Publications

Authors: Gärtner K, Gkouleli T, Heaney J, Grant P, Dominguez-Rodriguez S, Busby E, O’Sullivan D, Spyer MJ, Foster C, Rojo P, Persaud D, DeRossi A, Huggett J, Nastouli E, for the EPIICAL consortium

Published in:  27th Conference on Retroviruses and Opportunistic Infections, March 8th –11th, 2020 – Boston.

Authors: Waalewijn H, Mujuru HA, Amuge P, Cotton M, Bollen P, Chan M, Ali S, Variavan E, Makumbi S, Colbers A, Gibb D, Ford D, Burger D, Turkova A, and the ODYSSEY-trial team

Published in:  27th Conference on Retroviruses and Opportunistic Infections, March 8th –11th, 2020 – Boston.

Authors: Waalewijn H, Mujuru HA, Amuge P, Cotton M, Bollen P, Chan M, Ali S, Variavan E,Makumbi S, Colbers A, Gibb D, Ford D, Burger D, Turkova A, and the ODYSSEY-trial team

Published in: Oral presentation at 27th Conference on Retroviruses and Opportunistic Infections, March 8th –11th, 2020 – Boston.

Authors: Crichton S , Collins  IJ, Turkova A, Ene L, Galli L, Marczynska M, Navarro M, Naver L, Noguera-Julian A, Plotnikova Y, Scherpbier H, Volokha A, Voronin E, Judd A; on behalf of the European Pregnancy and Paediatric Infections Cohort Collaboration (EPPICC)

Published in: 27th Conference on Retroviruses and Opportunistic Infections, March 8th –11th, 2020 – Boston.

Abstract

Background: The World Health Organization (WHO) recommends abacavir as the preferred/alternative backbone for 1st line regimens in children with HIV from age 28 days. There are limited data available on safety and tolerability of abacavir in young infants aged <3 months.

Methods: We describe infant and regimen characteristics at the start of abacavir (including drug combinations and dosing) and outcomes up to 12 months after first use of abacavir. Outcomes include:

• drug discontinuations (defined as interruption of abacavir for >30 days),
• clinical adverse events (AE, reported from start of abacavir, and up to 30 days after discontinuation of abacavir) and
• viral load at 6 and 12 (±3) months after start of abacavir

Conclusions: Across children initiating abacavir in early life in Europe, it was safe and well tolerated, and discontinuations for safety concerns were rare. • Viral suppression was below the UN-AIDS 90% target which may reflect challenges of treatment in infancy.

View poster

Authors: Thorne C, Rasi V, Aebi-Popp K, Ene L, Floridia M, Mendoza-Palomar N, Prieto L, Ragone L, Sconza R, CGiaquinto C, Vannappagari V; for the Dolomite-EPPICC study group

Published in: Oral presentation at 27th Conference on Retroviruses and Opportunistic Infections, March 8th –11th, 2020 – Boston.

Abstract

BACKGROUND • In 2018, the Tsepamo Study, Botswana reported significant increased risk of NTD in women conceiving on DTG (0.94%) 1 leading to a safety alert • Updated analysis of NTD prevalence (08/2014 – 03/2019)2 • 5 NTDs/1,683 deliveries in women on DTG at conception (0.30%, 95% CI 0.13-0.69 vs 0.10%, 95% CI 0.06-0.17 for non-DTG ART at conception • The Antiretroviral Pregnancy Registry recently reported 1 NTD in 312 periconception DTG exposures (0.3%) 3 • The Dolomite Study was set up in 2017 to address use & safety of DTG in pregnancy and exposed infants in Europe and Canada; conducted within the NEAT-ID network and EPPICC (the European Pregnancy and Paediatric Infections Cohort Collaboration)

Aim: To assess pregnancy and neonatal outcomes following DTG use during pregnancy in real-world European settings • Objectives were to describe: • characteristics of pregnant women receiving DTG-based regimens • frequency of adverse pregnancy and birth outcomes, by earliest timing of DTG exposure

Method: Dolomite-EPPICC involves pooled analyses of prospectively collected individual patient data on DTG-exposed pregnancies from participating studies • Data specification based on a modified HIV Data Exchange Protocol (www.hicdep.org) • Data merger included • All pregnancies with any prenatal DTG exposure • With birth outcomes reported by Feb 2019 • Periconception DTG exposure was defined as initial exposure at ≤6 weeks of estimated gestational age (EGA)

Results: 453 pregnancies in 428 women included (Figure) • Pregnancies reported from six countries • 347 (76.6%) UK and Ireland, 45 (9.9%) Spain, 29 (6.4%) Switzerland, 29 (6.4%) Italy, 3 (0.7%) Romania

View poster

Authors: Jackson C, Bamford A, Crichton S, Goodall R,Goulder P, Klein N, Marques L, Paioni P, Riordan A, Spoulou V, Vieira VA, Collins IJ. On behalf of The European Pregnancy and Paediatric Infections Cohort Collaboration (EPPICC) study group

Published in:  27th Conference on Retroviruses and Opportunistic Infections, March 8th –11th, 2020 – Boston.

Authors: Rinaldi S, Pallikkuth S, de Armas L, Pahwa R, Dominguez S, Cotugno N, Rojo Conejo P, Nastouli E, Gartner K, Klein N, Foster C, De Rossi A, Carlo Giaquinto C, Rossi P, Palma P, Pahwa S and EPIICAL Consortium

Published in:  27th Conference on Retroviruses and Opportunistic Infections, March 8th –11th, 2020 – Boston.

Authors: Lain MG, Vaz P, Ismael N,  Cantarutti A, Porcu G, Palma P, Cotugno N, Bila D, Rinaldi S,  Pallikkuth S, Pahwa R, Taibo E, Esmeralda Karajeanes E, Giaquinto C, Pahwa S.

Published in:  27th Conference on Retroviruses and Opportunistic Infections, March 8th –11th, 2020 – Boston.

Authors: Morris SE, Dziobek-Garrett L, Yates AJ and the EPIICAL consortium

Published in: BMC Bioinformatics 2020;21(1):52

Background HIV/AIDS is responsible for the deaths of one million people every year. Although mathematical modeling has provided many insights into the dynamics of HIV infection, there is still a lack of accessible tools for researchers unfamiliar with modeling techniques to apply them to their own clinical data.

Authors: Ades AE, Thorne C, Soriano-Arandes A, et al.

Published in: Lancet Infect Dis. 2020 Feb 18

Abstract: Our understanding of congenital infections is based on prospective studies of women infected during pregnancy. The EU has funded three consortia to study Zika virus, each including a prospective study of pregnant women. Another multi-centre study has been funded by the US National Institutes of Health. This Personal View describes the study designs required to research Zika virus, and questions whether funding academics in the EU and USA to work with collaborators in outbreak areas is an effective strategy. 3 years after the 2015–16 Zika virus outbreaks, these collaborations have taught us little about vertical transmission of the virus. In the time taken to approve funding, agree contracts, secure ethics approval, and equip laboratories, Zika virus had largely disappeared. By contrast, prospective studies based on local surveillance and standard-of-care protocols have already provided valuable data. Threats to fetal and child health pose new challenges for global preparedness requiring support for the design and implementation of locally appropriate protocols. These protocols can answer the key questions earlier than externally designed studies and at lower cost. Local protocols can also provide a framework for recruitment of unexposed controls that are required to study less specific outcomes. Other priorities include accelerated development of non-invasive tests, and longer-term storage of neonatal and antenatal samples to facilitate retrospective reconstruction of cohort studies.

Authors: Celia C.

Published in: Oral presentation at 3rd international Conference on Zika Virus and aedes related infections, February 13th – 16th, 2020– Washington DC, USA.

Authors: Webster-Kerr K.

Published in: Oral presentation at 3rd international Conference on Zika Virus and aedes related infections, February 13th – 16th, 2020– Washington DC, USA.

Authors: Lue A.

Published in: Oral presentation at 3rd international Conference on Zika Virus and aedes related infections, February 13th – 16th, 2020– Washington DC, USA.

Authors: Cotugno N, Morrocchi E, Rinaldi S, et al; EPIICAL Consortium.

Published in: AIDS. 2020 Feb 3.

Objective To investigate long-term persistence of HIV-specific lymphocyte immunity in perinatally HIV-infected children treated within the first year of life.

Design Twenty perinatally HIV-infected children who received ART therapy within the first year of life (early treated) and with stable viral control (>5 years) were grouped according to their serological response to HIV.

Methods Western blot analysis and ELISA defined 14 HIV-seropositive and 6 seronegative patients. Frequencies of gp140-specific T-cell and B-cell, and T-cell cytokine production were quantified by flow cytometry in both seronegatives and seropositives. Transcriptional signatures in purified gp140-specific B-cell subsets, in response to in-vitro stimulation with HIV peptides was evaluated by multiplex RT-PCR.

Authors: Warris A, Pana ZD, Oletto A, et al. EUROCANDY study group.

Published in: Pediatr Infect Dis J. 2020;39(2):114-120

Background Data on Candida bloodstream infections in pediatric patients in Europe are limited. We performed a retrospective multicenter European study of the epidemiology and outcome of neonatal and pediatric candidemia.

Materials and methods All first positive blood cultures from patients ≤ 18 years of age with candidemia were registered. Patients’ demographic and clinical characteristics and causative Candida species were collected and analyzed. Regression analysis was used to identify factors independently associated with mortality.

Results One thousand three hundred ninety-five episodes of candidemia (57.8% male) were reported from 23 hospitals in 10 European countries. Of the 1395 episodes, 36.4% occurred in neonates (≤ 44 weeks postmenstrual age), 13.8% in infants (> 44 weeks postmenstrual age to 1 year) and 49.8% in children and adolescents. Candida albicans (52.5%) and Candida parapsilosis (28%) were the predominant species. A higher proportion of candidemia caused by C. albicans was observed among neonatal patients (60.2%) with highest rates of C. parapsilosis seen among infants (42%). Children admitted to hematology-oncology wards presented the highest rates of non-albicans Candida species. Candidemia because of C. albicans was more frequent than non-albicans Candida in Northern versus Southern Europe (odds ratio, 2.3; 95% confidence interval, 1.8-2.9; P < 0.001). The all-cause mortality at 30 days was 14.4%. All-cause mortality was higher among patients admitted to the neonatal or pediatric intensive care units than other wards. Over time, no significant changes in species distribution were observed.

Conclusions This first multicenter European study shows unique characteristics of the epidemiology of pediatric candidemia. The insights obtained from this study will be useful to guide clinical management and antifungal stewardship.

Authors: Pereira Gusmão Maia Z, Mota Pereira F, do Carmo Said RF, et al.

Published in: Emerg Microbes Infect. 2020;9(1):53-57

Abstract Between June 2017 and August 2018, several municipalities located in Bahia state (Brazil) reported a large increase in the number of patients presenting with febrile illness similar to that of arboviral infections. Using a combination of portable whole genome sequencing, molecular clock and epidemiological analyses, we revealed the return of the CHIKV-ECSA genotype into Bahia. Our results show local persistence of lineages in some municipalities and the re-introduction of new epidemiological strains from different Brazilian regions, highlighting a complex dynamic of transmission between epidemic seasons and sampled locations. Estimated climate-driven transmission potential of CHIKV remained at similar levels throughout the years, such that large reductions in the total number of confirmed cases suggests a slow, but gradual accumulation of herd-immunity over the 4 years of the epidemic in Bahia after its introduction in 2014. Bahia remains a reservoir of the genetic diversity of CHIKV in the Americas, and genomic surveillance strategies are essential to assist in monitoring and understanding arboviral transmission and persistence both locally and over large distances.

Authors: Donà D, Barbieri E, Daverio M, Lundin R, Giaquinto C, Zaoutis T, Sharland M

Published in: Antimicrob Resist Infect Control.2020;9:3

Background Antibiotics are the most common medicines prescribed to children in hospitals and the community, with a high proportion of potentially inappropriate use. Antibiotic misuse increases the risk of toxicity, raises healthcare costs, and selection of resistance. The primary aim of this systematic review is to summarize the current state of evidence of the implementation and outcomes of pediatric antimicrobial stewardship programs (ASPs) globally.

Methods MEDLINE, Embase and Cochrane Library databases were systematically searched to identify studies reporting on ASP in children aged 0-18 years and conducted in outpatient or in-hospital settings. Three investigators independently reviewed identified articles for inclusion and extracted relevant data.

Results Of the 41,916 studies screened, 113 were eligible for inclusion in this study. Most of the studies originated in the USA (52.2%), while a minority were conducted in Europe (24.7%) or Asia (17.7%). Seventy-four (65.5%) studies used a before-and-after design, and sixteen (14.1%) were randomized trials. The majority (81.4%) described in-hospital ASPs with half of interventions in mixed pediatric wards and ten (8.8%) in emergency departments. Only sixteen (14.1%) studies focused on the costs of ASPs. Almost all the studies (79.6%) showed a significant reduction in inappropriate prescriptions. Compliance after ASP implementation increased. Sixteen of the included studies quantified cost savings related to the intervention with most of the decreases due to lower rates of drug administration. Seven studies showed an increased susceptibility of the bacteria analysed with a decrease in extended spectrum beta-lactamase producers E. coli and K. pneumoniae; a reduction in the rate of P. aeruginosa carbapenem resistance subsequent to an observed reduction in the rate of antimicrobial days of therapy; and, in two studies set in outpatient setting, an increase in erythromycin-sensitive S. pyogenes following a reduction in the use of macrolides.

Conclusions Pediatric ASPs have a significant impact on the reduction of targeted and empiric antibiotic use, healthcare costs, and antimicrobial resistance in both inpatient and outpatient settings. Pediatric ASPs are now widely implemented in the USA, but considerable further adaptation is required to facilitate their uptake in Europe, Asia, Latin America and Africa.

Authors: S. Rinaldi, V. Dinh, S. Pallikkuth, L. De Armas, R. Pahwa, N. Cotugno, E. Nastouli, C. Foster, P. Palma, S. Pahwa

Published in: Poster presented at 9^th International Workshop on HIV Persistence during Therapy; December, 2019; Miami, FL

Authors: Folgori L, Lutsar I, Standing JF, et al.

Published in: BMJ Open. 2019; 9:e032592

Authors: Blazquez-Gamero D, Soriano-Ramos M, Martinez de Aragon A, et al.

Published in: Pediatr Infect Dis J. 2019;38(11):1131-1137

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: Turner B, Ford D, Moore C, Gibb D, Turkova A,  White I, and ODYSSEY trial team

Published in: Oral Presentation atInternational Society for Clinical Biostatics; July 16th 2019

Authors: Giovannetti M, de Mendonca MCL, Fonseca V, et al.

Published in: J Virol. 2019;94(1). pii: e01623-19

Abstract The recent reemergence of yellow fever virus (YFV) in Brazil has raised serious concerns due to the rapid dissemination of the virus in the southeastern region. To better understand YFV genetic diversity and dynamics during the recent outbreak in southeastern Brazil, we generated 18 complete and nearly complete genomes from the peak of the epidemic curve from nonhuman primates (NHPs) and human infected cases across the Espírito Santo and Rio de Janeiro states. Genomic sequencing of 18 YFV genomes revealed the estimated timing, source, and likely routes of yellow fever virus transmission and dispersion during one of the largest outbreaks ever registered in Brazil. We showed that during the recent epidemic, YFV was reintroduced from Minas Gerais to the Espírito Santo and Rio de Janeiro states multiple times between 2016 and 2019. The analysis of data from portable sequencing could identify the corridor of spread of YFV. These findings reinforce the idea that continued genomic surveillance strategies can provide information on virus genetic diversity and transmission dynamics that might assist in understanding arbovirus epidemics.

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.