We report an adolescent with perinatal HIV-1 infection treated from 1 month of age. Despite persistent viremia until age 4, he exhibited negative or weakly reactive serologies and no detectable intact proviruses at 11 and 18 years. This case questions current definitions of seroconversion, HIV persistence and remission in children.

BACKGROUND:The health of children exposed but uninfected by human immunodeficiency virus (HIV) requires long-term assessment, in particular in terms of neurological and cognitive development. Numerous confounding factors have hampered such assessment, and published data are contradictory. METHODS:Using data from the French National Health Data System from 2012 to 2022, we conducted a population-based matched cohort study on all live-born single children, including those born to mothers with HIV, all prenatally exposed to antiretrovirals (ARVs). The primary outcome was the diagnosis of neurodevelopmental disorders according to the International Classification of Diseases, 10th Revision. The recourse to specialized consultations likely to indirectly reflect neurodevelopmental symptoms was also evaluated. Incidence was assessed using the Cox survival model. RESULTS:Of 6 667 363 live-born singletons, 9035 were born to mothers with HIV, all exposed to ARVs during pregnancy. Children were followed for up to 11 years (average, 5.5 years). Overall, the incidence of neurodevelopmental disorders among exposed children was higher than in the general population, even after matching for 5 sociodemographic criteria and gestational age (hazard ratio, 1.24 [95% confidence interval, 1.04-1.47]). It was not possible to dissect the respective role of maternal infection from that of maternal treatment, as all children were coexposed to HIV and ARVs. However, among those exposed to tenofovir-emtricitabine, the ritonavir-boosted darunavir-based combination was significantly associated with a higher combined incidence of neurodevelopmental disorders and related specialized consultations than other protease inhibitors (log-rank P < .001). CONCLUSIONS:Children exposed to HIV and ARVs in utero have a higher risk of developing neurodevelopmental disorders of multifactorial origin.

Objective: Most data published on adolescents living with HIV (ALH) have been collected before the large diffusion of second-generation integrase strand transfer inhibitors (INSTI) among the pediatric population. We analyzed the nationwide ANRS-MIE CO10 Pediatric cohort to assess the changes over time in health and social outcomes of French ALH. Design: The cohort enrolled children born in France since 1985 and, from 2005, children diagnosed with HIV at ≤13 years, including those born abroad if antiretroviral-naive at first medical care in France. Methods: Adolescents aged ≥10 years at their last visit were included in this analysis. Their characteristics were compared between three periods of birth (1985-1993, 1994–1999, 2000–2010). Results: Overall, 529 ALH were included. Their median age at first HAART initiation decreased from 94 to 29 months (p < 0·0001). At the last evaluation, the proportions of ALH receiving HAART, receiving INSTI, having HIV-RNA < 50 copies/mL and having CD4 count ≥500/μL increased over time (p < 0.0001), reaching 98·7%, 53·3%, 81·3% and 85·0%, respectively, for those born in 2000–2010. The proportion of maternal and paternal orphans decreased until 14·4% and 11·0%, respectively, for ALH born recently. Compared to middle adolescents (15–17 years) born in 1994–1999, those born in 2000–2010 demonstrated higher academic success (69·2% versus 42·3%) and less frequent academic failure (4·6% versus 6·2%). Conclusions: Despite spectacular improvement in their health and immunovirological status, ALH remain vulnerable compared to other French adolescents, with a higher risk of being orphan and/or experiencing academic failure. Specific interventions are required to improve their global quality of life.

Objective:Most data published on adolescents with HIV (AWH) have been collected before the large diffusion of second-generation integrase strand transfer inhibitors (INSTI) among the pediatric population. We analyzed the nationwide ANRS-MIE CO10 Pediatric cohort to assess the changes over time in health and social outcomes of French AWH. Design:The cohort enrolled children born in France since 1985 and, from 2005, children diagnosed with HIV at <= 13 years, including those born abroad if antiretroviral-naive at first medical care in France. Methods:Adolescents aged >= 10 years at their last visit were included in this analysis. Their characteristics were compared between three periods of birth (1985-1993, 1994-1999, 2000-2010). Results:Overall, 529 AWH were included. Their median age at first HAART initiation decreased from 94 to 29 months (P < 0.0001). At the last evaluation, the proportions of AWH receiving HAART, receiving INSTI, having HIV-RNA < 50 copies/mL and having CD4 count >= 500/mu l increased over time (P < 0.0001), reaching 987%, 53.3%, 81.3% and 850%, respectively, for those born in 2000-2010. The proportion of maternal and paternal orphans decreased until 14.4% and 11.0%, respectively, for AWH born recently. Compared to middle adolescents (15-17 years) born in 1994-1999, those born in 2000-2010 demonstrated higher academic success (692% versus 423%) and less frequent academic failure (4.6% versus 6.2%). Conclusions:Despite spectacular improvement in their health and immunovirological status, AWH remain vulnerable compared to other French adolescents, with a higher risk of being orphan and/or experiencing academic failure. Specific interventions are required to improve their global quality of life.

Background No study has compared the virological and immunological status of young people with perinatallyacquired HIV infection (P-HIV) with that of people with HIV adulthood (A-HIV) having a similar duration of infection. Methods 5 French cohorts of P-HIV and A-HIV patients with a known date of HIV-infection and receiving antiretroviral treatment (ART), were used to compare the following proportions of: virological failure (VF) defined as plasma HIV RNA >= 50 copies/mL, CD4 cell percentages and CD4:CD8 ratios, at the time of the most recent visit since 2012. The analysis was stratified on time since infection, and multivariate models were adjusted for demographics and treatment history. Findings 310 P-HIV were compared to 1515 A-HIV (median current ages 20.9 [IQR:14.4-25.5] and 45.9 [IQR:37.9-53.5] respectively). VF at the time of the most recent evaluation was significantly higher among P-HIV (22.6%, 69/306) than A-HIV (3.3%, 50/1514); p <= 0.0001. The risk of VF was particularly high among the youngest children (2-5 years), adolescents (13-17 years) and young adults (18-24 years), compared to A-HIV with a similar duration of infection: adjusted Odds-Ratio (aOR) 7.0 [95% CI: 1.7; 30.0], 11.4 [4.2; 31.2] and 3.3 [1.0; 10.8] respectively. The level of CD4 cell percentages did not differ between P-HIV and A-HIV. P-HIV aged 6-12 and 13-17 were more likely than A-HIV to have a CD4:CD8 ratio >= 1: 84.1% vs. 58.8% (aOR = 3.5 [1.5; 8.3]), and 60.9% vs. 54.7% (aOR = 1.9 [0.9; 4.2]) respectively. Interpretation P-HIV were at a higher risk of VF than A-HIV with a similar duration of infection, even after adjusting for treatment history, whereas they were not at a higher risk of immunological impairment. Exposure to viral replication among young patients living with HIV since birth or a very early age, probably because of lower adherence, could have an impact on health, raising major concerns about the selection of resistance mutations and the risk of HIV transmission. Funding Inserm - ANRS MIE. Copyright (c) 2024 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/).

Allogeneic hematopoietic stem cell transplantation (alloSCT) is curative for severe inborn errors of immunity (IEIs), with recent data suggesting alloSCT in adulthood is safe and effective in selected patients. However, questions remain regarding the indications for and optimal timing of transplant. We retrospectively compared outcomes of transplanted vs matched nontransplanted adults with severe IEIs. Seventy-nine patients (aged >= 15 years) underwent alloSCT between 2008 and 2018 for IEIs such as chronic granulomatous disease (n = 20) and various combined immune deficiencies (n = 59). A cohort of nontransplanted patients from the French Centre de R ' ef ' erence D ' eficits Immunitaires H ' er ' editaires registry was identified blindly for case-control analysis, with <= 3 matched controls per index patient, without replacement. The nontransplanted patients were matched for birth decade, age at last review greater than index patient age at alloSCT, chronic granulomatous disease or combined immune deficiencies, and autoimmune/lymphoproliferative complications. A total of 281 patients were included (79 transplanted, 202 nontransplanted). Median age at transplant was 21 years. Transplant indications were mainly lymphoproliferative disease (n = 23) or colitis (n = 15). Median follow-up was 4.8 years (interquartile range, 2.5-7.2). One-year transplant-related mortality rate was 13%. Estimated disease-free survival at 5 years was higher in transplanted patients (58% vs 33%; P = .007). Nontransplanted patients had an ongoing risk of severe events, with an increased mean cumulative number of recurrent events compared with transplanted patients. Sensitivity analyses removing patients with common variable immune deficiency and their matched transplanted patients confirm these results. AlloSCT prevents progressive morbidity associated with IEIs in adults, which may outweigh the negative impact of transplant-related mortality.

Background: Primary immunodeficiencies (PID) are a heterogeneous group of rare inborn immunity defects. As management has greatly improved, morbidity and mortality are reduced in this population, while our knowledge on pregnancy's unfolding and outcome remains scarce.Objective: We conducted a retrospective monocentric study to study pregnancy outcomes in women with PID.Methods: The study cohort consisted of women over 18 included in the national registry for PID (CEREDIH), living in the greater Paris area, reporting >= 1 pregnancy. Data were collected through a standardized questionnaire and medical records. We analyzed PID features, pregnancy course and outcome, and neonatal features (NCT04581460). Results: We studied 93 women with PID (27 combined immunodeficiencies, 51 predominantly antibody deficiencies, and 15 innate immunodeficiencies) and their 222 pregnancies (67, 119, and 36 in each group, respectively). One hundred fifty-four (69%) of 222 pregnancies led to 157 live births, including 4 severe preterm births (3%), in the range of pregnancy outcome in the French general population. In a multivariate model, poor obstetrical outcome (fetal loss or pregnancy termination) was associated with history of severe infection (adjusted odds ratio 0.28, 95% confidence interval 0.11-0.67, P 5 .005). Only 59% pregnancies were led with optimal anti-infective prophylaxis; severe infections were reported in only 2 pregnancies (1%). One infant died during the neonatal period.Conclusion: Pregnancy is achievable in women with a wide group of PID. Prematurity is increased and history of severe infection is associated with significant increase of fetal loss/ pregnancy termination. Adjustment of care during pregnancy needs to be better delivered.

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.

The paradigm type I interferonopathy Aicardi-Goutières syndrome (AGS) is most typically characterized by severe neurological involvement. AGS is considered an immune-mediated disease, poorly responsive to conventional immunosuppression. Premised on a chronic enhancement of type I interferon signaling, JAK1/2 inhibition has been trialed in AGS, with clear improvements in cutaneous and systemic disease manifestations. Contrastingly, treatment efficacy at the level of the neurological system has been less conclusive. Here, we report our real-word approach study of JAK1/2 inhibition in 11 patients with AGS, providing extensive assessments of clinical and radiological status; interferon signaling, including in cerebrospinal fluid (CSF); and drug concentrations in blood and CSF. Over a median follow-up of 17 months, we observed a clear benefit of JAK1/2 inhibition on certain systemic features of AGS, and reproduced results reported using the AGS neurologic severity scale. In contrast, there was no change in other scales assessing neurological status; using the caregiver scale, only patient comfort, but no other domain of everyday-life care, was improved. Serious bacterial infections occurred in 4 out of the 11 patients. Overall, our data lead us to conclude that other approaches to treatment are urgently required for the neurologic features of AGS. We suggest that earlier diagnosis and adequate central nervous system penetration likely remain the major factors determining the efficacy of therapy in preventing irreversible brain damage, implying the importance of early and rapid genetic testing and the consideration of intrathecal drug delivery.

The burden of CMV infection and disease is important in pediatric hematopoietic stem cell transplantation (HSCT), notably in the subgroup of patients with inborn errors of immunity (IEIs). Letermovir (LMV) is now a standard of care for CMV prophylaxis in adult sero-positive (R+) recipients, but is not yet labeled for children. Published pediatric studies are still scarce. We report a monocentric real-life use of LMV in 36 HSCT pediatric recipients with IEIs considered at high-risk of CMV infection including 14 patients between 2 and 12 months of age. A homogenous dosage proportional to the body surface area was used. Pharmacokinetic (PK) was performed in 8 patients with a median of 6 years of age (range 0,6;15). The cumulative incidence of clinically significant CMV infections (CS-CMVi) and the overall survival of patients under LMV were compared to a very similar historical cohort under (val)aciclovir prophylaxis. LMV tolerance was good. As compared to the historical cohort, the incidence of CS-CMVi was significantly lower in LMV group (5 out of 36 transplants (13.9%) versus 28 of the 62 HSCT (45.2%)) (p = 0.002). Plasma LMV exposures did not significantly differ with those reported in adult patients. In this high-risk pediatric HSCT cohort transplanted for IEIs, CMV prophylaxis with LMV at a homogenous dosage was well tolerated and effective in preventing CS-CMVi compared with a historical cohort.

Les déficits immunitaires primitifs (DIP) sont un groupe d'affections innées et rares du système immunitaire. Leur prise en charge a progressé sur les dernières décennies, permettant aux femmes de mener des projets de maternité, alors que les connaissances sur le déroulement et l'issue de la grossesse restent pauvres. Nous avons mené une étude monocentrique rétrospective à partir du registre national des DIP pour aider à améliorer la prise en charge des grossesses en contexte de DIP. La cohorte étudiée était constituée de femmes majeures inscrites dans le registre national des DIP, suivies dans la région et rapportant au moins une grossesse. Les données épidémiologiques, médicales et obstétricales ont été recueillies via un questionnaire standardisé et dans les dossiers médicaux. Nous avons étudié les caractéristiques des DIP, le déroulement et l'issue de la grossesse et les données néonatales. Nous avons étudié 93 femmes (27 atteintes de déficit combiné, 51 de déficit humoral et 15 de déficit de l'immunité innée), ayant eu 222 grossesses (67, 119 et 36 dans chaque groupe de DIP, respectivement). 49% des grossesses ont été menées avant le diagnostic de DIP. 154/222 grossesses (69%) ont conduit à 157 naissances vivantes, dont 4 grands prématurés (3%). Dans l'analyse multivariée, l'issue défavorable de la grossesse (perte foetale ou interruption médicale de grossesse) était associée à un antécédent d'infection grave (Odds Ratio ajusté de 0,28, IC95% 0,11–0,67, p=0,005). Alors que seulement 68% des grossesses étaient conduites sous une prophylaxie anti-infectieuse optimale, une infection grave n'a été rapportée qu'au cours de 2 grossesses (0,5%). Cependant, les naissances vivantes étaient plus fréquentes chez les patientes diagnostiquées au moment de la grossesse et sous prophylaxie optimale que chez les patientes non diagnostiquées sans prophylaxie (OR 3,23, IC95% 1,44-7,48, p=0,005). 11% des nouveaux nés avaient un petit poids pour l'âge gestationnel. Un enfant est décédé pendant la période néonatale. Les femmes atteintes de déficits immunitaires primitifs peuvent devenir mères. La prématurité semble plus fréquente et l'antécédent d'infection grave est associée aux pertes foetales/ interruptions de grossesse. L'adaptation du suivi des patientes pendant la grossesse et la gestion des prophylaxies anti-infectieuses doivent être optimisées. Aucun lien d'intérêt

Abstract: Effectiveness of anti-HIV in the prevention of perinatal transmission has been established. Assessing the tolerance of drug exposure during pregnancy is of the utmost importance given the number of children exposed. HIV integrase and the recombinase-activating gene enzyme involved in the establishment of the T-lymphocyte repertoire show structural similarity. The inhibition of recombinase-activating (RAG) gene by anti-integrases is observed in vitro, in a variable way according to the molecules. Here, we show that in utero exposure to raltegravir did not alter the T-lymphocyte repertoire of 12 newborns. These reassuring data merit verification for other anti-integrases. (ClinicalTrial.org NCT 04024150).

Sickle cell disease (SCD) and transfusion-dependent β-thalassemia (TDT) are the most prevalent monogenic disorders worldwide. Trial HGB-205 ( NCT02151526 ) aimed at evaluating gene therapy by autologous CD34 + cells transduced ex vivo with lentiviral vector BB305 that encodes the anti-sickling β A-T87Q -globin expressed in the erythroid lineage. HGB-205 is a phase 1/2, open-label, single-arm, non-randomized interventional study of 2-year duration at a single center, followed by observation in long-term follow-up studies LTF-303 ( NCT02633943 ) and LTF-307 ( NCT04628585 ) for TDT and SCD, respectively. Inclusion and exclusion criteria were similar to those for allogeneic transplantation but restricted to patients lacking geno-identical, histocompatible donors. Four patients with TDT and three patients with SCD, ages 13–21 years, were treated after busulfan myeloablation 4.6–7.9 years ago, with a median follow-up of 4.5 years. Key primary endpoints included mortality, engraftment, replication-competent lentivirus and clonal dominance. No adverse events related to the drug product were observed. Clinical remission and remediation of biological hallmarks of the disease have been sustained in two of the three patients with SCD, and frequency of transfusions was reduced in the third. The patients with TDT are all transfusion free with improvement of dyserythropoiesis and iron overload.

Long-term multilineage hematopoietic donor chimerism occurs sporadically in patients who receive a transplanted solid organ enriched in lymphoid tissues such as the intestine or liver. There is currently no evidence for the presence of kidney-resident hematopoietic stem cells in any mammal species. Graft-versus-host-reactive donor T cells promote engraftment of graft-derived hematopoietic stem cells by making space in the bone marrow. Here, we report full (over 99%) multilineage, donor-derived hematopoietic chimerism in a pediatric kidney transplant recipient with syndromic combined immune deficiency that leads to transplant tolerance. Interestingly, we found that the human kidney-derived hematopoietic stem cells took up long-term residence in the recipient's bone marrow and gradually replaced their host counterparts, leading to blood type conversion and full donor chimerism of both lymphoid and myeloid lineages. Thus, our findings highlight the existence of human kidney-derived hematopoietic stem cells with a self-renewal ability able to support multilineage hematopoiesis.

Mucopolysaccharidosis type I-H (MPS I-H) is a rare lysosomal storage disorder caused by α-L-Iduronidase deficiency. Early haematopoietic stem cell transplantation (HSCT) is the sole available therapeutic option to preserve neurocognitive functions. We report long-term follow-up (median 9 years, interquartile range 8–16.5) for 51 MPS I-H patients who underwent HSCT between 1986 and 2018 in France. 4 patients died from complications of HSCT and one from disease progression. Complete chimerism and normal α-L-Iduronidase activity were obtained in 84% and 71% of patients respectively. No difference of outcomes was observed between bone marrow and cord blood stem cell sources. All patients acquired independent walking and 91% and 78% acquired intelligible language or reading and writing. Intelligence Quotient evaluation ( n = 23) showed that 69% had IQ ≥ 70 at last follow-up. 58% of patients had normal or remedial schooling and 62% of the 13 adults had good socio-professional insertion. Skeletal dysplasia as well as vision and hearing impairments progressed despite HSCT, with significant disability. These results provide a long-term assessment of HSCT efficacy in MPS I-H and could be useful in the evaluation of novel promising treatments such as gene therapy.