Aim was to determine the dynamics of peripheral blood mononuclear cells (PBMC)- associated total HIV-1 DNA in successfully ART-treated HIV/HCV co-infected patients receiving DAA treatment and to ...explore possible virological hypotheses underlying the phenomenon.
Longitudinal, single-centre study measuring total HIV-1 DNA before the start of DAA, at the end of treatment (EOT), and 3 months after treatment. Univariable and multivariable analyses were used to assess factors associated with HIV-1 DNA increase ≥0.5 Log copies/million PBMC. Episomal 2-LTR forms, residual HIV-1 viremia and proviral DNA quasispecies evolution were also investigated.
119 successfully ART-treated HIV/HCV co-infected patients were included. Median baseline HIV-1 DNA was 3.84 Log copies/million PBMC (95%CI 3.49-4.05), and no significant variation with respect to baseline was found at EOT and after 3 months of DAA termination. In 17% of cases an increase ≥0.5 Log copies/million PBMC was observed at EOT compared to baseline. HIV-1 DNA increase was independently associated with lower baseline HIV-1 DNA, longer HIV suppression, raltegravir-based ART and previous exposure to interferon/ribavirin for HCV treatment. In none of the patients with HIV-1 DNA increase, 2-LTR forms were detected at baseline, while in 2 cases 2-LTR forms were found at EOT, without association with residual HIV-1 RNA viremia. No evidence of viral evolution was observed.
In successfully ART-treated HIV/HCV co-infected patients receiving DAA, PBMC-associated total HIV-1 DNA was quite stable over time, but some patients showed a considerable increase at EOT when compared to baseline. A significantly higher risk of HIV DNA increase was found, in presence of lower cellular HIV reservoir at baseline. Activation of replicative-competent virus generating new rounds of viral replication seems unlikely, while mobilization of cell-associated HIV from tissue reservoirs could be hypothesized.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The emerging threat represented by SARS-CoV-2 variants, demands the development of therapies for better clinical management of COVID-19. MAD0004J08 is a potent Fc-engineered monoclonal antibody (mAb) ...able to neutralize in vitro all current SARS-CoV-2 variants of concern (VoCs) including the omicron variant even if with significantly reduced potency. Here we evaluated data obtained from the first 30 days of a phase 1 clinical study (EudraCT N.: 2020-005469-15 and ClinicalTrials.gov Identifier: NCT04932850). The primary endpoint evaluated the percentage of severe adverse events. Secondary endpoints evaluated pharmacokinetic and serum neutralization titers. A single dose administration of MAD0004J08 via intramuscular (i.m.) route is safe and well tolerated, resulting in rapid serum distribution and sera neutralizing titers higher than COVID-19 convalescent and vaccinated subjects. A single dose administration of MAD0004J08 is also sufficient to effectively neutralize major SARS-CoV-2 variants of concern (alpha, beta, gamma and delta). MAD0004J08 can be a major advancement in the prophylaxis and clinical management of COVID-19.
Molecular investigation of primary HIV infections (PHI) is crucial to describe current dynamics of HIV transmission. Aim of the study was to investigate HIV transmission clusters (TC) in PHI referred ...during the years 2013-2020 to the National Institute for Infectious Diseases in Rome (INMI), that is the Lazio regional AIDS reference centre, and factors possibly associated with inclusion in TC. These were identified by phylogenetic analysis, based on population sequencing of
; a more in depth analysis was performed on TC of B subtype, using ultra-deep sequencing (UDS) of
. Of 270 patients diagnosed with PHI during the study period, 229 were enrolled (median follow-up 168 (IQR 96-232) weeks). Median age: 39 (IQR 32-48) years; 94.8% males, 86.5% Italians, 83.4% MSM, 56.8% carrying HIV-1 subtype B. Of them, 92.6% started early treatment within a median of 4 (IQR 2-7) days after diagnosis; median time to sustained suppression was 20 (IQR 8-32) weeks. Twenty TC (median size 3, range 2-9 individuals), including 68 patients, were identified. A diagnosis prior to 2015 was the unique factor associated with inclusion in a TC. Added value of UDS was the identification of shared quasispecies components in transmission pairs within TC.
The optimal therapeutic approach for primary HIV infection (PHI) is still debated. We aimed to compare the viroimmunological response to a four- versus a three-drug regimen, both INSTI-based, in ...patients with PHI. This was a monocentric, prospective, observational study including all patients diagnosed with PHI from December 2014 to April 2018. Antiretroviral therapy (ART) was started, before genotype resistance test results, with tenofovir/emtricitabine and either raltegravir plus boosted darunavir or dolutegravir. Cumulative probability of virological suppression VS (HIV-1 RNA< 40 cp/mL), low-level HIV-1 DNA LL-HIVDNA (HIV-1 DNA < 200 copies/106PBMC), and CD4/CD8 ratio ≥1 were estimated using Kaplan−Meier curves. Factors associated with the achievement of VS, LL-HIVDNA, and CD4/CD8 ≥ 1 were assessed by a Cox regression model. We enrolled 144 patients (95.8% male, median age 34 years): 110 (76%) started a four-drug-based therapy, and 34 (24%) a three-drug regimen. Both treatment groups showed a comparable high probability of achieving VS and a similar probability of reaching LL-HIVDNA and a CD4/CD8 ratio ≥1 after 48 weeks from ART initiation. Higher baseline HIV-1 RNA and HIV-1 DNA levels lowered the chance of VS, whereas a better preserved immunocompetence increased that chance. Not statistically significant factors associated with LL-HIVDNA achievement were found, whereas a higher baseline CD4/CD8 ratio predicted the achievement of immune recovery. In PHI patients, the rapid initiation of either an intensified four-drug or a standard three-drug INSTI-based regimen showed comparable responses in terms of VS, viral reservoir size, and immunological recovery.
Background: There is conflicting evidence for how HIV influences COVID-19 infection. The aim of this study was to compare characteristics at presentation and the clinical outcomes of people living ...with HIV (PLWH) versus HIV-negative patients (non-PLWH) hospitalized with COVID-19. Methods: Primary endpoint: time until invasive ventilation/death. Secondary endpoints: time until ventilation/death, time until symptoms resolution. Results: A total of 1647 hospitalized patients were included (43 (2.6%) PLWH, 1604 non-PLWH). PLWH were younger (55 vs. 61 years) and less likely to be with PaO2/FiO2 < 300 mmHg compared with non-PLWH. Among PLWH, nadir of CD4 was 185 (75−322) cells/μL; CD4 at COVID-19 diagnosis was 272 cells/μL (127−468) and 77% of these were virologically suppressed. The cumulative probability of invasive mechanical ventilation/death at day 15 was 4.7% (95%CI 1.2−17.3) in PLWH versus 18.9% (16.9−21.1) in non-PLWH (p = 0.023). The cumulative probability of non-invasive/invasive ventilation/death at day 15 was 20.9% (11.5−36.4) in PLWH versus 37.6% (35.1−40.2) in non-PLWH (p = 0.044). The adjusted hazard ratio (aHR) of invasive mechanical ventilation/death of PLWH was 0.49 (95% CI 0.12−1.96, p = 0.310) versus non-PLWH; similarly, aHR of non-invasive/invasive ventilation/death of PLWH was 1.03 (95% CI 0.53−2.00, p = 0.926). Conclusion: A less-severe presentation of COVID-19 at hospitalization was observed in PLWH compared to non-PLWH; no difference in clinical outcomes could be detected.
Abstract
In order to investigate safety and immunogenicity of SARS-CoV-2 vaccine third dose in people living with HIV (PLWH), we analyze anti-RBD, microneutralization assay and IFN-γ production in ...216 PLWH on ART with advanced disease (CD4 count <200 cell/mm
3
and/or previous AIDS) receiving the third dose of a mRNA vaccine (BNT162b2 or mRNA-1273) after a median of 142 days from the second dose. Median age is 54 years, median CD4 nadir 45 cell/mm
3
(20–122), 93% HIV-RNA < 50 c/mL. In 68% of PLWH at least one side-effect, generally mild, is recorded. Humoral response after the third dose was strong and higher than that achieved with the second dose (>2 log
2
difference), especially when a heterologous combination with mRNA-1273 as third shot is used. In contrast, cell-mediated immunity remain stable. Our data support usefulness of third dose in PLWH currently receiving suppressive ART who presented with severe immune dysregulation.
HIV-associated neurocognitive disorders (HAND) have been suggested as persistent even with effective antiretroviral therapy (ART). Aims were to evaluate HAND prevalence and associated factors, in a ...large cohort of people-with-HIV (PWH).
ART-treated PWH, underwent a neuropsychological examination through a battery of 12 tests exploring 5 different domains, between 2009 and 2020, were included in this cross-sectional analysis. HAND were classified according to Frascati's criteria. Participants were defined as complaining or not-complaining if a cognitive complaint was reported or not. Chi-square for trend and multivariable logistic regression were fitted.
Overall, 1424 PWH were enrolled during four three-years periods. HAND prevalence was 24%; among complainers (572/1424), it was 38%, higher than among not-complainers (15%). Over the study period, a decreasing HAND prevalence was found in the entire population (P < 0.001) and in complaining (P < 0.001); in not-complaining it remained stable (P = 0.182). Factors associated with HAND were older age, lower educational level, lower current CD4+ T-cell count and HCV co-infection. Compared to nonnucleoside reverse transcriptase inhibitors, receiving dual and integrase strand transfer inhibitor (INSTI)-based therapies was associated with a decreased risk of HAND, as well as being tested in more recent years.
In this large cohort of ART-treated PWH, mostly virologically suppressed, a remarkable decreasing HAND prevalence was observed. Besides HIV- and patient-related factors, the reduced risk of HAND found with dual and INSTI-based regimens along with a more recent ART initiation, could suggest a potential role of new treatment strategies in this decline, due to their greater virologic efficacy and better tolerability.
Introduction
Chronic liver disease leads to neurocognitive impairment (NCI) and more advanced liver fibrosis is associated with greater deficits. Further, cognitive performances do not differ ...significantly among patients affected by diverse types of chronic liver diseases. Thus, it would be useful to have a clinical tool associated with early cognitive change applicable to the HIV‐infected population with high HCV prevalence. Aim of the analysis was to assess the association between NCI and aspartate aminotransferase‐platelet ratio index (APRI) or Fibrosis‐4, which are non‐invasive scores used to assess liver fibrosis.
Materials and Methods
Single‐centre, retrospective, cross‐sectional analysis of cART‐treated HIV‐infected patients undergoing neuropsychological assessment (NPA) by a set of 14 standardized and comprehensive tests on five different domains: concentration and speed of mental processing; mental flexibility; memory, fine motor functioning; visual‐spatial and constructional abilities. NPA obtained from the same patient were included, if collected while receiving different cART. Patients were classified as having NCI, if they scored >1 SD below the normative mean in at least two tests, or below >2 SD in one test. HIV‐associated neurocognitive disorders (HAND) were classified according to Frascati's criteria, controlling for confounding comorbidities. Univariable analysis and multivariable logistic regression models were carried out.
Results
A total of 556 HIV‐infected cART‐treated patients from 2006 to 2013 were included: male 78%; IVDUs 14%; CDC stage C 31%; median CD4 nadir 200/mm3; median current CD4 501/mm3; undetectable HIV‐RNA in 368 (67%); and HCV‐positivity in 150 (29%). Frequency among score levels was for FIB‐4: min‐1.44=404 (73%), 1.45–3.25=118 (21%), 3.26‐max=28 (5%); for APRI: min‐0.5=414 (75%), 0.5–1.5=112 (20%), 1.5‐max=24 (4%). Median FIB‐4 and APRI were 0.98 and 0.27 in HIV+/HCV‐ and 1.40 and 0.50 in HIV+/HCV+ individuals, respectively. HAND was found in 176 (32%): 91 ANI, 73 MND, 12 HAD. Association of variables with NCI are shown in Table 1.
Conclusions
In this large population, HAND was not associated with commonly used non‐invasive liver fibrosis scores. As aetiology of cognitive dysfunction in HIV mono‐ and HCV co‐infected patients is multifactorial and partially unknown, our results support the hypothesis of a direct or indirect effect on cognitive function of the viruses, rather than the consequence of alterations residing outside the brain.
Introduction
Central nervous system (CNS) penetration‐effectiveness (CPE) rank was proposed in 2008 as an estimate of penetration of ARV regimen into the CNS, and validated as predictor of CSF HIV‐1 ...replication. Results on predictive role of CPE on neurocognitive and clinical outcome were conflicting.
Materials and Methods
Retrospective, cross‐sectional analysis of neurocognitive profile in HIV‐infected cART‐treated patients. All patients underwent neuropsychological (NP) assessment by standardized battery of 14 tests on 5 different domains. People were classified as having NCI if they scored >1 standard deviation (SD) below the normal mean in at least two tests, or >2 SD below in one test. Linear and logistic regression analyses were fitted using as outcome Npz8 and impaired/not impaired respectively.
Results
A total of 660 HIV‐infected cART‐treated individuals from 2009 to 2014, contributing a total of 1003 tests (mean age 49 (IQR 43–56), male 82%; median current CD4 586/mm3; 18% HCV infected; HIV‐RNA <40 cp/mL in 84%). Current ARV regimen was 2NRTIs+1NNRTI 50.3%, 2NRTI+1PI/r in 32.6%, NRTI sparing in 11.1%. Mean CPE of current regimens was 6.6 (95% CI 6.5–6.7). As per test multivariable analysis, higher CPE values were associated to poor NP tasks (Beta=−0,09; 95% CI −0,14 −0,03; p=0.002 at multivariable linear regression). The association between higher CPE and increased NCI risk was confirmed at multivariable logistic regression, with a 1.24‐fold risk of NCI occurrence for each point increase of CPE of current regimen at the time of NP testing (see Table 1). In a sensitivity analysis performed only on patients at the first NP test, the association between higher CPE and poor NP tasks and enhanced NCI risk was only marginally confirmed (Beta=−0,05; −0,12–0,02; p=0,19; OR 1,13 0,95–1,34; p=0.17). Older age, longer time from HIV diagnosis, current CD4 count <350 cell/mm3 and lower education level were all associated to an increased risk of NCI.
Conclusions
In our analysis, higher CPE rank is associated to poorly performing at NP tasking. Even if selection bias could not be excluded due to retrospective cross‐sectional design, these results fitted with the direct correlation between high CPE and HIV dementia recently recorded in a large observational database. We think that CPE use to guide ART in patients neurocognitively impaired should be revised.
Abstract
Background
Data on SARS-CoV-2 vaccine immunogenicity in PLWH are currently limited. Aim of the study was to investigate immunogenicity according to current CD4 T-cell count
Methods
PLWH on ...ART attending a SARS-CoV-2 vaccination program, were included in a prospective immunogenicity evaluation after receiving BNT162b2 or mRNA-1273. Participants were stratified by current CD4 T-cell count (poor CD4 recovery, PCDR: <200/mm3; intermediate CD4 recovery, ICDR: 200–500/mm3; high CD4 recovery, HCDR: >500/mm3). RBD-binding IgG, SARS-CoV-2 neutralizing antibodies (nAbs) and IFN-γ release were measured. As control group, HIV-negative healthcare workers (HCWs) were used
Findings
Among 166 PLWH, after 1 month from the booster dose, detectable RBD-binding IgG were elicited in 86.7% of PCDR, 100% of ICDR, 98.7% of HCDR, and a neutralizing titre ≥1:10 elicited in 70.0%, 88.2%, and 93.1%, respectively. Compared to HCDR, all immune response parameters were significantly lower in PCDR. After adjusting for confounders, current CD4 T-cell <200/mm3 significantly predicted a poor magnitude of anti-RDB, nAbs and IFN-γ response. As compared with HCWs, PCDR elicited a consistently reduced immunogenicity for all parameters, ICDR only a reduced RBD-binding antibody response, whereas HCDR elicited a comparable immune response for all parameters
Conclusion
Humoral and cell-mediated immune response against SARS-CoV-2 were elicited in most of PLWH, albeit significantly poorer in those with CD4 T-cell <200/mm3 versus those with >500 cell/mm3 and HIV-negative controls. A lower RBD-binding antibody response than HCWs was also observed in PLWH with CD4 T-cell 200–500/mm3, whereas immune response elicited in PLWH with a CD4 T-cell >500/mm3 was comparable to HIV-negative population
Humoral and cell-mediated immune-response against SARS-CoV-2 were elicited in PLWH, significantly poorer in those with CD4 T-cell <200/mm3vs those with >500 cell/mm3and HIV-negative controls; immune response in PLWH with a CD4 T-cell >500/mm3 was comparable to HIV-negative population.
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