In infants, the mode of acquisition of CC17 group B Streptococcus (GBS), the hypervirulent clone responsible for late-onset disease (LOD), remains elusive.
In a prospective multicenter study in ...France, we evaluated GBS colonization in mother-baby pairs with 2 months of follow-up between 2012 and 2015. Criteria included positivity for GBS colonization at antenatal screening or at delivery. Maternal vaginal samples and infant oral cavity and stool samples were analyzed at delivery, 21 ± 7 days (D21), and 60 ± 7 days (D60) post-delivery.
A total of 890 mother-baby pairs were analyzed. GBS colonized 7%, 21%, and 23% of the infants at birth, D21, and D60, respectively, of which 10%, 11%, and 13% were identified as CC17 GBS. Concordance between maternal and infant GBS type was 96%. At D21, the main risk factors for infant colonization by GBS were simultaneous maternal colonization of the vagina (odds ratio OR, 4.50; 95% confidence interval CI, 1.69-15.61) and breast milk (OR, 7.93; 95% CI, 3.81-17.14). Importantly, 38% (95% CI, 23%-56%) of infants colonized by CC17 GBS appeared colonized for the first time at D60 vs 18% (95% CI, 14%-24%; P < .049) of infants colonized by non-CC17 GBS. Multivariate analysis showed a higher risk for de novo infant colonization by CC17 at D60 than by other GBS (OR, 2.45; 95% CI, 1.02-5.88).
The high incidence of CC17 GBS in LOD is likely due to an enhanced post-delivery mother-to-infant transmission.
The early initiation of antiretroviral therapy (ART) in HIV-1-infected infants reduces mortality and prevents early CD4 T-cell loss. However, the impact of early ART on the immune system has not been ...thoroughly investigated in children over five years of age or adolescents. Here, we describe the levels of naive CD4 and CD8 T lymphocytes (CD4/CD8T
), reflecting the quality of immune reconstitution, as a function of the timing of ART initiation (early (<6 months) versus late (≥24 months of age)).
The ANRS-EP59-CLEAC study enrolled 27 children (5-12 years of age) and nine adolescents (13-17 years of age) in the early-treatment group, and 19 children (L-Ch) and 21 adolescents (L-Ado) in the late-treatment group. T lymphocytes were analyzed by flow cytometry and plasma markers were analyzed by ELISA. Linear regression analysis was performed with univariate and multivariate models.
At the time of evaluation, all patients were on ART and had a good immunovirological status: 83% had HIV RNA loads below 50 copies/mL and the median CD4 T-cell count was 856 cells/µL (interquartile range: 685-1236 cells/µL). In children, early ART was associated with higher CD8T
percentages (medians: 48.7% vs. 31.0%,
= 0.001), and a marginally higher CD4T
(61.2% vs. 53.1%,
= 0.33). In adolescents, early ART was associated with low CD4T
percentages and less differentiated memory CD8 T cells. CD4T
and CD8T
levels were inversely related to cellular activation and gut permeability.
In children and adolescents, the benefits of early ART for CD8T
were clear after long-term ART. The impact of early ART on CD4T
appears to be modest, because pediatric patients treated late respond to HIV-driven CD4 T-lymphocyte loss by the
production of T
cells in the thymus. Our data also suggest that current immune activation and/or gut permeability has a negative impact on T
levels.
ClinicalTrials.gov, identifier NCT02674867.
To identify factors associated with vaginal colonization and persistence by group B
Streptococcus
(GBS) and by the hypervirulent neonatal CC-17 clone in late pregnancy and after delivery, a ...multicentre prospective observational cohort with 3-month follow-up was established in two university hospitals, Paris area, France. Pregnant women were recruited when antenatal screening for GBS vaginal colonization at 34–38 weeks of gestational age was positive. Vaginal samples were analysed by conventional culture methods at antenatal screening, delivery, and 21 and 60 days following delivery. Identification of the hypervirulent neonatal GBS CC-17 was performed. Colonization was defined as persistent when all vaginal samples were positive for GBS. A total of 754 women were included. GBS vaginal colonization was persistent in 63% of the cases (95% CI 59%–67%). Persistent colonization was more likely in women born in Sub-Saharan Africa compared with women born in France (OR = 1.88, 95% CI 1.05–3.52), and GBS CC-17 was overrepresented in women born in Sub-Saharan Africa (OR = 2.09, 95% CI 1.20–3.57). Women born in Sub-Saharan Africa are at higher risk for GBS vaginal persistence than women born in France. This observation correlates with an increased prevalence of the hypervirulent GBS CC-17 in the former group, which likely reflect variations linked to ethnicity and vaginal community-state types and might account for the increased susceptibility of black neonates to GBS infections.
Abstract
Objectives
Because NRTIs can have fetal toxicities, we evaluated a perinatal NRTI-sparing strategy to prevent perinatal HIV transmission. Our primary objective was to determine the ...proportion maintaining a viral load (VL) of <50 copies/mL up to delivery on darunavir/ritonavir monotherapy, without requiring treatment intensification.
Methods
In a one-arm, multicentre Phase 2 clinical trial, eligible patients in the first trimester of pregnancy on ART with plasma VL < 50 copies/mL received maintenance monotherapy with darunavir/ritonavir, 600/100 mg twice daily. VL was monitored monthly. ART was intensified in the case of VL > 50 copies/mL. Neonates received nevirapine prophylaxis for 14 days.
Results
Of 89 patients switching to darunavir/ritonavir monotherapy, 4 miscarried before 22 weeks’ gestation, 2 changed treatment for elevated liver enzymes without virological failure, and 83 were evaluable for the main outcome. Six had virological failure confirmed on a repeat sample (median VL = 193 copies/mL; range 78–644), including two before switching to monotherapy. In these six cases, ART was intensified with tenofovir disoproxil fumarate/emtricitabine. The success rate was 75/83, 90.4% (95% CI, 81.9%–95.7%) considering two patients with VL missing at delivery as failures, and 77/83, 92.8% (95% CI, 84.9%–97.3%) when considering them as successes since both had undetectable VL on darunavir/ritonavir throughout pregnancy. In ITT, the last available VL before delivery was <50 copies/mL in all of the patients. There was no case of perinatal HIV transmission.
Conclusions
Darunavir/ritonavir maintenance monotherapy required intensification in nearly 10% of cases. This limits its widespread use, thus other regimens should be evaluated in order to limit exposure to antiretrovirals, particularly NRTIs, during pregnancy.
Abstract
Background
Early combined antiretroviral therapy (cART) limits the total HIV-DNA load in children. However, data on its impact in older children and adolescents remain scarce. This study ...compares HIV reservoirs in children (5–12 years) and adolescents (13–17 years) who started cART <6 months (early E- group) or >2 years (late L- group).
Methods
The ANRS-EP59-CLEAC study prospectively enrolled 76 patients perinatally infected with HIV-1 who reached HIV-RNA <400 copies/mL <24 months after cART initiation, regardless of subsequent viral suppression (E-group: 27 children, 9 adolescents; L-group: 19 children, 21 adolescents). Total and integrated HIV-DNA were quantified in blood and in CD4+ T-cell subsets. A substudy assessed HIV reservoir inducibility after ex vivo peripheral blood mononuclear cell (PBMC) stimulation.
Results
Total HIV-DNA levels were lower in early- versus late-treated patients (children: 2.14 vs 2.87 log copies/million PBMCs; adolescents: 2.25 vs 2.74 log; P < .0001 for both). Low reservoir was independently associated with treatment precocity, protective HLA, and low cumulative viremia since cART initiation. The 60 participants with undetectable integrated HIV-DNA started cART earlier than other patients (4 vs 54 months; P = .03). In those with sustained virological control, transitional and effector memory CD4+ T cells were less infected in the E-group than in the L-group (P = .03 and .02, respectively). Viral inducibility of reservoir cells after normalization to HIV-DNA levels was similar between groups.
Conclusions
Early cART results in a smaller blood HIV reservoir until adolescence, but all tested participants had an inducible reservoir. This deserves cautious consideration for HIV remission strategies.
Initiating antiretroviral therapy (ART) early in infancy results in a smaller blood human immunodeficiency virus (HIV) reservoir until adolescence. Low HIV-DNA levels in children and adolescents correlated independently with age of treatment initiation, protective HLA, and low cumulative viremia since combined ART initiation.
In the ANRS French Perinatal Cohort, we compared outcomes in 830 HIV1-exposed infants who received either nevirapine (NVP) or zidovudine postnatal prophylaxis. At 1 month, anemia grade ≥2 was less ...frequent on NVP than zidovudine (2.9% vs. 8.0%; P = 0.01), favoring the use of NVP as a first choice prophylaxis in infants at low risk of HIV acquisition.
Abstract
Background
Safety data about rilpivirine use during pregnancy remain scarce, and rilpivirine plasma concentrations are reduced during second/third trimesters, with a potential risk of viral ...breakthroughs. Thus, French guidelines recommend switching to rilpivirine-free combinations (RFCs) during pregnancy.
Objectives
To describe the characteristics of women initiating pregnancy while on rilpivirine and to compare the outcomes for virologically suppressed subjects continuing rilpivirine until delivery versus switching to an RFC.
Methods
In the ANRS-EPF French Perinatal cohort, we included women on rilpivirine at conception in 2010–18. Pregnancy outcomes were compared between patients continuing versus interrupting rilpivirine. In women with documented viral suppression (<50 copies/mL) before 14 weeks of gestation (WG) while on rilpivirine, we compared the probability of viral rebound (≥50 copies/mL) during pregnancy between subjects continuing rilpivirine versus those switching to RFC.
Results
Among 247 women included, 88.7% had viral suppression at the beginning of pregnancy. Overall, 184 women (74.5%) switched to an RFC (mostly PI/ritonavir-based regimens) at a median gestational age of 8.0 WG. Plasma HIV-1 RNA nearest delivery was <50 copies/mL in 95.6% of women. Among 69 women with documented viral suppression before 14 WG, the risk of viral rebound was higher when switching to RFCs than when continuing rilpivirine (20.0% versus 0.0%, P = 0.046). Delivery outcomes were similar between groups (overall birth defects, 3.8/100 live births; pregnancy losses, 2.0%; preterm deliveries, 10.6%). No HIV transmission occurred.
Conclusions
In virologically suppressed women initiating pregnancy, continuing rilpivirine was associated with better virological outcome than changing regimen. We did not observe a higher risk of adverse pregnancy outcomes.
BACKGROUND:High rates of liver enzyme elevation (LEE) in women receiving antiretroviral treatment (ART) during pregnancy have been reported, but causes remain unclear. We estimated the prevalence and ...risk factors of LEE in a national prospective multicenter cohort.
METHODS:We studied 5748 pregnant women living with HIV enrolled in the French Perinatal Cohort 2005–2014, treated with ART, with no active hepatitis B or C coinfection. Adjusted hazard ratio (aHR) was estimated using Cox models with ART as time-dependent variable, separately for women on ART at conception and those initiating ART during pregnancy.
RESULTS:LEE (grade ≥ 1) was observed in 16.7%, grade 3–4 in 2%. Among women with LEE, 6.7% had pre-eclampsia, 9.8% intrahepatic cholestasis of pregnancy, and 1.4% other identified medical causes. Most LEEs (82.2%) were unexplained. In women with unexplained LEE, LEE was the reason for hospitalization in 51 (6%) women, cesarean section in 13 (2%), induction of labor in 3 (0.4%), and change in ART regimen in 49 (6%) women. Unexplained LEE was associated with higher risk of preterm births, P < 0.001. Among women on ART at conception, the risk of unexplained LEE was lower with NNRTI-based regimens than with PI-based regimensaHR = 0.5 (0.3–0.7), with no difference among the PI drugs. Most women initiating ART during pregnancy were on a PI-based regimen (89%). Among them, LEE was less frequent for women on nelfinavir vs. lopinavir/r aHR = 0.4 (0.2–0.8).
CONCLUSIONS:Rates of LEE among pregnant women living with HIV are high and impact obstetrical care management. The possible role of PIs needs further investigation.
OBJECTIVE:To determine whether changing antiretroviral therapy (ART) during pregnancy because of concern about fetal risks led to poorer virological outcomes.
METHODS:All pregnancies in women with ...HIV-1 infection enrolled in the national multicenter prospective French Perinatal cohort at 14 week gestation or more were included between January 2005 and December 2015, if the mother was on ART at conception with a plasma viral load <50 copies/mL. The reasons for a change in the ART were analyzed according to treatment guidelines at the time of the pregnancy and defined as for safety concerns in the absence of reported maternal intolerance. Virological and pregnancy outcomes were studied by survival analysis and logistic regression adjusted for a propensity score established for each patient according to baseline characteristics.
RESULTS:Of 7079 pregnancies in the overall cohort, 1797 had ART at conception with a viral load <50 copies/mL before 14 week gestation. Of these, 22 changed regimens in the first trimester for intolerance, and 411 of the remaining 1775 (23%) solely for safety concerns. The proportion of change was higher when the initial treatment was not recommended in the national guidelines (OR adjusted23.1 14.0–38.2), than when it was an alternative option (ORa2.2 1.3–3.7), as compared to recommended first-line regimens. Treatment changes for safety concerns did not lead to poorer virological control, compared with pregnancies without such changes (19.3% vs. 15.6%, HRa1.0 0.7–1.4).
CONCLUSIONS:Changing ART early in pregnancy to regimens considered safer for pregnancy, and neonatal health did not have a destabilizing effect on viral suppression.
Virus-specific CD8+ T cells play a central role in HIV-1 natural controllers to maintain suppressed viremia in the absence of antiretroviral therapy. These cells display a memory program that confers ...them stemness properties, high survival, polyfunctionality, proliferative capacity, metabolic plasticity, and antiviral potential. The development and maintenance of such qualities by memory CD8+ T cells appear crucial to achieving natural HIV-1 control. Here, we show that targeting the signaling pathways Wnt/transcription factor T cell factor 1 (Wnt/TCF-1) and mTORC through GSK3 inhibition to reprogram HIV-specific CD8+ T cells from noncontrollers promoted functional capacities associated with natural control of infection. Features of such reprogrammed cells included enrichment in TCF-1+ less-differentiated subsets, a superior response to antigen, enhanced survival, polyfunctionality, metabolic plasticity, less mTORC1 dependency, an improved response to γ-chain cytokines, and a stronger HIV-suppressive capacity. Thus, such CD8+ T cell reprogramming, combined with other available immunomodulators, might represent a promising strategy for adoptive cell therapy in the search for an HIV-1 cure.
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