Optimizing the antiretroviral treatment focusing on long-term effectiveness and a person-centered approach. Consensus Guidance Using a Delphi Process.

Definitive data on the long-term success of the latest antiretroviral therapy (ART) strategies are still lacking. A panel of infectious diseases specialists was convened to develop a consensus on how to tailor and follow ART over time. Panelists used a Delphi technique to develop a list of statements describing preferred management approaches for ART and patient monitoring and quality of life evaluation. Ninety infectious diseases specialists from several Infectious Diseases Centers in Italy participated in the consensus process. A consensus was reached on virological and immunological parameters to use to monitor long-term efficacy of antiretroviral treatment, while there was no consensus on the use of specific inflammation and immune-activation markers in clinical routine. The panel agreed on the need for an antiretroviral treatment with the lowest impact on bone, kidney and cardiovascular toxicity and on the utility of quality-of-life monitoring during the standard follow up of people living with HIV. The consensus statements developed by a panel of infectious diseases specialists may provide guidance to practitioners for a person-centered approach aimed at obtaining long-term virological and clinical success for people living with HIV.

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.

The presence of resistance-associated mutations in reverse transcriptase gene is associated with cerebrospinal fluid HIV-1 escape: A multicentric retrospective analysis.

Higher risk of cerebrospinal fluid escape (CVE) has been associated with the use of specific antiretroviral (ARV) classes, such as protease inhibitors. We assessed whether archived resistance-associated mutations (RAMs) can mediate this relationship by identifying patients treated with incompletely active antiretroviral regimens. A retrospective multicentric study on 282 adult people with HIV on antiretroviral therapy (ART) and available historical plasma genotype resistance testing (HGRT) for reverse transcriptase (RT) and protease genes between 2001 and 2021. The odds ratio for demographic, clinic-, and ART-related variables and CVE was estimated by multivariable modeling. HGRT-adjusted central nervous system effectiveness penetration (CPE) score was computed in modeling the risk. Median age, plasma VL, and CD4 count were 49 years, <50 copies/mL, and 310 cells/µL. CVE was detected in 51 participants (17.0%). No difference in CVE prevalence was observed according to ART type, number of ARVs or ARV classes. Participants with CVE had more frequently plasma (52.9% vs. 32.1%, p = 0.005) and CSF RAMs in RT (n = 63, 57.1% vs. 28.6%, p = 0.029), but not in protease gene. The presence of plasma RAMs in RT associated with increased odds of CVE in adjusted analyses (aOR 3.9, p < 0.001) and in models restricted to plasma viral load ≤50 copies/mL (n = 202; aOR 4.3, p = 0.003). CVE risk decreased by 40% per each point increase in HGRT-adjusted CPE score in multivariable models (p < 0.001). Rather than the type of ARV classes or of ART regimens, functional mono or dual regimens caused by the presence of RAMs affecting ART components may explain the majority of cases of CVE.

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.

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.

Screening Accuracy of Mini Addenbrooke's Cognitive Examination Test for HIV-Associated Neurocognitive Disorders in People Ageing with HIV.

Aging and increased cardiovascular risk are major drivers for HIV-associated neurocognitive disorders (HAND), for which accurate screenings are lacking. Mini-Addenbrooke's Cognitive Examination (MACE) reliably detects vascular and neurodegenerative cognitive decline among HIV-negative patients. We evaluated MACE diagnostic accuracy in detecting HAND in people living with HIV (PLWH) and we compared it with the International HIV Dementia Scale (IHDS). A single-centre double-blind study of diagnostic accuracy on adult outpatient PLWH without neurocognitive confounding was performed. MACE and IHDS were administered in 5 and 10 min by clinicians, followed by the reference standard battery (14 tests) by neuropsychologists. HAND diagnosis was based on the modified version of Frascati's criteria by Gisslén to reduce false positives. Exploratory cut-offs were evaluated for MACE. Diagnostic accuracy and clinical utility parameters were assessed. 231 patients were enrolled. 75.7% men with a median age, education, and length of infection of 54 (48-59), 10 (8-13) and 16 (5-25) years. HAND prevalence was 48.5% (38.9% asymptomatic impairment). Compared to IHDS, MACE sensitivity (89.3% vs 70.5%), specificity (94.1% vs 63.0%), correct classification rate (86.5% vs 66.7%), J index (0.83 vs 0.34), AUROC (0.97 vs 0.79), agreement with the gold standard (k 0.84 vs 0.33) and effect size in distinguishing HAND vs non-HAND (d 2.11 vs 1.15) were higher. Among PLWH aged 65 years and above (n = 37) MACE performance was consistently better than IHDS. The quick and easy-to-perform MACE could possess an accurate and useful screening performance for HAND in otherwise neurocognitively healthy cohorts of PLWH.

Efficacy of tiapride in the treatment of psychiatric disorders: A systematic review.

BACKGROUND: Tiapride is an atypical antipsychotic used to treat alcohol withdrawal, aggressiveness and agitation, headache, dyskinesias, tic and Tourette's disorder. More recently, it has been proposed for the treatment of delirium and agitation in hospitalised patients with COVID-19. Although its safety profile makes it suitable for use in vulnerable populations, the use of tiapride for psychiatric disorders is limited. This work aims to systematically review the available evidence on the efficacy and tolerability of tiapride in individuals with a psychiatric disorder. METHODS: We searched PubMed, Embase, PsycINFO, GreyLit, OpenGrey, and ProQuest up to March 2020 for randomised controlled trials focussing on the use of tiapride in the treatment of individuals with a psychiatric disorder (e.g., mood disorder, schizophrenia spectrum, substance use disorder). The Risk of Bias 2 was performed for the quality assessment of the included studies. RESULTS: We identified 579 records. Of them, six studies (published between 1982 and 2010) were included in the review. Four studies referred to alcohol withdrawal, and two to the management of agitation in elderly patients with dementia. None of the studies reported significant differences between tiapride and other active comparators in terms of efficacy and tolerability. The overall risk of bias was moderate to high. CONCLUSION: Tiapride may be considered as a relatively safe treatment option for selected patients with alcohol withdrawal or agitation in dementia. However, solid evidence of its efficacy in the scientific literature is lacking. High-quality trials remain necessary to fully sustain its use in clinical practice.

Real-life Evidence of Lower Lung Virulence in COVID-19 Inpatients Infected with SARS-CoV-2 Omicron Variant Compared to Wild-Type and Delta SARS-CoV-2 Pneumonia.

In vitro and animal models described lower replication capacity and virulence of SARS-CoV-2 Omicron lineage in lower respiratory airways compared to wild type and other variants of concern (oVOCs). Among adult subjects admitted to our hospital (Turin, Italy) due to wild type, oVOCs, and Omicron SARS-CoV-2-related pneumonia (n = 100 for each lineage), the cases of Omicron pneumonia showed lower degree of lung parenchyma involvement (aß -1.471, p = 0.037), less tendency to parenchyma consolidation (aOR 0.500, p = 0.011), and better respiratory functions (assessed by ambient air arterial blood gas analysis). After adjusting for demographic, previous immunity, and comorbidities, Omicron pneumonia still associated with lower risk of respiratory failure (for severe respiratory failure, Wild-type versus Omicron aOR 15.6, p = 0.005 and oVOCs versus Omicron aOR 31.7, p < 0.001). These observations are in line with preliminary findings from in vitro and animal models and could explain why Omicron infection has been associated with lower mortality and hospitalization in human.

Risk for SARS-CoV-2 Infection in Healthcare Workers, Turin, Italy.

We measured severe acute respiratory syndrome coronavirus 2 spike protein subunits S1/S2 antibodies by using capillary electrophoresis and a chemiluminescence immunoassay for 5,444 active healthcare workers in Italy. Seroprevalence was 6.9% and higher among participants having contact with patients. Seroconversion was not observed in 37/213 previously infected participants.

Low Tenofovir Plasma Exposure in HIV Oral Pre-exposure Prophylaxis Recipients with Gastrointestinal Disorders.

Four pre-exposure prophylaxis (PrEP) users with gastro-intestinal disorders (sleeve gastrectomy, terminal ileitis, celiac disease or chronic diarrhea) and receiving oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) were included. Despite a self-reported high adherence, trough plasma tenofovir concentrations (after a supervised intake) were significantly lower than those observed in PrEP recipients without gastrointestinal disorders [21 (±9.1) vs. 138 (±85) ng/mL]. PrEP users with gastrointestinal disorders may need increased TDF doses or alternative prophylactic measures.

Spinning pupil aberration measurement for anisoplanatic deconvolution.

The aberrations in an optical microscope are commonly measured and corrected at one location in the field of view, within the so-called isoplanatic patch. Full-field correction is desirable for high-resolution imaging of large specimens. Here we present, to the best of our knowledge, a novel wavefront detector, based on pupil sampling with subapertures, measuring the aberrated wavefront phase at each position of the specimen. Based on this measurement, we propose a region-wise deconvolution that provides an anisoplanatic reconstruction of the sample image. Our results indicate that the measurement and correction of the aberrations can be performed in a wide-field fluorescence microscope over its entire field of view.

Medication burden and clustering in people living with HIV undergoing therapeutic drug monitoring.

AIM: People living with HIV (PLWH) have a high burden of comorbidities and concomitant medication use. The aim of this study was to analyse the prevalence, predictors and patterns of polypharmacy (PP) in a large therapeutic drug monitoring (TDM) registry. METHODS: We searched our TDM registry and categorized co-medications into 26 drug classes. We included patients with at least one medication recorded: PP and severe polypharmacy (sPP) were defined as the concomitant use of ≥5 or ≥10 nonantiretroviral/nonantitubercular drugs. Multivariable binary logistic analysis were conducted for identifying PP/sPP predictors. A hierarchical average-linkage cluster analysis was performed among drug classes. RESULTS: We included 2432 participants (1158 PLWH) aged 49.6 years (± 14.4) in the 2016-2020 period. A higher number of concomitant medications (4 vs 3.1, P < .001) and a higher prevalence of PP (26.1% vs 21.8%, P = .015) were recorded in controls. At multivariable binary logistic analysis older age, female gender and HIV-positive serostatus (P = .015) were independent predictors of PP; older age and year of inclusion were independent predictors of sPP. Cluster analysis showed that patients receiving oral drug for type 2 diabetes have a high probability of receiving several other drugs; a cluster of co-medications was observed with opioids, diuretics and central nervous system-affecting drugs. CONCLUSION: We observed a moderately high prevalence of polypharmacy in middle-aged PLWH: advanced age and female gender were associated with the greatest prevalence. The observation of co-medication clusters suggests groups of comorbidities but also identifies groups of patients at risk of similar drug-to-drug interactions.

Efficacy of amisulpride for depressive symptoms in individuals with mental disorders: A systematic review and meta-analysis.

BACKGROUND: Depressive symptoms occur in several psychiatric disorders, often in the absence of a formal diagnosis of depression. We aimed to evaluate the efficacy and the tolerability of amisulpride, both alone and as augmentation therapy, in the treatment of depressive symptoms in individuals with any major psychiatric disorder. METHODS: We searched PubMed, Embase, PsycINFO, GreyLit, OpenGrey and ProQuest up to March 2020 for randomised controlled trials focussing on the treatment of an acute depressive episode in any major psychiatric disorder. A random-effect meta-analysis was performed to synthesize the findings on depressive symptoms (primary outcome), response rate and tolerability. RESULTS: We retrieved 11 studies including 2065 patients with a diagnosis of dysthymia (eight studies), major depression (one study) or schizophrenia (two studies). Amisulpride 50 mg/day was associated with a larger reduction of depressive symptoms compared to placebo (standardised mean difference [SMD] = -0.70, CI 95% -0.92, -0.49; I2  = 0.0%), and was found to be comparable to selective serotonin reuptake inhibitors (SSRIs; SMD = -0.08, CI 95% -0.23, 0.06, I2  = 0.0%), amineptine, imipramine and amitriptyline in the treatment of dysthymia (three studies, not pooled). In individuals with schizophrenia, amisulpride administered at higher doses (>400 mg/day) was comparable to olanzapine and risperidone (two studies, not pooled). In terms of tolerability, amisulpride was superior to placebo for dysthymia (odds ratio [OR] = 3.94, CI 95% 1.07, 14.48; I2  = 0.0) and comparable with SSRIs (OR = 0.94, CI 95% 0.55, 1.62; I2  = 0.0%). CONCLUSION: Treatment with amisulpride could be a valid choice for selected individuals with dysthymia or depressive symptoms in the context of schizophrenia. More studies on the efficacy and tolerability of amisulpride are needed to draw firm conclusions on its potential benefits in other psychiatric disorders.

Population pharmacokinetics and pharmacogenetics of ritonavir-boosted darunavir in the presence of raltegravir or tenofovir disoproxil fumarate/emtricitabine in HIV-infected adults and the relationship with virological response: a sub-study of the NEAT001/ANRS143 randomized trial.

OBJECTIVES: NEAT001/ANRS143 demonstrated non-inferiority of once-daily darunavir/ritonavir (800/100 mg) + twice-daily raltegravir (400 mg) versus darunavir/ritonavir + tenofovir disoproxil fumarate/emtricitabine (245/200 mg once daily) in treatment-naive patients. We investigated the population pharmacokinetics of darunavir, ritonavir, tenofovir and emtricitabine and relationships with demographics, genetic polymorphisms and virological failure. METHODS: Non-linear mixed-effects models (NONMEM v. 7.3) were applied to determine pharmacokinetic parameters and assess demographic covariates and relationships with SNPs (SLCO3A1, SLCO1B1, NR1I2, NR1I3, CYP3A5*3, CYP3A4*22, ABCC2, ABCC10, ABCG2 and SCL47A1). The relationship between model-predicted darunavir AUC0-24 and C24 with time to virological failure was evaluated by Cox regression. RESULTS: Of 805 enrolled, 716, 720, 347 and 361 were included in the darunavir, ritonavir, tenofovir and emtricitabine models, respectively (11% female, 83% Caucasian). No significant effect of patient demographics or SNPs was observed for darunavir or tenofovir apparent oral clearance (CL/F); coadministration of raltegravir did not influence darunavir or ritonavir CL/F. Ritonavir CL/F decreased by 23% in NR1I2 63396C>T carriers and emtricitabine CL/F was linearly associated with creatinine clearance (P<0.001). No significant relationship was demonstrated between darunavir AUC0-24 or C24 and time to virological failure [HR (95% CI): 2.28 (0.53-9.80), P=0.269; and 1.82 (0.61-5.41), P=0.279, respectively]. CONCLUSIONS: Darunavir concentrations were unaltered in the presence of raltegravir and not associated with virological failure. Polymorphisms investigated had little impact on study-drug pharmacokinetics. Darunavir/ritonavir + raltegravir may be an appropriate option for patients experiencing NRTI-associated toxicity.

Pharmacogenetic determinants of kidney-associated urinary and serum abnormalities in antiretroviral-treated HIV-positive patients.

Tenofovir disoproxyl fumarate (TDF) has been associated with renal tubular abnormalities, phosphaturia and proteinuria (retinol binding protein, RBP, loss): vitamin D (VD) and PTH affect these markers. Aim was to understand if some single nucleotide polymorphisms (SNPs) were predictors of renal abnormalities in an Italian cohort of HIV-affected patients. DNA was analyzed through real-time PCR, urinary RBP corrected by creatinine (uRBP/Cr). The majority of patients received TDF. Abnormal uRBP/Cr was more frequent in TDF recipients: eGFR <90 mL/min and TDF were predictors in the whole cohort, whereas eGFR <90 mL/min, TDF concentrations and CYP24A1-3999TT in TDF-treated patients. Phosphate levels were higher low VD level patients: age <50 years, CYP27B1 + 2838CC genotype and non-European ancestry were predictors. PTH levels were border-line higher in TDF patients: non-European ancestry, females, TDF, VD levels < 30 ng/mL and SLC28A2-124CT/TT and ABCC2-24CC were predictors. For the first time, SNPs were associated with PTH, phosphate, calcium and tubular dysfunction in HIV-infected patients.

A review of the potential mechanisms of neuronal toxicity associated with antiretroviral drugs.

Highly active antiretroviral treatment has led to unprecedented efficacy and tolerability in people living with HIV. This effect was also observed in the central nervous system with the nowadays uncommon observation of dementias; yet in more recent works milder forms are still reported in 20-30% of optimally treated individuals. The idea of a subclinical neuronal toxicity induced by antiretrovirals has been proposed and was somehow supported by the late-emerging effects associated with efavirenz use. In this manuscript we are reviewing all the potential mechanisms by which antiretroviral drugs have been associated with in vitro, ex vivo, or in vivo toxicity to cells pertaining to the central nervous system (neurons, astrocytes, oligodendrocytes, and endothelial cells). These include direct or indirect effects and pathological pathways such as amyloid deposition, damage to small cerebral vessels, and impairment in neurotransmission. The aim of this review is therefore to provide a detailed description of the available literature in order to guide further clinical research for improving patients' neurocognition and quality of life.

Pilot prospective open, single-arm multicentre study on off-label use of tocilizumab in patients with severe COVID-19.

OBJECTIVES: No agent has yet been proven to be effective for the treatment of patients with severe COVID-19. METHODS: We conducted a pilot prospective open, single-arm multicentre study on off-label use of tocilizumab (TCZ) involving 63 hospitalised adult patients (56 males, age 62.6±12.5) with severe COVID-19. Clinical and laboratory parameters were prospectively collected at baseline, day 1, 2, 7 and 14. No moderate-to-severe adverse events attributable to TCZ were recorded. RESULTS: We observed a significant improvement in the levels of ferritin, C-reactive protein, D-dimer. The ratio of the partial pressure of oxygen (Pa02) to the fraction of inspired oxygen (Fi02) improved (mean±SD Pa02/Fi02 at admission: 152±53; at day 7: 283.73±115.9, at day 14: 302.2±126, p<0.05). The overall mortality was 11%; D-dimer level at baseline, but not IL-6 levels were predictors of mortality. TCZ administration within 6 days from admission in the hospital was associated with an increased likelihood of survival (HR 2.2 95%CI 1.3-6.7, p<0.05). CONCLUSIONS: In hospitalised adult patients with severe COVID-19, TCZ could be a safe option. An improvement in respiratory and laboratory parameters was observed. Future controlled trials in patients with severe illness are urgently needed to confirm the definite benefit with IL-6 target therapy.

Efficient implementation of the Shack-Hartmann centroid extraction for edge computing.

Adaptive optics (AO) is an established technique to measure and compensate for optical aberrations. One of its key components is the wavefront sensor (WFS), which is typically a Shack-Hartmann sensor (SH) capturing an image related to the aberrated wavefront. We propose an efficient implementation of the SH-WFS centroid extraction algorithm, tailored for edge computing. In the edge-computing paradigm, the data are elaborated close to the source (i.e., at the edge) through low-power embedded architectures, in which CPU computing elements are combined with heterogeneous accelerators (e.g., GPUs, field-programmable gate arrays). Since the control loop latency must be minimized to compensate for the wavefront aberration temporal dynamics, we propose an optimized algorithm that takes advantage of the unified CPU/GPU memory of recent low-power embedded architectures. Experimental results show that the centroid extraction latency obtained over spot images up to 700×700 pixels wide is smaller than 2 ms. Therefore, our approach meets the temporal requirements of small- to medium-sized AO systems, which are equipped with deformable mirrors having tens of actuators.

Incidence and risk factors for liver enzyme elevation among naive HIV-1-infected patients receiving ART in the ICONA cohort.

OBJECTIVES: To evaluate the incidence and risk factors for liver enzyme elevations (LEE) in patients initiating first-line ART in the ICONA prospective observational cohort, between June 2009 and December 2017. PATIENTS AND METHODS: In total, 6575 ART-naive patients were selected, initiating two NRTIs with the third drug being a boosted PI (n=2436; 37.0%), an NNRTI (n=2384; 36.3%) or an integrase strand transfer inhibitor (INSTI) (n=1755; 26.7%). HBV surface antigen and HCV RNA were detected in 3.9% and 5.8% of the study population. Inverse probability weighted Cox regression analysis was used to calculate the HRs, according to first-line regimen, for LEE, defined as ALT or AST increases of ≥2.5× upper limit of normal (ULN) for patients with normal baseline values or ≥2.5× baseline for patients with higher baseline values. RESULTS: One hundred and eighty-three LEE occurred over 20722 patient-years of follow-up. After adjusting for the main confounders, the risk of LEE halved with INSTIs compared with NNRTIs (HR 0.46, 95% CI 0.25-0.86), with a significant reduction in the raltegravir group (HR 0.11, 95% CI 0.02-0.84 using the NNRTI class as reference). HRs for LEE were significantly higher in subjects with HBV or HCV coinfection, in patients with poorly controlled HIV infection and in those who acquired HIV through homosexual transmission. CONCLUSIONS: In our study, INSTI use almost halved the risk of LEE compared with other regimens. This finding could be particularly important for choosing ART in patients with risk factors for liver toxicity such as HCV and HBV coinfections.

The "milky way" galaxy of HIV-related central nervous system immune reaction syndromes.

The landscape of central nervous system HIV infection is rapidly changing, leading to the recognition of a new constellation of overlapping syndromes and to a better insight for the elder ones. Among these, progressive multifocal leukoencephalopathy (PML) still poses several diagnostic and therapeutic challenges; nevertheless, recent developments in understanding PML in patients with multiple sclerosis may have benefitted HIV-positive patients suffering from PML too. We describe a peculiar case of PML-immune reconstitution inflammatory syndrome (IRIS) presenting a punctate pattern with "milky way" appearance on magnetic resonance imaging. Despite the fact that brain imaging and histopathology remain the mainstays for extricating through the expanding galaxy of HIV-related central nervous system dysimmune syndromes and although punctate pattern has been already well acknowledged as a suggestive finding of PML among patients on natalizumab, this radiological presentation is still poorly recognised in AIDS-related PML cases, leading to possible life-threatening diagnostic delays. This is also the first report about intravenous immunoglobulin treatment in AIDS-related PML-IRIS; the favourable clinical and radiological outcome of our case and the preliminary administrations of intravenous immunoglobulins in natalizumab-associated PML-IRIS from literature support probable benefits also among HIV-positive patients.