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).
IMPORTANCEConvalescent plasma (CP) has been generally unsuccessful in preventing worsening of respiratory failure or death in hospitalized patients with COVID-19 pneumonia. OBJECTIVE To evaluate the efficacy of CP plus standard therapy (ST) vs ST alone in preventing worsening respiratory failure or death in patients with COVID-19 pneumonia. DESIGN, SETTING, AND PARTICIPANTS This prospective, open-label, randomized clinical trial enrolled (1:1 ratio) hospitalized patients with COVID-19 pneumonia to receive CP plus ST or ST alone between July 15 and December 8, 2020, at 27 clinical sites in Italy. Hospitalized adults with COVID-19 pneumonia and a partial pressure of oxygen-to-fraction of inspired oxygen (PaO 2 /FiO 2 ) ratio between 350 and 200 mm Hg were eligible. INTERVENTIONS Patients in the experimental group received intravenous high-titer CP (Ն1:160, by microneutralization test) plus ST. The volume of infused CP was 200 mL given from 1 to a maximum of 3 infusions. Patients in the control group received ST, represented by remdesivir, glucocorticoids, and low-molecular weight heparin, according to the Agenzia Italiana del Farmaco recommendations. MAIN OUTCOMES AND MEASURESThe primary outcome was a composite of worsening respiratory failure (PaO 2 /FiO 2 ratio <150 mm Hg) or death within 30 days from randomization. RESULTSOf the 487 randomized patients (241 to CP plus ST; 246 to ST alone), 312 (64.1%) were men; the median (IQR) age was 64 (54.0-74.0) years. The modified intention-to-treat population included 473 patients. The primary end point occurred in 59 of 231 patients (25.5%) treated with CP and ST and in 67 of 239 patients (28.0%) who received ST (odds ratio, 0.88; 95% CI, 0.59-1.33; P = .54). Adverse events occurred more frequently in the CP group (12 of 241 [5.0%]) compared with the control group (4 of 246 [1.6%]; P = .04). CONCLUSIONS AND RELEVANCEIn patients with moderate to severe COVID-19 pneumonia, hightiter anti-SARS-CoV-2 CP did not reduce the progression to severe respiratory failure or death within 30 days. (continued) Key Points Question Is convalescent plasma useful in preventing worsening respiratory failure or death in patients with COVID-19 pneumonia? Findings In this randomized clinical trial of 487 patients with COVID-19 pneumonia and a partial pressure of arterial oxygen-to-fraction of inspired oxygen (PaO 2 /FiO 2 ) ratio between 350 and 200 mm Hg at enrollment, the rate of the primary clinical end point (need for mechanical ventilation, defined as PaO 2 /FiO 2 ratio <150 mm Hg, or death) was not significantly different between the convalescent plasma group and the control group. Meaning In this trial, convalescent plasma did not reduce the progression to severe respiratory failure or death within 30 days.
Early COVID-19 treatments can prevent progression to severe disease. However, real-life data are still limited, and studies are warranted to monitor the efficacy and tolerability of these drugs. We retrospectively enrolled outpatients receiving early treatment for COVID-19 in 11 infectious diseases units in the Tuscany region of Italy between 1 January and 31 March 2022, when Omicron sublineages BA.1 and BA.2 were circulating. Eligible COVID-19 patients were treated with sotrovimab (SOT), remdesivir (RMD), nirmatrelvir/ritonavir (NRM/r), or molnupiravir (MOL). We gathered demographic and clinical features, 28-day outcomes (hospitalization or death), and drugs tolerability. A total of 781 patients (median age 69.9, 66% boosted for SARS-CoV-2) met the inclusion criteria, of whom 314 were treated with SOT (40.2%), 205 with MOL (26.3%), 142 with RMD (18.2%), and 120 with NRM/r (15.4%). Overall, 28-day hospitalization and death occurred in 18/781 (2.3%) and 3/781 (0.3%), respectively. Multivariable Cox regression showed that patients receiving SOT had a reduced risk of meeting the composite outcome (28-day hospitalization and/or death) in comparison to the RMD cohort, while no significant differences were evidenced for the MOL and NRM/r groups in comparison to the RMD group. Other predictors of negative outcomes included cancer, chronic kidney disease, and a time between symptoms onset and treatment administration > 3 days. All treatments showed good safety and tolerability, with only eight patients (1%) whose treatment was interrupted due to intolerance. In the first Italian multicenter study presenting real-life data on COVID-19 early treatments, all regimens demonstrated good safety and efficacy. SOT showed a reduced risk of progression versus RMD. No significant differences of outcome were observed in preventing 28-day hospitalization and death among patients treated with RMD, MOL, and NRM/r.
Background: Two-drug regimens are increasingly used in clinical practice as switch strategies. We compared the efficacy and safety of two dolutegravir (DTG)-based dual therapies: DTG plus lamivudine (3TC group) versus DTG plus rilpivirine (RPV group). Methods: In a multicentre cohort of virologically suppressed (HIV RNA <50 copies/ml) HIV+ patients switching to DTG+3TC or DTG+RPV we analysed the incidence of virological failures (VF) and treatment discontinuations (TD), as well as their predictors. Results: We analysed 416 patients, 229 in the 3TC group and 187 in the RPV group. The 3TC group, during 344.4 person-years of follow-up (PYFU), had 10 VF without the emergence of resistance mutations, while 30 patients discontinued the regimen. In the RPV group, during 371.0 PYFU, there were 5 VF (1 developed non-nucleoside reverse transcriptase inhibitor mutations Y181C and E138Q) and 13 TD. The estimated probability of remaining free from VF at 48 weeks showed no significant difference between groups (log-rank 0.172). We found a higher risk of VF in patients with peak viral load >500,000 copies/ml in both treatment groups (log-rank P=0.004 in each group). The estimated probability of remaining in the study regimen at week 48 was 89.0% with DTG+3TC and 96.1% with DTG+RPV (log-rank 0.015). After adjusting for potential confounders, treatment group was not associated with TD. A significant decrease in total cholesterol was observed at week 48 in both groups while renal function remained unchanged. Conclusions: DTG+RPV and DTG+3TC were compared in populations with different characteristics in clinical practice: both regimens showed good effectiveness and improved lipid profile.The association of dolutegravir (DTG) with either rilpivirine (RPV) or lamivudine (3TC), appears promising in maintaining virological suppression while reducing long-term toxicity in treated HIV-positive patients [1][2][3]. While randomized controlled trials comparing DTG plus RPV with standard triple therapy showed the non-inferiority of the two-drug regimen [4] and ongoing trials are exploring the efficacy of DTG plus 3TC as first-line and maintenance therapy, little is still known about the efficacy and tolerability of DTG-based two-drug regimens in clinical practice, since most studies conducted so far have limited sample size or short follow-up time [5][6][7]. In our multicentre cohort, we tried to investigate and compare the efficacy and safety of DTG plus 3TC versus DTG plus RPV.
Background Currently, no data are available on the burden of morbidity and mortality in people living with HIV-1 (PLWH) harboring a 4-class drug resistant (4DR) virus (NRTI, NNRTI, PI, INSTI). The study aimed to assess the incidence of clinical events or death in this population. Methods Cohort study on PLWH, from the PRESTIGIO Registry, with a documented 4DR virus.The burden of disease was defined as the occurrence of any new event including AIDS-defining event (ADE) or non-AIDS-defining event (NADE) or death for any cause, after 4DR evidence (baseline).Cox regression models evaluated factors associated with the risk of new clinical events/death. Results Among 148 PLWH followed for a median of 47 months (IQR=32-84) since 4DR evidence, 38 PLWH had 62 new events or died for any cause [incidence rate, 9.12/100-PYFU (95%CI=6.85-11.39)]: 12 deaths (6 AIDS-related and 6 non-AIDS-related), 18 ADE, 32 NADE; 20 of the 38 NADE (45%) of the incident clinical events were malignancies. The 4-year cumulative incidence of death was 6% (95%CI=3%-13%) and that of ≥1 event or death was 22% (95%CI=16%-31%). A higher risk of new clinical events/death was more likely in PLWH with previous clinical events (aHR=2.67, 95%CI=1.07-6.67) and marginally associated with lower baseline CD4+/CD8+ ratio (aHR=0.82, 95%CI=0.65-1.02). Conclusions PLWH harbouring 4DR have a high burden of disease with a worrying incidence of malignancies, strongly advising for close prevention and monitoring interventions as well as access to innovative therapeutic strategies, especially in people with a history of clinical events and low CD4+/CD8+ ratio.
Objectives The aim of the study was to analyse the prevalence of integrase resistance mutations in integrase strand transfer inhibitor (INSTI)‐experienced HIV‐1‐infected patients and its predictors. Methods We selected HIV‐1 integrase sequences from the Antiviral Response Cohort Analysis (ARCA) database, derived from INSTI‐experienced patients between 2008 and 2017. Differences in the prevalence of resistance to raltegravir (RAL), elvitegravir (EVG) and dolutegravir (DTG) were assessed by χ2 test and predictors of resistance were analysed by logistic regression. Results We included 462 genotypes from INSTI‐exposed individuals: 356 ‘INSTI‐failing' patients and 106 ‘previously INSTI‐exposed' patients (obtained a median of 42 weeks after INSTI discontinuation [interquartile range (IQR) 17–110 weeks]). Overall, at least low‐level resistance (LLR) to any INSTI (Stanford 8.5 algorithm) was detected in 198 (42.9%) cases. The most frequent INSTI resistance mutation was N155H, followed by Q148H/K/R, G140A/C/S, E138A/K/T and Y143C/H/R. Y143R and E138A were more prevalent in viral subtype B versus non‐B [5.2 versus 1.5%, respectively (P = 0.04), and 3.1 versus 0%, respectively (P = 0.02)]. Overall, the Q148H/K/R plus G140A/C/S and/or E138A/K/T pattern, defining an intermediate level of resistance to DTG, was detected in 70 (15%) cases. Independent predictors of at least LLR to any INSTI were current use versus past use of INSTIs, a lower genotypic sensitivity score (GSS) for contemporary antiretroviral drugs used, and having an integrase sequence obtained in calendar year 2016 as compared to 2008–2009. Conclusions The results support integrase resistance testing in INSTI‐experienced patients. Emergence of INSTI resistance is facilitated by the reduced genetic barrier of the regimen as a consequence of resistance to companion drugs. However, INSTI resistance may become undetectable by standard population sequencing upon INSTI discontinuation.
Introduction Long-term comparative immunologic response to 13-valent pneumococcal conjugate vaccine (PCV13) versus 23-valent polysaccharide vaccine (PPV23) among HIV-infected adults has not yet been investigated. Methods In this prospective pilot study, we quantified in HIV-positive adults serotype-specific IgG concentrations of the 12 pneumococcal serotypes shared by both vaccines 5 years after vaccination with two doses of PCV13 8 weeks apart (group 1) or one dose of PPV23 (group 2) and compared them with those assessed prior to vaccination (BL) and after 1 year (T1). Comparison of immunogenicity was based on geometric mean concentration (GMC), proportion of individuals with ≥ twofold increase from BL in specific antibody concentration against ≥ 2 serotypes and percentage of individuals with serotype-specific IgG ≥ 0.35 μg/ml, ≥ 1 μg/ml and ≥ individual serotype-specific correlates of protection. Results We included 91 subjects (median CD4 + 650 cells/µl, > 90% with HIV-RNA < 50 copies/ml); patients in groups 1 ( n = 42) and 2 ( n = 49) were homogeneous for the main characteristics. GMCs were significantly higher in the PCV13 group than in the PPV23 group for serotype 19F ( p = 0.003). Both vaccines revealed higher significant GMCs to most serotypes compared with BL, i.e., eight in group 1 vs. seven in group 2. With respect to T1, GMCs decreased significantly in the PCV13 group for eight vs. ten serotypes in the PPV23 group. More participants in the PCV13 group had ≥ 2 increase from BL in antibody levels to ≥ 2 serotypes compared with the PPV23 group (78.6% vs. 59.2%, p = 0.042). Overall, the percentage of subjects with serotype-specific IgG ≥ 0.35 μg/ml, ≥ 1 μg/ml and ≥ individual serotype-specific correlates of protection was similar between groups. Conclusion In this study with HIV-positive adults with a favorable viro-immunologic profile, both vaccines were shown to achieve a long-term durable serologic response. We found minor differences in immunogenicity between the two vaccines, which favored PCV13 over PPV23 5 years after immunization. Trial Registration ClinicalTrials.gov identifier, NCT02123433. Electronic supplementary material The online version of this article (10.1007/s40121-019-0256-z) contains supplementary material, which is available to authorized users.
Background INSTIs have become a pillar of first-line ART. Real-world data are needed to assess their effectiveness in routine care. Objectives We analysed ART-naive patients who started INSTI-based regimens in 2012–19 whose data were collected by INTEGRATE, a European collaborative study including seven national cohorts. Methods Kaplan–Meier analyses assessed time to virological failure (VF), defined as one viral load (VL) ≥1000 copies/mL, two consecutive VLs ≥50 copies/mL, or one VL ≥50 copies/mL followed by treatment change after ≥24 weeks of follow-up, and time to INSTIs discontinuation (INSTI-DC) for any reason. Factors associated with VF and INSTI-DC were explored by logistic regression analysis. Results Of 2976 regimens started, 1901 (63.9%) contained dolutegravir, 631 (21.2%) elvitegravir and 444 (14.9%) raltegravir. The 1 year estimated probabilities of VF and INSTI-DC were 5.6% (95% CI 4.5–6.7) and 16.2% (95% CI 14.9–17.6), respectively, and were higher for raltegravir versus both elvitegravir and dolutegravir. A baseline VL ≥100 000 copies/mL [adjusted HR (aHR) 2.17, 95% CI 1.55–3.04, P < 0.001] increased the risk of VF, while a pre-treatment CD4 count ≥200 cells/mm3 reduced the risk (aHR 0.52, 95% CI 0.37–0.74, P < 0.001). Predictors of INSTI-DC included use of raltegravir versus dolutegravir (aHR 3.03, 95% CI 2.34–3.92, P < 0.001), use of >3 drugs versus 3 drugs (aHR 2.73, 95% CI 1.55–4.79, P < 0.001) and starting ART following availability of dolutegravir (aHR 0.64, 95% CI 0.48–0.83, P = 0.001). Major INSTI mutations indicative of transmitted drug resistance occurred in 2/1114 (0.2%) individuals. Conclusions This large multi-cohort study indicates high effectiveness of elvitegravir- or dolutegravir-based first-line ART in routine practice across Europe.
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