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.

Cutaneous granulomas with primary immunodeficiency in children: a report of 17 new patients and a review of the literature.

BACKGROUND: Paediatric cutaneous granuloma with primary immunodeficiency (PID) is a rare condition. The physiopathology is unclear, and treatment is challenging. We report on 17 paediatric cases and review the literature. OBJECTIVES: To make dermatologists and dermatopathologists aware of the diagnostic value of skin granulomas in paediatric PID. METHODS: We collected data on 17 patients with cutaneous granulomas and PID registered with us and also reviewed 33 cases from the literature. RESULTS: Cutaneous granuloma was the presenting feature of the PID in 15 of the 50 collated cases. The lesions presented as red-brownish nodules and infiltrated ulcerative plaques, predominantly on the face and limbs. Scleroderma-like infiltration on a single limb was observed in 10% of the cases. The associated PID was ataxia-telangiectasia (52%), combined immunodeficiency (24%), cartilage-hair hypoplasia (6%) and other subtypes (18%). The granulomas were mostly sarcoidal, tuberculoid, palisaded or undefined subtypes. In some patients, several different histopathologic granulomatous patterns were found in the same biopsy. Some granulomas were associated with the presence of a vaccine strain of rubella virus. CONCLUSION: Cutaneous granulomas associated with a PID have a variable clinical presentation. A PID can be suspected when crusty, brownish lesions are found on the face or limbs. The concomitant presence of several histological subtypes in a single patient is suggestive of a PID.

Value of chest X-ray in TB diagnosis in HIV-infected children living in resource-limited countries: the ANRS 12229-PAANTHER 01 study.

OBJECTIVE: To evaluate inter-reader agreement and diagnostic accuracy of chest radiography (CXR) in the diagnosis of tuberculosis (TB) in children with human immunodeficiency virus (HIV) infection. DESIGN: HIV-infected children with clinically suspected TB were enrolled in a prospective study conducted in Burkina Faso, Cambodia, Cameroon and Viet Nam from April 2010 to December 2014. Three readers-a local radiologist, a paediatric pulmonologist and a paediatric radiologist-independently reviewed the CXRs. Inter-reader agreement was then assessed using the κ coefficient. Diagnostic accuracy of CXR was assessed in culture-confirmed cases and controls. RESULTS: A total of 403 children (median age 7.3 years, interquartile range 3.5-9.7; 49.6% males) were enrolled. Inter-reader agreement was as follows: between local radiologist and paediatric pulmonologist, κ = 0.36 (95%CI 0.27-0.45); local radiologist and paediatric radiologist, κ = 0.16 (95%CI 0.08-0.24); and paediatric pulmonologist and paediatric radiologist, κ = 0.30 (95%CI 0.21-0.40). Among 51 cases and 151 controls, after a consensus, CXR had a sensitivity of 71.4% (95%CI 58.8-84.1) and a specificity of 50.0% (95%CI 41.9-58.1). Alveolar opacities and enlarged lymph nodes on CXR had limited specificity for TB (64.7% and 70.2%, respectively). Miliary and/or nodular opacities patterns on CXR were more specific to TB (specificity 94.3%). CONCLUSION: CXR showed poor-to-fair inter-reader agreement and limited diagnostic accuracy for TB in HIV-infected children, likely due to comorbidities. Radiological criteria for this specific population require further investigation.

Rapid detection of carbapenemase activity: benefits and weaknesses of MALDI-TOF MS.

Matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) has been introduced as an identification procedure for bacteria and fungi. The MALDI-TOF MS-based analysis of resistance to ß-lactam antibiotics has been applied to detect hydrolysis of carbapenems by different bacterial strains. However, the detection of enzymatic carbapenem degradation by MALDI-TOF MS lacks well-standardized protocols and several methods and models of interpretation using different calculations of ratio-of-peak intensities have been described in the literature. Here, we used faropenem and ertapenem hydrolysis as model compounds. In an attempt to propose a universal protocol, the hydrolysis was regularly monitored during 24 h using well-characterized bacterial strains producing different types of carbapenemases (KPC, IMP, NDM, VIM, and OXA-48). Variable responses and different timing for detectable hydrolysis, depending on the enzyme produced, were observed. KPC degrades its template antibiotics very quickly (15 min for some KPC producers) compared to other types of enzymes (more than 90 min for other enzymes). Prior bacterial lysis was shown to be of no interest in the modulation or optimization of the hydrolytic kinetics. The adequate detection of carbapenem hydrolysis would, therefore, require several MALDI-TOF MS readouts for the timely detection of rapid hydrolysis without missing slow hydrolysis. This enzymatic constraint limits the implementation of a standard protocol in routine microbiology laboratories.

Next-Generation Sequencing for Diagnosis and Tailored Therapy: A Case Report of Astrovirus-Associated Progressive Encephalitis.

A boy with X-linked agammaglobulinemia experienced progressive global motor decline, cerebellar syndrome, and epilepsy. All standard polymerase chain reactions for neurotropic viruses were negative on cerebrospinal fluid and brain biopsy. Next-generation sequencing allowed fast identification of a new astrovirus strain (HAstV-VA1/HMO-C-PA), which led to tailor the patient's treatment, with encouraging clinical monitoring over 1 year.

An update on pediatric invasive aspergillosis.

Invasive aspergillosis (IA) is a major cause of morbidity and mortality in immunocompromised adults and children, the number of which has been continuously increasing in the last decades. The purpose of our review was to provide epidemiological, clinical, and biological data and antifungal treatment options in the pediatric population. Several biological assays (galactomannan enzyme immunoassay, ß-D-glucan, detection of Aspergillus spp. DNA) have proven useful adjuncts for the diagnosis of IA in adult studies. However, data on these assays in children is limited by small sample sizes and sometimes conflicting results concerning their sensitivity/specificity. Pediatric treatment recommendations are mainly extrapolated from results of clinical trials performed in adults. It is thus necessary to develop new antifungal formulations specifically adapted to the pediatric population and to evaluate their pharmacokinetic/pharmacodynamic profile, their safety, and their effectiveness in infants and children.

Practice variation in long-term secondary stroke prevention in The Netherlands.

BACKGROUND: Stroke guidelines emphasize the importance of adequate vascular risk factor assessment and management in transient ischemic attack (TIA) and ischemic stroke patients, but it is not clear how these guidelines are applied in routine clinical practice. The limited data that are available indicate that TIA and ischemic stroke patients often do not receive the recommended interventions. The aim of this study was to investigate practice variations in long-term secondary stroke prevention in The Netherlands. METHODS: Between June and December 2013, an invitation for a web-based survey was sent to 90 Dutch neurologists with a special interest in stroke neurology. This web-based survey contained questions regarding the organization of outpatient care for TIA and ischemic stroke patients after initial hospital assessment, pharmacologic treatment, and nonpharmacologic strategies for long-term secondary prevention. RESULTS: In total, 84 (93%) neurologists completed the survey. Although nearly all respondents reported that they follow-up TIA and ischemic stroke patients after initial hospital assessment, the number of follow-up visits and the follow-up duration were variable. A similar variation was found in treatment targets levels for both blood pressure and low-density lipoprotein cholesterol. Regarding nonpharmacologic strategies for long-term secondary stroke prevention, most respondents inform their TIA and ischemic stroke patients about the importance of smoking cessation. There is considerably less attention for the other lifestyle risk factors. CONCLUSIONS: We found considerable practice variation in long-term secondary stroke prevention. These variations may have an impact on the risk for stroke recurrence and cardiovascular disease in general.

[HIV and pregnancy: 2013 guidelines from the French expert working group]. / Infection par le VIH et grossesse: nouvelles recommandations 2013 du groupe d'experts français.

With effective antiretroviral therapy, the risk of mother to child transmission (MTCT) is now under 1%. The 2013 French guidelines emphasize early antiretroviral lifelong antiretroviral therapy. Thus, the current trend for women living with HIV is to take antiretroviral therapy before, during and after their pregnancies. A major issue today is the choice of antiretroviral drugs, to maximize the benefits and minimize the risks of fetal exposure. This requires interdisciplinary care. The use of effective therapies permits gradual but profound changes in obstetric practice. When maternal plasma viral load is controlled (<50 copies/ml), obstetrical care can be more similar to standards in HIV-negative women. Prophylactic cesarean section is recommended when the viral load in late pregnancy is above 400 copies/mL. Intravenous zidovudine during labor is recommended only if the last maternal viral load is>400 copies/mL or in case of complications such as preterm delivery, bleeding or chorio-amnionitis during labor. In case of premature rupture of membranes before 34 weeks, a multidisciplinary decision should be made, based on gestational age and control of maternal viral load; if the woman is under antiretroviral therapy and especially if her viral load is undetectable, steroids and antibiotics should be offered and pregnancy can be continued except in case of signs or symptoms of chorio-amnionitis. Breastfeeding is not recommended in women living with HIV in France, as in industrialized countries. Prophylaxis in the newborn is usually zidovudine for 1 month. In case of significant exposure to HIV perinatally, in particular when, maternal viral load is>1000 copies/mL, prophylactic combination therapy is recommended. Monitoring of the child is necessary to determine whether or not it is free of HIV infection and to monitor possible adverse effects of perinatal exposure to antiretroviral drugs.

Very prolonged liposomal amphotericin B use leading to a lysosomal storage disease.

Amphotericin B is a powerful polyene antifungal drug used for treating systemic fungal infections and is usually administered for a short period. Side effects after prolonged use are unknown in humans. Here we report the case of a 28-year-old man suffering from chronic granulomatous disease (CGD), treated for invasive cerebral aspergillosis with liposomal amphotericin B (L-AmB) for a very long time (8 consecutive years). We describe the efficacy and safety of this treatment in the long term. Aspergillosis was kept under control as long as L-AmB therapy was maintained, but relapsed when the dose was reduced. No overt renal toxicity was noted. The patient gradually developed hepatosplenomegaly and pancytopenia. Abnormalities of bone marrow were similar to the sea-blue histiocyte syndrome. Liver biopsy showed images of nodular regenerative hyperplasia related to CGD as well as a histiocytic storage disease. We discuss the very prolonged use of L-AmB leading to the development of a lysosomal storage disease.

Adrenal enzyme impairment in neonates and adolescents treated with ritonavir and protease inhibitors for HIV exposure or infection.

BACKGROUND: Human deficiency virus (HIV) protease inhibitors (PIs) are widely used drugs whose effects are pharmacologically enhanced by ritonavir, a potent cytochrome P450 inhibitor. We reported previously that prophylactic postnatal ritonavir-PI therapy in HIV-exposed neonates was associated with increases in plasma 17-hydroxyprogesterone (17-OHP) and dehydroepiandrosterone sulfate (DHEA-S). AIMS: To further investigate adrenal function in neonates and adolescents given ritonavir-PI. METHODS: Adrenal function was assessed prospectively in 3 HIV-exposed neonates given short-term prophylactic treatment and 3 HIV-infected adolescents given long-term treatment. Plasma cortisol, 17-OHP, 17-OH-pregnenolone, DHEA-S, and androstenedione were measured before and after ACTH administration. RESULTS: None of the patients had clinical signs of adrenal dysfunction. The only neonate exposed to ritonavir-PI in utero had up to 3-fold increases in plasma 17-OHP. Increases in 17-OH-pregnenolone of up to 3.1-fold were noted in 4 of the 6 patients, and all 6 patients had elevations in DHEA-S (up to 20.4-fold increase) and/or DHEA (up to 4.7-fold) and/or androstenedione (up to 5.2-fold). All these parameters improved after treatment completion. CONCLUSION: Neonates and adolescents given ritonavir-PI exhibit a similar adrenal dysfunction profile consistent with an impact on multiple adrenal enzymes. These abnormalities require evaluation, given the potentially long exposure times.

Live rubella virus vaccine long-term persistence as an antigenic trigger of cutaneous granulomas in patients with primary immunodeficiency.

Granulomas may develop as a response to a local antigenic trigger, leading to the activation of macrophages and T-lymphocytes. Primary immunodeficiency (PID) is associated with the development of extensive cutaneous granulomas, whose aetiology remains unknown. We performed high-throughput sequencing of the transcriptome of cutaneous granuloma lesions on two consecutive index cases, and RT-PCR in a third consecutive patient. The RA27/3 vaccine strain of rubella virus-the core component of a universally used paediatric vaccine-was present in the cutaneous granuloma of these three consecutive PID patients. Controls included the healthy skin of two patients, non-granulomatous cutaneous lesions of patients with immunodeficiency, and skin biopsy samples of healthy individuals, and were negative. Expression of viral antigens was confirmed by immunofluorescence. Persistence of the rubella vaccine virus was also demonstrated in granuloma lesions sampled 4-5 years earlier. The persistence of the rubella virus vaccine strain in all three consecutive cutaneous granuloma patients with PID strongly suggests a causal relationship between rubella virus and granuloma in this setting.

Safety of hematopoietic stem cell transplantation from hepatitis B core antibodies-positive donors with low/undetectable viremia in HBV-naïve children.

Scarce data exist on allogeneic hematopoietic stem cell transplantation (HSCT) outcomes in hepatitis B virus (HBV)-naïve recipients from HBV-experienced donors. Long-term follow-up is herein reported for 17 allogeneic HSCT performed in 13 HBV-naïve children from HBc-antibodies-positive donors between 2006 and 2012. Four donors were HBs-antigen-positive, with detectable but low viremia in 2 cases (<2 log10IU/ml). HBV-DNA was undetectable in all transplanted cell products. Recipients' HBV prophylaxis consisted of pre-transplant vaccination, polyvalent immune globulins, specific anti-HBV immune globulins, and/or oral lamivudine in 3, 12, 8, and 8 children, respectively. No case of HBV transmission occurred based on negative close monitoring of recipients' HBV serology and plasma HBV-DNA during a median follow-up of 22 months. In case of undetectable viremia in the donor, prophylaxis with vaccination and/or immune globulins in the recipient seems to be sufficient and lamivudine prophylaxis might be unnecessary to prevent viral transmission. In case of undetectable viremia in the donor, a systematic screening of HBV DNA in the stem cell product might be unnecessary to confirm the low risk of viral transmission. Prior exposure to HBV in the donor should not be considered a contraindication to HSCT.

[Pediatric aids, 30 years later]. / Le sida pédiatrique, 30ans plus tard.

Thirty years after the first descriptions of AIDS in children in May 1983, the risk of viral transmission from mother to child has been reduced to almost zero and the disease in infected children has become an asymptomatic condition, stable in the long-term, thanks to antiretroviral drugs. Unbelievable though it may have seemed until the mid-1990s, children infected during the perinatal period are now growing up to be adults in a chronic, stable, asymptomatic medical condition with often satisfactory personal, family, and social lives. The French perinatal epidemiological cohort, which was set up in 1984 and has included more than 18,000 mother-child pairs to date, traces the steps in this extraordinary revolution in the prevention and treatment of HIV-1 infection in children.

Non-disclosure of a pregnant woman's HIV status to her partner is associated with non-optimal prevention of mother-to-child transmission.

Our objective was to study relations between non-disclosure of HIV to partner, socio demographics and prevention of HIV mother-to-child transmission (PMTCT), among HIV-infected pregnant women enrolled in the French Perinatal Cohort (ANRS-EPF-CO1) from 2005 to 2009 (N = 2,952). Fifteen percent of the women did not disclose their HIV status to their partner. Non-disclosure was more frequent in women diagnosed with HIV infection late in pregnancy, originating from Sub-Saharan Africa or living alone, as well as when the partner was not tested for HIV. Non-disclosure was independently associated with non optimal PMTCT: late initiation of antiretroviral therapy, detectable viral load at delivery and lack of neonatal prophylaxis. Nonetheless, the rate of transmission did not differ according to disclosure status. Factors associated with non-disclosure reflect vulnerability and its association with non optimal PMTCT is a cause for concern although the impact on transmission was limited in this context of universal free access to care.

CNS involvement at the onset of primary hemophagocytic lymphohistiocytosis.

OBJECTIVES: To differentiate onset of CNS involvement in primary hemophagocytic lymphohistiocytosis (HLH) from that of other CNS inflammatory diseases and to identify early symptoms linked to abnormal cognitive outcome. METHODS: Forty-six children with primary HLH who had neurologic evaluation within 2 weeks and brain MRI within 6 months of diagnosis were included. Initial symptoms, CSF study, brain MRI, and neurologic outcome were assessed. Brain MRIs were compared with those of 44 children with acute disseminated encephalomyelitis (ADEM). RESULTS: At disease onset, 29 children (63%) had neurologic symptoms and 7 (15%) had microcephaly. Twenty-three (50%) children had abnormal CSF study, but only 15 (33%) had abnormal brain MRI. The latter showed that patients with HLH, unlike patients with ADEM, had symmetric periventricular lesions, without thalamic and brainstem involvement and with infrequent hyposignal intensity on T1. At the end of follow-up (3.6 ± 3.6 years), 17 of the 28 (61%) surviving patients had normal neurologic status, 5 (18%) had a severe neurologic outcome, and 6 (21%) had mild cognitive difficulties. Abnormal neurologic outcome was not influenced by age or type of genetic defect, but by the presence of neurologic symptoms, MRI lesions, or abnormal CSF study at onset. Early clinical and MRI symptoms may regress after treatment. CONCLUSION: Neurologic symptoms are frequent at the onset of primary HLH and are mostly associated with abnormal CSF findings, but with normal brain MRI. In cases of abnormal brain MRI, the observed lesions differ from those of ADEM.

Phototoxicity and photocarcinogenesis associated with voriconazole.

The antifungal voriconazole was given its marketing authorization in 2002. Several kinds of adverse effects have been reported, including acute and chronic cutaneous adverse effects, mainly due to a phototoxicity mechanism. More recently, some authors have reported that voriconazole was involved in the occurrence of multiple and often-aggressive cutaneous squamous cell carcinomas if the treatment was maintained for a long time. According to safety data in studies assessing voriconazole effectiveness, 8% of outpatients may experience phototoxic events. An overview of the different types of phototoxicity and of the concerned population was given by the 61 published case reports of photo-induced voriconazole-related skin adverse events (including 18 cases of squamous cell carcinomas). The most likely mechanisms may be phototoxicity directly related to either voriconazole or to its N-oxide main metabolite, and an interaction with retinoid metabolism; moreover, immunodeficiency may enhance the risk of skin cancer. Several issues remain to be investigated, and studies are needed concerning the phototoxicity and photocarcinogenesis of voriconazole and the prognosis of chronic non-malignant skin lesions. Voriconazole prescription must be associated with strict photoprotection; in case of a phototoxic adverse event, another azole may be recommended.