BackgroundResistance to CCR5 inhibitors, such as maraviroc and vicriviroc is characterized by reduction of maximal percent inhibition which indicates the use of an inhibitor-bound conformation of CCR5 for human immunodeficiency virus-1(HIV-1) entry. It is accompanied by substitutions in gp120 and gp41. Variable domain 3 (V3) plays the most important role, but substitutions outside V3 could also be involved in phenotype resistance. In this work, we investigated how mutations in variable regions of the viral envelope protein gp120 can contribute to CCR5 inhibitor resistance.MethodsResistant isolates were selected by passaging CC1/85 and BaL viruses with sub-inhibitory MVC and VCV concentrations. Mutations in gp160 were identified and mutants containing V2 (V169M), V3 (L317W) and V4 (I408T) were constructed.ResultsMVC and VCV susceptibility and viral tropism were assessed by single cycle assay. Mutant I408T showed 4-fold change (FC) increase in the half maximal inhibitory concentration (IC50) to MVC, followed by L317W (1.52-FC), V169M (1.23-FC), V169M/I408T (4-FC) L317W/I408T (3-FC), V169M/L317W (1.30-FC), and V169M/L317W/I408T (3.31-FC). MPI reduction was observed for mutants I408T (85%), L317W (95%), V169M/I408T (84%), L317W/I408T (85%) and V169M/L317W/I408T (83%). For VCV, I408T increased the IC50 by 2-FC and few mutants showed MPI reduction less than 95%: I408T (94%), L317W/I408T (94%) and V169M/L317W/I408T (94%). All mutants remained R5-tropic and presented decreased infectivity.ConclusionsThese results suggest that mutations in the V4 loop of HIV-1 may contribute to MVC and VCV resistance alone or combined with mutations in V2 and V3 loops.

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cHere, we evaluated the in vitro anti-HIV-1 activity of the experimental CCR5 inhibitor VCH-286 as a single agent or in combination with various classes of HIV-1 inhibitors. Although VCH-286 used alone had highly inhibitory activity, paired combinations with different drug classes led to synergistic or additive interactions. However, combinations with other CCR5 inhibitors led to effects ranging from synergy to antagonism. We suggest that caution should be exercised when combining CCR5 inhibitors in vivo.

Introduction This retrospective, observational study aimed to analyze and assess adherence, persistence, dosing, and use of concomitant medications of seven self-administered target drugs (abatacept, golimumab, secukinumab, tocilizumab, ustekinumab, apremilast, and tofacitinib) that are currently available in Canada for the treatment of inflammatory arthritis (IA). Methods We used IQVIA’s longitudinal claims databases, which include private drug plans and public plans. Patients with IA identified using a proprietary indication algorithm who initiated treatment with any of the target drugs between January 2015 and February 2019 were selected and followed for 12 months. Results Golimumab and apremilast had the highest proportion of patients (~ 75%) who were bio-naïve and secukinumab had the fewest bio-naïve patients (~ 43%). The oral therapies, apremilast and tofacitinib, had the lowest percentage of adherent patients (73% and 71%) followed by abatacept (83%), while the remaining drugs had adherence around 90%. Secukinumab and tofacitinib had the highest 12-month persistence rate (63% and 61%), while abatacept and apremilast had the lowest persistence rate (52% and 47%). Oral corticosteroid (OCS) use was not significantly associated with adherence. Tocilizumab, secukinumab, and ustekinumab had the highest proportion of patients (> 20%) with dose escalation at 3–4 months from index. OCS and conventional disease-modifying antirheumatic drugs (cDMARD) use decreased in post-index period across all target drugs. Conclusion This study identified substantial differences in patient baseline characteristics. Patients on injectable biologics were more likely to be adherent compared with those on oral drugs, possibly owing to longer dosing intervals. Other outcomes at 12 months appeared similar as evidenced by tapering of concomitant medications, although differences in persistence and dose escalation were noted.