HIV-2 Integrase Polymorphisms and Longitudinal Genotypic Analysis of HIV-2 Infected Patients Failing a Raltegravir-Containing Regimen

Abstract

To characterize the HIV-2 integrase gene polymorphisms and the pathways to resistance of HIV-2 patients failing a raltegravir-containing regimen, we studied 63 integrase strand transfer inhibitors (INSTI)-naïve patients, and 10 heavily pretreated patients exhibiting virological failure while receiving a salvage raltegravir-containing regimen. All patients were infected by HIV-2 group A. 61.4% of the integrase residues were conserved, including the catalytic motif residues. No INSTI-major resistance mutations were detected in the virus population from naïve patients, but two amino acids that are secondary resistance mutations to INSTIs in HIV-1 were observed. The 10 raltegravir-experienced patients exhibited resistance mutations via three main genetic pathways: N155H, Q148R, and eventually E92Q - T97A. The 155 pathway was preferentially used (7/10 patients). Other mutations associated to raltegravir resistance in HIV-1 were also observed in our HIV-2 population (V151I and D232N), along with several novel mutations previously unreported. Data retrieved from this study should help build a more robust HIV-2-specific algorithm for the genotypic interpretation of raltegravir resistance, and contribute to improve the clinical monitoring of HIV-2-infected patients.

The Nucleoside Analog BMS-986001 Shows GreaterIn VitroActivity against HIV-2 than against HIV-1

“…Newer ARVs, including generic FTC and tenofovir disoproxil fumarate (TDF), ritonavir-boosted darunavir, and the INSTI raltegravir, have recently been made available to a limited number of HIV-2-infected patients in some West African HIV treatment programs. While these compounds may be beneficial, concerns regarding the extensive cross-resistance seen within the NRTI and PI classes in HIV-2 remain (5,7,9,19,21,22,25,54,67,68), and emergent resistance to raltegravir has been reported in HIV-2-infected individuals (18,20,23,24,26,27,69,70). Our analysis suggests that BMS-986001 might help fill the need for newer HIV-2-active ARVs.…”

“…Mutations that diminish the activity of NRTIs, PIs, and INSTIs have been reported in HIV-2 isolates from ARV-treated patients (9,(18)(19)(20)(21)(22)(23)(24)(25)(26)(27), and up to 30% of HIV-2-infected patients living in West Africa show evidence of multiclass (NRTI and PI) resistance (19,22). Once resistance emerges, HIV-2-infected individuals are left with few (if any) options for effective treatment.…”

Assessment of the Cavidi ExaVir Load Assay for Monitoring Plasma Viral Load in HIV-2-Infected Patients

“…As a reference comparative assay, we used an in-house qPCR based assay that is in current use at reference institutions in Portugal and other European countries (4,5,10,(38)(39)(40)(41)54). The associations between viral load and CD4 ϩ T cell counts or antiretroviral therapy status were similar for measurements obtained with ExaVir Load and qPCR.…”

“…In such settings, commercial nonnucleic acid-based methods, such as the Cavidi ExaVir Load assay, can be a good alternative considering the low cost, simple and standardized procedure, and limited physical requirements (60). Moreover, in African countries such as Cape Verde (13,14,61), Guinea-Bissau (62), Gambia (63), and Senegal (64,65), where HIV-1 and HIV-2 cocirculate, but also in Portugal (38)(39)(40) and France (66,67), the characteristics of the ExaVir Load assay make it useful to measure viral load in patients infected with HIV-1 and/or HIV-2, provided that the serologic diagnosis of HIV-1 or HIV-2 infection is well established in advance.…”

“…The performance of the ExaVir Load assay was compared to that of the reference in-house qPCR used in Portugal (5,(38)(39)(40), which quantifies HIV-2 RNA copy number in the plasma by targeting a conserved region within the long terminal repeat (LTR) of the HIV-2 genome (41). Our patients were from Cape Verde Islands, which is a West African country located off the shore of Senegal, where HIV-1 and HIV-2 cocirculate (13,14,42).…”