Meeting Minutes - April 16, 2015

Office of AIDS Research Advisory Council
Fortieth Meeting
April 16, 2015

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

Members Present: Dr. Rochelle Walensky (Chair), Dr. Jack Whitescarver (Executive Secretary), Mr. Moisés Agosto-Rosario, Dr. Stefano M. Bertozzi^, Dr. Myron S. Cohen, Dr. Steven Deeks^, Dr. Clemente Diaz, Dr. Monica Gandhi, Dr. Igor Grant, Dr. Roy M. Gulick, Dr. Daniel R. Kuritzkes, Mr. Justin C. McArthur, Dr. Ronald T. Mitsuyasu, Mr. Mitchell J. Warren, Dr. Darrell P. Wheeler, Dr. Craig M. Wilson

^ Participated by Teleconference

Ex Officio Members Present: Dr. Victoria Davey, U. S. Department of Veterans Affairs; Dr. Carl W. Dieffenbach, Division of AIDS, National Institutes of Allergy and Infectious Diseases; Dr. Jonathan Mermin, Centers for Disease Control and Prevention; Dr. Nelson L. Michael, U. S. Department of Defense

Invited Speakers and Guests: Dr. Jintanat Ananworanich, Dr. James W. Curran, Dr. Emily J. Erbelding, Dr. Robert Ferris, Dr. Roger I. Glass, Dr. Rohan Hazra, Dr. Walid Heneine, Dr. Julia J. MacKenzie, Dr. John R. Mascola, Ms. Allison McDougall, Dr. Paul Sato, Dr. Kimberly Struble, Ms. Natalie Tomitch, Dr. Heather Watts

WELCOME AND MEETING OVERVIEW

The National Institutes of Health (NIH) Office of AIDS Research Advisory Council (OARAC) convened its 40th meeting on April 16, 2015 at the Fishers Lane Conference Center in Rockville, MD.

Rochelle Walensky, M.D., MPH, OARAC Chair and Professor in the Department of Medicine, Massachusetts General Hospital, Harvard Medical School, welcomed OARAC members, OARAC Working Group members, and invited speakers and guests.

APPROVAL OF MINUTES

The minutes of the November 13, 2014 OARAC meeting were approved as written.

CONFLICT OF INTEREST STATEMENTS

Jack Whitescarver, Ph.D., Office of AIDS Research (OAR) Director and OARAC Executive Secretary, asked members to sign and turn in their conflict of interest forms. The OARAC is legally required to collect these forms prior to every meeting.

DIRECTOR'S REPORT

Dr. Whitescarver noted the following personnel changes:

• Douglas Lowy, M.D., is serving as Acting Director of the National Cancer Institute (NCI) following Harold Varmus’, M.D., resignation.
• Eric Goosby, M.D., formerly U.S. Global AIDS Coordinator for the President’s Emergency Plan for AIDS Relief (PEPFAR), has been appointed as the United Nations Secretary General Special Envoy on Tuberculosis (TB). Dr. Goosby oversaw the implementation of PEPFAR and was a strong supporter of collaborations with NIH.

Dr. Whitescarver thanked the following outgoing OARAC members for their dedication and commitment: Stefano Bertozzi, Ph.D., Myron Cohen, M.D., Steven Deeks, M.D., Igor Grant, M.D., Dr. Walensky, Mitchell Warren, M.D., and Craig Wilson, M.D. Dr. Whitescarver announced that this would be his last OARAC meeting as he is resigning as Director of OAR.  He announced that Wendy Wertheimer, Senior Advisor in the OAR is resigning as well.  The OARAC and guests gave Dr. Whitescarver a standing ovation in recognition of his outstanding service.

Dr. Whitescarver reported that OAR is currently working on the budget for FY2016.

Dr. Whitescarver announced that James Curran, M.D., Professor and Dean at the Rollins School of Public Health at Emory University and former Assistant Surgeon-General for the Centers for Disease Control and Prevention (CDC), would set the stage for the day’s discussions. Dr. Curran has served as chair of the OARAC and chair of the OAR Portfolio Assessment Working Group.

UPDATE ON OARAC WORKING GROUPS FOR TREATMENT AND PREVENTION GUIDELINES Working Group

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

Roy Gulick, M.D., Professor of Medicine and Chief of the Division of Infectious Diseases at Weill Medical College of Cornell University, announced that the Panel on Antiretroviral Guidelines for Adults and Adolescents released a guidelines update on April 8, 2015.

Key revisions in this guidance include the following:

• The number of recommended antiretroviral regimens has gone from 10 to five; one is based on a protease inhibitor and the other four are integrase-based, including:
  • Dolutegravir/abacavir/lamivudine
  • Dolutegravir + tenofovir/emtricitabine
  • Elvitegravir/cobicistat/tenofovir/emtricitabine
  • Raltegravir-boosted darunavir + tenofovir/emtricitabine
• Two regimens were moved from ‘Recommended’ to ‘Alternative’ status as a result of a synthesized comparative literature review:
  • Efavirenz/tenofovir/emtricitabine
  • Atazanavir + tenofovir/emtricitabine
• The Guidelines include a new “Clinical Case Scenario” table to guide clinicians on choosing an initial antiretroviral therapy (ART) regimen.
• Other revisions include:
  • Management of first- and second-line virologic failure
  • Poor CD4 responses and persistent inflammation despite viral suppression
  • Drug resistance and ART selection in HIV-2 infection
  • Management of hepatitis C virus (HCV) co-infection
  • A new table on the mechanisms of drug interactions
  • Updated drug interactions

The panel held its second annual one-day retreat on April 15, 2015. Thirty-nine members attended with five additional members joining by teleconference. Key agenda items included:

• A mobile app for the dissemination of federal treatment guidelines, developed by the guidelines working groups under the aegis of OARAC
• Discussion of a  “Customer Satisfaction Survey” for providers to give feedback on the guidelines
• A comparison of five international ART guidelines
• A discussion of industry sponsored versus non-industry sponsored clinical trials
• A reflection on the development of ART guidelines from 1993 to the present day

Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents

The panel for the development of guidelines for the prevention and treatment of opportunistic infections (OI) in HIV-infected adults and adolescents released guideline updates on October 28, 2014. The panel instituted real-time monitoring efforts (e.g. quarterly leadership calls) to ensure the guidelines reflect the most current scientific knowledge. The most active working groups in the OI panel include those addressing HCV, hepatitis B virus (HBV), human papillomavirus (HPV), TB, and cryptococcus.
New developments in the 2015 guidelines include the following:

• Linkage to the American Association for the Study of Liver Diseases – Infectious Diseases Society of America (AASLD – IDSA) website to address the rapidly changing management of HBV and cryptococcal co-infection
• Minor changes in specific drug and diagnostic test recommendations
• A change in terminology from “chronic maintenance” to “secondary prophylaxis”

Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Exposed and HIV-Infected Children

Rohan Hazra, M.D., Chief of Maternal and Pediatric Infectious Diseases at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) provided an update on the status of the Pediatric OI Guidelines. The last guideline release was published on November 6, 2013 at AIDSinfo.nih.gov and was also published in full as a supplement in the Pediatric Infectious Diseases Journal. A revision to these guidelines is in process and on target for completion by late 2016.

Details on the Pediatric OI Guideline revision process include the following:

Administrative details:

• The external co-chairs for the Pediatric OI Guideline revision are Dr. Mark Abzug (University of Colorado—Denver) and Dr. Sharon Nachman (SUNY—StonyBrook)
• The lead authors and supporting writers for each OI topic are confirmed
• The kick-off call for the 2016 Pediatric OI Panel was held on January 30, 2015
• There is no change in the topics for the 2016 guideline revision
• Every topic will be reviewed and updated within 2 years; all sections will be reviewed and revised by December 2016. Individual topic updates will be posted online to maintain a public version of the most up-to-date recommendations

Review process changes:
The upcoming Pediatric OI Guideline revision will include a more rigorous and transparent evidence review process, including:

• The use of a modified Grading of Recommendations Assessment, Development, and Evaluation (GRADE) process to review clinical and scientific evidence
• The use of a standardized literature search by a National Library of Medicine librarian
• Inclusion of a succinct narrative summary with its underlying, quality-rated evidence

Collaborations:

• The new guidelines will involve greater collaboration with other guidelines groups:
  • Pediatric ART Guideline members are assigned to the writing teams for TB, HCV, and HBV co-infection for harmonization.
  • There will be bi-directional sharing of section updates with the Adult OI Guidelines.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Dr. Hazra presented updates to the Pediatric ART Guidelines, which were published on March 5, 2015. Changes from the previous version of the Pediatric ART Guidelines include:

• Clarification that the AMPLICOR® HIV-1 DNA test is no longer commercially available
• A simplified and expanded section on when to start combination ART (cART)
• Updated dosing recommendations from the Pediatric Drug Working Group
• Approval of atazanavir for infants 3 months of age who weigh at least 10 kg
• Separate sections on the use of elvitegravir and cobicistat
• A new section entitled “Specific Issues in Antiretroviral Therapy for Neonates”
• Possible shortening of the next revision of the Pediatric ART Guidelines

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

Dr. Hazra noted that the latest revision to the Perinatal Guidelines is in progress, with publication anticipated by June 2015. Details on the Perinatal Guideline revision include:

• Official liaisons for this revision are Dr. Howard Minkoff (American Congress of Obstetricians and Gynecologists) and Dr. Rana Chakraborty (American Academy of Pediatrics)
• There is a new section for pregnancy in women with perinatal HIV infection
• There is a simplified and standardized drug information table and drug appendix
• Details on changes to this guideline will be presented at the next OARAC meeting

INTRODUCTION TO THE HIV DRUGS DATABASE APP

Ms. Allison McDougall from ICF International demonstrated a new component of AIDSinfo, an HIV drugs database app for iOS and Android devices, developed in response to the need for patients and providers to easily access information from evidence-based treatment guidelines.  AIDSInfo is managed by the National Library of Medicine with support from OAR and NIAID, and provides the latest guidelines and AIDS clinical trial information.  Features of the new app include:

• More than 100 drugs for the treatment of HIV and concomitant conditions
• Options to filter drugs based on drug class or approval status
• Two easy search options
• Information for patients and healthcare professionals
• Notifications of updates to clinical guidelines
• Bookmark feature for drugs of interest
• Alarms to keep track of when to take medications
• Notepad feature
• Information in Spanish and English
• Pictures of medications
• The U.S. Food and Drug Administration (FDA) drug labels from the NIH’s DailyMed website

Further information is available by emailing Ms. McDougall at amcdougall@icfi.com or AIDSinfo at contactus@aidsinfo.nih.gov

INTRODUCTION OF OARAC TOPIC – MAXIMIZING U.S. AGENCY PARTNERHIPS FOR INTERNATIONAL HIV/AIDS RESEARCH

Dr. Curran, Professor and Dean at the Rollins School of Public Health at Emory University, provided the impetus for the day’s discussion on maximizing U.S. agency partnerships for international HIV/AIDS research. Highlights from Dr. Curran’s talk include the following points:

• HIV is still a relatively new disease; however, the extent and nature of the epidemic quickly sets HIV apart from other infectious diseases. Today AIDS is the leading cause of death in 25-44 year olds and the leading cause of death in Africa.
• Implementing agencies of PEPFAR, such as CDC and NIH, have saved an enormous number of lives in Africa through the administration of ART.
• Challenges to collaboration include the diverse mandates of U.S. federal agencies.
• The United States has invested billions of dollars to fund thousands of researchers across the world; as a result, there are numerous opportunities for collaboration.

Dr. Curran tasked the OARAC with addressing the following questions:

• Which projects in your agency lend themselves to collaboration?
• Which resources in your agency are available for sharing?
• What are your agency’s methods for identifying research priorities?
• Can you identify ways to save money, increase efficiency, and accelerate research?

PREVENTION Military HIV Research Program and the National Institute of Allergy and Infectious Diseases: A Model for Federal Government Partnership

Nelson L. Michael, Ph.D., a Colonel in the Medical Corps for the U.S. Military HIV Research Program (MHRP), described the MHRP partnerships for HIV/AIDS prevention, care, treatment, and research.

The rationale for the involvement of the Department of Defense (DoD) in HIV/AIDS research

• Infectious diseases are a constant threat to both soldiers and global citizens in conflict and peacetime.
• U.S. Military researchers have already contributed to the development of multiple vaccines for influenza, hepatitis A (Hep A), adenovirus, Ebola, HIV, dengue, and malaria.
• The MHRP has seven global research locations; these sites cover the range of HIV subtypes and are ideal for testing an HIV vaccine.

How the MHRP collaborations add value in combating infectious diseases across the globe

• The MHRP and the National Institute of Allergy and Infectious Diseases (NIAID) have partnered to capitalize on the strengths of each organization.
• The MHRP has developed strong partnerships with non-governmental organizations (NGOs) and local communities in order to set the foundation for testing vaccines.
• The MHRP and the PEPFAR collaborate in Africa to engage the civilian and military populations, develop the in-country capacity and infrastructure to sustain research efforts, and create an ethical framework for clinical research.

The MHRP’s work in the development of an HIV vaccine

• The Thai HIV Vaccine Study (RV144)
  • RV144 was the first HIV vaccine trial to demonstrate efficacy in preventing HIV infection.
  • This international collaboration involved the government of Thailand, the NIAID, the MHRP, and 16,000 Thai participants.
  • The efficacy of this vaccine was approximately 60% at 1 year and 31.2% efficacy at 3.5 years. Both efficacy and the immune response waned after 6 months.
  • A NIAID-sponsored trial began in 2015 in Southern Africa building on the successes of RV144.
  • Subsequent studies have determined some immune correlates of HIV infection in the RV144 trial.
• The Pox-Protein Public Private-Partnership (P5)
  • Established in 2010, the P5 involves multiple stakeholders, including Sanofi Pasteur, the Bill & Melinda Gates Foundation, the MHRP, the HIV Vaccine Trials Network (HVTN), Novartis, and the NIAID.
  • The P5 partnership seeks to develop an HIV vaccine based on a poxvirus vector and HIV protein.
• Modified Vaccinia Ankara carrying HIV-1 envelope and gag-pol proteins (MVA-CMDR)
  • MVA-CMDR was developed by scientists at the Walter Reed Army Institute of Research (WRAIR) and the NIAID, and it is currently in clinical trials.
• A new vaccine candidate involving a prime-boost strategy with Adenovirus 26 and MVA-based vaccine vectors
  • This new vaccine candidate is the result of a collaboration between the NIAID, Harvard University, Beth Israel Deaconess Medical Center, and Crucell/Johnson & Johnson, and will undergo evaluation in a Phase I clinical trial in 2015.
• HIV-V-A004 (APPROACH Trial)
  • HIV-V-A004 is a clinical trial of adenovirus-based HIV vaccines in healthy HIV-uninfected adults. It is a large study including 400 subjects randomized to one of seven vaccination regimens and involves collaboration with Janssen, a pharmaceutical company of Johnson & Johnson.

The MHRP’s involvement with clinical trials examining patients with acute HIV infections

• RV254: Acute HIV infection
  • RV254 involves collaboration between the MHRP and the Thai Red Cross in Bangkok and includes more than 200 volunteers with acute HIV infections. Results thus far indicate that very early ART limits the size of the latent HIV reservoir.
• RV217: The Early Capture HIV Cohort Study (ECHO)
  • RV217 is a pilot acute infection study at four network sites in East Africa and Thailand. To date, 108 acute infections have been identified.

How the MHRP/DoD and NIH have created a successful strategic partnership

• The MHRP budget includes approximately $28 million from the DoD but also close to $90 million from other sources, including the PEPFAR and the NIAID.
• The mission, capabilities, resources, and long-term objectives of the two agencies are not interchangeable but mutually reinforcing.
• The NIH/NIAID mission is distinct from the military directives of the MHRP.
• These agencies have the demonstrated capacity to jointly combat the burdens of infectious disease across the globe.

The HIV Biomedical Research Portfolio of the U.S. Agency for International Development – Opportunities for Inter-Agency Synergies

Robert Ferris, M.D., Chief of the Division of Technical Leadership & Research at the U.S. Agency for International Development (USAID), described USAID’s mandate and research efforts and how its resources lends itself to collaboration. Highlights from Dr. Ferris’s talk include:

USAID capabilities and collaborations

• USAID’s mission is to end extreme poverty, promote resilient democratic societies, and advance national security and prosperity in more than 100 primarily developing countries around the world.
• USAID has been involved with the PEPFAR in HIV prevention and other efforts.
• USAID has provided support to the International AIDS Vaccine Initiative (IAVI) since 1999, resulting in clinical testing of HIV vaccine candidates, development of novel HIV vaccines, and strengthening of the leadership and scientific and clinical capacity in developing countries:
  • USAID-supported IAVI clinical research centers have a wide range of capabilities, including clinical facilities, volunteers, laboratories, and access to high-risk populations. USAID’s trial sites are complementary to those of the MHRP and the NIAID.
  • Over the past 14 years, USAID has supported 17 HIV vaccine clinical trials with good enrollment numbers and high retention rates.
  • USAID is shifting to large epidemiological studies with IAVI, such as examining HIV incidence in high-risk volunteers, identifying new broadly neutralizing antibodies (bNAbs), and collecting mucosal samples in key populations.
  • USAID supports a sophisticated laboratory network that provides a powerful platform for research.
  • USAID promotes training and skills development for its staff.

USAID’s efforts in the development of microbicides for the prevention of HIV infection

• USAID has a long history of supporting research and development of a variety of microbicides for the prevention of HIV infection in women. The current USAID portfolio includes:
  • The Carraguard study was the first phase III USAID-supported microbicide trial.
  • The Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 trial was the first study to demonstrate the proof of concept that topical tenofovir gel can prevent HIV infection in women.
  • The Ring Study and A Study to Prevent Infection with a Ring for Extended Use (ASPIRE) trials are examining the ability of a microbicide ring to prevent HIV infection in women.

USAID’s future collaboration efforts

• USAID is in the process of developing collaborations for the following projects:
  • Phase II trials for the development of long-acting antiretroviral agents for HIV prevention
  • Development of an interagency agreement (IAA) with the CDC to select and prioritize agents for HIV prevention in primate models
  • New USAID projects in 2015 with a focus on resistance, gender, increasing uptake, and implementation models for young women
  • Partnership with the Bill & Melinda Gates Foundation to support regulatory activities and reduce the cost of dapivirine ring manufacturing
• USAID believes in engaging civil society to prepare countries for the introduction of microbicides for HIV prevention.
• Priority areas for collaboration include HIV vaccine trials, HIV prevention studies and other vaccine studies against diseases prevalent in the developing world.

Discussion

• The rate of HIV infection in some regions of Africa is incredibly high and effective HIV prevention agents are urgently needed. Interagency collaboration will help with implementation and scale-up efforts once a safe intervention is determined.
• CAPRISA proved that microbicides could be effective in preventing HIV infection; however, this result was not replicated in a larger trial. Microbicides need to be acceptable and practical for daily use to ensure maximum effectiveness.
• USAID efforts on capturing individuals with early HIV infections could be leveraged to examine the effect of very early interventions in different HIV subtypes.
• Civil society plays a vital role in the successful implementation of any HIV prevention and treatment program. Understanding cultural differences in adherence and acceptance will increase the likelihood of an intervention’s success.
• Talks thus far have provided excellent examples of what has been done with collaborative research and infrastructure building. Collaborations should focus on concrete projects to determine ways to work together on larger, future endeavors.
• The ultimate utility in collecting large numbers of virus neutralizing antibodies is uncertain. Researchers are still discovering new epitopes, which may yield valuable scientific insights; as such, there is still value in pursuing this scientific line of inquiry.
• Participants enquired into the markers of success for the evaluation of USAID efforts in HIV prevention. An advisory committee provides valuable feedback on USAID’s efforts against HIV/AIDS. Collaboration with host governments and other partners ensures that interventions are practical and sustainable.

Antiretroviral Prophylaxis for HIV Prevention: Lessons from Macaque Models

Walid Heneine, Ph.D., Chief of the Laboratory Branch of the Division of HIV/AIDS Prevention at the CDC, discussed the macaque model for the prevention of HIV infection and how this model informs human clinical Pre-Exposure Prophylaxis (PrEP) trials. Highlights include the following:

Background on human clinical PrEP trials

• Human clinical trials of topical and systemic HIV PrEP agents have demonstrated diverse efficacy; some trials provide close to 100% protection among adherent users of PrEP agents, while other trials demonstrate little or no efficacy, for example:
  • The FDA approved an oral PrEP agent, Truvada, in 2012 for the prevention of HIV infection. The CDC published guidelines on the use of Truvada for PrEP in 2014 and several implementation studies are underway.
  • The efficacy of topical or mucosal PrEP agents, however, is unclear; the FACTS 001 study did not confirm the efficacy of a 1% tenofovir gel in preventing HIV infection in young women. Researchers are currently investigating the use of an intravaginal ring with dapivirine for PrEP in this population.

CDC animal models to test PrEP agents

• CDC repeat-exposure macaque models combine physiologic HIV transmission and pharmacology and were accurate in predicting the efficacy of PrEP agents in human clinical trials. Several benefits of the macaque model include the ability to:
  • Examine both rectal and vaginal virus transmission
  • Measure infection over multiple transmissions per animal
  • Advance the most promising PrEP agents to human clinical trials
  • Save money on the costs of Phase IIb/III trials
• Macaque studies can inform the design of human clinical trials and vice versa. For example, newer agents can be tested in animal models for similar or better efficacy rates to Truvada. Similarly, the FACTS 001 trial demonstrated that adherence to topical PrEP agents is a major concern, informing the design of next-generation delivery forms that can be tested in animal models.
• Next generation PrEP agents in development include systemic treatments such as intermittent Truvada, long-acting injectables, and other new drugs as well as topical agents, such as new vaginal gels, rectal gels, and intravaginal rings:
  • Intermittent oral Truvada showed excellent efficacy in an animal model of rectal infection.
  • A long-acting injectable integrase inhibitor under development by GlaxoSmithKline showed 100% protection in animal models of rectal and vaginal infection, with the potential to greatly increase adherence among users.
  • The integrase inhibitor, raltegravir, showed good efficacy up to three hours post coitus in a macaque model of vaginal infection. This PrEP agent may be more suitable for young women than other shorter-acting topical PrEP agents.
  • Administration of oral maraviroc, an entry inhibitor, in an animal model of rectal infection did not protect against infection; this study demonstrates how the animal model can stop unsuccessful prevention methods from proceeding to human clinical trials.
  • Researchers are examining multiple rectal gel formulations that might be particularly relevant for the U.S. epidemic; interestingly, a 1% maraviroc gel resulted in greater than 1000-fold higher rectal concentrations than oral dosing.
  • Researchers are using macaque models to test intravaginal rings to deliver PrEP agents: the rings are FDA-approved for contraception and the single application may result in better adherence than gels for young women.
• Animal models also can be used to test conditions that might modify the efficacy of PrEP agents, such as drug resistance, co-treatment with Depo-Provera, and co-infection with other sexually transmitted diseases.

Benefits and methods of collaborating with the CDC for animal testing

• Animal testing saves time and money by narrowing the number of potential PrEP agents to those with the highest likelihood of success in human clinical trials.
• The NIAID Division of AIDS (DAIDS) established an IAA in 2010 to support CDC animal models for the testing of PrEP agents. Details on this IAA include:
  • Waivers overcoming the prohibition on the transfer of funds between agencies allowed investigators to have access to CDC animal models.
  • This type of collaboration greatly accelerated microbicide and PrEP preclinical research.
• NIH funded a CDC HIV/AIDS Clinical Trials Unit in collaboration with Emory University.
  • This collaboration resulted in the capacity to conduct phase I-III clinical trials in Thailand and Kenya.

Discussion

• Participants discussed the limitations of animal studies in predicting the outcomes of human studies; for example, different drug dissociation rates between animals and humans. While these limitations are important to acknowledge, animal models are still useful in informing human studies.
• Animal models should be considered as early as possible in the development of a prevention or treatment agent to gain the most value in informing human clinical trials.
• Pharmacokinetic (PK) and pharmacodynamic (PD) data should be used to mimic the human clinical exposure of a drug or viral agent.
• Participants praised the collaborative endeavors of the CDC in making animal models available for HIV prevention and treatment studies.

Translating Research Results into Programs

Julia MacKenzie, Ph.D., Senior Technical Advisor for the Office of Research and Science at the Office of the U.S. Global AIDS Coordinator and Health Diplomacy/PEPFAR, presented the successes of the PEPFAR program since its inception in 2003, challenges facing the program moving forward, and collaborations to address challenges in the control of HIV/AIDS.

Successes of the PEPFAR program

• 6.7 million people are on life-saving ART.
• 1 million babies were born HIV-free.
• 4.7 million men received Voluntary Medical Male Circumcision (VMMC).
• 17 million people (including 5 million orphans) received care and support.
• The United States has provided more than $52 billion to HIV/AIDS and TB programs as well as the Global Fund to Fight AIDS, Tuberculosis, and Malaria since 2004.

Challenges facing the PEPFAR program

Key challenges include:

• Reaching HIV-positive men with the highest likelihood to spread the infection
• Reaching adolescent girls and young women (AGYW) at high risk for infection
• Attaining high treatment coverage for pediatric patients and patients with TB
• Addressing discrimination that prevents access to and delivery of services
• Mapping the impact of an intervention at the community level
• Quickly expanding high quality routine viral load monitoring
• Increasing quality assurance for HIV rapid testing

Collaborations to address challenges faced by the PEPFAR

• The Determined, Resilient, AIDS-free, Mentored, and Safe (DREAMS) initiative – This collaboration involves the PEPFAR, the Bill & Melinda Gates Foundation, and Nike and provides services to AGYW at high risk for HIV infection.
• The Accelerating Children’s HIV/AIDS Treatment (ACT) initiative – This collaboration includes the PEPFAR and the Children’s Investment Fund Foundation (CIFF) to provide ART to 300,000 children living with HIV in Africa.
• The Medical Education Partnership Initiative (MEPI) and Nursing Education Partnership Initiative (NEPI) – These initiatives allow the PEPFAR to fund African medical institutions to increase the number of in-country nurses and doctors.
• Combination prevention and Treatment as Prevention (TasP) trials – Funded by the PEPFAR and run by NIH and the CDC, these trials examine if rapid scale up of interventions can dramatically slow down the epidemic at the local level.
• Prevention of Mother to Child Transmission efforts (PMTCT) – The PEPFAR is involved in a network to reduce the transmission of HIV from a mother to her child.
• Generation of high-quality, sub-national estimates of HIV infection – The PEPFAR is collaborating with the Joint United Nations Programme on HIV/AIDS (UNAIDS) to generate sub-national estimates of HIV infection rates.
• Implement improved HIV prevention, treatment, and care – The PEPFAR and NIH are working closely to improve the implementation of services.
• Improve evaluation of existing interventions – The PEPFAR is using the NIAID-developed research consortium of International Epidemiologic Databases to Evaluate AIDS (IeDEA) to evaluate existing HIV treatment programs.
• Conduct secondary analyses of PEPFAR programmatic data – The PEPFAR is seeking interagency support, particularly at NIH, in the analysis of its programmatic data to examine the quality of services provided at the site level in real time.

Discussion

• Several participants asked how the PEPFAR could develop delivery models to quickly capitalize on the positive results of an intervention study; for example, vaginal rings delivering ART as PrEP. The HIV community desires fast, effective implementation and is collaborating with NIH to develop programs on how best to achieve this goal.
• Participants enquired as to how the PEPFAR identifies the most pressing implementation science questions. The peer-review process for NIH does not always deliver research relevant for the implementation of PEPFAR programs. The PEPFAR is seeking to improve collaborations with NIH on promoting implementation science research.
• Participants asked about the quality of the PEPFAR programmatic data. Collaborations are needed to robustly address the quality and utility of PEPFAR programmatic data.

NIH Collaborations with the PEPFAR on Implementation Science

Emily Erbelding, M.D., Deputy Director of the Division of AIDS at NIAID, described the NIH/PEPFAR portfolio on implementation science and mechanisms for promoting this research in the future.

Current NIH/PEPFAR portfolio on implementation science

• She defined implementation science as translating what we know works under the best conditions to actually doing it under real-world conditions.
• NIH/PEPFAR collaboration combines PEPFAR-generated implementation science research questions with NIH grant stewardship.
• Past funding opportunity announcements (FOAs) on implementation science involved collaboration with a number of NIH Institutes, Centers, and Offices and provided a total of $37 million to 76 awardees.
• Examples of NIH/PEPFAR implementation science projects for the treatment and prevention of HIV include:
  • Methods to implement VMMC – The PEPFAR encouraged methods to improve male circumcision rates, including designing operating theaters, training doctors on the procedure, and developing devices to assist in the removal of foreskin.
  • Early infant male circumcision (EIMC) – It is much easier and safer to perform circumcisions on infant boys. The PEPFAR tested two models of EIMC delivered either in a facility or community setting.
  • HIV Prevention Trials Network (HPTN) 071, or the Population Effects of Antiretroviral Therapy to Reduce HIV Transmission (PopART) trial – This large randomized trial will examine the effectiveness of universal testing and immediate ART initiation on rates of HIV infection.
  • Community efforts through the Sustainable East Africa Research in Community Health (SEARCH) consortium – This consortium examines if universal testing and treatment can dramatically slow down the spread of HIV at the community level.

Future NIH/PEPFAR implementation science research

• NIH and the PEPFAR have developed a new FOA to fund projects that address priority implementation science questions in HIV prevention, care, and treatment.
  • The FOA was submitted to the NIAID council in January 2015 for potential implementation in 2016.
  • This FOA has $4 million per year in set aside funds for a total of 5 years; the anticipated number of awards is 10 to 15.
  • Priority areas for this FOA include methods to identify hot spots of HIV infection, improve delivery of effective prevention and treatment services, increase retention in treatment programs, improve rates of virologic suppression, and improve implementation of treatments for PMTCT.
  • The budget for in-country personnel and project costs must support at least 80% of the direct costs.
  • The application must develop a path to independence for an in-country investigator.

Discussion

• The high requirement for in-country support may hinder attracting qualified U.S. health services researchers to the field. However, the priority of the FOA is to build on in-country assets to ensure the sustainability of PEPFAR efforts.
• Participants questioned whether the R01 mechanism was the best way to address PEPFAR’s highest research priorities. It may be more appropriate for the PEPFAR to decide the best way to move forward and then fund the best team to carry out the research plan.
• Participants discussed the differences between the IeDEA databases, which collect patient level data on ART outcomes, versus PEPFAR databases, which collect programmatic information on various treatment sites.

 OPEN DISCUSSION ON HIV PREVENTION EFFORTS

• Participants discussed the ramifications of negative results of PrEP agents in animal models. For topical PrEP agents, it is possible to determine whether mucosal drugs levels are similar between monkeys and humans. For systemic PrEP agents, the link between systemic drug levels and prevention outcomes is less clear. If animal models provide some biologic plausibility for the effectiveness of a treatment, judicious risk-taking in human clinical trials may be necessary to answer the research question.
• As the global HIV/AIDS epidemic matures, researchers are beginning to see the emergence of comorbidities, such as heart disease and cancer in HIV-positive individuals. Participants discussed collaborations with USAID and other academic partners to look at cardiovascular disease and mental health in HIV-positive populations. The World Health Organization also is addressing the treatment of comorbidities in its next HIV guidelines release.
• Participants noted the importance of addressing mental health illness in implementation science research. A one-size-fits-all approach to HIV prevention and treatment will not likely reach populations with mental illness.
• Participants discussed the importance of implementation science to HIV prevention and treatment research efforts. The demonstrated heterogeneity in success at different PEPFAR sites can provide the basis for implementation science research. Participants noted the need for implementation science researchers on review panels for research in this field.

NEW AGENTS FOR PREVENTION, CURE, AND TREATMENT HIV Antibodies for Prevention and Therapy

John Mascola, M.D., Director of the Vaccine Research Center at NIAID, described the use of HIV-1 monoclonal antibodies for the prevention and treatment of HIV and presented interagency partnerships for clinical trials.

Background on HIV-1 neutralizing antibodies

• Neutralizing antibodies (Nabs) are usually isolated from long-term infected individuals and are important because they define the major epitope of the HIV-1 envelope glycoprotein (Env), which can be used as immunogens in vaccine design.
• Different permutations of the HIV Env trimer, such as viral spike mimics and epitope-specific immunogens, can be expressed for use in different vaccination strategies.
• The emergence of NAbs illuminates the process of how antibodies mature over time to become broadly neutralizing and defines the process that needs to occur with a vaccine.
• NAbs have some distinguishing characteristics that make vaccine design challenging, including a high level of affinity maturation, the ability to bind both protein and glycans, an unusually long complementarity determining region 3 of the heavy chain CDRH3, and a propensity to deletion mechanisms.
• The most effective NAbs result from a coevolution of the virus and the host following long-term infection.

Studying NAbs for prevention of HIV

• The rationale for studying NAbs for HIV prevention is based on the success of antibodies in preventing infection in non-human primates. However, there is no evidence that antibodies can prevent HIV infection in humans or what level of antibody is needed for protection.
• An antibody under study for the prevention of HIV is the CD4 binding site antibody, VRC01, which binds to 80-90% of HIV viruses in all clades and can be maintained at plasma levels that prevent infection for up to 8 weeks with a single infusion in non-human primates.
• Researchers are analyzing HIV antibodies for the prevention of HIV infection in high-risk adults as well as infants during breastfeeding by addressing what level of antibody is needed to protect and how long the antibody will last. These studies are conducted in collaboration with HPTN, HVTN, and the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) network.
• Efforts are ongoing to extend the half-life of NAbs against HIV through mutagenesis, potentially increasing their utility as preventative agents. For example, MedImmune’s YTE mutation increases the half-life three to four fold over the parent antibody.

Studying NAbs for the treatment of HIV

• Researchers are also examining the utility of HIV antibodies for the treatment of HIV.
• For example, the CD4 binding site antibody, VRC01, has been shown to decrease viral load after a single infusion in HIV-1 infected individuals.
  • Experiments conducted in collaboration with the MHRP will examine VRC01 and ART for the treatment of individuals in the early stages of HIV infection.
  • Experiments conducted in collaboration with the AIDS Clinical Trials Group (ACTG) will address the effectiveness of VRC01 and ART in individuals with longer, established HIV infections.

Future directions and summary

• Future directions for antibody research in the prevention and treatment of HIV include developing antibodies with longer half-lives and higher potency, examining subcutaneous dosing every 6 months for HIV prevention, and determining the effectiveness of two highly potent antibodies for HIV treatment to prevent viral escape.

Discussion

• Participants noted the need for collaboration between groups involved with ART and antibodies for the treatment of HIV.
• The decision of which antibody to use for clinical trials is multifactorial. An antibody may be incredibly potent but only target half of the circulating HIV strains. It is estimated that less than one-half of the antibodies examined in the lab have potential for clinical evaluation.
• As antibodies are injectable therapies, mechanisms are needed to educate individuals on the nature of antibodies for the prevention and treatment of HIV.

Clinical Studies of New Interventions for HIV Remission: Collaboration between NIH and the MHRP

Dr. Jintanat Ananworanich, Associate Director for Therapeutics Research in the Clinical Trials Unit of the MHRP, described the joint studies between NIH and the MHRP examining the processes involved in early HIV infection and treatments to elicit a function cure in patients in the early stages of infection.

MHRP and NIH Collaborations

• RV217/ECHO – This trial is a collaboration between the MHRP and the NIAID to determine the processes involved in the earliest stages of HIV infection. Researchers collect biological samples from HIV-negative study participants twice a week to better understand the biological processes that occur prior to the detection of HIV antibodies.
• RV254/SEARCH 010 – This large collaborative trial between the MHRP, NIH, and the Thai Red Cross (TRC), seeks to detect very early HIV infections by screening participants using tests that detect the presence of HIV nucleic acid prior to the production of HIV antibodies. Early ART resulted in a lower number of cells harboring HIV-integrated DNA and a smaller HIV reservoir in CD4+ T cells. This trial is an excellent example of successful collaboration between the Thai government and U.S. military and government research institutions.
• International NeuroHIV Cure Consortium (INHCC) – The study population from the RV254 trial provided the resources for studying the effect of HIV infection on the central nervous system. This consortium includes researchers at University of California—San Francisco and Yale University, in conjunction with scientists at the MHRP, the National Institute of Mental Health (NIMH), and the National Institute of Neurological Disorders and Stroke (NINDS).
• RV411 – This NIAID-funded HIV remission trial examines treatment of patients in the earliest stages of HIV infection.
• RV397 – This NIAID-funded trial examines if treatment with the bNAb VRC01 can induce remission is those with long-term viral load suppression.
• RV398 – In this trial, researchers will examine the effects of treatment with bNAb VRC01 in the very early stages of infection.

Identifying research priorities and opportunities for collaboration

• Existing mechanisms to identify research priorities include regular teleconferences with four acute HIV-infection working groups and other researchers at the annual acute HIV infection scientific meeting.
• Current research priorities for the MHRP include the use of adenovirus and poxvirus vectors for vaccine development (RV405 trial) and the use of latency-reversing agents (LRAs) and bNAbs in combination therapies.
• Dr. Ananworanich noted that in order to make significant gains in HIV remission research, trials with multiple combination therapies are necessary. While an individual therapy may not work alone, it may have efficacy when used in combination with other treatment modalities.
• The path to combination cure research includes parallel animal models and human studies, access to research sites and funding, and a streamlined regulatory review and approval process.

Conclusion

• Collaborations between NIH and the MHRP involve sharing technology, data sets, laboratory resources, training opportunities, and access to clinical sites.
• These collaborations also have resulted in the development of roadmaps to safer, faster, and more successful combination cure research.

Discussion

• Participants commended the collaboration that resulted in such a large cohort of participants to study early HIV infection and also appreciated the efforts to examine the effects of HIV infection on the central nervous system.
• Participants discussed the possibility of using the RV254 cohort to better understand transmission processes. Dr. Ananworanich noted that there is evidence of efforts to prevent transmission among study participants; however, the efforts of dedicated behavioral scientists would be needed to generate reliable data on social behaviors.
• Participants discussed how much the efficacy of individual treatments should factor in to their utility in combination treatments. Dr. Ananworanich emphasized that combination therapies are the most likely path to remission and cure of HIV infection. All individual therapies are viable candidates for testing in combination treatments.
• Participants agreed that more research is needed into the mechanisms of viral control and, in particular, identifying markers that relate to viral control.

FDA Perspectives on Long-Acting Antiretrovirals for HIV Prevention and Cure Clinical Trials

Kimberly Struble, Pharm. D., Medical Team Leader in the Division of Antiviral Products at the FDA, provided the FDA’s perspectives on the development of long-acting antiretrovirals for the prevention of HIV.

Development of long-acting antiretroviral agents for HIV prevention

• The development of long-acting antiretroviral agents for HIV prevention can occur through modification of oral drugs that are already approved for the treatment of HIV to an injectable or other delivery system or through the creation of a new investigational long-acting agent for HIV prevention.
• The dosing of an oral agent approved for the treatment of HIV can be used to inform the dosing of an injectable form of that drug to prevent HIV.
• A new long-acting agent for the prevention of HIV can proceed without an immediate release dosage form and would follow the typical drug development pathway.
• Clinical trials are needed to determine the safety and efficacy of either repurposed oral agents or new injectable agents for the prevention of HIV because:
  • The plasma concentration needed to achieve HIV prevention may differ than that needed for HIV treatment.
  • There are no validated biomarkers to confirm that protection from HIV has been achieved.

Preclinical considerations for long-acting antiretroviral agents for HIV prevention

• Animal models for the validation of long-acting agents for HIV prevention do not exist and the FDA does not require primate vaginal or rectal viral challenge studies.
• However, animal studies and in vitro experiments can generate supportive data to help determine a dose to pursue in human clinical studies.
• The FDA welcomes exploratory analyses into assessing drug concentrations in different biologic matrices, such as plasma, cervicovaginal, and rectal tissues, to determine which tissue provides the best correlation between drug concentration and efficacy.
• Other PK/PD considerations in preclinical trial development include understanding how long the agent protects against HIV after discontinuation of the product, monitoring for viral resistance following discontinuation, and ensuring the absence of drug-drug interactions when starting oral therapy after long-acting therapy has been discontinued.
• The need for an oral lead-in prior to dosing with a long-acting agent depends on a number of factors, including the ability of a long-acting agent to maintain protective drug concentrations and the tendency of the long-acting agent to induce a hypersensitivity reaction; it is easier to identify and treat individuals on oral immediate release products than on agents with prolonged exposure times.
• In order to mitigate the risks associated with clinical trials with no oral lead-in, investigators can develop strict enrollment criteria, begin the trial with a small number of subjects, stagger dosing, have stringent stopping rules, and involve an unblinded medical monitor to oversee safety.

Clinical considerations for long-acting antiretroviral agents for HIV prevention

• Clinical trials for the evaluation of antiretroviral agents for HIV prevention should be well controlled and have sufficient sample size to account for the low incidence of seroconversion.
• Enrolling sexually active or high-risk individuals allows researchers to enroll fewer subjects and may facilitate faster drug development times.
• Studies should include diversity in the patient populations at high risk for HIV infection, including women at high risk, men-who-have-sex-with-men (MSM), serodiscordant couples, and intravenous drug users.
• Researchers should assess how the number, frequency, and volume of injections might affect subject retention.
• The use of an oral PrEP agent as the comparator of choice depends upon local acceptance of these agents.
• The use of an active control in non-inferiority studies presents a methodological challenge, as subject adherence is a large determinant of the preventative effect.

Clinical considerations for HIV cure trials

• Initial clinical trials examining agents to cure HIV should focus on safety, by using the lowest dose and duration time, enrolling stable patients with higher CD4 counts and undetectable HIV RNA, and monitoring for drug interactions, genotoxicity, mutagenicity, and carcinogenicity.
• Prior to interrupting ART to ascertain if a drug therapy resulted in an HIV cure, monoclonal antibodies must show a decline in HIV RNA and ‘Kick and Kill’ agents must show an impact on the size of the latent reservoir.
• Patient safety monitoring is important in HIV cure trials, including measuring CD4 levels, developing plans to restart ART, having multiple ART regimens on hand in case of resistance, and counseling participants on the risks of HIV transmission while off ART.

Discussion

• Participants discussed the challenges in conducting efficacy trials where adherence remains a large determinant of a product’s success. It may be possible to look only at adherent individuals for some efficacy trials; ongoing conversations on how to address this issue are important in developing consensus on this issue.
• The costs and large numbers of study participants needed for HIV prevention studies are problematic; it may be possible to share placebo arms across multiple studies for cost savings.
• The FDA does not currently mandate the use of Truvada for the control arm of PrEP studies. Researchers should understand their study population’s acceptance of PrEP agents like Truvada in the development of their clinical trial.
• Participants noted the importance of enrolling high-risk adolescent populations in PrEP trials and the challenges and ethics of obtaining parental consent.
• Participants discussed the co-administration of contraception in patients on ART and noted the importance of monitoring for drug-drug interactions and making sure that patients understand the roles of contraception and ART.

International Research Opportunities in Women’s Health

Heather Watts, M.D., Senior Technical Advisor for PMTCT and Maternal health in the Office of the Global AIDS Coordinator and Health Diplomacy of the PEPFAR, described PEPFAR’s six primary areas of focus in women’s health and listed ways for interested stakeholders to collaborate.

PEPFAR’s areas of focus for women’s health

• PMTCT – The prevention of HIV infection from mother to child requires the identification and treatment of HIV-positive pregnant women. As of 2014, PEPFAR programs identified more than half of HIV-positive pregnant women in the world. As a result of PEPFAR’s efforts, approximately 86% of HIV-infected pregnant women are on ART.

Future priorities in this focus area include prioritizing efforts in areas with a high incidence of HIV, increasing the numbers of HIV-positive women on ART, improving adherence to ART during breastfeeding, and improving following-up of mother and child after birth. Additional efforts outside of HIV prevention include management of TB, malaria, and other sexually transmitted diseases as well as improving the health and involvement of the male partner.

• Maternal support – HIV prevalence is strongly correlated to maternal mortality; in 2008, approximately 18% of all maternal deaths were attributed to HIV infection. A meta-analysis demonstrated a relative risk of 7.74 for maternal death for women infected with HIV. Some contributors of this increased risk of death include pneumonia, sepsis, and endometritis. Prevention and early treatment of HIV-positive women is a key step in decreasing maternal mortality rates.

The Saving Mothers Giving Life initiative is a public-private partnership between U.S. government agencies, pharmaceutical companies, and the governments of Uganda and Zambia to improve the speed and quality of health care delivered to pregnant women in African countries. Phase 1 results indicate a 35% reduction of maternal mortality in Uganda and Zambia after one year of program implementation. 
Future priorities in maternal health include improving the safety and delivery of drugs regimens for HIV, TB, and other infectious diseases, as well as developing methods to reduce stigma and encourage testing and treatment among pregnant women.

• Family planning – The PEPFAR is integrating family planning efforts into the larger HIV prevention and treatment program. A family planning task force administers $25 million to deliver contraceptives to each of the five countries involved in this initiative.

Future areas of research include using family planning as an opportunity to introduce PrEP to young women, addressing whether or not hormonal contraception increases the risk of acquiring or transmitting HIV, and investigating drug interactions among contraceptives, ART, and other medications.

• Cervical cancer prevention – HIV infected women have an increased risk of cervical cancer; as a result, HIV infection and cervical cancer are highly correlated, resulting in 275,000 deaths a year. The PEPFAR administers about $4 million per year at more than 250 sites in Africa for cervical cancer screening and treatment efforts and is a founding member of the Pink Ribbon Red Ribbon partnership to address cervical and breast cancer in sub-Saharan Africa.

Priorities in this focus area include determining the most cost-effective screening methods, offering multiple treatment options for precancerous lesions, and providing treatment for invasive cancers.

• Gender issues – The PEPFAR believes that improving the inequities among women in Africa is a vital step in reducing HIV infection rates. A Violence Against Children Survey in five countries demonstrates a significant number of children experience unwanted sexual contact before the age of 18; the PEPFAR is using the results of surveys such as this to change gender-related public policy.

Some of the PEPFAR’s other activities to reduce gender inequities include offering reproductive health services, developing interventions to prevent violence based on gender, and engaging men and boys to address masculine and sexual norms and behaviors.

• HIV prevention in AGYW – Young women in Africa have the highest risk by far of acquiring HIV. UNAIDS estimates that in 2012, approximately 5500 women between the ages of 15 and 24 acquire HIV per week in East and Southern Africa.

The DREAMS partnership between the PEPFAR, the Bill & Melinda Gates Foundation, and the Nike Foundation provides evidence-based interventions to address HIV risk behaviors and improve the lives of AGYW to reduce new HIV infections by 40% by 2017. The DREAM intervention comprises multiple components, including sexual and reproductive health services, violence prevention, counseling, parenting programs, and PrEP demonstration projects.
The PEPFAR also provides $45 million per year to USAID to support microbicide development, introduction, and tailoring to support women’s efforts to protect themselves against HIV infection.

Conclusions

• The PEPFAR is committed to the prevention and treatment of HIV in women and the care of women and children’s health overall.
• Addressing the high rate of HIV infections in AGYW needs an intensified focus.
• There are several mechanisms for interested stakeholders to collaborate with the PEPFAR on women’s health initiatives, including implementation science studies, supplements, investigator-initiated grants, network collaboration, and analysis of program data.

Discussion

• Participants discussed whether PEPFAR programmatic data was able to accurately determine the effect of PMTCT efforts on incidence of HIV infection. Additional data points regarding the number of women on treatment, maintained on treatment, and when a woman ends breast feeding should improve the utility of PEPFAR data for correlating treatment with HIV incidence.
• Participants noted that offering large numbers of interventions such as the DREAM package may have an impact on HIV incidence; however, determining which components were successful at the local level may prove challenging. The PEPFAR is ascertaining which interventions are the most appropriate for its stakeholders’ needs. Understanding which components are successful should make the intervention more efficient and financially sustainable.

The Medical Education Partnership Initiative

Roger Glass, Ph.D., Director of the John E. Fogarty International Center (FIC) of NIH, described the MEPI initiative and the collaborative efforts of FIC and OAR. 

MEPI background and purpose

• The goal of MEPI is to improve the number and quality of resident health care workers who remain in-country to provide local health services.
• The PEPFAR and NIH provided MEPI with more than $130 million for 5 years (2010-2015); OAR was the first to contribute to this endeavor.
• MEPI has made 13 awards to institutions in 12 African countries and also has funded one award to a coordinating center.
• Initial MEPI awards spurred in-country interest from medical school deans and the Ministers of Health and Education, resulting in a growth of medical and research education in a total of 34 African and 31 U.S. and U.K. institutions.

Key MEPI Achievements and future directions

• MEPI has built in-country research capacity, including increased training for students and faculty and the ability to sustain research through independent grant awards.
  • For example, an award to the University of Zimbabwe resulted in the improvement of mental health education and research capacity as well as the development of a clinical research program for cardiovascular diseases.
• MEPI has created offices for research in ethics, grants management, and research support.
• MEPI has strengthened partnerships within each participating country as well as with outside financial donors.
• MEPI provided funds for participants to have tablet devices for clinic consultations, which contain applications for the diagnosis and treatment of HIV/AIDS.
• Current MEPI grants end on August 31, 2015; funding over the next 5 years will improve the research capacity of junior faculty at existing MEPI locations.

FIC and OAR collaborations to improve HIV/AIDS research

• FIC and OAR, under the leadership of Dr. Whitescarver, have invested in building global research capacity since the 1980s:
  • The Fogarty AIDS International Training & Research Program (AITRP) has provided training for more than 2,000 doctors and researchers in 100 developing countries since 1988. These in-country research efforts remain financially sustainable due to their ability to secure outside funding.
  • The Global Health Program for Fellows & Scholars has provided training to more than 80 medical students, fellows, and post-doctoral associates, more than half of whom are researching HIV-related topics.
  • The Fogarty International Research Ethics Training Program seeks to develop culturally relevant curriculum and train future leaders in bioethics; ethics remains a critical component of successful HIV treatment and research initiatives.

Discussion

• Participants agreed that MEPI and other FIC initiatives have resulted in large returns on investments, which should be more widely publicized. A large proportion of in-country leadership in HIV research have benefitted from FIC programs and funding.

TRANS-NIH INITIATIVES NIH Bilateral Initiatives

Ms. Natalie Tomitch, Health Scientist Administrator in the OAR, described the international interagency partnerships led and supported by OAR.

Highlights of NIH bilateral partnerships

NIH has bilateral partnerships with scientific organizations in India, China, Russia, South Africa, and Brazil, with the goal of addressing shared research questions and advancing knowledge. They provide a unique collaborative opportunity for U.S. scientists and provide access to populations not available in the United States.
Details on each of the collaborative partnerships are described below:

• U.S. – India Collaborative Research Partnership on the Prevention of HIV/AIDS: This collaboration involves the Indian Council of Medical Research (ICMR), Department of Biotechnology (DBT), and eight Institutes, Centers, and Offices with NIH. OAR is the sole funder for this collaboration and fosters trans-NIH participation. Thus far, 62 projects have been funded in four funding cycles; OAR is providing $2 million per year for 12 projects in the FY2013-FY2015 round of support. The joint administrative structure of this collaboration includes trainings, workshops and consultations, and serves as a model for other international partnerships. Efforts are underway to attract new Indian stakeholders to the partnership.

The U.S. – India partnership has resulted in concrete scientific benefits for HIV/AIDS researchers and patients, including new collaborations, access to patients infected with HIV type C, linkage between cancer and HIV registries, training, and technology transfers. This partnership also has increased awareness of cancer associated with HIV infection as well as an understanding of the role of drugs and alcohol in HIV transmission.

• U.S. – China Biomedical Collaborative Research Program: This partnership formalizes a 30-year old, informal collaboration between the national Natural Science Foundation of China (NSFC) and NIH. This partnership is the broadest and largest of all of NIH bilateral collaborations. There are 109 projects funded in three funding cycles; OAR is providing $1.45 million per year for eight projects. An activity associated with this program is the U.S.-China Research Toward a Cure Initiative, part of an NIH effort announced by the President of the United States in 2013.

• U.S. – Russia Biomedical Research Collaboration: This collaboration coordinates HIV/AIDS research efforts between the Russian Foundation for Basic Research (RFBR) and seven NIH Institutes, Centers, and Offices. OAR is the sole funder for this partnership and has awarded 24 grants in two funding cycles. Efforts are ongoing to evaluate the scientific achievements of this collaboration.

• U.S. – South Africa Collaborative Research Program: The South African Medical Research Council (MRC) and NIH have a unique joint funding arrangement where the MRC provides money to NIH to issue and review Requests for Applications (RFAs) for research into HIV/AIDS and related comorbidities. NIH issued three FOAs and awarded 31 grants in FY2015. The MRC has strengthened its research grant, consultation, and management capacities.

• U.S. – Brazil Collaborative Research Program: This collaboration includes the Brazil Ministry of Health (MS) and Ministry of Science & Technology (MCTI) as well as three Institutes, Centers, and Offices within NIH, focusing on infectious diseases such as HIV/AIDS. Twenty one-year grants will be awarded in FY2015, with seven of those funded by OAR. This partnership includes the Science Without Borders Program, an initiative where Brazilian scientists receive training at NIH.

Challenges and opportunities

There are several challenges in the administration of international collaborations. For example, evaluating the success of a program depends on a number of factors, such as scientific benefit and consideration of different perspectives between grants management and scientific staff. Bureaucratic hurdles can result in delays in funding, and approval and differences in scientific priorities can complicate the scoring of research projects. NIH does not have 100 percent control over these processes; however, this is counterbalanced by the fact that NIH contributes only 50 percent of the costs.

Evaluation of international partnerships has improved due to the recent approval of survey instruments, which will examine the quality of collaborations and communications. Recent feedback on the U.S.-China bilateral initiative has been positive. Challenges moving forward include multi-year funding support and biospecimen sharing.

NIH Bilateral Initiatives: The U.S.-China Collaboration on Research Toward a Cure for HIV

Dr. Paul Sato, a Medical Officer for OAR, described the U.S.-China Collaboration on Research Toward a Cure for HIV.

A total of 10 NIH Institutes, Centers, and Offices are involved in this international partnership, with the extramural component led by the NIAID. This U.S.-China partnership is the first to issue an FOA on research for a cure for HIV, to be awarded in 2015. Both the NIH and NSFC provide funds for the FOA and applications must be approved by both funding organizations. All projects for this FOA must involve collaborations between investigators in the United States and China, both working on a common research question.
There are a number of research activities supported by this FOA, including but not limited to:

• Determination of the mechanisms of HIV-1 latency
• Identification of viral reservoirs that are reactivated after cessation of ART
• Development of assays to measure HIV-1 reservoirs
• Understanding of how reservoirs are affected by very early treatment post infection

Research activities not supported by this FOA include the following:

• Clinical trials of drugs, biologics, or diagnostics
• Research unrelated to HIV or AIDS (SIV and SHIV research is allowed)
• Research not paired with an investigator in the partnering country

Discussion

Participants discussed the financial and political stability of the U.S.-China partnership. Thus far, the Chinese government has been supportive of the research collaboration and adequate funds are available for the proposed research.

CONCLUDING DISCUSSION

Participants discussed several ways to improve the speed and ease of collaborations both within and between U.S. federal agencies. The day’s meeting described numerous opportunities for collaborations among agencies such as USAID and the PEPFAR. A small working group with representatives from relevant federal agencies should share institutional knowledge regarding how to set up intramural and extramural collaborations. In addition, there should be more opportunities for staff below the senior level to meet, communicate, and collaborate between federal agencies.

Participants discussed ways to determine research priorities among different agencies. Participants noted a need for information sharing in all aspects of HIV/AIDS research, particularly implementation science. International agencies should consider meeting to identify the most pressing global research priorities and questions.

There is an urgent need to accelerate the delivery of new treatment regimens to the HIV-infected patient population. Participants noted the need for collaboration with the FDA and other regulatory agencies to speed up the approval process for new HIV medications.

PUBLIC COMMENTS

No members of the public requested time to comment.

CLOSING COMMENTS

Dr. Walensky thanked members of the OARAC and invited speakers and guests for their participation in the 40th meeting of the OARAC. She thanked Dr. Whitescarver and Ms. Wertheimer again for their many years of service to the OAR.

ADJOURN

Dr. Walensky adjourned the 40th meeting of the OARAC at 4:30 p.m. on April 16, 2015.

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

/Rochelle Walensky, MD/
Rochelle Walensky, MD, MPH, Chair