The first evidence that Orthopoxvirus induced the expansion in vivo and the recall of effector innate Vδ2 T-cells was described in a macaque model. Although, an engagement of αβ T-cells specific response in patients infected with human monkeypox (Mpox) was demonstrated, little is known about the role of γδ T-cells during Mpox infection. IFN-γ-producing γδ T-cells in the resistance to poxviruses may a key role in inducing a protective type 1 memory immunity. We analyzed the kinetics of Vδ2 T-cell response from the acute phase up to three months after Mpox infection. Fourteen MSM subjects (5 PWH, 35.7%) were enrolled in a longitudinal study from May to July 2022. Blood samples were collected in the early phase of infection (T1, T2) and at 3 months (T3M) post-symptom onset. Vδ2 T-cell profiles (CD45RA/CCR7), activation/exhaustion markers (CD38/HLA-DR/CD57/PD-1/TIM-3), cytokine production (IFN-γ/TNF-α) and CD107a expression were assessed by multiparametric flow cytometry. Ten healthy donors (HD) were used as a control group. At T1, Vδ2 T-cell frequency of patients decreased, and effector memory Vδ2 T-cells increased with respect to HD. Activation/exhaustion markers were higher than HD. Vδ2 functionality decreased at T1 related to HD, and it was associated with CD38 and HLA-DR higher expression as well as TIM-3. Vδ2 T-cells restored their profile at T3M. The presence of effector/activated Vδ2 T-cells in the early stages of Mpox infection and their capability to activate quickly, producing pro-inflammatory cytokines, may be useful to enhance the early adaptive response to human Mpox, maintaining a protective memory/effector T-cell response.

The impact of anti-Spike monoclonal antibody (mAbs) treatment on the immune response of COVID19-patients is poorly explored. In particular, a comparison of the immunological influence of different therapeutic regimens has not yet been performed. Aim of the study was to compare the kinetic of innate and adaptive immune response as well as the SARS-CoV-2 specific humoral and T cell response in two groups of SARS-CoV-2-infected patients treated with two different mAbs regimens: Bamlanivimab/Etesevimab (BAM/ETE) or Casirivimab/Imdevimab (CAS/IMD). SARS-CoV-2-infected patients (n = 39) with mild/moderate disease were enrolled before (T0) and after 7 days (T7) and 30 day (T30) from mAbs infusion. Patients were divided in two groups on the basis of the mAb regimen: BAM/ETE (n = 15) and CAS/IMD (n = 24). The phenotype/function of immune cell subsets was evaluated by flow-cytometry and by ELISA. The Spike-specific T cell response (IFN-γ) and anti-Nucleocapside IgG were evaluated by chemiluminescence assay. SARS CoV-2 RNA in nasal swabs was evaluated by RT-PCR. Eleven out of the thirty-nine enrolled patients tested negative at T7, among which nine (81.8 %) had been treated with CAS/IMD regimen. A comparable increase in CD4 and CD8 T cells was observed in both treatment groups. Moreover, a reduction of CD38 expression on T (CD4, CD8 and Vδ2) and on NK cells was observed in both groups, as well as a reduction overtime of the perforin expression in T (CD8, Vδ2) and in NK cells reaching significance only in CAS/IMD-treated patients. The SARS-CoV-2-specific T cells response increased at T7 in BAM/ETE-treated patients and at T30 in CAS/IND group. Of note, at T30 SARS-CoV2-specific T cells was higher in CAS/IMD than in BAM/ETE group. Furthermore, the titre of anti-N IgG increased overtime in both groups with a faster kinetic in CAS/IMD group. The spontaneous production of inflammatory cytokines by monocytes and neutrophils was similar the two mAb regimens, as well as the level of plasmatic IL-6. Finally, patients were also analysed according to sex. The male group showed a higher frequency of activated CD4 T cells, NKG2A-expressing CD8 T cells and perforin-expressing Vδ2 T cells compared to female group. Moreover, a higher specific T cell response at T30 was observed in the male compared to female group. In conclusion, these results show similar effects of both mAb regimens in restoring T and NK cell homeostasis and in reducing inflammation. In contrast, CAS/IMD allows a better humoral and cellular SARS-CoV2 specific immunization.

OBJECTIVES:No previous studies specifically explored the switch from efavirenz to bictegravir (BIC)-containing three-drug antiretroviral regimens. This study aimed to evaluate the efficacy and safety outcomes of a treatment switch from efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF) given once daily (OD) or on alternate days (ATAD) to BIC/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) in virologically suppressed people with HIV (PWH). METHODS:A pilot, single-arm, prospective study was conducted. RESULTS:Overall, 234 PWH were enrolled. 217 of 234 (92.7%, 95% confidence interval [CI], 88.6-95.7%) participants had HIV-RNA <40 cp/ml at 48 weeks. Virological failure occurred in three participants, none with documented resistance, and all resuppressed without antiretroviral therapy change. After 48 weeks, a slight increase in cluster of differentiation (CD)4 cell count was observed from the baseline (+ 59 cells/mmc, 95% CI, 31; 86, P <0.001), but not in CD4/CD8 ratio. A slight increase in creatinine (mean change +0.11 mg/dl, 95% CI 0.10; 0.13, P <0.001) and a decrease in total cholesterol (mean change -8 mg/dl, 95% CI -14; -3, P = 0.001) were also observed. CONCLUSIONS:Our data showed that BIC/FTC/TAF demonstrated high virologic and immunologic efficacy and an excellent safety profile.

Currently, tecovirimat has been authorised for emergency use in the treatment of severe mpox (formerly known as monkeypox).1European Medicines Agency Tecovirimat SIGA.https://www.ema.europa.eu/en/documents/assessment-report/tecovirimat-siga-epar-public-assessment-report_en.pdfDate: 2021Date accessed: February 27, 2023Google Scholar However, to date, studies on the pharmacokinetics and pharmacodynamics of tecovirimat in the genital compartment are absent. With the aim of investigating the penetration of tecovirimat into seminal fluid, plasma and semen were obtained from three individuals admitted to hospital with severe mpox and treated with the standard dose of oral tecovirimat (600 mg twice daily) for 14 days.1European Medicines Agency Tecovirimat SIGA.https://www.ema.europa.eu/en/documents/assessment-report/tecovirimat-siga-epar-public-assessment-report_en.pdfDate: 2021Date accessed: February 27, 2023Google Scholar Tecovirimat concentrations were measured using a modified and validated liquid chromatography with a tandem mass spectrometry method.2Oleinik GA Koval VV Usova SV Shishkina LN Chernonosov AA Development and validation of a method of liquid chromatography coupled with tandem mass spectrometry for quantification of ST-246 (Tecovirimat) in human plasma.Molecules. 2022; 27: 3577Crossref PubMed Scopus (5) Google Scholar Additionally, in the same individuals, the monkeypox virus DNA (MPXV-DNA) load in the seminal fluid was evaluated at baseline, during, and after tecovirimat treatment, using real-time PCR. Patients' characteristics, concomitant treatments, and MPXV-DNA results from different samples before starting tecovirimat, were recorded (appendix p 2). In all three patients, viral loads in semen samples collected at baseline were weakly positive (cycle threshold of 32–38). After tecovirimat initiation, MPXV-DNA in semen was undetectable after 11 days of treatment for patient one (corresponding to 17 days since illness onset), 6 days of treatment for patient two (15 days since illness onset), and 7 days of treatment for patient three (16 days since illness onset; appendix p 3). Additionally, semen continued to be negative in all patients after the end of treatment (appendix p 3). Tecovirimat concentrations detected in semen samples at the steady state were 50·3 ng per mL, 60·7 ng per mL, and 70·7 ng per mL with a semen to plasma ratio of 0·14, 0·17, and 0·13 for patients one, two and three, respectively (appendix p 3). To the best of our knowledge, this is the first description of tecovirimat penetration into the genital tract of men with mpox. Similar compartmentalisation results were observed from pharmacokinetics studies in monkeys, which showed penetration of tecovirimat into the cerebrospinal fluid (CSF) with a ratio of CSF to plasma of about 0·10.1European Medicines Agency Tecovirimat SIGA.https://www.ema.europa.eu/en/documents/assessment-report/tecovirimat-siga-epar-public-assessment-report_en.pdfDate: 2021Date accessed: February 27, 2023Google Scholar Tecovirimat is a small molecule that is lipophilic and about 80–90% bound to blood plasma proteins. In addition, the drug is not a substrate for efflux transporters.1European Medicines Agency Tecovirimat SIGA.https://www.ema.europa.eu/en/documents/assessment-report/tecovirimat-siga-epar-public-assessment-report_en.pdfDate: 2021Date accessed: February 27, 2023Google Scholar We can speculate that tecovirimat could be distributed into the seminal fluid through passive diffusion of unbound drug fraction and that active transport of tecovirimat out of this compartment should be minimal. The concentrations of tecovirimat found in semen samples of our patients exceeded the published 50% inhibitory concentration of MPXV in vitro (4·8 ng per ml)3Frenois-Veyrat G Gallardo F Gorgé O et al.Tecovirimat is effective against human monkeypox virus in vitro at nanomolar concentrations.Nat Microbiol. 2022; 7: 1951-1955Crossref PubMed Scopus (26) Google Scholar by more than ten-fold. In all our patients, we observed sustained clearance of MPXV-DNA from semen samples approximately after the first week of treatment, according to tecovirimat pharmacokinetics steady-state levels.1European Medicines Agency Tecovirimat SIGA.https://www.ema.europa.eu/en/documents/assessment-report/tecovirimat-siga-epar-public-assessment-report_en.pdfDate: 2021Date accessed: February 27, 2023Google Scholar Although spontaneous viral clearance is a probable hypothesis considering the baseline low viral loads of our patients and the viral kinetics previously described in this compartment for untreated patients,4Palich R Burrel S Monsel G et al.Viral loads in clinical samples of men with monkeypox virus infection: a French case series.Lancet Infect Dis. 2023; 23: 74-80Summary Full Text Full Text PDF PubMed Scopus (68) Google Scholar, 5Suñer C Ubals M Tarín-Vicente EJ et al.Viral dynamics in patients with monkeypox infection: a prospective cohort study in Spain.Lancet Infect Dis. 2022; 23: 445-453Summary Full Text Full Text PDF PubMed Scopus (40) Google Scholar the drug concentrations found in semen might be relevant in terms of transmission, potential antiviral resistance, and potential viral sanctuaries (eg, lingering virus observed in monkeys).6Liu J Mucker EM Chapman JL et al.Retrospective detection of monkeypox virus in the testes of nonhuman primate survivors.Nat Microbiol. 2022; 7: 1980-1986Crossref PubMed Scopus (8) Google Scholar We declare no competing interests. MT and AM contributed equally to the manuscript. The study was done as a part of biological studies on emerging infections approved by the Ethical Committee of the Lazzaro Spallanzani Institute (approval number 14/2015 and amendments). This work was supported by the Italian Ministry of Health (Ricerca Corrente—line 2). The patients provided written informed consent to the use of their data and clinical samples for the research purposes of the present study. We thank the patients and nursing and laboratory staff. Download .pdf (.13 MB) Help with pdf files Supplementary appendix

Background: A rapid ART initiation approach can be beneficial in people with advanced HIV disease, in consideration of their high morbidity and mortality. The aim of our study was to evaluate the feasibility, efficacy and safety of rapid ART start with BIC/FTC/TAF in this setting. Methods: Pilot, single-centre, single-arm, prospective, phase IV clinical trial conducted in a tertiary Italian hospital. Thirty ART-naive people presenting with advanced HIV-1 diagnosis (defined as the presence of an AIDS-defining event and/or CD4 cell count < 200 mu L), were enrolled. Main exclusion criteria were active tuberculosis, cryptococcosis and pregnant/breastfeeding women. BIC/FTC/TAF was started within 7 days from HIV diagnosis. The primary endpoint was clinical or virologic failure (VF). Immunological parameters, safety, feasibility, neurocognitive performances and patient-reported outcomes were assessed as well. Results: Over the study period, 40 (34%) of 116 patients diagnosed with HIV infection at INMI Spallanzani had advanced disease, of whom 30 (26%) were enrolled. The proportion of participants with HIV-RNA < 50 cp/mL was 9/30 (30%) at week (w) 4, 19/30 (63%) at w12, 24/30 (80%) at w24, 23/30 (77%) at w36 and 27/30 (90%) at w48. Two unconfirmed VF occurred. No ART discontinuation due to toxicity or VF was observed. No ART modification was performed based on the review of genotype and no mutations for the study drugs were detected. Mean CD4 cells count changed by 133 cells/mu L at BL to 309 cells/mu L at w 48 and 83% of participants had a CD4 > 200 cells/mu L at w 48. Two participants developed IRIS and one was diagnosed with disseminated TB and needed an ART switch. Interpretations: Our results support the feasibility, efficacy and safety of BIC/FTC/TAF as a rapid ART strategy in patients with advanced HIV disease. (c) 2023 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ )

A 59-year-old treatment-naive patient with advanced HIV infection presented with a severe and protracted course of mpox (formerly known as monkeypox) that did not respond to the current mpox treatment options. The patient worsened clinically, and developed new mucocutaneous lesions and necrotic evolution of pre-existing ones, along with multiple bilateral lung nodules and the appearance of a tracheal necrotic lesion. Although severe forms of mpox have been observed in people with severe immune system deficiency, including those with advanced HIV presentation, the immunological mechanisms underlying this observation have not yet been fully explained. To our knowledge, this is the first account of a necrotising mpox in a person living with HIV, with viral shedding for more than 11 months and a comprehensive immunological description. Moreover, we documented the virus' persistence by detecting mpox virus DNA from multiple sites and quantified anti-monkeypox virus IgA, IgM, IgG, and neutralising antibodies in serum samples. The severe HIV-driven immune depression and the presence of other co-infections might skew and impair immune responses, thus contributing to the persistence of monkeypox virus infection. Further investigations of immune responses to monkeypox virus infection in people with severe immunosuppression are required to improve management and prevention.

OBJECTIVE:To investigate the pharmacokinetics (PK) of tecovirimat in subjects with Mpox. METHODS:This monocentric, prospective, observational study enrolled subjects with Mpox who received standard treatment with oral tecovirimat. Plasma samples for PK assessment were collected at steady state (5-8 days after initiation of antiviral therapy), before and 3, 5, 7 and 12 h after tecovirimat administration. Drug concentrations were determined by validated liquid chromatography coupled with tandem mass spectrometry. PK parameters were calculated using Phoenix 8.1. RESULTS:Overall, 14 male patients hospitalized for severe Mpox with ongoing tecovirimat treatment were enrolled in this study. Six of the 14 patients were living with human immunodeficiency virus (HIV), all of whom were on antiretroviral therapy (ART) and virologically suppressed at the time of hospitalization. Significant differences in tecovirimat PK were observed in subjects without HIV compared with subjects with HIV. In subjects with HIV, the maximum tecovirimat plasma concentration (39%, P≤0.0001), minimum tecovirimat plasma concentration (42%, P=0.0079) and area under the curve from zero to the last measured time-point (40%, P≤0.0001) were significantly lower compared with subjects without HIV, but all concentrations remained above the in-vitro calculated 90% inhibitory concentration. No significant associations were found between demographic/clinical data and tecovirimat PK. All patients recovered completely within 14 (range 6-36) days of treatment initiation. CONCLUSIONS:This study found a significant decrease in plasma exposure of tecovirimat in Mpox patients with HIV on effective ART compared with those without HIV, with no evident impact on clinical outcomes. Although these results need to be confirmed in larger studies, they may provide useful information on the PK of tecovirimat.

BACKGROUND:Remdesivir is the first antiviral drug against SARS-CoV-2 approved for use in COVID-19 patients. OBJECTIVES:To study the pharmacokinetic inter-individual variability of remdesivir and its main metabolite GS-441524 in a real-world setting of COVID-19 inpatients and to identify possible associations with different demographic/biochemical variables. METHODS:Inpatients affected by SARS-CoV-2 infections, undergoing standard-dose remdesivir treatment, were prospectively enrolled. Blood samples were collected on day 4, immediately after (C0) and at 1 h (C1) and 24 h (C24) after infusion. Remdesivir and GS-441524 concentrations were measured using a validated UHPLC-MS/MS method and the AUC0-24 was calculated. At baseline, COVID-19 severity (ICU or no ICU), sex, age, BMI and renal and liver functions were assessed. Transaminases and estimated glomerular filtration rate (e-GFR) were also evaluated during treatment. Linear regression, logistic regression and multiple linear regression tests were used for statistical comparisons of pharmacokinetic parameters and variables. RESULTS:Eighty-five patients were included. The mean (CV%) values of remdesivir were: C0 2091 (99.1%) ng/mL, C1 139.7 (272.4%) ng/mL and AUC0-24 2791 (175.7%) ng·h/mL. The mean (CV%) values of GS-441524 were: C0 90.2 (49.5%) ng/mL, C1 104.9 (46.6%) ng/mL, C24 58.4 (66.9) ng/mL and AUC0-24 1976 (52.6%) ng·h/mL. The multiple regression analysis showed that age (P &lt; 0.05) and e-GFR (P &lt; 0.01) were independent predictors of GS-441524 plasma exposure. CONCLUSIONS:Our results showed a high interpatient variability of remdesivir and GS-441524 likely due to both age and renal function in COVID-19 inpatients. Further research is required to understand whether the pharmacokinetics of remdesivir and its metabolites may influence drug-related efficacy or toxic effect.

To date, vitamin D seems to have a significant role in affecting the prevention and immunomodulation in COVID-19 disease. Nevertheless, it is important to highlight that this pro-hormone has other several activities, such as affecting drug concentrations, since it regulates the expression of cytochrome P450 (CYP) genes. Efavirenz (EFV) pharmacokinetics is influenced by CYPs, but no data are available in the literature concerning the association among vitamin D levels, seasonality (which affects vitamin D concentrations) and EFV plasma levels. For this reason, the aim of this study was to evaluate the effect of 25-hydroxy vitamin D (25(OH)D3) levels on EFV plasma concentrations in different seasons. We quantified 25(OH)D3 by using chemiluminescence immunoassay, whereas EFV plasma concentrations were quantified with the HPLC–PDA method. A total of 316 patients were enrolled in Turin and Rome. Overall, 25(OH)D3levels resulted in being inversely correlated with EFV concentrations. Some patients with EFV levels higher than 4000 ng/mL showed a deficient 25(OH)D3 concentration in Turin and Rome cohorts and together. EFV concentrations were different in patients without vitamin D supplementation, whereas, for vitamin D-administered individuals, no difference in EFV exposure was present. Concerning seasonality, EFV concentrations were associated with 25(OH)D3 deficiency only in winter and in spring, whereas a significant influence was highlighted for 25(OH)D3 stratification for deficient, insufficient and sufficient values in winter, spring and summer. A strong and inverse association between 25(OH)D3and EFV plasma concentrations was suggested. These data suggest that vitamin D is able to affect drug exposure in different seasons; thus, the achievement of the clinical outcome could be improved by also considering this pro-hormone.

Sofosbuvir plus daclatasvir achieves high rates of sustained virologic response (SVR), with no differences according to HIV serostatus. However, only limited information is available on the pharmacokinetic variability of sofosbuvir and daclatasvir in HIV/HCV-coinfected patients. The aim of this study was to identify patient-, treatment-, and disease-related factors that are significantly associated with sofosbuvir and daclatasvir plasma trough concentrations (Ctrough), including liver and renal function, among HIV/HCV-coinfected persons. In this observational cohort pilot study, HIV/HCV-coinfected patients undergoing sofosbuvir plus daclatasvir treatment were prospectively enrolled. Biochemical and viro-immunological parameters were assessed at baseline, week 4 (W4), end of treatment (EOT), and after EOT. The FIB-4 score and CKD-EPI equation were used to estimate liver disease and glomerular filtration rate (eGFR), respectively. For sofosbuvir, sofosbuvir metabolite (GS-331007), and daclatasvir, Ctrough was measured at W4 and week 8 (W8), and the mean of the values at those two time points (mean-Ctrough) was calculated. The Mann–Whitney test and Spearman’s rank correlation were used to evaluate the correlations between the mean-Ctrough of each direct-acting antiviral (DAA) and the considered variables. Thirty-five patients were included (SVR 94%). An increased GS-331007 mean-Ctrough was significantly correlated with a decreased eGFR at W4 (rho = −0.36; p = 0.037) and EOT (rho = −0.34; p = 0.048). There was a significant correlation between daclatasvir mean-Ctrough and FIB-4 at all time points: baseline (rho = −0.35; p = 0.037), W4 (rho = −0.44; p = 0.008), EOT (rho = −0.40; p = 0.023), and after EOT (rho = −0.39; p = 0.028). In HIV/HCV-coinfected patients in a real-world setting, exposure to a high GS-331007 Ctrough was associated with a slight decrease in renal function, while advanced hepatic impairment was significantly associated with a lower daclatasvir Ctrough. Though the clinical and therapeutic relevance of these findings may be limited, increasing clinicians’ knowledge regarding DAA exposure in difficult-to-treat patients could be relevant in single cases, and further investigations are warranted.

Mann-Whitney test).However, based on the association between baseline IC 50 values .100nM and poor virological response during 8 day fostemsavir monotherapy, 9 there was only one virus that could be less susceptible to the activity of fostemsavir in vivo (sample CI-147290).Interestingly, this virus harboured the unusual amino acid variant proline at the key fostemsavir resistance codon 426 of the gp120 coding region.Indeed, the most prevalent amino acid variants occurring at codon 426 in env sequences retrieved from the Los Alamos National Laboratory Database are M (93.6%),L (4.8%) and I/ K/R (0.5% each) in CRF02_AG and M (67.9%),R (21.6%), L (8.2%) and K (1.3%) in subtype B. To investigate the role of the different variants, we constructed the M426P, L, K and R site-directed mutants in the NL4-3 subtype B backbone and tested their susceptibility to temsavir (Table 1).Indeed, the M426P mutant was 4-fold less susceptible than the wild-type M426, although it was not as resistant as the canonical M426L mutant, suggesting that the rarely occurring P variant could contribute to the observed phenotype in sample CI-147290, together with other undetermined changes.Limited availability of the RNA extract did not allow further analysis of the role of the M426P mutation and other polymorphisms in this isolate.In conclusion, our data expand previous reports on natural HIV-1 susceptibility to temsavir, indicating that patients harbouring MDR CRF02_AG infection can benefit from fostemsavir treatment.Thus, the only naturally less susceptible group M lineage remains CRF01_AE. 3However, as shown by the CI-147290 isolate in our dataset and by other uncommon cases across different subtypes, 4 rare variants with reduced in vitro susceptibility to fostemsavir may well occur independently of subtype due to the extraordinary polymorphism of HIV-1 gp120.

Background: Remdesivir is a prodrug of the nucleoside analogue GS-441524 and is under evaluation for treatment of SARS-CoV-2-infected patients. Objectives: To evaluate the pharmacokinetics of remdesivir and GS-441524 in plasma, bronchoalveolar aspirate (BAS) and CSF in two critically ill COVID-19 patients. Methods: Remdesivir was administered at 200mg loading dose on the first day followed by 12days of 100mg in two critically ill patients. Blood samples were collected immediately after (C-0) and at 1 (C-1) and 24h (C-24) after intravenous administration on day 3 until day 9. BAS samples were collected on Days 4, 7 and 9 from both patients while one CSF on Day 7 was obtained in one patient. Remdesivir and GS-441524 concentrations were measured in these samples using a validated UHPLC-MS/MS method. Results: We observed higher concentrations of remdesivir at C-0 (6- to 7-fold higher than EC50 from in vitro studies) and a notable decay at C-1. GS-441524 plasma concentrations reached a peak at C-1 and persisted until the next administration. Higher concentrations of GS-441524 were observed in the patient with mild renal dysfunction. Mean BAS/plasma concentration ratios of GS-441524 were 2.3% and 6.4% in Patient 1 and Patient 2, respectively. The CSF concentration found in Patient 2 was 25.7% with respect to plasma. GS-441524 levels in lung and CNS suggest compartmental differences in drug exposure. Conclusions: We report the first pharmacokinetic evaluation of remdesivir and GS-441524 in recovered COVID-19 patients. Further study of the pharmacokinetic profile of remdesivir, GS-441524 and the intracellular triphosphate form are required.

The immunological mechanisms underlying the clinical presentation of SARS-CoV-2 infection and those influencing the disease outcome remain to be defined. Myeloid-derived suppressor cells (MDSC) have been described to be highly increased during COVID-19, however, their role remains elusive. We performed an in depth analysis of MDSC in 128 SARS-CoV-2 infected patients. Polymorphonuclear (PMN)-MDSC expanded during COVID-19, in particular in patients who required intensive care treatments, and correlated with IL-1β, IL-6, IL-8, and TNF-α plasma levels. PMN-MDSC inhibited T-cells IFN-γ production upon SARS-CoV-2 peptides stimulation, through TGF-β- and iNOS-mediated mechanisms, possibly contrasting virus elimination. Accordingly, a multivariate regression analysis found a strong association between PMN-MDSC percentage and fatal outcome of the disease. The PMN-MDSC frequency was higher in non-survivors than survivors at the admission time, followed by a decreasing trend. Interestingly, this trend was associated with IL-6 increase in non-survivors but not in survivors. In conclusion, this study indicates PMN-MDSC as a novel factor in the pathogenesis of SARS-CoV2 infection, and open up to new therapeutic options.

BackgroundSofosbuvir (SOF) plus daclatasvir (DCV) achieved high rates of sustained virologic response (SVR) with no difference according to HIV serostatus. Only limited information is available on the pharmacokinetics variability of SOF and DCV in HIV/HCV co-infected patients. Aim was to evaluate the association of plasma drug concentrations (Ctrough) of SOF and of DCV with patient-, treatment-, and disease-related factors in the real-world setting of HIV/HCV co-infected persons.MethodsHIV/HCV co-infected patients, undergoing SOF plus DCV treatment, were prospectively enrolled. At baseline, week4 (W4), end of treatment (EOT), and after-EOT, biochemical and viro-immunological parameters were assessed. FIB-4 score and CKD-EPI equation were used for estimation of liver disease and glomerular filtration rate (eGFR), respectively. SOF, SOF metabolite (GS-331007), and DCV Ctrough were measured at W4 and week8 (W8), and the mean value (mean-Ctrough) was calculatedResultsThirty-five patients were included (SVR 94%). Increasing GS-331007 mean-Ctrough significantly correlated with decreasing eGFR at W4 (rho=-0.36; p=0.037) and EOT (rho=-0.34; p=0.048). Between DCV mean-Ctrough and FIB-4, a significant correlation was observed at all time-points: baseline (rho=-0.35; p=0.037), W4 (rho=-0.44; p=0.008), EOT (rho=-0.40; p=0.023), after-EOT (rho=-0.39; p=0.028).ConclusionIn HIV/HCV co-infected patients receiving SOF plus DCV, plasma drug concentrations are associated with renal dysfunction for GS-331007 and with liver impairment for DCV. Though clinical and therapeutically relevance of these findings may apparently be limited, growth of clinicians’ knowledge on DAA exposure in difficult-to-treat patients, as cirrhotic and renal impaired subjects, can be relevant in single cases.

OBJECTIVE:Antiretrovirals with long half-lives, such as tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) and efavirenz (EFV), are suitable for reduced frequency dosing, with potential for improved adherence and reduced toxicity and costs. The objective of this study was to investigate the noninferiority of the TDF/FTC/EFV fixed-dose combination on alternate-days versus standard regimen in virologically suppressed patients. DESIGN:A randomized-controlled open-label noninferiority trial enrolling HIV-1-infected patients treated for at least 6 months with TDF/FTC/EFV fixed-dose combination, virologically suppressed (<40 HIV-RNA copies/ml) with EFV plasma concentrations greater than 1000 ng/ml, were randomized to maintain TDF/FTC/EFV standard-of-care regimen (SOC, Arm A) or to switch to TDF/FTC/EFV on AlTernAte Days (ATAD, Arm B). METHODS:Primary end-point was the proportion of patients with less than 40 HIV-RNA copies/ml at week 48. RESULTS:One hundred and ninety-seven patients were randomized (98 in the SOC and 99 in the ATAD arm). One hundred and seventy-nine (90.3%) were men, median age 43.2 years, 133 (67.5%) MSM. CD4+ T-cell count at baseline was 706 cells/μl in SOC and 632 cells/μl in ATAD arm. At week 48, 95 (96.9%) patients in SOC and 93 (93.9%) in ATAD had a virological response (-3.0% overall risk difference, 95% CI: -8.86%/2.86%). Median change from baseline at week 48 in CD4+ T-cell count was 29.4 cells/μl (95% CI: 2.5/56.4) in SOC (P = 0.008) and 61.0 cells/μl (95% CI: 32.1/89.9) in ATAD (P < 0.001). Median change of EFV concentration at week 48 from baseline was -6.5 ng/ml (95% CI: -103/55) in SOC (P = 0.877) and -1124 ng/ml (95% CI: -1375/-928) in ATAD arm (P < 0.001). CONCLUSION:Despite a significant decrease of EFV exposure, TDF/FTC/EFV on ATAD was noninferior to SOC regimen through 48 weeks.