Neurosymptomatic HIV-1 CSF escape is associated with replication in CNS T cells and inflammation.

During antiretroviral therapy (ART), most people living with HIV-1 have undetectable HIV-1 RNA in their plasma. However, they occasionally present with new or progressive neurologic deficits and detectable HIV-1 RNA in the cerebrospinal fluid (CSF), a condition defined as neurosymptomatic HIV-1 CSF escape (NSE). We explored the source of neuropathogenesis and HIV-1 RNA in the CSF during NSE by characterizing HIV-1 populations and inflammatory biomarkers in CSF from 25 individuals with NSE. HIV-1 populations in the CSF were uniformly drug resistant and adapted to replication in CD4+ T cells, but differed greatly in genetic diversity, with some having low levels of diversity similar to those observed during untreated primary infection and others having high levels like those during untreated chronic infection. Higher diversity in the CSF during NSE was associated with greater CNS inflammation. Finally, optimization of ART regimen was associated with viral suppression and improvement of neurologic symptoms. These results are consistent with CNS inflammation and neurologic injury during NSE being driven by replication of partially drug-resistant virus in CNS CD4+ T cells. This is unlike nonsuppressible viremia in the plasma during ART, which typically lacks clinical consequences and is generated by virus expression without replication.

Central Nervous System Disorders with Auto-Antibodies in People Living with HIV.

People living with HIV (PLWH) may present atypical neurological complications. Recently, autoimmune manifestations of the central nervous system (CNS) have been described. We retrospectively described the features of PLWH presenting with acute neurological symptoms with positive anti-CNS antibodies. We analyzed relevant CSF characteristics. Twelve patients were identified, with demyelinating, inflammatory, or no MRI lesions. We observed CSF inflammatory features. Aspecific CSF anti-CNS antibodies were found in all subjects and a specific antibody (second-level blotting panel) was found in one. The cases presented a slow resolution of symptoms with sequelae. More studies are needed to better describe the spectrum and prognosis of autoimmune CNS diseases in PLWH.

Switching to Low Neurotoxic Antiretrovirals to Improve Neurocognition Among People Living With HIV-1-Associated Neurocognitive Disorder: The MARAND-X Randomized Clinical Trial.

BACKGROUND: The pathogenesis of HIV-associated neurocognitive (NC) impairment is multifactorial, and antiretroviral (ARV) neurotoxicity may contribute. However, interventional pharmacological studies are limited. METHODS: Single-blind, randomized (1:1), controlled trial to assess the change of NC performance (Global Deficit Score, GDS, and domain scores) in PLWH with NC impairment randomized to continue their standard of care treatment or to switch to a less neurotoxic ARV regimen: darunavir/cobicistat, maraviroc, emtricitabine (MARAND-X). Participants had plasma and cerebrospinal fluid HIV RNA< 50 copies/mL, R5-tropic HIV, and were on ARV regimens that did not include efavirenz and darunavir. The change of resting-state electroencephalography was also evaluated. The outcomes were assessed at week 24 of the intervention through tests for longitudinal paired data and mixed-effect models. RESULTS: Thirty-eight participants were enrolled and 28 completed the follow-up. Global Deficit Score improved over time but with no difference between arms in longitudinal adjusted models. Perceptual functions improved in the MARAND-X, while long-term memory improved only in participants within the MARAND-X for whom the central nervous system penetration-effectiveness (CNS penetration effectiveness) score increased by ≥3. No significant changes in resting-state electroencephalography were observed. CONCLUSIONS: In this small but well-controlled study, the use of less neurotoxic ARV showed no major beneficial effect over an unchanged regimen. The beneficial effects on the memory domain of increasing CNS penetration effectiveness score suggest that ARV neuropenetration may have a role in cognitive function.

Serum and CSF biomarkers in asymptomatic patients during primary HIV infection: a randomized study.

It is debated whether central nervous system involvement begins during acute HIV infection in persons without meningitis/encephalitis and if specific antiretroviral drugs or combinations would be beneficial. Neurologically asymptomatic participants enrolled in a randomized and controlled study comparing three combination antiretroviral regimens (tenofovir alafenamide/emtricitabine plus dolutegravir, darunavir or both) during primary HIV infection were enrolled. Serum and cerebrospinal fluid (CSF) were collected at baseline, 12 and 48 (serum only) weeks after treatment initiation. Single Molecule Array was used to measure neurofilament light chain (NFL), total tau protein (Tau), Brain-Derived Neurotrophic Factor (BDNF), Glial Fibrillary Acidic Protein (GFAP), Ubiquitin C-terminal Hydrolase (UCH-L1). We assessed the longitudinal change in biomarkers over time as well as the change in the prevalence of serum NFL concentrations above previously published age-adjusted cut-offs (7 pg/mL if 5-18 years, 10 pg/mL if 18-51 years, 15 pg/mL if 51-61 years, 20 pg/mL if 61-70 years and 35 pg/mL if >70 years). Serum was available from 47 participants at all time points while CSF was in 13 and 7 participants (baseline/W12). We observed a significant direct serum-to-CSF correlation for NFL (rho = 0.692, p = 0.009), GFAP (rho = 0.659, p = 0.014) and BDNF (rho = 0.587, p = 0.045). Serum (rho = 0.560, p = 0.046) and CSF NFL (rho = 0.582, p = 0.037) concentrations were directly associated with CSF HIV RNA levels. We observed a significant decrease over time in serum NFL (p = 0.006) and GFAP (p = 0.006) but not in the other biomarkers. No significant difference was observed among the treatment arms. At baseline, serum and CSF age-adjusted NFL levels were above age-adjusted cut-offs in 23 (48.9%) and 4 participants (30.8%); considering serum NFL, this proportion was lower at weeks 12 (31.9%, p = 0.057) and 48 (27.7%, p = 0.13). A relevant proportion of neurologically asymptomatic participants had abnormal CSF and serum NFL levels during primary HIV infection. NFL and GFAP decreased in serum following combination antiretroviral therapy without significant differences among the treatment arms.

Dual ß-lactams for the treatment of Mycobacterium abscessus: a review of the evidence and a call to act against an antibiotic nightmare.

Mycobacterium abscessus complex is a group of rapidly growing non-tuberculous mycobacteria (NTM), increasingly emerging as opportunistic pathogens. Current treatment options for these microorganisms are limited and associated with a high rate of treatment failure, toxicity and recurrence. In search of new therapeutic strategies, interest has grown in dual ß-lactam (DBL) therapy, as research recently discovered that M. abscessus cell wall synthesis is mainly regulated by two types of enzymes (d,d-transpeptidases and l,d-transpeptidases) differently susceptible to inhibition by distinct ß-lactams. In vitro studies testing several DBL combinations have shown synergy in extracellular broth cultures as well as in the intracellular setting: cefoxitin/imipenem, ceftaroline/imipenem, ceftazidime/ceftaroline and ceftazidime/imipenem. The addition of specific ß-lactamase inhibitors (BLIs) targeting M. abscessus ß-lactamase did not significantly enhance the activity of DBL combinations. However, in vivo data are lacking. We reviewed the literature on DBL/DBL-BLI-based therapies for M. abscessus infections to raise greater attention on this promising yet overlooked treatment option and to guide future preclinical and clinical studies.

Symptomatic and Asymptomatic Neurocognitive Impairment, ART Adherence and HIV Control: A 4-Year Observational Study.

We assessed whether symptomatic neurocognitive impairment (NCI) and asymptomatic NCI -of which the clinical relevance is debated- affect HIV control and the role of ART adherence in this relationship. Observational study on the relationship between NCI and viral control during the 2 years before and the 2 after the neurocognitive evaluation (NCE) of 322 PLWH on ART. Viral load (VL) was defined as undetectable, very low-level (VLLV), low-level (LLV), or high-level viremia (HLV), and classified overtime as persistent (p; ≥2 consecutive values in the same worst category), viral failure (VF; ≥1 HLV requiring ART changes), or optimal control. Adherence was the proportion of days covered by ART. Frascati criteria were used. Adjusted models were performed for factors associated with viral control. Mediation analyses informed causality in the path from NCI to viral control through adherence. Sensitivity analyses were focused on the year following NCE for only participants with optimal viral control before. Among the participants (53 ± 10 years, CD4 + T-cells 630/µL), 41.6% and 10.8% presented asymptomatic and symptomatic NCI. Over 3,304 VLs, 8.4% and 22.1% of participants had VF and pLLV/pVLLV. Both symptomatic and asymptomatic NCI were independently associated with VF (aRRR = 8.5; aRRR = 4.3) and pVLLV/pLLV (aRRR = 4.3; aRRR = 2.1). Specific cognitive domains showed independent associations with VL categories (models' P < 0.001). Adherence partially mediated these relationships (models' P < 0.001). Sensitivity analysis confirmed these findings. Prevalence and severity of poor viral control increased as the severity of NCI increased, with ART adherence mediating this relationship. The current "asymptomatic" attribution used by Frascati's criteria could overlook clinical risks.

Plasma, intracellular and lymph node antiretroviral concentrations and HIV DNA change during primary HIV infection: Results from the INACTION P25 study.

Despite its effectiveness, combination antiretroviral treatment (cART) has a limited effect on HIV DNA reservoir, which establishes early during primary HIV infection (PHI) and is maintained by latency, homeostatic T-cells proliferation, and residual replication. This limited effect can be associated with low drug exposure in lymphoid tissues and/or suboptimal adherence to antiretroviral drugs (ARVs). The aim of this study was to assess ARV concentrations in plasma, peripheral blood mononuclear cells (PBMCs) and lymph nodes (LNs), and their association to HIV RNA and HIV DNA decay during PHI. Participants were randomised to receive standard doses of darunavir/cobicistat (Arm I), dolutegravir (Arm II) or both (Arm III), with a backbone of tenofovir alafenamide and emtricitabine. Total HIV DNA was measured using digital-droplet PCR in PBMCs at baseline, 12 and 48 weeks. Drug concentrations in plasma and PBMCs were determined at 2, 12 and 48 weeks (LNs at 12 weeks) by UHPLC-MS/MS. Seventy-two participants were enrolled, mostly male (n=68), with a median age of 34 years and variable Fiebig stages (V-VI 57.7%, I-II 23.9%, and III-IV 18.3%). Twenty-six patients were assigned to Arm I, 27 to Arm II and 19 to Arm III. After 48 weeks, most patients had undetectable viremia, with minor differences in HIV RNA decay between arms. Patients with Fiebig I-II showed faster HIV RNA and HIV DNA decay. Intracellular tissue penetration was high for nucleoside analogues and low-moderate for darunavir and dolutegravir. Only tenofovir diphosphate concentrations in PBMCs showed correlation with HIV DNA decay. Overall, these results indicate that the timing of treatment initiation and intracellular tenofovir penetration are primary and secondary factors, respectively, affecting HIV reservoir.

Association between tight junction proteins and cognitive performance in untreated persons with HIV.

BACKGROUND: HIV-associated neurocognitive disorders (HAND) still affects persons with HIV (PWH) and their pathogenesis is not completely understood. We aimed to explore the association between plasma and cerebrospinal fluid (CSF) markers of blood-brain barrier (BBB) impairment and HAND in untreated PWH. DESIGN: Cross-sectional study. METHODS: We enrolled untreated PWH, who underwent blood examinations and lumbar puncture to measure inflammation (IL-15, TNF-α), BBB damage (zonulin and tight junction proteins, tight junction proteins: occludin, claudin-5) and endothelial adhesion molecules (VCAM-1, ICAM-1). A comprehensive neurocognitive battery was used to diagnose HAND (Frascati criteria). RESULTS: Twenty-one patients (21/78, 26.9%) patients presented HAND (100% ANI). HAND patients displayed more frequently non-CNS AIDS-defining conditions, lower nadir CD4 + T cells and increased CD4 + T-cell exhaustion (lower CD4 + CD127 + and CD4 + CD45RA + T-cell percentages), in comparison to individuals without cognitive impairment. Furthermore, HAND was characterized by higher plasma inflammation (IL-15) but lower CSF levels of biomarkers of BBB impairment (zonulin and occludin). The association between BBB damage with HAND was confirmed by fitting a multivariable logistic regression. CSF/plasma endothelial adhesion molecules were not associated with HAND but with a poor performance in different cognitive domains. CONCLUSION: By showing heightened inflammation and BBB impairment, our study suggests loss of BBB integrity as a possible factor contributing to the development of HAND in untreated PWH.

Host single nucleotide polymorphisms and biomarkers of neuronal damage and inflammation in people living with HIV.

OBJECTIVES: Blood-brain barrier impairment is frequent in people living with human immunodeficiency virus (PLWHIV), affecting the penetration of target cells and antiretrovirals into the central nervous system, through transporters (e.g. ABCB1), leading to neuroinflammation. This study aimed to identify variants of genes encoding transporters able to predict neuroinflammation biomarker levels. METHODS: Cerebrospinal fluid (CSF) and plasma samples were obtained from PLWHIV. The CSF biomarkers were quantified by commercial assays. Genetic variants were evaluated through real-time polymerase chain reaction (PCR). RESULTS: A total of 107 PLWHIV (163 samples) were included in the study: 79% were male, median age was 48.5 years, CD4% was 25%, and HIV-associated neurocognitive disorder (HAND) was observed in 17.8%. The ABCB1 2677G>T genetic variant showed a different allelic distribution according to the clinical group (P = 0.026). In linear regression analyses, HIV-related central nervous system disorders, ABCG2 1194+928CC genotype, log viral load, CSF-to-serum albumin ratio, ß-1,42 levels, and CSF proteins were retained in the final model as factors independently associated with CSF neopterin levels; CSF proteins and integrase inhibitor use were associated with CSF tau level in the multivariate model. Phospho-tau regression analysis reported the ABCB1 2677GT/TT genotype and CSF proteins as predictors in the final model; sex, protease inhibitors, neopterin, and ABCB1 2677 GT/ TT genotype were predictors in the multivariate regression for ß-1,42. CONCLUSIONS: For the first time, pharmacogenetic and clinical features were found to be predictors of neuro-inflammation biomarkers.

Longitudinal analysis of CSF HIV RNA in untreated people with HIV: Identification of CSF controllers.

Interindividual variation of human immunodeficiency virus (HIV) RNA setpoint in cerebrospinal fluid (CSF) and its determinants are poorly understood, but relevant for HIV neuropathology, brain reservoirs, viral escape, and reseeding after antiretroviral interruptions. Longitudinal multicentric study on demographic, clinical, and laboratory correlates of CSF HIV RNA in 2000 follow-up visits from 597 people with HIV (PWH) off antiretroviral therapy (ART) and with plasma HIV RNA > the lower limit of quantification (LLQ). Factors associated with CSF control (CSFC; CSF HIV RNA < LLQ while plasma HIV RNA > LLQ) and with CSF/plasma discordance (CSF > plasma HIV RNA > LLQ) were also assessed through mixed-effects models. Posthoc and sensitivity analyses were performed for persistent CSFC and ART-naïve participants, respectively. Over a median follow-up of 2.1 years, CSF HIV RNA was associated with CD4+ and CD8+ T cells, CSF leukocytes, blood-brain barrier (BBB) integrity, biomarkers of iron and lipid metabolism, serum globulins, past exposure to lamivudine, and plasma HIV RNA (model p < 0.0001). CSFC (persistent in 7.7% over 3 years) and CSF/plasma discordance (persistent in <0.01% over 1 year) were variably associated with the same parameters (model p < 0.001). Sensitivity analyses confirmed most of the previous associations in participants never exposed to ART. Persistent CSFC was associated with higher CD4+ T-cell count nadir (p < 0.001), lower serum globulins (p = 0.003), and lower CSF leukocytes (p < 0.001). Without ART, one in 13 PWH had persistently undetectable CSF HIV RNA, while persistent CSF/plasma discordance was extremely rare over years. Immune responses, inflammation, BBB permeability, and iron and lipid metabolism were all associated with HIV replication in CSF.

Use of different anticholinergic scales and their correlation with anticholinergic symptom burden in a cohort of people living with HIV.

OBJECTIVES: How to detect the clinical impact of anticholinergic (AC) burden in people with HIV (PWH) remains poorly investigated. We cross-sectionally described the prevalence and type of AC signs/symptoms and the screening accuracy of three AC scales in detecting their presence in a modern cohort of PWH. METHODS: We calculated AC Burden Scale (ABS), AC Risk Score (ARS) and AC Drug Score (ADS) in 721 adult PWH and recorded the presence of AC signs/symptoms over the previous 3 months. High AC risk was defined by ABS score ≥2, and ARS or ADS score ≥3. Comparisons among the scale were based on Cohen's inter-rater agreement, and their screening accuracy was assessed by receiver operating characteristics (ROC) curves and performance measures. RESULTS: We enrolled 721 PWH, of whom 72.0% of participants were male; the median age was 53 years, and 164 participants (22.7%) were on at least one AC drug. Among these, 28.6% experienced at least one AC sign/symptom. Agreement in AC risk classification was substantial only between ARS and ADS (k = 0.6). Lower and higher risk of AC signs/symptoms was associated with dual regimens [adjusted OR (aOR) = 0.12 versus three-drug regimens, P = 0.002] and increasing number of AC drugs (aOR = 12.91, P < 0.001). Depression and COPD were also associated with higher risk of AC signs/symptoms in analysis unadjusted for number of AC drugs. ABS and ADS showed the best area under the ROC curve (AUROC) of 0.85 (0.78-0.92) and 0.84 (0.75-0.92; P < 0.001 for both). However, at the cut-off used for the general population, the sensitivity of all three scales was very low (34.0%, 46.8% and 46.8%). CONCLUSIONS: Up to one-fourth of participants in our cohort were exposed to at least one AC drug, and among them AC signs/symptoms affected more than one-fourth. Both polypharmacy (as number of antiretrovirals and of co-medications with AC properties) and to a lesser extent specific comorbidities shaped the risk of developing AC signs/symptoms. Sensitive screenings for AC risk in PWH should prefer ABS or ADS based on lower cut-offs than those suggested for the general population.

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.

Distinct effects of SSRIs and SNRIs on Soluble Biomarkers in Blood and Cerebrospinal Fluid of people with HIV.

BACKGROUND: Persistent inflammation affects people with HIV (PWH) despite antiretroviral therapy (ART). Selective serotonin and serotonin-norepinephrine reuptake inhibitors (SSRIs, SNRIs), HMG-CoA reductase-inhibitors (statins), and angiotensin-converting enzyme inhibitors (ACEIs) have immuno-modulant properties. We evaluated the potential impact of these drugs on inflammation and neurodegeneration in PWH. METHODS: Cross-sectional single-center (U.S.) analysis in 184 PWH on ART with plasma HIV RNA < 200 cp/mL. All participants had 10 biomarkers measured in blood and cerebrospinal fluid (CSF). To reduce dimensionality, hierarchical clustering and principal components (PCs) analysis were employed. The analyses were adjusted for duration of the drugs and and clinical conditions. RESULTS: Participants were mostly middle-aged men, with median CD4+ T-cells of 620/µL. In adjusted models, SSRI use was associated with three PCs: higher CSF and plasma Aß42 and CSF CCL2 (aß=0.14, p = 0.040); lower CSF 8-oxo-dG, total tau, and sCD14 (aß=-0.12, p = 0.042); higher plasma sCD14 with lower sCD40L (aß=0.15, p = 0.042). SNRI use was associated with higher values of CSF and plasma neopterin and CSF sTNFR-II (aß=0.22, p = 0.004). Statins and ACEIs showed no association. CONCLUSIONS: SSRIs and SNRIs had distinct biomarker signatures. SSRIs were associated with reduced neurodegeneration, immune activation and oxidative stress in CSF, suggesting a role of SSRIs as adjunctive therapy in PWH.

Changes in Cerebrospinal Fluid, Liver and Intima-media-thickness Biomarkers in Patients with HIV-associated Neurocognitive Disorders Randomized to a Less Neurotoxic Treatment Regimen.

The prevalence of neurocognitive impairment in people living with HIV is estimated between 30 and 50%. The pathogenesis of HIV-associated neurocognitive disorders is complex and multifactorial. Aim of the study was to measure the change in CSF biomarkers, Fibroscan and IMT measurements in PLWH with HAND randomized to a less neurotoxic regimen, or continuing their treatment. Adult patients with HAND were screened and enrolled if presenting no major resistance associated mutations, no HIV viral replication, not on efavirenz or darunavir, with R5-tropic HIV and without major confounding conditions. Lumbar puncture, IMT and Fibroscan measurements were performed. After 1:1 randomization to a less neurotoxic regimen consisting of darunavir/cobicistat plus emtricitabine plus maraviroc, or mantaining actual care, tests were repeated after 24 weeks: CSF biomarkes (HIV RNA, tau, p-tau, Beta-amyloid1-42, S100Beta and neopterin) were included. Non-parametric tests (Mann-Whitney and Wilcoxon's) were used. 28 participants completed the study. Male and European ancestry were prevalent; median age was 55 years (51-60). All patients were virally suppressed; median CD4 + count was 626 cell/uL (469-772). Baseline characteristics were similar between the study arms. A significant decrease in CSF p-tau and an increase in CSF neopterin and NFL were observed. We observed a significant reduction in liver stiffness at W24. Despite a small sample size we observed changes in neuromarkers and in hepatic stiffness in patients randomized to the experimental arm. We observed changes in CSF biomarkers (lower phosphorylated-tau and higher neopterin and NFL) that need to be replicated in large cohorts. Subclinical neurotoxicity may be observed in patients with HAND and warrants prospective studies.

Beyond the Syndemic of Opioid Use Disorders and HIV: The Impact of Opioids on Viral Reservoirs.

People with HIV are more likely to have opioid use disorder and to be prescribed opioids for chronic pain than the general population; however, the effects of opioids on the immune system and HIV persistence have not been fully elucidated. Opioids may affect HIV reservoirs during their establishment, maintenance, and reactivation by enhancing HIV infectivity and replication due to upregulation of co-receptors and impairment of innate antiviral responses. Opioids may also modulate immune cell functioning and microbial translocation and can reverse viral latency. In this review, we summarize the current findings for and against the modulating effects of opioids on HIV cellular and anatomical reservoirs, highlighting the current limitations that affect in vitro, ex vivo, and in vivo studies in the field. We propose further research targets and potential strategies to approach this topic.

Real-Life Experience on Dolutegravir and Lamivudine as Initial or Switch Therapy in a Silver Population Living with HIV.

BACKGROUND: Clinical trials and real-life studies have granted the efficacy and safety of dolutegravir and lamivudine (DTG/3TC) in naïve and experienced people living with HIV (PLWH), but there are no long-term data in elderly people. We herein describe our real-life cohort of PLWH who were ≥65 years of age (PLWH ≥ 65) who started or were switched to DTG/3TC, single-tablet regimen, or DTG plus 3TC. METHODS: We considered laboratory/clinical parameter changes from the baseline to the last follow-up time point available for each person by the paired Wilcoxon test and analyzed factors associated with virological failure (VF) and discontinuation. RESULTS: We included 112 PLWH with a median age of 66 (IQR: 65-70) years, 77.6% males; 84.8% of people had multimorbidity, 34.8% were on polypharmacy, and only 5.4% were naïve to treatment. Reasons to be switched to DTG/3TC were: abacavir removal (38.7%), treatment simplification (33.1%), and PI discontinuation (28.2%). The median treatment durability was 6 (IQR: 5.4-7) years. No significant changes were detected in metabolic, renal, immunological, or cardiovascular biomarkers during follow-up. HIV RNA undetectability was maintained in 104 (92.8%) individuals for whom follow-up evaluation was available. We observed eight discontinuations (two deaths, two VFs, two early intolerances, one significant weight gain, and one switch to long-acting therapy). No factors were significantly associated with VF or discontinuation. CONCLUSIONS: This is the first study on DTG/3TC in PLWH ≥ 65 with a follow-up longer than 5 years. DTG/3TC was found to be safe and effective, neutral on metabolic parameters, and with a low discontinuation rate for toxicity or VF.

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.

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.