Evaluating new and improved therapies for treatment of HIV infection and its associated complications is a high priority for the Branch, and research is conducted through a variety of mechanisms, including clinical trials networks (such as the NICHD Domestic and International Pediatric and Maternal HIV Clinical Studies Network, International Maternal, Pediatric, Adolescent AIDS Clinical Trials [IMPAACT] Network, and Adolescent Medicine Trials Network for HIV/AIDS Interventions) and investigator-initiated grants. HIV infection in children and pregnant women has unique aspects. Therapeutic agents must be evaluated separately in children because of well-documented changes in drug pharmacokinetics and pharmacodynamics during the transition from newborn to adulthood. Additionally, because of changes in drug pharmacokinetics and pharmacodynamics associated with pregnancy, it is essential to evaluate therapeutic drugs that will be used for treatment of HIV or associated infections in pregnant women. Drugs may have increased risks of toxicity during pregnancy and may have negative effects on pregnancy and infant outcomes, such as increased risk of preterm birth.
There are also many important differences between the manifestations of HIV in infected children and infected adults that may require specific characteristics of therapeutic agents for use in pediatrics (e.g., central nervous system penetration). Children may have increased susceptibility to antiretroviral agent toxicities because of their continuing growth and development (e.g., toxic effects of drugs on bone development). Additionally, perinatal transmission is a mode of transmission unique to pediatrics. HIV disease in children with perinatal HIV infection progresses more rapidly (both clinically and immunologically), probably because HIV infection is superimposed upon a naive and immature immune system and the still-developing organ systems of the infant. Finally, comorbid serious non-AIDS sequelae and other HIV-associated complications resulting from chronic immune dysregulation are surfacing in aging adults with HIV infection. Similarly, it is largely unknown what impact such immune activation may have on the long-term end-organ (cardiovascular, kidney, neurocognitive, liver, etc.) outcomes of children with lifelong exposure to HIV and its therapy.
HIV frequently involves the neurologic system in children, causing developmental delay and encephalopathy, and it can severely affect children's physical growth early in the course of infection. Evaluation of the effect of therapeutics on these unique pediatric manifestations of HIV is crucial. Additionally, the range of opportunistic infections that complicate the immunologic dysfunction secondary to HIV infection in children differs from that in adults.
Because most HIV-infected children reside in resource-limited settings, studying optimal management of HIV infection in children and pregnant women co-infected with tuberculosis (TB), hepatitis, malaria, and other diseases endemic to such settings is critical. Data are lacking on the pharmacokinetics of drugs to treat these diseases even in children and pregnant women who are not infected with HIV, and studies of the interactions of anti-HIV drugs with drugs to treat these infections are crucial.
Research to find a cure for HIV infection among children has been jump-started by the recent report of a 4-year-old child born with HIV infection who was treated with antiretroviral drugs and did not have detectable levels of virus (using conventional testing methods) despite not taking HIV medication for over 2 years. More information is needed to identify where HIV hides—sometimes called the HIV reservoir—how this reservoir is established and maintained in children, and to identify ways to control and eliminate this viral reservoir. To stimulate research in this area, the NICHD issued RFA-HD-14-026: Evaluation of the Latent Reservoir in HIV-Infected Infants and Children with Early Antiretroviral Treatment and Virologic Control (R01), in collaboration with NIAID and NIMH. The IMPAACT Network has designed a proof-of-concept clinical trial to test the hypothesis that very early treatment can control the HIV reservoir in infants with perinatal HIV infection.
Examples of scientific research areas include:
- Pharmacokinetic and safety studies
- Pharmacokinetics and safety of antiretroviral drugs in HIV-infected infants, children, adolescents, and pregnant and postpartum women, including novel extended release platforms for these populations
- Treatment of HIV-associated infections (e.g., TB, malaria, and hepatitis) in HIV-infected infants, children, adolescents, and pregnant and postpartum women, including pharmacokinetic and safety studies and studies of interactions between antiretroviral and antimicrobial agents
- Treatment of HIV-associated non-infectious complications in HIV-infected infants, children, adolescents, and pregnant and postpartum women
- Optimizing antiretroviral therapy in HIV-infected infants, children, adolescents, and pregnant and postpartum women with HIV-associated co-infections or co-morbidities such as malnutrition
- Antiretroviral drug resistance
- Biomedical prevention studies
- Evaluation of antiretroviral oral pre-exposure prophylaxis regimens to prevent HIV infections among key risk populations of adolescents and young adults, including novel extended release drug platforms
- Evaluation of vaccines to prevent HIV and HIV-related infectious diseases in infants, children, adolescents, and pregnant and postpartum women
- Evaluation of microbicides, in collaboration with the Microbicide Trials Network, and other drug-based modalities to prevent HIV and HIV-related infectious diseases in infants, children, adolescents, and pregnant and postpartum women
- Optimizing malaria prevention in children
- HIV cure in infants, children, and adolescents
- Characterizing the latent reservoir in children, including the use of animal models for pathogenesis of viral reservoirs in infants; development of tools to measure and quantify HIV in reservoirs in children; and identification of the tissues/cell types that constitute the latent reservoir and the viral, host, and immune mechanisms underlying the persistence of HIV infection despite effective antiretroviral therapy
- Evaluation of the impact of early infection and treatment on the developing brain
- Investigation of the role of immune activation, inflammation, and their mediators on HIV persistence in various tissues of perinatally infected infants and children
- Evaluation of cure/functional cure studies in children, including the effect of antiretroviral therapy and adjunctive strategies on the HIV reservoir and immune-based strategies