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Margolis D.A.,Glaxosmithkline | Brinson C.C.,Central Texas Clinical Research | Smith G.H.R.,Maple Leaf Medical Clinic | de Vente J.,Living Hope Foundation | And 11 more authors.
The Lancet Infectious Diseases | Year: 2015

Background: In phase 1 trials, the HIV-1 integrase strand transfer inhibitor cabotegravir (GSK1265744) was well tolerated, both alone, and in combination with the non-nucleoside reverse transcriptase inhibitor rilpivirine. We assessed cabotegravir plus rilpivirine, as a two-drug oral antiretroviral regimen, for the maintenance of viral suppression in antiretroviral-naive HIV-1-infected individuals. Methods: In the phase 2b Long-Acting antireTroviral Treatment Enabling (LATTE) trial, a multicentre study done in Canada and the USA, antiretroviral-naive HIV-1-infected adults (aged ≥18 years) were randomly allocated in a 1:1:1:1 ratio to oral cabotegravir 10 mg once a day, 30 mg once a day, 60 mg once a day, or oral efavirenz 600 mg once a day with dual nucleoside reverse transcriptase inhibitors (NRTIs) for 24 weeks of induction. Patients who were virologically suppressed by week 24 received a two-drug maintenance regimen consisting of their randomly allocated cabotegravir dose plus oral rilpivirine 25 mg or continued efavirenz plus NRTIs for an additional 72 weeks. Patients and investigators were masked to doses of cabotegravir received for 96 weeks, but not to the assignment of cabotegravir or efavirenz. The primary endpoint was the proportion of patients with fewer than 50 copies per mL of HIV-1 RNA (US Food and Drug Administration snapshot algorithm) at week 48. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, NCT01641809. Findings: Of 243 patients randomly allocated and treated, 156 (86%) of 181 patients in the cabotegravir groups (52 [87%] of 60, 51 [85%] of 60, and 53 [87%] of 61 patients in the 10 mg, 30 mg, and 60 mg groups, respectively) and 46 (74%) of 62 in the efavirenz group had fewer than 50 copies per mL of HIV-1 RNA after induction therapy. After patients in the cabotegravir groups were changed over from dual NRTIs to rilpivirine at week 24, 149 (82%; 95% CI 77-88) patients in the cabotegravir groups (48 [80%; 70-90], 48 [80%; 70-90], and 53 [87%; 78-95] patients in the 10 mg, 30 mg, and 60 mg groups, respectively) versus 44 (71%; 60-82) in the efavirenz group were virologically suppressed at week 48, and 137 (76%; 69-82) receiving cabotegravir (41 [68%; 57-80], 45 [75%; 64-86], and 51 [84%; 74-93] patients in the 10 mg, 30 mg, and 60 mg groups, respectively) versus 39 (63%; 51-75) in the efavirenz group were virologically suppressed at week 96. Treatment-related adverse events were reported by 93 (51%) cabotegravir-treated patients (28 [47%], 32 [53%], and 33 [54%] patients in the 10 mg, 30 mg, and 60 mg groups, respectively) and 42 (68%) efavirenz-treated patients. Six (3%) patients in the cabotegravir groups (one [2%], one [2%], and four [7%] patients in the 10 mg, 30 mg, and 60 mg groups, respectively) withdrew because of treatment-emergent adverse events compared with nine (15%) in the efavirenz group. Interpretation: Cabotegravir plus dual NRTI therapy had potent antiviral activity during the induction phase. As a two-drug maintenance therapy, cabotegravir plus rilpivirine provided antiviral activity similar to efavirenz plus dual NRTIs until the end of week 96. Combined efficacy and safety results lend support to our selection of oral cabotegravir 30 mg once a day for further assessment. LATTE precedes studies of the assessment of longacting injectable formulations of both drugs as a two-drug regimen for the treatment of HIV-1 infection. Funding: ViiV Healthcare and Janssen Research and Development. © 2015 Elsevier Ltd.

Naccarato M.,St. Michaels Hospital | Yoong D.,St. Michaels Hospital | Kovacs C.,Maple Leaf Medical Clinic | Gough K.,St. Michaels Hospital | Gough K.,University of Toronto
Antiviral Therapy | Year: 2012

The cytochrome P450 isoforms primarily involved in clobazam metabolism are CYP3A4 and 2C19. Drugs that modulate these enzymes would then be expected to alter the exposure of clobazam and its major metabolites. Etravirine, a second-generation non-nucleoside reverse transcriptase inhibitor has been shown to induce CYP3A4, while inhibiting CYP2C9 and CYP2C19. We report a case in which a potential drug interaction between clobazam and etravirine may have led to increased concentrations of clobazam and its pharmacologically active metabolite, N-desmethylclobazam, causing neurotoxic symptoms. ©2012 International Medical Press.

Kim C.J.,Kings College | Kovacs C.,Maple Leaf Medical Clinic | Chun T.-W.,U.S. National Institutes of Health | Kandel G.,Li Ka Shing Knowledge Institute | And 7 more authors.
Journal of Acquired Immune Deficiency Syndromes | Year: 2014

Elite controllers (ECs) maintain undetectable HIV viral loads without antiretroviral therapy (ART) but are at increased risk of serious non-AIDS conditions (SNA). We assessed the impact of ART in ECs on gut immune dysfunction and biomarkers predicting SNA (blood CD4/CD8 ratio, plasma IL-6, D-dimer levels). At baseline, ECs had elevated IL-6 and D-dimer levels and reduced CD4/CD8 ratio compared with HIV-uninfected controls, but no difference in microbial translocation or gut CD4 subsets. ART increased CD4/CD8 ratio but did not normalize IL-6 and D-dimer levels. EC SNA pathogenesis may be independent of gut immune dysfunction, and resolution may require prolonged ART. Copyright © 2014 by Lippincott Williams & Wilkins.

Chun T.-W.,U.S. National Institutes of Health | Murray D.,U.S. National Institutes of Health | Justement J.S.,U.S. National Institutes of Health | Blazkova J.,U.S. National Institutes of Health | And 8 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2014

Several highly potent and broadly neutralizing monoclonal antibodies against HIV have recently been isolated from B cells of infected individuals. However, the effects of these antibodies on the persistent viral reservoirs in HIV-infected individuals receiving antiretroviral therapy (ART) are unknown. We show that several HIV-specific monoclonal antibodies - in particular, PGT121, VRC01, and VRC03 - potently inhibited entry into CD4+T cells of HIV isolated from the latent viral reservoir of infected individuals whose plasma viremia was well controlled by ART. In addition, we demonstrate that HIV replication in autologous CD4+T cells derived from infected individuals receiving ART was profoundly suppressed by three aforementioned and other HIV-specific monoclonal antibodies. These findings have implications for passive immunotherapy as an approach toward controlling plasma viral rebound in patients whose ART is withdrawn.

Yue F.Y.,University of Toronto | Lo C.,University of Toronto | Sakhdari A.,University of Toronto | Lee E.Y.,University of Toronto | And 10 more authors.
Journal of Immunology | Year: 2010

We examined the role of CD4+ T cell IL-21 production in viral control of HIV infection. HIV-infected individuals had greater circulating IL-21-producing CD4+ T cells in blood compared with uninfected volunteers. HIV-specific IL-21-producing CD4+ T cells were detected in blood during untreated acute and chronic HIV infection, and elevated frequencies of these cells correlated with relative viral control. These cells had an effector memory or end effector phenotype and expressed CXCR5. HIV-specific CD8+ T cells exhibited high levels of IL-21R, indicating sensitivity to IL-21. Low or aviremic long-term nonprogressors, however, showed absent or low HIV-specific IL-21 CD4+ T cells, but more easily detectable HIV-specific IL-2-producing CD4+ T cells, suggesting changing requirements for particular γ-chain cytokines depending on Ag abundance. Thus, IL-21-producing CD4+ T cells are induced in viremic HIV infection and likely contribute to viral control by affecting CD8 + T cell maintenance. Copyright © 2010 by The American Association of Immunologists, Inc.

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