An evaluation of elvitegravir plus cobicistat plus tenofovir alafenamide plus emtricitabine as a single-tablet regimen for the treatment of HIV in children and adolescents

Introduction: Approximately 2.1 million of the estimated 36 million infected with HIV are children or adolescents. International guidelines for HIV-1 Infection suggest starting antiretrovirals (ARV) at the moment of diagnosis. Many factors limit the optimization of antiretroviral therapy in children and adolescents: lack of pediatric formulations, poor adherence, metabolic and pharmacokinetic changes associated withnormal child development and puberty. Areas covered: Three integrase inhibitors are approved by the US Food and Drug Administration and by European Medical Agency for children and adolescents with HIV-1 infection. Raltegravir is approved for children aged 4\ua0weeks to 18\ua0years, while dolutegravir and elvitegravir co-formulated with cobicistat, emtricitabine, and tenofovir alafenamide (E/C/FTC/TAF) are approved for children from 6\ua0years of age. This article evaluates E/C/FTC/TAF as a treatment option. Expert opinion: E/C/FTC/TAF was well tolerated, and the antiretroviral activity and tolerability data of this combination support the use in children and adolescents. However, the studies regarding E/C/FTC/TAF in children and adolescents are scant. Consequently, additional studies investigating its safety and efficacy in children are paramount

Salvage therapy or simplification of salvage regimens with dolutegravir plus ritonavir-boosted darunavir dual therapy in highly cART-experienced subjects : an Italian cohort

Background: Dolutegravir plus darunavir provide a high genetic barrier to HIV-1 resistance and are suitable for simple salvage regimens. Methods: All HIV-1-infected subjects treated with dolutegravir plus boosted darunavir dual therapy between March 2011 and September 2015 were included in an observational cohort. Data were collected at baseline and at weeks 4, 12, 24 and 48. Results: We enrolled 113 subjects. After week 24, one was lost at follow-up, one dropped out for grade 2 elevation of liver enzymes, one died from illicit drug abuse and one from cancer-related sepsis. The mean age was 51, 26.5% were female and 9.7% were non-Caucasian. Twenty had never experienced failure. A total of 99 had reverse-transcriptase (RT) mutations, 87 had protease inhibitor mutations and 12 had integrase strand transfer inhibitor (INSTI) mutations. Viraemic patients declined from baseline to week 24 from 43.4% to 6.2%, the remainder being due to high baseline viraemia or adherence issues. The proportion of subjects with viraemia 1\u201349 copies/ml remained at 20.4% while those in whom no virus was detected (NVD) increased from 36.3% to 73.5% by week 24. All the 47 subjects who had a 48-week follow-up had <50 copies/ml and 42 (89.4%) had NVD. 18 subjects had reduced sensitivity to darunavir (Stanford median score 15, range 15\u201340), but none rebounded, 6 having a 24-week and 7 a 48-week follow-up. The median variation in serum creatinine was -0.01 (range +0.2 to -0.21) mg/dl. Conclusions: This dual regimen provides a simple salvage regimen and proved safe and effective in this cohort

Durability of dolutegravir plus boosted darunavir as salvage or simplification of salvage regimens in HIV-1 infected, highly treatment-experienced subjects

Background: Dolutegravir (DTG) plus boosted darunavir (bDRV) is a compact, adherence-friendly salvage regimen with the highest genetic barrier to HIV-1 resistance. Objective: Aim of the present study is to assess the long term (96-week) safety and efficacy of DTG + bDRV in a of multidrug-experienced HIV-1 infected patients, simplifying or building rescue regimens. Methods: All HIV-1-infected subjects from eleven Italian centers switched to DTG + bDRV between March 2014 and September 2015 were included and followed for minimum 96 weeks. Results: The cohort comprises 130 subjects, switched from 42 different, complex or at least twice-daily regimens, mainly for simplification (44.6%), viral failure (30.0%) or toxicity (16.6%). At baseline 118 had documented resistance to 1\u20135 antiretroviral classes and 12 lacked genotypic results either for historical reasons or for problems with primer annealing; 52 (40%) had uncontrolled viral replication, three above 500.000 copies/mL. At week 96 two showed 6550 HIV-1 RNA copies/mL, 23 had 1\u201349 copies/mL and 101 had no virus detected. The proportion of subjects presenting abnormal values at baseline significantly decreased for serum glucose, creatinine, AST, total cholesterol and triglycerides. Conclusions: These long-term data confirm the reliability of the two-drug regimen consisting of bDRV plus DTG in salvage settings in HIV-1 infection

Overall tolerability of Integrase Inhibitors in clinical practice: results from a multicenter Italian cohort

Background. International guidelines recommend the use of INI-based regimens as first line ARV in both na\uefve and experienced HIV-infected patients. Materials and Methods. We analyzed a multicenter cohort of HIV-infected patients, both na\uefve and experienced, starting a ARV including an INI. Chi-square test and non-parametric tests were used to assess differences in categorical and continuous variables, respectively. Kaplan-Meyer survival analysis were performed to estimate the probability of maintaining the study-drug and Cox-regression analysis to evaluate predictors of discontinuation. Results. We enrolled 4343 patients: 3143 (72.4%) were males, with a median age of 49 years (IQR 41-55). Na\uefve patients were 733 (16.9%), of whom 168 (22.9%) AIDS-presenters. Overall, 2282 patients (52.5%) started DTG, 1426 (32.8%) RAL and 635 (14.7%) EVG. During 10032 PYFU, we observed 1278 discontinuations (13 per 100PYFU); 448 of them (35%) due to simplification and 355 (28%) to toxicities (98 for CNS toxicity). Reasons of discontinuation were different between INIs. Estimated probability of maintaining DTG at 3 and 4 years were 81.5% (95%CI 80.5-82.5) and 76.3% (95%CI 73.9-78.7), respectively; RAL 61.6% (95%CI 60.2-63.0) and 54.1% (95%CI 52.7-55.5); EVG 71.6% (95%CI 69.2-74.0) and 68.3% (95%CI 65.3-71.3) (p&lt;0.001). At a multivariable analysis, being on a RAL-based ARV (vs DTG, aHR 2.9, 95%CI 2.3-3.6, p&lt;0.001), a EVG-based ARV (vs DTG, aHR 1.3 95%CI 1.1-1.7, p=0.049) and a peak HIV-RNA&gt;500k cp/mL (aHR 1.3, 95%CI 1.1-1.6, p=0.006) predicted INI discontinuation. Conclusions. Our data confirm the good tolerability of INIs in clinical practice. Differences emerge between the three drugs in reasons for discontinuation

Uncovering a Massive z∼7.7 Galaxy Hosting a Heavily Obscured Radio-loud Active Galactic Nucleus Candidate in COSMOS-Web

In this Letter, we report the discovery of the highest redshift, heavily obscured, radio-loud (RL) active galactic nucleus (AGN) candidate selected using JWST NIRCam/MIRI, mid-IR, submillimeter, and radio imaging in the COSMOS-Web field. Using multifrequency radio observations and mid-IR photometry, we identify a powerful, RL, growing supermassive black hole with significant spectral steepening of the radio spectral energy distribution (f1.28 GHz ∼ 2 mJy, q24 μm = −1.1, α1.28−3 GHz = − 1.2, Δα = − 0.4). In conjunction with ALMA, deep ground-based observations, ancillary space-based data, and the unprecedented resolution and sensitivity of JWST, we find no evidence of AGN contribution to the UV/optical/near-infrared (NIR) data and thus infer heavy amounts of obscuration (NH > 1023 cm−2). Using the wealth of deep UV to submillimeter photometric data, we report a singular solution photo-z of zphot = 7.7-+0.30.4 and estimate an extremely massive host galaxy (log M* = 11.92 0.5M) hosting a powerful, growing supermassive black hole (LBol = 4−12x × 1046 erg s−1). This source represents the farthest known obscured RL AGN candidate, and its level of obscuration aligns with the most representative but observationally scarce population of AGN at these epochs. © 2024 Institute of Physics Publishing. All rights reserved.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]