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International audience; BACKGROUND: Strategies to prevent postnatal mother-to-child transmission of HIV-1 in Africa, including infant prophylaxis, have never been assessed past 6 months of breastfeeding, despite breastfeeding being recommended up to 12 months after birth. We aimed to compare the efficacy and safety of infant prophylaxis with the two drug regimens (lamivudine or lopinavir-ritonavir) to prevent postnatal HIV-1 transmission up to 50 weeks of breastfeeding.METHODS: We did a randomised controlled trial in four sites in Burkina Faso, South Africa, Uganda, and Zambia in children born to HIV-1-infected mothers not eligible for antiretroviral therapy (CD4 count >350 cells per μL). An independent researcher electronically generated a randomisation schedule; we then used sequentially numbered envelopes to randomly assign (1:1) HIV-1-uninfected breastfed infants aged 7 days to either lopinavir-ritonavir or lamivudine (paediatric liquid formulations, twice a day) up to 1 week after complete cessation of breastfeeding or at the final visit at week 50. We stratified the randomisation by country and used permuted blocks of four and six. We used a study label on drug bottles to mask participants, study physicians, and assessors to the treatment allocation. The primary outcome was infant HIV-1 infection between age 7 days and 50 weeks, diagnosed every 3 months with HIV-1 DNA PCR, in the modified intention-to-treat population (all who attended at least one follow-up visit). This trial is registered with ClinicalTrials.gov, number NCT00640263.FINDINGS: Between Nov 16, 2009, and May 7, 2012, we enrolled and randomised 1273 infants and analysed 1236; 615 assigned to lopinavir-ritonavir or 621 assigned to lamivudine. 17 HIV-1 infections were diagnosed in the study period (eight in the lopinavir-ritonavir group and nine in the lamivudine group), resulting in cumulative HIV-1 infection of 1.4% (95% CI 0.4-2.5) and 1.5% (0.7-2.5), respectively. Infection rates did not differ between the two drug regimens (hazard ratio [HR] of lopinavir-ritonavir versus lamivudine of 0.90, 95% CI 0.35-2.34; p=0.83). Clinical and biological severe adverse events did not differ between groups; 251 (51%) infants had a grade 3-4 event in the lopinavir-ritonavir group compared with 246 (50%) in the lamivudine group.INTERPRETATION: Infant HIV-1 prophylaxis with lopinavir-ritonavir was not superior to lamivudine and both drugs led to very low rates of HIV-1 postnatal transmission for up to 50 weeks of breastfeeding. Infant pre-exposure prophylaxis should be extended until the end of HIV-1 exposure and mothers should be informed about the persistent risk of transmission throughout breastfeeding.FUNDING: INSERM/National Agency for Research on AIDS and Viral Hepatitis (including funds from the Total Foundation), European Developing Countries Clinical Trials Partnership, Research Council of Norway.

OBJECTIVE : To investigate whether mother-to-child transmission (MTCT) management and rate differed between African immigrants and French-born women delivering in France. METHODS : MTCT strategies were studied among human immunodeficiency virus type 1-infected women delivering between 1984 and 2007 in the multicenter French Perinatal Cohort, according to geographical origin. RESULTS : Among 9245 pregnancies (in 7090 women), the proportion of African mothers increased from 12% in 1984-1986 to 64% in 2003-2004. African women had later access to care than French women, even in recent years (1997-2004). They more often discovered their HIV infection during pregnancy (40.6 vs. 11.5%, P < 0.001), started prenatal care in the third trimester (14.1 vs. 9.8%, P < 0.001) and started antiretroviral therapy after 32 weeks gestation (7.6 vs. 4.1%, P < 0.001). The association with late treatment initiation disappeared when adjusted for late HIV diagnosis and prenatal care (adjusted odds ratio 1.0, 95% confidence interval 0.7-1.4). African and French women did not differ in terms of access to highly active antiretroviral therapy, nor for substandard management such as vaginal delivery with uncontrolled viral load, lack of intrapartum and postpartum treatment or breastfeeding. The MTCT rate was higher for African than for French women receiving antiretroviral therapy (1.8 vs. 0.8%, P = 0.02), but the difference was no longer significant after adjustment for main transmission risk factors (adjusted odds ratio = 1.7, 95% confidence interval 0.8-3.7, P = 0.17). MTCT did not differ among 2110 term deliveries with maternal viral load less than 400 copies/ml, (0.8 vs. 0.6%, P = 0.5). CONCLUSION : African immigrants more often had late HIV screening in pregnancy than French-born women, but had similar access to MTCT prevention, once the infection was diagnosed.

Antiretroviral treatment interruption (TI) is not recommended in HIV-infected children. We aimed to evaluate the context and consequences of TI in clinical practice.We investigated the probability and risk factors of a first TI in the 483 children treated with combined ART (cART) in the ANRS French national pediatric cohort. Immunologic and virologic outcomes were compared between patients with TI (TI group) and those on continuous treatment (matched control group), from a baseline defined as the age at first interruption for the TI child and the corresponding age for the control child.At least one TI ≥ 3 months occurred in 42.4% of patients, at a median age of 8.0 years, for a median duration of 12.1 months. After cART initiation, the risk of TI was 7.0% (5.0-9.6) at 1 year and 30.3% (26.1-35.0) at 5 years and was higher for children starting treatment before 2000 and for children starting cART before 6 months of age. AIDS-free survival was similar, but severe immunosuppression occurred earlier in the TI group than in the control group (adjusted HR = 3.1; 1.0-9.1; P = 0.04). Four years after baseline, the proportion of patients with CD4% ≥ 25% was lower in the TI group than in the control group (52.0% vs. 72.0%; P0.01), even among children restarting cART at least 6 months earlier (aRR = 0.5; 0.3-0.9; P = 0.03).The risk of TI in clinical practice has decreased but remains high. In intent-to-treat analysis, TI was associated with a greater risk of subsequent immunosuppression, even after cART resumption.

X-linked lymphoproliferative disease (XLP1) is a rare immunodeficiency characterized by severe immune dysregulation and caused by mutations in the SH2D1A/SAP gene. Clinical manifestations are varied and include hemophagocytic lymphohistiocytosis (HLH), lymphoma and dysgammaglobulinemia, often triggered by Epstein-Barr virus infection. Historical data published before improved treatment regimens shows very poor outcome. We describe a large cohort of 91 genetically defined XLP1 patients collected from centers worldwide and report characteristics and outcome data for 43 patients receiving hematopoietic stem cell transplant (HSCT) and 48 untransplanted patients. The advent of better treatment strategies for HLH and malignancy has greatly reduced mortality for these patients, but HLH still remains the most severe feature of XLP1. Survival after allogeneic HSCT is 81.4% with good immune reconstitution in the large majority of patients and little evidence of posttransplant lymphoproliferative disease. However, survival falls to 50% in patients with HLH as a feature of disease. Untransplanted patients have an overall survival of 62.5% with the majority on immunoglobulin replacement therapy, but the outcome for those untransplanted after HLH is extremely poor (18.8%). HSCT should be undertaken in all patients with HLH, because outcome without transplant is extremely poor. The outcome of HSCT for other manifestations of XLP1 is very good, and if HSCT is not undertaken immediately, patients must be monitored closely for evidence of disease progression.

Background Primary-HIV-1-infection in newborns that occurs under antiretroviral prophylaxis that is a high risk of drug-resistance acquisition. We examine the frequency and the mechanisms of resistance acquisition at the time of infection in newborns. Patients and Methods We studied HIV-1-infected infants born between 01 January 1997 and 31 December 2004 and enrolled in the ANRS-EPF cohort. HIV-1-RNA and HIV-1-DNA samples obtained perinatally from the newborn and mother were subjected to population-based and clonal analyses of drug resistance. If positive, serial samples were obtained from the child for resistance testing. Results Ninety-two HIV-1-infected infants were born during the study period. Samples were obtained from 32 mother-child pairs and from another 28 newborns. Drug resistance was detected in 12 newborns (20%): drug resistance to nucleoside reverse transcriptase inhibitors was seen in 10 cases, non-nucleoside reverse transcriptase inhibitors in two cases, and protease inhibitors in one case. For 9 children, the detection of the same resistance mutations in mothers' samples (6 among 10 available) and in newborn lymphocytes (6/8) suggests that the newborn was initially infected by a drug-resistant strain. Resistance variants were either transmitted from mother-to-child or selected during subsequent temporal exposure under suboptimal perinatal prophylaxis. Follow-up studies of the infants showed that the resistance pattern remained stable over time, regardless of antiretroviral therapy, suggesting the early cellular archiving of resistant viruses. The absence of resistance in the mother of the other three children (3/10) and neonatal lymphocytes (2/8) suggests that the newborns were infected by a wild-type strain without long-term persistence of resistance when suboptimal prophylaxis was stopped. Conclusion This study confirms the importance of early resistance genotyping of HIV-1-infected newborns. In most cases (75%), drug resistance was archived in the cellular reservoir and persisted during infancy, with or without antiretroviral treatment. This finding stresses the need for effective antiretroviral treatment of pregnant women.

The endothelial dysfunction associated with Hematopoietic Stem Cell Transplantation (HSCT) is responsible for pleomorphic complications that arise during the post-tranplant period: sinusoidal obstruction syndrome (SOS), pulmonary arterial hypertension (PAH), capillary leak syndrome (CLS) and transplantation-associated thrombotic microangiopathy (TA-TMA). Numerous factors may induce these endothelial damages. Circulating endothelial cells (CEC) emerge as a potent marker of endothelial lesion in a variety of disorders but their monitoring in HSCT has been little investigated so far. Methods Thirty-six pediatric patients treated in the department of Immuno-Hematology at the Necker-Enfants-Malades Hospital who received allogeneic HSCT after full intensity conditioning regimen for non-malignant disorders including inherited immunodeficiencies, metabolic diseases or hemoglobin disorders were enrolled in the study between April 2011 and December 2012. CEC were monitored at 5 time points: before conditioning (day -15), at time of transplant (day 0) and during the post-transplantation period (at day +15, day +30 and eventually day +60 if the patient was still hospitalized). Blood samples were not collected in period of sepsis to avoid any confounding factor7. Results Among the thirty-six patient enrolled, four patients were excluded because of incomplete follow-up. Thirty-two patients completed the study, and their data were analyzed. Vascular complications occurred in 10 patients (31% patients) and are detailed in Figure 1C. Of note, all patients who developed SOS were under defibrotide prophylaxis. Two patients developed CLS in association with grade IV GVH. TA-TMA occurred in two patients and resolved in both after cyclosporine withdrawal. Patients with vascular events (VE) had significant higher CEC counts as compared to patients without endothelial complication at day +15 (p = 0.0122) and day +30 (p=0.0046). The increase of CEC counts was significantly higher in patients with VE during the first 15 days (p=0.0175) and during the first month post transplantation (p=0.0005) as compared to patient without VE. Strikingly, detection of high CEC counts in patients with major vascular events (ie. PAH, CLS and TA-TAM) was preceding the onset of clinical manifestations by a median of 18.5 days (range, 8-42). We didn’t find any correlation on univariate analysis between CEC counts and the following variables: the underlying disease, the intensity of conditioning regimen, the existence of CMV reactivation, graft versus host disease or death. Conclusion We observed that the occurrence of vascular complications is associated with an early rise (in the first 15 days) of CEC count. Interestingly, the increase in the number of CEC is preceding the onset of major endothelial complications. Thus, monitoring of CEC in routine could be a useful prognostic tool that could allow early therapeutic intervention. Disclosures: No relevant conflicts of interest to declare.