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Katlama C.,University Pierre and Marie Curie | Clotet B.,Hospital Universitari Germans Trias i Pujol | Mills A.,Private Practice | Trottier B.,Clinique Medicale lActuel | And 9 more authors.
Antiviral Therapy | Year: 2010

Background: Durable efficacy and long-term safety of antiretroviral therapy are important goals in the management of treatment-experienced patients. The 96-week efficacy and safety of the non-nucleoside reverse transcriptase inhibitor (NNRTI) etravirine were evaluated in the Phase III DUET trials. Methods: HIV type-1-infected treatment-experienced adults with viral loads >5,000 copies/ml and NNRTI and protease inhibitor resistance were randomized to receive etravirine 200 mg or placebo, each twice daily and in combination with a background regimen of darunavir/ritonavir twice daily, nucleoside/nucleotide reverse transcriptase inhibitors and optional enfuvirtide. The primary end point was the proportion of patients with viral load <50 copies/ml (intent-to-treat analysis, time-to-loss of virological response algorithm) at week 24. Results from both trials were combined in the pre-specified pooled 96-week analysis. Results: In total, 599 patients received etravirine and 604 received placebo. At week 96, 57% of patients in the etravirine group versus 36% in the placebo group had a viral load <50 copies/ml (P<0.0001); 91% and 88% of patients, respectively, had maintained this response from week 48. Mean increases in CD4+ T-cell count from baseline at week 96 were 128 cells/mm3 with etravirine versus 86 cells/mm3 with placebo (P<0.0001). With the exception of rash, which was reported more frequently with etravirine than placebo (21% versus 12%, respectively; P<0.0001), the safety and tolerability profile of etravirine was similar to placebo over the treatment period. Conclusions: Etravirine, in combination with an antiretroviral background regimen, provided durable virological and immunological responses with no new safety concerns in treatment-experienced patients over 96 weeks in the DUET trials. ©2010 International Medical Press. Source

Trottier B.,Clinique Medicale lActuel | Di Perri G.,University of Turin | Peeters M.,Tibotec BVBA | Vingerhoets J.,Tibotec BVBA | And 2 more authors.
HIV Clinical Trials | Year: 2010

Purpose: This subgroup analysis of the phase 3 DUET trials examined the impact of the background regimen on virologic response to etravirine in treatment-experienced patients. Methods: Patients received etravirine 200 mg or placebo, both twice daily with a background regimen of darunavir/ritonavir, investigator-selected nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), and optional enfuvirtide. Virologic response at week 48 (viral load <50 HIV-1 RNA copies/mL) was analyzed by the number and activity of background agents. Results: Baseline phenotypic sensitivity score (PSS), enfuvirtide use, darunavir fold change in 50% effective concentration (FC), and number of baseline darunavir resistance-associated mutations (RAMs) were significant predictors of response to etravirine (P <.0001, P =.0018, P <.0001, and P =.0120, respectively). The number of active NRTIs was not a significant predictor of response (P =.0626). The highest response rates in etravirine-treated patients were associated with PSS ≥2, de novo enfuvirtide use, darunavir FC ≥10, ≥1 darunavir RAM, and ≥2 active NRTIs. Virologic response was consistently higher in etravirine-treated patients than placebo-treated patients, regardless of the activity of the background regimen. Response rates according to baseline PSS were 46% to 79% in the etravirine group versus 6% to 75% in the placebo group. Conclusion: The results of this subanalysis demonstrate higher virologic response rates with increased activity of the background regimen in both treatment groups, with the highest responses achieved in patients using ≥2 active agents in addition to etravirine. © 2010 Thomas Land Publishers, Inc. Source

Hardy I.,Center Hospitalier Of Luniversite Of Montreal Chum | Brenner B.,McGill University | Quashie P.,McGill University | Thomas R.,Clinique Medicale lActuel | And 6 more authors.
Journal of Antimicrobial Chemotherapy | Year: 2015

Objectives: Dolutegravir has been recently approved for treatment-naive and -experienced HIV-infected subjects, including integrase inhibitor (INI)-experienced patients. Dolutegravir is a second-generation INI that can overcome many prior raltegravir and elvitegravir failures. Here, we report the evolution of resistance to dolutegravir in a highly treatment-experienced patient harbouring the major N155H mutation consequent to raltegravir treatment failure. Methods: Genotypic and phenotypic analyses were done on longitudinal samples to determine viral resistance to INIs. Integrase amino acid sequence interactions with raltegravir and dolutegravir were assessed by molecular modelling and docking simulations. Results: Five mutations (A49P, L68FL, T97A, E138K and L234V) were implicated in emergent dolutegravir resistance, with a concomitant severe compromise in viral replicative capacity. Molecular modelling and docking simulations revealed that dolutegravir binding to integrase was affected by these acquired dolutegravir mutations. Conclusions: Our findings identify a novel mutational pathway involving integrase mutations A49P and L234V, leading to dolutegravir resistance in a patient with the N155H raltegravir mutation. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. Source

Brouillette M.-J.,McGill University | Fellows L.K.,McGill University | Fellows L.K.,Montreal Neurological Institute | Palladini L.,McGill University | And 3 more authors.
BMC Neurology | Year: 2015

Background: Up to half of all people with HIV infection have some degree of cognitive impairment. This impairment is typically mild, but nonetheless often disabling. Although early detection of cognitive impairment offers the greatest hope of effective intervention, there are important barriers to this goal in most clinical settings. These include uncertainty about how self-reported cognitive symptoms relate to objective impairments, and the paucity of bedside measurement tools suitable for mild deficits. Clinicians need guidance in interpreting cognitive symptoms in this population, and a brief cognitive measurement tool targeted to mild impairment. We addressed these two problems together here. The objective of this study was to determine the extent to which performance on cognitive tests and self-reported cognitive symptoms form a unidimensional construct. Methods: Two hundred three HIV+ individuals completed the Montreal Cognitive Assessment, computerized cognitive tasks and a questionnaire eliciting cognitive symptoms. Rasch measurement theory was applied to determine whether patient-reported and performance items could be combined to measure cognition as a unidimensional latent construct. Results: Performance-based items and cognitive symptoms are arranged hierarchically along the same continuum of cognitive ability, forming a measure with thresholds covering a broad spectrum of ability that has good internal reliability. The cognitive symptoms that fit the measurement model relate to important aspects of everyday life, providing evidence that the identified construct is meaningful. Conclusions: This finding lays the foundation for a rapid measure of cognitive ability in people with HIV infection that is feasible for routine clinical use, and shows that some cognitive symptoms are systematically related to performance in this population. © 2015 Brouillette et al. Source

Routy J.-P.,McGill University | Tremblay C.L.,University of Montreal | Angel J.B.,University of Ottawa | Trottier B.,Clinique Medicale lActuel | And 9 more authors.
HIV Medicine | Year: 2012

Objectives: Conflicting results have been reported regarding the ability of valproic acid (VPA) to reduce the size of HIV reservoirs in patients receiving suppressive highly active antiretroviral therapy (HAART). In a randomized multicentre, cross-over study, we assessed whether adding VPA to stable HAART could potentially reduce the size of the latent viral reservoir in CD4 T cells of chronically infected patients. Methods: A total of 56 virologically suppressed patients were randomly assigned either to receive VPA plus HAART for 16 weeks followed by HAART alone for 32 weeks (arm 1; n=27) or to receive HAART alone for 16 weeks and then VPA plus HAART for 32 weeks (arm 2; n=29). VPA was administered at a dose of 500mg twice a day (bid) and was adjusted to the therapeutic range. A quantitative culture assay was used to assess HIV reservoirs in CD4 T cells at baseline and at weeks 16 and 48. Results: No significant reductions in the frequency of CD4 T cells harbouring replication-competent HIV after 16 and 32 weeks of VPA therapy were observed. In arm 1, median (range) values of IU per log 10 billion (IUPB) cells were 2.55 (range 1.20-4.20), 1.80 (range 1.0-4.70) and 2.70 (range 1.0-3.90; P=0.87) for baseline, week 16 and week 48, respectively. In arm 2, median values of IUPB were 2.55 (range 1.20-4.65), 1.64 (range 1.0-3.94) and 2.51 (range 1.0-4.48; P=0.50) for baseline, week 16 and week 48, respectively. Conclusions: Our study demonstrates that adding VPA to stable HAART does not reduce the latent HIV reservoir in virally suppressed patients. © 2012 British HIV Association. Source

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