Publications

Authors: Goncalves BS, Nogueira RMR, Bispo de Filippis AM, Horta MAP

Published in: Trans R Soc Trop Med Hyg. 2019;113(11):670-677

Authors: Domínguez-Rodríguez S, Tagarro A. Palma P, et al.

Published in: JAIDS 2019;82(5):483-490

Authors: Schröter J.

Published in: Poster presented at 4th Workshop on Virus Dynamics, October 21st-23rd, 2019 -Paris, FR

Authors: Li G, Bielicki JA, Ahmed ASMNU, et al.

Published in: Arch Dis Child.2091;0:1-6

Authors:Simitsopoulou M, Kadiltzoglou P, Kyrpitzi D, Roilides E.

Published in: Int J Biol Med Res.2019;10(1):6591-6596

Authors: Jacqz-Aigrain E, Leroux S, Thomson AH, et al.

Published in: J Antimicrob Ther 2019; 74(8):2128-2138

Authors: Torres MC, de Bruycker Nogueira F, Fernandes CA, et al.

Published in: PLoS One. 2019;14(12):e0225879

Abstract The Asian/American genotype of dengue virus serotype 2 (DENV-2) has been introduced in Brazil through the state of Rio de Janeiro around 1990, and since then it has been spreading and evolving, leading to several waves of dengue epidemics throughout the country that cause a major public health problem. Of particular interest has been the epidemic of 2008, whose highest impact was evidenced in the state of Rio de Janeiro, with a higher number of severe cases and mortality rate, compared to previous outbreaks. Interestingly, no circulation of DENV-2 was witnessed in this region during the preceding 9-year period. By early 2010, phylogenetic analysis of the 2008 epidemic strain revealed that the outbreak was caused by a new viral lineage of the Asian/American genotype, which was pointed as responsible for the outbreak severity as well. The same scenario is repeating in 2019 in this state; however, only a few cases have been detected yet. To provide information that helps to the understanding of DENV-2 dynamics in the state of Rio de Janeiro, and thereafter contribute to public health control and prevention actions, we employed phylogenetic studies combined with temporal and dynamics geographical features to determine the origin of the current viral strain. To this effect, we analyzed a region of 1626 nucleotides entailing the Envelope/NS1 viral genes. Our study reveals that the current strain belongs to the same lineage that caused the 2008 outbreak, however, it is phylogenetically distant from any Brazilian strain identified so far. Indeed, it seemed to be originated in Puerto Rico around 2002 and has been introduced into the state in late 2018. Taking into account that no DENV-2 case was reported over the last decade in the state (representing a whole susceptible children generation), and the fact that a new viral strain may be causing current dengue infections, these results will be influential in strengthening dengue surveillance and disease control, mitigating the potential epidemiological consequences of virus spread.

Authors: Brenes-Chacón H, Ávila-Agüero ML, Camacho-Badilla K, Naranjo-Zuñiga G, Benavides-Lara A,  Soriano-Fallas A

Published in: ID Week, Washington DC, October 2nd – 6th 2019

Authors: Gärtner K, Gkouleli T, Heaney J, et al; on behalf of the EPIICAL consortium

Published: Poster presented at HIV Cure and Reservoir Symposium, September, 16th-20th, 2019 -Ghent, BE

Authors: Schwarz ER, Pozor MA, Pu R, et al.

Published in: Viruses. 2019;11(9)

Abstract Zika virus (ZIKV) is a vertically and sexually transmissible virus resulting in severe congenital malformation. The goal of this study was to develop an ovine model of ZIKV infection. Between 28–35 days gestation (DG), four pregnant animals were infected with two doses of 6 × 106 PFU of ZIKV; four control animals received PBS. Animals were evaluated for 45 days (D) post-infection (PI) and necropsies were performed. Viral RNA was detected in infected ewe peripheral blood mononuclear cells (PBMC) during the first week PI; however, all fluids and tissues were negative upon culture. Anti-ZIKV IgM (1:400) and neutralizing antibodies were detected in all infected animals. Clinical disease, virus, or ZIKV antibodies were not detected in control ewes. After two weeks PI, fetal loss occurred in two infected animals, and at necropsy, three infected animals had placental petechiation and ecchymosis and one had hydramnion. Fetal morphometrics revealed smaller cranial circumference to crown-rump length ratios (p < 0.001) and relative brain weights (p = 0.038) in fetuses of infected animals compared with control fetuses. Immunophenotyping indicated an increase in B cells (p = 0.012) in infected sheep. Additionally, in vitro experiments using both adult and fetal cell lines demonstrated that ovine cells are highly permissive to ZIKV infection. In conclusion, ZIKV infection of pregnant sheep results in a change in fetal growth and gestational outcomes.

Authors: Sulleiro E, Rando A, Alejo I, et al.

Published in: Clin Microbiol Infect. 2019;25(5):633.e5-633.e9

Objectives The aim was to describe pregnancy outcomes after Zika virus (ZIKV) infection in a non-endemic region.

Methods According to the Spanish protocol issued after the ZIKV outbreak in Brazil in 2015, all pregnant women who had travelled to high-burden countries were screened for ZIKV. Serological and molecular tests were used to identify ZIKV-infected pregnant women. They were classified as confirmed ZIKV infection when reverse transcription (RT) PCR tested positive, or probable ZIKV infection when ZIKV immunoglobulin M and/or immunoglobulin G and ZIKV plaque reduction neutralization tests were positive. Women found positive using molecular or serological tests were prospectively followed-up with ultrasound scans and neurosonograms on a monthly basis until delivery; magnetic resonance imaging and amniotic fluid testing were performed after signed informed consent. Samples of placenta, and fetal and neonatal tissues were obtained.

Results Seventy-two pregnant women tested positive for ZIKV infection: ten were confirmed by RT-PCR, and 62 were probable cases based on serological tests. The prevalence of adverse perinatal outcomes was 33.3% (three out of nine, 95% CI 12.1-64.6%): two cases of congenital ZIKV syndrome (CZS) and one miscarriage, all born to women infected in the first trimester of gestation. All ZIKV-confirmed women had persistent viraemias beyond 2 weeks (median 61.50 days; IQR 35.50-80.75). Amniotic fluid testing was only positive in the two fetuses with anomalies.

Conclusions The prevalence of perinatal adverse outcomes for women with ZIKV-confirmed infection was 33.3%. Amniocentesis for ZIKV RT-PCR is recommended when fetal abnormalities are found. Intensive prenatal and postnatal follow-up of ZIKV-infected pregnancies is advised in confirmed cases.

Authors: Sulleiro E, Rando A, Alejo I, et al.

Published in: Travel Med Infect Dis. 2019;29:69-71

No abstract available

Authors: Siqueira Mello A, Pascalicchio Bertozzi APA, Rodrigues MMD, et al.

Published in: Am J Case Rep. 2019 May 21;20:723-725

Background The Zika virus is an arbovirus that has as main source of transmission the bite of infected insects of the genus Aedes and has been associated with cases of congenital malformation and microcephaly in neonates. However, other sources of transmission have been identified since the emergence of this virus in the world population, such as vertical transmission by semen and possibly other body fluids such as vaginal secretion and breast milk.
Case Report An infant, born to a mother whose previous delivery was a baby with severe microcephaly, was normal and was negative for Zika virus at birth but developed secondary microcephaly 1 month later, that persisted. The baby was exclusively breast-fed and Zika virus was present in the mother’s milk.
Conclusions We report the detection of Zika virus exclusively in the breast milk of a woman after her second delivery of an infant, who later developed microcephaly. This case is consistent with possible vertical transmission.

Authors: Vedovello D, Witkin SS, Silva ACB, et al.

Published in: J Neurovirol 2019 Sep 9. doi: 10.1007/s13365-019-00797-0

Abstract Paired maternal and newborn urine and amniotic fluid from 138 subjects collected during a Zika virus (ZIKV) outbreak was analyzed for ZIKV by gene amplification (RT-qPCR), and the findings were correlated with clinical symptoms and neurological anomalies in the babies. ZIKV was detected in 1 of 9 symptomatic women (11.1%) and in 19 of 129 asymptomatic women (14.7%). Neurological manifestations were present in 19 babies (13.7%), 10 of 20 (50%) positive and 9 of 119 (7.6%) negative (p < 0.001) for ZIKV. Twelve (8.6%) urines collected during gestation were ZIKV-positive; only 2 remained positive for ZIKV postpartum. Six (4.1%) newborn urines collected within 1 day of delivery were ZIKV-positive cases. In 3 of these cases, ZIKV was detected in mother’s urine pre- and postpartum and in both mother’s urine and babies’ urine. Four of the amniotic fluid samples (2.9%) were ZIKV-positive. Among ZIKV-negative babies with neurological sequel, 87.5% were female; in contrast, 72.7% ZIKV-positive babies with neurological abnormalities were male (p = 0.019). We conclude that during a ZIKV outbreak, clinical symptoms and ZIKV detection in biological fluids are poor predictors of infection and adverse neurologic sequel in newborns.

Authors: Sulleiro E, Frick MA, Rodó C, et al.

Published in: Medicine (Baltimore). 2019;98(20):e15532

Introduction Zika virus (ZIKV) has caused one of the most challenging global infectious epidemics in recent years because of its causal association with severe microcephaly and other congenital malformations. The diagnosis of viral infections usually relies on the detection of virus proteins or genetic material in clinical samples as well as on the infected host immune responses. Serial serologic testing is required for the diagnosis of congenital infection when diagnostic molecular biology is not possible.

Patient concerns A 2-year-old girl, born to a mother with confirmed ZIKV infection during pregnancy, with a confirmed ZIKV infection in utero, showed at birth a severe microcephaly and clinical characteristics of fetal brain disruption sequence compatible with a congenital ZIKV syndrome (CZS).

Diagnosis ZIKV-RNA and ZIKV-IgM serological response performed at birth and during the follow-up time tested always negative. Serial serologic ZIKV-IgG tests were performed to assess the laboratory ZIKV diagnosis, ZIKV-IgG seroreversion was observed at 21 months of age. ZIKV diagnosis of this baby had to be relied on her clinical and radiological characteristics that were compatible with a CZS.

Interventions The patient was followed-up as per protocol at approximately 1, 4, 9, 12, 18-21, and 24 months of age. Neurological, radiological, audiological, and ophthalmological assessment were performed during this period of time. Prompt rehabilitation was initiated to prevent potential adverse long-term neurological outcomes.

Outcomes The growth of this girl showed a great restriction at 24 months of age with a weight of 8.5 kg (-2.5 z-score) and a head circumference of 40.5 cm (-4.8 z-score). She also had a great neurodevelopmental delay at the time of this report.

Conclusions We presume that as a consequence of prenatal ZIKV infection, the fetal brain and other organs are damaged before birth through direct injury. Following this, active infection ends during intrauterine life, and as a consequence the immune system of the infant is unable to build up a consistent immune response thereafter. Further understanding of the mechanisms taking part in the pathogenesis of ZIKV congenital infection is needed. This finding might change our paradigm regarding serological response in the ZIKV congenital infection.

Authors: Kaguelidou F, Le Roux E, Mangiarini L, et al.; GAPP consortium

Published in: BMJ Open. 2019;9(2):e023296

Authors: de Leeuw TG, Mangiarini L, Lundin R, et al; GAPP consortium

Published in: Trials. 2019; 20(1):368

Background Gabapentin has shown efficacy in the treatment of chronic neuropathic or mixed pain in adults. Although pediatric pain specialists have extensive experience with gabapentin for the treatment of neuropathic pain, its use is off-label. Its efficacy and safety in this context have never been shown. The aim of this trial is to compare gabapentin with placebo as add-on to morphine for the treatment of severe chronic mixed or neuropathic pain in children. This trial is part of the European Union Seventh Framework Programme project Gabapentin in Paediatric Pain (GAPP) to develop a pediatric use marketing authorization for a new gabapentin suspension.

Methods/design The GAPP-2 study is a randomized, double-blind, placebo-controlled, multicenter superiority phase II study in children with severe chronic neuropathic or mixed pain. Its primary objective is to evaluate the efficacy of a gabapentin liquid formulation as adjunctive therapy to morphine. Sixty-six eligible children 3 months to 18 years of age with severe pain (pain scores ≥ 7), stratified in three age groups, will be randomized to receive gabapentin (to an accumulating dose of 45 to 63 mg/kg/day, dependent on age) or placebo, both in addition to morphine, for 12 weeks. Randomization will be preceded by a short washout period, and treatment will be initiated by a titration period of 3 weeks. After the treatment period, medication will be tapered during 4 weeks. The primary endpoint is the average pain scores in the two treatment groups (average of two measures each day for 3 days before the end-of-study visit [V10] assessed by age-appropriate pain scales (Face, Legs, Activity, Cry, Consolability scale; Faces Pain Scale–Revised; Numeric Rating Scale). Secondary outcomes include percentage responders to treatment (subjects with 30% reduction in pain scale), number of episodes of breakthrough pain, number of rescue interventions, number of pain-free days, participant dropouts, quality of life (Pediatric Quality of Life Inventory), and acceptability of treatment. Outcomes will be measured at the end-of-study visit after 12 weeks of treatment at the optimal gabapentin dose. Groups will be compared on an intention-to-treat basis.

Discussion We hope to provide evidence that the combination of morphine and gabapentin will provide better analgesia than morphine alone and will be safe. We also aim to obtain confirmation of the recommended pediatric dose.

Authors: Waalewijn H, Bollen PDJ, Moore C, Kekitiinwa A, et al. The ODYSSEY Trail Team

Published in: Oral Presentation at 10th IAS Conference, July, 21-24th 2019

Authors: Tedder RS, Dicks S, Ijaz S, et al.

Published in: PLoS One. 2019;14(8):e0215708

Abstract The accurate diagnosis and seroprevalence investigations of Zika virus (ZKV) infections remain complex due to cross reactivity with other flaviviruses. Two assay formats, both using labelled Zika virus NS1 antigen as a revealing agent (a double antigen binding assay, DABA, and an immunoglobulin Ig capture assay, G capture) were initially developed and compared with the indirect EuroimmunZ assay for the detection of anti-Zika antibody. Of 147 pre-Zika period serum samples, 39 (27%) were reactive in the EuroimmunZ or the DABA assays, 28 sera concordantly so. Such false reactivity was influenced by the serotype of Dengue virus (DV) to which individuals had been exposed to. Thus, of sera from patients undergoing secondary Dengue virus infection of known serotype, 91%, 45% and 28% of Dengue virus serotype 2, 3 and 4 respectively were reactive in one or more of the three assays. A novel method of quenching false sero-reactivity was therefore developed for the DABA and G capture assays. Initial addition of a single homologous Dengue virus serotype 3 NS1Ag quench significantly ablated false reactivities in the pre-Zika period sera. An equipotent quadrivalent quench comprising homologous Dengue virus serotypes 1 to 4 NS1Ag was shown to be optimum yet retained sensitivity for the detection of specific anti-Zika antibody. Comparing DABA and G capture assays using quenched and unquenched conjugates in comparison with EuroimmunZ early in the course of PCR-confirmed infection indicated that a significant component of the apparent early anti-ZIKA antibody response is likely to be due to a Zika virus-driven anamnestic anti-Dengue virus response. The increased specificity provided by homologous antigen quenching is likely to provide a significant improvement in sero-diagnostics and to be of clinical value.

Authors: Kraemer MUG, Reiner RC Jr, Brady OJ, et al.

Published in: Nat Microbiol. 2019;4:900

Abstract The global population at risk from mosquito-borne diseases—including dengue, yellow fever, chikungunya and Zika—is expanding in concert with changes in the distribution of two key vectors: Aedes aegypti and Aedes albopictus. The distribution of these species is largely driven by both human movement and the presence of suitable climate. Using statistical mapping techniques, we show that human movement patterns explain the spread of both species in Europe and the United States following their introduction. We find that the spread of Ae. aegypti is characterized by long distance importations, while Ae. albopictus has expanded more along the fringes of its distribution. We describe these processes and predict the future distributions of both species in response to accelerating urbanization, connectivity and climate change. Global surveillance and control efforts that aim to mitigate the spread of chikungunya, dengue, yellow fever and Zika viruses must consider the so far unabated spread of these mosquitos. Our maps and predictions offer an opportunity to strategically target surveillance and control programmes and thereby augment efforts to reduce arbovirus burden in human populations globally.

Authors: Foster C, Dominguez S, Tagarro A, Nastouli E, Gkouleli R, Heaney J, PalmaP, Rossi P, Giaquinto C, Rojo P

Published: 10th IAS Conference on HIV Science, July 21rd-24th 2019, Mexico City

Background Future strategies aimed at achieving antiretroviral therapy (ART)-free HIV remission are likely to target individuals with a limited size of viral reservoir. We investigated factors associated with a low reservoir measured as total HIV-1 DNA in PBMCs in perinatally infected children (PaHIV) from 5 European centers in the EPIICAL consortium.

Authors: Heaney J, Busby E, Gärtner K, Grant P, Spyer MJ, O’Sullivan DM, Gkouleli T, Marcelin AG, Pillay D, Foster C, Rojo P, Palma P, Muñoz Fernández MA, deRossi A, Huggett JF, Nastouli E

Published: International Workshop on HIV Pediatrics, July 19th-20th, 2019. P_102

Background Despite effective antiretroviral therapy(ART), HIV persists as integrated provirus generating latent viral reservoirs even in the absence of detectable plasma viremia.

Latently infected cells, primarily CD4+ T cells, have the potential to release progeny virus and contribute to viral rebound after treatment interruption or HIV-1 remission.

Robust assays are needed to monitor the viral reservoir, and remission, as emerging therapeutic approaches aimed at achieving ART-free HIV remission, or cure, are likely to target individuals with low levels of total HIV-1 DNA. The current gold standard for measuring specific DNA amounts in clinical diagnostics and research is quantitative PCR (qPCR), whereas digital PCR (dPCR) is a more recent technology that has become commercially available since 2011.

Authors: Wilder-Smith A, Wei Y, Araújo TVB et al;Zika Virus Individual Participant Data Consortium

Published in: BMJ Open. 2019;9(6):e026092. doi: 10.1136/bmjopen-2018-026092.

Authors: Colbers A, Bollen P, Freriksen J, Konopnicki D, Weizsäcker K, Hidalgo Tenorio C, Moltó J, Taylor G, Alejandre I,  van Crevel R, Burger D; on behalf of the PANNA network

Published: 26th Conference on Retroviruses and Opportunistic Infections, March 4th – 7th, 2019– Seattle. P_758.

Authors: Colbers A, Bollen P, Freriksen J, Konopnicki D, Weizsäcker K, Hidalgo Tenorio C, Moltó J, Taylor G, Alejandre I,  van Crevel R, Burger D.

Published: Oral presentation at 9th edition of the International Workshop on HIV & Women, March 2nd-3rd 2019, Seattle

Authors: Kreitchmann R, Schalkwijk S, Best B, et al.

Published in: Antivir Ther. 2019;24(2):95-103

Background Limited data exist on efavirenz pharmacokinetics in HIV-positive pregnant women and neonatal washout.

Methods HIV-infected pregnant women receiving 600 mg efavirenz once daily had intensive steady-state 24-h pharmacokinetics profiles during the second trimester (2T), third trimester (3T) and 6-12 weeks postpartum (PP). Maternal and umbilical cord blood samples were drawn at delivery and neonatal washout pharmacokinetics were determined. Therapeutic targets were the estimated 10th percentile efavirenz area under the concentration-time curve (AUC) in non-pregnant historical controls (40.0 μg•h/ml) and a trough concentration (C24 h) of 1 μg/ml. Data were prospectively collected within two trials: IMPAACT P1026s (United States) and PANNA (Europe).

Results Among 42 women studied, 15, 42 and 40 had efavirenz pharmacokinetic data available in 2T, 3T and PP, respectively. Median (range) 3T age 33 (20.7-43.5) years, weight 74 (50-132) kg and gestational age 33.4 (28.4-37.9 weeks). Efavirenz AUC during the 3T (60 μg•h/ml) was similar to that reported in non-pregnant adults (58 μg•h/ml). Exposure in the 2T was lower, but within the 0.80-1.25 range. C24concentrations during pregnancy were lower compared to historical controls on 600 mg efavirenz, however, they were similar to the C24concentrations after equally potent dose of 400 mg efavirenz. Cord blood/maternal plasma concentration ratio (range) was 0.67 (0.36-0.95). Among 23 infants with washout data available, median (interquartile range) elimination half-life was 65.6 h (40.6-129). HIV RNA viral loads at delivery were <400 and <50 copies/ml for 96.7% and 86.7% of women, respectively. In 3T and PP, respectively, 8/41 (19%) and 6/40 (15%) had AUC below target; 7/41 (17%) and 3/39 (8%) had C24 below target.

Conclusions Efavirenz exposure was similar during pregnancy compared with PP, C24 was in line with C24 after 400 mg equipotent efavirenz dosing. Efavirenz readily crossed the placenta and infant elimination half-life was over twice that of maternal participants.

Authors: Schalkwijk S, Ter Heine R, Colbers A, et al.

Published in: J Antimicrob Chemother. 2019;30 [Epub ahead of print]

Background Darunavir 800 mg once (q24h) or 600 mg twice (q12h) daily combined with low-dose ritonavir is used to treat HIV-positive pregnant women. Decreased total darunavir exposure (17%-50%) has been reported during pregnancy, but limited data on unbound exposure are available.

Objectives To evaluate total and unbound darunavir exposures following standard darunavir/ritonavir dosing and to explore the value of potential optimized darunavir/ritonavir dosing regimens for HIV-positive pregnant women.

Patients and Methods A population pharmacokinetic analysis was conducted based on data from 85 women. The final model was used to simulate total and unbound darunavir AUC0-τ and Ctrough during the third trimester of pregnancy, as well as to assess the probability of therapeutic exposure.

Results Simulations predicted that total darunavir exposure (AUC0-τ) was 24% and 23% lower in pregnancy for standard q24h and q12h dosing, respectively. Unbound darunavir AUC0-τ was 5% and 8% lower compared with post-partum for standard q24h and q12h dosing, respectively. The probability of therapeutic exposure (unbound) during pregnancy was higher for standard q12h dosing (99%) than for q24h dosing (94%).

Conclusion The standard q12h regimen resulted in maximal and higher rates of therapeutic exposure compared with standard q24h dosing. Darunavir/ritonavir 600/100 mg q12h should therefore be the preferred regimen during pregnancy unless (adherence) issues dictate q24h dosing. The value of alternative dosing regimens seems limited.

Authors: Tagarro A, Dominguez Rodriguez S, Puthanakit T, et al.

Published: Oral presentation at 27th Conference on Retroviruses and Opportunistic Infections, March 4th-7th, 2019 – Seattle, WA

Abstract: Early antiretroviral therapy (ART) in children is associated with better clinical and virological outcome. Few data are available about long-term outcome of children starting ART in the neonatal period. Our hypothesis is that HIV-perinatally infected neonates initiating ART within <7 days of life have a better long-term clinical and virological response than neonates treated ≥7 days and ≤28 days of life.

44 children with perinatal HIV aged ≤28 days at start of ART were included from 4 cohorts (11%UK, 52% Spain, 7% Italy, and 29% Thailand). Primary endpoints were clinical – mortality, and progression to AIDS – and virological: time to suppression, time to virological failure, and proportion of time suppressed. Data were collected up to 15-years of follow-up. Those subjects who received triple postpartum prophylaxis and subsequently transitioned to ART within <15 days were considered as starting ART from date of prophylaxis initiation. A flexible spline interval censored survival model was applied adjusting for CD4 and viral load (VL) at the start of ART.

57% were female and 35% preterm. Median follow-up was 11.5[IQR 8.2-15.6] years. No patient died. 84% received postpartum prophylaxis. At ART initiation, children were aged 15.5 [0.00;24.2] days, with CD4 total 2766[2126;3368], CD4:CD8 2.5[1.6;3.1], and log10VL 4.2[2.9;5.2] copies/ml. 36/44 (83%) ever suppressed (VL≤50). Time to viral suppression was 0.57[0.25;1.04] years. 12/44 (34%) had subsequent virological failure after suppression (median time to failure, 2.40 [1.01;9.61] years). Participants had 2.9 ±1.8 ART regimen switches, 26% progressed to AIDS. 19/44 (43%) patients started ART <7 days of age. Viral load was higher in children treated <7 days (log10VL 4.4 [4.2;5.4] vs 3.3 [2.9;4.4], p=0.018). Time to suppression was shorter in those treated in the first 7 days of life (18.9[7;41.7] y 44.1[24.6;61.0] weeks, p = 0.038). The probability of suppression decreased by 24% for each week the ART initiation was delayed (aHR=0.76 [0.6;0.97], p=0.035, Figure 1). No differences were observed in progression to AIDS, ART switches, time to immunological recovery (CD4:CD8>1), time to virological failure or proportion of time suppressed.

Even among children initiating ART<28 days of age, children starting ART in the first week of life suppress earlier. There was similar long-term clinical, virological and immunological outcomes in children treated <7 days vs. 7 to 28 days.

Authors: Gray ER, Heaney J, Ferns RB, Sequeira PC, Nastouli E, Garson JA

Published in: J Virol Methods. 2019;268:17-23

Abstract Dengue is a vector-transmitted viral infection that is a significant cause of morbidity and mortality in humans worldwide, with over 50 million apparent cases and a fatality rate of 2.5 % of 0.5 million severe cases per annum in recent years. Four serotypes are currently co-circulating. Diagnosis of infection may be by polymerase chain reaction, serology or rapid antigen test for NS1. Both pan-serotype and serotype-specific genome detection assays have been described, however, achieving adequate sensitivity with pan-serotype assays has been challenging. Indeed, as we show here, inspection of components and cycling parameters of a pan-serotype RT-qPCR assay in use in laboratories worldwide revealed insufficient probe stability to accommodate potential nucleotide mismatches, resulting in false-negatives. A minor–groove binder (MGB)-modified version of the probe was designed and its performance compared with that of the original probe in 32 samples. Eight of the samples were undetected by the original probe but detected by the MGB modified probe and six out of seven of these that could be serotyped belonged to serotype 4. Sequencing of the region targeted by the probe in these samples revealed two mismatches which were also universally present in all other serotype 4 sequences in a public database. We therefore recommend adoption of this MGB modification in order to reduce the risk of false-negative results, especially with dengue serotype 4 infections.

Authors: Hayashida K, Orba Y, Sequeira PC, et al.

Published in: PLoS Negl Trop Dis. 2019;13(6):e0007480

Abstract Detection and sequencing of chikungunya virus (CHIKV) genome was performed using a combination of a modified reverse transcription loop-mediated isothermal amplification (RT-LAMP) method and a MinION sequencer. We developed the protocol for drying all the reagents for the RT-LAMP in a single reaction tube. Using this system, the CHIKV genome was effectively amplified under isothermal conditions, and used as a template for MinION sequencing with a laptop computer. Our in-house RT-LAMP method and MinION sequencing system were also validated with RNAs and serum samples from recent outbreaks of CHIKV patients in Brazil. The obtained sequence data confirmed the CHIKV outbreaks and identified the genotype. In summary, our established inexpensive on-site genome detection and sequencing system is applicable for both diagnosis of CHIKV infected patients and genotyping of the CHIKV virus in future outbreak in remote areas.

Authors: Hsia Y, Lee BR, Versporten A, et al; GARPEC and Global-PPS networks.

Published in: Lancet Glob Health. 2019;7(7):e861-e871

Authors: Balasegaram M, Pécoul B, Gray G, Sharland M, Swaminathan S.

Published in: Lancet Infect Dis. 2019;19(6):573-574

Abstract Newborn babies, infants, and children are substantially affected by antimicrobial resistance. Globally, infectious diseases remain a major cause of morbidity and mortality in children, and an estimated 214 000 newborn babies died from drug-resistant bacterial infections in 2015

Authors: Mavian C, Dulcey M, Munoz O, Salemi M, Vittor AY, Capua I.

Published in: Viruses. 2019; 11(1):11

Abstract During the past ten years, an increasing number of arbovirus outbreaks have affected tropical islands worldwide. We examined the available literature in peer-reviewed journals, from the second half of the 20th century until 2018, with the aim of gathering an overall picture of the emergence of arboviruses in these islands. In addition, we included information on environmental and social drivers specific to island setting that can facilitate the emergence of outbreaks. Within the context of the One Health approach, our review highlights how the emergence of arboviruses in tropical islands is linked to the complex interplay between their unique ecological settings and to the recent changes in local and global sociodemographic patterns. We also advocate for greater coordination between stakeholders in developing novel prevention and mitigation approaches for an intractable problem.

Authors: O’Brien S, Sharland M, Zaoutis T

Published in: AMR CONTROL 2019-2020; online edition

Abstract It is time to prioritize children’s needs in the context of antimicrobial resistance (AMR). Children, especially babies and young infants, are particularly vulnerable to the rise in drug-resistant infection and need treatments that are adapted to their specific needs. Yet, there are almost no clinical trials looking into children’s antibiotics. This lack of prioritization threatens the attainment of the UN Sustainable Development Goals. The Global Antibiotic Research & Development Partnership (GARDP), Penta, St George’s, University of London and global partners are working together to tackle AMR in children. They call on governments, researchers, industry and more – to join them.

Authors: Queiroz A,Dantas Pinto IF, Lima M, et al.

Published in: Front Microbiol. 2019;10:753

Abstract Zika virus (ZIKV) is an arthropod-borne virus (arbovirus) in the Flavivirus genus of the Flaviviridae family. Since the large outbreaks in French Polynesia in 2013-2014 and in Brazil in 2015, ZIKV has been considered a new public health threat. Similar to other related flavivirus, ZIKV is associated with mild and self-limiting symptoms such as rash, pruritus, prostration, headache, arthralgia, myalgia, conjunctivitis, lower back pain and, when present, a short-term low grade fever. In addition, ZIKV has been implicated in neurological complications such as neonatal microcephaly and Guillain-Barré syndrome in adults. Herein, serum lipidomic analysis was used to identify possible alterations in lipid metabolism triggered by ZIKV infection. Patients who presented virus-like symptoms such as fever, arthralgia, headache, exanthema, myalgia and pruritus were selected as the control group. Our study reveals increased levels of several phosphatidylethanolamine (PE) lipid species in the serum of ZIKV patients, the majority of them plasmenyl-phosphatidylethanolamine (pPE) (or plasmalogens) linked to polyunsaturated fatty acids. Constituting up to 20% of total phospholipids in humans, plasmalogens linked to polyunsaturated fatty acids are particularly enriched in neural membranes of the brain. The biosynthesis of plasmalogens requires functional peroxisomes, which are important sites for viral replication, including ZIKV. Thus, increased levels of plasmalogens in serum of ZIKV infected subjects suggest a link between ZIKV life cycle and peroxisomes. Our data provide important insights into specific host cellular lipids that are likely associated with ZIKV replication and may serve as platform for antiviral strategy against ZIKV.

Authors: Rackow A, Ehmen C, von Possel R, et al.

Published in: Clin Chem. 2019;65(3):451-461.

Background The cellular surface molecule HsTOSO/FAIM3/HsFcμR has been identified as an IgM-specific Fc receptor expressed on lymphocytes. Here, we show that its extracellular immunoglobulin-like domain (HsFcμR-Igl) specifically binds to IgM/antigen immune complexes (ICs) and exploit this property for the development of novel detection systems for IgM antibodies directed against Crimean-Congo hemorrhagic fever virus (CCHFV) and Zika virus (ZIKV).

Methods His-tagged HsFcμR-Igl was expressed in Escherichia coli and purified by affinity chromatography, oxidative refolding, and size-exclusion chromatography. Specific binding of HsFcμR-Igl to IgM/antigen ICs was confirmed, and 2 prototypic ELISAs for the detection of anti-CCHFV and anti-ZIKV IgM antibodies were developed. Thereby, patient sera and virus-specific recombinant antigens directly labeled with horseradish peroxidase (HRP) were coincubated on HsFcμR-Igl-coated ELISA plates. Bound ICs were quantified by measuring turnover of a chromogenic HRP substrate.

Results Assay validation was performed using paired serum samples from 15 Kosovar patients with a PCR-confirmed CCHFV infection and 28 Brazilian patients with a PCR-confirmed ZIKV infection, along with a panel of a priori CCHFV/ZIKV-IgM-negative serum samples. Both ELISAs were highly reproducible. Sensitivity and specificity were comparable with or even exceeded in-house gold standard testing and commercial kits. Furthermore, latex beads coated with HsFcμR-Igl aggregated upon coincubation with an IgM-positive serum and HRP-labeled antigen but not with either component alone, revealing a potential for use of HsFcμR-Igl as a capture molecule in aggregation-based rapid tests.

Conclusions Recombinant HsFcμR-Igl is a versatile capture molecule for IgM/antigen ICs of human and animal origin and can be applied for the development of both plate- and bead-based serological tests.

Authors: Collaborative Initiative for Paediatric HIV Education and Research (CIPHER) Global Cohort Collaboration.

Published in: Lancet HIV. 2019;6(2):e105-e115.

Background Estimates of incidence of switching to second-line antiretroviral therapy (ART) among children with HIV are necessary to inform the need for paediatric second-line formulations. We aimed to quantify the cumulative incidence of switching to second-line ART among children in an international cohort collaboration.

Methods In this international cohort collaboration study, we pooled individual patient-level data for children younger than 18 years who initiated ART (two or more nucleoside reverse-transcriptase inhibitors [NRTI] plus a non-NRTI [NNRTI] or boosted protease inhibitor) between 1993 and 2015 from 12 observational cohort networks in the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER) Global Cohort Collaboration. Patients who were reported to be horizontally infected with HIV and those who were enrolled in trials of treatment monitoring, switching, or interruption strategies were excluded. Switch to second-line ART was defined as change of one or more NRTI plus either change in drug class (NNRTI to protease inhibitor or vice versa) or protease inhibitor change, change from single to dual protease inhibitor, or addition of a new drug class. We used cumulative incidence curves to assess time to switching, and multivariable proportional hazards models to explore patient-level and cohort-level factors associated with switching, with death and loss to follow-up as competing risks.

Findings At the data cutoff of Sept 16, 2015, 182 747 children with HIV were included in the CIPHER dataset, of whom 93 351 were eligible, with 83 984 (90·0%) from sub-Saharan Africa. At ART initiation, the median patient age was 3·9 years (IQR 1·6–6·9) and 82 885 (88·8%) patients initiated NNRTI-based and 10 466 (11·2%) initiated protease inhibitor-based regimens. Median duration of follow-up after ART initiation was 26 months (IQR 9–52). 3883 (4·2%) patients switched to second-line ART after a median of 35 months (IQR 20–57) of ART. The cumulative incidence of switching at 3 years was 3·1% (95% CI 3·0–3·2), but this estimate varied widely depending on the cohort monitoring strategy, from 6·8% (6·5–7·2) in settings with routine monitoring of CD4 (CD4% or CD4 count) and viral load to 0·8% (0·6–1·0) in settings with clinical only monitoring. In multivariable analyses, patient-level factors associated with an increased likelihood of switching were male sex, older age at ART initiation, and initial NNRTI-based regimen (p<0·0001). Cohort-level factors that increased the likelihood of switching were higher-income country (p=0·0017) and routine or targeted monitoring of CD4 and viral load (p<0·0001), which was associated with a 166% increase in likelihood of switching compared with CD4 only monitoring (subdistributional hazard ratio 2·66, 95% CI 2·22–3·19).

Interpretation Our global paediatric analysis found wide variations in the incidence of switching to second-line ART across monitoring strategies. These findings suggest the scale-up of viral load monitoring would probably increase demand for paediatric second-line ART formulations.

Authors: European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) study group in EuroCoord

Published in: HIV Med. 2019;20(5):291-307

Objectives Combination neonatal prophylaxis (CNP) is recommended in high‐risk situations for the prevention of mother‐to‐child HIV transmission, although data on its safety are limited. The aim of the study was to identify whether neonatal prophylaxis (NP) type is associated with the risk of severe anaemia or neutropaenia.

Methods An individual patient data meta‐analysis was conducted within six European cohorts, in infants at high risk for acquiring HIV infection. Adjusted logistic regression models were used to assess the risk of National Institute of Allergy and Infectious Diseases, Division of AIDS (DAIDS) grade 3–4 anaemia/neutropaenia at ages 0–6 months. Mixture models of haemoglobin (Hb) level and log₁₀‐transformed neutrophil count (NC) were used to explore associations with NP type at ages 0–18 months.

Results Of 1836 infants, 25% were preterm, 1149 (63%) had antenatal combination antiretroviral therapy (cART) exposure and 395 (22%) received NP (125 received CNP with three drugs). Overall, 117 (6.7%) infants had grade 3–4 anaemia at age 0–6 months and 140 (9.1%) had grade 3–4 neutropaenia. The presence of grade 3–4 anaemia or neutropaenia was not associated with NP type [adjusted odds ratio (aOR) 1.04 for one‐drug NP and 1.60 for three‐drug NP versus two‐drug NP (P = 0.879 and P = 0.277, respectively) for anaemia; aOR 1.33 for one‐drug NP and 1.98 for three‐drug NP versus two‐drug NP (P =0.330 and P =0.113, respectively) for neutropaenia], but was associated with preterm delivery. Overall, 7746 Hb and NC results were available for 1836 infants up to age 18 months; no significant differences in predicted Hb level or NC were apparent by NP type.

Conclusions A small proportion of infants experienced grade 3–4 haematological adverse events; risk of anaemia or netropenia was not associated with type of NP.

Authors: Collins IJ; European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) study group in EuroCoord

Published in: Clin Infect Dis. 2019; 28. pii: ciz253. doi: 10.1093/cid/ciz253. [Epub ahead of print]

Background In HIV-positive adults, low CD4 cell counts despite fully suppressed HIV-1 RNA on antiretroviral therapy (ART) have been associated with increased risk of morbidity and mortality. We assessed the prevalence and outcomes of poor immune response (PIR) in children on suppressive ART.

Methods Sixteen cohorts from the European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) contributed data. Children aged<18 years at ART initiation, with sustained viral suppression (VS) (≤400copies/mL) for ≥1 year were included. The prevalence of PIR (defined as WHO advanced/severe immunosuppression for age: CD4%<30% in children aged<12 months, CD4%<25% in 12-35 months, CD4%<20% in 36-59 months; CD4%<15%/CD4<350 cells/mm3 in ≥5-years) at 1 year of VS was described. Factors associated with PIR were assessed using logistic regression. Rates of AIDS or death on suppressive ART were calculated by PIR status.

Results Of 2318 children included, median age was 6.4 [IQR, 2.1, 10.4] years and 68% had advanced/severe immunosuppression at ART initiation. At 1 year of VS, 12% had PIR. In multivariable analysis, PIR was associated with older age and worse immunological stage at ART start, hepatitis-B coinfection and residing in Thailand (all p≤0.03). Rates of AIDS/death (95% CI) per 100,000 person-years were 1052 (547, 2022) among PIR versus 261 (166, 409) among immune responders; rate ratio of 4.04 (1.83, 8.92), p<0.001.

Conclusions One in eight children in our cohort experienced PIR despite sustained viral suppression. While the overall rate of AIDS/death was low, children with PIR had four-fold increase in risk of event as compared to immune responders.

Authors: Thomas R, Velaphi S, Ellis S, et al.

Published in: Expert Opin Pharmacother. 2019;20(4):415-422. 

Introduction The incidence of healthcare-associated multidrug resistant bacterial infections, particularly due to carbapenem resistant organisms, has been on the rise globally. Among these are the carbapenem resistant Acinetobacter baumannii and Enterobacteriaceae, which have been responsible for numerous outbreaks in neonatal units. The polymyxins (colistin and polymyxin B) are considered to be the last resort antibiotics for treating such infections. However, pharmacokinetic and pharmacodynamic data on the use of polymyxins in neonates and children are very limited, and there are safety concerns.

Areas Covered In this review, the authors summarize the global burden of multidrug resistance, particularly carbapenem resistance, in the neonatal and paediatric population, and the potential wider use of polymyxins in treating these infections.

Expert Opinion Both colistin and polymyxin B have similar efficacy in treating multidrug resistant infections but have safety concerns. However, polymyxin B appears to be a better therapeutic option, with more rapid and higher steady state concentrations achieved compared to colistin and less reported nephrotoxicity. There is virtually no data in neonates and children currently; there is therefore an urgent need for pharmacokinetic and safety trials in these populations to determine the optimal drug and dosing regimens and provide recommendations for their use against carbapenem resistant infections.

Authors: Donà D, Luise D, La Pergola E, et al.

Published in: Antimicrob Resist Infect Control. 2019;8:13. 

Authors: Fidler KJ, Foster C, Lim EJ, et al.; for Collaborative HIV Paediatric Study (CHIPS) Steering Committee

Published in: Pediatr Infect Dis J. 2019;38(2):146-148

Abstract We assessed HIV antibody prevalence in children with perinatally acquired HIV in England. Eighteen percent (10/55) of those starting combination antiretroviral therapy <6 months of age were seronegative at median age 9.1 years and had lower viral load at diagnosis and combination antiretroviral therapy start and fewer viral rebounds, than 45 of 55 seropositives. Implications for patient selection for HIV cure research, and interpretation of routine antibody testing, are discussed.

Authors: Chiappini E, Bianconi M, Dalzini A, et al.

Published in: Antimicrob Resist Infect Control. 2019;8:13

Background Premature aging and related diseases have been documented in HIV-infected adults. Data are now emerging also regarding accelerated aging process in HIV-infected children.

Methods A narrative review was performed searching studies on PubMed published in English language in 2004-2017, using appropriate key words, including “aging”, “children”, “HIV”, “AIDS”, “immunosenescence”, “pathogenesis”, “clinical conditions”.

Results Premature immunosenescence phenotype of B and T cells in HIV-infected children is mediated through immune system activation and chronic inflammation. Ongoing inflammation processes have been documented by increased levels of pathogen-associated molecular patterns (PAMPS), increased mitochondrial damage, higher levels of pro-inflammatory cytokines, and a positive correlation between sCD14 levels and percentages of activated CD8⁺ cells. Other reported features of premature aging include cellular replicative senescence, linked to an accelerated telomeres shortening. Finally, acceleration of age-associated methylation pattern and other epigenetic modifications have been described in HIV-infected children. All these features may favor the clinical manifestations related to premature aging. Lipid and bone metabolism, cancers, cardiovascular, renal, and neurological systems should be carefully monitored, particularly in children with detectable viremia and/or with CD4/CD8 ratio inversion.

Conclusion Aging processes in children with HIV infection impact their quality and length of life. Further studies regarding the mechanisms involved in premature aging are needed to search for potential targets of treatment.

Authors: Bollen P, Turkova A, Mujuru H, et al. for the ODYSSEY Trial Team

Published in: 26th Conference on Retroviruses and Opportunistic Infections, March 4th – 7th, 2019– Seattle. P_830

Authors: Schröter J.

Published: Oral presentation at 26th International HIV Dynamics & Evolution, March 24th-27th, 2019, Cascais, PT

Authors: European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) Study Group

Published in: Aids. 2019;33(2):295-304.

Objectives The aim of this study was to investigate whether specific nucleoside reverse transcriptase inhibitor (NRTI) backbones are associated with risk of adverse pregnancy outcomes among pregnant women starting antiretroviral therapy (ART).

Design Seven observational studies across eight European countries of pregnancies in HIV-positive women.

Methods Individual-level data were pooled on singleton pregnancies conceived off-ART in which a single combination ART regimen was initiated at least 2 weeks before delivery, and ending in a live birth in 2008-2014. Preterm delivery (PTD) was defined as less than 37 gestational weeks and small-for-gestational-age (SGA) as less than 10th percentile according to INTERGROWTH standards. Poisson regression models were fitted to investigate associations between NRTI backbones and PTD/SGA.

Results Out of 7193 pregnancies, 45% (3207) were in UK/Ireland, 44% (3134) in Ukraine. 10% (722/7193) of deliveries were preterm and 11.1% (785/7089) of newborns SGA. The most common NRTI backbones were zidovudine (ZDV)-lamivudine (3TC) (71%), tenofovir (TDF)-XTC (16%) and abacavir (ABC)-3TC (10%) with TDF-containing backbone use increasing over time. Overall, 77% of regimens contained ritonavir-boosted lopinavir (LPV/r). There was no association between NRTI backbone and PTD in main adjusted analyses [adjusted prevalence ratios (aPRs) 0.97 (95% confidence interval, 95% CI 0.73-1.28] for ABC-3TC and aPR 1.06 (95% CI 0.83-1.35) for TDF-XTC, both vs. ZDV-3TC) or in 4720 pregnancies on LPV/r [aPR 1.03 (95% CI 0.74-1.43) for ABC-3TC and aPR 1.16 [0.85-1.57] for TDF-XTC, both vs. ZDV-3TC]. Infants exposed to ABC-3TC or TDF-XTC in utero were less likely to be SGA than those exposed to ZDV-3TC [aPR 0.72 (95% CI 0.53-0.97) and aPR 0.70 (95% CI 0.53-0.93), respectively].

Conclusion Results support the safety of TDF-XTC backbones initiated in pregnancy with respect to gestation length and birthweight.

Authors: Martinez de Tejada B; European Pregnancy and Paediatric HIV Cohort Collaboration Study Group.

Published in: J Acquir Immune Defic Syndr. 2019;80(3):316-324

Background To investigate the association between efavirenz (EFV) use during conception or first trimester (T1) of pregnancy and the occurrence of birth defects.

Setting Seven observational studies of pregnant HIV-positive women across 13 European countries and Thailand.

Methods Individual-level data were pooled on singleton pregnancies included in participating cohorts in 2002-2015. Birth defects were coded according to ICD-10 and the EUROCAT classification. We performed mixed-effects logistic regression models to assess the association between EFV exposure in utero and likelihood of birth defects.

Results We included 24,963 live births from 21,093 women. At conception, 30.2% (7537) women were on a non-EFV-based regimen, 4.8% (1200) on EFV, and 65% (16,226) were unexposed to antiretroviral therapy (ART). There were 412 infants with ≥1 birth defect, a prevalence of 1.65% (95% confidence interval: 1.50 to 1.82). Limb/musculoskeletal and congenital heart defects were the most common defects reported. Birth defects were present in 2.4%, 1.6%, and 1.3% of infants exposed to non-EFV, EFV, and unexposed to ART during conception/T1 (P = 0.135), respectively. The association between exposure to ART during conception/T1 and birth defects remained nonsignificant in adjusted analyses, as did exposure to EFV versus non-EFV (adjusted odds ratio 0.61; 95% confidence interval: 0.36 to 1.03, P = 0.067). Among the 21 birth defects in 19 infants on EFV, no neural tube defects were reported.

Conclusions Prevalence of birth defects after exposure to EFV-based compared with non-EFV-based ART in conception/T1 was not statistically different in this multicohort study, and even lower. EFV is at least as safe as other ART drugs currently recommended for antenatal use.

Authors: Chan MK, Goodall R, Judd A, et al.

Published in: Aids. 2019; 33(7):1155-1165

Objective To identify predictors of faster time to virological suppression among infants starting combination antiretroviral therapy (cART) early in infancy.

Design Cohort study of infants from Europe and Thailand included in studies participating in the European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC).

Methods Infants with perinatal HIV starting cART aged <6 months with ≥1 viral load (VL) measurement within 15 months of cART initiation were included. Multivariable interval-censored flexible parametric proportional hazards models were used to assess predictors of faster virological suppression, with timing of suppression assumed to lie in the interval between last VL≥400 and first VL<400copies/ml.

Results Of 420 infants, 59% were female and 56% from Central/Western Europe, 26% UK/Ireland, 15% Eastern Europe and 3% Thailand; 46% and 54% started a boosted protease inhibitor- or non-nucleoside reverse transcriptase inhibitor- based regimen, respectively. At cART initiation, the median age, CD4% and VL were 2.9 (IQR:1.4-4.1) months, 34 (IQR:24-45)% and 5.5 (IQR:4.5-6.0) log10copies/ml, respectively. Overall, an estimated 89% (95%CI:86-92%) achieved virological suppression within 12 months of cART start. In multivariable analysis, younger age (aHR:0.84 per month older; P < 0.001), higher CD4% (aHR:1.11 per 10% higher; P = 0.010) and lower log10 VL (aHR:0.85 per log10 higher; P < 0.001) at cART initiation independently predicted faster virological suppression.

Conclusion We observed a significant independent effect of age at cART initiation, even within a narrow 6 months window from birth. These findings support the earliest feasible cART initiation in infants and suggest that early therapy influences key virological and immunological parameters that could have important consequences for long term health.

Authors: Bamford A, Turkova A, Lyall H, et al.; for PENTA Steering Committee

Published in: HIV Med. 2018;19(1):e1-e42.

Abstract The 2015 Paediatric European Network for Treatment of AIDS (PENTA) guidelines provide practical recommendations on the management of HIV-1 infection in children in Europe and are an update to those published in 2009. Aims of treatment have progressed significantly over the last decade, moving far beyond limitation of short-term morbidity and mortality to optimizing health status for adult life and minimizing the impact of chronic HIV infection on immune system development and health in general. Additionally, there is a greater need for increased awareness and minimization of long-term drug toxicity. The main updates to the previous guidelines include: an increase in the number of indications for antiretroviral therapy (ART) at all ages (higher CD4 thresholds for consideration of ART initiation and additional clinical indications), revised guidance on first- and second-line ART recommendations, including more recently available drug classes, expanded guidance on management of coinfections (including tuberculosis, hepatitis B and hepatitis C) and additional emphasis on the needs of adolescents as they approach transition to adult services. There is a new section on the current ART ‘pipeline’ of drug development, a comprehensive summary table of currently recommended ART with dosing recommendations. Differences between PENTA and current US and World Health Organization guidelines are highlighted and explained.

Authors: Cotugno N, Morrocchi E, Pepponi I, et al.

Published in: J Immunol. 2018; 200 (1 ) 182.34;

Abstract Early initiation of ART in HIV vertically infected infants influences specific immunity by limiting Ag exposure and reducing the viral reservoir size. Currently these patients represent ideal candidates for testing immune therapeutic strategies towards HIV-remission. However a proportion of these early ART treated children (ET) show an undetectable HIV Ab response. It is still unknown whether such profile is associated with a lower ability of these children to mount HIV specific responses once the Ag is re-encountered.

In the present study, we investigated whether HIV specific B-cells persist in seronegative (SN) patients, and the associated gene signatures after re-encountering the virus in vitro. We enrolled 20 ET (6 SN and 14 seropositive, SP), who initiated ART at a mean age of 4.4±3.6 mo. and under durable viral control (> 2 years). We found that gp140+ B-cells, analyzed by FACS, persist in SN patients with a similar frequency of SP. Further analysis revealed a higher percentage of HIV-specific IgM cells in SN CD27+ IgD+ memory subset compared to SP (P=0.002). In addition we investigated by multiplexed RT-PCR, gene expression dynamics after in vitro stimulation with HIV peptides mix. Our results on sorted HIV specific IgM+ cells showed up-regulation of Blimp1 expression only in SP (fold change=1.9; p=0.03), suggesting an impairment of plasma cell differentiation in IgM+gp140+ B-cells in SN patients. Our results firstly reveal that HIV specific B-cell response persists in SN ET, and predominantly resides in the IgM memory compartment. We hypothesize that such responses could be targeted by novel strategies aiming at HIV remission in HIV early treated children.