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Introduction: Tenofovir alafenamide (TAF) is approved for paediatric use in fixed-dose combination tablets, but efficacy and safety data in children are limited. We conducted a systematic review on the efficacy/effectiveness and safety of TAF in infants, children and adolescents living with HIV., Methods: We searched MEDLINE, Embase, the Cochrane Library, clinical trial registries, reference lists and relevant conferences to identify literature published January 2009-March 2021. We included clinical trials and observational studies assessing the efficacy/effectiveness or safety of TAF through ≥6 months of treatment in participants aged 0-19 years., Results and Discussion: Overall 3626 abstracts and 371 full papers were screened. Four single-arm, innovator-funded trials (341 participants) and a pooled analysis of those trials were identified. All four trials included treatment-experienced and virally suppressed children or adolescents. One trial also included treatment-naïve adolescents with baseline viral load >1000 copies/ml. The risk of bias was rated as low in one study and unclear in the other three owing to missing data on study design (all conference presentations). At 48 weeks, 92% (46/50) of treatment-naïve participants were virally suppressed (one trial). Among treatment-experienced participants with viral load at 48 weeks, 214 of 224 participants were virally suppressed. Across the studies, one grade 3/4 adverse event was considered drug-related (intermediate uveitis). There were three discontinuations for adverse events (grade 2 anxiety and insomnia, grade 1 iridocyclitis [drug-related] and grade 1 pulmonary tuberculosis [unrelated to treatment]). One accidental death occurred across the four studies. In the pooled analysis of 223 participants, the median change in bone mineral density z-score (height- and age-adjusted) from baseline to 48 weeks was -0.12 (interquartile range [IQR] -0.46, 0.17) to 0.05 (IQR not reported) for spine, and -0.09 (IQR -0.33, 0.07) to 0.09 (IQR not reported) for total body less head. Weight-for-age z-scores increased by 0.25 from baseline to 48 weeks., Conclusions: Four single-arm trials were identified in this systematic review, with initial evidence suggesting good viral suppression and no obvious safety concerns in children and adolescents on TAF-containing regimens over 24-48 weeks. However, further comparative and longer-term safety data are needed in children and adolescents, including on weight and metabolic changes., (© 2022 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Introduction: Globally about 1.7 million children were living with HIV in 2020. Two integrase strand transfer inhibitors, dolutegravir and raltegravir, are increasingly used in children. We conducted a systematic review to assess the effectiveness and safety of dolutegravir and raltegravir in children and adolescents living with HIV, aged 0-19 years., Methods: Sources included MEDLINE, Embase, the Cochrane Library, clinical trial registries, abstracts from key conferences and reference list searching. Observational studies and clinical trials published January 2009-March 2021 were eligible. Outcomes included efficacy/effectiveness (CD4 counts and viral load) and/or safety outcomes (mortality, grade 3/4 adverse events and treatment discontinuation) through 6 months or more post-treatment initiation. Risk of bias was assessed using previously published tools appropriate for the study design. Narrative syntheses were conducted., Results and Discussion: In total, 3626 abstracts and 371 papers were screened. Eleven studies, including 2330 children/adolescents, reported data on dolutegravir: one randomized controlled trial (RCT; low risk of bias), one single-arm trial (unclear risk of bias) and nine cohort studies (three low risk of bias, two unclear risk and four high risk). Ten studies, including 649 children/adolescents receiving raltegravir, were identified: one RCT (low risk of bias), one single-arm trial (low risk of bias) and eight cohort studies (four low risk of bias, three unclear risk and one high risk). Viral suppression levels in children/adolescents at 12 months were high (>70%) in most studies assessing dolutegravir (mostly second- or subsequent-line, or mixed treatment lines), and varied from 42% (5/12) to 83% (44/53) at 12 months in studies assessing raltegravir (mostly second- or subsequent-line). Across all studies assessing dolutegravir or raltegravir, grade 3/4 adverse events (clinical and/or laboratory) were reported in 0-50% of subjects, few resulted in discontinuation, few were drug related and no deaths were attributed to either drug., Conclusions: These reassuring findings suggest that dolutegravir and raltegravir are effective and safe as preferred regimens in children and adolescents living with HIV. With the rollout of dolutegravir in paediatric populations already underway, it is critical that data are collected on safety and effectiveness in infants, children and adolescents, including on longer-term outcomes, such as weight and metabolic changes., (© 2022 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

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 are supportive of systematic ethical investigation of new drugs in pregnancy, coordinating surveillance efforts, mobilizing key stakeholders and promoting transparency and accountability for all involved., Conclusions: With more than 19 million women living with HIV worldwide, ensuring greater inclusion of pregnant women in research on novel therapeutics is a priority to support drug optimization and effective introduction of innovations for treatment and prevention of HIV., (© 2022 World Health Organization; licensed by IAS.)

Introduction: As new antiretrovirals (ARVs), including long-acting ARVs for treatment and prevention, are approved and introduced, surveillance during pregnancy must become the safety net for evaluating birth outcomes, especially those that are rare and require large numbers of observations. Historically, drug pharmacovigilance in pregnancy has been limited and fragmented between different data sources, resulting in inadequate data to assess risk. The International Maternal Pediatric Adolescent AIDS Clinical Trials Network and World Health Organization convened a Workshop which reviewed strengths and weaknesses of existing programs and discussed an improved framework to integrate existing safety data sources and promote harmonization and digitalization., Discussion: This paper highlights that although robust sources of safety data and surveillance programs exist, key challenges remain, including unknown denominators, reporting bias, under-reporting (e.g. in voluntary registries), few data sources from resource-limited settings (most are in North America and Europe), incomplete or inaccurate data (e.g. within routine medical records). However, recent experiences (e.g. with safety signals) and current innovations (e.g. electronic record use in resource-limited settings and defining adverse outcomes) provide momentum and building blocks for a new framework for active surveillance of ARV safety in pregnancy. A public health approach should be taken using data from existing sources, including registries of pregnancy ARV exposure and birth defects; observational surveillance and cohort studies; clinical trials; and real-world databases. Key facilitators are harmonization and standardization of outcomes, sharing of materials and tools, and data linkages between programs. Other key facilitators include the development of guidance to estimate sample size and duration of surveillance, ensuring strategic geographic diversity, bringing partners together to share information and engaging the community of women living with HIV., Conclusions: Looking ahead, critical steps to safely introduce new ARVs include (1) adopting harmonized standards for measuring adverse maternal, birth and infant outcomes; (2) establishing surveillance centres of excellence in areas with high HIV prevalence with harmonized data collection and optimized electronic health records linking maternal/infant data; and (3) creating targets and evaluation goals for reporting progress on implementation and quality of surveillance in pregnancy. The platform will be leveraged to ensure that appropriate contributions and strategic actions by relevant stakeholders are implemented., (© 2022 World Health Organization; licensed by IAS.)

Introduction: Adolescents living with HIV are subject to multiple co-morbidities, including growth retardation and immunodeficiency. We describe growth and CD4 evolution during adolescence using data from the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER) global project., Methods: Data were collected between 1994 and 2015 from 11 CIPHER networks worldwide. Adolescents with perinatally acquired HIV infection (APH) who initiated antiretroviral therapy (ART) before age 10 years, with at least one height or CD4 count measurement while aged 10-17 years, were included. Growth was measured using height-for-age Z-scores (HAZ, stunting if <-2 SD, WHO growth charts). Linear mixed-effects models were used to study the evolution of each outcome between ages 10 and 17. For growth, sex-specific models with fractional polynomials were used to model non-linear relationships for age at ART initiation, HAZ at age 10 and time, defined as current age from 10 to 17 years of age., Results: A total of 20,939 and 19,557 APH were included for the growth and CD4 analyses, respectively. Half were females, two-thirds lived in East and Southern Africa, and median age at ART initiation ranged from <3 years in North America and Europe to >7 years in sub-Saharan African regions. At age 10, stunting ranged from 6% in North America and Europe to 39% in the Asia-Pacific; 19% overall had CD4 counts <500 cells/mm 3 . Across adolescence, higher HAZ was observed in females and among those in high-income countries. APH with stunting at age 10 and those with late ART initiation (after age 5) had the largest HAZ gains during adolescence, but these gains were insufficient to catch-up with non-stunted, early ART-treated adolescents. From age 10 to 16 years, mean CD4 counts declined from 768 to 607 cells/mm 3 . This decline was observed across all regions, in males and females., Conclusions: Growth patterns during adolescence differed substantially by sex and region, while CD4 patterns were similar, with an observed CD4 decline that needs further investigation. Early diagnosis and timely initiation of treatment in early childhood to prevent growth retardation and immunodeficiency are critical to improving APH growth and CD4 outcomes by the time they reach adulthood., (© 2022 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Introduction: While pregnant people have been an important focus for HIV research, critical evidence gaps remain regarding prevention, co-infection, and safety and efficacy of new antiretroviral therapies in pregnancy. Such gaps can result in harm: without safety data, drugs used may carry unacceptable risks to the foetus or pregnant person; without pregnancy-specific dosing data, pregnant people face risks of both toxicity and undertreatment; and delays in gathering evidence can limit access to beneficial next-generation drugs. Despite recognition of the need, numerous barriers and ethical complexities have limited progress. We describe the process, ethical foundations, recommendations and applications of guidance for advancing responsible inclusion of pregnant people in HIV/co-infections research., Discussion: The 26-member international and interdisciplinary Pregnancy and HIV/AIDS: Seeking Equitable Study (PHASES) Working Group was convened to develop ethics-centred guidance for advancing timely, responsible HIV/co-infections research with pregnant people. Deliberations over 3 years drew on extensive qualitative research, stakeholder engagement, expert consultation and a series of workshops. The guidance, initially issued in July 2020, highlights conceptual shifts needed in framing research with pregnant people, and articulates three ethical foundations to ground recommendations: equitable protection from drug-related risks, timely access to biomedical advances and equitable respect for pregnant people's health interests. The guidance advances 12 specific recommendations, actionable within the current regulatory environment, addressing multiple stakeholders across drug development and post-approval research, and organized around four themes: building capacity, supporting inclusion, achieving priority research and ensuring respect. The recommendations describe strategies towards ethically redressing the evidence gap for pregnant people around HIV and co-infections. The guidance has informed key efforts of leading organizations working to advance needed research, and identifies further opportunities for impact by a range of stakeholder groups., Conclusions: There are clear pathways towards ethical inclusion of pregnant people in the biomedical research agenda, and strong agreement across the HIV research community about the need for - and the promise of - advancing them. Those who fund, conduct, oversee and advocate for research can use the PHASES guidance to facilitate more, better and earlier evidence to optimize the health and wellbeing of pregnant people and their children., (© 2021 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Introduction: Despite the coordinated efforts by several stakeholders to speed up access to HIV treatment for children, development of optimal paediatric formulations still lags 8 to 10 years behind that of adults, due mainly to lack of market incentives and technical complexities in manufacturing. The small and fragmented paediatric market also hinders launch and uptake of new formulations. Moreover, the problems affecting HIV similarly affect other disease areas where development and introduction of optimal paediatric formulations is even slower. Therefore, accelerating processes for developing and commercializing optimal paediatric drug formulations for HIV and other disease areas is urgently needed., Discussion: The Global Accelerator for Paediatric Formulations (GAP-f) is an innovative collaborative model that will accelerate availability of optimized treatment options for infectious diseases, such as HIV, tuberculosis and viral hepatitis, affecting children in low- and middle-income countries (LMICs). It builds on the HIV experience and existing efforts in paediatric drug development, formalizing collaboration between normative bodies, research networks, regulatory agencies, industry, supply and procurement organizations and funding bodies. Upstream, the GAP-f will coordinate technical support to companies to design and study optimal paediatric formulations, harmonize efforts with regulators and incentivize manufacturers to conduct formulation development. Downstream, the GAP-f will reinforce coordinated procurement and communication with suppliers. The GAP-f will be implemented in a three-stage process: (1) development of a strategic framework and promotion of key regulatory efficiencies; (2) testing of feasibility and results, building on the work of existing platforms such as the Paediatric HIV Treatment Initiative (PHTI) including innovative approaches to incentivize generic development and (3) launch as a fully functioning structure., Conclusions: GAP-f is a key partnership example enhancing North-South and international cooperation on and access to science and technology and capacity building, responding to Sustainable Development Goal (SDG) 17.6 (technology) and 17.9. (capacity-building). By promoting access to the most needed paediatric formulations for HIV and high-burden infectious diseases in low-and middle-income countries, GAP-f will support achievement of SDG 3.2 (infant mortality), 3.3 (end of AIDS and combat other communicable diseases) and 3.8 (access to essential medicines), and be an essential component of meeting the global Start Free, Stay Free, AIDS Free super-fast-track targets., (© 2018 World Health Organization; licensee IAS.)

Introduction: Advances in biomedical technologies provide potential for adolescent HIV prevention and HIV-positive survival. The UNAIDS 90-90-90 treatment targets provide a new roadmap for ending the HIV epidemic, principally through antiretroviral treatment, HIV testing and viral suppression among people with HIV. However, while imperative, HIV treatment and testing will not be sufficient to address the epidemic among adolescents in Southern and Eastern Africa. In particular, use of condoms and adherence to antiretroviral therapy (ART) remain haphazard, with evidence that social and structural deprivation is negatively impacting adolescents' capacity to protect themselves and others. This paper examines the evidence for and potential of interventions addressing these structural deprivations., Discussion: New evidence is emerging around social protection interventions, including cash transfers, parenting support and educational support ("cash, care and classroom"). These interventions have the potential to reduce the social and economic drivers of HIV risk, improve utilization of prevention technologies and improve adherence to ART for adolescent populations in the hyper-endemic settings of Southern and Eastern Africa. Studies show that the integration of social and economic interventions has high acceptability and reach and that it holds powerful potential for improved HIV, health and development outcomes., Conclusions: Social protection is a largely untapped means of reducing HIV-risk behaviours and increasing uptake of and adherence to biomedical prevention and treatment technologies. There is now sufficient evidence to include social protection programming as a key strategy not only to mitigate the negative impacts of the HIV epidemic among families, but also to contribute to HIV prevention among adolescents and potentially to remove social and economic barriers to accessing treatment. We urge a further research and programming agenda: to actively combine programmes that increase availability of biomedical solutions with social protection policies that can boost their utilization.