Despite Great Strides, More is Needed in Pediatric AIDS Research

Laura Guay

When the Elizabeth Glaser Pediatric AIDS Foundation (EGPAF) was established in 1988, most AIDS research was focused on adults, not on the unique pathways of transmission to children or the distinct medical challenges facing HIV-positive children.  Elizabeth’s tenacity in fighting for her own children helped ensure that all children were not forgotten as scientists tackled the mysteries of HIV and AIDS. Since then, the scientific and medical advancements in the fields of (PMTCT) and HIV care and treatment have been extraordinary. Scientifically, we know how to prevent transmission of HIV from mothers to their children. The UNAIDS 2010 report on the global AIDS epidemic reflects increased momentum toward the elimination of pediatric HIV and AIDS worldwide, and documents significant progress in increasing access to services to prevent mother-to-child transmission (PMTCT) of HIV, reducing new infections in children, and providing treatment for children (Figure 1a). Despite this success, there were still an estimated 370,000 new pediatric HIV infections in 2009 – more than 1,000 preventable infections every day.1

Pediatric research remains essential to ensuring the survival and well-being of HIV positive children, and ultimately achieving the goal of eliminating pediatric HIV and AIDS. The pediatric AIDS research agenda encompasses critical basic science, clinical and operational research questions (Table 1). Many priority research questions are unique to infants, children and adolescents, hence it is vitally important that research resources be devoted specifically to this population.

With critical support from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institutes of Health has announced that it will fund a pediatric-specific leadership group in the upcoming re-structuring of the National Institute of Allergy and Infectious Diseases HIV clinical trials networks.2 The proposed areas of focus for this research network include the testing of vaccines to prevent HIV infection in adolescents and infants born to HIV-positive women, which cannot wait until a vaccine is found to be effective in adults (Table 1). Just as antiretroviral drugs (ARVs) were shown to provide significant protection against mother-to-child transmission of HIV long before studies of similar regimens showed protection against heterosexual HIV transmission in adults, an HIV vaccine may protect breastfeeding infants even if it is not effective in adults with sexual or intravenous exposure.

With known HIV exposure from a single identifiable source for a limited duration, studying mother-infant pairs with and without HIV transmission provides a unique opportunity to answer basic immunology, virology and neonatal immunity questions that can advance our scientific knowledge about HIV transmission.

The new 2010 WHO guidelines for the use of ARVs for the prevention of mother-to-child transmission and antiretroviral therapy (ART) for treatment of infants and children represent significant changes and progress in the prevention of infection and treatment of those living with HIV.3, 4 Implementation of these new guidelines must be accompanied by additional clinical research as several recommendations are based on extrapolation of data from clinical trials, without a strong evidence base. For example, clinical trials are underway to address the safety and efficacy of extending maternal or infant ARV prophylaxis during breastfeeding from the previously studied six months period to the currently recommended 12 months, however additional data are needed on the long-term safety of in-utero exposure to ARVs. Determining the cost effectiveness of the new regimens and their impact on HIV- free survival in infants will allow more effective decision-making for program scale-up. Identifying HIV- positive pregnant women who require ART for their own health is a critical component of the PMTCT guidelines, however this is challenging in settings with limited access to CD4 cell counts. The development and testing of inexpensive, simple point-of-care CD4 testing that can be performed in the lowest level health facilities, as well as point-of-care early infant diagnosis (EID) and viral load monitoring, will significantly advance HIV prevention, care and treatment efforts for infants and adults. Similarly, research is needed on innovative ways to use new technologies, such as mobile health initiatives, to improve the effectiveness of PMTCT and treatment programs. Since approximately half of untreated children with HIV infection will die before their second birthday, identifying strategies to maximize early HIV diagnosis and rapid initiation of ART with appropriate drug formulations in infected infants is key to improving child survival.

Although there are important basic and clinic research questions remaining, our failure to achieve virtual elimination of pediatric HIV and AIDS, and universal access to care and treatment for mothers and children globally is a failure not of science, but of implementation.  The translation of results obtained in clinical trials into routine health services in the field has been met with considerable barriers. The PEARL study, conducted in facilities with PMTCT services in four African countries, demonstrated progressive drop-out at every step in the PMTCT cascade. When combined with the number of women who never access antenatal services, the effectiveness of PMTCT programs is substantially reduced.5 The transition to the most effective regimens for PMTCT will make little overall difference in national transmission rates unless the challenges of limited health service delivery, access and uptake that prevent large numbers of HIV positive pregnant women from receiving any ARV are addressed. Research is crucial to provide health ministries, funders and implementing staff evidence-based, innovative, effective, and scalable interventions with demonstrated impact on overcoming current barriers to effective PMTCT programs.

In response to the critical need for operations and implementation research, UNICEF, WHO and UNAIDS, in collaboration with the George Washington University and EGPAF, held an expert technical consultation on operations research.6 The goal of the consultation was to identify the highest priority operations research questions to promote the rapid national scale-up of PMTCT and pediatric HIV care support and treatment (CST) programs. Attendees identified 20 priority research questions in the areas of PMTCT, Pediatric CST, integration of PMTCT and MNCH services, and health systems (Table 1). The International AIDS Society held a parallel consultation that included generation of priority clinical research questions for PMTCT and pediatric treatment (Table 1).7 These consultations provide a research framework to guide governments, researchers, and funders in prioritizing pediatric HIV activities.

In summary, while significant progress has been made in the field of pediatric HIV and AIDS globally, considerable research gaps remain. We cannot afford to lose the momentum of the last decade as we enter a new one. Continued strong advocacy for resources to ensure the pediatric HIV/AIDS research agenda is addressed as a high priority is required until we achieve an HIV-free generation.

Table 1: Priority Pediatric HIV/AIDS Research Areas
(Identified from three key consultations)

Priority pediatric clinical research areas proposed for a new NICHD/NIAID sponsored pediatric, maternal and child health HIV clinical trials network:
1. Define optimal, safe drug doses for antivirals and anti-infectives (e.g. new tuberculosis medicines) used in infants, children, adolescents, as well as pregnant women and women who have recently given birth
2. Management of HIV-related co-infections, co-morbidities and consequences of chronic antiretroviral drug exposure;
3. Build on established findings involving prevention of mother-to-child transmission of HIV and other associated infectious diseases;
4. Target the prevention of HIV infection among adolescents in resource-limited and domestic settings through collaborative studies with other clinical trials networks;
5. Improve diagnostics for use in children affected by HIV and associated diseases; and
6. Evaluate the safety and immunogenicity of vaccines designed to protect against HIV and other infectious co-morbidities in infants, children, adolescents, pregnant women, and women who breastfeed their babies.

 

UNICEF/WHO/UNAIDS Expert Consultation on Operational Research on PMTCT and Paediatric HIV

Maximizing PMTCT effectiveness
1. What are effective strategies for provision and monitoring of CD4 testing and antiretroviral treatment (ART) for eligible pregnant and breastfeeding women?
2. For postpartum prophylaxis during breastfeeding:
a. What are effective strategies for implementation?
b. What is the comparative effectiveness of infant versus maternal prophylaxis?
3. What are feasible and valid methods to measure PMTCT effectiveness for both maternal and infant outcomes at both the program and population levels?
4. What are the community strategies to effectively increase PMTCT uptake?
5. How can family and male partner involvement be increased? Does family and male partner involvement increase PMTCT uptake and successful completion of the cascade?

Pediatric HIV and AIDS care, support, and treatment
1. What is the optimal model for delivery of comprehensive care and treatment for HIV-infected infants and children?
2. What are the best models to provide care and support services to exposed infants?
3. What are the interventions at the program, facility, community, and household levels that have greatest impact on retention in care, especially in the first 12 months of life?
4. What are the best interventions to support implementation and uptake of infant feeding recommendations?
5. How can the maximum number of HIV-infected infants and children be identified early?

Integration of HIV programs within broader Maternal, Newborn and Child Health (MNCH) programs
1. What is the feasibility and impact of integrating provider initiated testing and counseling (PITC) services and care for HIV-exposed infants into routine MNCH services?
2. What is the feasibility and impact of providing ART for eligible pregnant women in antenatal clinics (ANC)?
3. What is the appropriate timing, content, and setting within MNCH services to ensure the integration and provision of family planning (FP) services to HIV-positive women?
4. How can community health workers and peers increase utilization of MNCH and HIV/AIDS services?
5. What are the benefits, challenges, cost-effectiveness, and effects on service utilization of integrating PITC into expanded program on immunization (EPI) services for children under five?

Health systems in the context of PMTCT and pediatric CST
1. Task shifting: What is the effect and impact of task shifting on PMTCT and pediatric CST scale-up in various settings, at various levels of the health care system and among different cadres of health workers?
2. Data: What is the effect of different approaches to data collection on data quality and data use at all levels of the health care system?
3. Governance: What is the effect of innovative approaches for improving sub-national planning and management of health services, using PMTCT and Pediatric CST as tracer interventions?
4. Financial accountability and management: What are cost-efficient models for delivering PMTCT and Pediatric CST within the broader context of MNCH services?
5. Logistics: What is the impact of various approaches to supply chain management on PMTCT services / scale-up (availability .... outcome)?

 

Consensus Statement: Asking the Right Questions: Advancing an HIV Research Agenda for Women and Children.
Clinical Research: PMTCT and Paediatric Treatment
1. Invest in innovative drug manufacturing and delivery systems (e.g., dissolvable films, microtablets) to address the need for appropriate paediatric formulations.
2. Evaluate a range of weight-adjusted dosage recommendations and fixed dose combinations (FDCs) for children.
3. Invest in innovative TB and HIV diagnostics and monitoring to facilitate paediatric and early infant diagnosis and treatment.
4. Review currently enrolled clinical trials and conduct necessary clinical studies to evaluate the impact of co-morbid conditions and their treatment on drug dosage and toxicity, with priority given to TB, malaria and malnutrition.
5. Ensure a more comprehensive pharmacovigilance system by expanding the existing antiretroviral pregnancy registry to include low- and middle-income country cohorts/pilots and establishing an appropriate follow-up registry to evaluate the impact of ARV exposure in utero or during extended infant prophylaxis on uninfected children in resource-limited settings.
6. Review existing data and currently enrolled trials to establish optimal treatment strategies for children.

References

1 2010 UNAIDS Report on the Global AIDS Epidemic
2 AIDS.gov
3 Antiretroviral Drugs for Treating Pregnant Women and Preventing HIV Infections in Infants: Recommendations for a public health approach. 2010 version. World Health Organization
4 Antiretroviral Therapy for HIV Infection in Infants and Children: Towards Universal Access: Recommendations for a public health approach. 2010 version. World Health Organization
5 Stringer E, Ekouevi D, Coetzee D, et al. Coverage of Nevirapine-Based Services to Prevent Mother-to-Child HIV Transmission in 4 African Countries. JAMA. 2010;304(3):293-302
6 UNICEF
7 International AIDS Society

Dr. Laura Guay serves a dual appointment of vice president of research for the Elizabeth Glaser Pediatric AIDS Foundation and as research professor at The George Washington University School of Public Health and Health Services.