The following information describes the branch's research programs and program areas.
Program Officials: Bill Kapogiannis and Sonia Lee
Domestic and international epidemiologic and clinical information indicate that HIV transmission and acquisition among adolescents and young adults continues to increase. The Centers for Disease Control and Prevention (CDC) estimates that in the United States, youth ages 13 to 24 years accounted for 21% of all new HIV diagnoses in 2018. That same year, approximately 7, 944 youth were diagnosed with HIV in the United States. Most new diagnoses among youth were among young gay and bisexual youth; heterosexual transmission is the predominant mode of HIV acquisition in adolescent females. In developing countries, youth, particularly young women, are on the front lines of the HIV epidemic. The World Health Organization (WHO) estimates that more than 30% of all new HIV cases globally are estimated to occur among youth. In sub-Saharan Africa, two out of three new HIV cases among adolescents ages 15-19 years were girls. Furthermore, WHO estimates that HIV/AIDS is currently the second leading cause of death among adolescents globally. Interventions to prevent HIV transmission to youth are critically needed, including behavioral interventions (in youth both with and without HIV) and studies of HIV vaccines, microbicides, and pre-exposure prophylaxis in uninfected, at-risk youth.
Treatment of adolescents with HIV is complicated by unique challenges and management demands. To improve individual outcomes and reduce secondary transmission events, strict adherence to all components of the continuum of care for populations with HIV is critical. Even in the best of circumstances, however, among adults (without the complexity of psychosocial challenges common to adolescents), long-term viral suppression is achieved in only 23% of those entering care. Further complicating care for youth with HIV are the higher rates of undiagnosed HIV, lower rates of linkage to and retention in care, and low antiretroviral adherence rates with resultant poor viral suppression. Trials are urgently needed to study the continuum of care among both domestic and international youth populations to identify strategies that can substantially improve achievement of essential milestones along the care continuum and ultimately help youth with HIV achieve durable viral suppression. Also needed are trials to study newer drug schedules and formulations that allow simpler regimens, evaluation of programs to promote antiretroviral treatment adherence in youth, and clinical trials to evaluate therapies that may exploit the immunologic resilience of youth who recently acquired HIV. Domestically, through the Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN), the branch is supporting interventional research in youth from pre-adolescent age through 24 years, in addition to the Pediatric HIV/AIDS Cohort Study (PHACS). International research in adolescent HIV acquisition, disease, and prevention is an expanding area for the branch, in collaboration with other HIV/AIDS research networks supported by NIH. Notably, the branch is supporting the Prevention and Treatment through a Comprehensive Care Continuum for HIV-affected Adolescents in Resource Constrained Settings program .
Program Official: Sonia Lee
With the availability of treatment, increasing numbers of children who acquired HIV perinatally are now surviving into adolescence and young adulthood in the United States, presenting new treatment and secondary prevention challenges. Internationally, the recent massive scale-up of antiretroviral treatment programs for children in sub-Saharan Africa has resulted in an approximate quadrupling of the number of children receiving therapy globally. These children, now expected to survive or already surviving into adolescence, young adulthood, and beyond, will face the consequences of prolonged HIV and long-term antiretroviral therapy on multiple organs and systems in the body. These consequences may be exacerbated by endemic diseases and co-morbidities, such as malnutrition, not seen in resource-rich countries such as the United States. In addition to the long-term complications of HIV and its treatment, many survivors of perinatal HIV face a multitude of transitions. These include the usual challenges of adolescence and young adulthood, such as school, career choices, reproductive health, and plans for marriage and families, and the transition to adult medical HIV and non-HIV care. Understanding how HIV and its treatment affect growth and development, sexual maturation, organ function, and socialization of adolescents who acquired HIV perinatally and young adults is critical.
MPIDB is actively conducting research related to the long-term effects of HIV and its therapy in youth who acquired HIV perinatally both domestically (for example, PHACS) and internationally (for example, https://grants.nih.gov/grants/guide/rfa-files/RFA-HD-16-033.html) Areas of research interest include:
- Prevalence, incidence, management, and outcomes of antiretroviral drug resistance
- Neurodevelopmental, cognitive, academic, vocational, behavioral, and social outcomes; brain imaging correlates and other surrogate markers of these outcomes
- Consequences of HIV-associated long-term immune activation and premature aging for youth who acquired HIV perinatally
- Substance use
- Adherence to medication regimens and medical care
- Transition to adult-based care
- Nutrition, growth, and metabolism
- Bone health
- Sexual maturation and health, reproductive capacity and choices, pregnancy outcomes and complications, and behaviors that pose risk for transmission of HIV
- Cardiovascular complications and cardiovascular disease risk; noninvasive imaging to assess risk of premature atherosclerosis and cardiac and vascular dysfunction; evaluation of surrogate markers predictive of cardiovascular disease
- Genetic and epigenetic—including mitochondrial—effects of antiretrovirals and HIV
- Peripheral nervous system complications
- Hepatic complications, including co-infections with hepatitis B and C, and other viral infections associated with malignancies
- Pulmonary complications
- Renal complications
Program Official: Sonia Lee
Unique considerations for infants, children, and adolescents with respect to the pathogenesis of HIV warrant research specifically focused on these populations. As potent therapy has become available, HIV has become more of a chronic disease than a terminal condition in both adults and children. A recent study found that more than half of children with perinatally acquired HIV in the United States are older than age 15 years. Additionally, recent trends in immigration indicate increasing prevalence of children diagnosed with perinatally acquired HIV who were born internationally. As access to antiretroviral therapy expands, studies from resource-limited countries are beginning to show similar survival of this population into adolescence and young adulthood. Increased survival of children with HIV has been associated with challenges in maintaining adherence to long-term therapy and in selecting successive antiretroviral drug regimens. This is complicated further by the limited availability of pediatric formulations and of pharmacokinetic and safety data in children and the development of extensive drug resistance in multidrug-experienced children. In resource-limited countries, pediatric HIV and its therapy is complicated further by the presence of endemic diseases, such as tuberculosis (TB), hepatitis, and malaria, and co-morbidities, such as malnutrition, that may exacerbate HIV disease and further complicate therapy.
Current specific areas of research on HIV in children and adolescents in the antiretroviral era both domestically and internationally include:
- Epidemiology/natural history with a focus on children in and from resource-limited countries
- Optimizing linkage to care, monitoring of therapy, adherence and durability of therapy, and development of drug resistance
- Short- and long-term outcomes of HIV and its treatment in children along the entire spectrum of HIV care, including transitions to adult care, and patient and site-level factors associated with these outcomes
- Evaluation of epidemiology, treatment, and prevention of important co-infections in children, particularly TB, malaria, hepatitis, and other high-priority infections
- In collaboration with the United Nations Programme on HIV/AIDS and WHO, improving the global estimates of the pediatric HIV epidemic
- Biomedical complications of HIV and its therapies
- Growth, endocrinologic, bone, and dental issues (including nutritional effects)
- Sexual maturation and reproductive capacity
- Body composition changes and tissue redistribution syndromes
- Cardiovascular complications and cardiovascular disease risk
- Mitochondrial effects of exposure to antiretroviral drugs
- Psychosocial and behavioral research
- Neurodevelopmental, language and hearing, cognitive, academic, vocational, and behavioral outcomes
- Disclosure of HIV status to children in low- and middle-income country settings
- Adherence to therapy, including implementation and utilization of innovative technologies to assess and support adherence
- Assay development
- Pediatric HIV diagnostic and monitoring assays and strategies relevant to developing-country settings
- TB diagnostics
- Point-of-care technologies
Program Official: Denise Russo
MPIDB also has a strong focus on HIV in women. Globally, HIV disproportionately affects women and young girls. Heterosexual transmission is the primary route by which women acquire HIV. A range of factors contribute to women’s increased susceptibility to HIV-1 acquisition, including biology, and structural and socioeconomic factors such as gender inequality, but knowledge about the role of these factors remains limited. The complex interactions of HIV and its treatment with endogenous hormonal fluctuations over the course of a woman’s life, from puberty through menopause—including exogenous hormonal utilization—are also not well understood. Branch-funded research in this area includes investigator-initiated grants and clinical trials networks; NICHD, the National Institute of Allergy and Infectious Diseases, and other NIH participating organizations also co-fund the Multicenter AIDS Cohort Study/Women’s Interagency HIV Study Combined Cohort Study , the largest domestic cohort of men and women either with or at risk for HIV. Areas of research interests include:
- Natural history of HIV in women: Risk factors for HIV acquisition and disease progression, use of and response to antiretroviral therapy, and complications of HIV and its therapy
- Gender-specific manifestations of HIV: Differences in immunologic and virologic parameters of HIV disease, and the gender-specific clinical manifestations of HIV (e.g., cervical cancer)
- Impact of therapy on HIV in women: Benefits in slowing disease progression and improving survival; complications of therapy; interactions with other chronic infections, such as hepatitis C virus; and impact on concomitant conditions, such as genital neoplasia
- Interactions of HIV acquisition and HIV disease progression with endogenous and exogenous hormones: The relationship between hormones and interaction of menopause and changes related to aging on HIV, viral load, and genital viral shedding, and complications of therapy, including pharmacologic interactions between hormonal replacement or contraceptive treatment and antiretroviral therapies
- HIV sexual transmission: Enhanced understanding of the biologic mechanisms of transmission to women, and prevention of heterosexual transmission through use of microbicides or pre-/post-exposure antiretroviral prophylaxis
Program Official: Sonia Lee
A major focus of the branch is the prevention of perinatal transmission both domestically and internationally. Perinatal transmission studies in pregnant women must consider potential effects of in utero drug exposures on the fetus and possible delayed effects in later childhood. Therefore, studies are needed that look at long-term follow-up of uninfected children who are perinatally exposed to increasingly complex antiretroviral regimens to evaluate for delayed adverse consequences of such exposure.
Additionally, because of changes in pregnancy that affect drug pharmacokinetics and pharmacodynamics, it is essential to evaluate drugs that will be used for prevention or treatment of HIV or associated infections in pregnant and lactating 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.
MPIDB supports a large portfolio of domestic and international investigator-initiated grants in addition to maternal and infant studies within clinical trials networks. The branch, in collaboration with other institutes, supports clinical trials within the NICHD Domestic & International Pediatric & Maternal HIV & Other High-Priority Infectious Diseases Clinical Studies Network (NICHD Network) and the International Maternal, Pediatric, Adolescent AIDS Clinical Trials (IMPAACT) Network. The branch also supports observational studies in the PHACS and the International epidemiologic Databases to Evaluate AIDS. These projects are pursuing research focused fon the following areas:
- HIV in pregnancy
- Effect of HIV on pregnancy and the fetus
- Effect of pregnancy on therapy for HIV, with a focus on differing susceptibility to certain drug toxicities in pregnant women and the effect of drugs on the fetus and infant
- Pharmacokinetics and safety of antiretroviral and other antimicrobial agents in pregnant and lactating women and their infants
- Special considerations associated with adherence in pregnant and postpartum women
- Conception, pregnancy, and risk of HIV acquisition
- Primary prevention, including antiretroviral pre-exposure prophylaxis of HIV in pregnant and lactating women in high-prevalence areas
- Prevention of Perinatal Transmission
- Evaluation of interventions to reduce and ultimately eliminate perinatal transmission globally
- Evaluation of novel approaches for more effective implementation of proven interventions for perinatal transmission in resource-limited settings (in partnership with the President’s Emergency Plan For AIDS Relief and other agencies)
- Novel approaches to identification of HIV and to linkage and retention in care, particularly in resource-limited settings, for women with HIV and their children
- Novel approaches to prevention of perinatal transmission, such as immune-based interventions
- Effects of in utero antiretroviral exposure
- Pregnancy outcome and birth defects with antiretroviral drug exposure
- Surveillance for long-term complications of fetal/infant exposure to drugs used to prevent perinatal transmission and treat pregnant and lactating women
- Co-infections in pregnancy
- The interaction of HIV and its treatment with malaria and its treatment in pregnant women, including drug pharmacokinetics and safety, and optimizing malaria prevention
- The interaction of HIV and TB in pregnant and lactating women
- The impact of sexually transmitted infections (STIs) including hepatitis in pregnancy and the prevention of perinatal transmission of STIs and hepatitis
Program Officials: Sonia Lee, Bill Kapogiannis, and Sai Majji
As HIV research has become more global in nature, research gaps in children and pregnant women related to many HIV-associated co-infections, such as TB, hepatitis, and malaria, have become evident. MPIDB has responded by promoting and funding new research related to these HIV-associated infectious pathogens.
Additionally, the National Institute of Allergy and Infectious Diseases–NICHD-funded IMPAACT Network has broadened its focus to include TB, respiratory syncytial virus, malaria, hepatitis, and investigation of vaccines to prevent HIV-related or other high-priority infectious diseases in children, adolescents, and pregnant women. MPIDB is increasing its research portfolio in infectious diseases, including Zika, TB, malaria, and hepatitis.
Zika, for example, is an important research area. Although it is spread primarily through the bites of infected Aedes aegypti mosquitoes, other forms of transmission—notably perinatal and sexual transmission—also occur. The virus has been linked to microcephaly, in addition to other problems detected in pregnancies and among fetuses and infants infected with Zika virus before birth, such as miscarriage, stillbirth, absent or poorly developed brain structures, eye defects, hearing deficits, and impaired growth.
MPIDB is also expanding its research portfolio to address the major infectious causes of morbidity and mortality in children worldwide. Although great strides have been made in reducing infectious mortality in children in resource-limited countries, infections continue to be a leading cause of child mortality in such settings. Globally, infectious diseases such as pneumonia, diarrhea, and malaria are the leading causes of mortality in children younger than age 5. Infections acquired in utero or in the immediate postnatal period play a prominent role in perinatal and childhood morbidity and mortality. A number of these infections may be mild or subclinical for the mother; nevertheless, vertical transmission can result in devastating consequences for the infant.
Areas of interest include the following aspects of infectious diseases with high morbidity and mortality rates in pediatric and maternal populations:
- Understanding disease epidemiology in different contexts, including agriculturally important animals that affect human health
- Prevention (vaccines and other strategies, such as antivirals to prevent hepatitis and cytomegalovirus) for high-priority infectious diseases
- Treatment, including pharmacokinetics and safety of antimicrobials in pediatric and pregnant/breastfeeding populations
- Effect of infectious diseases (and their treatment) on maternal and pregnancy outcomes, the placenta, the fetus, and the child
Examples of relevant diseases include:
- Zika, TB, hepatitis B and C viruses, and malaria in non-HIV-infected populations
- Congenital infections, including interactions with the human placenta: cytomegalovirus, toxoplasmosis, herpes simplex, Chagas disease, syphilis, and others
- Diarrhea and respiratory pathogens with morbidity/mortality in children/pregnant women
Program Official: Sonia Lee
Evaluating new and improved therapies for treatment of HIV and its associated complications is a high priority, and research is conducted through a variety of mechanisms, including clinical trials networks (such as the NICHD Network, IMPAACT Network, and ATN) and investigator-initiated grants. HIV treatment in children 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.
There are also many important differences between the manifestations of HIV in children and 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). 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 disease. Evaluation of the effect of therapeutics on these unique pediatric manifestations of HIV is crucial. 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.
Because most children with HIV reside in resource-limited settings, studying optimal management of HIV in children co-infected with 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 who do not have 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 among children is an important area. For example, more information is needed to identify where HIV hides, how this reservoir is established and maintained in children, and ways to control and eliminate it. 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.