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Objectives: To investigate whether efavirenz (EFV) or 8-hydroxy-EFV (8-OH-EFV) plasma levels are associated with neurocognitive impairment and central nervous system (CNS) side effects. Methods: We conducted a cross-sectional analysis to explore the potential links between EFV/8-OH-EFV levels and cognitive performance or CNS-related side effects in patients screened within a randomized trial involving a switch from EFV to rilpivirine. The Mann–Whitney test was employed to compare drug levels in patients with or without cognitive impairment, depression, anxiety, sleep disorder or CNS symptoms. Additionally, Spearman's test was used to assess correlations between drug levels and test scores. Results: Among 104 patients, neither EFV nor 8-OH-EFV levels were linked to cognitive impairment, although trends towards higher EFV levels were observed in those with impaired executive function (p = 0.055) and language performances (p = 0.021). On the other hand, elevated 8-OH-EFV levels, but not EFV levels, were associated with more CNS side effects (222 vs. 151 ng/mL, p = 0.027), depressive symptoms (247 vs. 164 ng/mL, p = 0.067) and sleep impairment (247 vs. 164 ng/mL, p = 0.078). Consistently, a trend towards a correlation between EFV levels and lower z-scores in executive function and motor function was observed, while 8-OH-EFV levels, but not EFV levels, were directly correlated with symptom scores. Conclusions: Higher levels of 8-OH-EFV were associated with CNS side effects, while EFV levels were only marginally associated with cognitive performance, thus suggesting that EFV and its metabolite may act differently in determining detrimental neurological effects.

Objectives: To assess the effectiveness of bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) among people poorly represented in clinical trials and potentially at higher risk of suboptimal response to ART. Methods: Observational cohort study on persons with HIV (PWH) enrolled in ICONA who started BIC/FTC/TAF as initial therapy or as switching regimen while virologically suppressed. Primary endpoint was time to treatment failure (TF): new AIDS/death or virological failure (VF) or discontinuation for toxicity/failure. Secondary endpoints were time to treatment discontinuation for toxicity (TDT) and to VF. Groups of interest were those aged >50 years, female sex, and advanced HIV disease at first ART start. Probability of the events overall and according to groups and adjusted HR for every endpoint were calculated by Kaplan–Meier curves and Cox regression models. Results: Nine hundred and thirty-three ART-naive and 1655 ART-experienced PWH initiated BIC/FTC/TAF. Over a median follow-up of 69.8 weeks, 89 (9.6%) PWH at their first regimen experienced TF. PWH aged >50 years had 1.83-fold (95% CI: 1.19–2.83) higher risk of TF; PWH with advanced HIV disease had 2.21-fold (95% CI: 1.53–3.82) higher risk; there were no differences in TF according to sex. Over a median follow-up of 146.3 weeks, 109 (6.6%) out of 1655 switching PWH experienced TF; no differences were found in the risk of TF, TDT and VF according to groups of interest. Conclusions: Overall, BIC/FTC/TAF is well tolerated and virologically effective in the real-world scenario for ART-naive and -experienced PWH. Older ART-naive PWH and those with advanced HIV disease may respond less well as the burden of diseases might compromise treatment efficacy.

Objective: Delirium is a common feature in COVID-19 patients. Although its association with in-hospital mortality has previously been reported, data concerning postdischarge mortality and delirium subtypes are scarce. We evaluated the association between delirium and its subtypes and both in-hospital and postdischarge mortality. Methods: This multicenter longitudinal clinical-based study was conducted in Monza and Brescia, Italy. The study population included 1,324 patients (median age: 68 years) with COVID-19 admitted to 4 acute clinical wards in northern Italy during the first pandemic waves (February 2020 to January 2021). Delirium within 48 hours of hospital admission was assessed through validated scores and/or clinically according to DSM-5 criteria. The association of delirium—and its subtypes—with in-hospital and postdischarge mortality (over a median observation period of 257 [interquartile range: 189–410] days) was evaluated through Cox proportional hazards models. Results: The 223 patients (16.8%) presenting delirium had around 2-fold increased in-hospital (hazard ratio [HR] = 1.94; 95% CI, 1.38–2.73) and postdischarge (HR = 2.01; 95% CI, 1.48–2.73) mortality than those without delirium. All delirium subtypes were associated with greater risk of death compared to the absence of delirium, but hypoactive delirium revealed the strongest associations with both in-hospital (HR=2.03; 95% CI, 1.32–3.13) and postdischarge (HR=2.22; 95% CI, 1.52–3.26) mortality. Conclusions: In patients with COVID-19, early onset delirium is associated not only with in-hospital mortality but also with shorter postdischarge survival. This suggests that delirium detection and management are crucial to improving the prognosis of COVID-19 patients.

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.

Background: Electronic health databases are used to identify people at risk of poor outcomes. Using electronic regional health databases (e-RHD), we aimed to develop and validate a frailty index (FI), compare it with a clinically based FI, and assess its association with health outcomes in community-dwellers with SARS-CoV-2. Methods: Data retrieved from the Lombardy e-RHD were used to develop a 40-item FI (e-RHD-FI) in adults (i.e., aged ≥18 years) with a positive nasopharyngeal swab polymerase chain reaction test for SARS-CoV-2 by May 20, 2021. The considered deficits referred to the health status before SARS-CoV-2. The e-RHD-FI was validated against a clinically based FI (c-FI) obtained from a cohort of people hospitalized with COVID-19 and in-hospital mortality was evaluated. e-RHD-FI performance was evaluated to predict 30-day mortality, hospitalization, and 60-day COVID-19 WHO clinical progression scale, in Regional Health System beneficiaries with SARS-CoV-2. Results: We calculated the e-RHD-FI in 689,197 adults (51.9% females, median age 52 years). On the clinical cohort, e-RHD-FI correlated with c-FI and was significantly associated with in-hospital mortality. In a multivariable Cox model, adjusted for confounders, each 0.1-point increment of e-RHD-FI was associated with increased 30-day mortality (Hazard Ratio, HR 1.45, 99% Confidence Intervals, CI: 1.42–1.47), 30-day hospitalization (HR per 0.1-point increment = 1.47, 99%CI: 1.46–1.49), and WHO clinical progression scale (Odds Ratio = 1.84 of deteriorating by one category, 99%CI 1.80–1.87). Conclusion: The e-RHD-FI can predict 30-day mortality, 30-day hospitalization, and WHO clinical progression scale in a large population of community-dwellers with SARS-CoV-2 test positivity. Our findings support the need to assess frailty with e-RHD.

BacKGrOUnd: Older people hospitalized for cOvid-19 are at highest risk of death. Frailty assessment can detect heterogeneity in risk among people of the same chronological age. We investigated the association between frailty and in-hospital and medium-term mortality in middle-aged and older adults with COVID-19 during the first two pandemic waves. meTHOdS: This study is an observational multicenter study. We recorded sociodemographic factors (age, sex), smoking status, date of symp-tom onset, biological data, need for supplemental oxygen, comorbidities, cognitive and functional status, in-hospital mortality. We calculated a Frailty Index (FI) as the ratio between deficits presented and total deficits considered for each patient (theoretical range 0-1). We also assessed the clinical Frailty Scale (cFS). mortality at follow-up was ascertained from a regional registry. reSULTS: in total, 1344 patients were included; median age 68 years (Q1-Q3, 56-79); 857 (64%) were men. median cFS score was 3 (Q1-Q3 2-5) and was lower in younger vs. older patients. median Fi was 0.06 (Q1-Q3 0.03-0.09) and increased with increasing age. Overall, 244 (18%) patients died in-hospital and 288 (22%) over a median follow-up of 253 days. FI and CFS were significantly associated with risk of death. In two different models using the same covariates, each increment of 0.1 in Fi increased the overall hazard of death by 35% (Hr=1.35, 95%ci 1.23-1.48), similar to the hazard for each increment of cFS (Hr=1.37, 95%ci 1.25-1.50). cOncLUSiOnS: Frailty, assessed with the Fi or cFS, predicts in-hospital and medium-term mortality and may help estimate vulnerability in middle-aged and older cOvid-19 patients.

In patients with COVID-19, frailty has been shown to better predict outcomes than age alone. We investigated factors associated with mechanical ventilation (MV) during hospitalization for COVID-19 among older adults in a multicentre study during the first two waves in Italy. Using data from the FRACOVID project, we included consecutive patients admitted to the participating centres during the first and second waves. We recorded sociodemographics, comorbidities, time since symptom onset, ventilatory support at admission, and chest X-ray findings. Frailty was assessed using a frailty index (FI). Results are reported as hazard ratios (HR) with 95%CI. 1,344 patients were included; 487 females (36.2%), median age 68 (56; 79) years; 52.4% had hypertension, 10.6% had chronic obstructive pulmonary disease, 15.2% were obese. Median FI was 0.088 (0.03, 0.20), and 67% had bilateral consolidations at admission. Median time since symptom onset was 7 days (4, 10). During hospitalization, 47 patients (3.6%, 95%CI 0.33-13.6%) received MV. Multivariable Cox regression analysis found that the likelihood of intubation decreased with increasing age (HR 0.945 (95%CI 0.921-0.969), p[removed]110bpm (HR 3.429 (95%CI 1.583-7.429), p=0.0018), and need for continuous positive airway pressure (CPAP) at admission (HR 2.626 (95%CI 1.330-5.186), p=0.0054) were significantly associated with a greater likelihood of intubation. Older patients are less likely to receive intubation, while those with heart rate >110 bpm and need for CPAP at admission are more likely to receive MV during hospitalization for COVID-19.

Objectives: We investigated the association between persistent low-level viraemia, measured as viraemia copy-years (VCY), and all-cause mortality. Methods: We included 3271 HIV-infected patients who initiated their first combined ART (cART) during 1998- 2012 enrolled in the multicentre Italian MASTER cohort. VCY was defined as the area under the curve of plasma viral load (pVL) and expressed in log10 copies.years/mL. VCY was evaluated from cART initiation until the end of follow-up [VCY-overall (VCY-o)], and stratified into before [VCY-early (VCY-e)] and after [VCY-late (VCY-l)] the eighth month from starting cART, and as the ratio of VCY-l to follow-up duration (VCY-l/FUD). Results: The risk of death increased of about 40% for higher than the median levels of VCY-o and VCY-e. Compared with subjects with permanently suppressed pVL after the eighth month from starting cART, mortality increased by 70% for those with VCY-l =≥3 log10 copies.years/mL, and by about 20-fold for those with VCY-l/FUD =≥2.3 log10 copies/mL. Patients who maintained low levels of VCY-l (<,3 log10 copies.years/mL) or VCY-l/FUD (<,2.3 log10 copies/mL) had a risk of death similar to patients with permanently suppressed pVL. CD4 cell count at baseline was predictive of high risk of death only in subjects with VCY-l =≥3 log10 copies.years/mL. Conclusions: The risk of death did not increase in HIV-infected patients with low levels of VCY-l compared with patients with permanent virological suppression.

The Italian MASTER (MAnagement Standardizzato di TErapia antiRetrovirale, standardized management of antiretroviral therapy) cohort is a hospital-based multicentre, open, dynamic HIV cohort established in the mid 1990s, with retrospective patient enrolment from 1986 to 1997 and subsequent prospective recruitment. At that time, no institutional system of surveillance of HIV infection was available, apart from the registration of AIDS cases. Accurate, precise and up-to-date data on HIV infection were therefore needed. To this end, we established a network of various HIV infection treatment centres in Italy, using a common clinical chart and an electronic database for data collection and management. The MASTER cohort enrols all HIV-infected patients, both treatment naïve and treatment experienced, in care at several HIV clinics throughout the country in order to represent the epidemiological and clinical scenario of HIV infection in Italy. A Steering Committee guarantees the scientific accuracy of the cohort. The Committee is made up of members from each centre and controls data quality by verifying the completeness, accuracy and updating of data collected by each centre. Furthermore, a working group proposes new studies, carries them out, analyses and discusses the findings and writes the final papers, under the supervision of the Steering Committee. The committee also verifies the consistency of the final paper with the initial proposal before its submission to a journal for publication. In performing these activities, the working group is supported by a data manager, a statistician and an epidemiologist. The main objectives of this cohort study are: (i) to create a hospital-based database of HIV-positive subjects for clinical and epidemiological research projects; (ii) to monitor the epidemiological pattern of HIV infection in Italy; (iii) to monitor highly active antiretroviral therapy (HAART) effectiveness and safety, and HIV drug resistance emergence; (iv) to in

We report interim 24-weeks efficacy data of ATLAS-M trial, a phase IV, multicentre, open-label, randomized study designed to show 48-weeks, non-inferior efficacy (margin of -12%) of treatment simplification to atazanavir/ritonavir (ATV/r)+lamivudine (3TC) versus maintaining 3-drugs ATV/r-based cART.

Background: Tat is a key HIV-1 virulence factor, which plays pivotal roles in virus gene expression, replication, transmission and disease progression. After release, extracellular Tat accumulates in tissues and exerts effects on both the virus and the immune system, promoting immune activation and virus spreading while disabling the host immune defense. In particular, Tat binds Env spikes on virus particles forming a virus entry complex, which favors infection of dendritic cells and efficient transmission to T cells via RGD-binding integrins. Tat also shields the CCR5-binding sites of Env rendering ineffective virus neutralization by anti-Env antibodies (Abs). This is reversed by the anti-Tat Abs present in natural infection or induced by vaccination.Findings: Here we present the results of a cohort study, showing that the presence of anti-Tat Abs in asymptomatic and treatment-naïve HIV-infected subjects is associated with containment of CD4+ T-cell loss and viral load and with a delay of disease progression. In fact, no subjects with high anti-Tat Ab titers initiated antiretroviral therapy during the three years of follow-up. In contrast, no significant effects were seen for anti-Env and anti-Gag Abs. The increase of anti-Env Ab titers was associated with a reduced risk of starting therapy only in the presence of anti-Tat Abs, suggesting an effect of combined anti-Tat and anti-Env Abs on the Tat/Env virus entry complex and on virus neutralization.Conclusions: Anti-Tat immunity may help delay HIV disease progression, thus, targeting Tat may offer a novel therapeutic intervention to postpone antiretroviral treatment or to increase its efficacy. © 2014 Bellino et al.; licensee BioMed Central Ltd

BACKGROUND: The aim of this study was to explore the effects of HCV co-infection on virological effectiveness and on CD4+ T-cell recovery in patients with an early and sustained virological response after HAART. METHODS: We performed a longitudinal analysis of 3,262 patients from the MASTER cohort, who started HAART from 2000 to 2008. Patients were stratified into 6 groups by HCV status and type of anchor class. The early virological outcome was the achievement of HIV RNA <500 copies/ml 4-8 months after HAART initiation. Time to virological response was also evaluated by Kaplan-Meier analysis. The main outcome measure of early immunological response was the achievement of CD4+ T-cell increase by [greater than or equal to]100/mm3 from baseline to month 4-8 in virological responder patients. Late immunological outcome was absolute variation of CD4+ T-cell count with respect to baseline up to month 24. Multivariable analysis (ANCOVA) investigated predictors for this outcome. RESULTS: The early virological response was higher in HCV Ab-negative than HCV Ab-positive patients prescribed PI/r (92.2% versus 88%; p = 0.01) or NNRTI (88.5% versus 84.7%; p = 0.06). HCV Ab-positive serostatus was a significant predictor of a delayed virological suppression independently from other variables, including types of anchor class. Reactivity for HCV antibodies was associated with a lower probability of obtaining [greater than or equal to]100/mm3 CD4+ increase within 8 months from HAART initiation in patients treated with PI/r (62.2% among HCV Ab-positive patients versus 70.9% among HCV Ab-negative patients; p = 0.003) and NNRTI (63.7% versus 74.7%; p < 0.001). Regarding late CD4+ increase, positive HCV Ab appeared to impair immune reconstitution in terms of absolute CD4+ T-cell count increase both in patients treated with PI/r (p = 0.013) and in those treated with NNRTI (p = 0.002). This was confirmed at a multivariable analysis up to 12 months of follow-up. CONCLUSION