Meeting Minutes - April 10, 2014

Office of AIDS Research Advisory Council
Thirty-eighth Meeting
April 10, 2014

National Institutes of Health
U.S. Department of Health and Human Services
5635 Fishers Lane Conference Center
Rockville, MD

Members Present: Dr. Jack Whitescarver (Executive Secretary), Dr. Stefano Bertozzi*, Dr. Myron S. Cohen, Dr. Steven Deeks, Dr. Monica Gandhi*†, Dr. Igor Grant*, Dr. Roy M. Gulick, Dr. Priscilla Hsue†, Dr. Daniel R. Kuritzkes†, Dr. David Malebranche, Dr. Ronald T. Mitsuyasu*†, Mr. Mitchell J. Warren, Dr. Darrell P. Wheeler, Dr. Craig M. Wilson

*Participated by teleconference
†Membership pending clearance

Ex Officio Members Present: Dr. Myron Cohen, National Advisory Allergy and Infectious Diseases Council; Dr. Carl W. Dieffenbach, Director, NIAID Division of AIDS; Dr. Nabila El-Bassel, National Advisory Council on Drug Abuse; Dr. Roy M. Gulick, Working Group on Clinical Practice for the Treatment of HIV Infection; COL Nelson L. Michael, M.D., Ph.D., Walter Reed Army Institute of Research

OARAC Working Group Members Present:  Mr. Moisés Agosto-Rosario, Dr. Judith D. Auerbach, Ms. Dawn Averitt, Dr. Charles C.J. Carpenter, Dr. Ralph J. DiClemente, Dr. Wafaa El-Sadr, Dr. Paul Volberding*

*Participated by teleconference

Invited Speakers and Guests:  Mr. Kevin Fisher, Dr. Richard Kaslow, Dr. George K. Siberry Dr. Ronald Swanstrom,

WELCOME AND MEETING OVERVIEW

The National Institutes of Health Office of AIDS Research Advisory Council (OARAC) convened its thirty-eighth meeting on April 10, 2014 at 8:30 a.m. at the Fishers Lane Conference Center in Rockville, Maryland.

Dr. Jack Whitescarver, OAR Director and OARAC Executive Secretary, welcomed OARAC members, OARAC Working Group members, invited speakers, and guests.  He informed the Council that unfortunately Dr. Rochelle Walensky, Acting OARAC Chair, was unable to attend the meeting due to illness, and indicated that he would serve as chair and Drs. Judith Auerbach and Charles Carpenter would facilitate the discussions.

APPROVAL OF MINUTES

The minutes of the November 14, 2013 OARAC meeting were approved as written.

CONFLICT OF INTEREST STATEMENTS

OARAC members were reminded to review and sign their conflict-of-interest forms, and submit them to OAR staff.

UPDATE FROM THE OARAC TREATMENT AND PREVENTION GUIDELINES WORKING GROUPS

Dr. George Siberry, of the Maternal and Pediatric Infectious Disease Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), provided updates on the Guidelines for the Use of Antiretroviral Agents (ARV) in Pediatric HIV Infection the Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States, and the Guidelines for the Prevention and Treatment of Opportunistic Infections (OIs) Among HIV-Exposed and HIV-Infected Children. 

The revised Pediatric ARV Guidelines were published on February 12, 2014, with the following changes:

• A focus on the diagnosis of HIV in exposed infants receiving HIV prophylaxis and the potential need for retesting after prophylaxis ends;

• A continued recommendation for universal antiretroviral therapy (ART) for all infants younger than 12 months and a permissive recommendation for all children older than 12 months, with the strength of the recommendation based on CD4 count;

• Simplified drug tables with new dosing recommendations;

• A new section on modifying ART regimens for simplification or safety in children on effective ART.

The Pediatric Guidelines Working Group also might consider a new section on specific issues and considerations for HIV-infected newborns including:

• Neonatal prophylaxis, with attention to the “Mississippi baby cure case”;

• Key safety issues;

• The lack of dosing information for pre-term and low birth weight infants;

• A planned clinical trial for potential “cure regimens.”

The revised Perinatal Guidelines were published on March 28, 2014. Changes in these guidelines include:

• A new table on pre-exposure prophylaxis (PrEP) studies for serodiscordant couples who want to conceive;

• A simplified and standardized table and appendix on the safety and toxicity of individual ARV drugs;

• Promotion of two dual-nucleoside reverse transcriptase inhibitor (NRTI) regimen backbones to preferred status, with no changes in preferred protease inhibitors (PIs); and

• The promotion of raltegravir from alternative to preferred status.

On the basis of data from the French Perinatal Cohort Study, the Perinatal Guidelines Working Group also recommended:

• Intravenous zidovudine (ZDV) should be used during delivery for women with a viral load> 1,000 copies/ml;

• ZDV can be omitted for women with a viral load <1,000 copies/ml if there are no concerns about ART adherence; and

Currently, there is no general recommendation for HIV treatment of HIV-exposed infants without demonstration of infection. The updated Pediatric OI Guidelines were published in November 2013.

• An executive summary of the guidelines has been published in the Journal of the Pediatric Infectious Disease Society; and

• The full guidelines are published in in the Pediatric Infectious Disease Journal. These updated guidelines were endorsed by the American Academy of Pediatrics.

Status of the Pediatric Guidelines Panel:

• The current co-chairs of the Guidelines Working Group (WG) are willing to continue to serve as co-chairs;

• There are no plans to make changes in the guidelines topics, and the WG plans to ensure that each guideline is reviewed at least every 2 years;

• Updates will be posted on the AIDSinfo website as they are finalized and cleared; and

• The group will collaborate with other guidelines working groups, including writing joint sections on hepatitis B (HBV) and tuberculosis (TB), and sharing updates with the Adults and Adolescents WG.

Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents:

Dr. Roy Gulick, Professor in the Department of Medicine and Chief in the Division of Infectious Diseases at Weill Medical College of Cornell University discussed the Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents.  The Working Group for these Guidelines monitors the field in real-time to ensure the information reported is current.  A new revision of the guidelines is expected to be released on May 1, 2014. He reviewed the changes that will be included in the new revision, but emphasized that these changes should be kept confidential until publication.  He reported that six members of the Working Group have completed their terms, and five new members have joined the Working Group. 
He acknowledged the work of all of the Chairs and over 200 members of all of the Guidelines Working Groups convened under the aegis of OARAC, who volunteer their time to serve on these critical federal panels.

Discussion

Clarification was requested about the Pediatric Guidelines recommendation regarding PrEP vs treatment during pregnancy.  Dr. Siberry reported that the changes within the Perinatal Guidelines focused on PrEP use in serodiscordant couples around the time of attempted conception. There was also discussion on the utility of ART in the HIV-infected partner for treatment as prevention.

DIRECTOR’S REPORT

Dr. Whitescarver announced the following personnel changes:

• Dr. Deborah Birx, former Director of the Global AIDS Program at the Centers for Disease Control and Prevention (CDC), has been named U.S. Global AIDS Coordinator of the United States President’s Emergency Plan for AIDS Relief (PEPFAR);

• Mr. Douglas Brooks, M.S.W. has been appointed, to be the new Director of the White House Office of National AIDS Policy (ONAP);

• Dr. John Ruffin, Director of the National Institute of Minority Health and Health Disparities (NIMHD), has announced his retirement.  Dr. Yvonne Maddox, who served as Deputy Director of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), will serve as Acting Director of NIMHD;

• Dr. Robert Kaplan, Director of the NIH Office of Behavioral and Social Sciences Research (OBSSR), will be leaving NIH to serve as Chief Science Officer at the Agency for Healthcare Research and Quality;

• Dr. George Koob, an expert on alcohol and drug addiction and the neurobiology of alcohol addiction, has joined the National Institute on Alcohol Abuse and Alcoholism (NIAAA) as its new Director;

• Dr. Robert  Eisinger, a member of the staff of  OAR for more than twenty years, has left to serve as Director of the Office of Research and Science in the Office of the Global AIDS Coordinator at the Department of State; and

• Ms. Joan Romaine, who previously served as the NIH liaison to the White House Office of National AIDS Policy and as the AIDS Coordinator at NIAID, has joined OAR to lead the Program Planning and Analysis section.

INTRODUCTION TO THE PRIORITY-SETTING PROCESS FOR NIH AIDS RESEARCH

Dr. Whitescarver reported that during hearings in both the United States House of Representatives and Senate, questions were raised about the process NIH uses to set overall research priorities.   From these questions, it was clear that Congressional appropriators are looking very closely at how the NIH budget is spent.  The November 2013 OARAC meeting focused discussion on the scientific opportunities in HIV/AIDS research.  At that meeting, Dr. Francis Collins, the Director of NIH, charged OARAC with identifying the highest priority areas in HIV/AIDS research that would serve as guidance for the NIH and OAR investments in AIDS research over the next three to five years. Today’s OARAC agenda is a follow-up to that  November 2013 OARAC meeting, and will address in greater detail the next steps in setting the trans-NIH research priorities during the current period of budgetary constraint.  

Dr. Whitescarver reported that he established a Working Group of OARAC, chaired by Dr. Charles Carpenter, to help OAR identify the highest research priorities.  Dr. Whitescarver introduced Dr. Carpenter, a former Chair of OARAC, and thanked him for taking on another assignment. 

Dr. Carpenter reminded OARAC members of the parameters of Dr. Collin’s charge, and the serious implications of the current funding situation.  He emphasized the importance of identifying scientific research priorities in the context of limited resources and recent advances in prevention, care, and support. He stated that while the focus of the November meeting was on scientific opportunities,  today’s meeting is aimed at amplifying discussion on matters addressed at the November meeting and in the Working Group’s subsequent discussions and deliberations on AIDS research priorities. This OARAC meeting also is an opportunity for members to provide additional input that can be incorporated in the Working Group report to Dr. Collins.

Dr. Judith Auerbach, Executive Secretary for the OARAC Working Group (OWG), reviewed the priority setting process used by the Working Group. She described the information materials used by the Group to guide their discussions as well as the in-person meetings and teleconferences that have taken place thus far.  She explained that OAR staff reviewed the existing trans-NIH research portfolio in consultation with staff at NIH Institutes, Centers, and Offices (ICOs), and identified several cross-cutting issues related to AIDS-funding allocations and spending that required more in depth discussion with the OARAC.  It is intended that today’s discussions address some of these issues. She emphasized that the overarching goal is to ensure that the NIH AIDS research portfolio supports the most promising and important research. 
Dr. Auerbach described the next steps in the process to complete the Working Group report for Dr. Collins.  The Working Group is scheduled to meet on April 11 to incorporate the input from today’s OARAC meeting and continue its deliberations to produce the draft report for Dr. Collins. The draft report will be shared with OARAC, and additional input will be solicited from external stakeholders.  With that input, the OARAC Working Group will finalize the document and Dr. Whitescarver will submit the report to Dr. Collins.  The report will be presented at the June meeting of the Advisory Committee to the NIH Director. 

Today’s OARAC meeting is divided into presentations and discussions of the major scientific areas of the Working Group report.

PREVENTION

Dr. Myron Cohen, J. Herbert-Bate Distinguished Professor of Medicine, Microbiology and Immunology, and Epidemiology and Director of the Institute for Global Health and Infectious Diseases at the University of North Carolina, Chapel Hill presented key priorities for HIV prevention research.  He began his presentation emphasizing that traditional silos no longer work in the HIV field because prevention, treatment, and cure research all now overlap.  He stressed the importance of research aimed at better understanding HIV transmission, as knowledge of this process informs research on HIV prevention, enables more precisely defining HIV incidence, and presents unique opportunities for research on HIV treatment. He discussed the importance of continued investment in strategies to identify acutely infected individuals and emphasized the need to establish new point-of-care HIV testing assays that have been properly field-tested. 
Dr. Cohen identified key opportunities for HIV prevention:

• Targeted behavioral interventions prior to infection present the best opportunity for HIV prevention and treatment. Structural interventions, such as voluntary male medical circumcision, condom use, and treatment of sexually transmitted diseases (STDs) that are dynamic and require further intensive study; 

• Determination and implementation of appropriate interventions, or combinations of preventions that will be the key to success; 

• Research on behavioral economics and cash transfers that can contribute to improved quality of life and facilitate an individual’s ability to avoid high risk behaviors and reduce new HIV-infection rates.  An example of this approach is being studied in HPTN 068 which examines the effects of cash transfer for the prevention of HIV in young South African women; 

• Studies that examine precoital and coital interventions that prevent infection when the virus can still be eliminated are important research areas.  He noted that within the next few years, results of current HIV studies could yield fundamental discoveries that could profoundly change HIV prevention research. 

• Vaccine studies, such as the RV144 trials and work on the cytomegalovirus (CMV) vector; topical ARV studies, such as those on tenofovir gel, the dapivirine ring, and injectable PrEP; and particularly promising studies of broadly neutralizing antibodies were discussed as additional important opportunities for HIV prevention; and

• Treatment of infected individuals that includes the use of ART to suppress viremia, and renders HIV-infected individuals less contagious (treatment as prevention) has great potential for prevention.   However, treatment must also take into account other factors, such as substance abuse and adherence that can affect the outcome and success of treatment. 

Dr. Cohen called for focusing attention within prevention research on particular at-risk populations, such as young adolescent women in resource-constrained countries and young black men who have sex with men in the U.S. 

Closing his presentation he noted that this is a critical time of new and exciting ideas, interventions, and opportunities in HIV prevention research that deserve attention. 

Discussion

The meeting participants raised the following points for consideration:

• The need for a specific recommendation to address implementation science, to identify methods to effectively deliver proven strategies in real-world settings;

• The importance of continued adherence research, such as:

  • Integrating behavioral and social scientists into study teams to address research questions on the desirability, utility, and integration of interventions applicable to daily life;

  • Consideration of population differences in adherence behaviors, pharmacokinetics, and thresholds of intervention exposure;

  • Tailoring adherence support strategies that take into account  the impact of psychopathology or neurocognitive impairment on adherence;

  • Addressing the intersection of violence,  HIV infection, and post-traumatic stress disorder, and its effect on adherence;

  • Focusing on models of adherence based on demonstrated best practices; and

  • Focusing attention on the role of bias, on the part of both the patient and provider, and its influence on adherence.

• Increased attention on the need to ensure appropriate diversity of study participants  and to address cultural and social competency;

• The importance of studying the ability of broadly neutralizing antibodies to prevent HIV transmission and viral escape;

• Commitment to securing stable long-term resources to continue to address complex research questions;

• Maintaining funding resources to ensure that NIH-supported clinical trial sites endure, and allow continuity of eligible and qualified studies.  The relevance of continued discussion on standard of care in the research setting; and

• The importance of utilizing existing investments, such as the Centers for AIDS Research (CFARs) program, and collaborations and partnerships between NIH and other agencies.

TREATMENT

Dr. Roy Gulick addressed the key issues in the area of HIV treatment.  He noted that in 2014, the HIV/AIDS field has 28 approved drugs, with seven first-line regimens listed as preferred in the DHHS guidelines.  Three one-pill, once-daily regimens have been approved, a fourth is under review by the Food and Drug Administration (FDA), and a fifth is in Phase III clinical trials.  Virologic response rates are currently higher than 85% in clinical trials and 75% in clinical cohorts, and the life expectancy among HIV-infected individuals in treatment is close to that of the general population.  He stated that future research must focus on five areas:

• Developing improved HIV treatments with research on new agents with different mechanisms of action, new targets, and reduced toxicity;

• Developing new formulations that improve convenience, improve management of immunologic failure, and reduce treatment costs through regimen simplification or generic drugs;

• Research on prevention or optimal management of coinfections including research on disease diagnosis, new drugs, drug-drug interactions, and disease management. TB, hepatitis B (HBV), hepatitis C (HCV), and human papillomavirus (HPV) were cited as the more important co-infections while OIs and STDs are still important, but should be considered lower priority;

• Prevention, assessment, and management of comorbidities including the intersection among host factors, the effects of HIV on the immune system and inflammation, and the effects of drugs themselves are important areas for investigation.  Increased understanding is needed of the etiology, epidemiology, and pathogenesis of HIV-related comorbidities. End-stage organ diseases (e.g., renal, cardiovascular, or hepatic), aging and frailty, and mental health and substance abuse are important comorbidities to study; and

• Extending the benefits of HIV treatment to all patients and better understanding of how and why patients fall off the care continuum is an important area of research.  This would include more behavioral and social science research and population-based studies to improve testing, entry into care, and retention.  Population differences in treatment response and toxicity among adolescents, older adults, or elite controllers also should be studied. Dr. Gulick noted the need to focus on young gay men of color, citing an MMWR report that of all new infections in 2012, 25% were in individuals aged 12 to 24 years, three-quarters of them were men having sex with men (MSM), and 60% were unaware of their infection.

Another component of treatment research is research toward a cure, which will be covered later by Dr. Daniel Kuritzkes.

Discussion

The following points were raised by the meeting participants:

• The need for pharmacokinetics research that elucidates interactions between rates of drug release including long acting agents, individual variations in drug metabolism, and the effects of these interactions on steady-state levels.  This includes research in the context of aging and comorbidities, such as substance abuse;

• During this era of increasing development of generic drugs, it is important to examine whether industry will continue support for the identification of new drug targets, and how diminished drug development impacts HIV treatment in the face of growing ARV resistance.  High importance is also placed on drug development research that targets viral reservoirs

• Developing a comprehensive population based emergency approach to treatment to determine how to effectively extend treatment to young, gay men of color.  This includes increasing enrollment in clinical trials, developing potential structural interventions, and addressing the community and structural barriers to implementing effective treatments; and

• The need to offer resistance testing in resource-limited settings, which highlights the development of new tests, and implementation science studies to facilitate adoption of effective tests.

CO-MORBIDITIES

Dr. Steven Deeks, Professor of Medicine University of California, San Francisco, addressed the critical area of HIV-related Co-Morbidities.  He acknowledged that existing ARVs work very well, but they do not fully restore long-term health. He cited data from two cohort studies suggesting:  

• Heart disease risk is up to 1.5 times higher among well-treated, HIV-infected adults, compared with uninfected adults;

• Increased risk has been observed in diseases affecting other organ systems, such as osteopenia, osteoporosis, liver disease, and kidney disease among HIV-infected individuals;

• Aging appears to be affected by infection, treatment, or other factors common to HIV;

• Cancer rates, metabolism, and co-infection with TB, HCV, or malaria also are affected by HIV infection;

• Dr. Deeks emphasized that an integrated approach is vital to address the effect of HIV across multiple organ systems.  Research in two broad research areas was suggested as an approach to improve understanding of the effect of HIV on morbidity:

  • The immune dysfunction associated with HIV that persists in the majority of patients, regardless of treatment.  The key research issues related to HIV-associated immune dysfunction include:

    • The impact of chronic inflammation on health;

    • Whether these effects are distinct from the effects of inflammation in the general population;

    • How research on inflammation in the context of  HIV/AIDS can influence research on other chronic diseases and whether research in other disciplines can be applied to HIV/AIDS research;

    • The persistence of inflammation during antiretroviral therapy;

    • The connection between dysbiosis and HIV-associated inflammation and immune dysfunction; and

    • The definition of immunosenescence.

• Problematic aging, which is predicted by factors such as social isolation, mental health impairment, chronic inflammation and immune dysfunction, and polypharmacy.  These factors occur in HIV uninfected adults between 50-60 years of age but are phenotypically evident about a decade later. HIV-infected adults on ART exhibit many of these predictive factors and their manifestations much earlier in life and for longer periods of time. Research is needed to determine how to measure these factors, and identify the pathways that are unique to HIV.

For both areas, Dr. Deeks emphasized the need for multidisciplinary and synergistic research among HIV and non-HIV scientists.  HIV research could have an impact on non-HIV-related research.

Discussion

• It was noted that a major question raised from the presentations thus far regarded the criteria for allocating HIV/AIDS research dollars to areas, such as comorbidities, that may have relation to HIV infection, but may also exist independently. Therefore, co-funding with HIV/AIDS-designated dollars and non-HIV/AIDS dollars was cited as one approach to bring disciplines together. Examples of such co-funded studies from the National Heart, Lung, and Blood Institute and the National Cancer Institute were discussed.

• Other points raised include:

  • The importance of including central nervous system (CNS) research, along with neuroinflammation, as a direct contribution to HIV/AIDS research, rather than as an adjunct, since neurocognitive functioning affects behaviors, such as risk behaviors, adherence, and substance use;

  • The need to understand how inflammation in HIV-infected patients compares with inflammation seen in other non-HIV-related inflammatory diseases;

  • The need to Explore the interplay between the genetic aspects of HIV infection and those for comorbidities;

  • The importance of comparative effectiveness studies on lower-cost treatment and prevention approaches for comorbidities among HIV-infected patients at risk for these diseases;

  • The need to consider reducing investments in observational and cohort-based studies in order to explore the mechanisms underlying observed disease; and

  • The need to consider the potential return on investment during the process of planning research projects.

Dr. Deeks concluded the discussion by noting:

• The influence of lifestyle factors, such as smoking or alcohol and drug use on outcomes and how they should be addressed in research;

• The need for more funding focused on  HIV-specific issues; and

• The utility of research on premature aging in HIV as a model to better understand aging in the general population.

CURE

Dr. Daniel Kuritzkes, Professor of Medicine and Chief of the Division of Infectious Diseases at Harvard Medical School and Brigham and Women’s Hospital, presented critical issues in research toward a cure.  He began his presentation by also acknowledging the extraordinary effectiveness of ART, but suggested that additional resources should be devoted to cure research because of the complexities of managing lifelong ART, the adverse effects associated with HIV persistence, the potential risk for transmission, and the continued stigma associated with HIV infection.  He also pointed out that we are in a time of new opportunities in HIV research because of an improved understanding of HIV persistence, the identification of new targets, testable hypotheses arising from new treatment approaches, and the potential utility of animal models to better understand HIV pathogenesis and cure. The example of the “Mississippi baby” cure case was used to illustrate the potential for sustained remission of HIV infection.

Dr. Kuritzkes highlighted several key issues that need to be better understood to advance HIV cure research:

• Mechanisms underlying HIV latency;

• Defining the HIV reservoir;

• The intersection between the virology and immunology of HIV persistence. For example, the role of innate and adaptive immunity in controlling the reservoir;

• Interventions that might facilitate a cure, such as hematopoietic stem cell transplantation and interventions that utilize the immune system to eliminate HIV or induce a sustained ART-free remission;

• Utility of  animal models such as non-human primates and small animal models, particularly the humanized mouse model, to characterize the reservoir and validate potential interventions;

• Mechanisms for individual investigators, research centers, and research networks to rapidly advance promising leads for cure interventions; 

• Assays needed to assess  the biologic effects of cure interventions, and the need to establish the parameters and biomarkers for treatment interruptions;

• The need to devote attention to unique populations, including exposed or infected newborns, acutely infected individuals, and patients with long term viral suppression on ART, balanced with ensuring the generalizability of cure interventions.

Dr. Kuritzkes concluded by noting the need to recognize both the regulatory and ethical issues that impact research in the cure field, and the value of collaborations between investigators and regulatory agencies, in order to build a regulatory pathway for promising HIV cure interventions that mitigate research risks.   Dr. Kuritzkes also emphasized the importance of ensuring that stakeholder expectations in this research area are realistic.

Discussion

Meeting participants raised the following points:

• The field needs to prioritize behavioral and social sciences questions related to patient perceptions of a cure, and what interventions and risks patients will find acceptable. Currently, investigators and funders differ on the level of risk they are willing to accept, and this also may differ from the risks HIV-infected individuals are willing to accept;

• Sufficient infrastructure should be established to support cure research, including the development of appropriate primate models, and increasing the number of investigators to conduct the research;

• Prioritizing stakeholder engagement in the process of designing  clinical trials;

• The need to apply the same statistical rigor used in human studies to animal studies.  For example, investigators determine the sample size required for both animal studies and human studies in order to address specific questions and prevent the pursuit of nonproductive research paths; and

• The need to balance research on special populations with the need for generalizable interventions. However, research specifically focused on special populations might identify important signals that can be broadly translated into public health tools.

BASIC SCIENCE

Dr. Ronald Swanstrom, Professor of Biochemistry and Biophysics in the Lineberger Cancer Center, University of North Carolina, Chapel Hill, presented on key issues in basic science.  He provided examples of the long lead time from scientific discovery to the appearance of that discovery in the clinical setting and as public knowledge.  He highlighted the role of the National Institute of General Medical Sciences (NIGMS) in advancing the traditional paradigm of discovery to gain insight for drug designs.  He also noted the importance of including new technologies in discovery science to answer long-standing questions that deserve focus including:

• The use of short inhibitory RNAs (siRNA) screens for determining host genes involved in HIV replication or the use of tagged viral proteins to identify and validate important cellular interactions;

• New technologies that enable the interrogation of larger RNA structures and give rise to new lines of research on viral RNA, in addition to the biological information contained within these structures;

• The use of deep sequencing of viral populations in HIV-infected individuals  allow researchers to identify or redefine viral lineages;

• The use of molecular epidemiological studies that assess clade and subtype in regions with less viral diversity that could have implications for vaccine development by providing a stronger, less complex signal for determining efficacy;

• The discovery of CRISPR/Cas, the bacterial defense mechanism that provides a new tool to potentially excise integrated HIV from host DNA and address the latent provirus in various cell types; and

• The discovery of similar innate immune responses, such as APOBEC3G, tetherin, TRIM5 proteins, and many others that are still being identified in human cells.

Dr. Swanstrom pointed out that new knowledge about the virus and host protein interactions present new targets. New inhibitors will be developed to address the new targets. The HIV/AIDS research community will need to determine the best method of choosing candidates to move forward including the assays available to screen for toxicity, pharmacogenetics, and other factors.  Dr. Swanstrom concluded by addressing several key lessons learned in basic science research experience:

• Although there is always the temptation to think enough is known, researchers in the field never know as much as they think they do;

• Great insights are rare, unpredictable, and often partially understood;

• Most knowledge is acquired incrementally and not linearly;

• The understanding of basic biology is limited and colored by the tools investigators use. New tools provide new views and the ability to generate new hypotheses; and

• Discovery science precedes strong, hypothesis-driven science.

While acknowledging that the current focus is on research priorities for the short term, Dr. Swanstrom cautioned OAR to not lose sight of the importance of basic science and its associated infrastructure as a long-term engine for HIV/AIDS research. He suggested the following research priorities:

• Methods for delivering drugs/treatments to CD4 cells, specifically to target latent proviruses;

• Identifying the “real” latent reservoir.  Studying HIV in the CNS is challenging, requires a multidisciplinary approach, and is uniquely important for  understanding pathogenesis;

• Tackling immunosuppression with therapeutic vaccines;

• Developing drug depots that will change the way therapy and drug metabolism are viewed when delivered internally rather than orally;

• Understanding viral accessory proteins, which point to cell pathways exploited by the virus during transmission and replication;

• Studying the use of CMV vectors as a potential new immunization strategy; and

• The development of model systems that are reasonable surrogates for HIV infection in humans and can be validated.

Dr. Swanstrom concluded by acknowledging that HIV and other fields can inform each other, but it may be difficult to predict when other field can inform HV research. He reiterated some examples of how expertise from other ICs and non-HIV investigators has been used to benefit HIV research. With respect to prioritization, Dr. Swanstrom suggested that basic science projects be required to include a specific AIDS-related aim or population and to cite whether the potential impact of the study will be specific to HIV.

Discussion

Several OARAC members noted that the critical areas identified by Dr. Swanstrom are only the tip of the iceberg.  They echoed his point that there is still not enough known in the HIV/AIDS field, and much more research remains to be done. Other members underscored the importance of understanding the specialized features of the CNS compartment in HIV infection.

BEHAVIORAL AND SOCIAL SCIENCES

Dr. Ralph DiClemente, Professor of Public Health in the Rollins School of Public Health and Associate Director of the Emory/Atlanta Center for AIDS Research, presented highlights from the deliberations of the OAR Working Group that reviewed the behavioral and social science research portfolio. He emphasized the need to focus on high-risk populations, particularly black MSM and black women. 
He discussed the Behavioral and Social Science Working Group report that was presented at a previous OARAC meeting by Dr. Auerbach, and which focused on the following eight priorities:

• Research on individuals living with HIV/AIDS to enhance identification of, linkage to, and retention in care. This research also focuses on understanding and addressing gaps in the HIV care continuum;

• Research on individuals at high risk for HIV infection. This research utilizes behavioral and social science to examine the social determinants influencing adherence to prevention measures, such as PrEP and condom use. Work in this area also can address stigma, self-regulation skills, and the sustainability of a behavioral change. He noted that interventions to reduce stigma will be critical;

• The development of innovative methods and frameworks to guide behavioral and social science intervention research. This could include using new technologies, such as social media and mobile health, multiphase strategies to optimize adherence, and new designs for treatment trials.  Research in this area also can lead to the development of dynamic intervention models that could address the multiple competing issues that impact individuals’ lives;

• Understanding the impact of social, structural, and policy factors associated with risk, vulnerability, and resilience and developing higher-level interventions to address the various levels of influence on behavior. This area requires a socio-ecological approach encompassing the many levels that influence behavior;

• Implementation science to study how to disseminate the diverse array of evidence-based behavioral and social science interventions;

• Examining the interaction between the HIV epidemic and other epidemics, such as: HCV, TB, substance abuse, mental illness, and interpersonal partner violence;

• Research on the comparative effectiveness of behavioral and social science interventions, and  combined biomedical and behavioral interventions for preventing HIV infection that include  measures of cost-effectiveness; and

• Identifying the optimal combination of biomedical, behavioral, and structural interventions for the most effective HIV prevention.

Discussion

Participants noted that current hypothesis-driven approaches to research may be overly academic.  Observational research that is based on the naturally occurring heterogeneity of a population is not rewarded.  The approach to prevalence and adherence research is similar to clinical trials that test a single hypothesis.  There is a perception that research is penalized during review if it deviates from traditional approaches.  This limits the use of formative research tools such as focus groups to assess interventions.  It was noted that the Working Group faces the challenge of integrating the silos that define HIV research areas. It was suggested that the priority research categories, mentioned in the charge from Dr. Collins, could be used to provide orientation for the overarching issues to guide prioritization.
Other important considerations for the Working Group included:

• The importance of adequate funding for longer-term follow-up of interventions, and to integrate measures that address key drivers of HIV infection, such as homelessness, food insecurity, and violence against women;

• Integration of biomedical, behavioral, and social sciences research approaches to encourage, measure, and increase adherence;

• The need to support more interventional studies, rather than observational studies, to address risk factors;

• Prioritizing the integration of cultural competency experts in research and clinical care;

• The opportunity to leverage the increased availability of industry funding for HCV research, to integrate the HIV and HCV research communities;

• The need for dynamic interventions to address other stresses or challenges, that influence adherence and HIV risk, such as psychopathology or cognitive problems, and maximize the potential for prevention;

• Promoting community ownership of interventions to ensure their sustainability after the study is completed.  This could include connecting community members with mentors from the research team; and

• Incorporating questions concerning scalability at the beginning of study designs.

IMPLEMENTATION SCIENCE

Dr. Wafaa El-Sadr, Chief of the Center for Infectious Disease Epidemiologic Research (CIDER), Director of the International Center for AIDS Care and Treatment Program (ICAP) at Columbia University, Mailman School of Public Health and Professor of Medicine and Epidemiology at Columbia University, presented key issues in Implementation Science.  She opened her presentation by categorizing research into the three domains of discovery, implementation, and scalability. She noted that many evidence-based interventions fail to achieve the desired impact because of the inability to conduct reliable implementation and scalability research.  Dr. El-Sadr suggested that bridging the gap between research findings and their impact on disease burden requires investigators to consider both the implementation and the scalability of a discovery.  She also pointed out that implementation and scalability research can identify and enrich questions for discovery.

Dr. El Sadr noted that implementation science evaluates strategies to improve the uptake of, access to, retention in, and effectiveness of an intervention. For example, all aspects of the HIV care continuum including prevention, treatment, and management of OIs, have associated cascades, with adherence as the most distal part. Investigators should conduct implementation research throughout all steps within the cascade. In addition, these steps require combined interventions. As investigators are designing studies for a potential intervention, and thinking about implementation and scale-up, they should also consider ways of combining their intervention with others. Dr. El-Sadr emphasized the importance of having strong evidence of efficacy in an intervention before it is incorporated into an implementation science framework.

Implementation science is a rigorous research area and requires:

• Clearly articulated questions and rigorous research design;

• Interdisciplinary approaches; and

• Attention to measurement and generalizability.

She noted that demonstration projects often are confused with implementation science. However, demonstration projects pay less to scientific rigor or the measurement of generalizability of an effect.

Dr. El-Sadr asserted the alignment of implementation and scalability research with the NIH mission, specifically the “application of knowledge to enhance health, lengthen life, and reduce illness and disability.” Dr. Collins had cited implementation science as an opportune research area for further exploration, and noted the importance of ensuring that research findings reach communities in need.

Discussion

It was noted that implementation science is inherently multidisciplinary by nature, and investigators enter this field through different pathways. The following issues were raised for consideration by the OARAC Working Group:

• Implementation science is viewed as a high priority by the advocacy community;

• The need for a clearly articulated definition of implementation science, including the appropriate role for NIH in this field vs. the role of other agencies. (Some members proposed identifying important questions related to implementation and scalability, rather than expending effort to narrow the definition). 

  • Interagency agreement is also important to define parameters for determining that an intervention is proven.  Lack of agreement among agencies impedes implementation;

• Including implementation sciences research in the NIH budget;

• The need to determine  the research questions necessary to address gaps in the treatment and prevention cascade;

• The importance of understanding the best methods for optimizing technology and managing implementation; and

• The importance of epidemiology in implementation science.

An NIMHD- supported community-based participatory research (CBPR) initiative was described. This initiative involves three phases: a 3-year planning phase; a competitive phase, providing 5 years of support for developing and studying interventions; and a dissemination phase for interventions that prove efficacious.  For each phase, researchers partnered with target communities.  OAR provided funding for three of the CBPR projects. 

STAKEHOLDER PRIORITIES

Mr. Kevin Fisher, Policy Director for Global Advocacy for HIV Prevention (AVAC), presented recommendations that had been submitted in a letter by the Research Working Group of the Federal AIDS Policy Partnership, representing a large number of community and scientific organizations.  He acknowledged that the OARAC Working Group had undertaken a challenging yet important task, and noted the accomplishments in HIV/AIDS research since the 1996 Levine Report.

The Research Working Group of the Federal AIDS Policy Partnership recommendations addressed two overarching themes:

• Focusing research on the needs of key populations, which is important not only for equity, but to boost the effectiveness of interventions; and

• Focusing on implementation science, which aligns with the translational aspect of the NIH mission, and leverages current collaborations between NIH and other agencies, such as CDC and PEPFAR.

The Research Working Group of the Federal AIDS Policy Partnership offered specific recommendations in three priority areas:

• The treatment and prevention cascade:  recommendations addressed gaps in targeted HIV prevention, engagement and retention in HIV care, and treatment in children and adults;

• Comorbidities and aging:  recommendations focused on the comorbidities associated with HIV disease progression, aging-associated disease that is increasingly prevalent among individuals living with HIV, and the impact of age over time.  Mr. Fisher suggested making use of existing research cohorts to design a “Framingham-like study for HIV”; and

• HIV cure:  recommendations focused on improving assays to measure residual virus and developing interventions to eliminate the virus.

Mr. Fisher highlighted recommendations for improving HIV testing technologies, including scalable point-of-care technologies that can detect the earliest infection.  He also noted the need for research on new biomedical prevention approaches, including new vaccine approaches and long-acting ARV-based prevention.

GENERAL DISCUSSION

Discussion focused primarily on the importance of training as a cross-cutting issue.  Participants expressed concern that fewer new and younger researchers were entering the field of infectious disease research.  There was particular concern regarding African-American researchers, who are under-represented in the field, even though the epidemic disproportionately affects the African-American community.  Participants discussed the importance of establishing mentoring relationships to attract and retain researchers from minority groups, especially African-American investigators. Current efforts to promote diversity were discussed, including existing research and training programs as well as the NIH-wide task force aimed at enhancing existing mechanisms to promote diversity.  Members suggested establishing 3- to 5-year metrics for training and mentoring investigators and seeking collective buy-in for those metrics.
Other points during this discussion included:

• The significant benefit in continued support of research on mucosal sites; and

• The importance of continued support for basic sciences research as a foundation for clinical, translational, intervention, and implementation science research.

CLOSING COMMENTS

Dr. Auerbach and Dr. Whitescarver thanked everyone for attending the meeting.  Dr. Whitescarver stressed that OARAC will have the opportunity to review and approve the final report of the OARAC Working Group before it is presented to Dr. Collins.  Dr. Whitescarver reiterated that the Working Group is not trying to find programs to shut down, but rather identifying the highest priority research areas in AIDS research.

Dr. Whitescarver concluded the meeting by announcing that the next OARAC meeting will focus on the topic of HIV and inflammation.

ADJORN

The meeting was adjourned at 4:30 p.m. on April 10, 2014

/Jack Whitescarver, Ph.D./
Jack Whitescarver, Ph.D., Executive Secretary