In-vitro phenotypic susceptibility of HIV-2 clinical isolates to the integrase inhibitor S/GSK1349572

Charpentier, Charlotte; Larrouy, Lucile; Collin, Gilles; Damond, Florence; Matheron, Sophie; Chêne, Geneviève; Nie, Ting; Schinazi, Raymond; Brun‐Vézinet, Françoise; Descamps, Diane

doi:10.1097/qad.0b013e32833f9e36

Cited by 33 publications

(28 citation statements)

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“…With regard to the HIV-2 therapeutic arsenal, in cases of NRTI and protease inhibitor resistance, the only active drug class is integrase inhibitors [20, 30], and possibly the CCR5 inhibitor maraviroc [31]. However, the use of integrase inhibitors may be limited in pretreated patients who harbor NRTI-resistant viruses because of the low genetic barrier to resistance of this drug class, and who require a combination with fully active drugs.…”

Section: Discussionmentioning

confidence: 99%

Genotypic resistance profiles of HIV-2-treated patients in West Africa

Charpentier

Eholié

Anglaret

et al. 2014

Aids

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Objective To assess the virological response, genotypic resistance profiles, and antiretroviral plasma concentrations in HIV-2 antiretroviral-treated (antiretroviral therapy, ART) patients in Côte d‘Ivoire. Methods A cross-sectional survey was conducted among HIV-2 patients receiving ART. Plasma HIV-2 viral load was performed using the Agence Nationale de Recherche sur le SIDA et les hépatites virales (ANRS) assay. Protease and reverse transcriptase sequencing was performed using in-house methods and antiretroviral plasma concentrations were assessed using ultra performance liquid chromatography combined with tandem mass spectrometry. Results One hundred and forty-five HIV-2-treated patients were enrolled with a median CD4+ cell count of 360 cells/µl (interquartile range, IQR = 215–528). Median duration of ART was 4 years (IQR = 2–7) and 74% of patients displayed viral load less than 50 copies/ml. Median plasma HIV-2 RNA among patients with viral load more than 50 copies/ml was 3016 copies/ml (IQR = 436–5156). Most patients (84%) received a lopinavir/ritonavir-based regimen. HIV-2 resistance mutations to nucleoside reverse transcriptase inhibitors and protease inhibitors were detected in 21 of 25 (84%) and 20 of 29 (69%) samples, respectively. The most prevalent nucleoside reverse transcriptase inhibitor resistance mutations were M184I/V (90%), Q151M (24%), and S215F/Y (24%). The most prevalent protease inhibitor resistance mutations were V47A (60%) and I54M (30%). Median CD4+ cell counts were 434 cells/µl (292–573) and 204 cells/µl (122–281) in patients with viral load less than 50 copies/ml and those exhibiting virological failure (P < 0.0001), respectively. The proportions of patients with adequate antiretroviral plasma concentrations were 81 and 93% in patients displaying virological failure and in those with viral load less than 50 copies/ml, respectively (P = 0.046), suggesting good treatment adherence. Conclusion We observed adequate drug plasma concentrations and virological suppression in a high proportion of HIV-2-infected patients. However, in cases of virological failure, the limited HIV-2 therapeutic arsenal and cross-resistance dramatically reduced treatment options.

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Section: Discussionmentioning

confidence: 99%

Genotypic resistance profiles of HIV-2-treated patients in West Africa

Charpentier

Eholié

Anglaret

et al. 2014

Aids

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“…Reports of transmitted INSTIresistance mutations remain anecdotal (Boyd, Maldarelli et al 2011, Hurt 2011. In regard to natural polymorphisms and resistance-associated mutations, it is important to note that INSTIs remain active against viruses containing such integrase variations (Charpentier, Larrouy et al 2010, Canducci, Ceresola et al 2011, Kobayashi, Yoshinaga et al 2011). Furthermore, DTG was shown to efficaciously reduce viral loads in INSTI-exposed individuals who had previously experienced treatment failure with emergent RAL-and EVGresistance mutations, though DTG efficacy was notably lower in such individuals compared to INSTI-naïve individuals (Eron, Clotet et al 2013, Castagna, Maggiolo et al 2014, Akil, Blick et al 2015.…”

Section: Implications Of Insti Drug Resistance In Different Hiv Subtymentioning

confidence: 99%

Differences among HIV-1 subtypes in drug resistance against integrase inhibitors

Han

Mésplède

Wainberg

2016

Infection, Genetics and Evolution

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“…Currently, ART for HIV-2 relies entirely on compounds that were developed, optimized, and licensed for use for the treatment of HIV-1 (specifically, HIV-1 group M, subtype B) (5). The limited activity of many of these drugs against HIV-2 is a major obstacle to treatment; HIV-2 is intrinsically resistant to nonnucleoside reverse transcriptase (RT) inhibitors, the fusion inhibitor enfuvirtide (T-20), and the majority of the protease inhibitors (PIs) used for HIV-1 ART (6-11) but is sensitive to both integrase strand transfer inhibitors (INSTIs) and nucleoside reverse transcriptase inhibitors (NRTIs), with the 50% effective concentrations (EC 50 s) of these drugs for HIV-2 being comparable to those seen for HIV-1 (12)(13)(14)(15)(16)(17). In West Africa, the most widely used regimen for first-line HIV-2 treatment is ritonavir-boosted lopinavir (LPV/r) plus two NRTIs (typically, AZT and lamivudine [3TC]).…”

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

Smith

Raugi

et al. 2015

Antimicrob Agents Chemother

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Treatment options for individuals infected with human immunodeficiency virus type 2 (HIV-2) are restricted by the intrinsic resistance of the virus to nonnucleoside reverse transcriptase inhibitors (NNRTIs) and the reduced susceptibility of HIV-2 to several protease inhibitors (PIs) used in antiretroviral therapy (ART). In an effort to identify new antiretrovirals for HIV-2 treatment, we evaluated the in vitro activity of the investigational nucleoside analog BMS-986001 (2=,3=-didehydro-3=-deoxy-4=-ethynylthymidine; also known as censavudine, festinavir, OBP-601, 4=-ethynyl stavudine, or 4=-ethynyl-d4T). In single-cycle assays, BMS-986001 inhibited HIV-2 isolates from treatment-naive individuals, with 50% effective concentrations (EC 50 s) ranging from 30 to 81 nM. In contrast, EC 50 s for group M and O isolates of HIV-1 ranged from 450 to 890 nM. Across all isolates tested, the average EC 50 for HIV-2 was 9.5-fold lower than that for HIV-1 (64 ؎ 18 nM versus 610 ؎ 200 nM, respectively; mean ؎ standard deviation). BMS-986001 also exhibited full activity against HIV-2 variants whose genomes encoded the single amino acid changes K65R and Q151M in reverse transcriptase, whereas the M184V mutant was 15-fold more resistant to the drug than the parental HIV-2 ROD9 strain. Taken together, our findings show that BMS-986001 is an effective inhibitor of HIV-2 replication. To our knowledge, BMS-986001 is the first nucleoside analog that, when tested against a diverse collection of HIV-1 and HIV-2 isolates, exhibits more potent activity against HIV-2 than against HIV-1 in culture.

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In-vitro phenotypic susceptibility of HIV-2 clinical isolates to the integrase inhibitor S/GSK1349572

Cited by 33 publications

References 10 publications

Genotypic resistance profiles of HIV-2-treated patients in West Africa

Genotypic resistance profiles of HIV-2-treated patients in West Africa

Differences among HIV-1 subtypes in drug resistance against integrase inhibitors

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

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