Publications

22

Mar, 2021

Because we all have to grow up”: supporting adolescents in Uganda to develop core competencies to transition towards managing their HIV more independently

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Authors: Chloe Lanyon, Janet Seeley, Stella Namukwaya, Victor Musiime, Sara Paparini, Helen Nakyambadde, Christine Matama, Anna Turkova, Sarah Bernays

 

Published in: Journal of International Aids Society

 

Abstract

Introduction: Sustaining optimal adherence is the major challenge facing adolescents living with HIV (ALHIV), particularly in low-resource settings, where “second-line” is often the last accessible treatment option. We explored the knowledge and skills adolescents need in order to maintain improved adherence behaviours, and the specific ways clinicians and caregivers may support young people to do so more independently.

Methods: We conducted individual, in-depth interviews with 20 ALHIV aged 10 to 18 years in Uganda in 2017 to 2018. All participants had recently commenced second-line treatment as part of a clinical trial. We used thematic qualitative analysis to examine adherence experiences and challenges while on first-line therapy, as well as specific supports necessary to optimise treatment-taking longer-term.

Results: Adherence difficulties are exacerbated by relatively rapid shifts from caregiver-led approaches during childhood, to an expectation of autonomous treatment-taking with onset of adolescence. For many participants this shift compounded their ongoing struggles managing physical side effects and poor treatment literacy. Switching to second-line typically prompted reversion back to supervised adherence, with positive impacts on self-reported adherence in the immediate term. However, this measure is unlikely to be sustainable for caregivers due to significant caregiver burden (as on first line), and provided little opportunity for clinicians to guide and develop young people’s capacity to successfully adopt responsibility for their own treatment-taking.

Conclusions: As ALHIV in sub-Saharan Africa are attributed increasing responsibility for treatment adherence and HIV management, they must be equipped with the core knowledge and skills required for successful, self-directed care. Young people need to be relationally supported to develop necessary “adherence competencies” within the supportive framework of a gradual “transition” period. Clinic conversations during this period should be adolescent-focussed and collaborative, and treatment-taking strategies situated within the context of their lived environments and support networks, to facilitate sustained adherence. The disclosure of adherence difficulties must be encouraged so that issues can be identified and addressed prior to treatment failure.

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22

Mar, 2021

Increased incidence of precocious and accelerated puberty in females during and after the Italian lockdown for the coronavirus 2019 (COVID-19) pandemic

 

Authors: Stefano Stagi, Salvatore De Masi, Erica Bencini, Stefania Losi, Silvia Paci, Maria Parpagnoli, Franco Ricci, Daniele Ciofi and Chiara Azzari

Published in: Italian Journal of Pediatrics

 

Abstract

Background: The timing of puberty in girls is occurring at an increasingly early age. While a positive family history is recognised as a predisposing factor for early or precocious puberty, the role of environmental factors is not fully understood.

Aims of the study: To make a retrospective evaluation of the incidence of newly diagnosed central precocious puberty (CPP) and the rate of pubertal progression in previously diagnosed patients during and after the Italian lockdown for COVID-19, comparing data with corresponding data from the previous 5 years. To determine whether body mass index (BMI) and the use of electronic devices increased during lockdown in these patients.

Patients and methods: The study included 49 females with CPP. We divided the patients into two groups: group 1, patients presenting a newly diagnosed CPP and group 2, patients with previously diagnosed slow progression CPP whose pubertal progression accelerated during or after lockdown. We collected auxological, clinical, endocrinological and radiological data which were compared with data from two corresponding control groups (patients followed by our Unit, March to July 2015–2019). Patients’ families completed a questionnaire to assess differences in the use of electronic devices before and during lockdown.

Results: Thirty-seven patients presented newly diagnosed CPP (group 1) and 12, with previously diagnosed but untreated slow progression CPP presented an acceleration in the rate of pubertal progression (group 2). The number of new CPP diagnoses was significantly higher than the mean for the same period of the previous 5 years (p < 0.0005). There were no significant differences between patients in group 1 and control group 1 regarding time between appearance of B2 and CPP diagnosis, although group 1 patients had a significantly earlier chronological age at B2, a more advanced Tanner stage at diagnosis (p < 0.005), higher basal LH and E2 levels, higher LH peak after LHRH test (p < 0.05) and increased uterine length (p < 0.005) and ovarian volume (p < 0.0005). The number of patients with previously diagnosed CPP whose pubertal development accelerated was also statistically higher compared to controls (p < 0.0005). In this group, patients’ basal LH (p < 0.05) and E2 levels (p < 0.0005) became more markedly elevated as did the LH peak after LHRH test (p < 0.05). These patients also showed a significantly accelerated progression rate as measured by the Tanner scale (p < 0.0005), uterine length (p < 0.005), and ovarian volume (p < 0.0005). In both group 1 and group 2, BMI increased significantly (p < 0.05) and patients’ families reported an increased use of electronic devices (p < 0.0005).

Conclusion: Our data show an increased incidence of newly diagnosed CPP and a faster rate of pubertal progression in patients with a previous diagnosis, during and after lockdown compared to previous years. We hypothesize that triggering environmental factors, such as the BMI and the use of electronic devices, were enhanced during lockdown, stressing their possible role in triggering/influencing puberty and its progression. However, more studies are needed to determine which factors were involved and how they interacted.

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22

Mar, 2021

COVID-19 Infections among Students and Staff in New York City Public Schools

 

Authors: Jay K. Varma, MD, Jeff Thamkittikasem, MPA, Katherine Whittemore, MPH, Mariana Alexander, MSc, Daniel H. Stephens, MD, Kayla Arslanian, JD, Jackie Bray, MPH, Theodore G. Long, MD

Published in: American Academy of Pediatrics

 

Abstract:

Background: The 2019 novel coronavirus disease (COVID-19) pandemic led many jurisdictions to close in- person school instruction.

Methods: We collected data about COVID-19 cases associated with New York City public schools from polymerase chain reaction (PCR) testing performed in each school on a sample of asymptomatic students and staff and from routine reporting . We compared prevalence from testing done in schools to community prevalence estimates from statistical models. We compared cumulative incidence for school-associated cases to all cases reported to the city. School-based contacts were monitored to estimate the secondary attack rate and possible direction of transmission.

Results: To assess prevalence, we analyzed data from 234,132 persons tested for SARS-CoV-2 infection in 1,594 New York City public schools during October 9–December 18, 2020; 986 (0.4%) tested positive. COVID-19 prevalence in schools was similar to or less than estimates of prevalence in the community for all weeks. To assess cumulative incidence, we analyzed data for 2,231 COVID-19 cases that occurred in students and staff compared with the 86,576 persons in New York City diagnosed during the same period; the overall incidence was lower for persons in public schools compared with the general community. Of 36,423 school-based close contacts, 191 (0.5%) subsequently tested positive for COVID-19; the likely index case was an adult for 78.0% of secondary cases.

Conclusions: We found that in-person learning in New York City public schools was not associated with increased prevalence or incidence overall of COVID-19 infection compared with the general community.

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22

Mar, 2021

Behavioural and Emotional Changes during COVID-19 Lockdown in an Italian Paediatric Population with Neurologic and Psychiatric Disorders

 

Authors: Eugenia Conti, Giuseppina Sgandurra, Giacomo De Nicola Tommaso Biagioni, Silvia Boldrini, Eleonora Bonaventura, Bianca Buchignani, Stefania Della Vecchia, Francesca Falcone, Caterina Fedi et al.

Published in: MDPI

Abstract: On 11 March 2020, a national lockdown was imposed by the Italian government to contain the spread of COVID19 disease. This is an observational longitudinal study conducted at Fondazione Stella Maris (FSM), Italy to investigate lockdown-related emotional and behavioural changes in paediatric neuropsychiatric population. Families having children (1.5–18 years) with neuropsychiatric disorders referred to FSM have been contacted and proposed to fulfil two online questionnaires (General questionnaire and Child Behaviour Check List (CBCL)) to (i) compare (paired two-sample t-tests) the CBCL scores during lockdown with previous ones, and (ii) investigate the influence (multiple linear regression models) of variables such as age, diagnosis grouping (neurological, neurodevelopmental, emotional, and behavioural disorders) and financial hardship. One hundred and forty-one parents fulfilled the questionnaires. Anxiety and somatic problems increased in 1.5–5 years subpopulation, while obsessive-compulsive, post-traumatic and thought problems increased in 6–18 years subpopulation. In the regression models, younger age in the 1.5–5 years subpopulation resulted as “protective” while financial hardship experienced by families during lockdown was related to psychiatric symptoms increasing in the 6–18 years subpopulation. Some considerations, based on first clinical impressions, are provided in text together with comments in relation to previous and emerging literature on the topic.

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19

Mar, 2021

Vaccinating Children against Covid-19 — The Lessons of Measles

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Authors: Perri Klass, M.D. and Adam J. Ratner, M.D., M.P.H.

Published in: The New England Journal of Medicine

 

Introduction: Imagine a highly contagious virus circulating in the community. Many infected children have fever and some general misery but recover without incident. Rarely, devastating complications occur, leading to hospitalization, severe illness, and occasional deaths. Susceptible adults fare worse, with higher rates of poor outcomes. Would you want your child vaccinated against this disease?

You guessed we were talking about measles, right?

As the first SARS-CoV-2 vaccines are rolled out to the highest-risk groups, the current stage of the Covid-19 pandemic is pregnant with possibility. Even as cases multiply and new restrictions loom, we gaze longingly toward the next few months, hoping vaccines will deliver us. Vaccination could liberate us to return to school or work, celebrate holidays, eat in restaurants, travel, run marathons, and [fill in your own deprivations]. Early announcements of vaccine efficacy send stocks soaring, and suddenly everyone knows about phase 3 trials and cold-chain logistics. We look to vaccines to give us back our world.

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19

Mar, 2021

Characteristics of SARS-CoV-2 patients dying in Italy Report based on available data on March 1st, 2021

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Authors: Luigi Palmieri, Elvira Agazio, Xanthi Andrianou, Pierfrancesco Barbariol, Antonino Bella, Eva Benelli, Luigi Bertinato, Matilde Bocci, Stefano Boros, Giovanni Calcagnini, Marco Canevelli, Federica Censi, Alessandra Ciervo, Elisa Colaizzo, Martina Del Manso, Corrado Di Benedetto, Chiara Donfrancesco, Massimo Fabiani, et al.

Published in: Epicentro

 

Sample: The present report describes the characteristics of 96,149 SARS-CoV-2 patients dying in Italy*, as reported by the Integrated Covid-19 Surveillance System coordinated by the National Institute of Health-ISS. Geographic distribution across the 19 regions and 2 autonomous provinces of Trento and Bozen is presented in Table 1. Absolute number and percentage of deaths are reported according to the 3 phases that characterized the pandemic from the beginning in 2020 to the 1st of March 2021: the first wave (March-May 2020), the low incidence phase (June-September 2020), and the second wave (October 2020 – March 2021), the latter is still ongoing. The surveillance data on deaths are constantly updated and consolidated and both activities require time to be carried out. Each Region has its own organization for updating data and related execution times. Therefore, when reading the data by Region, it is necessary to take into account that the timing of notification, control, verification and updating of data varies from Region to Region and from period to period; this may involve variations (increasing and/or decreasing) and differences both with the data already published in the previous reports, and with the data published by the Civil Protection. It should also be considered that the regional differences in the percentage of deaths reported in the table should not be interpreted in terms of risk. In fact, case fatality depends on the number of infections occurring in each region over a period of time compatible with the possible observation of the fatal event. In this regard, it should also be taken into account that the difference between the number of infections and the notified cases may vary regionally and over time as a function of different test access strategies adopted during the epidemic, thus distorting the comparison of regional case fatality.

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19

Mar, 2021

Virological and immunological features of SARS COV 2 infected children who who developed neutralizing antibodies

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Authors: Nicola Cotugno, Alessandra Ruggiero, Francesco Bonfante, Paolo Rossi, Anita De Rossi, Paolo Palma et al.

Published in: Cell Reports

 

Summary: As the global COVID-19 pandemic progresses, it is paramount to gain knowledge on adaptive immunity to SARS-CoV-2 in children to define immune correlates of protection upon immunization or infection. We analyzed anti-SARS-CoV-2 antibodies and their neutralizing activity (PRNT) in 66 COVID-19-infected children at 7 (±2) days after symptom onset. Individuals with specific humoral responses presented faster virus clearance and lower viral load associated with a reduced in vitro infectivity. We demonstrated that the frequencies of SARS-CoV-2-specific CD4+CD40L+ T cells and Spike-specific B cells were associated with the anti-SARS- CoV-2 antibodies and the magnitude of neutralizing activity. The plasma proteome confirmed the association between cellular and humoral SARS-CoV-2 immunity, and PRNT+ patients show higher viral signal transduction molecules (SLAMF1, CD244, CLEC4G). This work sheds lights on cellular and humoral anti-SARS-CoV-2 responses in children, which may drive future vaccination trial endpoints and quarantine measures policies.

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11

Mar, 2021

DOLUTEGRAVIR-BASED ART IS SUPERIOR TO NNRTI/PI- BASED ART IN CHILDREN AND ADOLESCENTS

 

Authors: Anna Turkova1, for the ODYSSEY/PENTA-20 Trial Team

Published in: CROI 2021

 

Abstract: ODYSSEY is an international multi-centre randomised non-inferiority trial evaluating dolutegravir (DTG) + 2NRTIs versus standard-of-care (SOC) in children starting rst- or second-line ART.

Methods: The primary outcome is a Kaplan-Meier estimated proportion of treatment failure dened as conrmed viral load (VL) ≥400c/mL after week 36, lack of virological response by 24 weeks with ART switch, death or new/recurrent WHO4/severe WHO3 event by 96 weeks. Non-inferiority margin is 10% (12% for rst-/second-line subgroups).

Results: 707 children ≥14kg were randomised (Uganda 47%, Zimbabwe 21%, South Africa 20%, Thailand 9%, Europe 4%); 350 to DTG; 357 to SOC. Median (range) age was 12.2 years (2.9-18); weight 31kg (14-85); 51% male. 311 children started rst-line (92% efavirenz among SOC); 396 second-line (72% lopinavir/ritonavir, 25% atazanavir/ritonavir among SOC). Median follow-up was 142 weeks; 687 (97%) reached the primary endpoint or were seen on/after 96 weeks. 48 (14%) DTG vs 75 (22%) SOC had treatment failure by 96 weeks; difference (95% CI) –7.7% (-13.2, -2.3); p=0.006. 40 vs 67 were virological failures and 8 vs 8 were WHO3/4 events/death. Treatment effects were similar in rst- and second-line, with no evidence of heterogeneity (p=0.20; g). 13 (4%) children randomised to DTG changed regimen during follow-up vs 32 (9%) SOC (excluding NRTI changes and changes for growth, simplication, guideline change, stock-out) (p=0.004); 2 vs 21 changes were for treatment failure. At 48 and 96 weeks, proportion with cross-sectional VL<50c/mL and change in CD4 count from baseline were similar between arms. There were 65 SAEs (35 children) in DTG versus 46 (42) in SOC (p=0.45), including 2 vs. 3 deaths; 119 (73 children) grade ≥3 adverse events in DTG vs 135 (88) in SOC (p=0.23). At week 96, mean change in total cholesterol from baseline was -5 mg/dL (95% CI -8,-2) in DTG versus 10 mg/dL (7,13) in SOC (difference (DTG-SOC) -15 (-19,-11); p<0.001). Weight, height and BMI increased marginally more in DTG than SOC (differences (SE) between arms 1kg (0.4), 0.7cm (0.3), 0.3kg/m2 (0.1) respectively at 96 weeks).

Conclusion: DTG-based ART was superior to SOC based on treatment failure by 96 weeks in children/adolescents starting rst- or second-line. There were no safety concerns on DTG. These results support WHO guidelines which recommend DTG-based regimens as preferred ART for children ≥14kg starting rst- or second-line ART, allowing harmonisation with adult treatment programmes.

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23

Feb, 2021

What does 95% COVID-19 vaccine efficacy really mean?

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Author: Piero Olliaro

Published in: The Lancet

Introduction: It is imperative to dispel any ambiguity about how vaccine efficacy shown in trials translates into protecting individuals and populations. The mRNA-based Pfizer1,2 and Moderna3 vaccines were shown to have 94–95% efficacy in preventing symptomatic COVID-19, calculated as 100 × (1 minus the attack rate with vaccine divided by the attack rate with placebo). It means that in a population such as the one enrolled in the trials, with a cumulated COVID-19 attack rate over a period of 3 months of about 1% without a vaccine, we would expect roughly 0·05% of vaccinated people would get diseased. It does not mean that 95% of people are protected from disease with the vaccine—a general misconception of vaccine protection also found in a Lancet Infectious Diseases Editorial.

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19

Feb, 2021

ODYSSEY clinical trial design: a randomised global study to evaluate the efficacy and safety of dolutegravir-based antiretroviral therapy in HIV-positive children, with nested pharmacokinetic sub-studies to evaluate pragmatic WHO-weight-band based dolutegravir dosing

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Authors: Cecilia L. Moore, Anna Turkova , Hilda Mujuru , Adeodata Kekitiinwa, Abbas Lugemwa, Cissy M. Kityo, Linda N. Barlow-Mosha, et al, ODYSSEY trial team

Published in: BMC Infectious Diseases

 

Background: Dolutegravir (DTG)-based antiretroviral therapy (ART) is highly effective and well-tolerated in adults and is rapidly being adopted globally. We describe the design of the ODYSSEY trial which evaluates the efficacy and safety of DTG-based ART compared with standard-of-care in children and adolescents. The ODYSSEY trial includes nested pharmacokinetic (PK) sub-studies which evaluated pragmatic World Health Organization (WHO) weight-band-based DTG dosing and opened recruitment to children < 14 kg while dosing was in development.

Methods: ODYSSEY (Once-daily DTG based ART in Young people vS. Standard thErapY) is an open-label, randomised, non-inferiority, basket trial comparing the efficacy and safety of DTG + 2 nucleos(t) ides (NRTIs) versus standard-of-care (SOC) in HIV-infected children < 18 years starting first-line ART (ODYSSEY A) or switching to second-line ART (ODYSSEY B). The primary endpoint is clinical or virological failure by 96 weeks.

Results: Between September 2016 and June 2018, 707 children weighing ≥14 kg were enrolled; including 311 ARTnaïve children and 396 children starting second-line. 47% of children were enrolled in Uganda, 21% Zimbabwe, 20% South Africa, 9% Thailand, 4% Europe. 362 (51%) participants were male; median age [range] at enrolment was 12.2 years [2.9–18.0]. 82 (12%) children weighed 14 to < 20 kg, 135 (19%) 20 to < 25 kg, 206 (29%) 25 to < 35 kg, 284 (40%) ≥35 kg. 128 (18%) had WHO stage 3 and 60 (8%) WHO stage 4 disease. Challenges encountered include: (i) running the trial across high- to low-income countries with differing frequencies of standard-of-care viral load monitoring; (ii) evaluating pragmatic DTG dosing in PK sub-studies alongside FDA- and EMA-approved dosing and subsequently transitioning participants to new recommended doses; (iii) delays in dosing information for children weighing 3 to < 14 kg and rapid recruitment of ART-naïve older/heavier children, which led to capping recruitment of participants weighing ≥35 kg in ODYSSEY A and extending recruitment (above 700) to allow for ≥60 additional children weighing between 3 to < 14 kg with associated PK; (iv) a safety alert associated with DTG use during pregnancy, which required a review of the safety plan for adolescent girls.

Conclusions: By employing a basket design, to include ART-naïve and -experienced children, and nested PK substudies, the ODYSSEY trial efficiently evaluates multiple scientific questions regarding dosing and effectiveness of DTG-based ART in children.

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