Background Tocilizumab blocks pro-inflammatory activity of interleukin-6 (IL-6), involved in pathogenesis of pneumonia the most frequent cause of death in COVID-19 patients. Methods A multicenter, single-arm, hypothesis-driven trial was planned, according to a phase 2 design, to study the effect of tocilizumab on lethality rates at 14 and 30 days (co-primary endpoints, a priori expected rates being 20 and 35%, respectively). A further prospective cohort of patients, consecutively enrolled after the first cohort was accomplished, was used as a secondary validation dataset. The two cohorts were evaluated jointly in an exploratory multivariable logistic regression model to assess prognostic variables on survival. Results In the primary intention-to-treat (ITT) phase 2 population, 180/301 (59.8%) subjects received tocilizumab, and 67 deaths were observed overall. Lethality rates were equal to 18.4% (97.5% CI: 13.6–24.0, P = 0.52) and 22.4% (97.5% CI: 17.2–28.3, P < 0.001) at 14 and 30 days, respectively. Lethality rates were lower in the validation dataset, that included 920 patients. No signal of specific drug toxicity was reported. In the exploratory multivariable logistic regression analysis, older age and lower PaO2/FiO2 ratio negatively affected survival, while the concurrent use of steroids was associated with greater survival. A statistically significant interaction was found between tocilizumab and respiratory support, suggesting that tocilizumab might be more effective in patients not requiring mechanical respiratory support at baseline. Conclusions Tocilizumab reduced lethality rate at 30 days compared with null hypothesis, without significant toxicity. Possibly, this effect could be limited to patients not requiring mechanical respiratory support at baseline. Registration EudraCT (2020-001110-38); clinicaltrials.gov (NCT04317092).

The prevalence and factors associated with an increased risk of renal dysfunction in HIV-infected patients receiving or not receiving antiretroviral therapy (ART) have been poorly evaluated in observational settings. MethodsPatients in the ICONA Foundation cohort with at least two creatinine values available while still ART-naïve were enrolled in the study. A logistic regression analysis was performed to identify predictors of an estimated glomerular filtration rate (eGFR)o90 mL/min/1.73 m 2 at baseline. The incidence and predictors of a 420% reduction in eGFR from pre-combination ART (cART) levels (or a decrease from ! 90 to o90 mL/min/1.73 m 2 ) were evaluated by Poisson regression. ResultsA total of 1505 patients were included in the study; 363 (24%) had eGFRo90 mL/min/1.73 m 2 at baseline. Older patients [odds ratio (OR) 1.58 per 10 years older; Po0.00001], female patients (OR 2.41 vs. male patients; Po0.00001), those who had diabetes and/or hypertension (OR 2.36 vs. neither; Po0.03) and patients with higher baseline CD4 count (OR 1.06 per 100 cells/mL higher; Po0.03) showed a greater risk of eGFRo90 mL/min/1.73 m 2 . Ninety-six patients experienced an eGFR decrease of 420% from pre-cART levels (6.8 per 100 person-years). Older age [relative risk (RR) 1.41 per 10 years older; P 5 0.005], female gender (RR 2.25 vs. male; P 5 0.003) and current exposure to didanosine (ddI), tenofovir and protease inhibitors were the major determinants. ConclusionsWe observed a relatively high rate of mild renal dysfunction in the absence of ART. In addition to traditional risk factors such as older age and diabetes/hypertension, female gender and current use of ddI, tenofovir and protease inhibitors were associated with a greater risk of decreased renal function as measured by eGFR.Keywords: antiretroviral exposure, estimated glomerular filtration rate (eGFR), renal impairment [7][8][9][10][11], there are a number of other factors potentially influencing the onset of renal disorders through different mechanisms, whose prevalence may be different in an HIV-positive population compared with the general population. Indeed, patients' longer survival following the introduction of cART may be considered as an additional risk for renal dysfunction, as long-term toxic events associated with the prolonged used of ART have been observed (e.g. metabolic alterations, diabetes, hypertension and cardiovascular events) [12][13][14]. It has been hypothesized that antiretroviral medications may have a direct effect in increasing the risk of renal dysfunction, and a variety of cART-related effects, including proteinuria, renal tubular damage, interstitial nephritis and overall declines in glomerular filtration rates, have been noted [15][16][17][18][19][20][21][22][23].The potential role of tenofovir in renal toxicity is a current clinical research question. As a consequence of its tolerability, convenient dosing and efficacy, this nucleoside reverse transcriptase inhibitor (NRTI) has been widely used as a component of cART regimens. There are...

ObjectivesMicrobial translocation (MT) through the gut accounts for immune activation and CD4+ loss in HIV and may influence HCV disease progression in HIV/HCV co-infection. We asked whether increased MT and immune activation may hamper anti-HCV response in HIV/HCV patients.Methods98 HIV/HCV patients who received pegylated-alpha-interferon (peg-INF-alpha)/ribavirin were retrospectively analyzed. Baseline MT (lipopolysaccharide, LPS), host response to MT (sCD14), CD38+HLA-DR+CD4+/CD8+, HCV genotype, severity of liver disease were assessed according to Early Virological Response (EVR: HCV-RNA <50 IU/mL at week 12 of therapy or ≥2 log10 reduction from baseline after 12 weeks of therapy) and Sustained Virological Response (SVR: HCV-RNA <50 IU/mL 24 weeks after end of therapy). Mann-Whitney/Chi-square test and Pearson's correlation were used. Multivariable regression was performed to determine factors associated with EVR/SVR.Results71 patients displayed EVR; 41 SVR. Patients with HCV genotypes 1–4 and cirrhosis presented a trend to higher sCD14, compared to patients with genotypes 2–3 (p = 0.053) and no cirrhosis (p = 0.052). EVR and SVR patients showed lower levels of circulating sCD14 (p = 0.0001, p = 0.026, respectively), but similar T-cell activation compared to Non-EVR (Null Responders, NR) and Non-SVR (N-SVR) subjects. sCD14 resulted the main predictive factor of EVR (0.145 for each sCD14 unit more, 95%CI 0.031–0.688, p = 0.015). SVR was associated only with HCV genotypes 2–3 (AOR 0.022 for genotypes 1–4 vs 2–3, 95%CI 0.001–0.469, p = 0.014).ConclusionsIn HIV/HCV patients sCD14 correlates with the severity of liver disease and predicts early response to peg-INF-alpha/ribavirin, suggesting MT-driven immune activation as pathway of HIV/HCV co-infection and response to therapy.

Increased occurrence of sexual dysfunction (SD) among patients treated with highly active antiretroviral therapy (HAART) has been reported. To assess prevalence of self-reported SD and to identify factors related to this alteration with special focus to its relationship with adherence behavior, we conducted an intercohort analysis among HIV-infected persons treated with HAART. In an anonymous questionnaire investigating HAART nonadherence, patients were asked to report the occurrence of dysfunction in sexual activity over the previous 4 weeks. Among 612 participants, 125 (21%) reported some degree of SD. "Moderate"/"severe" alterations were reported in 6% and were independently associated with self-reported worsening of viro-immunological parameters (OR 3.90; 95% CI 1.08-14.18), higher symptom score (OR 1.13; 95% CI 1.05-1.22), and reporting abnormal fat accumulation (OR 4.33; 95% CI 1.55-12.11). Furthermore, nonadherent persons had an increased risk of SD (OR 3.44; 95% CI 1.30-9.08). In conclusion, patients' perceived SD represents a relevant problem for HIV-infected persons treated with antiretrovirals and is strongly associated with suboptimal HAART adherence.

No abstract