By Carl W. Dieffenbach, Ph.D., Director of the Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health
September 11, 2017
Take a moment to imagine the future of the HIV pandemic, and how we as the research community can make that future better. Do you envision that 10 years from now, we have long-acting prevention and treatment strategies that are effective for at least 6 months, or an HIV vaccine with efficacy greater than 60 percent? Perhaps you see a functional cure in a large percentage of people living with HIV, a reduced burden of TB co-infection and non-infectious co-morbidities, or normal life expectancies for antiretroviral therapy (ART)-treated people.
Meeting these goals would be a realization of NIH’s mission to drive the scientific discoveries that improve health and save lives. To accelerate this progress, we must first answer a big question: How can NIH most effectively advance the HIV research enterprise to reach these ends? This is the question we will answer in the coming months, informed by input from the research community.
The NIH HIV research agenda is grounded in three key areas: non-vaccine prevention, vaccines and therapeutics. We plan to create three clinical trials networks, one to address each of these disciplines. Since these research areas overlap and intersect, we will encourage cross-network collaboration and partnership for innovation.
Currently, pediatric HIV research is conducted in one network, which has contributed to remarkable successes in preventing perinatal HIV transmission and treating pediatric HIV. Closing the chapter on perinatal transmission, pediatric research must now become part of HIV research across the lifespan, fully integrated into the research agendas guiding the prevention, vaccine, and therapeutics networks. Strategies for adolescents are the next frontier in prevention research, and for younger children we will focus on cure, vaccine and co-infections research. Pediatric needs must be recognized as paramount in all three networks as cutting-edge science is developed. In fact, NIH will most likely need to expand the enrollment capacity of the clinical trials networks and sites to conduct studies involving children and adolescents.
Vaccines and Prevention
The goal of the HIV prevention research agenda is to develop modalities that are safe, effective and acceptable. In May, I wrote about how HIV prevention and vaccine research are inextricably linked. Developing a safe and effective HIV vaccine would be the most transformative prevention modality and is the highest priority in HIV research.
The overarching goal of the HIV vaccine research agenda is to evaluate promising HIV vaccine concepts for safety, efficacy and durability. When a threshold of safety is achieved, we can begin evaluating the concept in pediatric populations. When a threshold of efficacy is achieved, we must define the correlates of protection to inform future research and move the products into larger trials in adolescent and pediatric populations. Should vaccine candidates prove efficacious, we will also need to establish an understanding of the durability of protection and bridge from Phase 2b/3 studies to licensure so these products can reach the populations that need them most. While the complexities of vaccine research necessitate specialization within one network dedicated to the pursuit of an HIV vaccine, seamless collaboration with the broader HIV prevention research effort will be critical to developing an array of prevention tools.
Thanks to innovation from NIH-funded scientists, now we have effective prevention tools including daily oral pre-exposure prophylaxis (PrEP), post-exposure prophylaxis (PEP), voluntary medical male circumcision, and a dapivirine vaginal ring. However, as we think about what other tools to develop with the greatest likelihood of substantially reducing new infections, certain criteria emerge. We must develop prevention modalities that are safe, desired and highly effective. These tools should provide systemic protection irrespective of route of exposure. With long-acting injectables, implantables and sustained-release oral formulations currently in development, we must determine what gaps exist in the prevention toolkit, and work to fill them. Prevention strategies must be targeted to the populations at greatest risk, particularly adolescents and young adults, who bear the greatest burden of new infections worldwide.
New sustained-release and long-acting HIV treatments could deliver even better patient outcomes, and improve adherence to these lifesaving medications. An achievable goal in the next decade is to establish the efficacy of long-acting formulations that are fully suppressive and dosed at every six months or longer.
Despite the advancements in ART, pediatric populations lack equal access to new and more effective therapies. The therapeutics research field must continue to evaluate formulations for safety, pharmacology, pharmacokinetics and virologic suppression in children of all ages. We must assist licensure, which will facilitate global availability for the safest and most effective medications for all HIV-infected people, beginning at birth. This type of safety evaluation also must examine newer forms of ART in pregnancy.
As people with HIV continue to live longer, we recognize that HIV co-infections can have a significant impact on their health. As an example, tuberculosis (TB) is the world’s deadliest HIV co-infection, and the TB and HIV epidemics have debilitating, synergistic interactions. It is no longer sufficient to treat HIV alone. It is critical that we define shorter and more effective treatment regimens for both drug-sensitive and drug-resistant TB, and improve preventive therapy and treatment for extra-pulmonary disease in all appropriate ages. Significant gaps exist in our knowledge about TB in the areas of biomarkers, diagnostics, and drug susceptibility testing. Unique aspects of pediatric TB require additional research to define diagnostics. Evaluation of TB vaccines designed to prevent acquisition and/or latency reactivation remains a critical long-term goal. Curative strategies for hepatitis B coinfection will also be a major priority.
To address the growing rates of non-infectious comorbidities that affect people with HIV as they age, it is essential the research community define the shared, underlying mechanisms for these comorbidities, and partner to address the highest priority end organ diseases.
Whether through clearance, control or by silencing the persistent viral reservoir, the goal of developing a safe and scalable cure in children and adults remains part of the HIV research paradigm. Additionally, novel exploratory methods to induce remission (e.g., gene therapy) as well as mechanistic studies on the drivers of HIV persistence (e.g., immune activation) may have a limited role in the cure research agenda.
Collaboration and Partnerships
Since this conversation began earlier this year, I have heard the research community call strongly not only for continued biomedical and behavioral innovation, but also for enhanced access to and implementation of these innovations in the field. This is critical to ending the pandemic as we know it and can only be accomplished in partnership with other players in the HIV response. The story of HIV drug development, as a series of partnerships between the community, government, academia and the pharmaceutical industry, is perhaps the last century’s single greatest success story in medicine. We are committed to continuing this approach.
The next iteration of the HIV research enterprise will need to be even more flexible and collaborative. Experts from multiple networks must join forces for interdisciplinary pursuits like therapeutic HIV vaccines and vaccines for diseases relevant to HIV-positive children. We will also need to continue partnering with the pharmaceutical industry to assure successful completion of licensure trials, and manufacturing and distribution at a global scale. To accelerate our progress in controlling HIV, we must continue to work closely with global partners like the President’s Emergency Plan for AIDS Relief, foreign governments and the World Health Organization to address implementation issues abroad, and with our federal partners and local health networks in the United States.
I invite you to continue to share your thoughts with us as we answer big questions about the future of HIV clinical research. Comments will be accepted until November 30, 2017. I will make a formal presentation on the network refinement in January 2018 at NIAID’s AIDS Research Advisory Committee meeting.