Comparison of the pharmacokinetics of raltegravir given at 2 doses of 400 mg by swallowing versus one dose of 800 mg by chewing in healthy volunteers: a randomized, open-label, 2-period, single-dose, crossover phase 1 study.

BACKGROUND: The pharmacokinetics of raltegravir (RAL) in HIV patients is characterized by high interindividual and intraindividual variability. We documented previously that HIV patients taking RAL at 400 mg bid by chewing the tablets had significantly higher drug absorption and reduced pharmacokinetic variability than patients taking the drug by swallowing the tablets. This study extends our previous findings. METHODS: An open-label, 2-period crossover study compared the pharmacokinetics of 2 doses of RAL given at 400 mg every 12 hours (that mimics a bid administration) by swallowing with 1 dose of 800 mg (that mimics a qd administration) by chewing the tablets in 12 healthy volunteers. RAL plasma concentrations were measured by a chromatographic method coupled with mass spectrometry. RESULTS: Subjects taking RAL by chewing had significantly higher drug exposure (RAL area under the curve[AUC](0-24): 40722 ± 14843 versus 21753 ± 12229 ng · h/mL, P < 0.0001) and reduced pharmacokinetic variability compared with those taking the drug by swallowing the whole tablet, with no difference in the minimum RAL concentrations (RAL C(min): 36 ± 23 versus 43 ± 23 ng/mL, P = 0.298). Subjects taking RAL by chewing the tablets had significantly higher drug absorption and reduced pharmacokinetic variability compared with those taking the drug by swallowing. No differences were observed in the minimum RAL concentrations. CONCLUSIONS: RAL at 800 mg once daily by chewing the tablets may represent a novel therapeutic option for the treatment of HIV being associated with higher drug absorption, reduced pharmacokinetic variability, and potentially better compliance compared with patients swallowing the 400-mg bid intact tablets.

GRAd-COV2 vaccine provides potent and durable humoral and cellular immunity to SARS-CoV-2 in randomized placebo-controlled phase 2 trial.

The ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and heterologous immunization approaches implemented worldwide for booster doses call for diversified vaccine portfolios. GRAd-COV2 is a gorilla adenovirus-based COVID-19 vaccine candidate encoding prefusion-stabilized spike. The safety and immunogenicity of GRAd-COV2 is evaluated in a dose- and regimen-finding phase 2 trial (COVITAR study, ClinicalTrials.gov: NCT04791423) whereby 917 eligible participants are randomized to receive a single intramuscular GRAd-COV2 administration followed by placebo, or two vaccine injections, or two doses of placebo, spaced over 3 weeks. Here, we report that GRAd-COV2 is well tolerated and induces robust immune responses after a single immunization; a second administration increases binding and neutralizing antibody titers. Potent, variant of concern (VOC) cross-reactive spike-specific T cell response peaks after the first dose and is characterized by high frequencies of CD8s. T cells maintain immediate effector functions and high proliferative potential over time. Thus, GRAd vector is a valuable platform for genetic vaccine development, especially when robust CD8 response is needed.

One-year durability of anti-spike IgG to SARS-CoV-2: Preliminary data from the anticrown prospective observational study one year durability of COVID-19 anti-spike IgG.

Data are presented of 368/503 post-COVID-19 outpatients followed within the AntiCROWN Cohort who have a one-year control and a baseline assessment of anti-S1/S2 antibodies, detected with the The LIAISON® SARS-CoV-2 S1/S2 IgG solution by DiaSorin. Loss of response occurred in 4 subjects having a baseline level below 50 AU/mL.

Correction to: Patient-Reported Outcomes in an Observational Cohort of HIV-1-Infected Adults on Darunavir/Cobicistat-Based Regimens: Beyond Viral Suppression.

In the original version of this article, in Fig. 2b the formatting on the x-axis of the graph has been published incorrectly.

Patient-Reported Outcomes in an Observational Cohort of HIV-1-Infected Adults on Darunavir/Cobicistat-Based Regimens: Beyond Viral Suppression.

OBJECTIVE: This prospective, multicenter, non-interventional cohort study enrolling human immunodeficiency virus (HIV)-1-infected, virally suppressed adult outpatients in Italy aimed to describe results obtained from patient-reported outcome questionnaires regarding treatment satisfaction and symptom perceptions in HIV-1-positive patients who switched to cobicistat-boosted darunavir antiretroviral regimens, coming from ritonavir-boosted protease inhibitors. METHODS: Patients entered this study between June 2016 and February 2017, once their treating physician had considered them eligible for cobicistat-boosted darunavir-based treatment as per clinical practice. Patients' satisfaction regarding regimen and current symptom burdens were assessed using two previously validated, patient-reported outcome questionnaires: HIV Treatment Satisfaction Questionnaire (HIV-TSQ) and HIV Symptoms Distress Module (HIV-SDM). These questionnaires were administered at prespecified time-points: enrollment (Visit 1), 4-8 weeks later (Visit 2), and 48 ± 6 weeks after study enrollment (Visit 4). Data of patient-reported outcome total scores for both questionnaires are presented as median with 25th-75th percentiles. Questionnaires scores were analyzed overall and stratified by gender when applicable. A p value of less than 0.05 was considered statistically significant. A sensitivity analysis was conducted to evaluate the role of lost to follow-up, using the "last observation carried forward" method. RESULTS: A total of 348 patients were enrolled in this study; 296 patients (208 male and 88 female) provided both evaluable HIV-TSQ and HIV-SDM at enrollment and at 4-8 weeks, while 250 patients (174 male and 76 female) provided questionnaire data at enrollment and at 48 ± 6 weeks. The total scores of HIV-TSQ showed improvements in patient satisfaction in the overall population both at Visit 2 and Visit 4 (p < 0.001, sign test) and also when stratified by gender throughout the study period. In addition, the overall burden of symptoms, as shown by the HIV-SDM scores, decreased. CONCLUSIONS: Switching to a cobicistat-boosted darunavir-based therapy led to overall increased patient satisfaction and reduced symptom burden when compared with previous regimens. The use of patient-reported outcomes in clinical daily practice could provide a useful tool towards achieving guideline goals to achieve "fourth 90", having 90% of virally suppressed patients with a good health-related quality of life.

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 weeks to 18 years, while dolutegravir and elvitegravir co-formulated with cobicistat, emtricitabine, and tenofovir alafenamide (E/C/FTC/TAF) are approved for children from 6 years 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.

Dolutegravir plus rilpivirine dual therapy in treating HIV-1 infection.

INTRODUCTION: The HIV-infected population is aging and comorbidities and polypharmacological regimens are increasing. To reduce toxicity and drug burden researchers are evaluating the efficacy, safety and durability of dual therapies as a switch option in subjects who have achieved stable virologic suppression. Initially effective dual combinations relied on protease inhibitors but when dolutegravir, the first integrase inhibitor to display a high genetic barrier, became commercially available, many physicians began to use it in a variety of dual regimens, generating several observational cohorts. Areas covered: This review covers the most recent data from observational cohorts and randomized clinical trials concerning the switch to the dual combination of dolutegravir plus rilpivirine and the reasons that lead to consider this option. Also, viral failures, due to poor adherence or to other factors, and drug resistance are investigated. Articles which are searchable on MEDLINE/PubMed and from the main national/international congresses in the field of HIV therapy are reviewed. Expert opinion: The observation period for this regimen is getting longer and data showing its efficacy in maintaining HIV-1 RNA < 50 copies/mL are now consolidated. Metabolic data suggest some benefit in the lipid profile, improvement in bone mineral density and reduced bone reabsorption.

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 1-5 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 ≥50 HIV-1 RNA copies/mL, 23 had 1-49 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.

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 1-49 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 15-40), 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.