The following information describes the branch's research programs and program areas.
Program Staff: 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 22% of all new HIV diagnoses in 2015. That same year, approximately 8,800 youth were diagnosed with HIV in the United States; 81% were gay or bisexual males. 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 in 2016, there were an estimated 260,000 new HIV infections among adolescents. In sub-Saharan Africa, two our of three newly infected 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 (both with HIV-infected and -uninfected youth) and studies of HIV vaccines, microbicides, and pre-exposure prophylaxis (PrEP) in uninfected, at-risk youth.
Treatment of HIV-infected adolescents 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 HIV-infected populations is critical. But even in the best of circumstances, 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 infected youth are the higher rates of undiagnosed HIV infection, 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 infected youth 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 recently infected youth. 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. International research in adolescent HIV infection, disease, and prevention is an expanding area for the branch, in collaboration with other HIV/AIDS research networks supported by NIH.
Program Staff: Rohan Hazra
With the availability of treatment, increasing numbers of children infected 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 infection and long-term antiretroviral therapy on multiple organs and systems in the body, which 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 infection and its treatment, many survivors of perinatal HIV infection face a multitude of transitions, including 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 perinatally HIV-infected adolescents and young adults is critical.
MPIDB is actively conducting research related to the long-term effects of HIV and its therapy in perinatally infected youth both domestically (for example, the Pediatric HIV/AIDS Cohort Study) and internationally (for example, RFA-HD-16-033: HIV-infected adolescents: Transitioning from the Pediatric to the Adult Care Setting). 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 perinatally infected youth
- Substance use and abuse
- 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 Staff: Rohan Hazra
Unique considerations for infants, children, and adolescents with respect to the pathogenesis of HIV infection warrant research specifically focused on these populations. As potent therapy has become available, HIV infection 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 perinatally HIV-infected children in the United States are older than age 15 years. Studies from resource-limited countries are beginning to show similar survival of this population into adolescence and young adulthood as access to antiretroviral therapy expands. Increased survival of HIV-infected children has been associated with challenges in maintaining adherence to long-term therapy and in selecting successive antiretroviral drug regimens. This is further complicated 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 infection and its therapy is further complicated by the presence of endemic diseases, such as tuberculosis, 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 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 tuberculosis, 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
- Tuberculosis diagnostics
- Point-of-care technologies
Program Staff: Denise Russo and Nahida Chakhtoura
MPIDB also has a strong focus on HIV in women. Worldwide, HIV prevalence in women is increasing, and transmission during heterosexual intercourse is the primary means by which women become infected. A range of factors contribute to women's increased vulnerability to HIV-1 acquisition, including biology and structural and socioeconomic factors that define gender inequality in different contexts, 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 and the National Institute of Allergy and Infectious Diseases also co-fund the Women's Interagency HIV Study (WIHS) , the largest domestic cohort of HIV-infected and at-risk women. Areas of research interests include:
- Natural history of HIV infection in women: Risk factors for HIV acquisition and disease progression, use of and response to antiretroviral therapy, and complications of HIV infection and its therapy
- Gender-specific manifestations of HIV: Differences in immunologic and virologic parameters of HIV disease, and the gender-specific clinical manifestations of infection with HIV (e.g., cervical cancer)
- Impact of therapy on HIV infection 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 infection, 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 Staff: Nahida Chakhtoura
A major focus of the branch is the prevention of MTCT both domestically and internationally. MTCT 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 must conduct 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 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.
MPIDB supports a large portfolio of domestic and international investigator-initiated grants in addition to studies within clinical trials networks the branch supports, including the NICHD Domestic and International Pediatric and Maternal HIV Clinical Studies Network in collaboration with the International Maternal, Pediatric, Adolescent AIDS Clinical Trials (IMPAACT) Network, observational studies in the Pediatric HIV/AIDS Cohort Study, and through collaborations with the President's Emergency Plan for AIDS Relief (PEPFAR). These projects are pursuing research focused on the following areas:
- HIV in pregnancy
- Effect of HIV infection on pregnancy and the fetus
- Effect of pregnancy on therapy for HIV infection, 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 women and their infants
- Special considerations associated with adherence in pregnant and postpartum women
- Conception, pregnancy, and risk of HIV acquisition
- Primary prevention of HIV in pregnant and lactating women in high-prevalence areas
- Prevention of MTCT
- Evaluation of interventions to reduce and ultimately eliminate MTCT globally
- Evaluation of novel approaches for more effective implementation of proven interventions for MTCT in resource-limited settings (in partnership with PEPFAR and other agencies—see RFA-HD-12-210: NIH/PEPFAR Collaboration for Advancing Implementation Science in Prevention of Maternal-Child HIV Transmission and RFA HD14-027: Safety and Effectiveness of Triple Antiretroviral Drug Strategies for Prevention of Mother to Child HIV Transmission)
- Novel approaches to identification of HIV infection and to linkage and retention in care, particularly in resource-limited settings, for HIV-infected women and their children
- Novel approaches to prevention of MTCT, 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 infections 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 tuberculosis in pregnant and lactating women
- The impact of infectious hepatitis in pregnancy and prevention of mother-to-child transmission of infectious hepatitis
Program Staff: Rohan Hazra and Bill Kapogiannis
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 tuberculosis(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 International Maternal, Pediatric, Adolescent AIDS Clinical Trials (IMPAACT) Network has broadened its focus to include TB, 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 mother-to-child 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 of 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 years. 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
- 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, and others
- Diarrhea and respiratory pathogens with morbidity/mortality in children/pregnant women
Program Staff: Rohan Hazra
Evaluating new and improved therapies for treatment of HIV infection 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 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 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 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). 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. 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 HIV-infected children reside in resource-limited settings, studying optimal management of HIV infection 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 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 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 to identify ways to control and eliminate it. To stimulate research in this area, 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.