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.

Separation between HIV-positive women and their children: the French prospective study, 1986 through 1993.

OBJECTIVES: We studied the risk and circumstances of separation (due to either maternal death or drug use) between women infected by human immunodeficiency virus (HIV) type 1 and their children. METHODS: This analysis was based on the French Prospective Study of Infants Born to HIV-seropositive Women (1986 through 1993). Data recorded at each follow-up visit included the mother's effective presence with the child and the child's care after separation. RESULTS: A child's cumulative risk of long-term or permanent separation from his or her mother was 37% at 60 months. Maternal drug use was associated with an added risk during the child's first years (adjusted relative risk [RR]=3.4, 95% confidence interval [CI]=2.3, 5.0). The risk among drug users was even higher when the mother used injection drugs during pregnancy (adjusted RR=2.9, 95% CI=1.9, 4.3). Risk of early separation related to drug use tended to diminish since survey initiation. After separation, 57% of the children were placed through child welfare services and 43% were cared for by relatives. CONCLUSIONS: In the French Prospective Study, 2% to 3% of HIV-infected children were separated each year from their mothers as a result of the mothers death from acquired immunodeficiency syndrome (AIDS). Separations related to drug use have decreased over the years, and the family is becoming the most frequent carer after separation.

Chondrosarcoma of the larynx.

A case of a low grade chondrosarcoma of the cricoid cartilage which had been diagnosed initially as a chondroma is presented. The tumour recurred twice after limited surgical resections. Total laryngectomy was inevitable due to near total involvement of the cricoid cartilage and subsequent histological examination revealed a low grade chondrosarcoma. We have discussed in brief, the diagnosis and treatment of chondrosarcomas of the larynx and support the view of conservative surgical management for low grade tumours as they are slow growing and metastases are infrequent. A total laryngectomy may be reserved for salvage or primarily when more than half of the cricoid cartilage needs to be resected. Histological grading reveals the biological behaviour of the tumour and CT scans help in planning the surgery. A regular follow-up is necessary for early detection of recurrences and metastases.

Long-term itraconazole prophylaxis against Aspergillus infections in thirty-two patients with chronic granulomatous disease.

We conducted a prospective, open study of oral itraconazole therapy (5 and then 10 mg/kg per day) to assess tolerance and potential efficacy in preventing fungal infections in patients with chronic granulomatous disease. Thirty-two patients were enrolled in one center between 1985 and 1991. Tolerance was excellent in all cases. Poor compliance was suspected in three cases. Two patients were excluded from efficacy analysis because itraconazole was used as part of therapy for pulmonary aspergillosis. Of 30 patients, 3 developed a fungal (Aspergillus) lung infection, an incidence 3.4/100 patient-years versus 11.5 in a historical control group that did not receive any prophylaxis (p = 0.13) and 9.55 in a historical group of patients who received daily ketoconazole prophylaxis (p = 0.19). The percentage of patients infected with Aspergillus was significantly different: 10% in the itraconazole group versus 34.4% in the untreated group (p = 0.013). These results require further evaluation through a comparative randomized trial to assess the possible benefit of itraconazole prophylaxis in patients with chronic granulomatous disease.

[Acquired and constitutional neutropenia in children]. / Neutropénies constitutionnelles et acquises de l'enfant.

The evaluation of a neutropenia first must document its etiology. Besides the particular etiological aspects in the newborn, neutropenia in a child may be 1) acquired, 2) constitutional, part of a complex genetic disease, 3) constitutional, isolated. Primary acquired neutropenia, also called benign chronic neutropenia, is the most frequent cause of chronic neutropenia in children; it is usually well tolerated and has a frequent favorable outcome in 12-14 months. Many complex genetic diseases include a neutropenia, among which several immunologic disorders that must be ruled out before considering the diagnosis of isolated constitutional neutropenia. Infantile agranulocytosis is the main primary constitutional neutropenia. It may be sporadic or hereditary (autosomal recessive or dominant inheritance) and is present at birth. It is profound, usually < 0.5 G/l (< 500/mm3) and exposes to severe pyogenic and fungal infections. In the neonatal period neutropenia must primarily suggest a bacterial infection, although other etiologies have to be known, particularly neonatal neutropenia caused by passive transfer of maternal antibodies and neutropenia related to gravidic maternal hypertension. The treatment of severe chronic neutropenia is directed towards the prevention of infections. It includes prophylactic antibiotherapy, the most commonly used one being the trimetroprim-sulfamethoxazole association, and granulocyte colony stimulating factor (G-CSF). G-CSF has considerably improved the condition of patients; it is usually well tolerated, but secondary effects have been reported (hypersplenism, glomerulonephritis, osteoporosis, vasculitis), and a potential leukemogenic risk has been evoked.

Bacillus Calmette-Guérin infection after vaccination of human immunodeficiency virus-infected children.

The use of Mycobacterium bovis/Bacillus Calmette-Guérin (BCG) to vaccinate against tuberculosis remains controversial. The development of tuberculosis in human immunodeficiency virus (HIV)-infected children demands specific evaluation of the risk/benefit ratio of BCG vaccination in this situation. In our institution 9 of 68 HIV-infected children vaccinated with BCG before the diagnosis of HIV infection was suspected developed vaccine-related complications: 7 of these children had a large satellite adenopathy with or without skin fistulae, whereas the other 2 had disseminated BCG infection beyond the satellite ganglion (involvement of the spleen and mesenteric and mediastinal lymph nodes in one case and the liver and lungs in the other). The children were vaccinated soon after birth; no particular problems were observed at that time, but complications appeared 3 to 35 months later. All but one of these children had a rapidly progressive form of HIV disease. The possibility of delayed local or disseminated BCG infection must be considered in analysis of the risk/benefit ratio of vaccination of HIV-infected children. The prognosis of HIV infection must be taken into account, even if the child is asymptomatic when vaccination is being considered.

Autoimmune hepatitis associated with anti-actin antibodies in children and adolescents.

The clinical, biochemical, morphological, and evolutive features of autoimmune hepatitis associated with serum smooth muscle antibodies of anti-actin specificity were retrospectively analyzed in 31 children and adolescents. Cirrhosis was present at diagnosis in all but six patients, including nine of the 12 diagnosed within 6 months from the onset. In 15 children, one or more associated diseases of an immune-mediated mechanism were present, including chronic arthritis, sclerosing cholangitis, inflammatory bowel disease, and cutaneous vasculitis. All patients were treated with prednisone and azathioprine with normalization or improvement of liver function tests: 28 children are currently alive after a mean follow-up of 4 years, 10 months. Treatment was interrupted in four patients only. Two patients died of liver failure in spite of immunosuppressive therapy before the era of liver transplantation. In spite of prolonged therapy, five other patients ultimately required liver transplantation during adolescence or early adulthood. These results (a) further define a group of autoimmune hepatitis in children characterized by the presence of serum anti-actin antibodies; (b) indicate that immunosuppressive therapy improves liver function, although in most cases it must be continued for a long period to maintain remission; and (c) suggest that progressive liver failure may occur in early adulthood and may require liver transplantation.

[Familial characteristics of children born to HIV-seropositive women]. / Analyse de la situation familiale des enfants nés de mère VIH-séropositive.

The family situation of 122 children followed at the Necker hospital is analysed in this study: 40% of these children live with both parents, while 22% live with one parent, 10% with their maternal grand mother and 28% are under the care of the Aide Sociale à l'Enfance (Social Services for Children). At this time, less stable family situations and the separation of a child from his mother are not due to the child's HIV status but rather to the social and family context. A better knowledge of these factors is essential to prevent future family separation. Increased awareness and training in this context is urgently needed by the personnel in care of these children as the situation will undoubtedly become even more serious in the next few years.

Reduction of graft failure by a monoclonal antibody (anti-LFA-1 CD11a) after HLA nonidentical bone marrow transplantation in children with immunodeficiencies, osteopetrosis, and Fanconi's anemia: a European Group for Immunodeficiency/European Group for Bone Marrow Transplantation report.

Forty-six infants and children suffering from either inherited immunodeficiency disorders (Wiskott-Aldrich syndrome, functional T-cell immunodeficiency with or without HLA class II expression deficiency), malignant osteopetrosis, or Fanconi's anemia received HLA-nonidentical bone marrow transplantation (BMT) from related donors. Bone marrow was T-cell depleted to reduce the risk of graft-versus-host disease (GVHD). To prevent graft failure, a mouse monoclonal antibody specific for the CD11a-lymphocyte function-associated antigen 1 (LFA-1) molecule was infused into the patients. Eleven patients received five infusions of 0.1 mg/kg every other day from day -3 to +5. Thirty-five patients received 0.2 mg/kg daily from day -3 to +6. The overall sustained engraftment rate was 72% instead of 26.1% in a historical control group of 24 patients similarly treated except for the infusion of the anti-LFA-1 antibody. No late rejection occurred. The T-cell depletion method (E-rosetting or Campath IM plus complement) resulted in different rate of engraftment (83.3% v 57.9%, respectively, P = .05). Engraftment rate was slightly but not significantly influenced by the degree of HLA incompatibility between donor and recipient. Acute GVHD of grade II or more occurred in 35.5% of the patients and the rate of chronic GVHD was 12.9%. The overall actuarial survival rate with a functional graft is 47.3% with a mean follow-up of 28.0 months for patients with immunodeficiency and osteopetrosis, while none of the four patients with Fanconi's anemia survived. The development of full T-cell functions took on the average 6 months and of full B-cell functions 10 months. Significant infectious problems developed in the majority of the patients during the posttransplant course. Epstein-Barr virus-induced B-cell proliferative syndromes were observed in seven patients, six of whom had Wiskott-Aldrich syndrome. Correction of immunodeficiency was comparable in terms of kinetics and quality with that observed in patients with severe combined immunodeficiency undergoing HLA-nonidentical BMT. Correction of osteopetrosis appears not to be different from what has been observed after HLA-identical BMT. The in vivo use of an anti-CD11a-LFA-1 antibody as an additional immunosuppressive therapy in HLA-nonidentical BMT may thus promote engraftment and survival with correction of the primary disease in a significant number of patients with life-threatening immunodeficiency and osteopetrosis, but not with Fanconi's anemia.

Altered expression of neutrophil peripheral benzodiazepine receptor in X-linked chronic granulomatous disease.

This study was aimed at determining whether the peripheral benzodiazepine receptor (PBZDR), which is abundantly expressed on mononuclear phagocytes, is involved in host defense mechanisms depending on phagocyte membrane-associated NADPH-oxidase complex. Analysis by reversible and covalent binding of PBZDR expression on human neutrophils shows that it is modulated during NADPH-oxidase activation with phorbol 12-myristate 13-acetate. Based on a series of 17 patients with chronic granulomatous disease (CGD), results show that PBZDR expression is dramatically impaired in X-linked CGD, an inherited disorder due to a mutation on the gene coding for cytochrome b558 NADPH-oxidase component, whereas it is unaffected in autosomal recessive CGD where cytochrome b558 is normally expressed, suggesting a link between PBZDR and cytochrome b558 expressions. PBZDR can be assigned by covalent binding to an 18-Kd membrane protein. These results suggest that the neutrophil PBZDR, which can accommodate the widely prescribed anxiolytic drug Valium (diazepam), is involved in host defense against pathogens, a function that could be affected by neuroimmune interactions.

[The accelerated phase of Chediak-Higashi syndrome]. / Phase accélérée de la maladie de Chediak-Higashi.

We have retrospectively analysed the clinical and biological features as well as the outcome of 18 accelerated phases having occurred in 11 patients with the Chediak-Higashi syndrome. This complication is very frequent and is characterized by a multi-visceral lymphohistiocytic infiltration with hemophagocytosis leading to pancytopenia, a bleeding disorder secondary to low fibrinogen level, hypertriglyceridemia and hemodilution. The accelerated phase of the Chediak-Higashi syndrome is identical to the manifestations of familial erythrophagocytic lymphohistiocytosis and of the viral-associated hemophagocytic syndrome. The outcome was invariably fatal before the use of etoposide (VP 16) in association with steroids and intrathecal methotrexate. Complete remission with this management regimen was observed in 7/7 cases. However, remissions were only transient. HLA identical bone marrow transplantation appeared to be the only therapeutic strategy capable of curing the disease (3/3 patients). Non transplanted patients relapsed and died as well as one patient who received a HLA non identical bone marrow transplantation. Due to the frequency and the severity of the accelerated phase of the Chediak-Higashi syndrome, HLA identical bone marrow transplantation should be proposed as early as possible after the onset of the accelerated phase.

[Neutropenias in children]. / Neutropénies de l'enfant.

Whereas the clinical expression of childhood neutropenias is fairly uniform, consisting mainly in infections, a wide variety of etiologies may be involved. Pathophysiologic mechanisms have not all been completely elucidated. We review the different etiologies of neutropenia in children using the classification that we believe is the most helpful to clinicians. The clinical features and management of primary chronic neutropenias are described in detail. On the basis of our experience we suggest a practical diagnostic strategy for investigating children with neutropenia.