The last and first frontier – emerging challenges for HIV treatment and prevention in the first week of life with emphasis on premature and low birth weight infants

Introduction The new “90-90-90” UNAIDS agenda proposes that 90% of all people living with HIV will know their HIV status, 90% of all people with diagnosed HIV infection will receive sustained antiretroviral therapy and 90% of all people receiving antiretroviral therapy will have viral suppression by 2020. By focusing on children, the global community is in the unique position of realizing an end to the paediatric HIV epidemic. Discussion Despite vast scientific advances in the prevention and treatment of paediatric HIV infection over the last two decades, in 2014 there were an estimated 220,000 new paediatric infections attributed to mother-to-child HIV transmission (MTCT) and 150,000 HIV-related paediatric deaths. Furthermore, adolescents remain at particularly high risk for acquisition of new HIV infections, and HIV/AIDS remains the second leading cause of death in this age group. Among the estimated 2.6 million children less than 15 years of age living with HIV infection, only 32% were receiving life-saving antiretroviral treatment. After decades of languishing, good progress is now being made to prevent MTCT. Unfortunately, efforts to scale up HIV treatment services have been less robust for children and adolescents compared with adult populations. These discrepancies reflect substantial gaps in essential services and numerous missed opportunities to prevent HIV transmission and provide effective life-saving antiretroviral treatment to children, adolescents and families. The road to an AIDS-free generation will require bridging the gaps in HIV services and addressing the particular needs of children across the developmental spectrum from infancy through adolescence. To reach the ambitious new targets, innovations and service improvements will need to be rapidly escalated at each step along the prevention-treatment cascade. Conclusions Charting a successful course to reach the 90-90-90 targets will require sustained political and financial commitment as well as the rapid implementation of a broad set of systematic improvements in service delivery. The prospect of a world where HIV no longer threatens the lives of infants, children and adolescents may finally be within reach.
Introduction Despite significant gains in access to early infant diagnosis (EID) over the past decade, most HIV-exposed infants still do not get tested for HIV in the first two months of life. For those who are tested, the long turnaround time between when the sample is drawn and when the results are returned leads to a high rate of loss to follow-up, which in turn means that few infected infants start antiretroviral treatment. Consequently, there continues to be high mortality from perinatally acquired HIV, and the ambitious goals of 90% of infected children identified, 90% of identified children treated and 90% of treated children with sustained virologic suppression by 2020 seem far beyond our reach. The objective of this commentary is to review recent advances in the field of HIV diagnosis in infants and describe how these advances may overcome long-standing barriers to access to testing and treatment. Discussion Several innovative approaches to EID have recently been described. These include point-of-care testing, use of SMS printers to connect the central laboratory and the health facility through a mobile phone network, expanding paediatric testing to other entry points where children access the health system and testing HIV-exposed infants at birth as a rapid way to identify in utero infection. Each of these interventions is discussed here, together with the opportunities and challenges associated with scale-up. Point-of-care testing has the potential to provide immediate results but is less cost-effective in settings where test volumes are low. Virological testing at birth has been piloted in some countries to identify those infants who need urgent treatment, but a negative test at birth does not obviate the need for additional testing at six weeks. Routine testing of infants in child health settings is a useful strategy to identify exposed and infected children whose mothers were not enrolled in programmes for the prevention of mother-to-child transmission. Facility-based SMS printers speed up the return of laboratory results and may be of value for other testing services apart from HIV infant diagnosis. Conclusions New tools and strategies for HIV infant diagnosis could have a significant positive impact on the identification and retention of HIV-infected infants. In order to be most effective, national programmes should carefully consider which ideas to implement and how best to integrate novel strategies into existing systems. There is no single solution that will work everywhere. Rather, a number of approaches need to be considered and should be linked in order to achieve the greatest impact on the continuum of care from testing to treatment.
Introduction There is new emphasis on identifying and treating HIV in the first days of life and also an appreciation that low birth weight (LBW) and preterm delivery (PTD) frequently accompany HIV-related pregnancy. Even in the absence of HIV, PTD and LBW contribute substantially to neonatal and infant mortality. HIV-exposed and -infected infants with these characteristics have received little attention thus far. As HIV programs expand to meet the 90-90-90 target for ending the HIV pandemic, attention should focus on newborn infants, including those delivered preterm or of LBW. Discussion In high prevalence settings, infant diagnosis of HIV is usually undertaken after the neonatal period. However, as in utero infection may be diagnosed at birth, earlier initiation of therapy may limit viral replication and prevent early damage. Globally, there is growing awareness that preterm and LBW infants constitute a substantial proportion of births each year. Preterm infants are at high risk for vertical transmission. Feeding difficulties, apnoea of prematurity and vulnerability to sepsis occur commonly. Feeding intolerance, a frequent occurrence, may compromise oral administration of medications. Although there is growing experience with post-exposure prophylaxis for HIV-exposed term newborn infants, there is less experience with preterm and LBW infants. For treatment, there are even fewer options for preterm infants. Only zidovudine has adequate dosing recommendations for treating term and preterm infants and has an intravenous formulation, essential if feeding intolerance occurs. Nevirapine dosing for prevention, but not treatment, is well established for both term and preterm infants. HIV diagnosis at birth is likely to be extremely stressful for new parents, more so if caring for preterm or LBW infants. Programs need to adapt to support the medical and emotional needs of young infants and their parents, where interventions may be lifesaving. Conclusions New focus is required for the newborn baby, including those born preterm, with LBW or small for gestational age to consolidate gains already made in early diagnosis and treatment of young children.
Introduction As access to prevention of mother-to-child transmission (PMTCT) efforts has increased, the total number of children being born with HIV has significantly decreased. However, those children who do become infected after PMTCT failure are at particular risk of HIV drug resistance, selected by exposure to maternal or paediatric antiretroviral drugs used before, during or after birth. As a consequence, the response to antiretroviral therapy (ART) in these children may be compromised, particularly when non-nucleoside reverse transcriptase inhibitors (NNRTIs) are used as part of the first-line regimen. We review evidence guiding choices of first- and second-line ART. Discussion Children generally respond relatively well to ART. Clinical trials show the superiority of protease inhibitor (PI)- over NNRTI-based treatment in young children, but observational reports of NNRTI-containing regimens are usually favourable as well. This is reassuring as national guidelines often still recommend the use of NNRTI-based treatment for PMTCT-unexposed young children, due to the higher costs of PIs. After failure of NNRTI-based, first-line treatment, the rate of acquired drug resistance is high, but HIV may well be suppressed by PIs in second-line ART. By contrast, there are currently no adequate alternatives in resource-limited settings (RLS) for children failing either first- or second-line, PI-containing regimens. Conclusions Affordable salvage treatment options for children in RLS are urgently needed.
Introduction As the global community makes progress towards the 90-90-90 targets by 2020, a key challenge is ensuring that antiretroviral drugs for children and adolescents are suitable to the context of resource-limited settings. Drug optimization aims to support the expanded use of more simplified, less toxic drug regimens with high barriers to drug resistance that require minimal clinical monitoring while maintaining therapeutic efficacy. This manuscript summarizes the progress made and outlines further critical steps required to ensure that the right drugs are available to start children and adolescents on treatment and to keep them virologically suppressed. Discussion Building upon previous work in drug optimization, several important steps were taken in 2014 to ensure alignment between WHO dosing recommendations and the requirements of regulatory bodies, to accelerate drug development, to reduce intellectual property barriers to generic production of combined formulations and rationalize drug selection in countries. The priority for the future is to improve access to antiretroviral therapy (ART) at the two ends of the paediatric age spectrum – infants and adolescents – where the treatment gap is greatest, and optimize drug sequencing with better use of available medicines for second- and third-line ART. Future efforts in this area will require continuous collaboration and coordination, and the promotion of innovative approaches to accelerate access to new drugs and formulations. Conclusions While significant progress has been made, additional efforts are needed to ensure that treatment targets are reached by 2020.
Introduction In 2014 the Joint United Nations Programme on HIV/AIDS defined the ambitious 90–90–90 targets for 2020, in which 90% of people living with HIV must be diagnosed, 90% of those diagnosed should be on sustained therapy and 90% of those on therapy should have an undetectable viral load. Children are considered to be a key focus population for these targets. This review will highlight key components of the epidemiology, prevention and treatment of tuberculosis (TB) in HIV-infected children in the era of increasing access to antiretroviral therapy (ART) and their relation to the 90–90–90 targets. Discussion The majority of HIV-infected children live in countries with a high burden of TB. In settings with a high burden of both diseases such as in sub-Saharan Africa, up to 57% of children diagnosed with and treated for TB are HIV-infected. TB results in substantial morbidity and mortality in HIV-infected children, so preventing TB and optimizing its treatment in HIV-infected children will be important to ensuring good long-term outcomes. Prevention of TB can be achieved by increasing access to ART to both children and adults, and appropriate provision of isoniazid preventative therapy. Co-treatment of HIV and TB is complicated by drug-drug interactions particularly due to the use of rifampicin; these may compromise virologic outcomes if appropriate corrective actions are not taken. There remain substantial operational challenges, and improved integration of paediatric TB and HIV services, including with antenatal and routine under-five care, is an important priority. Conclusions TB may be an important barrier to achievement of the 90–90–90 targets, but specific attention to TB care in HIV-infected children may provide important opportunities to enhance the care of both TB and HIV in children.
Introduction Nigeria has a high burden of children living with HIV and tuberculosis (TB). This article examines the magnitude of TB among children receiving antiretroviral treatment (ART), compares their ART outcomes with their non-TB counterparts and argues that addressing TB among children on ART is critical for achieving the 90–90–90 targets. Methods This was a facility-based, retrospective analysis of medical records of children aged
Introduction As highly active antiretroviral therapy (HAART) transforms human immunodeficiency virus (HIV) into a manageable chronic disease, new challenges are emerging in treating children born with HIV, including a number of risks to their physical and psychological health due to HIV infection and its lifelong treatment. Methods We conducted a literature review to evaluate the evidence on the physical and psychological effects of perinatal HIV (PHIV+) infection and its treatment in the era of HAART, including major chronic comorbidities. Results and discussion Perinatally infected children face concerning levels of treatment failure and drug resistance, which may hamper their long-term treatment and result in more significant comorbidities. Physical complications from PHIV+ infection and treatment potentially affect all major organ systems. Although treatment with antiretroviral (ARV) therapy has reduced incidence of severe neurocognitive diseases like HIV encephalopathy, perinatally infected children may experience less severe neurocognitive complications related to HIV disease and ARV neurotoxicity. Major metabolic complications include dyslipidaemia and insulin resistance, complications that are associated with both HIV infection and several ARV agents and may significantly affect cardiovascular disease risk with age. Bone abnormalities, particularly amongst children treated with tenofovir, are a concern for perinatally infected children who may be at higher risk for bone fractures and osteoporosis. In many studies, rates of anaemia are significantly higher for HIV-infected children. Renal failure is a significant complication and cause of death amongst perinatally infected children, while new data on sexual and reproductive health suggest that sexually transmitted infections and birth complications may be additional concerns for perinatally infected children in adolescence. Finally, perinatally infected children may face psychological challenges, including higher rates of mental health and behavioural disorders. Existing studies have significant methodological limitations, including small sample sizes, inappropriate control groups and heterogeneous definitions, to name a few. Conclusions Success in treating perinatally HIV-infected children and better understanding of the physical and psychological implications of lifelong HIV infection require that we address a new set of challenges for children. A better understanding of these challenges will guide care providers, researchers and policymakers towards more effective HIV care management for perinatally infected children and their transition to adulthood.
Introduction The number of children less than 15 years estimated to be living with HIV globally approximated 3.2 million in 2013. Young people aged 15 to 24 years living with HIV approximated 4 million. The survival of these children and adolescents into adulthood poses new and urgent challenges of transition from the paediatric to adolescent to adult healthcare settings due to emerging developmental, psychosocial and comorbid issues. In order to achieve treatment targets of 90–90–90 across the continuum of care for paediatric HIV by 2020, focused efforts on the implementation of appropriate healthcare transition plans across the lifespan, with a focus on adolescence, should be prioritized. Discussion Published data or empirical evidence examining implementation of transition models and association with clinical outcomes are limited. While some guidelines do exist that offer recommendations about how to promote seamless transitions, very few data are available to assess the adequacy of these guidelines and whether they are effectively adhered to in clinical care settings globally. Furthermore, paediatric and adolescent HIV infection, either acquired perinatally or behaviourally, is set apart from other chronic illnesses as a highly stigmatizing disease that disproportionately affects poor, minority and often marginalized populations. Focused efforts on adolescence as the touchstone for transition practices and policies need to be implemented. Conclusions Optimal healthcare for these vulnerable populations, particularly in resource-limited settings, will require HIV-specific transitional care services and programmes that are coordinated, collaborative, integrated and, importantly, evidence-based.
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.
Introduction Integration of HIV into child survival platforms is an evolving territory with multiple connotations. Most literature on integration of HIV into other health services focuses on adults; however promising practices for children are emerging. These include the Double Dividend (DD) framework, a new programming approach with dual goal of improving paediatric HIV care and child survival. In this commentary, the authors discuss why integrating HIV testing, treatment and care into child survival platforms is important, as well as its potential to advance progress towards global targets that call for, by 2020, 90% of children living with HIV to know their status, 90% of those diagnosed to be on treatment and 90% of those on treatment to be virally suppressed (90–90–90). Discussion Integration is critical in improving health outcomes and efficiency gains. In children, integration of HIV in programmes such as immunization and nutrition has been associated with an increased uptake of HIV infant testing. Integration is increasingly recognized as a case-finding strategy for children missed from prevention of mother-to-child transmission programmes and as a platform for diffusing emerging technologies such as point-of-care diagnostics. These support progress towards the 90–90–90 targets by providing a pathway for early identification of HIV-infected children with co-morbidities, prompt initiation of treatment and improved survival. There are various promising practices that have demonstrated HIV outcomes; however, few have documented the benefits of integration on child survival interventions. The DD framework is well positioned to address the bidirectional impacts for both programmes. Conclusions Integration provides an important programmatic pathway for accelerated progress towards the 90–90–90 targets. Despite this encouraging information, there are still challenges to be addressed in order to maximize the benefits of integration.