Ritonavir: 25 Years' Experience of Concomitant Medication Management. A Narrative Review.

Ritonavir is a potent inhibitor of the cytochrome P450 3A4 enzyme and is commonly used as a pharmacokinetic (PK) enhancer in antiviral therapies because it increases bioavailability of concomitantly administered antivirals. Decades of experience with ritonavir-enhanced HIV therapies and, more recently, COVID-19 therapies demonstrate that boosting doses of ritonavir are well tolerated, with an established safety profile. The mechanisms of PK enhancement by ritonavir result in the potential for drug-drug interactions (DDIs) with several classes of drugs, thus making co-medication management an important consideration with enhanced antiviral therapies. However, rates of DDIs with contraindicated medications are low, suggesting these risks are manageable by infectious disease specialists who have experience with the use of PK enhancers. In this review, we provide an overview of ritonavir's mechanisms of action and describe approaches and resources available to mitigate adverse events and manage concomitant medication in both chronic and short-term settings.

Intrathecal production of anti-Epstein-Barr virus viral capsid antigen IgG is associated with neurocognition and tau proteins in people with HIV.

OBJECTIVE: HIV and Epstein-Barr virus (EBV) co-infection has been linked to increased immune activation and larger HIV reservoir. We assessed whether anti-EBV humoral responses are associated with increased cerebrospinal fluid (CSF) inflammation and with neurocognitive impairment (NCI) in people with HIV (PWH). DESIGN: Cross-sectional analysis in 123 EBV-seropositive PWH either on antiretroviral therapy ( n  = 70) or not. METHODS: Serum and CSF anti-EBV viral capsid antigen immunoglobulin G (anti-EVI) and CSF EBV DNA were measured by commercial immunoassay and RT-PCR. Seventy-eight participants without neurological confounding factors underwent neurocognitive assessment (Global Deficit Score, GDS). CSF total tau and 181-phosphorylated-tau (ptau) were measured by immunoassays together with biomarkers of blood-brain barrier (BBB) integrity, immune activation, astrocytosis, and intrathecal synthesis. Logistic and linear regressions and moderation analysis were used to investigate the relationships between CSF anti-EVI, GDS, and biomarkers. RESULTS: Twenty-one (17.1%) and 22 participants (17.9%) had detectable CSF anti-EVI (10.5-416.0 U/ml) and CSF EBV DNA (25-971 copies/ml). After adjusting for BBB integrity, age, and clinical factors, the presence of CSF anti-EVI was only associated with serum levels of anti-EVI, and not with CSF EBV DNA. CSF anti-EVI, tau and ptau showed reciprocal interactions affecting their associations with GDS. After adjusting for demographics and clinical parameters, higher CSF anti-EVI levels were associated with worse GDS (aß 0.45, P  < 0.001), and CSF levels of tau and ptau had a moderation effect on the strength of this association (models' P  < 0.001). CONCLUSION: Humoral immune responses against EBV within the central nervous system may contribute to NCI in PWH through mechanisms that involve neuronal injury.

Pharmacological outlook of Lenacapavir: a novel first-in-class Long-Acting HIV-1 Capsid Inhibitor.

The evolution of antiretroviral therapy is now addressed to develop regimens consisting of two instead of three drugs and it is also increasingly oriented to develop long-acting parenteral formulations in order to increase treatment adherence and to reduce the multifaceted individual burden associated to daily intake of drugs. This new way was first paved by the dual association consisting of the INSTI Cabotegravir and the NNRTI Rilpivirine, whose formulations allow for a single administration every two months. In 2022 a new drug with a novel mechanism of action and a longer persistence of effective drug concentrations was made available in many countries for the treatment of drug-resistant HIV infection in association to other antiretrovirals. Lenacapavir is a first in class capsid inhibitor that exerts its inhibitory effect on HIV replication by binding to a structural protein of the capsid. This unprecedented mechanism of action actually differs from those of all prior antiretrovirals as Lenacapavir interferes with multiple stages rather than with a single enzyme. Such binding determines a series of inhibitory effects on sequential steps of the HIV life cycle and the net result is that of an impressive intrinsic antiretroviral potency, as testified both by in vitro studies and the 10-day monotherapy clinical study with single injections. The antiretroviral activity of Lenacapavir is unaffected by any mutation conferring resistance to older antiretrovirals. Lenacapavir is slowly released from the site of injection and this requires an initial coverage by its oral formulation (half-life: 10-12 days) in order to provide adequate pharmacokinetic exposure in the first days of treatment. The subcutaneous administration of Lenacapavir (half-life: 8-12 weeks) is then scheduled every 6 months. Lenacapavir is metabolized by CYP3A and UGT1A1, it is a substrate of Pgp and a moderate inhibitor of CYP3A. While co-administration with strong inducers of these enzymatic entities is contraindicated or it is not recommended in case of weaker inducers, few are the potential interactions of Lenacapavir as perpetrator (by its moderate inhibitory effect on CYP and weak inhibition of Pgp). In most such cases no preventive dosage adjustments are recommended and clinical monitoring only is advised. Lenacapavir overall characteristics thus meet the major clinical-pharmacologic expectations of this new era of antiretroviral development. A safe and truly potent antiviral drug, with a low metabolic interactive potential and a frequency of administration with the potential to be successfully employed beyond the current therapeutic indications.

Parietal resting-state EEG alpha source connectivity is associated with subcortical white matter lesions in HIV-positive people.

OBJECTIVE: Parietal resting-state electroencephalographic (rsEEG) alpha (8-10 Hz) source connectivity is abnormal in HIV-positive persons. Here we tested whether this abnormality may be associated with subcortical white matter vascular lesions in the cerebral hemispheres. METHODS: Clinical, rsEEG, and magnetic resonance imaging (MRI) datasets in 38 HIV-positive persons and clinical and rsEEG datasets in 13 healthy controls were analyzed. Radiologists visually evaluated the subcortical white matter hyperintensities from T2-weighted FLAIR MRIs (i.e., Fazekas scale). In parallel, neurophysiologists estimated the eLORETA rsEEG source lagged linear connectivity from parietal cortical regions of interest. RESULTS: Compared to the HIV participants with no/negligible subcortical white matter hyperintensities, the HIV participants with mild/moderate subcortical white matter hyperintensities showed lower parietal interhemispheric rsEEG alpha lagged linear connectivity. This effect was also observed in HIV-positive persons with unimpaired cognition. This rsEEG marker allowed good discrimination (area under the receiver operating characteristic curve > 0.80) between the HIV-positive individuals with different amounts of subcortical white matter hyperintensities. CONCLUSIONS: The parietal rsEEG alpha source connectivity is associated with subcortical white matter vascular lesions in HIV-positive persons, even without neurocognitive disorders. SIGNIFICANCE: Those MRI-rsEEG markers may be used to screen HIV-positive persons at risk of neurocognitive disorders.

Clinical pharmacology of the SingleTablet Regimen (STR) Bictegravir/Emtricitabine/Tenofovir Alafenamide (BIC/FTC/TAF).

In Italy a proportion of HIV patients exceeding 50% are diagnosed at advanced stages of disease. A sizeable proportion of patients under chronic HIV treatment has a story of poor adherence with archived resistance associated mutations, a condition implying some risks in case of treatment with dual regimens. Conventional three-drug regimens will remain necessary in the short-mid term, in order to avoid treatment failure and selection of drug resistance. Efficacy, tolerability, safety, genetic barrier, forgiveness and a good compatibility with concurrent medications are all features that describe the overall quality of BIC/FTC/TAF, a combination whose robustness will remain a point of reference for the next years.

Pillars of long-term antiretroviral therapy success.

BACKGROUND: Meeting the challenge of antiretroviral therapy (ART) whose efficacy can last a lifetime requires continuous updating of the virological, pharmacological, and quality of life outcomes to be pursued and a continuous review of literature data on the efficacy and tolerability of new drugs and therapeutic strategies. METHODS: With the aim of identifying open questions and answers about the current controversies in modern ART, we adapted the Design Thinking methodology to the needs of the design phase of a scientific article, involving a team of experts in HIV care. RESULTS: Five main pillars of treatment success were discussed: sustained virologic suppression over time; immunological recovery; pharmacological attributes; long-term tolerability and safety of ART; and people's satisfaction and quality of life. The definition of the outcomes to be achieved in each thematic area and the tools to achieve them were reviewed and discussed. CONCLUSIONS: Long-term treatment success should be intended as a combination of HIV-RNA suppression, immune recovery, and high quality of life. To achieve this, the regimen should be well-tolerated, with high potency, genetic barrier, and forgiveness, and should be tailored by a person-centered perspective, based on individual needs, preferences, and therapeutic history.

Real-life comparison of mortality in patients with SARS-CoV-2 infection at risk for clinical progression treated with molnupiravir or nirmatrelvir plus ritonavir during the Omicron era in Italy: a nationwide, cohort study.

Background: Comparative data on mortality in COVID-19 patients treated with molnupiravir or with nirmatrelvir plus ritonavir are inconclusive. We therefore compared all-cause mortality in community-dwelling COVID-19 patients treated with these drugs during the Omicron era. Methods: Data collected in the nationwide, population-based, cohort of patients registered in the database of the Italian Medicines Agency (AIFA) were used. To increase completeness of the recorded deaths and date correctness, a cross-check with the National Death Registry provided by the Ministry of the Interior was performed. We included in this study all patients infected by SARS-CoV-2 treated within 5 days after the test date and symptom onset between February 8 and April 30, 2022. All-cause mortalities by day 28 were compared between the two treatment groups after balancing for baseline characteristics using weights obtained from a gradient boosting machine algorithm. Findings: In the considered timeframe, 17,977 patients treated with molnupiravir and 11,576 patients with nirmatrelvir plus ritonavir were included in the analysis. Most patients (25,617/29,553 = 86.7%) received a full vaccine course including the booster dose. A higher crude incidence rate of all-cause mortality was found among molnupiravir users (51.83 per 100,000 person-days), compared to nirmatrelvir plus ritonavir users (22.29 per 100,000 person-days). However, molnupiravir-treated patients were older than those treated with nirmatrelvir plus ritonavir and differences between the two populations were found as far as types of co-morbidities were concerned. For this reason, we compared the weight-adjusted cumulative incidences using the Aalen estimator and found that the adjusted cumulative incidence rates were 1.23% (95% CI 1.07%-1.38%) for molnupiravir-treated and 0.78% (95% CI 0.58%-0.98%) for nirmatrelvir plus ritonavir-treated patients (adjusted log rank p = 0.0002). Moreover, the weight-adjusted mixed-effect Cox model including Italian regions and NHS centers as random effects and treatment as the only covariate confirmed a significant reduced risk of death in patients treated with nirmatrelvir plus ritonavir. Lastly, a significant reduction in the risk of death associated with nirmatrelvir plus ritonavir was confirmed in patient subgroups, such as in females, fully vaccinated patients, those treated within day 2 since symptom onset and patients without (haemato)-oncological diseases. Interpretation: Early initiation of nirmatrelvir plus ritonavir was associated for the first time with a significantly reduced risk of all-cause mortality by day 28 compared to molnupiravir, both in the overall population and in patient subgroups, including those fully vaccinated with the booster dose. Funding: This study did not receive funding.

Efficacy, safety, and tolerability of switching to long-acting cabotegravir plus rilpivirine versus continuing fixed-dose bictegravir, emtricitabine, and tenofovir alafenamide in virologically suppressed adults with HIV, 12-month results (SOLAR): a randomised, open-label, phase 3b, non-inferiority trial.

BACKGROUND: Cabotegravir plus rilpivirine is the only approved complete long-acting regimen for the maintenance of HIV-1 virological suppression dosed every 2 months. The SOLAR study aimed to compare long-acting cabotegravir plus rilpivirine every 2 months with continued once-daily bictegravir, emtricitabine, and tenofovir alafenamide for the maintenance of HIV-1 virological suppression in adults living with HIV. METHODS: SOLAR is a randomised, open-label, multicentre, phase 3b, non-inferiority study. The study was done in 118 centres across 14 countries. Participants with HIV-1 RNA less than 50 copies per mL were randomly assigned (2:1), stratified by sex at birth and BMI, to either long-acting cabotegravir (600 mg) plus rilpivirine (900 mg) dosed intramuscularly every 2 months or to continue daily oral bictegravir (50 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg). Participants randomly assigned to long-acting therapy had a choice to receive cabotegravir (30 mg) plus rilpivirine (25 mg) once daily as an optional oral lead-in for approximately 1 month. The primary efficacy endpoint was the proportion of participants with virological non-response (HIV-1 RNA ≥50 copies per mL; the US Food and Drug Administration snapshot algorithm, 4% non-inferiority margin; modified intention-to-treat exposed population) at month 11 (long-acting start with injections group) and month 12 (long-acting with oral lead-in group and bictegravir, emtricitabine, and tenofovir alafenamide group). The study is registered with ClinicalTrials.gov, NCT04542070, and is ongoing. FINDINGS: 837 participants were screened between Nov 9, 2020, and May 31, 2021, and 687 were randomly assigned to switch treatment or continue existing treatment. Of 670 participants (modified intention-to-treat exposed population), 447 (67%) switched to long-acting therapy (274 [61%] of 447 start with injections; 173 [39%] of 447 with oral lead-in) and 223 (33%) continued bictegravir, emtricitabine, and tenofovir alafenamide. Baseline characteristics were similar; median age was 37 years (range 18-74), 118 (18%) of 670 were female sex at birth, 207 (31%) of 670 were non-White, and median BMI was 25·9 kg/m2 (IQR 23·3-29·5). At month 11-12, long-acting cabotegravir plus rilpivirine showed non-inferior efficacy versus bictegravir, emtricitabine, and tenofovir alafenamide (HIV-1 RNA ≥50 copies per mL, five [1%] of 447 vs one [<1%] of 223), with an adjusted treatment difference of 0·7 (95% CI -0·7 to 2·0). Excluding injection site reactions, adverse events and serious adverse events were similar between groups. No treatment-related deaths occurred. More long-acting group participants had adverse events leading to withdrawal (25 [6%] of 454 vs two [1%] of 227). Injection site reactions were reported by 316 (70%) of 454 long-acting participants; most (98%) were grade 1 or 2. INTERPRETATION: These data support the use of long-acting cabotegravir plus rilpivirine dosed every 2 months as a complete antiretroviral regimen that has similar efficacy to a commonly used integrase strand transfer inhibitor-based first-line regimen, while addressing unmet psychosocial issues associated with daily oral treatment. FUNDING: ViiV Healthcare.

Extended and Continuous Infusion of Novel Protected ß-Lactam Antibiotics: A Narrative Review.

Consolidated data from pharmacokinetic and pharmacodynamic studies support the administration of ß-lactam antibiotics in prolonged infusion (i.e., extended or continuous) to optimize therapeutic efficacy by increasing the probability of attaining maximal bactericidal activity. This is the longest possible time during which the free drug concentrations are approximately four-fold the minimum inhibitory concentration between dosing intervals. In the context of antimicrobial stewardship strategies, achieving aggressive pharmacokinetic and pharmacodynamic targets is an important tool in the management of multi-drug resistant (MDR) bacterial infections and in the attainment of mutant preventing concentrations. However, prolonged infusion remains an unexploited resource. Novel ß-lactam/ß-lactamase inhibitor (ßL/ßLI) combinations (ceftolozane-tazobactam, ceftazidime-avibactam, meropenem-vaborbactam, and imipenem-cilastatin-relebactam) have been released in recent years to face the emerging challenge of MDR Gram-negative bacteria. Pre-clinical and real-life evidence has confirmed the promising role of prolonged infusion of these molecules in specific settings and clinical populations. In this narrative review we have summarized available pharmacological and clinical data, future perspectives, and current limitations of prolonged infusion of the novel protected ß-lactams, their application in hospital settings and in the context of outpatient parenteral antimicrobial therapy.

Analytical validation of a novel UHPLC-MS/MS method for 19 antibiotics quantification in plasma: Implementation in a LC-MS/MS Kit.

BACKGROUND: Therapeutic drug monitoring (TDM) for antibiotic drugs represents a consolidated practice to optimize the effectiveness and to limit the toxicity of specific drugs by guiding dosage adjustments. The comparison of TDM results with drug-specific pharmacokinetic/pharmacodynamic (PK/PD) parameters, based on killing dynamics and bacterial susceptibility, increases the probability of therapeutic success. PURPOSE: The aim of this study was the analytical validation of a new UHPLC-MS/MS assay for the quantification of 19 antibiotics divided in two different sets considering their chemical/pharmacological properties. This method has been implemented in an analytical LC-MS/MS Kit System by CoQua Lab s.r.l (Turin). METHODS: The analytical validation is developed in accordance with "ICH Harmonized Guideline M10 on bioanalytical method validation and study sample analysis" and "Guidelines for regulatory auditing of quality management system of medical device manufacturers". Method suitability in the clinical context was tested by analysing clinical samples from patients treated with antibiotic drugs. RESULTS: This method allows for simultaneous TDM of the following molecules: dalbavancin, daptomycin, linezolid, tedizolid, levofloxacin, moxifloxacin, meropenem, ertapenem, vaborbactam, avibactam, sulbactam, tazobactam, ceftazidime, ceftriaxone, ceftolozane, ceftobiprole, cefiderocol, ceftaroline and piperacillin. These drugs were quantified showing analytical performance parameters compliant with guidelines in terms of repeatability, reproducibility, robustness, bias, LOD, LOQ and linearity. The method was capable to successfully monitor drug concentrations in 65 samples from 52 patients undergoing treatment. CONCLUSION: The UHPLC-MS/MS method described in this work can be useful for TDM of the reported antimicrobial agents. The analytical protocol is rapid and suitable to be used in routine analysis.

Cerebrospinal Fluid CXCL13 as Candidate Biomarker of Intrathecal Immune Activation, IgG Synthesis and Neurocognitive Impairment in People with HIV.

Plasma C-X-C-motif chemokine ligand-13 (CXCL13) has been linked to disease progression and mortality in people living with HIV (PLWH) and is a candidate target for immune-based strategies for HIV cure. Its role in central nervous system (CNS) of PLWH has not been detailed. We described CSF CXCL13 levels and its potential associations with neurological outcomes. Cross-sectional study enrolling PLWH without confounding for CXCL13 production. Subjects were divided according to CSF HIV-RNA in undetectable (< 20 cp/mL) and viremics. CSF CXCL13, and biomarkers of blood-brain barrier (BBB) impairment, intrathecal synthesis, and immune activation were measured by commercial immunoturbidimetric and ELISA assays. All subjects underwent neurocognitive assessment. Sensitivity analyses were conducted in subjects with intact BBB only. 175 participants were included. Detectable CSF CXCL13 was more common in the viremic (31.4%) compared to the undetectable group (13.5%; OR 2.9 [1.4-6.3], p = 0.006), but median levels did not change (15.8 [8.2-91.0] vs 10.0 [8.1-14.2] pg/mL). In viremics (n = 86), CXCL13 associated with higher CSF HIV-RNA, proteins, neopterin, intrathecal synthesis and BBB permeability. In undetectable participants (n = 89), CXCL13 associated with higher CD4+T-cells count, CD4/CD8 ratio, CSF proteins, neopterin, and intrathecal synthesis. The presence of CXCL13 in the CSF of undetectable participants was associated with increased odds of HIV-associated neurocognitive disorders (58.3% vs 28.6%, p = 0.041). Sensitivity analyses confirmed all these findings. CXCL13 is detectable in the CSF of PLWH that show increased intrathecal IgG synthesis and immune activation. In PLWH with CSF viral suppression, CXCL13 was also associated with neurocognitive impairment.

COVID-19: A Possible Contribution of the MAPK Pathway.

BACKGROUND: COVID-19 is characterized by an uncontrolled inflammatory response with high pro-inflammatory cytokine production through the activation of intracellular pathways, such as mitogen-activated protein kinase (MAPK). Viruses are able to exploit the MAPK pathway to their advantage; this pathway relevance to severe COVID-19 is poorly described. The aim of this study was to quantify biomarkers involved in the MAPK pathway and to clarify its possible role in affecting some COVID-19-related clinical features. METHODS: H-RAS, C-RAF, MAPK1, MAPK2, and ERK were quantified through ELISA, and genetic polymorphisms were evaluated through real-time PCR. RESULTS: We prospectively recruited 201 individuals (158 positive and 43 negative for SARS-CoV-2): 35 were male, and their median age was 65 years. MAPK-related biomarker levels were increased in SARS-CoV-2-positive participants (n = 89) compared to negative ones (n = 29). Dyspnea was reported by 48%; this symptom was associated with PBMC C-RAF levels in positive participants (p = 0.022) and type of ventilation (p = 0.031). The highest degree of ventilation was used by 8% for invasive ventilation and 41% for continuous positive airway pressure (CPAP). CONCLUSIONS: This is the first study that showed a possible contribution of MAPK-related biomarkers in affecting COVID-19 clinical features, and this may be relevant for identifying COVID-19 positive participants at risk of serious complications.

COVID-19: Focusing on the Link between Inflammation, Vitamin D, MAPK Pathway and Oxidative Stress Genetics.

An uncontrolled inflammatory response during SARS-CoV-2 infection has been highlighted in several studies. This seems to be due to pro-inflammatory cytokines whose production could be regulated by vitamin D, ROS production or mitogen-activated protein kinase (MAPK). Several genetic studies are present in the literature concerning genetic influences on COVID-19 characteristics, but there are few data on oxidative stress, vitamin D, MAPK and inflammation-related factors, considering gender and age. Therefore, the aim of this study was to evaluate the role of single nucleotide polymorphisms in these pathways, clarifying their impact in affecting COVID-19-related clinical features. Genetic polymorphisms were evaluated through real-time PCR. We prospectively enrolled 160 individuals: 139 patients were positive for SARS-CoV-2 detection. We detected different genetic variants able to affect the symptoms and oxygenation. Furthermore, two sub-analyses were performed considering gender and age, showing a different impact of polymorphisms according to these characteristics. This is the first study highlighting a possible contribution of genetic variants of these pathways in affecting COVID-19 clinical features. This may be relevant in order to clarify the COVID-19 etiopathogenesis and to understand the possible genetic contribution for further SARS infections.

Antiretroviral Levels in the Cerebrospinal Fluid: The Effect of Inflammation and Genetic Variants.

Neurocognitive impairments are common in people living with HIV. Some conditions, such as chronic inflammation, astrocyte infection and an impaired blood-brain barrier (BBBi), along with host genetic variants in transporter genes, may affect antiretroviral (ARV) exposure in the cerebrospinal fluid (CSF). The aim of this study was to evaluate ARV CSF penetration according to compartmental inflammation, BBB permeability and single-nucleotide polymorphisms (SNPs) in drug transporter encoding genes. CSF neopterin (ELISA), plasma and CSF ARV concentrations (HPLC) and host genetic variants in ABCC2, HNF4α, SLCO1A2 and SLC22A6 (real-time PCR) were measured. Bi- and multivariate analyses were performed for single ARV and classes. We included 259 participants providing 405 paired plasma and CSF samples. CSF/plasma ratios (CPR) showed an increase for NRTIs and nevirapine with low penetrations for the majority of ARVs. At bi-variate analysis, several associations, including the effect of BBBi (emtricitabine, raltegravir), age (zidovudine and darunavir), and high CSF neopterin (NRTIs and border-line for PIs) were suggested. An association was found between genetic variants and integrase strand transfer (ABCC2 and HNF4α), non-nucleoside reverse transcriptase inhibitors (SLCO1A2), and protease inhibitors (SLC22A6). At multivariate analysis age, gender, BMI, and altered BBB were independent predictors of nucleoside reverse transcriptase CSF concentrations; age (for protease inhibitors) and body mass index and altered BBB (integrase strand transfer inhibitors) were also associated with ARV CSF exposure. We describe factors associated with CSF concentrations, showing that demographic, BBB integrity and, partially, genetic factors may be predictors of drug passage in the central nervous system.

Inflammation and intracellular exposure of dolutegravir, darunavir, tenofovir and emtricitabine in people living with HIV.

AIMS: Antiretroviral (ARV) therapy reduces inflammation and immune activation in people with HIV, but not down to the levels observed in people without HIV. Limited drug penetration within tissues has been argued as a potential mechanism of persistent inflammation. Data on the inflammation role on ARV plasma/intracellular (IC) pharmacokinetics (PK) through to expression of cytochrome P450 3A/membrane transporters are limited. The aim of this study was to investigate the correlation between inflammation markers (IM) and plasma/IC PK of ARV regimen in HIV-positive patients. METHODS: We included ART-experienced patients switching to three different ARV regimens. Plasma and IC ARV drug concentration means at the end of dosing interval (T0 ), IM on samples concomitantly with ARV PK determination: sCD14, CRP, IL-6 and LPS were analysed. RESULTS: Plasma and IC drug concentrations were measured in 60 samples. No significative differences between CRP, sCD14, IL-6 and LPS values in the three arms were observed. A significant inverse correlation between tenofovir plasma concentration and sCD14 (rho = -0.79, P < .001), and between DRV IC/plasma ratio and Log10 IL-6 concentrations (rho = -0.36, P = .040), and a borderline statistically significant positive trend between DRV plasma concentration and sCD14 (rho = 0.31, P = .070) were suggested. Furthermore, a borderline statistically significant inverse trend between DTG IC concentrations and sCD14 (rho = -0.34, P = .090) was observed in 24 patients on DTG-based triple therapy. CONCLUSIONS: Our preliminary data support the hypothesis of lower DRV and DTG IC concentrations and lower TFV plasma exposure in patients with higher plasma IM suggesting an interplay between HIV drug penetration and persistent inflammation in cART-treated HIV-positive patients.

Influence of UGT1A1 and SLC22A6 polymorphisms on the population pharmacokinetics and pharmacodynamics of raltegravir in HIV-infected adults: a NEAT001/ANRS143 sub-study.

Using concentration-time data from the NEAT001/ARNS143 study (single sample at week 4 and 24), we determined raltegravir pharmacokinetic parameters using nonlinear mixed effects modelling (NONMEM v.7.3; 602 samples from 349 patients) and investigated the influence of demographics and SNPs (SLC22A6 and UGT1A1) on raltegravir pharmacokinetics and pharmacodynamics. Demographics and SNPs did not influence raltegravir pharmacokinetics and no significant pharmacokinetic/pharmacodynamic relationships were observed. At week 96, UGT1A1*28/*28 was associated with lower virological failure (p = 0.012), even after adjusting for baseline CD4 count (p = 0.048), but not when adjusted for baseline HIV-1 viral load (p = 0.082) or both (p = 0.089). This is the first study to our knowledge to assess the influence of SNPs on raltegravir pharmacodynamics. The lack of a pharmacokinetic/pharmacodynamic relationship is potentially an artefact of raltegravir's characteristic high inter and intra-patient variability and also suggesting single time point sampling schedules are inadequate to thoroughly assess the influence of SNPs on raltegravir pharmacokinetics.

Seropositivity and reactivations of HSV-1, but not of HSV-2 nor VZV, associate with altered blood-brain barrier, beta amyloid, and tau proteins in people living with HIV.

Among 128 adult people living with HIV and no neurological conditions confounding the cerebrospinal fluid results, the presence of HSV-1 chronic infection (detected either by serology or PCR), but not of HSV-2 and VZV, independently associated with higher odds of blood-brain barrier impairment, abnormally increased cerebrospinal fluid levels of tau and phosphorylated-181 tau, and decreased concentrations of fragments 1-42 of beta amyloid compared to the seronegative counterpart. These associations were even stronger for seropositive participants with a positive history of at least one symptomatic reactivation of HSV-1.

Dolutegravir Discontinuation for Neuropsychiatric Symptoms in People Living with HIV and Their Outcomes after Treatment Change: A Pharmacogenetic Study.

Neuropsychiatric symptoms have been reported in patients receiving dolutegravir, a known inhibitor of the renal and neuronal-expressed organic anion transporter 2 (encoded by SLC22A2 gene). The effect of the genetic variant SLC22A2 808C>A on dolutegravir discontinuation was assessed and analyzed by real-time PCR. We enrolled 627 participants: CA/AA carriers showed a higher prevalence of pre-existing psychiatric comorbidities and use of antidepressants. After 27.9 months, 108 participants discontinued dolutegravir, 64 for neuropsychiatric symptoms. Patients with pre-existing psychiatric comorbidities were at higher risk of dolutegravir discontinuation, while patients carrying the SLC22A2 CA/AA genotype were not. Combining the two variables, an opposite effect of SLC22A2 variants according to pre-existing psychiatric disorders was observed. Using multivariate Cox models, the combined variable pre-existing psychiatric comorbidities/SLC22A2 variants and the use of non-tenofovir alafenamide containing antiretroviral regimens were predictors of dolutegravir discontinuation for neuropsychiatric symptoms. Within 30 days, the majority of participants had a complete resolution of symptoms (61.8%), while 32.7% and 5.5% had partial or no change after dolutegravir discontinuation, respectively. Discontinuation of dolutegravir for neuropsychiatric symptoms was not uncommon and more frequent in participants with pre-existing psychiatric disorders. We described an interaction between SLC22A2 genetic variant and psychiatric comorbidities. In 38.2% of patients, a complete neuropsychiatric symptoms resolution was not observed after dolutegravir discontinuation suggesting the involvement of additional factors.

Pharmacokinetic of Cefiderocol in Critically Ill Patients Receiving Renal Replacement Therapy: A Case Series.

Background: Cefiderocol is a novel parenteral siderophore cephalosporin, demonstrating enhanced activity against multidrug-resistant (MDR) Gram-negative bacteria and difficult-to-treat Acinetobacter baumannii (DTR-AB). Plasma-free trough concentration (fCtrough) over the minimum inhibitory concentration (MIC) was reported as the best pharmacokinetic parameter to describe the microbiological efficacy of cefiderocol. Materials and methods: We retrospectively described the pharmacokinetic and pharmacodynamic profile of three critically ill patients admitted to the intensive care unit, receiving cefiderocol under compassionate use to treat severe DTR-AB infections while undergoing continuous venovenous haemofiltration. Cefiderocol was administrated at a dosage of 2 g every 8 h infused over 3 h. Therapeutic drug monitoring (TDM) was assessed at the steady state. Cthrough was evaluated by assuming a plasma protein binding of 58.0%. The fCmin/MIC was calculated assuming a cefiderocol MIC equal to the PK-PD breakpoint of susceptibility ≤ 2. The association between the PK/PD parameters and microbiological outcome was assessed. Results: fCtrough/MIC were >12 in 2 patients and 2.9 in the 1 who rapidly recovered from renal failure. Microbiological cure occurred in 3/3 of patients. None of the 3 patients died within 30 days. Conclusions: A cefiderocol dosage of 2 g q8 h in critically ill patients with AKI undergoing CVVH may bring about a very high plasma concentration, corresponding to essentially 100% free time over the MIC for DTR-AB.