Meeting Minutes - November 13, 2014

Office of AIDS Research Advisory Council
Thirty-ninth Meeting
November 13, 2014

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. Monica Gandhi,* Dr. Roy M. Gulick, Dr. Priscilla Hsue,* Dr. Daniel R. Kuritzkes,* Dr. David Malebranche, Dr. Ronald T. Mitsuyasu,* Mr. Mitchell J. Warren, Dr. Darrell P. Wheeler, Dr. Craig M. Wilson

*Membership pending clearance
**Participated by teleconference

Ex Officio Members Present: Dr. Jonathan Mermin, Centers for Disease Control and Prevention; Dr. Myron S. Cohen, National Advisory Allergy and Infectious Diseases Council; Dr. Roy M. Gulick, Working Groups on Guidelines for the Treatment of HIV Infection

OARAC Working Group Members Present:  Dr. Julie Ake, Dr. James W. Curran, Dr. Satya Dandekar, Dr. Emily Erbelding, Dr. Yamil Gerena, Dr. Rohan Hazra, Dr. Peter W. Hunt, Dr. Rupert Kaul, Dr. Alan L. Landay, Dr. Michael M. Lederman, Dr. Otoniel Martinez-Maza, Dr. William E. Paul, Dr. Wendy Post, Dr. Irini Sereti, Dr. Barbara L. Shacklett, Dr. Kevin J. Tracey

WELCOME AND MEETING OVERVIEW

The National Institutes of Health Office of AIDS Research Advisory Council (OARAC) convened its 39th meeting on November 13, 2014, at the Fishers Lane Conference Center in Rockville, Maryland.

Dr. Rochelle Walensky, OARAC Chair, and Professor in the Department of Medicine, Center for Communicable Disease Dynamics, Harvard Medical School, welcomed OARAC members, OARAC Working Group members, invited speakers, and guests.

APPROVAL OF MINUTES

The minutes of the April 10, 2014, OARAC meeting were approved as written.

CONFLICT OF INTEREST STATEMENTS

Dr. Jack Whitescarver, Office of AIDS Research (OAR) Director and OARAC Executive Secretary, reminded members to review and sign their conflict-of-interest forms and submit them to OAR staff.

DIRECTOR'S REPORT

Dr. Whitescarver reminded members that NIH policy requires that all individuals who are appointed to serve as OARAC members must complete financial disclosure forms prior to their appointment and participation in the Council meetings, and OARAC is required to certify that fact before each meeting.

Dr. Whitescarver announced that Dr. Yvonne Maddox was named recently as Acting Director of the National Institute on Minority Health and Health Disparities following Dr. John Ruffin’s retirement as Director, and following her retirement as Deputy Director of the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Dr. Whitescarver reported that the Federal Government was under a Continuing Resolution until December 11, 2014, and there is no indication that there will be a shutdown.

Dr. Whitescarver praised Dr. James Curran, Dean of the Rollins School of Public Health at Emory University, for his efforts on behalf of the OAR and OARAC. He also announced that Dr. William Paul, Chief of the Laboratory of Immunology at the National Institute of Allergy and Infectious Diseases, and a past OAR Director, provided invaluable assistance in the development of the program for the meeting and would launch the discussion.

UPDATE ON OARAC WORKING GROUPS FOR TREATMENT AND PREVENTION GUIDELINES

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

Dr. Roy Gulick, Professor of Medicine and Chief of the Division of Infectious Diseases at Weill Medical College of Cornell University, reported that a revision of the guidelines was issued on May 1, 2014. New information includes the following:

• Reduced frequencies of CD4 monitoring were recommended.

• The “what to start” recommendations also were changed. The previous guidelines had a “preferred” category, which has been changed to a “recommended” category. At all pre-antiretroviral (ART) viral load levels seven regimens are recommended. An additional three regimens are recommended only if the pre-ART viral load is less than 100,000 copies per ml.  A third category of alternative regimens is also included.

• Some of the older ART therapies have been removed, for reasons of either toxicity or inconvenience; these are now listed in the guidelines. They include unboosted atazanavir, boosted fosamprenavir, maraviroc, nevirapine, boosted saquinavir, zidovudine, and 3TC.

• A new section was added on cost considerations in ART that lists the average wholesale prices for branded and generic ART drugs.

The working group for these guidelines held a formal face-to-face retreat on the NIH campus on May 14, 2014. Thirty-four working group members attended in person, with another three attending by teleconference.

The following topics were reviewed and discussed:

• The overall goals and readability of the guidelines

• How evidence is evaluated and rated in the guidelines

• Web site usage

• Creation of a mobile application for the guidelines

• Future updates and next steps.

The working group will formally propose an annual face-to-face all-day meeting either the day before or the day after the April 2015 OARAC meeting. The group also will plan to update the guidelines annually in early May.

A new section of the guidelines that included a drug interaction table on the use of many of the newly approved hepatitis C direct-acting antiviral drugs and how they interact with ART was released the day of this meeting.

A guidelines revision is anticipated in spring 2015 that will include the following:

• Incorporation of the use of cobicistat instead of ritonavir-boosted protease inhibitors

• What to start based on different patient types and the optimal regimens for different case scenarios

• Updates in the management of treatment-experienced patients

• Revision of drug interaction tables

• Proposal of a 1-day retreat in April 2015

• Release of a mobile app to be available by fall of 2015.

Guidelines on Opportunistic Infections in HIV-Infected Adults and Adolescents

Dr. Gulick reported that the guidelines have been updated and were released recently. The panel for these guidelines held an in-person leadership meeting on October 8, 2014.

This panel has several working groups to consider the different opportunistic infections (OIs). The most active of these in the last year have been the hepatitis C, human papillomavirus, tuberculosis (TB), and cryptococcal working groups.  New developments in the guidelines this year include the following:

• Real-time monitoring

• Recognition of the rapidly changing management of hepatitis C

• Linking of the guidelines to the new AASLD–IDSA [American Association for the Study of Liver Diseases–Infectious Diseases Society of America] Website guidelines

• Changes in the management of Immune Reconstitution Inflammatory Syndrome (IRIS) for TB and cryptococcal disease

• Minor changes in specific drug and diagnostic test recommendations

• A change in terminology from “chronic maintenance” to “secondary prophylaxis.”

Dr. Rohan Hazra, Medical Officer at the Eunice Kennedy Shriver National Institute of Child Health and Human Development, provided updates on the Guidelines for the Prevention and Treatment of Opportunistic Infections Among HIV-Exposed and HIV-Infected Children (Pediatric Opportunistic Infections Guidelines), the Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection (Pediatric ART Guidelines), and the Recommendations for the Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women and Interventions To Reduce Perinatal HIV Transmission in the United States (Perinatal Guidelines).

Pediatric OI Working Group

The Pediatric Opportunistic Infections Guidelines were published on November 6, 2013. The Pediatric Guidelines Working Group is working on a revision to the guidelines, and each topic will be reviewed and updated within 2 years; hepatitis B and C and TB will be updated annually; and other topics will be updated when new clinical data become available.

Pediatric ART Guidelines Panel

The Pediatric ART Guidelines Panel published its most recent guideline updates in February 2014 and has a revision in process, with an anticipated release in February 2015.

The next revision will include:

• Simplification and expansion of recommendations on when to start ART.

• A review of pediatric pharmacokinetic and safety data

• Update on dosing recommendations

• Approval of atazanavir for infants of 3 months of age and weighing at least 10 kg

• Separate sections on elvitegravir and cobicistat

•  A new section on specific issues and ART for neonates.

The Panel is also considering substantially shortening the guidelines document.  

Perinatal Guidelines Panel

Revision of the Perinatal Guidelines is in progress. The new guidelines are scheduled to be issued in spring of 2015. Changes include the following:

• A new section for pregnancy in women who were perinatally infected.

• The nevirapine toxicity section was removed and incorporated into other sections.

• A review of dosing issues in pregnancy.

UPDATE ON PRIORITY-SETTING REVIEW

Dr. Curran reviewed the history of the priority-setting portfolio review: At the November 2013 OARAC meeting, Dr. Francis Collins, Director of the NIH, charged OARAC with identifying the highest-priority areas in AIDS research.  Dr. Collins asked OARAC to outline the highest-priority AIDS research in the areas of prevention, treatment, including research toward a cure, and HIV-related comorbidities, taking into account the crosscutting areas of basic science, training, and information dissemination.  The OARAC Priority-Setting Working Group was established by Dr. Whitescarver with Dr. Charles Carpenter, Director of the Lifespan/Tufts/Brown Center for AIDS Research, serving as Chair, and Dr. Rochelle Walensky representing OARAC. The report on HIV research priorities was submitted on May 28, 2014, and presented to the Advisory Committee to the NIH Director in June.

Principles that guided the report included the following:

• HIV research should emphasize prevention, care, and treatment that has the most impact in populations that are most affected.

• Basic biomedical behavioral and social science research underlies the identification, development, testing, and implementation of prevention, care, and treatment strategies.

• The most effective strategies are evidence-based, and the implementation of a combination of multiple evidence-based strategies appropriate to a particular setting is necessary.

• The co-occurring and intersecting biologic, social, and environmental factors that influence transmission, acquisition, pathogenesis, and treatment must be addressed simultaneously.

• HIV/AIDS research does not address just the single disease but also the many coinfections and comorbidities that occur in conjunction with HIV, and has resulted in a multitude of crossover benefits.

After the OARAC process was completed, Dr. Whitescarver established a panel of outside reviewers to conduct an assessment of the NIH AIDS portfolio. This group was chaired by Dr. Curran with four charges from Dr. Whitescarver:

• Develop a trans-NIH guidance/definition for what is AIDS research or AIDS–related, for the purpose of receiving partial or total AIDS funding.

• Assess whether the grants that are coming up for re-competition in the next few years are sufficiently AIDS-related and of a sufficiently high science priority for the allocation of AIDS research funding.

• Assess how the current portfolio reflects the science priorities identified by the first working group.

• Identify methods for optimizing science priorities in the future.

Other activities undertaken by the portfolio review group included:

• Review of the low priority extramural research projects from FY2013 previously reviewed by OAR staff to determine which projects should be considered of higher priority or remain on the low priority listing. 

• Providing recommendations on the percentage of AIDS funding each IC can allocate to various types of projects (proportional funding of AIDS-related grants).  

• Mapping the current AIDS portfolio to the research priorities identified by the OARAC Priority-Setting Group not only to show how the priorities are being funded but also to identify gaps in addressing the research priorities.

In response to the recommendations from the OARAC Priority-Setting Group, OAR staff have developed draft definitions of AIDS and AIDS- related research in order to alleviate inconsistencies and to provide guidance to the NIH Institutes, Centers, and Offices (ICO's) in the use of AIDS dollars.

Another question posed by Dr. Collins in his initial address to OARAC was how might the OAR be more efficient and effective in proactively reviewing grants to determine if they are appropriate for AIDS funding? OAR developed a draft of issues and possible solutions including:

• Approval of funding announcements, (Requests for Application and Funding Opportunity Announcements) and;

• Review of the grants before they are sent through the peer review process at the Center for Scientific Review; or assignment of grants to the ICOs.

Dr. Curran concluded by saying that the OARAC Priority-Setting Group’s report reaffirmed and added focus to the OAR-established priorities and emphasized the need to relinquish existing silos in research and to focus research on the areas with the greatest potential to result in population-level impact among those hardest hit by the HIV epidemic.  Preliminary analysis of the current AIDS research portfolio suggests that the NIH AIDS program is addressing priority areas, but that there is room for OAR to shift funds to areas that are evolving as the highest priorities.  Additional refined procedures are necessary to ensure the optimal stewardship of the NIH AIDS research funds by the OAR, in collaboration with the ICs and the Office of the Director.

Discussion

Clarification was requested on areas no longer considered to be priorities and areas anticipated to receive reduced funding. Dr. Curran stated that basic science studies on co-infecting pathogens, and studies marginally related HIV are under review.

Meeting participants expressed concern about how the OARAC could ensure that funding from projects identified as low priority will be available for higher priority AIDS research expenditures and not lost from AIDS research entirely.  Dr. Walensky stated that the priorities identified by the OARAC Priority-Setting Group were incredibly well aligned with the most recent Trans-NIH Plan for HIV-Related Research, and that the OAR will have control over realignment of future projects within the priorities.   

INTRODUCTION TO THE OARAC TOPIC

Dr. William Paul, Chief of the Laboratory of Immunology at NIAID, and former Director of the Office of AIDS Research, introduced the meeting topic. He began by stating that inflammatory responses play a central role in disease progression. Immune activation, which can be regarded as a synonym for inflammation in this context, is a key element in viral replication and in driving HIV disease progression; it does so by altering the behavior of both naive and memory T-cell populations.

Dr. Paul presented data demonstrating that individuals who have the highest level of inflammation have a six-fold greater likelihood of death than those in the lowest quartile. He said that this kind of work makes clear that the level of inflammation is a critical element in the pathogenesis and progression of HIV disease. He concluded by saying that inflammation shares center stage in pathogenesis, and, on a molecular level, may provide additional drug targets for the future.

INTRODUCTION TO INFLAMMATION—CAUSE AND EFFECT

Dr. Kevin Tracey, President and CEO of the Feinstein Institute for Medical Research, began his presentation by stating that the overwhelming majority of immunology interest has always focused on the response to infectious challenge.  However, in the last 10 years or less, an understanding of the molecular mechanisms has arisen that explains how sterile tissue injury also activates inflammation, so inflammation does not always mean infection. 
Highlights from Dr. Tracey’s presentation included:

• There is a convergence on the signaling of both the infectious and the sterile activators sensed by the innate immune system.  This is half of the frontline of host defense, and the other half is the nervous system in which sensory neurons can be activated by cytokines, directly by products of bacteria without going through the macrophage first, or chemical factors that can trigger inflammation.

• At the earliest onset of inflammation, there is activation of neural pathways that regulate the severity of the inflammation.  Understanding those neural pathways provides an opportunity to develop therapies that do not target the immune cells directly but target neurons directly, which may offer some significant promise for treating inflammation in the future. 

• The regulation of cytokines in diseases caused by an excessive amount of inflammation or an excessive amount of cytokines can be targeted, and the system can be manipulated to therapeutic advantage.  A nerve stimulator used to drive an electrical signal down the vagus nerve can turn off the TNF production in the spleen and decrease the effects of inflammation.

Dr. Tracy concluded by saying that there will be ongoing trials of the vagus nerve stimulator in inflammatory bowel disease and rheumatoid arthritis that may be helpful in understanding how to treat future AIDS patients as well.

GENITAL TRACT INFLAMMATION AND HIV TRANSMISSION

Dr. Barbara Shacklett, Associate Professor in the Department of Medical Microbiology and Immunology at the University of California, Davis, stated that it is important to remember that HIV transmission can involve the entire reproductive tract, not just the lower genital tract region, and that large histologic differences exist between the lower tract and the upper tract that can affect transmission (viral penetration).

Studies presented by Dr. Shacklett showed:

• SIV is quickly found throughout the reproductive tract including occasionally in the ovaries of female rhesus macaques injected inter-vaginally with the virus.

• The entire female genital tract is a site of HIV-susceptible cells, including CD4 T cells, dendritic cells, and macrophages. The immunologic and histologic features of the upper female genital tract may render this region even more susceptible to HIV transmission and early viral dissemination than was previously appreciated.

• Women who had genital inflammation in the CAPRISA 004 study were at increased risk of HIV infection.   Elevated genital fluid concentrations of four chemokines were associated with increased risk of HIV infection.  All four of these are chemokines that are able to participate in recruitment of HIV target cells, in particular MIP [macrophage inflammatory protein]-1 alpha and beta, which bind to CCR5 but also can recruit CCR5-positive target cells.  In macaques, production of these and other inflammatory cytokines has been shown to be essential for recruitment for CD4 target cells.

Dr. Shacklett concluded by saying that areas for further study include  determining  the links between this increased inflammation in the genital tract in some women, the role for sex hormones, the role of aging, and the female genital tract microbiome.

HIV INFECTION, IMMUNE ACTIVATION, AND THE INFLAMMATORY CASCADE

Dr. Peter Hunt, Associate Professor of Medicine in the HIV/AIDS Division at the University of California, San Francisco, began his presentation by framing the issue of why there is a focus on immune activation in the modern treatment era of HIV.  He emphasized that there is still a gap in life expectancy between the general population and HIV-infected patients, particularly in patients who begin therapy at CD4 counts below 350.  There also is a 20-year difference in life expectancy between people who start therapy later and those who start earlier in the course of disease.

Dr. Hunt noted that it is important to  recognize that many morbidities typically associated with the aging process are increased in treated HIV infection—including cardiovascular disease, several but not all non-AIDS cancers, osteoporosis and bone fractures, liver and kidney disease, cognitive decline, and even frailty, a syndrome of multi-morbidity seen in geriatric populations.  Right now, in some regions in sub-Saharan Africa, more than 15 percent of the entire adult population over the age of 50 is HIV-infected, and that percentage is going to increase over time as more people have access to treatment. Therefore, this increased risk of age-associated morbidity will be superimposed on an aging epidemic internationally.

Dr. Hunt cited a number of studies that led to the following conclusions:

• HIV may activate the innate immune system directly by activating toll-like receptors or via accessory proteins, indirectly via microbial translocation, or further indirectly via immunodeficiency, causing reactivation or failure to control other coinfections like cytomegalovirus (CMV).
• Despite ART, HIV decreases life expectancy and increases several age-associated morbidities.
• Immune activation and inflammation persist despite ART and may predict these morbidities.
• Earlier association of morbidity may decrease the degree of persistence in immune activation.
• More effective targeted interventions directed at the underlying causes of inflammation are needed to decrease HIV expression from cells, and better and safer interventions are needed to intervene in CMV and other coinfections.
• A better understanding of pathways driving disease is needed so that expensive interventional trials can be prioritized.

Discussion

The following points were raised by the meeting participants:

Participants asked about available evidence related to adverse events or complications associated with stimulation of the vagus nerve, and evidence that the response can be regulated through intermittent stimulation.

Participants discussed data that suggest a very different inflammatory signature in women in sub-Saharan Africa from that in Western populations. What drives this inflammation is unclear but may be due to changes in the genital tract or in the host microbiome (bacterial, viral, fungal etc.).  There is currently a lack of data on the role of rectal inflammation and risk of transmission, which represents a gap in the research. 

ANIMAL MODELS OF INFLAMMATION, VIRAL RESERVOIRS, MUCOSAL MICROENVIRONMENTS, AND IMMUNOPATHOGENESIS

Dr. Satya Dandekar, Professor of Microbiology and Chair of the Department of Medical Microbiology and Immunology at the University of California, Davis, focused her presentation on demonstrating that animal models provide an opportunity to apply innovative strategies to study inflammation and viral reservoirs at the site of action.

Dr. Dandekar made several key points:

• The impact of inflammation and immune activation can be seen at all stages of HIV infection, beginning with viral transmission, where the inflammatory status of the host may increase the susceptibility of that host to the infection, and the magnitude of inflammation that is induced may determine the outcome at the viral entry site. 

• Inflammation and immune activation play a major role in viral dissemination and persistence in pathogenesis, and all the markers of inflammation originate from the disruption or dysfunction of the cells located in the tissue microenvironments.

• Non-human primate models have generally served HIV research because their physiology, immunology, tissue structure, and the cell makeup in phenotype and function are very comparable to humans.

• Natural hosts of infection such as sooty mangabeys and African Green Monkeys have evolved to live with chronic SIV infection by restricting viral target cell availability, appropriate regulation of the immune system response and rapid restoration of CD4 T cell depletion in the gut, whereas non-natural hosts (macaques and humans) have not.

She concluded by highlighting areas that need further research including:

• Understanding the inflammatory and anti-inflammatory mechanisms that are present as the host transitions from acute to chronic infection
• How the natural host’s immune system protects the gut mucosa and epithelial barrier integrity – what are the renewal and repair mechanisms that maintain an intact gut?

What are the viral gene products that are able to modulate host cell functions and responses to infection in the tissue micro-environment?

ROLE OF INFLAMMATION IN RESERVOIR ESTABLISHMENT, LATENCY, AND VIRAL REACTIVATION

Dr. Steven Deeks, Professor of Medicine in Residence, University of California, San Francisco, spoke about how immune dysfunction and inflammation have an impact on HIV persistence and how this might affect whether or not there is a cure for HIV.

Dr. Deeks presented the following points:

• During long-term therapy HIV persists primarily in lymph node tissues, often in B-cell follicles, but not much is known about the nature of this reservoir, and what cell types in the tissues are infected.

• It is not known how all the HIV-associated inflammation and immune dysfunction affects the reservoir.  Because chronic inflammation has a huge impact on the architecture of lymphoid tissues and the generation of fibrosis, these inflammatory environments may have either indirect or direct effects on where the virus resides in lymph node tissues.

• How does the host-immune environment influence the size and the distribution of the reservoir? Chronic HIV infection is a state of persistent inflammation; there are multiple different pathways; they play out in different tissues; and, presumably, they might have differential effects on the size of the reservoir. 

• In individuals on ART, it has been shown that the more immune activation and inflammation there is, the more virus there is.

Dr. Deeks summarized his recommendations on where the field should focus future efforts on the issues of immune dysfunction and inflammation in HIV persistence:

• Determining where HIV resides in the tissue.

• The impact on persistence of fibrosis in immune dysfunction.

• The contribution to persistence of the spleen, the brain, the testes, and other tissues that are inflammatory, particularly in humans.

• Demonstration that HIV has a direct impact on T-cell proliferation.

• Examining whether immune processes and dysfunction studied in adults are applicable to HIV-infected children and infants.

• Studying to what degree activated cells are enriched for virus.

Discussion

Participants discussed various ideas and studies related to the preceding presentations, including:

• Effector cells of the reservoir are likely enriched for defective, replication incompetent virus.

• Targeting CMV may be a way to suppress inflammation as well as block microbial translocation in effector tissue and the vasculature, but less so in inductive lymphoid tissue

• Treating HIV infection earlier may not diminish the need for a treatment agenda in reducing immune activation and inflammation. It is not yet known whether early treatment will completely normalize immune activation, but the problem is greatest in individuals who delay therapy

• Untreated and treated disease are fundamentally different, so reducing inflammation and immune activation may or may not be beneficial depending on the status of the host response to the pathogen.

HEART AND VASCULAR DISEASE AND INFLAMMATION

Dr. Wendy Post, Professor of Medicine at Johns Hopkins University, focused her presentation on a number of potential reasons for why HIV-infected patients may be at increased risk for cardiovascular disease (CVD), including the effects of ART, the HIV infection itself and inflammatory response, and associations between inflammatory and immune activation markers in cardiovascular disease.

Dr. Post summarized several studies related to cardiovascular disease and inflammation, including:

• The Multicenter AIDS Cohorts Study (MACS) cardiac CT imaging study showed that non-calcified plaque is more prevalent and extensive in HIV-infected men, suggesting increased risk for cardiovascular events. Additionally, men with more advanced HIV infection, as demonstrated by a lower-nadir CD4 T-cell count and greater number of years on ART, have a prevalence of coronary stenosis greater than 50 percent.

• The Strategies for Management of Antiretroviral Therapy (SMART) study revealed that patients on treatment interruption protocols were at increased risk for cardiovascular disease, suggesting that HIV viremia is a contributing factor for CVD risk.

• Arterial Inflammation in the ascending aorta of HIV-infected individuals is increased as measured by monocyte activation, which was associated with immunodeficiency and HIV viral replication.

• HIV controllers in the absence of antiretroviral therapy showed more subclinical atherosclerosis than uninfected controls.

Dr. Post mentioned low nadir CD4 T cell count as a factor for CVD in all studies discussed, and outlined several therapeutic schemes being studied including the use of aspirin, statins, and low dose methotrexate, as well as life style modifications. She concluded her presentation by highlighting gaps in research in this area including;

• Determining the use of inflammatory biomarkers to predict risk of CVD in HIV- infected patients, as well as what marker(s) should be measured.
• Determining what should be used to treat individuals with elevated markers of CVD and examining the assessment of the tolerability, adverse events, and efficacy of these treatments in HIV infected patients?
• Studying whether earlier treatment of HIV with antiretroviral therapy reduces the risk for CVD events?

IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME (IRIS)

Dr. Irini Sereti, Chief of the HIV Pathogenesis Unit at the National Institute of Allergy and Infectious Diseases, began her presentation by pointing out that during the very early phase of ART, morbidity remains fairly high, which is closely tied to severe immunosuppression. Individuals who start therapy with very low CD4 counts, particularly less than 100/ul, have significant high mortality during the first 6–12 months on ART. One reason for this is that these individuals often have serious opportunistic infections (OIs) and are at risk for other co-morbidities.

Dr. Sereti then defined IRIS as the worsening of a manifestation or sometimes the atypical presentation of an infection when HIV patients begin ART.  The incidence of IRIS varies greatly, and can be anywhere from 4 to 50 percent, usually occurring within the first 6 months of therapy.  Studies show the vast majority of IRIS events are related to pre-existing mycobacterial infections, both TB and mycobacterium avium complex, along with cryptococcus and herpes viruses. Other pathogens like pneumocystis or histoplasmosis, and viruses such as JC virus or hepatitis B, also have been implicated.  IRIS occurs in the setting of overall successful HIV virologic suppression. The three major clinical predictors for IRIS are: severe CD4 lymphopenia when therapy is initiated; preexisting infection, even if it is subclinical; and a shorter treatment of the infection prior to starting ART.

Dr. Sereti made the following concluding points:

• Late presenters both in the United States and globally are at risk of developing IRIS. 
• The definition of IRIS is imperfect, which hampers diagnosis. Additionally, IRIS may be under-recognized. Therefore better biomarkers for diagnosis, prognosis, and treatment are needed.
• There is a lack of targeted, preventive, or therapeutic interventions for IRIS. 
• The pathogenesis is a reversal of immunosuppression, with participation of innate and adaptive dysregulated responses. 
• The long-term consequences of IRIS are unknown. As this is an inflammatory immune response, are patients at increased risk of non-infectious complications?
• Biomarkers in animal models of IRIS may assist with diagnosis and help in the identification of targets for treatment.

ROLE OF INFLAMMATION AND IMMUNE ACTIVATION ON THE DEVELOPMENT AND TREATMENT OF HIV-ASSOCIATED AND NON-AIDS-DEFINING MALIGNANCIES

Dr. Otoniel Martinez-Maza, Professor of Obstetrics and Gynecology, Microbiology, Immunology, and Molecular Genetics at the University of California, Los Angeles, stated that he would speak mainly about AIDS and non-Hodgkin’s lymphomas, which are heterogeneous cancers, primarily B-cell cancers, with several subtypes, including Burkitt’s lymphoma, diffuse large B-cell lymphoma, and primary central nervous system (CNS) lymphoma.  He focused on results reported from the MACS and other prospective cohort studies, including:

• ART has resulted in a marked decrease in AIDS-defining cancers, particularly in Kaposi's sarcoma and primary CNS lymphoma.  But the risk for diffuse large B-cell lymphoma is still elevated in the ART era, and the risk for Burkitt’s lymphoma is essentially unchanged in ART-treated populations.  Lymphoma is now the most common AIDS-defining cancer in people who have access to ART and is a prominent cause of death in these populations. 

• Non-AIDS-defining cancers are increasing in HIV-infected populations.  It is unclear whether this is due to individuals living longer with HIV infection, to the effects of HIV infection, or to treatment of the effects, and/or to other factors such as chronic inflammation and immune system activation driven both by antigen exposure and polyclonal antibodies.

• Models examining the cause of lymphomas showed that as a result of chronic inflammation, a variety of genotoxic outcomes are observed that directly impact mechanisms involved in DNA modifying events such as oncogene mutations and tumor suppressor gene inactivation leading to cancer.

Dr. Martinez-Maza concluded by citing studies demonstrating that high levels of biomarkers of immune activation and microbial translocation are strongly associated with the risk for subsequent development of lymphoma.  This is not completely dependent on HIV infection, as these associations are seen in HIV-uninfected populations, as well as preceding HIV seroconversion. ART does not normalize these biomarkers and is consistent with an ongoing elevated risk for Non-Hodgkin’s Lymphoma and other cancers.

Discussion

Meeting participants and presenters raised the following issues:

• Much of IRIS is a consequence of inactive immune activation, but there also is a rapid adaptive immune response with elevated expression of cytokines.
• Principal component analysis has been conducted with HIV-infected and 
  uninfected people to identify groupings of cytokines and biomarkers that are associated with HIV comorbidities such as hepatitis C infection, as well as smoking and obesity.  This analysis may be useful for identifying markers associated with inflammation and other comorbidities in this population.
• A cardiovascular study shows that both HIV-infected men and women have an increase in the incidence of new carotid plaque.
• There must be a minimum of T-cell activity with Hodgkin’s disease, because Hodgkin’s is a mixture of T and B cells interacting, and it could be presumed that people who are massively immunosuppressed due to their HIV infection could have Hodgkin’s without clinical manifestations, because they do not have enough reactive T cells to develop a cancer.

INFLAMMAGING AS A FACTOR IN HIV DISEASE PROGRESSION

Dr. Alan Landay, Professor and Chair of the Department of Immunology–Microbiology at Rush University, began his presentation by stating that by 2017, more than 50 percent of the HIV-infected population in the United States will be over the age of 50.  In considering prevention and cure strategies in that population, it is necessary to determine how inflammation affects vaccine responses. This includes normal host responses like flu, pneumococcal, or other vaccine responses, as well as potential HIV vaccine responses.

Dr. Landay presented data from several studies to demonstrate the following points:

• Soluble markers of inflammation and coagulation, but not T-cell activation, are predictors of non-AIDS-defining events in suppressive therapy.

• CMV has been linked with immune activation, aging, and non-communicable diseases, and is a critical part of the aging and HIV equation.

• Monocytes are central to the development of non-communicable diseases, driven by HIV, and other co-infections.  Monocytes or other myeloid cells also are the harbor for CMV.  These factors lead to monocyte activation, inflammation, immune senescence, telomere shortening, and eventually immune aging and multi-morbidity.

• There is an increase in microbial translocation in the normal aging process. The microbiome located in the gut, the female genital tract, the lungs, and the skin need to be considered in studying inflammation and aging in HIV infected populations.

• Many of the inflammatory innate immune changes that are being seen in HIV disease are also seen during the normal aging process.

Dr. Landay concluded his presentation by stating that research is being conducted into the emergence of immune signatures to predict immune aging and risk of non-communicable diseases, both through soluble markers and by examining translocation, with the desired end result being a signature of accelerated immune aging and risk of non-communicable diseases.

TREATMENT STRATEGIES FOR HIV AND ASSOCIATED INFLAMMATION

Dr. Michael Lederman, Professor of Medicine at Case Western Reserve University, began by defining aspects of immune dysregulation that include a variety of functional and phenotypic abnormalities, including abnormal distribution of circulating monocytes, that are perturbed in terms of their maturation phenotypes. They are inflammatory, and they also have a pro-coagulant phenotype.  Associated with this are increased instances of systemic inflammation as well as coagulation.

Dr. Lederman raised several points:

• An increased risk of morbid events, typically non-AIDS events, and mortality is linked to high levels of inflammatory cytokines and a pro-coagulant phenotype, which is observed before and after the start of antiretroviral therapy and represents a set point in the natural history of infection.

• All the cytokine markers associated with inflammation and pro-coagulation are correlated with each other; however, it is unclear whether or how they contribute to causality in the development of morbid outcomes.  There are numerous potential drivers of this cytokine combination, and they include the presence of co-pathogens, perturbations in pro-inflammatory lipid metabolism, and persistent viral replication.

• Immune system regulatory dysfunction and considerable gut leakage that results in microbial translocation are elements that may also contribute to the inflammatory environment.

Dr. Lederman then discussed approaches to treatment of these drivers of inflammation and immune activation such as:

• Blocking upstream cytokine drivers of immune activation such as IL-6
• Blocking downstream mediators of inflammation
• Blocking microbial translocation and decreasing lipid levels using therapies such as the LPS binding resin “Almer” or statins.
• Treating CMV with acyclovir and other herpes drugs
• Intensifying antiretroviral therapies
• Attenuating inflammation and coagulation by treating dysregulation and lymph node architecture (fibrosis)

Dr. Lederman concluded by posing the question—to treat or not to treat? The toxicities of most anti-inflammatory drugs are known. It is important to note that most of the opportunistic complications of immune deficiency are seen in the absence of ART, or within the first 6-12 months on therapy.  The real cost of not treating is the failure to prevent the accelerated risk of morbidities.  It is essential to identify individuals with HIV infection and get them on therapy as early as possible, because early treatment protects against T-cell activation and dilutes the inflammatory milieu.

WHAT INFLAMMATION MEANS FOR HIV PREVENTION: VACCINES, MICROBICIDES, AND OTHER BIOMEDICAL INTERVENTIONS

Dr. Rupert Kaul, Professor in the Departments of Medicine and Immunology and Head of the Division of Infectious Diseases at the University of Toronto, spoke on the consequences of inflammation on prevention strategies.

Dr. Kaul presented the following key points:

• Inflammation in the genital track as a result of changes in the genital microbiome due to topical agents is associated with increased HIV acquisition.  Cervical alpha defensins, which have direct anti-HIV effects in vitro, are reduced in response to genital infections leading to an increased risk of HIV acquisition. A consistent elevation in inflammatory cytokines is also associated with an increased risk of HIV acquisition.  This acquisition risk is correlated with an increase in target cell recruitment and disruption of epithelial integrity.  These points should be considered in development of an effective microbicide.

• Herpes simplex 2 positivity is associated with about a threefold increased risk of HIV acquisition; this includes asymptomatic herpes.  The fact that most of the herpes-specific T cells found in the genital tract are alpha 4 beta 7 CD4-positive implies that an effective vaccine should target mucosal tissues with activated antigen-specific T-cell response.  This has implications for HIV vaccines as well as other vaccines in an individual exposed to HIV.  A balance between susceptibility and protection in a given a vaccine is crucial. Vigorous HIV-specific T-cell responses, antibody responses, and innate antibody responses are desirable; what is not desirable is CD4 activation and homing to mucosal sites.

Dr. Kaul summarized his presentation by stating that mucosal inflammation may trump the protective effect of some biological interventions, and that careful mucosal assessment is needed for directly applied mucosal interventions. Increased research is needed to determine how systemic interventions and infections increase HIV susceptibility; and these concepts should be applied to HIV-infected individuals.

Discussion

Several points were discussed by meeting participants:

The biology between populations from resource-rich and resource-limited settings is going to be similar, as the same monocyte activation inflammation will be important.  However, people die of different diseases in these settings. At least two studies have linked T-cell activation to mortality in resource-limited settings during early treatment, whereas those strong associations are not seen domestically.  Inflammation and immune dysfunction and the resulting morbid outcomes should be addressed both domestically and internationally.

Recommendations regarding studies and initiatives to prioritize moving forward were discussed and include:

• Targeting treatments or therapies that have worked for other diseases and that have a good clinical precedent or for which there is good mechanistic understanding.

• Initiatives or strategies that could have broad global applicability and impact should be prioritized; for example, aspirin interventions could easily be rolled out in sub-Saharan Africa.

• Many individual biomarkers are linked to disease, but the observational studies should be pushed further. Modeling techniques can be applied to at least some of the cohort study data in order to provide better insights regarding interventional targets.

PUBLIC COMMENTS

No members of the public requested time to comment.

CLOSING COMMENTS

Dr. Walensky thanked the speakers and participants for an exciting program and discussion.

ADJOURN

Dr. Walensky adjourned the 39th meeting of the OARAC at 4:30 p.m. on November 13, 2014, and said she looked forward to seeing Council members at the next meeting on April 16, 2015.

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

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