Meeting Minutes - November 5, 2009

Office of AIDS Research Advisory Council
Twenty-Ninth Meeting
November 5, 2009

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

Members Present: Dr. James W. Curran (Chair), Dr. Jack Whitescarver (Executive Secretary), Ms. Dawn Averitt Bridge, Dr. Sharon E. Frey, Dr. Gary W. Harper, and Dr. Betsy C. Herold

Ex Officio Members Present: Dr. John G. Bartlett, Dr. Ralph J. DiClemente, Dr. Carl W. Dieffenbach, Dr. Igor Grant, Dr. Diana M. Lopez, Dr. Jonathan Mermin, Dr. Christel H. Uittenbogaart, and Dr. Ronald O. Valdiserri

Invited Speakers and Guests: Dr. Victoria A. Cargill, Dr. Robert H. Carter, Dr. Anthony S. Fauci, Dr. Jay H. Hoofnagle, Dr. Thomas R. Insel, Dr. Diane M. Lawrence, Dr. Yvonne T. Maddox, Dr. Paolo G. Miotti, Ms. Georgeanne E. Patmios, Dr. Thomas C. Quinn, and Dr. Robert Yarchoan

Welcome and Meeting Overview

The National Institutes of Health (NIH) Office of AIDS Research Advisory Council (OARAC) convened its twenty-ninth meeting at 8:30 a.m. at the Fishers Lane Conference Center in Rockville, Maryland.  Dr. James W. Curran, Chair, welcomed the OARAC members, invited speakers, and guests.

The topic of the meeting was Opportunities for Research Collaborations on HIV-Associated Comorbidities, Coinfections, and Complications.  Dr. Curran noted the importance of interdisciplinary collaborations with scientists who typically focus on illnesses that are associated with HIV/AIDS, but are not AIDS-defining illnesses.  He stated that meeting presentations would address domestic and international perspectives on this topic; collaborative opportunities among NIH Institutes; and an update from Dr. Fauci on the recent Thai HIV vaccine trial.

The minutes of the April 23, 2009 OARAC meeting were approved as submitted.

Director’s Report

Dr. Jack Whitescarver, Director of the Office of AIDS Research (OAR), welcomed everyone to this meeting of the OARAC. He also welcomed Dr. Ralph DiClemente as the newest ex officio member to the Council. Dr. DiClemente represents the National Institute of Mental Health’s National Advisory Mental Health Council. Dr. DiClemente is Charles Howard Candler Professor of Public Health and Associate Director for Prevention Sciences of the Emory/Atlanta Center for AIDS Research. He holds concurrent appointments as Professor in the Departments of Pediatrics, Medicine, and Psychiatry at the Emory University School of Medicine; and he also serves as Adjunct Professor at Morehouse School of Medicine.

Dr. Whitescarver provided an update on OAR’s actions to recent recommendations by OARAC. In follow up to OARAC’s October 2008 meeting on Genomics and HIV, OAR is working with several key ICOs to develop new programs. One of those initiatives will focus on human immunology which may target some of the topics that will be discussed at today’s meeting.

Dr. Whitescarver referred council members and guests to the summary of the Director’s Report in the meeting folder.

Conflict of Interest Statements

Dr. Curran asked Council members to review and sign the conflict of interest statement provided to them. He reminded the council members of the importance of this exercise.

DIRECTOR’S REPORT

Dr. Jack Whitescarver, Director of the Office of AIDS Research (OAR), welcomed everyone to this meeting of the OARAC. He also welcomed Dr. Igor Grant, a new ex officio member to the Council, who represents the Advisory Council of the National Institute on Drug Abuse (NIDA). Dr. Grant is Distinguished Professor of Psychiatry and Director of the NIH Neurobehavioral Research Programs at the University of California, San Diego. He is a neuropsychiatrist whose academic interests focus on the effects of various diseases on the brain and behavior, with an emphasis on translational studies on HIV infection and drugs of abuse.

NIH Personnel Changes

Dr. Whitescarver noted several recent personnel changes at NIH. He stated that Dr. Francis Collins, former Director of the National Human Genome Research Institute (NHGRI), was sworn in on August 17, 2009 as the 16th Director of NIH. Dr. Kathy Hudson, who previously served at NHGRI and then at Johns Hopkins University as Director of the Genetics and Policy Center, was appointed to the newly established position of NIH Chief of Staff.

Dr. Whitescarver reported that Dr. Duane Alexander moved from his position as Director of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) to Senior Scientific Advisor to the Director of the Fogarty International Center (FIC). Dr. Susan Shurin, Deputy Director of the National Heart, Lung, and Blood Institute (NHLBI), will serve as Acting Director of NICHD.

Dr. Whitescarver stated that Dr. Elizabeth Nabel will be stepping down as the Director of NHLBI in December to become the President and CEO of Brigham and Women's Hospital in Boston. An Acting Director for NHLBI has not yet been named.

Dr. Whitescarver noted that the position of Director of NHGRI remains vacant following Dr. Collins’ resignation in the summer of 2008. The Acting Director is Dr. Alan Guttmacher.

Dr. Whitescarver reported that Dr. Ruth Kirschstein, an icon within the NIH community for more than 50 years, died in October. He discussed Dr. Kirschstein’s critical role in the early days of the AIDS epidemic, when she was Director of the National Institute of General Medical Sciences. Dr. Kirchstein established the NIH Office of Research on Women's Health and served as Deputy Director and Acting Director of NIH. In recent years she served as Senior Advisor to the Director of NIH.

Dr. Whitescarver noted that Dr. Collins has an opportunity to make a significant number of critical appointments to shape the NIH.

Budget Overview

Dr. Whitescarver stated that because Congress has not completed the Fiscal Year (FY) 2010 Appropriations bill, NIH will be on a continuing budget resolution at the FY 2009 level until at least December 18, 2009. He noted that the House has approved an appropriations bill and the Senate has released a committee report for the FY 2010 budget.

President’s National AIDS Strategy

Dr. Whitescarver reported that he was invited to brief Mr. Jeff Crowley, the new Director of the White House Office of National AIDS Policy, on the trans-NIH AIDS research program. Dr. Whitescarver noted that Mr. Crowley invited him to serve on the inter-agency task force that will develop the President’s National AIDS Strategy. In addition, OAR staff participated in the first two White House Town Hall Meetings on the President’s AIDS Strategy.

Recent and Upcoming Meetings

Dr. Whitescarver stated that another issue he discussed at the White House was the likely possibility that the International AIDS Society Conference will be held in Washington, D.C. in 2012. He noted that the Conference has not been held in the United States since the late 1980s because of the longstanding restriction on the entry of HIV-infected individuals into the country. This restriction recently was lifted, providing an opportunity for the United States to host the conference.

Dr. Whitescarver stated that he and other NIH staff attended the U.S.-Russia HIV/AIDS Prevention Science Research Workshop, which was sponsored by OAR and took place within the framework of the 3rd Eastern European and Central Asia AIDS Conference. The Workshop was a result of commitments made at the G8 Summit that the United States and Russia would collaborate on HIV vaccine research and follows-up a commitment by Secretary Clinton to increase health collaborations and health diplomacy around the world. The agreement was later expanded to include other areas of HIV prevention research.

Dr. Whitescarver reported that OAR co-sponsored, and NIH staff attended, the AIDS Vaccine Conference, which was held in October in Paris. He noted that results from the Thai HIV vaccine trial were presented there.

Genetics/Genomics Research Working Group

Dr. Whitescarver reported that he has established the Genetics/Genomics Research Working Group, comprised of non-government experts to provide ongoing advice and guidance to the OAR on this important topic that was discussed at a previous OARAC meeting. OAR also sponsored a workshop devoted to this subject. He also reported that OAR provided support for a number of projects in this area.

Addressing HIV-Related Health Disparities

Dr. Whitescarver stated that OAR will launch a number of new initiatives to address HIV-related disparities, including a new initiative that will focus on Hispanic and Latino communities. He also reported on an initiative with NIAID and other ICs and HHS agencies that is focused on the AIDS epidemic in the District of Columbia, which has the highest prevalence of HIV in the United States.

Meeting Overview

Dr. Whitescarver stated that several months ago, he convened a special meeting of ICO Directors and AIDS coordinators from a number of Institutes, including NIAID, NHLBI, NIAMS, NCI, NIDA, NIMH, NICHD, NIDDK, NIA, and the Clinical Center. The meeting was designed to promote more efficient trans-NIH collaboration through the NIH clinical trials networks to address newly emerging AIDS-related issues, particularly premature aging; malignancies; co-infections; cardiovascular, metabolic, and neurocognitive complications; and other co-morbidities. As a result of those discussions, he decided to devote this meeting of the Council to presentations by ICO leadership on their AIDS portfolios on this critical research and opportunities for collaboration. He noted that this Council is unique in many ways, including the fact that it includes representatives from a number of the largest Institutes who also serve as Ex Officio members. He noted that they will have a particularly useful role to play in our discussions today, and he asked each of the Ex Officio Council members to share the goals and recommendations arising from this Council meeting with the advisory councils they represent. This OARAC meeting is designed to continue those discussions and to further explore the roles that each of the ICOs can play in this research.

UPDATE ON OARAC WORKING GROUPS FOR TREATMENT AND PREVENTION GUIDELINES

Dr. John G. Bartlett, Professor of Medicine and Chief of Infectious Diseases at the Johns Hopkins University School of Medicine and Co-Chair of the Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents, presented an update on the activities of the OARAC Working Groups for Treatment and Prevention Guidelines.

Dr. Bartlett reported that the revised document, Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States, was released in April 2009. The revisions addressed new recommendations for use of antiretrovirals (ARVs) during pregnancy. The next update is scheduled for early 2010 and will include criteria for categorization of recommendations for the use of ARVs in pregnancy and will incorporate boxes that clearly identify recommendations for Strength and Quality as well as preferred, alternative, or special circumstances ratings.

Dr. Bartlett stated that the revisions of the Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infectionwill be released in early 2010. The update will include: boxed recommendations for Strength and Quality; major changes to the “What to Start” section; a modified drug appendix; and modifications to toxicity management hyperlinks.

Dr. Bartlett discussed the September 2009 release of the revised Guidelines for the Prevention and Treatment of Opportunistic Infections among HIV-Exposed and HIV-Infected Children. The update addressed: early diagnosis of HIV infection in infants; antiretroviral therapy (ART) and management of opportunistic infections (OIs); vaccination of HIV-infected children; and discontinuation of primary and secondary prophylaxis in children who experience immune reconstitution inflammatory syndrome (IRIS) while on ART.

Dr. Bartlett stated that revisions of the Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents were released in April 2009. The revisions addressed: when to start ART; management of IRIS; and specific pathogens.

Dr. Bartlett noted that the release of a revised Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents is expected on December 1, 2009 (World AIDS Day). The revisions will contain a new section on managing patients with HIV-2 infection, as well as updated drug interaction and adverse event tables. The revisions also will address: drug resistance testing; when to start ART; what drugs to start in treatment naive patients; hepatitis C virus (HCV) coinfection; and prevention of secondary transmission of HIV.

Dr. Bartlett presented the Working Group’s assessment of the research evidence needed to support future guidelines development. He reported that the development of the Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents requires evidence on: the efficacy of nucleoside reverse transcriptase inhibitor (NRTI)-sparing regimens; long term risks and benefits of ART; management of HIV-related central nervous system (CNS) toxicities; use of ART for HIV prevention; optimal use of ART with selected comorbidites; and agents to eliminate HIV reservoirs from the body.

Dr. Bartlett stated that the development of Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United Statesrequires evidence on: the risks and benefits of stopping ART postpartum; the safety of ART during pregnancy for the mother and the infant; the pharmacology of ART agents in pregnancy; and the optimal ART for neonates at risk for HIV due to drug resistance or late presentation of HIV infection by the mother.

Dr. Bartlett stated that the development of Guidelines for the Prevention and Treatment of Opportunistic Infections among HIV-Exposed and HIV-Infected Children would benefit from evidence on: the pharmacokinetics of ARV dosing in children who need treatment for active tuberculosis (TB); diagnosis of TB in children; the incidence and management of IRIS in children starting ART; and the immunogenicity and safety of childhood vaccines in HIV-infected children.

Dr. Bartlett stated that the development of Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infectionrequires evidence on: the long-term effects of ART on children with perinatally-acquired HIV; the optimal time to start ART in children over 1 year of age; the role of new drugs for children in different age groups; and OI issues.

Dr. Bartlett stated that the development of Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents would benefit from evidence on: shorter course TB treatment and non-rifamycin-based TB treatment; the pharmacologic management of OIs without specific drug therapies; when to start ART in individuals with acute OIs; the diagnosis and management of OI-associated IRIS; the effect of ART on hepatitis B virus (HBV) and HCV coinfections; oral agents for HCV; and effective vaccination for HBV.

Dr. Bartlett stated that about two-thirds of individuals infected with HIV die of non-AIDS-defining illnesses, such as premature aging, cancer, cardiovascular disease, liver disease, and others. He noted the need for more research on these comorbidities.

DISCUSSION

OARAC members, speakers, and guests discussed the interactions among HIV treatment and premature aging; multiple pharmacology; cognitive decline and other CNS complications; and peripheral nervous system complications. Dr. Bartlett stated that a neurologist will join the Working Group that he co-chairs.

HIV COINFECTION AND COMORBIDITIES

Dr. Victoria A. Cargill, Director of Minority Research and Clinical Studies, OAR, discussed the current challenges and complications of the epidemic from her experiences as a practicing physician in an AIDS clinic in Southeast Washington, D.C. She stated that the demographics of individuals presenting for care at the clinic reflect the statistics of the current epidemic in the United States. Approximately 95 percent of the HIV-infected patients at the D.C. clinic are from racially and ethnically diverse populations, the majority of whom are African American; about half are female. Patients include men-who-have-sex-with-men (MSM), women, adolescents, formerly incarcerated individuals, and individuals who are homeless or unstably housed. Some individuals have a dual or triple diagnosis of HIV infection, mental illness, and/or substance abuse. Other common features include poverty and an educational level of high school or less.

Dr. Cargill stated that coinfections commonly observed at the clinic include Hepatitis A, B, and C; TB; comorbid acute sexually transmitted infections; methicillin-resistant Staphylococcus aureus; bacterial vaginosis; and human papilloma virus (HPV). Dr. Cargill discussed a case study of a 36 year old female former crack cocaine user who presented with HIV and TB coinfection. The latter infection presented as large lobular growths which resolved with treatment.

Dr. Cargill reported that HIV-infected patients at the Southeast D.C. clinic often present with comorbidities, including lipoatrophy and lipodystrophy, premature aging, cardiovascular complications, metabolic complications, non-AIDS associated malignancies, and dementia. She stated that premature menopause, dementia, pre-existing health conditions, and stigmatizing cosmetic changes also are observed. She observed that poverty, racism, and HIV-associated stigma further confound HIV treatment and care. Dr. Cargill presented a case study of a 27 year old female former sex worker who developed ART-associated thinning of the arms, prominent veins in the legs, increased breast and abdominal girth, and increased serum lipid levels.

Dr. Cargill concluded that while gains have been made in HIV/AIDS treatment and quality of life for many HIV-infected individuals who have access to ART and can tolerate the side effects and other complications, significant morbidity persists and can be expected to increase, especially in marginalized and vulnerable populations.

DISCUSSION

OARAC members, speakers, and guests discussed HIV-associated coinfections and comorbidities, such as cognitive decline, substance abuse, and HCV. They also addressed the impact of poverty and stigma on HIV care and the impact of substance abuse on HIV viral load and treatment efficacy.

HIV COINFECTIONS AND COMORBIDITIES IN INTERNATIONAL CLINICS

Dr. Thomas C. Quinn, Associate Director for International Research, Division of Intramural Research, NIAID, and Professor of Medicine and Director of the Johns Hopkins Center for Global Health, Johns Hopkins University, provided an overview of the status and consequences of the rapid rollout of ART in developing countries and discussed HIV-associated comorbidities and coinfections.

Dr. Quinn stated that HIV-infected individuals on ART in developing countries do extremely well, except during the first three months of therapy when mortality is high. He stated that most early mortality is caused by comorbidities and coinfections associated with low CD4 counts, demonstrating the importance of access to healthcare for individuals newly infected with HIV. He stated that some ART-associated metabolic complications are caused by the practical necessity of using low cost, generic drugs which are not used in the United States.

Dr. Quinn reviewed the effect of HIV-associated comorbidities and coinfections in various organ systems. He stated, for example, that HIV-infected individuals on ART who have impaired renal function experience a mortality rate up to four times that of individuals with normal renal function.

Dr. Quinn reported that HIV/TB coinfection, including multidrug resistant and extremely drug resistant TB, is very common in Africa. Worldwide, TB is responsible for 23 percent of deaths in individuals with AIDS, and 25 percent of deaths from TB are due to HIV infection. He stated that TB risk is increased in individuals with low CD4 counts and high HIV viral loads. He discussed the need for earlier detection and treatment of TB; new drugs to combat drug resistance; and increased TB prophylaxis in HIV-infected individuals.

Dr. Quinn stated that about 4 to 8 million individuals in Asia and Africa are coinfected with HIV and chronic, active HBV. He stated that HIV/HBV coinfection results in accelerated progression of HBV, increased cirrhosis, possible risk of hepatocellular carcinoma, and many treatment complications. Dr. Quinn also discussed the impact of alcohol abuse on liver disease in HIV-infected Africans.

Dr. Quinn also discussed HIV-associated malignancies. He described the increasing incidence of Kaposi’s sarcoma (KS) in Africa. He stated that the incidence of KS lesions increases temporarily after the initiation of ART in HIV-infected individuals. He also noted that Burkitt’s lymphoma and cervical cancer are more prevalent in HIV-infected Africans. He noted that the HPV vaccine is not available in Africa, which has the highest rates of cervical cancer worldwide. He also stated that cervical cancer in HIV-infected individuals often is associated with low CD4 cell counts.

Dr. Quinn also discussed the geographic overlap of HIV and malaria. He stated that, in the absence of therapy, HIV and malaria coinfection is associated with higher Plasmodium parasitemia densities, severe anemia, increased mortality, and increased viral load. He noted that these risks are best documented in pregnant women with malaria who are also at increased risk for perinatal transmission of HIV.

DISCUSSION

OARAC members, speakers, and guests discussed the balance between the cost/quality of drugs used to treat HIV disease in developing countries; the prevention of OIs in individuals on ART; and models of healthcare delivery for HIV-infected individuals who are experiencing coinfections and/or comorbidities.

NIAID PRIORITIES FOR IC COLLABORATIONS WITH AIDS CLINICAL TRIALS NETWORKS TO ADDRESS COMORBIDITIES

Dr. Anthony S. Fauci, Director, NIAID, discussed the NIAID priorities for multi-Institute collaborations with the NIAID clinical trials networks to address comorbidities. He also discussed the findings from a recent Phase III HIV vaccine trial.

Dr. Fauci reviewed statistics showing the magnitude of the HIV/AIDS epidemic in the United States and globally. He also noted the extraordinary progress in AIDS research since 1981. Dr. Fauci discussed the dramatically increased life expectancy for HIV-infected individuals due to ART (for those with access to and who can tolerate the drugs) and noted the need for a comprehensive tool box of HIV prevention methods.

Dr. Fauci discussed the results of the recent Phase III HIV vaccine trial conducted in Thailand, which was the first to show efficacy of an HIV vaccine candidate. The trial included 16,000 participants, primarily heterosexual individuals, who were at relatively low risk of HIV acquisition. Results indicated that the vaccine candidate was 31 percent effective in preventing HIV acquisition. Dr. Fauci stated that the vaccine did not impact viral load in individuals who became HIV-infected, perhaps due to differences between immune responses to block acquisition and immune responses to control chronic viral replication.

Dr. Fauci then discussed the NIAID HIV/AIDS Clinical Trials Networks, which consist of the AIDS Clinical Trials Group (ACTG); the HIV Prevention Trials Network (HPTN); the HIV Vaccine Trials Network (HVTN); the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT); the International Network for Strategic Initiatives in Global HIV Trials (INSIGHT); and the Microbicide Trials Network (MTN).

Dr. Fauci discussed expanding the focus of the AIDS Clinical Trials Networks to study other infectious diseases and HIV-associated comorbidities. He stated that TB is one of the most obvious HIV coinfections to address, especially in developing countries. He also noted the global public health importance of respiratory infections, diarrheal diseases, malaria, vaccine preventable childhood diseases, and “neglected” tropical diseases.

Dr. Fauci discussed the changing face of the HIV/AIDS epidemic in the United States. He noted that morbidity and mortality due to classic AIDS-defining OIs and cancers have decreased, while morbidity and mortality due to non-AIDS-defining illness and conditions, such as liver disease, cardiovascular illness, diabetes and other metabolic conditions, non-AIDS defining malignancies, psychological/psychiatric conditions, neurocognitive impairment, age-related health concerns, and premature aging, have increased. Dr. Fauci discussed the need to treat the whole person, which includes treatment of HIV and its associated coinfections and comorbidities. Dr. Fauci stated that possible explanations for the changing burden of HIV/AIDS include the increasing clinical relevance of chronic underlying comorbid conditions with prolonged survival of HIV-infected individuals; the toxic effects of ART; and ARV-associated immune reconstitution, including reactivated inflammatory responses.

Dr. Fauci discussed the July 2009, NIAID Consultation on Developing Clinical Research Infrastructure for Infectious Diseases: 2010-2020. The group made five recommendations to NIAID: 1) develop multi-disease clinical research capacity by capitalizing on the infrastructure of the existing HIV/AIDS Clinical Trials Networks; 2) design flexibility to allow expansion and contraction of sites; 3) incorporate new expertise for an expanded infectious diseases clinical research portfolio; 4) increase the efficiency of the institutional review board (IRB) process (e.g., establish centralized IRBs); and 5) recognize that international sites and domestic sites require different considerations.

Dr. Fauci concluded by stating that collaborations with other NIH ICOs are critical to effectively address the changing face of the epidemic and the success of the reorganized NIAID HIV/AIDS Clinical Trials Networks.

DISCUSSION SESSION

OARAC members, speakers, and guests discussed the possible effects of immune-induced inflammation in vaccine clinical trials; use of the NIAID AIDS Clinical Trials Networks to explore neurocognitive impairment, respiratory infections, and diarrheal disease infections; and the importance of enrolling diverse and racial and ethnic populations in clinical research.

PRESENTATIONS ON INSTITUTE PRIORITIES

Oncologic Comorbidities in HIV Infection: Highlights of NCI Research Efforts
Dr. Robert Yarchoan, Director, Office of HIV and AIDS Malignancy, NCI, described the decline in the rate of many AIDS-defining cancers and increase in non-AIDS defining cancers as HIV-infected individuals live longer. Dr. Yarchoan cited evidence that cancer is the most frequent cause of death in HIV-infected individuals in the era of ART. He also noted the high attributable risk of death from lung cancer in this population and commented on the magnitude of the KS epidemic in Africa.

Dr. Yarchoan discussed the organizational structure of NCI AIDS research programs, including the central role of the newly established Office of HIV and AIDS Malignancy (OHAM) that is situated within the Office of the NCI Director. OHAM works with NCI leadership, the Divisions, and other Offices to manage the portfolio of AIDS and AIDS malignancy research; interfaces with the OAR and other ICs with regard to AIDS research and AIDS malignancies; and directly manages several research programs.

Dr. Yarchoan discussed the NCI AIDS-related basic and clinical research in domestic and international settings, including investigator-initiated research; the AIDS Malignancy Consortium (AMC); the NCI AIDS and Cancer Specimen Resource; NCI Specialized Programs of Research Excellence; and collaborations with FIC. He stated that NCI also supports research on bone marrow transplantation in HIV-infected individuals with lymphoid tumors; exploratory research on vaccines for AIDS-associated malignancies; and projects to sequence tumor genomes. He noted that NCI provides supplements to facilitate interactions between NCI-supported Comprehensive Cancer Centers, AMC, and the Centers for AIDS Research (CFAR), and works to improve enrollment of HIV-infected individuals in NCI-supported cancer trials.

Dr. Yarchoan stated that NCI partners with other ICOs in trans-NIH AIDS initiatives, including the NIAID-led CFAR; the Women’s Interagency HIV Study (WIHS); the Multicenter AIDS Cohort Study (MACS); the International epidemiological Databases to Evaluate AIDS (IeDEA); and the FIC-led AIDS International Training and Research Program (AITRP). He also noted that since 1997, NCI has regularly sponsored the International Conference on Malignancies in AIDS and Other Acquired Immunodeficiencies, the only meeting to focus specifically on HIV-associated malignancies.

Discussion

OARAC members, speakers, and guests discussed how to integrate cancer research into the NIAID AIDS Clinical Trials Networks; how to integrate basic and clinical research; potential collaboration on international clinical trials; the need for training of clinical research oncologists in Africa; the difference between relative risks and attributable risks on the perception of the impact of lung cancer and HIV; potential causes of lung cancer in HIV-infected individuals; the risk of other non-HIV-defining cancers; and the role of immune activation and viral load.

NICHD HIV Research /Scientific Priorities on HIV Comorbidities, Coinfections, and Complications

Dr. Yvonne T. Maddox, Deputy Director, NICHD, stated that NICHD has collaborated with other ICOs since the mid-1980s, to support domestic and international research on the management and prevention of HIV and its complications. She noted that the NICHD research priorities relate to specific populations: infants and children; adolescents; pregnant and non-pregnant women; and families.

Dr. Maddox stated that NICHD’s areas of high priority research on HIV comorbidites, coinfections, and complications include management and treatment studies in HIV-infected infants, children, and adolescents; the short- and long-term effects of in utero ARV drug exposure on HIV-exposed but uninfected infants; the impact of HIV infection and the effects of chronic therapy in children with perinatal HIV infection as they age; improving the diagnosis and management of coinfections in HIV-infected children and women; behavioral research in HIV-infected youth; the natural history of HIV disease in women in the ART era and gender-specific aspects of HIV comorbidities; the interaction of nutrition and HIV disease and its treatment; and the psychological consequences of HIV disease on children and families.

Dr. Maddox described research on the management and treatment of HIV disease and its complications in infants, children, and adolescents, including metabolic complications, mitochondrial toxicity, liver disease, renal disease, mental health, and IRIS. She highlighted research trials conducted by the NICHD International and Domestic Pediatric and Maternal HIV Clinical Trials Network, in collaboration with IMPAACT, and clinical trials conducted by the Adolescent Trials Network (ATN). She noted that many NICHD studies are conducted in collaboration with NIAID.

Dr. Maddox discussed surveillance activities for the short- and long-term effects of in utero ARV drug exposure on HIV-exposed but uninfected infants. She described domestic surveillance conducted by the Pediatric HIV/AIDS Cohort Study (PHACS) and Surveillance Monitoring for ART Toxicities (SMARTT) and international efforts by the NICHD International Site Development Initiative (NISDI), IeDEA, and MTN. She also discussed domestic research on the priority area of chronic HIV therapy in children with perinatal HIV infection, conducted through the PHACS Adolescent Master Protocol (AMP). She reviewed international studies on this topic conducted by NISDI and IeDEA.

Dr. Maddox also discussed NICHD research on improving the diagnosis and management of coinfections in HIV-infected children and women. She commented on research conducted through investigator-initiated research, collaborative trials with the Centers for Disease Control and Prevention (CDC) and IMPAACT; and the Prevention of Malaria and HIV Disease in Tororo project (PROMOTE). Dr. Maddox stated that NICHD behavioral research on HIV-infected youth addresses identification of HIV infection and linkage to care, especially in the developing world and for individuals involved in substance abuse.

Discussion

OARAC members, speakers, and guests discussed the aging of individuals perinatally infected with HIV; the research agenda of the ATN; and the impact of long-term ART on the developing brain.

NIA: Current Research Priorities in HIV/AIDS

Ms. Georgeanne E. Patmios, Assistant Director, Division of Behavioral and Social Research, NIA, provided an overview of HIV-related research at NIA. She discussed the clinical and translational research issues in the diagnosis and/or management of HIV infection and its consequences in older persons. She stated that the number of HIV-infected older individuals is increasing because many HIV-infected individuals are living longer, largely due to ART, and older individuals who are becoming newly infected.

Ms. Patmios discussed a NIA-supported workshop on medical complications in the management of HIV and AIDS in older individuals. She stated that this workshop led to extramural funding opportunities focused on clinical and translational research at the interface of aging and HIV. A NIA-supported workshop on thymic atrophy and aging led to investigator-initiated basic and clinical research on rejuvenating the aged immune system. Ms. Patmios reported that NIA also supports research on this topic through participation in the CFAR program.

Ms. Patmios summarized NIA’s programs in the area of aging, HIV, and the pathogenesis of neurological disease, highlighting NIA-supported workshops and investigator-initiated research. She also discussed collaborations with other ICOs and outside agencies to conduct research on behavioral and social issues related to HIV/AIDS. This research includes global partnerships; investigator-initiated research; and demographic and economic research. Ms. Patmios discussed two 2006 NIA-sponsored reports, one authored by the National Research Council and the other by the U.S. Census Bureau, which address the behavioral and social aspects of AIDS in aging populations in Sub-Saharan Africa.

Ms. Patmios also discussed NIA’s intramural AIDS research, which includes basic biomedical and behavioral and social sciences research.

Ms. Patmios described NIA’s involvement in upcoming workshops and meetings on aging and HIV/AIDS. She also suggested several areas for potential collaboration with the NIAID AIDS Clinical Trials Networks: 1) structure clinical trial design to include adequate numbers of older participants, participants with different duration of infection, and participants with comorbidities; 2) implement recruitment strategies targeting older minorities to study racial and ethnic differences in patterns and severity of comorbidities as they relate to aging, HIV infection, and response to therapy; 3) develop ancillary studies to address specific questions related to the development and progression of comorbidities and the impact of comorbidities on the response to protocol therapy; and 4) incorporate performance-based measures of physical and cognitive function as prognostic variables, treatment outcomes, and indicators of overall disease burden.

Discussion

OARAC members, speakers, and guests discussed NIA’s collaboration with the CFAR program and possible collaborations with various other NIH AIDS research programs; the risk for cancer in premature aging syndromes versus in the premature aging seen in HIV-infected individuals on ART; and the effects of long-term use of ART on cancer risk in older individuals.

NIDA’s Research Program: Priorities and Programs Update

Dr. Diane M. Lawrence, Associate Director, AIDS Research Program (ARP), NIDA, stated that the mission of ARP is to support the development, planning, and coordination of AIDS priority research within NIDA’s intramural and extramural programs to ensure an integrated vision and strategy.

Dr. Lawrence discussed NIDA’s crosscutting priorities in AIDS research, which include: HIV prevention, including research on drug abuse treatment as HIV prevention, secondary prevention, non-injection drug use, and the criminal justice system; HIV/AIDS treatment, including treatment of addiction and associated complications and comorbidities; training and infrastructure development; and international research. She described several recent NIDA initiatives that address these priorities. She stated that about 60 percent of NIDA’s international portfolio is HIV-related.

Dr. Lawrence discussed NIDA’s domestic and international priorities related to AIDS research. Priorities include: natural history and epidemiology; etiology and pathogenesis; therapeutics; and behavior and social science, including the study of neuropsychological, neurocognitive, and psychiatric sequelae.

Dr. Lawrence discussed NIDA’s research on HIV disease and the criminal justice system. She stated that NIDA is developing an RFA in collaboration with NIMH and NIAID to enhance the availability of HIV testing and treatment within the criminal justice system and to promote ART adherence by HIV-infected individuals upon their release back into the community.

Dr. Lawrence discussed NIDA FY 2010 funding opportunities for HIV/AIDS and drug use research, including: initiatives on the epigenomics of HIV/AIDS; vulnerable populations in the United States; interactions between tobacco use and HIV/AIDS; career development; and international research collaborations. Dr. Lawrence described several AIDS-related collaborations between NIDA and the HPTN, ATN, PHACS, WIHS, FIC, and the CFAR program.

Dr. Lawrence described opportunities for new partnerships through targeted initiatives that utilize the infrastructure and expertise of established clinical trials networks. She discussed studies that could address treatment issues in substance users; integrate biomedical and behavioral approaches in trial settings; study HCV coinfection and liver disease; explore neurologic complications of HIV/AIDS, substance use, and treatment; and investigate the impact of drug use on host responses to vaccine candidates. Other opportunities include collaborations with the NIDA-funded clinical cohorts.

Discussion

OARAC members, speakers, and guests discussed the importance of domestic and international research collaborations between NIDA and the National Institute on Alcohol Abuse and Alcoholism (NIAAA).

NIMH HIV/AIDS Scientific Priorities: Integrating Efforts with Multiple Stakeholders to Impact the Epidemic

Dr. Thomas R. Insel, Director, NIMH, described the NIMH HIV research program. He stated that the NIMH Division on AIDS and Health Behavior currently is undergoing organizational restructuring and that the Center for Mental Health Research on AIDS within the Division will focus on primary and secondary prevention, basic neuroscience, and clinical neuroAIDS research.

Dr. Insel discussed the NIMH Summit for Federal and External Consultation, which was held on September 20-21, 2009. The goal of the summit was to identify mechanisms to enhance the integrated NIMH HIV/AIDS scientific research agenda. He stated that NIMH would like to pursue research collaborations to develop and test strategic interventions that may reduce new HIV infections. He hopes that within the next 5 years the incidence of new infections in the United States can be decreased from about 56,000 per year to about 25,000 per year, with the goal of eventually eradicating the HIV epidemic.

Dr. Insel summarized selected Summit recommendations on strategic and focused approaches to international research; the balance between targeted and investigator-initiated research; collaboration with multiple networks and service delivery platforms; research in the highest risk populations in the United States; and integration of behavioral and social science in biomedical and combined intervention strategies.

Dr. Insel stated that NIMH developed a series of priorities in response to Summit recommendations. Priorities include evaluation of universal voluntary testing and treatment for prevention of HIV transmission; development and evaluation of strategies to address the HIV epidemic among MSM; development and evaluation of behavioral and social science aspects of biomedical strategies to avert incident HIV infections; and investigation of viral and host genetic factors regulating HIV-associated CNS disease. Dr. Insel also discussed NIMH’s research on disinhibition and other behavioral factors associated with the deployment of a partially effective HIV vaccine.

Dr. Insel discussed behavioral interventions to improve public health outcomes, including increasing intervention efficacy and durability; personalizing and targeting high risk groups; optimizing research while avoiding redundancy; and disseminating findings widely and with fidelity.

Dr. Insel provided an overview of NIMH’s collaborations in AIDS research, including multiple collaborations with networks including HPTN, ACTG, IMPAACT, INSIGHT, HVTN, the Comprehensive International Program of Research on AIDS (CIPRA), MTN, ATN, and PHACS. Areas of collaboration include the behavioral aspects of pre-exposure prophylaxis for the prevention of HIV infection and adherence to ART. Dr. Insel also commented on NIMH’s collaborations with the CDC that address dissemination strategies and translational science; implementation planning; research in racial and ethnic populations; HIV prevention; and treatment adherence.

Dr. Insel stated that NIMH is collaborating with the World Health Organization to develop Project Accept, a HIV prevention trial. This pilot study will test whether a community-level intervention based on modifying community norms can change the environmental context in which people make decisions about HIV risk. Communities in Africa and Thailand are being randomized to receive either a community-based HIV voluntary counseling and testing intervention plus standard clinic-based VCT (SVCT) or SVCT alone.

Discussion

OARAC members, speakers, and guests discussed the NIMH’s Summit recommendations for disseminating behavioral interventions for HIV prevention; the role of community-based interventions; the need to educate communities in HIV prevention; and the need to target young MSM for HIV prevention. Discussion also addressed disinhibition associated with HIV prevention interventions; theoretical versus actual behavioral responses of individuals at risk of infection; and the effects of societal behavior, policies, and structures (e.g. the availability of healthcare) on test and treat interventions domestically and internationally.

HIV-Related Research at the NIDDK

Dr. Jay H. Hoofnagle, Chief, Liver Disease Research Branch, Division of Digestive Diseases and Nutrition, NIDDK, reviewed the organizational structure of NIDDK and the Institute’s research interest in HIV and diabetes, heart disease and stroke, chronic renal failure, and chronic liver disease. He stated that, with the success of ART, these chronic diseases have become a major cause of morbidity and mortality in HIV-infected individuals.

Dr. Hoofnagle stated that the NIDDK Division of Extramural Affairs sponsors research in diabetes and insulin resistance, adipocyte biology, and lipodystrophy in HIV-infected individuals. He reviewed examples of research focused on the cellular and molecular causes of insulin resistance in HIV-infected individuals; the role of body fat distribution in insulin resistance and metabolic syndrome; and basic research on adipocyte biology. Dr. Hoofnagle stated that NIDDK also supports clinical and translational research projects on these topics

Dr. Hoofnagle noted that the Division of Kidney, Urologic, and Hematologic Diseases sponsors research on HIV nephropathy, drug-induced renal disease, and genitourinary transmission of HIV. He stated that HIV-associated neuropathy, or focal segmental glomerulosclerosis, is a progressive and potentially severe form of chronic renal disease. He also stated that research demonstrates that HIV-associated neuropathy is related to direct infection of renal epithelial cells and that HIV infection should be treated early.

Dr. Hoofnagle stated that the Division of Digestive Diseases and Nutrition supports HIV research related to obesity and nutrition, gastroenterology, and liver disease. He summarized research efforts focused on HIV and liver disease. He stated that NIDDK established the HBV Research Network in November 2008 to address issues in the pathogenesis, natural history, and management of chronic HBV. Dr. Hoofnagle stated that the Drug-Induced Liver Injury Network will conduct prospective clinical, mechanistic, and genetic studies in individuals with well-defined drug-induced liver injury, including HIV-infected individuals. Dr. Hoofnagle noted that NIDDK is creating a drug-induced liver injury Web site which probably will be available in May 2010.

Discussion

OARAC members, speakers, and guests discussed the possibility of collecting post-mortem brain tissue to study the effects of HIV, hepatitis, and liver disease on the CNS; the availability of data from the Viral Hepatitis C study; and IL28B, a gene associated with lack of response to HCV. Discussion also addressed the challenges to enrolling HIV-infected individuals in industry-funded therapeutic clinical trials on HBV and HCV; the merits of early treatment of HIV-infected individuals coinfected with hepatitis; and the need for prevention of HBV and hepatitis A in HIV-infected individuals.

NIAMS Support of Research Related to HIV/AIDS

Dr. Robert H. Carter, Deputy Director, NIAMS, stated that muscle atrophy, bone loss (osteoporosis), and the skin as a barrier to infection are three areas of intensive study in AIDS-related research at NIAMS.

Dr. Carter stated that NIAMS supports investigations on the molecular mechanisms of muscle atrophy, which include inflammation and metabolic changes, muscle disuse or damage, and treatment toxicity. NIAMS also supports research on pharmacologic, nutritional, and exercise approaches to blocking muscle degeneration and promoting muscle regeneration. He noted the relevance of this research to muscle atrophy in HIV-infected individuals.

Dr. Carter stated that bone loss may be caused by long-term HIV infection and ART, as well as aging. He discussed the complex interaction of bone with other parts of the body including the gut, the brain, and adipocytes. NIAMS-sponsored research on bone loss therapy emphasizes restoring bone and improving bone quality in specific populations. He suggested that studies of bone loss in HIV-infected individuals represent a potential area for collaboration with NIAID.

Dr. Carter described NIAMS-sponsored research on defense mechanisms of the skin. He suggested that this research could inform HIV vaccine development and other prevention strategies related to HIV infection routes through skin and mucosal epithelial tissues. He discussed several research topics, including the effectiveness of anti-microbial peptides in blocking infections; the role of Langerhan cells in antigen capture and immune response control; and the manipulation of immune cells in the epithelium to improve the host’s defenses against HIV infection.

Dr. Carter stated that NIAMS intramural research includes structural studies of HIV viral proteins and virion assembly.

Dr. Carter discussed the Patient-Reported Outcomes Measurement Information System, a Phase I project that is led by NIAMS and supported by the NIH Common Fund. Within this initiative, OAR and NIAMS are cofunding a project to create test measures of HIV/AIDS patient-reported outcomes in clinical settings.

Dr. Carter concluded by suggesting collaboration between NIAMS and the NIAID AIDS Clinical Trials Networks on studies of fundamental mechanisms of muscle, skin, and bone in the context of HIV disease and the prevention of HIV-associated comorbidities, as well as direct studies of the effects of HIV and ART on these systems.

Discussion

OARAC members, speakers, and guests discussed NIAMS-sponsored RFAs related to the ICO’s portfolio of ongoing AIDS research.

REPORT ON THE IMPLEMENTATION SCIENCE WORKSHOP

Dr. Paolo Miotti, Natural History and Epidemiology Coordinator, OAR, discussed the July 2009 Implementation Science Workshop, which was convened by OAR in collaboration with the Pangaea Global AIDS Foundation to address the gap in implementation (or translation) of scientific research findings to HIV/AIDS prevention, treatment, and care programs. The Workshop was held in Cape Town, South Africa in conjunction with the International AIDS Society meeting.

Dr. Miotti stated that the Workshop was prompted because scientific knowledge and financial resources to prevent and treat HIV/AIDS have increased considerably over the last decade, but the knowledge of how to make informed choices between competing interventions, transfer interventions from one setting or population to another, and deliver interventions effectively has not kept pace with the growth of HIV/AIDS services globally.

Dr. Miotti stated that investigators and program implementers from the United States and developing countries, including representatives from the NIH and from U.S. and international non-governmental organizations, attended the Workshop. He reported that the Workshop included an overview of the origins and the applications of implementation science, including the difficulties in the efficient implementation of clinical research findings to the care and treatment of people with HIV/AIDS.

Dr. Miotti commented that the Workshop participants developed recommendations on the need for implementation science research in the areas of: prevention of mother-to-child transmission; engaging and retaining individuals in HIV/AIDS care; integration of primary health care and HIV/AIDS services; structural interventions; human resources and health systems; and the scale-up of proven interventions. He noted that recommendations were also generated regarding: ensuring appropriate review of implementation science research grant applications; developing methodologies and standards of practice; coordinating with implementation agencies; and strengthening training opportunities in this field.

Dr. Miotti discussed plans to organize a meeting of representatives from various NIH Institutes to review the Workshop recommendations and discuss potential NIH initiatives in collaboration with other U.S. Government agencies.

Discussion

It was suggested that this issue will be central to the Administration’s overall strategy on global health.

ADDITIONAL STATEMENTS BY NIH ICs

Dr. Curran invited representatives of other NIH Institutes, Centers, and Offices who were not formally on the meeting agenda to discuss priorities for research and collaborations on HIV-associated comorbidities, coinfections, and complications.

National Center on Minority Health and Health Disparities

Dr. Francisco Sy, Director, Extramural Activities and Scientific Programs, National Center on Minority Health and Health Disparities (NCMHD) stated that the Center supports the Community-Based Participatory Research program. He stated that four grantees in this program are performing HIV/AIDS research. He also stated that NCMHD supports 11 investigator-initiated research grants on HIV/AIDS research.

National Institute of Dental and Craniofacial Research

Dr. Isaac Rodriguez-Chavez, Director, AIDS and Immunosuppression Program, National Institute of Dental and Craniofacial Research (NIDCR), stated that oral manifestations related to HIV/AIDS are a global problem of major significance. Dr. Rodriguez-Chavez stated that NIDCR collaborates on HIV/AIDS basic, translational, and clinical research with the NCI AMC and with the NIAID ACTG. He stated that NIDCR focuses on molecular and immunological mechanisms and interventions for oral manifestations of HIV; oral HIV transmission; inflammation; pain; AIDS-related oral pathogens; the immunopathogenesis of HIV in association with vaccine research; and HIV/AIDS diagnostics, prevention, and treatment.

FIC

Dr. Kenneth Bridbord, Director, International Training and Research, FIC, stated that HIV/AIDS represents the highest proportion of Fogarty’s budget, which focuses primarily on training, but also supports some research. He discussed Fogarty’s training investments to build sustainable research capacity in low and middle income countries in partnership with U.S. institutions. He also discussed collaborations with other ICOs to develop research infrastructure in international settings. Dr. Bridbord stated that future areas of interest include implementation science and an increased focus on non-communicable diseases, while maintaining a strong commitment to addressing communicable diseases. He also discussed plans to expand training to address other chronic infectious diseases in the international setting; increase collaborations with other U.S. Government agencies; and develop sustainable systems, including health care systems, in low and middle income countries.

NIAAA

Dr. Kendall Bryant, Coordinator, Alcohol and AIDS Research, NIAAA, described alcohol abuse and alcoholism as one of the primary comorbidities of HIV/AIDS. He stated that NIAAA’s research collaboration with the Veterans Aging Cohort Study primarily addresses the acquisition of HIV and how alcohol relates to risk behaviors and susceptibility to infection. He stated that NIAAA focuses primarily on behavioral research, supports some basic research, and is increasing the focus on integrated behavioral, basic, and translational research. Dr. Bryant suggested the development of collaborations to address the complex interactions among HIV/AIDS, alcohol abuse and alcoholism, and other co-occurring disorders.

Discussion

Dr. Whitescarver concluded the discussion noting that although they could not attend the Council meeting, representatives from NHLBI met with OAR and NIAID leadership to discuss possible research collaborations regarding cardiovascular complications. He stated that NHLBI recently published an article in the Journal of the American College of Cardiology in which NHLBI encouraged continued partnership of basic, clinical, cardiovascular, and infectious disease researchers in their efforts to answer the difficult questions in cardiovascular disease and HIV/AIDS. He stated that NHLBI supports RFAs in this area of research. He underscored the unique role of OAR in bringing the ICOs together to establish multi-ICO collaborations and the importance of this Council meeting in that regard.

OARAC encourages the ICOs to work closely with NIAID’s restructured networks to address HIV comorbidities, coinfections, and other complications. OARAC also is supportive of OAR’s coordination of these efforts.

PUBLIC COMMENTS

Dr. Paul Bohjanen, Associate Professor, Department of Microbiology, University of Minnesota, stated that more research is needed on cryptococcal meningitis. He cited CDC estimates that about 1 million HIV-infected individuals are infected with this illness, which causes about 700,000 deaths per year. Discussion among meeting attendees focused on under-diagnosis and under-treatment of cryptococcal meningitis; the prevalence of cryptococcal meningitis, especially in equatorial Africa; underestimates of mortality due to the illness; and NIAID-funded research on cryptococcal meningitis.

CLOSING COMMENTS

Dr. Curran thanked OARAC members, speakers, and guests for their participation. He especially thanked the Ex Officio members for the important role they play in both trans-NIH and trans-governmental linkages.

The meeting adjourned at 3:50 p.m. on November 5, 2009.

Signed:

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

/James W. Curran, M.D., M.P.H./
James W. Curran, M.D., M.P.H., Chair