Interviews on “The global research on therapeutic approaches for pediatric HIV infection”

Lynne M. Mofenson is a key member of the Independent Scientific Advisory Board, and provides external consultancy for EPIICAL. She is a pediatric infectious disease specialist who has spent her career doing research on prevention and treatment of pediatric and maternal HIV infection. She currently serves as Senior HIV Technical Advisor to the Research Program at the Elizabeth Glaser Pediatric AIDS Foundation, where she is assisting in evaluating implementation of many of the interventions on treatment and prevention that she helped to design while at NIH.

Interview with the ISAB about the relevance of the pediatric model to gain knowledge in HIV infection – Lynne M. Mofenson

Q. Could you please explain to us the relevance of conducting studies in the pediatric population and how HIV epidemiology has changed over time?

A. When I began my career in pediatric HIV research in the early 1980s, one in every four women living with HIV in the United States and nearly one in every two women in Africa transmitted HIV from mother to child during pregnancy, delivery, or, in Africa, breastfeeding. Additionally, almost half of infants infected with HIV died before the age of two years. Since the 1980s, we have seen remarkable advances in both prevention and treatment of HIV infection in children. With suppressive maternal antiretroviral therapy, the number of mother-to-child transmissions is now less than 1% in resource rich countries and under 5% in low resource countries where there is breastfeeding, and with early antiretroviral therapy, children living with HIV are now living into adolescence and young adulthood and having uninfected children of their own. However, despite progress, there were still 180,000 new infections in children in 2017 and 120,000 HIV-related deaths among children. We still have significant evidence gaps with regards to how to best diagnose, treat and deliver services to children living with HIV.

Q. How have the studies on pediatric HIV infection changed the current knowledge about the disease?

A. In 1994, the initial study of zidovudine to prevent mother-to-child HIV transmission, ACTG 076, was actually the first study to demonstrate treatment is prevention, serving to stimulate further research in this area in the adult population related to sexual transmission, shown by the results of HPTN 052 in 2016. Small studies showing the efficacy of very early treatment of HIV among HIV-infected neonates, such as the PACTG 356 study, in the early 2000’s, led to the CHER trial in 2008, which demonstrated that early treatment, regardless of CD4 cell count, within the first weeks of life resulted in a significant decrease in morbidity and mortality – 7 years before the START trial demonstrated this in adults in 2015. The Mississippi baby was the first demonstration that very early treatment – within hours of birth – could lead to significant duration of viral remission, and served to stimulate further trials in HIV cure in adults, as well as children.

Q. What are the main issues concerning HIV infected children to date?

A. Far too many children are still acquiring HIV and dying of AIDS-related illnesses. The lack of appropriate drug formulations for young children and the delay in obtaining pharmacokinetic and safety information on appropriate dosing for children and adolescents results in a significant delay in being able to use more potent new antiretroviral therapies in children and youth. While mother-to-child transmission has decreased, there are still new infections, and the vision of HIV treatment would be to initiate potent therapy within hours to days of birth to restrict the development of a viral reservoir and potentially allow curative interventions in children who have continued viral suppression on treatment. However, without appropriate formulations and dosing, the vision of very early treatment of children cannot occur. As children are now surviving into young adulthood with potent therapy, evaluation of the long-term effect of HIV infection and/or exposure to treatment on development of comorbidities, particularly non-communicable diseases, is needed as well as studies on how to intervene to reduce or prevent such comorbidities. Additionally, it is increasingly recognized that exposure to HIV infection and/or antiretroviral drugs during fetal and early infant development may have a short- and long-term impact on the health of children who escape HIV infection, and further data are needed to evaluate if such exposure does result in adverse consequences for the HIV-exposed but uninfected child, duration of such consequences, and how to treat or prevent them.

Q. In your opinion, how does the EPIICAL project address the needs of children living with HIV?

A. The EPIICAL project builds on earlier research demonstrating that children treated with suppressive antiretroviral therapy from early infancy represent a unique population of individuals treated within hours to days of infection resulting in restricted viral reservoirs and preserved immune system, and are the optimal group to study novel strategies to achieve treatment-free HIV remission. The first demonstration of the possibility of HIV remission (without requiring bone marrow transplantation!) was the Mississippi baby, and it is highly likely that studies of HIV remission among early-treated children, as opposed to adults, will be the optimal way to demonstrate remission (and potentially cure) might be possible. The goal of EPIICAL is to establish an international collaboration of experts from a broad spectrum of scientific expertise to further the study of early treatment in infancy, to develop the tools needed to characterize the immune/viral/genomic profiles of viral control that can be applied to children, and to form a platform for further studies of remission/cure such as use of HIV vaccine in children with early treatment and prolonged viral suppression. This is a unique, multidisciplinary collaboration that will strengthen the capacity of research in pediatric HIV remission/cure, with the goal of improving the long-term health of perinatally-infected children.

Jintanat Ananworanich is the leader of the pioneering Proof of Concept study in the EPIICAL project. She is Professor of Global Health at the Amsterdam Institute for Global Health and Development/University of Amsterdam in the Netherlands. She is based in Maryland, USA as the Associate Director for Therapeutics Research for the US Military HIV Research Program. Her primary research interests are in acute HIV infection, early treatment, neuro AIDS and HIV cure. She has published 300 articles in the field of HIV, ranging from basic science to clinical trials to public health epidemiology, and across the age span from infants to adults.

Interview on the recent relevant trials in the field of HIV and applicability in the pediatric population – Jintanat Ananworanich

Q. What are the more promising therapeutic approaches evaluated in children?

A. Broadly neutralizing antibodies given with antiretroviral therapy to infants newly infected with HIV hold promise in generating HIV-specific humoral and cellular immune responses that may lead to ART-free viremic control. These antibodies could also be evaluated in children who are virally suppressed on ART. Ideally at least three bNAbs should be used with an immune adjuvant that could stimulate the innate immunity and enhance clearance of infected cells by antibody-dependent cellular mechanisms.

There are several vaccine candidates that could be considered in pediatric trials.  EPIICAL is evaluating a prime-boost HIVIS DNA and MVA-CMDR vaccine regimen in early treated, long-term virally suppressed children from South Africa, Thailand and Italy. The HIVIS DNA is adjuvanted by a toll-like receptor 4 agonist aimed to enhance DNA uptake and HIV-specific immune responses.

Q. Which promising approach evaluated in adults could be applied in the pediatric population?

A. Broadly neutralizing antibodies, therapeutic HIV vaccines and cell-based therapies show promise in adults and could be applied to the pediatric population. Children have superior capacity to generate de-novo immune responses and immunotherapeutics may work better in children than in adults.

Q. Do immunotherapeutic strategies have potential advantages over the other approaches?

A. ART-free viremic control likely requires persistent, effective immune surveillance, and immunotherapeutics are the only strategy that can deliver this.

Q. Why are early-treated children a unique opportunity to evaluate new immunotherapeutic strategies?

A. Early-treated children have a small reservoir size, limited viral escape and preserved immunity. Therefore, they are ideal candidates for strategies towards a cure of HIV.