ART saves lives, and EID is the gateway into the pediatric treatment cascade. Despite recommendations from WHO to implement EID using nucleic acid amplification test at 4–6 weeks of life,15 only 9%–60% of infants exposed to HIV are tested before 2 months of age.33,34 This is primarily due to loss to follow-up between birth and first EID test.35 Moreover, it often takes over 4–10 weeks from obtaining samples to receiving results.36,37 Tragically, late treatment, illness, and deaths from HIV in infants remain common.
Routine HIV virologic testing at birth was added to existing diagnostic algorithms as a conditional recommendation in the 2016 WHO Guidelines.15 Its main goal is to lessen time to HIV diagnosis and ART initiation in infants infected with HIV in utero. Birth testing is particularly attractive for countries with a high rate of in-facility deliveries. Its cost-effectiveness and favorable outcomes were supported by mathematical modeling data from South Africa.38 To date, there are limited published data on the effects of birth EID on the infant testing and treatment cascade countries such as South Africa, Thailand, and Kenya that have adopted this strategy.
Linkage between testing and ART initiation, and retention in care are vital to achieving survival benefits of EID.35,39 Mobile health technology could improve linkage and retention in care. The HITSystem that was evaluated in Kenya provides a link between the laboratory, clinician, and caregiver. The system generates text messages to caregivers when EID results are available and prompts action, which has resulted in faster ART initiation and higher retention in care.40 MomConnect, a short-message service in South Africa, offers pregnancy advice and appointment reminders to pregnant women that could be extended to include EID reminders.41
Electronic health systems could be key in facilitating result notifications to health care workers and improving flow of information to key stakeholders including the ministries of health and implementation partners. Successfully piloted in South Africa, the national health laboratory service provides key stakeholders and clinical teams a weekly electronic list of HIV polymerase chain reaction test results performed per facility, district, or province. Infants diagnosed with HIV are actively traced by community health care workers and tracing teams based at a facility or district using a polymerase chain reaction registry that contains contact details of the caregiver.16 A similar web-based tracking system in Kenya has led to a shorter turnaround time from sample collection to patient notification.42 Next steps include continued evaluations of new technologies, and devising strategies for implementation in communities with high HIV burden, and limited access to telecommunication, electricity, and health services.
Children face a lifetime of ART and HIV stigma that makes finding a cure to HIV immensely important. In 2013, the case of the Mississippi baby propelled the interest of the public and the research community in early ART and HIV cure in children.43,44 Very early ART during the first 1–2 days of life in this infant subsequently led to undetectable viral load for 27 months after ART interruption at 18 months of age. The ability to maintain suppressed viremia in the absence of ART or HIV remission is also observed in adult cohorts,45 whose low HIV reservoir size after early treatment is a predominant feature.46
The Mississippi baby and the pediatric cure agenda in general provided an enormous impetus globally to identify and start treating infants as early as possible. Although only a few settings can engage in “cure” approaches, the approach shifted the timeline earlier along the cascade, drawing attention to the realities of delayed diagnosis, limited ARV options, and high rates of early morbidity and mortality in settings with high numbers of new infections.47 In the race to limit HIV reservoir seeding with early ART, the research and public health priorities merge. For example, in Thailand, researchers studying the HIV reservoirs and public health officers collaborated as part of the Active Case Management Network to increase the numbers of infants on ART and lower the age at ART initiation.48 Measures are being taken to strengthen EID programs and point of care virologic testing is gaining momentum,10,49–51 and applications now extend to monitoring of pediatric and adult HIV treatment.52,53 Over the past several years, new efforts have been made to find safe and potent ARVs with appropriate formulations and dosing for neonates and young infants54,55 (clinicaltrials.gov NCT01828073; NCT 02778204).
Studies of HIV persistence under therapy have generated unique opportunities to incorporate science into pediatric therapeutic agenda that is important for the long-term goal of improving child health. When viral replication is inhibited early with ART, children display low levels of cell-associated HIV DNA and HIV RNA,56–59 shorter half-life of replication-competent virus from latently infected cells,57,60 and their noninduced proviral genomes are mostly defective.61 Young children have high frequencies of naive CD4+ T cells that are likely more resistant to HIV.62 Adolescents on ART since infancy with more than a decade of viral suppression are a unique population: their viral reservoirs continue to decay and only traces of HIV can be detected in their blood CD4+ T cells.63
Exciting data from an infant nonhuman primate model showed that simian/HIV immunodeficiency virus can be eradicated when combined broadly neutralizing antibodies were instituted within the first day or second day of infection.64 This is highly relevant to the pediatric HIV cure agenda with known timing of infection affording immediate HIV diagnosis and treatment. The International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) is investigating broadly neutralizing antibody given in addition to ART to HIV-exposed (P1112, clinicaltrials.gov NCT02256631) and newly HIV-infected infants (P2008, clinicaltrials.gov NCT03208231). The global Early-treated Perinatally HIV-infected individuals: Improving Children's Actual Life with Novel Immunotherapeutic Strategies (EPIICAL) network is dedicated to advancing therapies for HIV cure in the early treated pediatric population.65 Unlike adults, children have an active thymus and immune regeneration ability that is key to mounting responses to vaccines. Vaccine responses in children can be as good or better compared with adults for both non-HIV66 and HIV vaccines.67–70 HIV-exposed uninfected infants who received ALVAC (canarypox vector containing env, gag, pol)/AIDSVAX (engineered gp120 protein) had 22-fold higher levels and longer durability of the correlate for HIV protection, anti V1V2 IgG, than adults in the RV144 Thai trial.69 Perinatally, HIV-infected children mounted higher HIV-specific immune responses to new epitopes after HIVIS DNA vaccine (7 plasmids of env, gag, Rev, and RT) compared with adults given the same vaccine.67 Together, these data support the notion that early treated children may be more likely to respond to immunotherapeutics for cure.71 Pediatric HIV cure research is poised to critically contribute to the global research efforts to curing HIV and to further drive the pediatric agenda to optimize treatments for the youngest children.
Emerging evidence of the potential benefits of very early treatment of HIV-infected neonates has propelled efforts to expand therapeutic options for infants. Currently, there are only 5 ARVs with appropriate formulations, dosing, and safety data to recommend their use in full-term neonates [zidovudine, lamivudine, nevirapine, lopinavir/ritonavir (at 2 weeks of age), and raltegravir].72,73 The dosage and therapeutic use of nevirapine in newborns is investigational. However, important strides are being made to accelerate the development, study, and availability of the most potent ARVs to treat young babies.12
Historically, there has been little impetus to develop ARVs for newborn treatment. With routine infant diagnosis scheduled for 6 weeks of life, most infants who were successfully diagnosed and engaged in care did not begin ART until well beyond the second month of life. Furthermore, distinct aspects of early life make both the development and study of drugs substantially more complex compared with adults and older children.72–74 The first months of life are a dynamic developmental period characterized by rapid physiologic changes that influence drug metabolism, and in turn, dosing and toxicities. High rates of prematurity, low birth weight, and concomitant health conditions among infants born to women living with HIV infection add another set of considerations when determining dosing and safety of new agents.75,76 The need for formulations other than liquids that are safe, acceptable, and feasible for use in low- and middle-income settings has further delayed access to new medications for infants.
The landscape of early infant treatment is slowly shifting, accelerated by collaboration among key stakeholders as well as the application of recommended innovations to drug development and study design.12 For example, after a long period of development, lopinavir/ritonavir pellets, an alternative to the poorly palatable, heat-sensitive liquid formulation, were approved for children older than 3 months.77,78 Dosing and acceptability of the new formulation were determined in the CHAPAS-3 study.77,78 The LIVING study is now evaluating the effectiveness of the pellet formulation in combination with zidovudine and lamivudine fixed-dose combination tablets under routine conditions in Sub-Saharan Africa in infants and young children who cannot swallow tablets (clinicaltrials.gov NCT02346487).79 In lieu of a separate study for children younger than 3 months, LIVING has been designed to include children starting treatment at birth to obtain safety and acceptability data for this age group. A lopinavir/ritonavir granule formulation and a four-in-one (lopinavir/ritonavir with abacavir and lamivudine) granule/powder product are anticipated to be available in the near future.”
Scientific networks and investigators have embraced the weight-band dosing approach in lieu of the age-range dosing approach traditionally used in pediatric pharmacokinetic studies. Investigators are now using sophisticated modeling and simulation techniques using data from older children and adults to inform dosing strategies for neonates and infants.72,73 Washout pharmacokinetic studies, measuring newborn blood levels during the first days to weeks of life of transplacentally transferred maternal ARVs, have also given insight into the behavior of specific agents during this period of rapid physiologic change. Raltegravir, available in a chewable tablet and a granule formulation, was recently approved for use in full-term neonates and is an excellent example of optimizing data sources to inform pediatric dosing.80 Investigators used pharmacokinetic data from older children and adults, a small phase I trial in newborns, and maternal washout studies to select a daily dosing regimen that was then tested and ultimately approved for very early treatment.81–83 Studies are underway to extend dosing to low birth weight babies. The development plan for dolutegravir is following a similar pathway, maximizing data sources, modeling pharmacokinetics and dosing, and testing doses in small mini-cohorts of children (clinicaltrials.gov NCT01302847).84,85 In parallel, efficacy and additional dosing and safety data are being studied in the ODYSSEY trial (clinicaltrials.gov NCT02259127). These combined efforts should lead to more rapid approval and availability of dolutegravir for all children including neonates.
Brain development begins during the first trimester and continues into early adulthood. The immaturity of the central nervous system (CNS) through adolescence makes it vulnerable to insults from HIV and its treatments, and places infants and children with HIV at particular risk of damage to developing structures and functions. Thus, timing of infant HIV infection (in utero, intrapartum, postnatal),86 maternal health status,87 and effective ART initiation are major determinants of frequency and severity of abnormalities. Although severe CNS effects from HIV (ie, encephalopathy) are uncommon since the introduction of earlier ART, more subtle neurobehavioral abnormalities remain in some children and may be related to host,88 viral,89 and treatment factors.90 There may be a critical window of opportunity when abnormalities can be prevented by early ART,91,92 but the precise timing is under investigation. The effects of early therapy on the CNS are being studied and include CNS penetration of ART drugs on neurologic outcome and use of comprehensive neurobehavioral assessments.93
HIV-exposed uninfected children born to mothers on ART during and after pregnancy form a growing population impacted by HIV. Exposures to HIV and perinatal ART have been related to potential acute as well as late neurobehavioral sequelae.98,108 Timing of exposure to a specific ARV agent and maternal immunologic and virologic status during pregnancy may be contributing factors.109 However, longer follow-up is needed particularly for newer ARVs. Moreover, available evidence has not unambiguously linked currently available ARVs to adverse clinical outcomes.
Although much of the earlier work characterized the neurobehavioral abnormalities, current research has focused on the prevention and rehabilitation of the deficits.110 Besides very early ART,91 ability-based and parent-based interventions may ameliorate some of the neurobehavioral deficits.111–113 Even as effective ART is available to prevent and treat infant HIV infection, long-term outcomes with respect to brain structure and function remain a concern and require continued monitoring and tailored preventive and rehabilitative interventions.
Scientific discovery, innovation, and collaboration are key drivers propelling efforts to improve diagnostics, optimize treatments, and enhance the health outcomes of children living with HIV infection. Scientists, policy makers, implementers, and industry have aligned to advance the pediatric therapeutic agenda and results are paying off. Key examples are the prioritized global research agenda, PAWG guidance, PADO prioritization list, and GAP-f. New medications and formulations for children are under development and a number of new ARVs are becoming available at a more rapid pace than ever before. Interest in very early treatment to achieve a cure and to prevent CNS disease have focused attention on treatment of neonates and given new urgency to efforts to improve the EID cascade and have potent, safe, and well-tolerated ARV regimens for youngest children.
The authors thank Oratai Butterworth for her help in formatting the manuscript.
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