EPIICAL

31

Mar, 2022

Determinants of B-Cell Compartment Hyperactivation in European Adolescents Living With Perinatally Acquired HIV-1 After Over 10 Years of Suppressive Therapy

 

Authors: Ruggiero A, Pascucci G.R, Cotugno N, Domínguez-Rodríguez S, Rinaldi S, Tagarro A, Rojo P, Foster C, Bamford A, De Rossi A, Nastouli E, Klein N, Morrocchi E, Fatou B, Smolen K.K, Ozonoff A, Di Pastena M, Luzuriaga K, Steen H, Giaquinto C, Goulder P, Rossi P, Levy O, Pahwa S, Palma P, the EPIICAL Consortium

Published in: Frontiers in Immunology 

23

Mar, 2022

Borrowing information across patient subgroups in clinical trials

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An article by investigators within the ODYSSEY trial has been published as Open Access into BMC Medical Research Methodology. The investigators aimed to evaluate a treatment effect in a pre-defined subgroup of interest while borrowing information from a separate patient subgroup, using a Bayesian analysis. A Bayesian analysis enables evidence from data to be combined with prior information from an external sample.

Phase III clinical trials demonstrate whether or not medical intervention is effective and safe in a specific population. For various reasons, investigators may choose to evaluate effectiveness and safety in a specific subgroup of patients within the main trial population, in addition to reporting on the whole population. A subgroup could be a small population that deserves to be studied in a standalone trial but could face difficulties in recruiting patients, for example, paediatric subpopulations. Using information for subgroups could potentially reduce the cost and duration of a trial and the risks and inconvenience to vulnerable participants.

In the ODYSSEY trial, investigators used Bayesian methods aimed to estimate a treatment effect in children weighing less than 14 kg, while borrowing information obtained from a larger subgroup of patients, the older children weighing at least 14kg or above, within the same trial.

The authors elicited clinical opinion about how similar treatment effect was expected to be in the two subgroups, and used this to inform the relative weights given to the two groups in a Bayesian analysis.

Clinical opinion demonstrated that substantial borrowing from the older children was supported. Experts chose on average to allocate a relative weight of 78% (reduced from 90% based on sample size) to data from children weighing 14 kg or more in a Bayesian analysis of the children weighing less than 14 kg. The total effective sample size in the Bayesian analysis was 386 children, providing 84% predictive power to exclude a difference of more than 10% between arms, whereas the 85 younger children weighing less than 14 kg provided only 20% power in a standalone frequentist analysis. Thus, borrowing information from the older children has lead to substantial increases in the power and precision of the treatment effect in the younger children, in comparison with an analysis based on the young children alone.

Read the full article here

23

Mar, 2022

Dolutegravir dosing for children with HIV weighing less than 20 kg

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The results of an ODYSSEY pharmacokinetic sub-study investigating dolutegravir (DTG) based antiretroviral (ARV) treatments for children weighing 3 to less than 20kg have recently been published in The Lancet HIV as an Open Access article.

DTG has been available for treating HIV in adults globally for many years with paediatric formulations only developed in recent years. Very little pharmacokinetic data were available in young children when the ODYSSEY trial was opened to young children. With this in mind, the team nested a sub-study to evaluate pharmacokinetics and safety and confirm the optimal dosing in children weighing 3 to less than 20kg.

72 children between the ages of 3 months and 11 years were enrolled into the sub-study. Children weighing 3 kg to less than 14 kg received 5 mg dispersible tablets of dolutegravir according to WHO weight bands and children weighing 14 kg to less than 20 kg received a 25 mg film-coated tablet once per day early in the trial or 25 mg dispersible tablets (five 5 mg tablets once per day) later in the trial.

Based on the findings of the study, children given dolutegravir dispersible tablets had appropriate dolutegravir exposures, whereas children weighing 14 kg to less than 20 kg given 25mg DTG in film-coated tablets had suboptimal drug levels. Overall, DTG was well tolerated, and the study identified no new safety issues in children. These results showed that dolutegravir dispersible tablets dosed in WHO weight bands is a suitable treatment option for children 3 to less than 20kg, making it possible for children of 4 weeks and older to receive dolutegravir treatment. The dispersible tablets are easily stored and transported and the dosing can be adapted to meet the needs of a growing child.

The data from this study have contributed to the recent decisions to license 5mg DTG dispersible tablets for use in children from 4 weeks of age weighing at least 3kg to less than 20kg by the US FDA and the EMA and informed current WHO antiretroviral guidelines which adopted FDA dosing. The sub-study has laid an important stepping stone towards alignment of treatment for children with adult recommendations.

Read the full article here

18

Mar, 2022

The subphenotypes of early-treated children living with HIV-1

 

Authors: S Domínguez-Rodríguez, A Tagarro, C Foster, P Palma, N Cotugno, AD Rossi, A Dalzini, SG. Pahwa, E Nastouli, K Gärtner, AG Marcelin, P Rossi, C Giaquinto, P Rojo

Presented at: CROI 2022

 

Abstract

Subphenotypes have been identified in several heterogeneous diseases. Having a specific subphenotype often has therapeutic implications or impacts disease progression. In this study, we aimed to assess if children with HIV may show subphenotypes according to clinical, virological and immunological features.

We collected data from 40 HIV+ children included in a cross-sectional multicentric study (CARMA Study, EPIICAL Consortium). All children commenced ART <2 years, suppressed (viral load (VL) <50 copies/ml) within 12 months and remained suppressed for >5 years. Immunological and virological assays were performed at a median of 12 years after ART initiation. We collected clinical and sociodemographic data, baseline VL, CD4 and CD8 data, age at ART, HIV DNA reservoir size, cell-associated RNA (CA-RNA), ultrasensitive VL, CD4 subsets (T effector CD25+, activated memory cells, Treg cells ), humoral-specific HIV response (T-bet B cells), innate response (CD56dim NK cells, NKp46+, perforin), exhaustion markers (PD-1, PD-L1, DNAM), CD8 senesence, and biomarkers for T-lymphocyte thymic output (TREC) and endothelial activation (VCAM). To build the subphenotypes, the most informative variables were selected using an unsupervised penalty selection. Hierarchical clustering was performed using Pearson correlation as distance metric and Ward.D2 as clustering method. Internal validation was applied to select the best number of clusters.

Three subphenotypes were revealed (Cluster 1 n=18, 45%; Cluster 2 n=11, 27.5%; Cluster 3 n=11, 27.5%). Cluster 1 (best controllers) consisted of early ART-treated patients with high baseline %CD4, low reservoir size, low WB score, high TREC values, and low VCAM values. In contrast, Cluster 3 (worst controller) consisted of later ART-treated patients with low baseline %CD4, high reservoir size, low TREC values, high innate response, immunosenescence markers and VCAM. Cluster 2 (low-level viremia, altered immune response) consisted of early-treated patients with low-level (10 to 50 c/mL) VL, high reservoir size but low CA-RNA, higher Treg CD4 than in the other clusters, low TREC, weak innate response and lower levels of T-bet expression.

Three subphenotypes with decreasing levels of viral control and increasing levels of immune well-being were discovered. Response to different therapies may be different across the different clusters.

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18

Mar, 2022

2-year outcome of early treated infants in Sub-Saharan Africa

 

Authors: A Tagarro, S Domínguez-Rodríguez, L Kuhn, T Nhampossa, K Otwombe, AJv Rensburg, N Klein, MG Lain, AI. Maiga, C Brehin, C Giaquinto, P Rossi, P Rojo

Presented at: CROI 2022

 

Abstract

The real-world evolution of very early treated children born with HIV in high-prevalence settings during first years of life is unclear. We assessed the probability of death, progression to AIDS, viral load (VL) suppression, immunosuppression, and continuation in care of a cohort of early treated children born with HIV.

EARTH-EPIICAL Cohort is underway at 2 rural and 4 urban sites in Mozambique, Mali, and South Africa (SA). Infants with HIV who started ART in the first 3 months of life, are followed at 2, 6 and 12 weeks, and then 6-monthly for 4 years. Hereby, we provide the probability of death, progression, suppression and continuation in care during the first 2 years of life with multivariable cox regression models were used. Backward stepwise elimination was applied to reach the final multivariable model.

212 participants were enrolled and followed during a median time of 17 [6.8;27.5] months; 84 reached 2 years of follow-up. ART started at 34 [26;74] days of life, mostly 3TC+ABC+LPV/r (65%). Adherence was suboptimal (<90%) in 56% of visits. 23 patients (10.8%) died, at a median of 2.5 [0.6;6.8] months of age. At 2 years, probability (P) of death was 12% (CI95%,7 to 17), (P) of progression was 11% (CI95%,6 to 16%), (P) of continuation in care, 80% (CI95%,74 to 86%), (P) of VL suppression was 46% (CI95%, 0.34-0.49), and (P) of severe IS, 54% (CI95%, 44 to 62). Death occurred predominantly in the first 6 months (74%); mostly due to pneumonia (43%), malnutrition (13%) or diarrhea (8.7%). (P) of death was associated with baseline VL 2.19 (1.4-3.3), and suboptimal adherence 2.88 (1.18-7.2). (P) of progression was associated with baseline VL 1.71 (CI95%,1.14-2.58), and weight for age 0.53 (CI95%,0.39-0.71). (P) of lost to follow up also was associated with baseline VL (HR, 1.60 (CI95%,1.06-2.40) and weight for age (HR, 1.67 (CI95%,1.11-2.50). (P) of suppression associated with baseline VL (HR, 0.60 (CI95%,0.51-0.71) and CD4% (HR, 1.04, (CI95%,1.01-1.06), p=0.01. (P) of severe IS was associated with baseline VL, (HR, 1.4 (CI95% 1.15-1.69), baseline CD4% (HR, 0.91 (0.88-0.93), baseline weight for age (HR, 0.86 (CI95%, 0.76-0.99), and Mozambique (HR 1.88 (CI95%, 1.16-3.1).

Despite early treatment and a close follow-up, death, progression, and severe IS remain high in children born with HIV in Africa, especially in the 6 first months. Additional strategies are required to improve the care of this population.

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18

Mar, 2022

Birth outcomes following prenatal exposure to dolutegravir: the DOLOMITE-EPPICC study

 

Authors: C Thorne, K Aebi-Popp, L Ene, M Floridia, AM Gamell, M Illan, H Peters, A Samarina, L Ragone, C Giaquinto, V Vannappagari

Presented at: CROI 2022

 

Abstract

Dolutegravir (DTG) is recommended and widely used during pregnancy for maternal viral suppression and preventing perinatal transmission of HIV. Our objective is to assess pregnancy and neonatal outcomes including birth defects following prenatal DTG use using real-world European data.

Dolomite-EPPICC is a multi-cohort European observational study of DTG use in pregnant women living with HIV and their infants. An analysis of prospectively collected data on all pregnancies with any prenatal DTG exposure and with birth outcomes was conducted among participating cohorts from Italy, Romania, the Russian Federation, Spain, Switzerland and UK/Ireland. Periconception exposure was defined as being within the first 6 weeks of gestation.

Overall, 550 pregnancies (540 singleton, 10 twin pregnancies) from 7 cohorts were included in the analysis resulting in 508 liveborn infants (491 singletons and 17 twins). Overall, 72.1% (365/506) pregnancies were in parous women. A total of 27 pregnancies ended in spontaneous abortion, 18 pregnancies were terminated and five ended in still birth. One termination was for neuronal migration disorder and severe microcephaly, with periconception DTG exposure. All stillbirths were exposed to periconception DTG, none with birth defects. Among the 508 liveborn infants, earliest DTG exposure was periconception for 326 (64.9%) infants, later in trimester 1 for 36 (7.2%) and in trimester 2/3 for 140 (27.9%); 6 had unknown timing of exposure. There were 21 infants with birth defects (4.1%, 95% CI 2.6, 6.2); one infant had 2 defects. The 22 defects were in the following systems: genitourinary (7), heart (4), limb (4 [polydactyly, 3]), gastrointestinal (2), chromosomal (1), other (4); no CNS defects were reported.

The prevalence rate for overall birth defects here is the same as recently reported from the Antiretroviral Pregnancy Registry for periconception exposure to DTG. Dolomite-EPPICC will continue to monitor use and safety of DTG-based regimens in pregnancy, noting that our sample size of periconception exposures is currently too small to exclude potential associations with rare birth defects like NTDs.

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15

Mar, 2022

What is PentaTr@ining

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PentaTr@ining (formerly ‘Tr@inforPedHIV’) is a groundbreaking training platform for healthcare professionals caring for children, adolescents and pregnant women living with infectious diseases – with a particular focus on HIV and congenital infections. Unique at its inception in 2005, it was established in the framework of the partnership between Penta and the European Society for Paediatric Infectious Diseases (ESPID). The course was initially designed to address topics related to the treatment of children with HIV/AIDS in Western and Eastern Europe. However, the great success of those first experiences has led Penta to adapt and export its training programmes to other resource-limited settings around the globe, including Africa, Asia and Latin America.

Led by a well-established teaching faculty, Penta has developed a scientifically rigorous and patient-centred training model. Our course speakers comprise a mixture of international, regional, and national experts to provide the best expertise and local knowledge. Through PentaTr@ining, healthcare workers are empowered by high-quality training from experienced frontline professionals in the management of HIV and other infectious diseases, and in teaching the clinical aspects of paediatric care. A key strategic aim of our courses is to enhance international networking and forge lasting links of benefit to healthcare providers and their patients, fostering future collaborations and support for clinical care and research.

To date we have carried out some 75 training courses, reaching over 6,000 healthcare workers in 37 countries. Training content has also been translated from English, and courses delivered across a variety of languages – namely Russian, Spanish, French, Georgian and Portuguese. We are currently expanding our teaching curricula on other clinical areas of our research activity (including microbial infections, fungal infections, hepatitis and COVID-19).

Early-bird rates are still available for our upcoming course ‘HIV & other Congenital Infections’. Don’t miss it, sign up here today! 

For more information about PentaTr@ining please visit our dedicated webpage or email us at: pentatraining@pentafoundation.org

14

Mar, 2022

WHO Paediatric ARV dosing dashboard

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The WHO have developed a Paediatric ARV dosing dashboard which aims to support health care workers, researchers and policy makers in decisions around ARV dosing for children. It includes a dosing tool to assist in selecting the correct dose for infants, children and adolescents less than 18 years old, background information to support WHO paediatric weight-band dosing recommendations for ARV drugs, and a tool for researchers who want to investigate various ARV dosages and calculate the expected drug exposure in children relative to adult targets after administration of various doses.

The tool generates advice on the preferred ARVs combinations, preferred formulation, and recommended dose based on the child’s weight, age, swallowing capability, concomitant use of TB treatment, gestational age (only for neonates), and previous medications used (only for 2nd line treatment). The dose recommendations are based on the WHO paediatric dosing annex and reflect the dosing recommendations of the Paediatric ARV Working Group (PAWG).

The tool will be periodically updated to reflect new evidence and new dosing recommendations as those become available.

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11

Mar, 2022

Respiratory Syncytial Virus–Associated Hospital Admissions and Bed Days in Children <5 Years of Age in 7 European Countries

 

Authors: X Wang, Y Li, L.V Fernandez, A.C Teirlinck, T Lehtonen, M.V Wijhe, L Stona, M Bangert, R.M Reeves, H Bøås, M.V Boven, T Heikkinen, C.K Johannesen, E Baraldi, D Donà, S Tong, H Campbell, Respiratory Syncytial Virus Consortium in Europe (RESCEU) Investigators

Published in: The Journal of Infectious Diseases

8

Mar, 2022

ZIKAction paediatric registry: maternal characteristics and clinical, radiological, and follow-up features of children born with congenital zika infection in brazil

 

Authors: B.L de Almeida, I.C de Siqueira, M.L.C Lage, L.S Lopes, A.L de Carvalho, M.M de Lima, M.d.F.N Goes, M.N Crispim, B.G.G Costa, C Giaquinto, G Fernandes, E Ruiz-Burga, C Thorne on belhaf of Zikaction consortium

Presented at: WSPID 2022

Abstract

Background: In 2015, Brazil experienced an unexpected increase in newborns with microcephaly. Subsequently, the association between microcephaly and Congenital Zika Infection (CZI) was confirmed.

Aims: This study, part of the ZIKAction Paediatric Registry, intends to describe clinical, radiological, neurodevelopmental, and laboratory features and follow-up of children with CZI in Bahia, Brazil.

Methods: This observational study had following inclusion criteria: intrauterine exposure to ZIKV, laboratory-confirmed CZI, or meeting the definition of suspected CZI, based on clinical and radiological features. Results: Of 129 participants, 57% were female. Most mothers (75%) had symptoms suggestive of Zika infection during pregnancy. Median gestational age at delivery was 38 weeks, with 19% delivered preterm. Median birth length and weight were 46cm and 2690g, respectively. Most infants (118, 91.5%) had microcephaly (median head circumference Zscore -3.51, IQR -4.69,-2.73), and 17 (13.2%) have arthrogryposis. During follow-up, 96% and 92% of children had hearing and ophthalmological assessments, with 21% and 57% having abnormalities respectively. Brain image was abnormal in all cases, with ventriculomegaly (70.1%), cerebral parenchyma calcifications (62.1%), and cortical atrophy (48.6%) were main findings. Median age at last follow-up was 5 years; to date, 54 (42%) participants needed hospitalization, 44 (35%) needed care in the emergency department, and two (1.5%) died.

Conclusion: CZI is an emerging disease shown to have a varied spectrum. Registry children were biased towards those with more severe disease, with several abnormalities and complications observed. Continued long-term follow-up is essential to understand the prognosis and clinical spectrum as these children reach school-age.

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