John Y. Killen, M.D., Director, DAIDS
The AIDS Subcommittee of the National Advisory Allergy and Infectious Diseases Council and the AIDS Research Advisory Committee (ARAC) met jointly on June 5, 2001, at the Natcher Building on the National Institutes of Health (NIH) campus in Bethesda, Maryland. Dr. Jack Killen chaired the meeting, which was open to the public.
Report from the Director - Dr. Killen
Dr. Killen welcomed the guest presenters and thanked Drs. Koup, Lehrman, and McIntosh, and Mr. Steve Wakefield, for their work on the committee.
Research - After much effort trying to determine how to best answer the question of when to start antiretroviral therapy, DAIDS concluded that a randomized clinical trial is not a feasible approach at this time. No one has been able to outline the shape of a trial that would garner sufficient support from investigators or from potential enrollees. Attention is now shifting to epidemiological approaches that could mine existing databases collected by large cohort studies and by managed care organizations in an effort to answer some of the questions associated with when to start therapy.
The SMART study-Strategic Management of Antiretroviral Therapy-will begin as a pilot "when to switch" study under the CPCRA. It will initially randomize 1,000 patients and, if proven feasible, will expand to 6,000 patients. The study will have two arms - one that will conserve treatments by using episodic antiretroviral treatment for the minimum amount of time needed to maintain CD4+ cells at or below 250 cells/mm3 and one that will maintain viral load as low as possible irrespective of CD4+ cell count by changing antiretroviral treatment when the viral load is not suppressed. Patients will be followed for seven years with the primary end point being clinical disease progression.
The only entry criteria are HIV infection and a baseline CD4+ cell count of 350 or less. Patients may be treatment naïve or on any combination of therapy. Sub-studies will examine the development of drug resistance, metabolic changes, lipid abnormalities, change in risk behavior, and cost effectiveness. Additional specimens will be collected and stored for retrospective analysis as new and improved assays are developed.
Treatment Research in the Developing World - Dr. Killen
Dr. Killen noted that the Durban AIDS conference marked a turning point in how we think about treatment in the developing world and it is likely that as a result, treatment will become increasingly available. NIH's role is to focus on research that can inform and shape the delivery of treatment in that part of the world.
After summarizing data on the introduction of therapy in Brazil, Dr. Killen offered slides from a recent visit to Uganda that vividly described the rudimentary and isolated nature of the medical facilities. As a result, research will need to be conducted in ways unlike what is the norm for most existing NIH sponsored projects.
Dr. Killen explained that the need for operations and health systems research is more than usual for NIH and will require a broaden way of definition of high priority research. Dr. Killen stressed the need to rethink some of the restrictions that are placed on the use of NIH funds right now. There is what, he called, a firewall between research dollars and care dollars that we do not usually cross; however, that paradigm works well only in the context of the U.S., where there are safety nets of health care and does not work in the developing world.
An African Perspective- Dr. Mugyenyi
Dr. Peter Mugyenyi, Joint Clinical Research Center, Kampala, Uganda said that the top issues in Africa are the need for an HIV vaccine and treatment. He summarized the "excuses" for not introducing antiretroviral (ARV) therapy on a widespread basis in Africa: the regimens are too complicated; the medical infrastructure insufficient; compliance problems will lead to widespread resistance; limited resources should be devoted to prevention; and donors consider treatment to be "a bottomless pit." But popular pressure for ARV is growing and threatening to destabilize governments. There is a growing awareness that the ARV drugs are not that expensive to manufacture and the unnecessary deaths increasingly are seen as a violation of human rights.
Uganda's "success" with prevention efforts still results in over 100,000 new infections a year and a prevalence rate of about 8 percent in 2001. While this is down from 14-16 percent in 1990, it remains unacceptably high. He called therapeutic intervention "the missing link" in controlling the epidemic and cost is the major constraint to wider availability of ARV. While treating HIV is expensive, not treating it is equally expensive. Zambia is losing more teachers to AIDS each year than its colleges are graduating. A 17 percent reduction in economic growth is projected for Sub-Saharan Africa because of AIDS, and the problem is increasing. A baseline viral load test costs more than a month of ARV, which points to the need to develop simpler, less expensive tools to monitor HIV and the effects of therapy. Prophylaxis and treatment of opportunistic infections (OIs) also must be made more affordable, and provide opportunities for collaboration with the U.S. in developing products and approaches that can be more cost effective.
He concluded by stating that the development of regional lab facilities and training health care professionals should be among the priorities.
Global AIDS Program (GAP) Initiative - Dr. Kaplan
Dr. Jonathan Kaplan, Centers for Disease Control (CDC), said the GAP program was initiated in 1999 with $100 million in FY 2000 and $457.5 million in FY 2001. Approximately a third of the funds are administered through CDC and two-thirds through the U.S. Agency for International Development (USAID).
The overall purpose of the program is to create and evaluate programs that can be sustained in Africa. Specific goals include: reduce transmission of HIV, improve the care and support of people living with HIV, and build capacity in terms of surveillance, data management, and laboratory testing. Guiding principles are to work with host governments and NGOs and to integrate these efforts into existing structures.
GAP has supported trials of Cotrimoxazole and INH prophylaxis for tuberculosis (TB) and a trial using small amounts of bleach added to drinking water supplies to gauge the impact on enteric illness.
Questions focused on how much money is being spent in the U.S. and in the host countries, and how involved host country nationals are with the "translational research." Dr. Kaplan was urged to involve the community in shaping program priorities and implementation to the greatest extent possible.
Role of Foundations and Partnerships - Dr. Pablos-Mendez
Dr. Ariel Pablos-Mendez, associate director of the Health Equity Programs at the Rockefeller Foundation, provided a conceptual framework for leveraging the intellectual, financial, and political resources necessary for successful public-private partnerships. Building consensus on goals and approaches is absolutely critical to success.
Industry has focused on developing "blockbuster" products with annual markets of $1 billion or more; diseases of the poor have been left without much of an investment. Rockefeller has therefore, focused on market failures and orphaned diseases, such as AIDS. The foundation hopes to play the role of "neutral broker" between government and the private sector, using its "social venture capital" to induce greater interest and investment in these areas.
The International AIDS Vaccine Initiative (IAVI) is a leading example of this approach. Similar efforts are focusing on broader immunization programs, malaria, and tuberculosis. Scientific Priorities and the Role of NIH - Dr. El-Sadr
Dr. Wafaa El-Sadr, Harlem Hospital Center, said that treatment is a promise that we have to deliver on in the developing world. In the U.S. treatment includes more than simply therapy, it is a mesh or web of health maintenance through the prevention of OIs and social services that strengthened adherence to ARV. In contrast, state-of-the-art HIV care in developing countries may involve symptomatic care or end-of-life or home-based care, but nothing more.
Dr. El-Sadr called for a better characterization of HIV and associated OIs, their epidemiology, and regional variations of their manifestations. Models of care need to be developed that contain a research component with a feedback loop to rapidly and continuously translate findings into clinical practice. She strongly supported the call for better, sustainable diagnostics for HIV and OIs, as well as an immediate focus on OIs prophylaxis and treatment as more sustainable than ARV.
She argued for simple trials asking simple questions, adapted to local conditions, with the development of regional lab and monitoring capacity. She emphasized the importance of integrating prevention and the treatment research as long as one does not compromise the other. One way to do that is by rolling over the "failures" of prevention trials into treatment trials and pursuing research on adherence.
NIH's role, as she described it, is to provide research expertise and training. Nurses are fundamental to care in developing countries and they need to be included in the research. Investigators need to buy into a collective agenda and to do this requires increased coordination and money.
She closed with a slide taken from the window of the bus on the way to the airport at Kampala, Uganda. It showed "rows and rows, blocks and blocks of coffin-makers." It was her reminder of the urgency of the situation, that people are "dying and dying."
During discussion, the coordinated nature of medical research in the Francophone African countries was noted. It was suggested that NIH undertake a long-range initiative using that as a model to develop and network research institutes in the Anglophone countries, which might also add an important element of sustainability.
Discussion - Dr. Killen said the major purpose of the presentations was to help the committee develop a common level of understanding of these issues, which will help future discussions and decisions about NIH supported research.
The CIPRA Initiative-Comprehensive International Programs for Research on AIDS-will lead to an emergence of a number of research centers of excellence in the developing world, but much of the existing effort is focused on prevention. We will need to find ways to build treatment into that.
It was noted that the needs of the developing world demand increased coordination of and communication between research activities and it was suggested that lessons could be learned from the international fight against malaria. Both technical capacity and human resources must be developed.
Finally, in discussing the need to change the paradigm that separates research and care, which drives NIH policy and funding decisions, it was noted that getting study sections to think innovatively is often difficult. Care will need to be taken in selection people who think of issues in this broader context.
Concept Review
Reagent Resources Support for AIDS Vaccine Development - Dr. Bradac
The objective of this initiative is to generate and acquire critical reagents needed for multisite AIDS vaccine studies carried out through the Simian Vaccine Evaluation Units, the HIV Vaccine Trials Network (HVTN), and other selected initiatives. It differs from other programs in that it is equipped to provide large scale, quality controlled reagents necessary for large trials. The current contract has been in place for nearly 10 years. A 7-year renewal is proposed, with an increase from the current FY expenditure of $2 million to $2.5 million. After clarifying discussion the committee voted to support renewal of the program.
Primate Immunology Laboratory - Dr. Miller
This contract supports state-of-the-art laboratories that evaluate simian immune responses to preventive HIV vaccines. It provides consistency and quality control in evaluating trials conducted at various sites, allowing comparisons of data across sites.
The new contract will add development of assays to evaluate mucosal responses and measure RNA at mucosal sites. It will expand from a panel of 6 to 25 primary viral isolates that are evaluated. It will add the capability to provide standardized protocol-training quality control for laboratories that are conducting cellular assays on site.
The current contract involves 650 monkeys spread over three contractors. The renewal/expansion would have a first year budget of $7 million, with 1-4 contract awards.
Reviewers emphasized the importance of centralizing and standardizing these functions from both scientific and cost-effectiveness perspectives. The committee approved renewal of the concept for this initiative.
Innovation Grants in AIDS Research - Dr. Dieffenbach
This is a new, three-year program that uses the R21 innovation grant mechanism. It will begin in FY 2003, with a first year goal of 30-40 awards. The $150,000 exploratory grants are seen as stepping-stones to a full RO1grant proposal. It builds upon a similar, very successful program in the vaccines arena, initiated in 1997, that has increased the number of conceptual approaches and the number of investigators involved with HIV vaccine research. Investigators are expected to devote at least 15 percent of their time to this project. Special emphasis panels will review the proposals.
The reviewers emphasized the need for special emphasis panels capable of dealing with innovation and approved renewal of the concept for this initiative.
Innovation Grants in Human Immunology - Dr. Plaeger
This new initiative will use the R21 grant mechanism, with a similar three-year term and goal of 30-40 awards. It differs from the previous proposal in that it is a trans-NIH initiative, with funding from a variety of Institutes, seeking a better understanding of the human immune system and disease. The hope is that researchers with various disease focuses will "cross-pollinate," bringing fresh approaches to the topic.
It is modeled after a 1998 trans-NIH "think tank" and initiative that produced one round of funding. Innovations that sprang from this exercise include development of the TREC assay [T-cell receptor excision circle assay] to measure thymic output of T-cells in humans, and in vivo use of gluterated glucose to measure lymphocyte turnover.
A March 2000 "think tank" identified focus areas for this program. They include gaining a better understanding of microenvironments in the human body; T-suppressor cells, particularly CD4-positive and CD25-positive cells; immune system homeostasis; and the effects of age and gender on development and function of the immune system. The committee voted to approve the concept for this initiative.
Women's Interagency HIV Study (WIHS) - Dr. Williams
This initiative supports the continuation/expansion of this epidemiological study, which began in 1994. It will be continued for five more years, with a first year cost of $12.9 million. The study has enrolled 1,561 women and is slated to enroll an additional 1,078 women beginning with the next fiscal year. The increased enrollment will ensure sufficient statistical power to evaluate clinical endpoints in the era of HAART. The cohort is over half African American and a quarter Latina, with low socioeconomic status, mirroring the HIV epidemic in women the U.S.
The depth and breadth of the issues being examined by the WIHS was commended during the review, however, it was also noted that none of the sites serve women in rural areas and none will be added under the expansion as is currently envisioned. HIV infection is growing rapidly among women of color in the rural South.
It was also noted that the use of the same statistical and data center [Johns Hopkins University] for the WIHS and the Multicenter AIDS Cohort Study (MACS) has resulted in and, will continue to result in, an increasing ability to compare and to contrast the natural history of this infection in both men and women. The committee voted to approve the concept for this initiative. back to top |