Determinants of radiological patterns and severity in immunocompromised adults with Metapneumovirus infection.

BACKGROUND: Human Metapneumovirus (HMPV) belongs to the Pneumoviridae family and is responsible for respiratory infections. Mild infections are well-recognized in children, while its precise impact in various categories of immunocompromised adults has not been well addressed. RESEARCH QUESTION: We retrospectively studied HMPV infections in immunocompromised adults followed in two large French university medical centers. STUDY DESIGN AND METHODS: We identified immunocompromised adults with positive HMPV Polymerase Chain Reaction (PCR) for 36 months and reviewed their medical charts. For lung transplant recipients (LTR), FEV1 was collected at baseline, during and after infection. Imaging was centralized and chest involvement was categorized by dominant CT patterns. We compared severe patients (requiring oxygen or ventilation) and non hypoxemic patients. RESULTS: Seventy-two patients were included, 27 were LTR, 25 had a hematological malignancy or were hematopoietic stem cell recipients, 20 had another immunocompromised status. Twenty patients (28%) presented a hypoxemic infection, requiring hospitalization and intensive care units transfers in 50/72 (69.4%) and 9/72 (12.5%) respectively, with only one death. Hypoxemia was less pronounced in LTRs (p = 0.014). Finally, age and dyspnea remained independent factors associated with hypoxemia (p < 0.005). The most frequent radiological patterns were bronchopneumonia (34.2%) and bronchiolitis (39.5% and 64.3% in the overall population and in LTRs respectively, p = 0.045). FEV1 improved in LTRs at one month and 85% had recovered their baseline FEV1 within 6 months. INTERPRETATIONS: In immunocompromised adults, HMPV infections required frequent hospitalizations and ICU transfers, while mortality is low. In LTRs, bronchiolitis pattern was predominant with short and long-term favorable outcome.

Bictegravir/emtricitabine/tenofovir alafenamide in paediatrics: Real-life experience from a French cohort (2019-2023).

OBJECTIVES: Although widely recommended, data on bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) efficacy in HIV-1-infected children/adolescents are mainly extrapolated from studies in adults and one paediatric trial in which subjects have good treatment adherence. This study aimed to provide data about the risk of virological failure (VF) and acquired genotypic resistance in children and adolescents receiving BIC/FTC/TAF in a real-world setting. METHODS: This retrospective monocentric study included 74 paediatric patients who received BIC/FTC/TAF during ≥6 months in 2019-2023. VF was defined as not achieving a plasma viral load <50 copies/mL within 6 months of BIC/FTC/TAF initiation or as experiencing virological rebound ≥50 copies/mL. RESULTS: Most patients were antiretroviral therapy (ART)-experienced (93.2%), previously exposed to integrase inhibitors (85.1%) and displayed viral suppression at baseline (67.6%). Their median age was 11.2 years [interquartile range (IQR): 8.8-15.2]. BIC/FTC/TAF introduction reduced treatment burden in most ART-experienced subjects. Genotypic susceptibility score of BIC/FTC/TAF was ≥2 in all cases. Median follow-up was 40 months (IQR: 21-46). VF occurred in 28 people (37.8%), more frequently in the case of VF versus viral suppression at baseline (68% vs. 26%, P = 0.02). BIC/FTC/TAF was interrupted for suspected intolerance in only one case (1.4%). Nucleoside reverse transcriptase inhibitor (NRTI) mutation (T69D/N) emerged in one patient (3.6% of VF) after 47 months of continuous detectable viraemia while on ART. No acquisition of mutations in the integrase gene was observed. CONCLUSION: Because of its high genetic barrier to resistance, BIC/FTC/TAF could be especially useful in the paediatric population, in which the risk of poor treatment adherence and VF is high.

High rates of antiretroviral coverage and virological suppression in HIV-1-infected children and adolescents.

OBJECTIVES: To assess the outcome of HIV-infected individuals attending one of the largest French pediatric HIV centers in 2016-2017 and to compare the rates of antiretroviral coverage and virological suppression with the UNAIDS targets. PATIENTS AND METHODS: The clinical and immuno-virological status of 163 HIV-1-infected children and adolescents attending Necker Hospital in Paris, France, were investigated. Virological suppression was defined as an HIV-1 viral load<50 copies/mL for at least six months. All genotypic resistance tests performed since birth were analyzed. RESULTS: Most patients were born in Sub-Saharan African countries (41.7%) or in France (38.0%). Their median age was 14 years [IQR 7.3-17.0]. Although 33.7% of individuals had a history of AIDS-defining clinical event(s), 86.5% of children/adolescents were free from HIV-related symptoms at their most recent evaluation. Antiretroviral coverage was high (98.2%; mainly including one integrase inhibitor [42.3%] or one protease inhibitor [23.9%]). At the last visit, most patients (82.8%) had normal CD4T lymphocytes counts (≥25%). Although 61.7% of antiretroviral-experienced children had resistance to≥1 drug class and 9.2% had triple-class resistance, 80.3% of patients receiving antiretrovirals for≥6 months (126/157) were virologically suppressed. International adoptees were more frequently virologically suppressed than other patients (96.0% versus 74.6%, P=0.02). CONCLUSIONS: Antiretroviral coverage exceeded the second UNAIDS 90 target aimed at ending the AIDS epidemic. The rate of virological suppression, one of the highest reported in children in high-income countries, is approaching the third UNAIDS 90 target and the rate observed in French HIV-infected adults on antiretrovirals.

Similar efficacy and safety of dolutegravir between age groups of HIV-1-infected paediatric and young adult patients aged 5 years and older.

OBJECTIVES: The aim of the study was to carry out a comparison of the safety and efficacy of dolutegravir-based regimens among age groups of HIV-1-infected paediatric and young adult patients. PATIENTS AND METHODS: This retrospective monocentric study included 109 patients infected since childhood who began receiving dolutegravir between January 2014 and December 2017. The patients were divided into three groups according to age at the time of dolutegravir initiation: 5-11, 12-17 and 18-25 years old. The primary endpoint was the proportion of patients achieving a plasma viral load (PVL) < 50 HIV-1 RNA copies/mL within 3 months of dolutegravir initiation (for patients with detectable viraemia at baseline), and maintaining virological suppression (PVL < 50 copies/mL) until the last follow-up visit (for all patients). RESULTS: Most of the subjects were antiretroviral-experienced (91.7%) and virologically suppressed at baseline (66.7%, 54.9% and 56.0% in the 5-11, 12-17 and 18-25 year age groups, respectively). Median follow-up was 24 months (range 6-54 months). Sustained virological success throughout follow-up was observed in 79.8% of patients, with similar rates among age groups (87.9%, 72.5% and 84.0%, respectively; P = 0.22). With reinforced measures to improve adherence, undetectable PVL was obtained at the last visit in 88.1% of patients, with similar proportions among age groups (93.9%, 84.3% and 88.0%, respectively; P = 0.51). No emergence of resistance mutations was observed in the 22 patients with virological failure. Dolutegravir was well tolerated; only one patient stopped treatment for severe drug-related side effects. CONCLUSIONS: The virological efficacy and safety of dolutegravir were similar among the three age groups. Because of its high genetic barrier to resistance, dolutegravir could be especially useful in the paediatric population, in which the risk of poor treatment adherence is high.

Comparative performance of the Biocentric Generic Viral Load, Roche CAP/CTM v1.5, Roche CAP/CTM v2.0 and m2000 Abbott assays for quantifying HIV-1 B and non-B strains: Underestimation of some CRF02 strains.

BACKGROUND: HIV-1 viral load testing is now recommended by the World Health Organization for every patient receiving antiretroviral therapy (ART). OBJECTIVES: The objective of this study is to evaluate the performance of commercial assays for their ability to quantify HIV-1 strains currently circulating in France. STUDY DESIGN: The performances of the Generic HIV-RNA assay from Biocentric were compared to those of the Roche CAP/CTM v1.5, Roche CAP/CTM v2.0 and Abbott m2000 RealTime HIV-1 assays. A total of 1885 HIV-1 plasma samples were tested, including 684 samples from patients included in the ANRS-Primo Cohort. RESULTS: We found a good concordance of quantification between the Roche v2.0 and the Biocentric assays, both of which were superior to the Roche v1.5 assay. We show moderate agreement between techniques; however, CRF02_AG strains and undetermined viruses were underestimated when quantified with the Roche CAP/CTM v2.0. In contrast, a comparison of the Biocentric and Abbott assay results showed strong agreement between assays, indicating that both are well suited for quantification of CRF02_AG strains. Moreover, a 2% underestimation of the B subtypes was observed with the Biocentric assay. CONCLUSIONS: These results have implications for viral load monitoring in Western Africa, where CRF02_AG strains are highly prevalent. Closer epidemiological surveillance and evaluation of commercial assays are still necessary to better evaluate the impact of the genetic evolution of circulating viruses on HIV-RNA quantification in the regions most affected by the HIV-1 epidemic.

Performance of genotypic algorithms for predicting tropism for HIV-1 CRF01_AE recombinant.

OBJECTIVES: There is no consensus about the performances of genotypic rules for predicting HIV-1 non-B subtype tropism. Three genotypic methods were compared for CRF01_AE HIV-1 tropism determination. METHODS: The V3 env region of 207 HIV-1 CRF01_AE and 178 B subtypes from 17 centers in France and 1 center in Switzerland was sequenced. Tropism was determined by Geno2Pheno algorithm with false positive rate (FPR) 5% or 10%, the 11/25 rule or the combined criteria of the 11/25, net charge rule and NXT/S mutations. RESULTS: Overall, 72.5%, 59.4%, 86.0%, 90.8% of the 207 HIV-1 CRF01_AE were R5-tropic viruses determined by Geno2pheno FPR5%, Geno2pheno FPR10%, the combined criteria and the 11/25 rule, respectively. A concordance of 82.6% was observed between Geno2pheno FPR5% and the combined criteria for CRF01_AE. The results were nearly similar for the comparison between Geno2pheno FPR5% and the 11/25 rule. More mismatches were observed when Geno2pheno was used with the FPR10%. Neither HIV viral load, nor current or nadir CD4 was associated with the discordance rate between the different algorithms. CONCLUSION: Geno2pheno predicted more X4-tropic viruses for this set of CRF01_AE sequences than the combined criteria or the 11/25 rule alone. For a conservative approach, Geno2pheno FPR5% seems to be a good compromise to predict CRF01_AE tropism.

What Is the most Important for Elite Control: Genetic Background of Patient, Genetic Background of Partner, both or neither? Description of Complete Natural History within a Couple of MSM.

BACKGROUND: We describe a homosexual man who strongly controlled HIV-1 for ten years despite lack of protective genetic background. METHODS: HIV-1 DNA was measured in blood and other tissues. Cell susceptibility was evaluated with various strains. HIV-1-specific (CD4 and CD8 activation markers and immune check points) and NK cells responses were assessed; KIRs haplotypes and HLA alleles were determined. FINDINGS: Two HIV-1 RNA copies/mL of plasma were detected in 2009, using an ultra-sensitive assay. HIV-DNA was detected at 1.1 and 2 copies/106 PBMCs in 2009 and 2015 respectively, at 1.2 copies/106 cells in rectal cells in 2011. WBs showed weak reactivity with antibodies to gp160, p55 and p25 from 2007 to 2014, remaining incomplete in 2017. CD4 T cells were susceptible to various strains including HIVKON, a primary isolate of his own CRF02_AG variant. CD8 T cells showed a strong poly-functional response against HIV-Gag, producing mainly IFN-γ; a robust capacity of antibody-dependant cell cytotoxicity (ADCC) was observed in NK cells. Case patient was group B KIR haplotype. Neutralizing antibodies were not detected. CD4 and CD8 blood T cells showed normal proportions without increased activation markers. Phylogenetic analyses identified the same CRF02_AG variant in his partner. The patient and his partner were heterozygous for the CCR5ΔD32 deletion and shared HLA-B*07, C*07 non-protective alleles. INTERPRETATION: This thorough description of the natural history of an individual controlling HIV-1 in various compartments for ten years despite lack of protective alleles, and of his partner, may have implications for strategies to cure HIV-1 infection.

Predominance of G9P[8] rotavirus strains throughout France, 2014-2017.

OBJECTIVES: Group A rotavirus is a major cause of acute gastroenteritis in young children worldwide. A prospective surveillance network has been set up in France to investigate rotavirus infections and to detect the emergence of potentially epidemic strains. METHODS: From 2014 to 2017, rotavirus-positive stool samples were collected from 2394 children under 5 years old attending the paediatric emergency units of 13 large hospitals. Rotaviruses were genotyped by RT-PCR with regard to their outer capsid proteins VP4 and VP7. RESULTS: Genotyping of 2421 rotaviruses showed that after a marked increase in G9P[8] (32.1%) during the 2014-2015 season, G9P[8] became the predominant genotype during the 2015-2016 and 2016-2017 seasons with detection rates of 64.1% and 77.3%, respectively, whereas G1P[8] were detected at low rates of 16.8% and 6.6%, respectively. Phylogenetic analysis of the partial rotavirus VP7 and VP4 coding genes revealed that all of these G9P [8] strains belonged to the lineage III and the P [8]-3 lineage, respectively, and shared the same genetic background (G9-P[8]-I1-R1-C1-M1-A1-N1-T1-E1-H1) as did most of previously detected G9P[8] strains and particularly the emerging G9P[8] strains from the 2004-2005 season in France. CONCLUSIONS: G9P[8] rotaviruses have become the predominant circulating genotype for the first time since their emergence a decade ago. In the absence of rotavirus immunization programmes in France, our data give an insight into the natural fluctuation of rotavirus genotypes in a non-vaccinated population and provide a base line for a better interpretation of data in European countries with routine rotavirus vaccination.

Clinical severity and molecular characteristics of circulating and emerging rotaviruses in young children attending hospital emergency departments in France.

Group A rotavirus (RVA) is the leading cause of acute gastroenteritis in young children worldwide. A prospective surveillance network has been set up to investigate the virological and clinical features of RVA infections and to detect the emergence of potentially epidemic strains in France. From 2009 to 2014, RVA-positive stool samples were collected from 4800 children <5 years old attending the paediatric emergency units of 16 large hospitals. Rotaviruses were then genotyped by RT-PCR with regard to their outer capsid proteins VP4 and VP7. Genotyping of 4708 RVA showed that G1P[8] strains (62.2%) were predominant. The incidence of G9P[8] (11.5%), G3P[8] (10.4%) and G2P[4] (6.6%) strains varied considerably, whereas G4P[8] (2.7%) strains were circulating mostly locally. Of note, G12P[8] (1.6%) strains emerged during the seasons 2011-12 and 2012-13 with 4.1% and 3.0% prevalence, respectively. Overall, 40 possible zoonotic reassortants, such as G6 (33.3%) and G8 (15.4%) strains, were detected, and were mostly associated with P[6] (67.5%). Analysis of clinical records of 624 hospitalized children and severity scores from 282 of them showed no difference in clinical manifestations or severity in relation to the genotype. The relative stability of RVA genotypes currently co-circulating and the large predominance of P[8] type strains may ensure vaccine effectiveness in France. The surveillance will continue to monitor the emergence of new reassortants that might not respond to current vaccines, all the more so as all genotypes can cause severe infections in infants.

Early initiation of combined antiretroviral therapy preserves immune function in the gut of HIV-infected patients.

Massive loss of lamina propria CD4(+) T cells, changes in the lymphatic architecture, and altered intestinal epithelial barrier leading to microbial translocation are the common features of HIV-1 infection and are not fully restored under combined antiretroviral therapy (cART). To better understand determinants of gut mucosal restoration, we have performed phenotypic and gene expression analyses of the gut from HIV-infected patients, naive or treated with cART initiated either at the early phase of the primary infection or later during the chronic phase. We found a depletion of T helper type 22 (Th22) and interleukin-17-producing cells in naive patients. These populations, except Th22 cells, were not restored under cART. Regulatory T cells/Th17 ratio was significantly increased in HIV-infected patients and was inversely correlated to the restoration of CD4(+) T cells but not to gut HIV DNA levels. Gene profile analysis of gut mucosal distinguished two groups of patients, which fitted with the timing of cART initiation. In their majority early, but not later treated patients, exhibited conserved intestinal lymphoid structure, epithelial barrier integrity and dendritic cell maturation pathways. Our data demonstrate that early initiation of cART helps to preserve and/or restore lymphoid gut mucosal homeostasis and provide a rationale for initiating cART during the acute phase of HIV infection.

[Virological tools for the diagnosis, the prognosis and the surveillance of congenital cytomegalovirus infections]. / Utilisation des tests virologiques pour le diagnostic, le pronostic et la surveillance des infections congénitales à cytomégalovirus.

Cytomegalovirus (CMV) infection is the main cause of congenital infection in industrialized countries. The virological tools used for the diagnosis of congenital CMV are serology for diagnosis of primary infection in the mother, CMV PCR in amniotic fluid for diagnosis of fetal infection, PCR in urine or saliva for neonatal diagnosis and PCR in dried blood spots on Guthrie cards for retrospective diagnosis in young children. The prognostic value of viral load in amniotic fluid, fetal blood and neonatal blood will be discussed. The performance of the virological tests for antenatal or postnatal screening of congenital CMV will also be discussed.

Effects of recombinant human interleukin 7 on T-cell recovery and thymic output in HIV-infected patients receiving antiretroviral therapy: results of a phase I/IIa randomized, placebo-controlled, multicenter study.

BACKGROUND: The immune deficiency of human immunodeficiency virus (HIV) infection is not fully corrected with ARV therapy. Interleukin-7 (IL-7) can boost CD4 T-cell counts, but optimal dosing and mechanisms of cellular increases need to be defined. METHODS: We performed a randomized placebo-controlled dose escalation (10, 20 and 30 µg/kg) trial of 3 weekly doses of recombinant human IL-7 (rhIL-7) in ARV-treated HIV-infected persons with CD4 T-cell counts between 101 and 400 cells/µL and plasma HIV levels <50 copies/mL. Toxicity, activity and the impact of rhIL-7 on immune reconstitution were monitored. RESULTS: Doses of rhIL-7 up to 20 µg/kg were well tolerated. CD4 increases of predominantly naive and central memory T cells were brisk (averaging 323 cells/µL at 12 weeks) and durable (up to 1 year). Increased cell cycling and transient increased bcl-2 expression were noted. Expanded cells did not have the characteristics of regulatory or activated T cells. Transient low-level HIV viremia was seen in 6 of 26 treated patients; modest increases in total levels of intracellular HIV DNA were proportional to CD4 T-cell expansions. IL-7 seemed to increase thymic output and tended to improve the T-cell receptor (TCR) repertoire in persons with low TCR diversity. CONCLUSIONS: Three weekly doses of rhIL-7 at 20 µg/kg are well tolerated and lead to a dose-dependent CD4 T-cell increase and the broadening of TCR diversity in some subjects. These data suggest that this rhIL-7 dose could be advanced in future rhIL-7 clinical studies. CLINICAL TRIALS REGISTRATION: NCT0047732.

Evaluation of an upgraded version of the Roche Cobas AmpliPrep/Cobas TaqMan HIV-1 test for HIV-1 load quantification.

We evaluated the performance of the prototype Cobas AmpliPrep/Cobas TaqMan HIV-1 test, version 2.0, using prospective and archived clinical samples initially underquantitated by the Cobas AmpliPrep/Cobas TaqMan HIV-1 test. The performance of the new test was significantly improved, and the majority of the underquantitation observed with the first-version test was eliminated.

Immune suppression as the etiology of failure to detect anti-HBc antibodies in patients with chronic hepatitis B virus infection.

A lack of anti-HBc antibodies during chronic hepatitis B virus infection is a serological pattern that is rarely observed. In our series of 39 patients with such a confirmed profile, mutations within the precore/core gene were rarely found and the lack of antibody detection was mostly explained by concurrent immunosuppression and the low sensitivities of the serological assays.