Summary
Primary and chronic human immunodeficiency virus (HIV) infection alters γδ T‐cell features. However, there is no evidence about early combined antiretroviral therapy (cART) and γδ T‐cell ...dynamics. In the present study, HIV‐positive individuals were divided into those with early primary infection (EPI) and those with late primary infection (LPI). The analysis of γδ T cells was performed by flow cytometry before and after therapy. Polyfunctional profile was assessed after in vitro peripheral blood mononuclear cell (PBMC) exposure to specific antigens. The results show that primary infection induced an expansion of Vδ1 T cells in LPI. Before treatment, a massive activation of γδ T‐cell subsets was observed in both groups of patients, that correlated with disease progression and was significantly reduced after cART introduction. Despite this, CD107A‐expressing Vδ1 T cells in both groups were significantly fewer than in healthy donors, but were restored by therapy introduction. Polyfunctional analysis of Vδ1 T cells from HIV‐positive individuals revealed a lower frequency of CD107A+ CCL‐4+ Vδ1 T‐cell subsets than healthy donors that persists after therapy. Functional profile of Vδ2 was similar to that in healthy donors before therapy but, at 6 months, a lower frequency of CD107A, interferon‐γ‐ or tumor necrosis factor‐α‐producing Vδ2 T cells was observed in the EPI group. Finally, individuals with LPI showed a lower frequency of quadruple‐functional Vδ2 T‐cell subset. In conclusion, during primary HIV infection, the baseline Vδ1 T‐cell activation is correlated with immune reconstitution potential. Moreover, an altered γδ polyfunctional profile occurred, persisting after cART. Further studies are needed to understand whether a longer treatment of primary infection may increase γδ T‐cell functionality.
Combined antiretroviral therapy reduces γδ T‐cell activation but fails to restore polyfunctionality.
Tecovirimat is a treatment option for severe mpox, although randomized clinical trials are ongoing. The aim of the study is to assess the effect of tecovirimat on healing time and the extent of viral ...clearance by target trial emulation using observational data. Clinical and virological data of patients hospitalized for mpox were collected. Samples from the upper respiratory tract (URT) were grouped in two time points: T1 (median 6 days from symptoms onset) and T2 (median 5 days from T1). Patients were followed‐up until recovery. Average treatment effect (ATE) in patients untreated versus treated with tecovirimat was estimated on time to healing and variation in viral load in URT, using a weighted and cloning analysis. Among the 41 patients included, 19 completed a course of tecovirimat. The median time from symptoms onset to hospitalization and to drug‐starting was 4 days and 10 days, respectively. No improvement in healing time in treated versus untreated was observed. No difference by treatment group in time to viral clearance was detected by ATE fitted in a subset of 13 patients after controlling for confounders. We found no evidence for a large effect of tecovirimat in shortening healing time and viral clearance. While awaiting the results of randomized studies, the use of tecovirimat should be restricted to the clinical trial setting.
Whole‐genome sequencing (WGS) has been widely used for the genomic characterization and the phylogenesis of mpox virus (MPXV) 2022 multi‐country outbreak. To date, no evidence has been reported on ...intra‐host evolution within samples collected over time from a single patient with long‐term infection. Fifty‐one samples were collected from five patients at different time points post‐symptom onset. All samples were confirmed as MPXV DNA positive, amplified by a multiplexed PCR amplicon, and sequenced by WGS. Complete MPXV genomes were assembled by reference mapping and then aligned to perform phylogenetic and hierarchical clustering analysis. Large intra‐host variability was observed among the MPXV genomes sequenced from samples of two immunocompromised with advanced HIV‐1 infection patients with prolonged MPXV shedding. Overall, 20 nucleotide mutations were identified in the 32 genomes from HIV patients, differently distributed in samples collected from different tissues and at different time points. No sequence compartmentalization nor variation was observed in the three patients with rapid viral clearance. MPXV exhibits adaptation to changing environments within the infected host and consequently demonstrates tissue compartmentalization. Further studies are needed to elucidate the role of this adaptation in forming a pool of genetic variability and contributing to viral persistence and its clinical implications.
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.
Pilot, single-centre, single-arm, prospective, phase IV clinical trial conducted in a tertiary Italian hospital. Thirty ART-naïve people presenting with advanced HIV-1 diagnosis (defined as the presence of an AIDS-defining event and/or CD4 cell count <200 µL), 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.
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/μL at BL to 309 cells/μL at w 48 and 83% of participants had a CD4 > 200 cells/µL at w 48. Two participants developed IRIS and one was diagnosed with disseminated TB and needed an ART switch.
Our results support the feasibility, efficacy and safety of BIC/FTC/TAF as a rapid ART strategy in patients with advanced HIV disease.
•Primary HIV infection strongly perturbs the plasmatic cytokines profile.•Despite 48 weeks of early ART some of factors persist altered.•G-CSF and MIP-1β soluble mediators are persistently altered ...and show an inverse correlation with the CD4/CD8 T cell ratio.
Antiretroviral treatment (ART) of Primary HIV Infection (PHI) has demonstrated virological and immunological benefits. The effect of early ART during PHI on the level of growth factors and chemokines modulating immune cell functions remains to be established. The aim of our work was to analyze the dynamics of 27 cytokines, chemokines and growth/regulation factors in plasma of HIV infected patients treated during PHI.
Patients with PHI (n = 43) were enrolled before, 24 and 48 weeks after therapy initiation. Quantification of soluble immune mediators was performed in plasma from HIV infected patients and healthy donors (HD, n = 7) by Luminex technology.
The cytokines profile was strongly perturbed in primary HIV infected patients when compared to healthy donors (HD). After 48 weeks of ART, some of these factors were restored to HD level (IL-2, IL-5, IL-7, IL-9, IL12p70, TNFα) while others persisted higher than HD (IL-6, IL-10, IL-13). Interestingly, a subset of chemokines, such as IL-8, MCP-1, RANTES and CCL27, and growth factors such as HGF, SCF and GM-CSF, increased during ART, reaching values significantly higher than HD after 48 weeks. Moreover, the G-CSF and MIP-1β soluble mediators were persistently altered and showed an inverse correlation with the CD4/CD8 T cell ratio.
The increase of chemokines with antiviral activity and of growth factors with hematopoietic and immunomodulatory properties may have beneficial effects. Other studies are mandatory to evaluate the effects of long lasting levels of these factors to clarify their possible role in the context of protection/pathogenesis.
Despite the higher transmissibility of Omicron Variant of Concern (VOC), several reports have suggested lower risk for hospitalization and severe outcomes compared to previous variants of SARS‐CoV‐2. ...This study, enrolling all COVID‐19 adults admitted to a reference hospital who underwent both the S‐gene‐target‐failure test and VOC identification by Sanger sequencing, aimed to describe the evolving prevalence of Delta and Omicron variants and to compare the main in‐hospital outcomes of severity, during a trimester (December 2021 to March 2022) of VOCs' cocirculation. Factors associated with clinical progression to noninvasive ventilation (NIV)/mechanical ventilation (MV)/death within 10 days and to MV/admission to intensive care unit (ICU)/death within 28 days, were investigated through multivariable logistic regressions. Overall, VOCs were: Delta n = 130/428, Omicron n = 298/428 (sublineages BA.1 n = 275 and BA.2 n = 23). Until mid‐February, Delta predominance shifted to BA.1, which was gradually displaced by BA.2 until mid‐March. Participants with Omicron VOC were more likely to be older, fully vaccinated, with multiple comorbidities and to have a shorter time from symptoms' onset, and less likely to have systemic symptoms and respiratory complications. Although the need of NIV within 10 days and MV within 28 days from hospitalization and the admission to ICU were less frequent for patients with Omicron compared to those with Delta infections, mortality was similar between the two VOCs. In the adjusted analysis, multiple comorbidities and a longer time from symptoms' onset predicted 10‐day clinical progression, while complete vaccination halved the risk. Multimorbidity was the only risk factor associated with 28‐day clinical progression. In our population, in the first trimester of 2022, Omicron rapidly displaced Delta in COVID‐19 hospitalized adults. Clinical profile and presentation differed between the two VOCs and, although Omicron infections showed a less severe clinical picture, no substantial differences for clinical progression were found. This finding suggests that any hospitalization, especially in more vulnerable individuals, may be at risk for severe progression, which is more related to the underlying frailty of patients than to the intrinsic severity of the viral variant.
Highlights • HIV-1 RNA is often detected by ultrasensitive methods in patients on successful ART. • HIV-1 DNA is detected in blood cells in virtually all patients on successful ART. • Switch from ...NNRTI or PI to raltegravir-based ART can decrease cellular HIV-1 DNA. • Residual HIV-1 RNA is not affected by switching from NNRTI or PI to RAL-based ART. • Switching to a RAL-based regimen may help to reduce the size of the HIV reservoir.
We evaluated the characteristics of HIV-1 molecular transmission clusters (MTCs) in 1890 newly diagnosed individuals infected with non-B subtypes between 2005 and 2017 in Italy.
Phylogenetic analyses ...were performed on
sequences to characterise subtypes/circulating recombinant forms and identify MTCs. MTCs were divided into small (SMTCs, 2-3 sequences), medium (MMTCs, 4-9 sequences) and large (LMTCs, ≥10 sequences). Factors associated with MTCs were evaluated using logistic regression analysis.
145 MTCs were identified and involved 666 individuals (35.2%); 319 of them (16.9%) were included in 13 LMTCs, 111 (5.9%) in 20 MMTCs and 236 (12.5%) in 112 SMTCs. Compared with individuals out of MTCs, individuals involved in MTCs were prevalently Italian (72.7% vs 30.9%, p<0.001), male (82.9% vs 62.3%, p<0.001) and men who have sex with men (MSM) (43.5% vs 14.5%, p<0.001). Individuals in MTCs were also younger (median (IQR) years: 41 (35-49) vs 43 (36-51), p<0.001) and had higher CD4 cell count in comparison with individuals out of MTCs (median (IQR): 10
/L: 0.4 (0.265-0.587) vs 0.246 (0.082-0.417), p<0.001). The viral load remained stable between the two groups (median (IQR) log
copies/mL: 4.8 (4.2-5.5) vs 5.0 (4.3-5.5), p=0.87). Logistic regression confirmed that certain factors such as being MSM, of Italian origin, younger age and higher CD4 cell count were significantly associated with MTCs.
Our findings show that HIV-1 newly diagnosed individuals infected with non-B subtypes are involved in several MTCs in Italy. These MTCs include mainly Italians and MSM and highlight the complex phenomenon characterising the HIV-1 spread. This is important especially in view of monitoring the HIV epidemic and guiding the public health response.
The aim of the study was to explore how viral resistance and antiretroviral central nervous system (CNS) penetration could impact on cognitive performance of HIV-infected patients.
We performed a ...multicentre cross-sectional study enrolling HIV-infected patients undergoing neuropsychological testing, with a previous genotypic resistance test on plasma samples. CNS penetration-effectiveness (CPE) scores and genotypic susceptibility scores (GSS) were calculated for each regimen. A composite score (CPE-GSS) was then constructed. Factors associated with cognitive impairment were investigated by logistic regression analysis.
A total of 215 patients were included. Mean CPE was 7.1 (95% CI 6.9, 7.3) with 206 (95.8%) patients showing a CPE≥6. GSS correction decreased the CPE value in 21.4% (mean 6.5, 95% CI 6.3, 6.7), 26.5% (mean 6.4, 95% CI 6.1, 6.6) and 24.2% (mean 6.4, 95% CI 6.2, 6.6) of subjects using ANRS, HIVDB and REGA rules, respectively. Overall, 66 (30.7%) patients were considered cognitively impaired. No significant association could be demonstrated between CPE and cognitive impairment. However, higher GSS-CPE was associated with a lower risk of cognitive impairment (CPE-GSSANRS odds ratio 0.75, P=0.022; CPE-GSSHIVDB odds ratio 0.77, P=0.038; CPE-GSSREGA odds ratio 0.78, P=0.038). Overall, a cutoff of CPE-GSS≥5 seemed the most discriminatory according to each different interpretation system.
GSS-corrected CPE score showed a better correlation with neurocognitive performance than the standard CPE score. These results suggest that antiretroviral drug susceptibility, besides drug CNS penetration, can play a role in the control of HIV-associated neurocognitive disorders.
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