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Item does not contain fulltext, Safe and effective paediatric formulations of the most promising antiretroviral drugs are crucial to advance the treatment and prevention of HIV in neonates, infants, children, and adolescents. The WHO Paediatric Drug Optimization for HIV (PADO-HIV) group brings together stakeholders and experts every 2-3 years to identify priority products and define research gaps in the development of new HIV drugs and formulations for children in low-income and middle-income countries. PADO-HIV 5 met from Sept 27 to Oct 15, 2021. The group evaluated HIV agents from known and novel drug classes, oral and parenteral long-acting formulations, and developments in broadly neutralising antibodies, and included focused sessions on neonates and new delivery technologies. A list of medium-term and long-term priorities was generated, and research questions were defined. This forward-looking analysis is intended to provide guidance to funders, drug developers, and researchers, and to accelerate access for children to the best HIV drugs and formulations.

Item does not contain fulltext, INTRODUCTION: Historical approaches to clinical development of novel therapeutics for treatment and prevention of HIV have led to unacceptable delays in the generation of data to support optimal antiretroviral drug use in pregnancy. Over the last 5 years, multiple stakeholders have voiced their concerns around the exclusion of pregnant women from drug trials, and some progress has been made to consolidate principles and forge consensus. Building on ongoing efforts, the World Health Organization (WHO) and the International Maternal Paediatric Adolescent AIDS Clinical Trials Network (IMPAACT) convened a technical consultation designed to move the discussion from theory to practice. DISCUSSION: Accelerating the inclusion of pregnant women in pre-licensure clinical trials, with a goal to have pharmacokinetics (PK) and preliminary safety data for all new HIV agents in pregnancy available at the time of drug approval, requires: (1) performing non-clinical developmental and reproductive toxicology studies early in drug development for all new HIV agents; (2) recognizing and acting on the central role of women of childbearing potential affected by HIV through the research being conducted and the dissemination of associated results; (3) enrolling pregnant women in studies to specifically determine pregnancy PK and preliminary safety, as soon as late non-clinical studies are completed with no negative signals, for all new HIV agents that have demonstrated preliminary evidence of safety and efficacy from phase 2 trials; (4) investigating adverse pregnancy and birth outcomes through dedicated pregnancy safety studies for all new priority HIV agents; and (5) expanding active surveillance of drug safety in pregnancy for rare events, such as birth defects. Strategic actions to pursue include developing tools and resources to support designing and implementing studies among pregnant and breastfeeding women, identifying and promoting modifications of the regulatory framework that ar

Item does not contain fulltext, Although 23 antiretroviral drugs are approved for use in adults, only six are approved by regulatory authorities for use in term neonates born to women with HIV, with even fewer options for preterm neonates. A major hurdle for approvals is the delay in the generation of pharmacokinetic and safety data for antiretrovirals in neonates. The median time between the year of approval from the US Food and Drug Administration of an antiretroviral agent for adults and the first publication date for pharmacokinetic data in neonates less than 4 weeks old is 8 years (range 2-23 years). In this Viewpoint, we address pharmacokinetic research gaps and priorities for current and novel antiretroviral use in neonates. We also consider the challenges and provide guidance on neonatal clinical pharmacology research on antiretroviral agents with the goal of stimulating research and expediting the availability of safe medications for the prevention and treatment of HIV in this vulnerable population.

Item does not contain fulltext, BACKGROUND: Concerns have been voiced that the exclusion of pregnant women from clinical trials results in a lack of safety and pharmacokinetic data for antiretroviral drugs (ARVs) in pregnancy, creating clear risks to pregnant women living with HIV (PWLHIV), and their infants. SETTING: The World Health Organization convened a Paediatric Antiretroviral Drug Optimization group meeting, December 10-12, 2018, in Geneva, Switzerland. METHODS: The group, comprised of clinicians, scientists, HIV program managers, regulators, and community representatives, were tasked to consider how ARVs are studied in PWLHIV, define alternative approaches to studying ARVs in PWLHIV, identify ways to shorten the timeline to determine safe use of new agents during pregnancy, and define strategies to collaborate with regulators and industry to change longstanding practices. RESULTS: Most new ARVs are not studied in pregnant populations until after drug licensure, primarily opportunistically among women who become pregnant while taking the ARV of interest. Acceleration of the timeline will require earlier completion of preclinical studies and a new paradigm, namely-under certain conditions-allow women who become pregnant while participating in phase III ARV studies the option of remaining on study and enroll pregnant women into phase III trials of new agents to obtain preliminary safety and dosing and efficacy data. CONCLUSION: A revision of the current approach to the study of antiretrovirals in pregnant women is urgently needed to improve timely access and safe use of new agents during pregnancy.

Contains fulltext : 235789.pdf (Publisher’s version ) (Open Access), Information on the extent of drug exposure to mothers and infants during pregnancy and lactation normally becomes available years after regulatory approval of a drug. Clinicians face knowledge gaps on drug selection and dosing in pregnancy and infant exposure during breastfeeding. Physiological changes during pregnancy often result in lower drug exposures of antiretrovirals, and in some cases a risk of reduced virologic efficacy. The International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) network and the World Health Organization (WHO)-convened Pediatric Antiretrovirals Working Group collaboratively organized a workshop of key stakeholders in June 2019 to define key standards to generate pharmacology data for antiretrovirals to be used among pregnant and lactating women; review the antiretroviral product pipeline; describe key gaps for use in low-income and middle-income countries; and identify opportunities to undertake optimal studies allowing for rapid implementation in the clinical field. We discussed ethical and regulatory principles, systemic approaches to obtaining data for pregnancy pharmacokinetic/pharmacodynamic (PK/PD) studies, control groups, optimal sampling times during pregnancy, and pharmacokinetic parameters to be considered as primary end points in pregnancy PK/PD studies. For lactation studies, the type of milk to collect, ascertainment of maternal adherence, and optimal PK methods to estimate exposure were discussed. Participants strongly recommended completion of preclinical reproductive toxicology studies prior to phase III, to allow study protocols to include pregnant women or to allow women who become pregnant after enrolment to continue in the trial. The meeting concluded by developing an algorithm for design and interpretation of results and noted that recruitment of pregnant and lactating women into clinical trials is critical.

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]