroviral replication. Raltegravir (RAL) (Isentress ® ; Merck Laboratories) is the first integrase inhibitor licensed for clinical use, approved both for treatment-naïve and antiretrovi- ral (ARV)-experienced HIV-infected patients [1,2]. Other integrase inhibitors are available, such as Stribild ® (Gilead Sciences), a tablet combination including elvitegravir (EVG) [3], and more recently dolutegravir (Tivicay ® ; GlaxoSmithKline) [4]. All are analogues of diketo acid, blocking the 3 ′ processing step in the cytoplasm and the strand transfer of viral DNA into the nucleus, known as integrase strand transfer inhibitors (INSTIs) [5]. Despite the capacity of INSTIs to inhibit viral replication, similar mutational pathways that reduce the activity of these ∗ Corresponding author. Tel.: +55 11 3068 2982; fax: +55 11 3068 2983. E-mail address: lubrigido@gmail.com (L.F. de Macedo Brigido). drugs have been described [6]. Treatment failure with RAL may be associated with the selection of mutations in at least four different pathways, including E92Q, Q148H/R/K, N155H and, less frequently, Y143R/H/C [7]. The mutations E92Q, Q148H/R/K and N155H also confer cross-resistance to EVG [6]. Addi- tional mutations such as F121Y that reduce susceptibility to RAL and EVG in vitro [8] have recently been documented in vivo [9]. In 2009, RAL was included among the ARV drugs available for salvage treatment of ARV-experienced patients in Brazil. This drug constitutes an important component of salvage regimens in Brazil, and most patients receiving adequate third-line drug combinations achieve virological suppression [10]. Failure of RAL-containing regi- mens is observed in certain patients, but information about this situation, a critical scenario where further salvage therapy options are usually limited, is scarce. The aim of the present study was to assess, in routine clinical conditions, the mutational profile to RAL in samples from HIV- infected patients failing a salvage regimen containing this ARV in Brazil. 0924-8579/$ – see front matter © 2013 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. http://dx.doi.org/10.1016/j.ijantimicag.2013.10.020