2018
Authors: Collaborative Initiative for Paediatric HIV Education and Research (CHIPER) Global Cohort Collaboration
Published in: PLoS Med. 2018;15(3):e1002514.
Background Globally, the population of adolescents living with perinatally acquired HIV (APHs) continues to expand. In this study, we pooled data from observational pediatric HIV cohorts and cohort networks, allowing comparisons of adolescents with perinatally acquired HIV in “real-life” settings across multiple regions. We describe the geographic and temporal characteristics and mortality outcomes of APHs across multiple regions, including South America and the Caribbean, North America, Europe, sub-Saharan Africa, and South and Southeast Asia.
Methods and Findings Through the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER), individual retrospective longitudinal data from 12 cohort networks were pooled. All children infected with HIV who entered care before age 10 years, were not known to have horizontally acquired HIV, and were followed up beyond age 10 years were included in this analysis conducted from May 2016 to January 2017. Our primary analysis describes patient and treatment characteristics of APHs at key time points, including first HIV-associated clinic visit, antiretroviral therapy (ART) start, age 10 years, and last visit, and compares these characteristics by geographic region, country income group (CIG), and birth period. Our secondary analysis describes mortality, transfer out, and lost to follow-up (LTFU) as outcomes at age 15 years, using competing risk analysis among the 38,187 APHs included, 51% were female, 79% were from sub-Saharan Africa and 65% lived in low-income countries. APHs from 51 countries were included (Europe: 14 countries and 3,054 APHs; North America: 1 country and 1,032 APHs; South America and the Caribbean: 4 countries and 903 APHs; South and Southeast Asia: 7 countries and 2,902 APHs; sub-Saharan Africa, 25 countries and 30,296 APHs). Observation started as early as 1982 in Europe and 1996 in sub-Saharan Africa, and continued until at least 2014 in all regions. The median (interquartile range [IQR]) duration of adolescent follow-up was 3.1 (1.5-5.2) years for the total cohort and 6.4 (3.6-8.0) years in Europe, 3.7 (2.0-5.4) years in North America, 2.5 (1.2-4.4) years in South and Southeast Asia, 5.0 (2.7-7.5) years in South America and the Caribbean, and 2.1 (0.9-3.8) years in sub-Saharan Africa. Median (IQR) age at first visit differed substantially by region, ranging from 0.7 (0.3-2.1) years in North America to 7.1 (5.3-8.6) years in sub-Saharan Africa. The median age at ART start varied from 0.9 (0.4-2.6) years in North America to 7.9 (6.0-9.3) years in sub-Saharan Africa. The cumulative incidence estimates (95% confidence interval [CI]) at age 15 years for mortality, transfers out, and LTFU for all APHs were 2.6% (2.4%-2.8%), 15.6% (15.1%-16.0%), and 11.3% (10.9%-11.8%), respectively. Mortality was lowest in Europe (0.8% [0.5%-1.1%]) and highest in South America and the Caribbean (4.4% [3.1%-6.1%]). However, LTFU was lowest in South America and the Caribbean (4.8% [3.4%-6.7%]) and highest in sub-Saharan Africa (13.2% [12.6%-13.7%]). Study limitations include the high LTFU rate in sub-Saharan Africa, which could have affected the comparison of mortality across regions; inclusion of data only for APHs receiving ART from some countries; and unavailability of data from high-burden countries such as Nigeria.
Conclusion To our knowledge, our study represents the largest multiregional epidemiological analysis of APHs. Despite probable under-ascertained mortality, mortality in APHs remains substantially higher in sub-Saharan Africa, South and Southeast Asia, and South America and the Caribbean than in Europe. Collaborations such as CIPHER enable us to monitor current global temporal trends in outcomes over time to inform appropriate policy responses.
2018
Authors: Marotta C, Giaquinto C, Di Gennaro F, et al.
Published in: BMC Public Health. 2018;18(1):703.
Background In 2013, Mozambique implemented task-shifting (TS) from clinical officers to maternal and child nurses to improve care for HIV positive children < 5 years old. A retrospective, pre-post intervention study was designed to evaluate effectiveness of a new pathway of care in a sample of Beira District Local Health Facilities (LHFs), the primary, local, community healthcare services.
Methods The study was conducted by accessing registries of At Risk Children Clinics (ARCCs) and HIV Health Services. Two time periods, pre- and post-intervention, were compared using a set of endpoints. Variables distribution was explored using descriptive statistics. T-student, Mann Whitney and Chi-square tests were used for comparisons.
Results Overall, 588 HIV infected children (F = 51.4%) were recruited, 330 belonging to the post intervention period. The mean time from referral to ARCC until initiation of ART decreased from 2.3 (± 4.4) to 1.1 (± 5.0) months after the intervention implementation (p-value: 0.000). A significant increase of Isoniazid prophylaxis (O.R.: 2.69; 95%CI: 1.7-4.15) and a decrease of both regular nutritional assessment (O.R. = 0.45; 95%CI: 0.31-0.64) and CD4 count at the beginning of ART (O.R. = 0.46; 95%CI: 0.32-0.65) were documented after the intervention.
Conclusions Despite several limitations and controversial results on nutrition assessment and CD4 count at the initiation of ART reported after the intervention, it could be assumed that TS alone may play a role in the improvement of the global effectiveness of care for HIV infected children only if integrated into a wider range of public health measures.
2018
Authors: Ford D, Turner R, Turkova A, et al.
Published in: J Acquir Immune Defic Syndr. 2018;78(1):S40-S48.
Abstract For HIV-infected children, formulation development, pharmacokinetic (PK) data, and evaluation of early toxicity are critical for licensing new antiretroviral drugs; direct evidence of efficacy in children may not be needed if acceptable safety and PK parameters are demonstrated in children. However, it is important to address questions where adult trial data cannot be extrapolated to children. In this fast-moving area, interventions need to be tailored to resource-limited settings where most HIV-infected children live and take account of decreasing numbers of younger HIV-infected children after successful prevention of mother-to-child HIV transmission. Innovative randomized controlled trial (RCT) designs enable several questions relevant to children’s treatment and care to be answered within the same study. We reflect on key considerations, and, with examples, discuss the relative merits of different RCT designs for addressing multiple scientific questions including parallel multi-arm RCTs, factorial RCTs, and cross-over RCTs. We discuss inclusion of several populations (eg, untreated and pretreated children; children and adults) in “basket” trials; incorporation of secondary randomizations after enrollment and use of nested substudies (particularly PK and formulation acceptability) within large RCTs. We review the literature on trial designs across other disease areas in pediatrics and rare diseases and discuss their relevance for addressing questions relevant to HIV-infected children; we provide an example of a Bayesian trial design in prevention of mother-to-child HIV transmission and consider this approach for future pediatric trials. Finally, we discuss the relevance of these approaches to other areas, in particular, childhood tuberculosis and hepatitis.
2018
Authors: Kawuma R, Seeley J, Mupambireyi Z, Cowan F, Bernays S; for REALITY Trial Team
Published in: Afr J AIDS Res. 2018;17(3):217-225
Abstract We examined the logic that individuals use to account for delaying HIV testing and/or initiating HIV treatment. Our qualitative study, situated within the REALITY trial (Reduction of EArly mortaLITY in HIV infected adults and children starting antiretroviral therapy), was conducted in Uganda and Zimbabwe in 2015. Forty-eight participants (different age groups, sex and viral load/WHO disease stage) were included. Each participant had 2 interviews (1 after 4 weeks of participation in the trial the other after 12 weeks). If a person could manage presenting symptoms, they felt they had “more time” before starting antiretroviral therapy (ART). Their reluctance to have an HIV test (despite deteriorating health) arose from a belief that they were not “sick”, that treatment was “not yet necessary”. People in our study did not consider themselves as presenting “late”, and treatment was not considered urgent as long as they considered their health to be “good enough”.
2018
Authors: Tierrablanca LE, Ochalek J, Ford D, et al; for BREATHER (PENTA 16) Trial Group
Published in: Medicine (Baltimore). 2018;97(5):e9698
Objectives To analyze the cost effectiveness of short-cycle therapy (SCT), where patients take antiretroviral (ARV) drugs 5 consecutive days a week and have 2 days off, as an alternative to continuous ARV therapy for young people infected with human immunodeficiency virus (HIV) and taking efavirenz-based first-line ARV drugs.
Methods We conduct a hierarchical cost-effectiveness analysis based on data on clinical outcomes and resource use from the BREATHER trial. BREATHER is a randomized trial investigating the effectiveness of SCT and continuous therapy in 199 participants aged 8 to 24 years and taking efavirenz-based first-line ARV drugs in 11 countries worldwide. Alongside nationally representative unit costs/prices, these data were used to estimate costs and quality adjusted life years (QALYs). An incremental cost-effectiveness comparison was performed using a multilevel bivariate regression approach for total costs and QALYs. Further analyses explored cost-effectiveness in low- and middle-income countries with access to low-cost generic ARV drugs and high-income countries purchasing branded ARV drugs, respectively.
Results At 48 weeks, SCT offered significant total cost savings over continuous therapy of US dollar (USD) 41 per patient in countries using generic drugs and USD 4346 per patient in countries using branded ARV drugs, while accruing nonsignificant total health benefits of 0.008 and 0.009 QALYs, respectively. Cost-effectiveness estimates were similar across settings with access to generic ARV drugs but showed significant variation among high-income countries where branded ARV drugs are purchased.
Conclusion SCT is a cost-effective treatment alternative to continuous therapy for young people infected with HIV in countries where viral load monitoring is available.
2018
Authors: Turkova A, Moore CL, Butler K, et al. for BREATHER (PENTA 16) Trial Group.
Published in: PLos One. 2018;13(4):e0196239.
Background Weekends off antiretroviral therapy (ART) may help engage HIV-1-infected young people facing lifelong treatment. BREATHER showed short cycle therapy (SCT; 5 days on, 2 days off ART) was non-inferior to continuous therapy (CT) over 48 weeks. Planned follow-up was extended to 144 weeks, maintaining original randomisation.
Methods BREATHER was an open-label, non-inferiority trial. Participants aged 8-24yrs with virologi- cal suppression on efavirenz-based first-line ART were randomised 1:1, stratified by age and African/non-African sites, to remain on CT or change to SCT. The Kaplan-Meier method was used to estimate the proportion of participants with viral rebound (confirmed VL?50 copies/mL) under intent-to-treat at 48 weeks (primary outcome), and in extended follow-up at 96, 144, and 192 weeks. SCT participants returned to CT following viral rebound, 3 VL blips or discontinuation of efavirenz.
Findings Of 199 participants (99 SCT, 100 CT), 97 per arm consented to extended follow-up. Median follow-up was 185.3 weeks (IQR 160.9–216.1). 69 (70%) SCT participants remained on SCT at last follow-up. 105 (53%) were male, baseline median age 14 years (IQR 12–18), median CD4 count 735 cells/μL (IQR 576–968). 16 SCT and 16 CT participants had con- firmed VL?50 copies/mL by the end of extended follow-up (HR 1.00, 95% CI 0.50–2.00). Estimated difference in percentage with viral rebound (SCT minus CT) by week 144 was 1.9% (90% CI -6.6–10.4; p = 0.72) and was similar in a per-protocol analysis. There were no significant differences between arms in proportions of participants with grade 3/4 adverse events (18 SCT vs 16 CT participants; p = 0.71) or ART-related adverse events (10 vs 12;
p = 0.82). 20 versus 8 serious adverse events (SAEs) were reported in 16 SCT versus 4 CT participants, respectively (p = 0.005 comparing proportions between groups; incidence rate ratio 2.49, 95%CI 0.71–8.66, p = 0.15). 75% of SAEs (15 SCT, 6 CT) were hospitalisations for a wide range of conditions. 3 SCT and 6 CT participants switched to second-line ART fol- lowing viral failure (p = 0.50).
Conclusions Sustainable non-inferiority of virological suppression in young people was shown for SCT versus CT over median 3.6 years. Standard-dose efavirenz-based SCT is a viable option for virologically suppressed HIV-1 infected young people on first-line ART with 3-monthly VL monitoring.
2018
Authors: Di Maio Ferreira FCPA, da Silva ASV, Bispo de Filippis AM, Brasil P
Published in: J Pediatric Infect Dis Soc. 2019 Jan 18
Abstract We report here a probable case of vertical transmission of chikungunya infection with confirmed maternal viremia close to labor that led to severe infection in the newborn. The newborn progressed with cutaneous lesions and irritability 2 months after vertical transmission, when chikungunya virus was detected in the infant’s CSF by a molecular diagnostic test (real-time polymerase chain reaction).
2018
Authors: Calvet GA, Brasil P, Siqueira AM, et al.
Published in: J Acquir Immune Defic Syndr. 2018;79:237-243
Background Zika virus (ZIKV) emergence in South America revealed the lack of knowledge regarding clinical manifestations in HIV-infected individuals.Objectives:We described the clinical characteristics, laboratory manifestations, differential diagnosis, and outcome of ZIKV infection in a large, single-center cohort of HIV-infected patients.
Methods HIV-infected patients aged 18 years and older with clinical suspected arboviral disease from an ongoing cohort were followed from February 2015 through December 2015. Acute serum samples were tested for ZIKV, dengue virus (DENV), and chikungunya virus by real-time reverse transcriptase polymerase chain reaction, anti-DENV immunoglobulin (Ig)M/IgG, and syphilis assays; convalescent samples were tested for anti-DENV IgM/IgG; and urine samples were tested for ZIKV by real-time reverse transcriptase polymerase chain reaction. ZIKV disease was defined according to the Pan American Health Organization (PAHO) guidelines.
Results Of 101 patients, ZIKV was confirmed in 43 cases and suspected in 34, and another diagnosis was assumed for 24 patients (dengue, secondary/latent syphilis, respiratory infections, human parvovirus B19, adverse drug reaction, musculoskeletal disorders, and acute gastroenteritis). ZIKV-confirmed and ZIKV-suspected patients reported similar signs and symptoms. Pruritic rash was the most common symptom, followed by myalgia, nonpurulent conjunctivitis, arthralgia, prostration, and headache. In the short-term follow-up [median 67.5 days (interquartile range: 32–104.5)], CD4 cell count (Z = −0.831, P = 0.406) and HIV viral load (Z = −0.447, P = 0.655) did not change significantly after ZIKV infection. There were no hospitalizations, complications, or deaths.
Conclusions Among HIV-infected patients with suspected arboviral disease, 42.6% were ZIKV-infected. CD4 cell counts and HIV viral load were not different after ZIKV infection. Differential diagnosis with other diseases and adverse drug reaction should be evaluated.
2018
Authors: Read JS, Torres-Velasquez B, Lorenzi O, et al.
Importance Little information is available regarding Zika virus (ZIKV) infection in children.
Objective To describe patients younger than 18 years who were infected with ZIKV and were enrolled in the Sentinel Enhanced Dengue and Acute Febrile Illness Surveillance System (SEDSS).
Design, Setting, and Participants Children infected with ZIKV with 7 or fewer days of fever or emancipated minors aged 14 to 17 years with a generalized maculopapular rash, arthritis or arthralgia, or nonpurulent conjunctivitis were eligible for enrollment on or before December 31, 2016, in Puerto Rico. Patients were evaluated using ZIKV polymerase chain reaction testing at 7 or fewer days after the onset of symptoms. Available ZIKV polymerase chain reaction–positive specimens were evaluated to determine viral loads.
Exposures Confirmed polymerase chain reaction–positive ZIKV infection.
Main Outcomes and Measures Clinical characteristics and viral loads of symptomatic children with confirmed ZIKV infection.
Results Of 7191 children enrolled in SEDSS on or before December 31, 2016, only those with confirmed ZIKV infection (351 participants) were included in this study. Participants who had confirmed ZIKV infection included 25 infants (7.1%), 69 children (19.7%) aged 1 to 4 years, 95 (27.1%) aged 5 to 9 years, and 162 (46.1%) aged 10 to 17 years. Among these, 260 patients (74.1%) presented for evaluation of ZIKV infection at fewer than 3 days after the onset of symptoms, 340 (96.9%) were discharged to home after evaluation, and 349 (99.4%) had fever, 280 (79.8%) had a rash, 243 (69.2%) had facial or neck erythema, 234 (66.7%) had fatigue, 223 (63.5%) had headache, 212 (60.4%) had chills, 206 (58.7%) had pruritus, and 204 (58.1%) had conjunctival hyperemia. Of 480 specimens collected (317 serum and 163 urine specimens) from 349 children, the median number of days after the onset of symptoms was lower for children who had serum specimens (1 day [interquartile range (IQR), 1-2 days]) than for children who had urine specimens (2 [1-3] days) (P < .001). Of 131 children who had both serum and urine specimens collected on the same day, the median viral load was higher in serum than in urine (median [IQR], 23 098 [8784-88 242] copies/mL for serum vs 9966 [2815-52 774] copies/mL for urine; P = .02). When a single serum sample from each of 317 patients was analyzed, there were no statistically significant differences in median viral loads according to age, sex, or disposition. However, the median serum viral load varied significantly according to the number of days after the onset of symptoms (0 days, 106 778 [IQR, 9772-1 571 718] copies/mL; 1 day, 46 299 [10 663-255 030] copies/mL; 2 days, 20 678 [8763-42 458] copies/mL; and ≥3 days, 15 901 [5135-49 248] copies/mL; P = .001).
Conclusions and Relevance This study represents the largest study to date of ZIKV infection in the pediatric population. Most children infected with ZIKV had fever, rash, and conjunctival hyperemia. The children usually presented for evaluation at fewer than 3 days after the onset of symptoms. Viral loads for ZIKV were higher in serum vs urine specimens. Median viral loads in serum specimens differed significantly according to the number of days after the onset of symptoms.
2018
Authors: Giovanetti M, Goes de Jesus J, Lima de Maia M, Junior JX, et al.
Published in: Clin Microbiol Infect.2018;24(10):1111-1112
Abstract On the basis of the upsurge in the number of newborns with neurologic disorders in the northeast, in November 2015 the Brazilian Ministry of Health declared a public health emergency of national concern [1]. On the basis of evidence for a potential association between microcephaly and other neurologic disorders and Zika virus (ZIKV) infection, the World Health Organization declared a public health emergency of international concern on 1 February 2016. Here we report genetic evidence of ZIKV RNA in the mother’s breast milk and in the serum and urine of a newborn with severe congenital defects.
2018
Authors: Azeredo EL, dos Santos FB, Barbosa LS, et al.
Published in: PLoS Curr. 2018 Feb 15;10
Background The current triple epidemic caused by dengue, zika and chikungunya constitutes a serious health problem in Brazil. The aim of this study was to investigate acute samples (up to the 7 days of symptoms) from patients presenting acute fever syndrome suspected as arboviral infection and characterize the clinical and laboratorial profile during the co-circulation of dengue, zika and chikungunya in Campo Grande, Mato Grosso do Sul (MS), midwest region of Brazil.
Methods All suspected cases (n=134) were tested by using serological and molecular diagnostic tests including DENV, ZIKV and CHIKV RT-PCR, Dengue nonstructural protein 1 (NS1) antigen capture ELISA, anti- DENV IgM ELISA and anti-CHIKV IgM ELISA. In addition, clinical, hematological and biochemical parameters of infected patients were analyzed.
Results It was observed that 79.1% of the blood samples were confirmed for ZIKV and/or DENV infection Of those, 38.0% patients were DENV monoinfected, 26.8% were ZIKV monoinfected and 13.4% were DENV/ZIKV co-infected. Seven patients presented Chikungunya IgM antibodies indicating a previous CHIKV infection. Common symptoms included fever, rash, arthralgia, myalgia, prostration, headache and conjunctivitis. Statistical analysis showed that pruritus and edema were associated with ZIKV infection while prostration and vomiting were more associated with dengue. Additionally, total protein and ALT levels were significantly different in DENV patients compared to ZIKV ones. Some DENV infected patients as well as co-infected needed hospitalization and venous hydration. Otherwise, most ZIKV infected patients presented mild clinical course. Among the pregnant women studied (n=11), three were ZIKV monoinfected while four were DENV monoinfected and two were DENV-1/ZIKV coinfected. In general, normal birth outcomes were observed except for the death due to respiratory insufficiency of one baby born to a mother coinfected with DENV-1/ZIKV.
Conclusions Herein, we provide evidence of the co-circulation of DENV, ZIKV and CHIKV infections in the Campo Grande, MS, Brazil, with a high frequency of DENV-1/ZIKV coinfection. Laboratorial diagnosis poses a challenge where those arboviruses are endemic and differential diagnosis proved to imperative for cases characterization. The knowledge about disease severity during arbovirus coinfections is still scarce and there are several issues emphasizing the importance of adequate management of patients at risk areas.
2018
Authors: Badolato-Corrêa J, Sánchez-Arcila JC, et al.
Published in: Immun Inflamm Dis.2018; 6(2):194–206
Introduction Zika virus (ZIKV) and dengue virus (DENV) co‐circulated during latest outbreaks in Brazil, hence, it is important to evaluate the host cross‐reactive immune responses to these viruses. So far, little is known about human T cell responses to ZIKV and no reports detail adaptive immune responses during DENV/ZIKV coinfection.
Methods Here, we studied T cells responses in well‐characterized groups of DENV, ZIKV, or DENV/ZIKV infected patients and DENV‐exposed healthy donors. We evaluated chemokine receptors expression and single/multifunctional frequencies of IFNγ, TNF, and IL2‐producing T cells during these infections. Even without antigenic stimulation, it was possible to detect chemokine receptors and IFNγ, TNF, and IL2‐producing T cells from all individuals by flow cytometry. Additionally, PBMCs’ IFNγ response to DENV NS1 protein and to polyclonal stimuli was evaluated by ELISPOT.
Results DENV and ZIKV infections and DENV/ZIKV coinfections similarly induced expression of CCR5, CX3CR1, and CXCR3 on CD4 and CD8 T cells. DENV/ZIKV coinfection decreased the ability of CD4+ T cells to produce IFNγ+, TNF+, TNF + IFNγ+, and TNF + IL2+, compared to DENV and ZIKV infections. A higher magnitude of IFNγ response to DENV NS1 was found in donors with a history of dengue infection, however, a hyporesponsiveness was found in acute DENV, ZIKV, or DENV/ZIKV infected patients, even previously infected with DENV.
Conclusion Therefore, we emphasize the potential impact of coinfection on the immune response from human hosts, mainly in areas where DENV and ZIKV cocirculate.
2018
Authors: Bollen P, Turkova A, Hilda Mujuru H, et al. The ODYSSEY Trial Team
Published in: 10th International Workshop on HIV Pediatrics, Amsterdam, 20-21st July 2018. Poster Number 22
2018
Authors: Moore CL, Kekitinwa A, Kaudha E, et al; the ODYSSEY Trial Team
Published in: 10th International Workshop on HIV Pediatrics, Amsterdam, July 20-21st, 2018. Poster Number 34
2018
Authors: Moreira-Soto A, Torres MC, Lima de Mendonça MC, et al.
Published in: Clin Microbiol Infect. 2018;24(9):1019.e1-1019.e4
Objectives Since December 2016, Brazil has experienced an unusually large outbreak of yellow fever (YF). Whether urban transmission may contribute to the extent of the outbreak is unclear. The objective of this study was to characterize YF virus (YFV) genomes and to identify spatial patterns to determine the distribution and origin of YF cases in Minas Gerais, Espírito Santo and Rio de Janeiro, the most affected Brazilian states during the current YFV outbreak.
Methods We characterized near-complete YFV genomes from 14 human cases and two nonhuman primates (NHP), sampled from February to April 2017, retrieved epidemiologic data of cases and used a geographic information system to investigate the geospatial spread of YFV.
Results All YFV strains were closely related. On the basis of signature mutations, we identified two cocirculating YFV clusters. One was restricted to the hinterland of Espírito Santo state, and another formed a coastal cluster encompassing several hundred kilometers. Both clusters comprised strains from humans living in rural areas and NHP. Another NHP lineage clustered in a basal relationship. No signs of adaptation of YFV strains to human hosts were detected.
Conclusions Our data suggest sylvatic transmission during the current outbreak. Additionally, cocirculation of two distinct YFV clades occurring in humans and NHP suggests the existence of multiple sylvatic transmission cycles. Increased detection of YFV might be facilitated by raised awareness for arbovirus-mediated disease after Zika and chikungunya virus outbreaks. Further surveillance is required, as reemergence of YFV from NHPs might continue and facilitate the appearance of urban transmission cycles.
2018
Authors: Bernays S, Namukwaya S, Mupambireyi Z, Nanduudu A, Mujuru H, Turkova A, Gibb DM, Seeley J, and the ODYSSEY Trial Team.
Published in: 10th International Workshop on HIV Pediatrics, Amsterdam, July 20-21st 2018. Poster number 117
2018
Authors: Turkova A, Bollen P, Kaudha E, et al. The ODYSSEY Trial Team
Published in: Oral Presentation at 10th International Workshop on HIV Pediatrics, Amsterdam, July 20-21st, 2018
2018
Authors: Anzinger J, Christie CD, Brown D, Bispo A, Nastouli E, Kozlakidis Z, Thorne C, Ades T, Lundin R, Giaquinto C
Published in: 2nd International Conference on Zika Virus and Aedes Related Infections, June 14th – 17th 2018, Tallin-Estonia
2018
Authors: Christie CD, Thorne C, Anzinger J, Bailey H, Palmer P, Morgan O, Bryan L, Mair S, Pierre R, Onyonyor A, Mitchell P, Melbourne-Chambers R, Webster-Kerr K, Lindo J, Lundin R, Brown D, Bispo A, Nastouli E, Giaquinto C
Published in: International Symposium on Zika Virus Research, June 4th – 6th 2018, Marseille – France
2018
Authors: Blohm GM, Lednicky JA, Márquez M, et al.
Published in: Clin Infect Dis. 2018;66(7):1120-1121
Abstract Zikavirus (ZIKV) is an emerging viral pathogen that continues to spread throughout different regions of the world. Herein we report a case that provides further evidence that ZIKV transmission can occur through breastfeeding by providing a detailed clinical, genomic, and virological case-based description.
2018
Authors: Rinaldi S, Cotugno N, Pallikkuth S, Pahwa R, Palma P, Pahwa S
Abstract Early initiation of antiretroviral therapy (ART) in vertically HIV-infected children provides an opportunity to limit the size of HIV reservoir. However, how the time of ART initiation impacts host HIV-specific immune responses is still poorly understood. In this study, we analyzed HIV-specific CD4 and CD8 T cell functionality in vertically HIV-infected children (age range 2.3–17.5yrs) enrolled at Bambino Gesù Children Hospital under suppressive ART and durable viral control (plasma HIV-RNA<50cp/mL). Children were designated as early treated (ET, n=8, ART initiated at age <6mo) or late treated (LT, n=7, ART initiated at age >1 year) with longer duration of ART in ET (p<0.05). Antigen-specific (CD40L+CD4+/CD107a+CD8+) T cells were evaluated in cryopreserved PBMC by flow cytometry for intracellular cytokines (IL2, IFN g, TNFα, IL21, Perforin, Granzyme B) following 12hr stimulation with GAG PTE peptides. Differences between groups were determined by Mann-Whitney t tests (P≤0.05).
Frequencies of GAG-specific CD8 and CD4 T cells were not different between ET and LT. Boolean analyses revealed that CD8 T cells of LT had a higher frequency of Granzyme B+ cells compared to ET whereas CD4 T cells were qualitatively superior in ET compared to LT and exhibited higher proportions of IL2, IFNg and TNFα producing T cells and enrichment of polyfunctional T cells.
Our results suggest that time of ART initiation in HIV-infected children has a long-term impact on the quality but not the quantity of the host HIV-specific T-cell immune responses. Larger studies are needed to confirm these results and to further evaluate their role in future strategies aiming at functional cure.
2018
Authors: Violari A, Chan M, Otwombe KN, Panchia R, Jean-Philippe P, Gibb D, Cotton M, Babiker A
HIV RNA viral load (VL) from stored samples was assessed 8 weeks after interruption and 12 weekly thereafter. Included were children with VL<400 c/ml at interruption and ≥1 VL measurement within 12 months. Multivariable stepwise Cox regression models (backwards elimination, exit probability p=0.05) were used to identify factors associated with time to viral rebound (confirmed VL≥400 c/ml). Follow-up was censored at ART reinitiation (if VL had not rebounded) or last VL measurement.
Of 183 children virally suppressed (VL<400) at interruption, 54% were from ART-40W and 61% were female. At enrolment, 81% received PMTCT, 81% had CDC stage N; median [IQR] birth weight was 3 [2.7,3.3]Kg. At ART start, median [IQR] age was 1.8 [1.5,2.1] months, CD4% 34 [29,40]%, CD4 count 1982 [1445,2745], CD8% 28 [22,34]% and VL 750000 [376000,750000] copies/ml. Median VL at rebound was 354615 [91040,750000] copies/ml, not significantly different between arms [ART-40W=418760; ART-96W=325000 copies/ml; P=0.19]. 86% of children suppressed within 40 weeks of ART start [88% ART-40W; 83% ART-96W; P=0.38]. Overall estimated cumulative probability of rebound (95% CI) at 2, 4, 6 and 8 months were 70% (63,76)%, 80% (74, 85)%, 94% (90,97)% and 99% (96,100)%, respectively. Median time to rebound was 1.8 (range: 0.9-13.1) months. One child (ART-40W) maintained viral suppression until last VL available. Five children were censored due to ART restart. In univariable analysis, among baseline demographic and clinical factors, CD4% was the strongest predictor of longer time to rebound based on the log likelihood ratio. In multivariable analysis, longer time to rebound was associated with higher birth weight, baseline CD4% and viral suppression within 40 weeks of ART start (Table). There was no evidence of significant effect of gender, baseline VL and CD8%, CDC stage, PMTCT, age at ART initiation (6-12weeks) and length of therapy (arm) or site. Sensitivity analyses produced similar results.
Most children rebounded by 13 months while one remained suppressed until the end of follow up. Age at ART initiation ranging from 6 to 12 weeks and length of therapy were not associated with longer time to rebound. Our findings may inform the design of clinical trials involving analytic treatment interruption in paediatric HIV.
2018
Authors: Cameron M, Rinaldi S, Richardson B, Cotugno N, Williams S, Pallikkuth S, de Armas LR, Cameron C, Pahwa R, Palma P, Pahwa S
Published: 25th Conference on Retroviruses and Opportunistic Infections, March 4th – 7th, 2018 – Boston. P_868
Abstract The study explores the impact of early ART on host immune response looking at HIV-specific CD4 T cell functionality and host transcriptome analysis.
2018
Authors: Chan M, Tagarro A, Zangari P, Ferns B, Foster C, De Rossi A, Nastouli E, Ángeles Muñoz-Fernández M, Gibb D, Rossi P, Giaquinto C, Babiker A , Palma P, Rojo Conejo P
Published: 25th Conference on Retroviruses and Opportunistic Infections, March 4th – 7th, 2018 – Boston. P_ 866
Abstract The study focused on the determinants of low viral reservoir in a large cohort of European early treated HIV-1 infected children. Timing of cArt initiation and timing spent on effective ART are main factors associated with low HIV-DNA
2018
Authors: Bollen P, Colbers A, Schalkwijk S, Velthoven-Graafland K, Konopnicki D, Weizsacker K, Hidalgo Tenorio C, van Crevel R, Burger D, on behalf of the PANNA network
Published: Oral presentation at 19th edition of the International Workshop on Clinical Pharmacology of Antiviral Therapy, May 22nd-24th 2018, Baltimore
2018
Authors: Colbers A, Schalkwijk S, Konopnicki D, Rockstroh J, Burger D, on behalf of the PANNA network
Published: Oral presentation at 19th edition of the International Workshop on Clinical Pharmacology of Antiviral Therapy, May 22nd-24th 2018, Baltimore.
2018
Authors: Rocca S, Zangari P, Cotugno N, et al.
Published in: J Pediatric Infect Dis Soc.2018; 28. doi:10
Background Assays to estimate human immunodeficiency virus (HIV) reservoir size require large amounts of blood, which represents a drawback especially in pediatric settings. We investigated whether HIV-antibody repertoire could estimate the viral reservoir size. Moreover, we assessed the magnitude of HIV-antibody response as a predictor of time of antiretroviral therapy (ART) initiation.
Methods Human immunodeficiency virus-antibody responses to 10 different viral proteins were evaluated by HIV Western blot (WB) kit and a WB score was assigned to each patient. Patients were classified in 2 subgroups based on the timing of ART initiation (early treated [ET], 0–24 weeks and late treated [LT], >24 weeks). Human immunodeficiency virus-deoxyribonucleic acid (DNA) was quantified using real-time quantitative polymerase chain reaction on total peripheral blood mononuclear cells. Logistic regression and principal component analysis were built on these data to test the ability of WB score to predict the expected value of HIV-DNA and the timing of ART initiation.
Results Sixty-nine perinatally HIV-infected children were evaluated. Reduced HIV-specific antibody responses and lower size of HIV-DNA were observed in ET compared with LT patients (P < .001 and P = .02, respectively). We found that WB score correlates with HIV-DNA (P = .032) and timing of ART initiation (P < .001). Based on the logistic regression analysis, we found that WB score can predict the HIV-DNA size and the timing of ART initiation with an Akaike information criterion of −118.13 and −151.51, respectively.
Conclusions Western blot score can estimate HIV-DNA size and timing of ART initiation in long-term virally suppressed children. This rapid, inexpensive, and easily reproducible tool can provide useful information to identify potential candidates for HIV remission studies.
2018
Authors: Cotugno N, Morrocchi E, Pepponi I, Rocca S, Cameron M, Rinaldi S, Di Cesare S, Pallikkuth S, Bernardi S, Klein N, Ananworanich J, Rossi P, Pahwa S, Palma P
Published: 25th Conference on Retroviruses and Opportunistic Infections, March 4th – 7th, 2018 – Boston. P_ 866
Abstract This fascinating study investigates whether HIV specific B cells persist in seronegative HIV infected seronegative patients and what are the associated gene signatures after re-encountering the virus.
2018
Authors: Tagarro A, Chan M, Zangari P, et al; on behalf of the EPIICAL Consortium
Published in: J Acquir Immune Defic Syndr. 2018;79(2):269-276
Background Future strategies aiming to achieve HIV-1 remission are likely to target individuals with small reservoir size.
Setting We retrospectively investigated factors associated with HIV-1 DNA levels in European, perinatally HIV-infected children starting ART <6 months of age.
Methods Total HIV-1 DNA was measured from 51 long-term suppressed children 6.3 years (median) after initial viral suppression. Factors associated with log10 total HIV-1 DNA were analyzed using linear regression.
Results At ART initiation, children were aged median [IQR] 2.3 [1.2,4.1] months, CD4% 37 [24,45] %, CD8% 28 [18,36] %, log10 plasma viral load (VL) 5.4 [4.4,5.9] copies/ml. Time to viral suppression was 7.98 [4.6,19.3] months. Following suppression, 13 (25%) children had suboptimal response [≥2 consecutive VL50-400 followed by VL<50] and/or experienced periods of virological failure [≥2 consecutive VL≥400 followed by VL<50]. Median total HIV-1 DNA was 43 [6,195] copies/106 PBMC. Younger age at therapy initiation was associated with lower total HIV-1 DNA (adjusted coefficient [AC] 0.12 per month older, p=0.0091), with a month increase in age at ART start being associated with a 13% increase in HIV DNA. Similarly, a higher proportion of time spent virally suppressed (AC 0.10 per 10% higher, p=0.0022) and absence of viral failure/suboptimal response (AC 0.34 for those with fail/ suboptimal response, p=0.0483) were associated with lower total HIV-1 DNA.
Conclusion Early ART initiation and a higher proportion of time suppressed are linked with lower total HIV-1 DNA. Early ART start and improving adherence in perinatally HIV-1 infected children minimize the size of viral reservoir.
2018
Authors: Judd A, Chappell E, Turkova A; for European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) Study Group in EuroCoord.
Published in: PLoS Med. 2018;15(1): e1002491
Background Published estimates of mortality and progression to AIDS as children with HIV approach adulthood are limited. We describe rates and risk factors for death and AIDS-defining events in children and adolescents after initiation of combination antiretroviral therapy (cART) in 17 middle- and high-income countries, including some in Western and Central Europe (W&CE), Eastern Europe (Russia and Ukraine), and Thailand.
Methods and Findings Children with perinatal HIV aged <18 years initiating cART were followed until their 21st birthday, transfer to adult care, death, loss to follow-up, or last visit up until 31 December 2013. Rates of death and first AIDS-defining events were calculated. Baseline and time-updated risk factors for early/late (≤/>6 months of cART) death and progression to AIDS were assessed. Of 3,526 children included, 32% were from the United Kingdom or Ireland, 30% from elsewhere in W&CE, 18% from Russia or Ukraine, and 20% from Thailand. At cART initiation, median age was 5.2 (IQR 1.4–9.3) years; 35% of children aged <5 years had a CD4 lymphocyte percentage <15% in 1997–2003, which fell to 15% of children in 2011 onwards (p < 0.001). Similarly, 53% and 18% of children ≥5 years had a CD4 count <200 cells/mm3 in 1997–2003 and in 2011 onwards, respectively (p < 0.001). Median follow-up was 5.6 (2.9–8.7) years. Of 94 deaths and 237 first AIDS-defining events, 43 (46%) and 100 (42%) were within 6 months of initiating cART, respectively. Multivariable predictors of early death were: being in the first year of life; residence in Russia, Ukraine, or Thailand; AIDS at cART start; initiating cART on a nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimen; severe immune suppression; and low BMI-for-age z-score. Current severe immune suppression, low current BMI-for-age z-score, and current viral load >400 c/mL predicted late death. Predictors of early and late progression to AIDS were similar. Study limitations include incomplete recording of US Centers for Disease Control (CDC) disease stage B events and serious adverse events in some countries; events that were distributed over a long time period, and that we lacked power to analyse trends in patterns and causes of death over time.
Conclusions In our study, 3,526 children and adolescents with perinatal HIV infection initiated antiretroviral therapy (ART) in countries in Europe and Thailand. We observed that over 40% of deaths occurred ≤6 months after cART initiation. Greater early mortality risk in infants, as compared to older children, and in Russia, Ukraine, or Thailand as compared to W&CE, raises concern. Current severe immune suppression, being underweight, and unsuppressed viral load were associated with a higher risk of death at >6 months after initiation of cART.
2018
Authors: IeDEA and COHERE Cohort Collaborations.
Published in: Clin Infect Dis. 2018;66(6):893-903.
Background Early initiation of combination antiretroviral therapy (cART), at higher CD4 cell counts, prevents disease progression and reduces sexual transmission of human immunodeficiency virus (HIV). We describe the temporal trends in CD4 cell counts at the start of cART in adults from low-income, lower-middle-income, upper-middle-income, and high-income countries (LICs, LMICs, UMICs, and HICs, respectively).
Methods We included HIV-infected individuals aged ≥16 years who started cART between 2002 and 2015 in a clinic participating in the International epidemiology Databases to Evaluate AIDS (IeDEA) or the Collaboration of Observational HIV Epidemiological Research in Europe (COHERE). Missing CD4 cell counts at the start of cART were estimated through multiple imputation. Weighted mixed-effect models were used to smooth trends in median CD4 cell counts.
Results A total of 951855 adults from 16 LICs, 11 LMICs, 9 UMICs, and 19 HICs were included. Overall, the modeled median CD4 cell count at the start of cART increased from 2002 to 2015, from 78/µL (95% confidence interval, 58–104/µL) to 287/µL (250–328/µL) in LICs, from 99/µL (71–140/µL) to 234/µL (192–285/µL) in LMICs, from 71/µL (49–104/µL) to 311/µL (255–379/µL) in UMICs, and from 161/µL (143–181/µL) to 327/µL (286–372/µL) in HICs. In LICs, LMICs, and UMICs, the increase was more pronounced in women; in HICs, the opposite was observed.
Conclusions Median CD4 cell counts at the start of cART increased in all income groups, but generally remained below 350/μL in 2015. Substantial additional efforts and resources are required to achieve earlier diagnosis, linkage to care, and initiation of cART.
2018
Authors: Germovesk E, Lutsar I, Kipepr K, et al.; for NeoMero Consortium
Published in: J Antimicrob Chemother. 2018;73(7):1908-1916
Background Sepsis and bacterial meningitis are major causes of mortality and morbidity in neonates and infants. Meropenem a broad-spectrum antibiotic, is not licensed for use in neonates and infants below 3 months of age and sufficient information on its plasma and CSF disposition and dosing in neonates and infants is lacking.
Objectives To determine plasma and CSF pharmacokinetics of meropenem in neonates and young infants and the link between pharmacokinetics and clinical outcomes in babies with late-onset sepsis (LOS).
Methods Data were collected in two recently conducted studies, i.e. Neo-Mero-1 (neonatal LOS) and Neo-Mero-2 (neonatal meningitis). Optimally timed plasma samples (n = 401) from 167 patients and opportunistic CSF samples (n = 78) from 56 patients were analysed.
Results A one-compartment model with allometric scaling and fixed maturation gave adequate fit to both plasma and CSF data; the CL and volume (standardized to 70 kg) were 16.7 (95% CI 14.7, 18.9) L/h and 38.6 (95% CI 34.9, 43.4) L, respectively. CSF penetration was low (8%), but rose with increasing CSF protein, with 40% penetration predicted at a protein concentration of 6 g/L. Increased infusion time improved plasma target attainment, but lowered CSF concentrations. For 24 patients with culture-proven Gram-negative LOS, pharmacodynamic target attainment was similar regardless of the test-of-cure visit outcome.
Conclusions Simulations showed that longer infusions increase plasma PTA but decrease CSF PTA. CSF penetration is worsened with long infusions so increasing dose frequency to achieve therapeutic targets should be considered.
2018
Authors: Tacconelli E, Sifakis F, Harbarth S, et al; for EPI-Net COMBACTE-MAGNET Group
Published in: Lancet Infect Dis. 2018;18(3):e99-e106.
Abstract Antimicrobial resistance poses a growing threat to public health and the provision of health care. Its surveillance should provide up-to-date and relevant information to monitor the appropriateness of therapy guidelines, antibiotic formulary, antibiotic stewardship programmes, public health interventions, infection control policies, and antimicrobial development. In Europe, although the European Antimicrobial Resistance Surveillance Network provides annual reports on monitored resistant bacteria, national surveillance efforts are still fragmented and heterogeneous, and have substantial structural problems and issues with laboratory data. Most incidence and prevalence data cannot be linked with relevant epidemiological, clinical, or outcome data. Genetic typing, to establish whether trends of antimicrobial resistance are caused by spread of resistant strains or by transfer of resistance determinants among different strains and species, is not routinely done. Furthermore, laboratory-based surveillance using only clinical samples is not likely to be useful as an early warning system for emerging pathogens and resistance mechanisms. Insufficient coordination of surveillance systems of human antimicrobial resistance with animal surveillance systems is even more concerning. Because results from food surveillance are considered commercially sensitive, they are rarely released publicly by regulators. Inaccurate or incomplete surveillance data delay a translational approach to the threat of antimicrobial resistance and inhibit the identification of relevant target microorganisms and populations for research and the revitalisation of dormant drug-discovery programmes. High-quality, comprehensive, and real-time surveillance data are essential to reduce the burden of antimicrobial resistance. Improvement of national antimicrobial resistance surveillance systems and better alignment between human and veterinary surveillance systems in Europe must become a scientific and political priority, coordinated with international stakeholders within a global approach to reduce the burden of antimicrobial resistance.
2018
Authors: Donà D, Zingarella S, Gastaldi A, et al.
Published in: PLoS One. 2018;13(2):e0193581.
Background Italian pediatric antimicrobial prescription rates are among the highest in Europe. As a first step in an Antimicrobial Stewardship Program, we implemented a Clinical Pathway (CP) for Community Acquired Pneumonia with the aim of decreasing overall prescription of antibiotics, especially broad-spectrum.
Materials and Methods The CP was implemented on 10/01/2015. We collected antibiotic prescribing and outcomes data from children aged 3 months-15 years diagnosed with CAP from 10/15/2014 to 04/15/2015 (pre-intervention period) and from 10/15/2015 to 04/15/2016 (post-intervention period). We assessed antibiotic prescription differences pre- and post-CP, including rates, breadth of spectrum, and duration of therapy. We also compared length of hospital stay for inpatients and treatment failure for inpatients and outpatients. Chi-square and Fisher’s exact test were used to compare categorical variables and Wilcoxon rank sum test was used to compare quantitative outcomes.
Results 120 pre- and 86 post-intervention clinic visits were identified with a diagnosis of CAP. In outpatients, we observed a decrease in broad-spectrum regimens (50% pre-CP vs. 26.8% post-CP, p = 0.02), in particular macrolides, and an increase in narrow-spectrum (amoxicillin) post-CP. Post-CP children received fewer antibiotic courses (median DOT from 10 pre-CP to 8 post-CP, p<0.0001) for fewer days (median LOT from 10 pre-CP to 8 post-CP, p<0.0001) than their pre-CP counterparts. Physicians prescribed narrow-spectrum monotherapy more frequently than broad-spectrum combination therapy (DOT/LOT ratio 1.157 pre-CP vs. 1.065 post-CP). No difference in treatment failure was reported before and after implementation (2.3% pre-CP vs. 11.8% post-CP, p = 0.29). Among inpatients we also noted a decrease in broad-spectrum regimens (100% pre-CP vs. 66.7% post-CP, p = 0.02) and the introduction of narrow-spectrum regimens (0% pre-CP vs. 33.3% post-CP, p = 0.02) post-CP. Hospitalized patients received fewer antibiotic courses post-CP (median DOT from 18.5 pre-CP to 10 post-CP, p = 0.004), while there was no statistical difference in length of therapy (median LOT from 11 pre-CP to 10 post-CP, p = 0.06). Days of broad spectrum therapy were notably lower post-CP (median bsDOT from 17 pre-CP to 4.5 post-CP, p <0.0001). No difference in treatment failure was reported before and after CP implementation (16.7% pre-CP vs. 15.4% post-CP, p = 1).
Conclusions Introduction of a CP for CAP in a Pediatric Emergency Department led to reduction of broad-spectrum antibiotic prescriptions, of combination therapy and of duration of treatment both for outpatients and inpatients.
2018
Authors: Chiappini E, Galli L, Lisi C, et al.
Published in: J Acquir Immune Defic Syndr. 2018;79(1):54-61.
Background Strategies for prevention of HIV-1 mother-to-child transmission (PMTCT) have been continuously optimized. However, cases of vertical transmission continue to occur in high-income countries.
Objectives To investigate changes in PMTCT strategies adopted by Italian clinicians over time and to evaluate risk factors for transmission.
Methods Data from mother-child pairs prospectively collected by the Italian Register, born in Italy in 1996-2016, were analyzed. Risk factors for MTCT were explored by logistic regression analyses.
Results Six thousand five hundred three children (348 infections) were included. In our cohort, the proportion of children born to foreign mothers increased from 18.3% (563/3078) in 1996%-2003% to 66.2% (559/857) in 2011-2016 (P < 0.0001). Combination neonatal prophylaxis use significantly (P < 0.0001) increased over time, reaching 6.3% (56/857) after 2010, and it was largely (4.2%) adopted in early preterm infants. The proportion of vaginal deliveries in women with undetectable viral load (VL) increased over time and was 9.9% (85/857) in 2011-2016; no infection occurred among them. In children followed up since birth MTCT, rate was 3.5% (96/2783) in 1996-2003; 1.4% (36/2480) in 2004-2010; and 1.1% (9/835) in 2011-2016. At a multivariate analysis, factors associated with MTCT were vaginal delivery with detectable or missing VL or nonelective caesarean delivery, prematurity, breastfeeding, lack of maternal or neonatal antiretroviral therapy, detectable maternal VL, and age at first observation. Previously described increased risk of offspring of immigrant women was not confirmed.
Conclusions Risk of MTCT in Italy is ongoing, even in recent years, underling the need for implementation of the current screening program in pregnancy. Large combination neonatal prophylaxis use in preterm infants was observed, even if data on safety and efficacy in prematures are poor.
2018
Authors: Mallewa J, Szubert AJ, Mugyenyi P, et al.
Published in: Lancet HIV. 2018;5(5):e231-e240
Background In sub-Saharan Africa, severely immunocompromised HIV-infected individuals have a high risk of mortality during the first few months after starting antiretroviral therapy (ART). We hypothesise that universally providing ready-to-use supplementary food (RUSF) would increase early weight gain, thereby reducing early mortality compared with current guidelines recommending ready-to-use therapeutic food (RUTF) for severely malnourished individuals only.
Methods We did a 2 × 2 × 2 factorial, open-label, parallel-group trial at inpatient and outpatient facilities in eight urban or periurban regional hospitals in Kenya, Malawi, Uganda, and Zimbabwe. Eligible participants were ART-naive adults and children aged at least 5 years with confirmed HIV infection and a CD4 cell count of fewer than 100 cells per μL, who were initiating ART at the facilities. We randomly assigned participants (1:1) to initiate ART either with (RUSF) or without (no-RUSF) 12 weeks’ of peanut-based RUSF containing 1000 kcal per day and micronutrients, given as two 92 g packets per day for adults and one packet (500 kcal per day) for children aged 5-12 years, regardless of nutritional status. In both groups, individuals received supplementation with RUTF only when severely malnourished (ie, body-mass index [BMI] <16-18 kg/m2 or BMI-for-age Z scores <-3 for children). We did the randomisation with computer-generated, sequentially numbered tables with different block sizes incorporated within an online database. Randomisation was stratified by centre, age, and two other factorial randomisations, to 12 week adjunctive raltegravir and enhanced anti-infection prophylaxis (reported elsewhere). Clinic visits were scheduled at weeks 2, 4, 8, 12, 18, 24, 36, and 48, and included nurse assessment of vital status and symptoms and dispensing of all medication including ART and RUSF. The primary outcome was mortality at week 24, analysed by intention to treat. Secondary outcomes included absolute changes in weight, BMI, and mid-upper-arm circumference (MUAC). Safety was analysed in all randomly assigned participants. Follow-up was 48 weeks. This trial is registered with ClinicalTrials.gov (NCT01825031) and the ISRCTN registry (43622374).
Findings Between June 18, 2013, and April 10, 2015, we randomly assigned 1805 participants to treatment: 897 to RUSF and 908 to no-RUSF. 56 (3%) were lost-to-follow-up. 96 (10·9%, 95% CI 9·0-13·1) participants allocated to RUSF and 92 (10·3%, 8·5-12·5) to no-RUSF died within 24 weeks (hazard ratio 1·05, 95% CI 0·79-1·40; log-rank p=0·75), with no evidence of interaction with the other randomisations (both p>0·7). Through 48 weeks, adults and adolescents aged 13 years and older in the RUSF group had significantly greater gains in weight, BMI, and MUAC than the no-RUSF group (p=0·004, 0·004, and 0·03, respectively). The most common type of serious adverse event was specific infections, occurring in 90 (10%) of 897 participants assigned RUSF and 87 (10%) of 908 assigned no-RUSF. By week 48, 205 participants had serious adverse events in both groups (p=0·81), and 181 had grade 4 adverse events in the RUSF group compared with 172 in the non-RUSF group (p=0·45).
Interpretation In severely immunocompromised HIV-infected individuals, providing RUSF universally at ART initiation, compared with providing RUTF to severely malnourished individuals only, improved short-term weight gain but not mortality. A change in policy to provide nutritional supplementation to all severely immunocompromised HIV-infected individuals starting ART is therefore not warranted at present.
Funding Joint Global Health Trials Scheme (UK Medical Research Council, UK Department for International Development, and Wellcome Trust).
2018
Authors: Kityo C, Szubert AJ, Siika A, et al.
Published in: PLoS Med. 2018; 15(12):e1002706
Background In sub-Saharan Africa, individuals infected with HIV who are severely immunocompromised have high mortality (about 10%) shortly after starting antiretroviral therapy (ART). This group also has the greatest risk of morbidity and mortality associated with immune reconstitution inflammatory syndrome (IRIS), a paradoxical response to successful ART. Integrase inhibitors lead to significantly more rapid declines in HIV viral load (VL) than all other ART classes. We hypothesised that intensifying standard triple-drug ART with the integrase inhibitor, raltegravir, would reduce HIV VL faster and hence reduce early mortality, although this strategy could also risk more IRIS events.
Methods and findings In a 2×2×2 factorial open-label parallel-group trial, treatment-naive adults, adolescents, and children >5 years old infected with HIV, with cluster of differentiation 4 (CD4) <100 cells/mm3, from eight urban/peri-urban HIV clinics at regional hospitals in Kenya, Malawi, Uganda, and Zimbabwe were randomised 1:1 to initiate standard triple-drug ART, with or without 12-week raltegravir intensification, and followed for 48 weeks. The primary outcome was 24-week mortality, analysed by intention to treat. Of 2,356 individuals screened for eligibility, 1,805 were randomised between 18 June 2013 and 10 April 2015. Of the 1,805 participants, 961 (53.2%) were male, 72 (4.0%) were children/adolescents, median age was 36 years, CD4 count was 37 cells/mm3, and plasma viraemia was 249,770 copies/mL. Fifty-six participants (3.1%) were lost to follow-up at 48 weeks. By 24 weeks, 97/902 (10.9%) raltegravir-intensified ART versus 91/903 (10.2%) standard ART participants had died (adjusted hazard ratio [aHR] = 1.10 [95% CI 0.82-1.46], p = 0.53), with no evidence of interaction with other randomisations (pheterogeneity > 0.7) and despite significantly greater VL suppression with raltegravir-intensified ART at 4 weeks (343/836 [41.0%] versus 113/841 [13.4%] with standard ART, p < 0.001) and 12 weeks (567/789 [71.9%] versus 415/803 [51.7%] with standard ART, p < 0.001). Through 48 weeks, there was no evidence of differences in mortality (aHR = 0.98 [95% CI 0.76-1.28], p = 0.91); in serious (aHR = 0.99 [0.81-1.21], p = 0.88), grade-4 (aHR = 0.88 [0.71-1.09], p = 0.29), or ART-modifying (aHR = 0.90 [0.63-1.27], p = 0.54) adverse events (the latter occurring in 59 [6.5%] participants with raltegravir-intensified ART versus 66 [7.3%] with standard ART); in events judged compatible with IRIS (occurring in 89 [9.9%] participants with raltegravir-intensified ART versus 86 [9.5%] with standard ART, p = 0.79) or in hospitalisations (aHR = 0.94 [95% CI 0.76-1.17], p = 0.59). At 12 weeks, one and two raltegravir-intensified participants had predicted intermediate-level and high-level raltegravir resistance, respectively. At 48 weeks, the nucleoside reverse transcriptase inhibitor (NRTI) mutation K219E/Q (p = 0.004) and the non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations K101E/P (p = 0.03) and P225H (p = 0.007) were less common in virus from participants with raltegravir-intensified ART, with weak evidence of less intermediate- or high-level resistance to tenofovir (p = 0.06), abacavir (p = 0.08), and rilpivirine (p = 0.07). Limitations of the study include limited clinical, radiological, and/or microbiological information for some participants, reflecting available services at the centres, and lack of baseline genotypes.
Conclusions Although 12 weeks of raltegravir intensification was well tolerated and reduced HIV viraemia significantly faster than standard triple-drug ART during the time of greatest risk for early death, this strategy did not reduce mortality or clinical events in this group and is not warranted. There was no excess of IRIS-compatible events, suggesting that integrase inhibitors can be used safely as part of standard triple-drug first-line therapy in severely immunocompromised individuals.
2018
Authors: Post FA, Szubert AJ, Prendergast AJ, et al; for Reduction of early mortality in HIV-infected adults and children starting an antiretroviral therapy (REALITY) trial team
Published in: Clin Infect Dis. 2018;66(2):S132-S139
Background In sub-Saharan Africa, 20%-25% of people starting antiretroviral therapy (ART) have severe immunosuppression; approximately 10% die within 3 months. In the Reduction of EArly mortaLITY (REALITY) randomized trial, a broad enhanced anti-infection prophylaxis bundle reduced mortality vs cotrimoxazole. We investigate the contribution and timing of different causes of mortality/morbidity.
Methods Participants started ART with a CD4 count <100 cells/µL; enhanced prophylaxis comprised cotrimoxazole plus 12 weeks of isoniazid + fluconazole, single-dose albendazole, and 5 days of azithromycin. A blinded committee adjudicated events and causes of death as (non-mutually exclusively) tuberculosis, cryptococcosis, severe bacterial infection (SBI), other potentially azithromycin-responsive infections, other events, and unknown.
Results Median pre-ART CD4 count was 37 cells/µL. Among 1805 participants, 225 (12.7%) died by week 48. Fatal/nonfatal events occurred early (median 4 weeks); rates then declined exponentially. One hundred fifty-four deaths had single and 71 had multiple causes, including tuberculosis in 4.5% participants, cryptococcosis in 1.1%, SBI in 1.9%, other potentially azithromycin-responsive infections in 1.3%, other events in 3.6%, and unknown in 5.0%. Enhanced prophylaxis reduced deaths from cryptococcosis and unknown causes (P < .05) but not tuberculosis, SBI, potentially azithromycin-responsive infections, or other causes (P > .3); and reduced nonfatal/fatal tuberculosis and cryptococcosis (P < .05), but not SBI, other potentially azithromycin-responsive infections, or other events (P > .2).
Conclusions Enhanced prophylaxis reduced mortality from cryptococcosis and unknown causes and nonfatal tuberculosis and cryptococcosis. High early incidence of fatal/nonfatal events highlights the need for starting enhanced-prophylaxis with ART in advanced disease.
2018
Authors: Siika A, McCabe L, Bwakura-Dangarembizi M, et al; for REALITY Trial Team
Published in: Clin Infect Dis. 2018;66(2):S140-S146
Background Severely immunocompromised human immunodeficiency virus (HIV)–infected individuals have high mortality shortly after starting antiretroviral therapy (ART). We investigated predictors of early mortality and “late presenter” phenotypes.
Methods The Reduction of EArly MortaLITY (REALITY) trial enrolled ART-naive adults and children ≥5 years of age with CD4 counts <100 cells/μL initiating ART in Uganda, Zimbabwe, Malawi, and Kenya. Baseline predictors of mortality through 48 weeks were identified using Cox regression with backwards elimination (exit P > .1).
Results Among 1711 included participants, 203 (12%) died. Mortality was independently higher with older age; lower CD4 count, albumin, hemoglobin, and grip strength; presence of World Health Organization stage 3/4 weight loss, fever, or vomiting; and problems with mobility or self-care at baseline (all P < .04). Receiving enhanced antimicrobial prophylaxis independently reduced mortality (P = .02). Of five late-presenter phenotypes, Group 1 (n = 355) had highest mortality (25%; median CD4 count, 28 cells/ μL), with high symptom burden, weight loss, poor mobility, and low albumin and hemoglobin. Group 2 (n = 394; 11% mortality; 43 cells/μL) also had weight loss, with high white cell, platelet, and neutrophil counts suggesting underlying inflammation/infec- tion. Group 3 (n = 218; 10% mortality) had low CD4 counts (27 cells/μL), but low symptom burden and maintained fat mass. The remaining groups had 4%–6% mortality.
Conclusions Clinical and laboratory features identified groups with highest mortality following ART initiation. A screening tool could identify patients with low CD4 counts for prioritizing same-day ART initiation, enhanced prophylaxis, and intensive follow-up.
2018
Authors: Favarato G, Bailey H, Burns F, et al.
Published in: Eur J Public Health. 2018;28(1):55-60
2018
Authors: European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) Study Group in EuroCoord.
Published in: Clin Infect Dis. 2018;66(4):594-603.
Background Global data on durability of first-line antiretroviral therapy (ART) in children with HIV is limited. We assessed time to switch to second-line therapy in 16 European countries and Thailand.
Methods Children <18-years initiating combination ART (≥2 nucleoside reverse transcriptase inhibitor (NRTI) plus non-NRTI (NNRTI) or boosted-protease inhibitor (PI)) were included. Switch to second-line was defined as: (i) change across drug class (PI to NNRTI or vice versa) or within PI-class plus change of ≥1 NRTI; (ii) change from single to dual PI; or (iii) addition of a new drug class. Cumulative incidence of switch was calculated with death and loss-to-follow-up as competing risks.
Results Of 3,668 children included, median [IQR] age at ART initiation was 6.1 [1.7,10.5] years. Initial regimens were 32% PI, 34% nevirapine (NVP), 33% efavirenz-based. Median duration of follow-up from ART start was 5.4 [2.9,8.3] years. Cumulative incidence of switch at 5 years was 21% (95% CI 20, 23), with lowest incidence in Russia/Ukraine and highest in UK/Ireland. Median time to switch was 30 [15, 58] months, two-thirds of switches were related to treatment failure. In multivariable analysis, older age, severe immunosuppression and higher viral load at ART start, and NVP-based initial regimens were associated with increased risk of switch. Among those switched, 65% had viral load <400c/mL at 12-months after start of second-line ART.
Conclusions One in five children switched to second-line by 5 years of ART, with two-thirds failure related. Advanced HIV, older age and NVP-based regimens were associated with increased risk of switch.
2018
Authors: Soriano-Arandes A, Rivero-Calle I, Nastouli E, et al.
Published in: Expert Rev Anti Infect Ther. 2018;16(3):243-254
Introduction: Zika virus (ZIKV) infection has caused the most challenging worldwide infectious epidemic outbreak in recent months. ZIKV causes microcephaly and other congenital malformations. There is a need to perform updated systematic reviews on ZIKV infection periodically because this epidemic is bringing up new evidence with extraordinary speed.
Areas covered: Evidence related to ZIKV infection in the gestational, perinatal, and early infant periods covering epidemiology, virology, pathogenesis, risk factors, time of infection during pregnancy, newborn symptoms, treatment, and vaccines. To this end, a search was performed using terms [‘Zika’] AND [‘Perinatal Infection’] OR [‘Congenital Infection’] in the PubMed® international electronic database. Out of a total of 1,538 articles published until 30 November 2017, we finally assessed 106 articles articles that were relevant to the research areas included in this study.
Expert commentary: ZIKV is a new teratogenic/neurotropic virus affecting fetuses. Many challenges are still far from being solved regarding the epidemiology, case definition, clinical and laboratory diagnosis, and preventive measures. An approach using ‘omics’ and new biomarkers for diagnosis, and a ZIKV-vaccine for treatment, might finally give us the tools to solve these challenges.
2018
Authors: Zangari P, Palma P, Cotugno N, et al.
Published in: J Virus Erad.2018;4: 51–54
Abstract: The first EPIICAL General Assembly meeting was held in an atmosphere of growing optimism. Many novel and exciting proposals for HIV research studies were discussed and are described above. The consortium aims to maintain this integrated developmental research on NDMTs, from predictive platforms to proof-of-concept studies, through the excellent collaborative effort made during the first 18 months of EPIICAL, some of which is described in this report. The emphasis on an innovative research platform is unique and may lead to optimisation of the management of perinatally HIV-infected children. Collectively, the updates and the discussions from the General Assembly attest to the benefit of nurturing an international collaborative effort on paediatric HIV research and confirm that EPIICAL is successfully on track.
2017
Authors: Rinaldi S, Cotugno N, Pallikkuth S, Palma P, Pahwa S; on behalf of the EPIICAL Consortium
Published: 8th Conference on HIV Persistence
Background Early initiation of antiretroviral therapy (ART) in vertically HIV-infected children provides an opportunity to limit the size of reservoir, but whether and how the time of ART treatment initiation can durably impact host immune responses associated with HIV infection is still unknown. In this study, we analyzed HIV-specific CD4 T cell functionality in vertically HIV-infected children in whom ART was initiated early or late after birth.
2017
Authors: Luck SE, Wieringa JW, Blazquez-Gamero D, et al.
Published in: Pediatr Infect Dis J. 2017;36(12):1205-1213
2017
Authors: European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) study group in EuroCoord.
Published in: Eur J Clin Pharmacol. 2017;73(4):463-468
Background Zidovudine (ZDV) has been associated with risk of haematological toxicity. Safety data from clinical trials is generally limited to 48 weeks. We assessed the short- and mid-term toxicity of ZDV/lamivudine (3TC) fixed-dose combination scored tablets in HIV-infected children followed in the European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) network.
Methods Fourteen cohorts provided data on patients <18 years of age taking ZDV/3TC scored tablets between 2008 and 2012. Rates of Division of AIDS (DAIDS) grade ≥3 laboratory adverse events (AEs) for hepatobiliary and haematological disorders were estimated by duration on drug (<12, 12–24, >24 months). Clinical adverse events and reasons for tablet discontinuation were described.
Results Of 541 patients on ZDV/3TC, 388 (72%) had weight and dose data available, of whom 350 (90%) weighed ≥14 kg and were eligible for tablet use; 161 (41%) were aged <10 years on an approved dose, 189 (49%) aged ≥10 years on an approved dose, and 30 (8%) were on an unapproved dose. Median age at ZDV/3TC start was 10 years, and 79% had taken ART previously (60% had prior exposure to ZDV/3TC). Overall rates of grade ≥3 AEs for absolute neutrophil counts, bilirubin, haemoglobin, platelet counts, white blood cell counts (WBC), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were ≤2/100 person years (PY) for patients taking approved doses. Two hundred thirty-three (43%) patients were not on ZDV/3TC tablets at most recent follow-up; a small number (17 (7%)) discontinued due to AEs (17 (7%)), and the most common reason for discontinuation was treatment simplification (73 (31%)).
Conclusions Scored ZDV/3TC tablets, both approved and taken off-label, appear to be well tolerated with few side effects. Few patients discontinued treatment due to toxicity. As ZDV/3TC tablets are taken with other antiretrovirals, it is difficult to infer association between toxicities and specific agents, highlighting the importance of widening long-term pharmacovigilance to a broader spectrum of drug combinations.
2017
Authors: Bernays S, Paparini S, Seeley J, Namukwaya Kihika S, Gibb D, Rhodes T.
Published in: BMJ Open. 2017;7(2):e012934
Objectives A qualitative study of the BREATHER (PENTA 16) randomised clinical trial, which compared virological control of Short Cycle Therapy (SCT) (5 days on: 2 days off) with continuous efavirenz (EFV)-based antiretroviral therapy (CT) in children and young people (aged 8–24) living with HIV with viral load <50 c/mL to examine adaptation, acceptability and experience of SCT to inform intervention development.
Setting Paediatric HIV clinics in the UK (2), Ireland (1), the USA (1) and Uganda (1).
Participants All BREATHER trial participants who were over the age of 10 and aware of their HIV diagnosis were invited to participate. 49 young people from both arms of the BREATHER trial (31 females and 18 males; 40% of the total trial population in the respective sites; age range 11–24) gave additional consent to participate in the qualitative study.
Results Young people from both trial arms had initial concerns about the impact of SCT on their health and adherence, but these decreased over the early months in the trial. Young people randomised to SCT reported preference for SCT compared with CT pre-trial. Attitudes to SCT did not vary greatly by gender or country. Once short-term adaptation challenges were overcome, SCT was positively described as reducing impact of side effects, easing the pressure to carry and remember medication and enabling more weekend social activities. Young people on both arms reported frequent medication side effects and occasional missed doses that they had rarely voiced to clinical staff. Participants liked SCT by trial end but were concerned that peers who had most problems adhering could find SCT disruptive and difficult to manage.
Conclusions To realise the potential of SCT (and mitigate possible risks of longer interruptions), careful dissemination and communication post-trial is needed. SCT should be provided alongside a package of monitoring, support and education over 3 months to allow adaptation.
2017
Authors: Namukwaya S, Paparini S, Seeley J, Bernays S.
Published in: Front Public Health. 2017;5:343.
Abstract: Despite great advances in pediatric HIV care, rates and the extent of full disclosure of HIV status to infected children remain low especially in resource-constrained setting. The World Health Organisation recommends that, by the age of 10-12 years old, children should be made fully aware of their HIV-positive status. However, this awareness is often delayed until much later in their adolescence. Few studies have been conducted to investigate what influences caregivers’ decision-making process in this regard in low-income settings. In this article, we present an analysis of care dyads of caregivers and HIV-positive young people in Kampala, Uganda, as part of the findings of a longitudinal qualitative study about young people’s adherence to antiretroviral therapy embedded in an international clinical trial (BREATHER). Repeat in-depth interviews were conducted with 26 young people living with HIV throughout the course of the trial, and once-off interviews with 16 of their caregivers were also carried out toward the end of the trial. In this article, we examine why and how caregivers decide to disclose a young person’s HIV status to them and explore their feelings and dilemmas toward disclosure, as well as how young people reacted and the influence it had on their relationships with and attitudes toward their caregivers. Caregivers feared the consequences of disclosing the young person’s positive status to them and disclosure commonly occurred hurriedly in response to a crisis, rather than as part of an anticipated and planned process. A key impediment to disclosure was that caregivers feared that disclosing would damage their relationships with the young people and commonly used this as a reason to continue to postpone disclosure. However, young people did not report prolonged feelings of blame or anger toward their caregivers about their own infection, but they did express frustration at the delay and obfuscation surrounding the disclosure process. Our findings can inform the ways in which mainstream HIV services support caregivers through the disclosure process. This includes providing positive encouragement to disclose fully and to be more confident in initiating and sustaining the timely process of disclosure.
2017
Authors: Hakim J, Musiime V, Szubert AJ; REALITY Trial Team
Published in: N Engl J Med. 2017;377(3):233-245
Background In sub-Saharan Africa, among patients with advanced human immunodeficiency virus (HIV) infection, the rate of death from infection (including tuberculosis and cryptococcus) shortly after the initiation of antiretroviral therapy (ART) is approximately 10%.
Methods In this factorial open-label trial conducted in Uganda, Zimbabwe, Malawi, and Kenya, we enrolled HIV-infected adults and children 5 years of age or older who had not received previous ART and were starting ART with a CD4+ count of fewer than 100 cells per cubic millimeter. They underwent simultaneous randomization to receive enhanced antimicrobial prophylaxis or standard prophylaxis, adjunctive raltegravir or no raltegravir, and supplementary food or no supplementary food. Here, we report on the effects of enhanced antimicrobial prophylaxis, which consisted of continuous trimethoprim-sulfamethoxazole plus at least 12 weeks of isoniazid-pyridoxine (coformulated with trimethoprim-sulfamethoxazole in a single fixed-dose combination tablet), 12 weeks of fluconazole, 5 days of azithromycin, and a single dose of albendazole, as compared with standard prophylaxis (trimethoprim-sulfamethoxazole alone). The primary end point was 24-week mortality.
ResultsA total of 1805 patients (1733 adults and 72 children or adolescents) underwent randomization to receive either enhanced prophylaxis (906 patients) or standard prophylaxis (899 patients) and were followed for 48 weeks (loss to follow-up, 3.1%). The median baseline CD4+ count was 37 cells per cubic millimeter, but 854 patients (47.3%) were asymptomatic or mildly symptomatic. In the Kaplan-Meier analysis at 24 weeks, the rate of death with enhanced prophylaxis was lower than that with standard prophylaxis (80 patients [8.9% vs. 108 [12.2%]; hazard ratio, 0.73; 95% confidence interval [CI], 0.55 to 0.98; P=0.03); 98 patients (11.0%) and 127 (14.4%), respectively, had died by 48 weeks (hazard ratio, 0.76; 95% CI, 0.58 to 0.99; P=0.04). Patients in the enhanced-prophylaxis group had significantly lower rates of tuberculosis (P=0.02), cryptococcal infection (P=0.01), oral or esophageal candidiasis (P=0.02), death of unknown cause (P=0.03), and new hospitalization (P=0.03). However, there was no significant between-group difference in the rate of severe bacterial infection (P=0.32). There were nonsignificantly lower rates of serious adverse events and grade 4 adverse events in the enhanced-prophylaxis group (P=0.08 and P=0.09, respectively). Rates of HIV viral suppression and adherence to ART were similar in the two groups.
Conclusions Among HIV-infected patients with advanced immunosuppression, enhanced antimicrobial prophylaxis combined with ART resulted in reduced rates of death at both 24 weeks and 48 weeks without compromising viral suppression or increasing toxic effects.
2017
Authors: Theys K, Libin P, Dallmeier K, et al.
Published in: PLoS Pathog. 2017;13(9):e1006528
In this letter, the authors address the need for curation and standardized annotation of ZIKV reference genomes in order to guide researchers and clinicians in genomic analyses and the translation of research findings.