Hypermutated viruses induced by APOBEC3 (apolipoprotein B mRNA-editing, enzyme-catalytic, polypeptide-like 3) proteins comprise some of the defective viruses in the HIV reservoir. Here, we assessed ...the proportion of APOBEC3-induced defective proviruses in HIV-positive patients before and after receiving dolutegravir + lamivudine dual therapy.
PBMCs of virologically suppressed patients enrolled in the ANRS 167 LAMIDOL trial, evaluating a switch from triple therapy to dolutegravir + lamivudine, were collected 8 weeks before (W-8) and 48 weeks after (W48) dual-therapy initiation. The Vif and RT regions were subject to next-generation sequencing. Bioinformatic algorithms were developed to identify APOBEC3-defective sequences and APOBEC3-related drug resistance mutations (APOMuts). All hypermutated sequences and those containing at least one stop codon were considered as defective.
One hundred and four patients were enrolled (median virological suppression duration: 4.2 years; IQR: 2.0-9.1). Proviral defective reads at W-8 and W48 were detected in Vif in 22% and 29% of patients, respectively, and in RT in 38% and 42% of patients, respectively. At least one APOMut was present in proviruses of 27% and 38% of patients at W-8 and W48, respectively. The ratio of APOMuts/number of potential APOMut sites was significantly higher at W48 (16.5%) than at W-8 (9.8%, P = 0.007). The presence of APOBEC3-defective viruses at W-8 was not associated with HIV total DNA level, nor with the third drug class received prior to switching to dolutegravir + lamivudine, nor with the duration of virological suppression.
Whereas no significant change in the proportion of patients with APOBEC3-defective proviruses was evidenced after 1 year of dolutegravir + lamivudine maintenance, enrichment in APOMuts was observed. Further longer-term studies are needed to assess the other forms of defective viruses with dual-therapy.
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.
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.
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.
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.
Background Maraviroc activity against HIV-2, a virus naturally resistant to different HIV-1 antiretroviral drugs, has been recently demonstrated. The aim of this study was to assess HIV-2 ...susceptibility to cenicriviroc, a novel, once-daily, dual CCR5 and CCR2 antagonist that has completed Phase 2b development in HIV-1 infection. Methods Cenicriviroc phenotypic activity has been tested using a PBMC phenotypic susceptibility assay against four R5-, one X4- and one dual-tropic HIV-2 clinical primary isolates. All isolates were obtained by co-cultivation of PHA-activated PBMC from distinct HIV-2-infected CCR5-antagonist-naive patients included in the French HIV-2 cohort and were previously tested for maraviroc susceptibility using the same protocol. HIV-2 tropism was determined by phenotypic assay using Ghost(3) cell lines. Results Regarding the 4 R5 HIV-2 clinical isolates tested, effective concentration 50% EC50 for cenicriviroc were 0.03, 0.33, 0.45 and 0.98 nM, similar to those observed with maraviroc: 1.13, 0.58, 0.48 and 0.68 nM, respectively. Maximum percentages of inhibition (MPI) of cenicriviroc were 94, 94, 93 and 98%, similar to those observed with maraviroc (93, 90, 82, 100%, respectively). The dual- and X4-tropic HIV-2 strains were resistant to cenicriviroc with EC50 >1000 nM and MPI at 33% and 4%, respectively. Conclusions In this first study assessing HIV-2 susceptibility to cenicriviroc, we observed an in vitro activity against HIV-2 R5-tropic strains similar to that observed with maraviroc. Thus, cenicriviroc may offer a once-daily treatment opportunity in the limited therapeutic arsenal for HIV-2. Clinical studies are warranted.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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