eBriefing

The Three Zeros of Eliminating HIV / AIDS

The Three Zeros of Eliminating HIV / AIDS
Reported by
Michael Linde

Posted July 19, 2013

Overview

The UNAIDS Getting to Zero strategy outlines a global effort to reach the "three zeros" of HIV/AIDS: zero new deaths, zero new infections, and zero discrimination. Over the past 30 years, significant progress has been made. According to UNAIDS, new infection rates have fallen by 50% or more in 25 countries. However, despite advances in science and policy, we remain far short of realizing the three zeros; achieving these goals requires renewed focus on preventing HIV transmission and disease progression. On May 17, 2013, advocacy and research leaders convened for The Three Zeros of Eliminating HIV/AIDS: Global Science and Policy, a symposium presented by the Academy's Microbiology & Infectious Diseases Discussion Group to review new HIV prevention, care, and treatment approaches; initiatives to control the spread of HIV; and communication and collaboration strategies. It highlighted achievements to date, including advances in vaccine development and treatment-as-prevention, and outlined work to be done, such as addressing structural violence, to reach the three zeros and end the HIV epidemic.

Use the tabs above to find a meeting report and multimedia from this event.

Presentations available from:
Myron S. Cohen, MD (The University of North Carolina at Chapel Hill)
Michele R. Decker, ScD, MPH (Johns Hopkins Bloomberg School of Public Health)
Luiz Loures, MD, MPH (UNAIDS)
Mary A. Marovich, MD (National Institute of Allergy and Infectious Diseases, NIH)
Nelson L. Michael, MD, PhD (Walter Reed Army Institute of Research)
Julio Montaner, MD (BC Centre for Excellence in HIV/AIDS, Canada)
Robert R. Redfield, MD (University of Maryland School of Medicine)
Annie Sparrow, MD, MPH (Mount Sinai Global Health)
Panel moderator: Jerome H. Kim, MD (Walter Reed Army Institute of Research)


The Microbiology & Infectious Diseases Discussion Group is proudly supported by




Mission Partner support for the Frontiers of Science program provided by Pfizer

Improving Collaborations and Communications: a NIAID Perspective


Mary A. Marovich (National Institute of Allergy and Infectious Diseases, NIH)
  • 00:01
    1. Introduction
  • 04:15
    2. Fostering collaborations; Big science projects
  • 12:47
    3. Consortia; Public-private partnerships
  • 24:27
    4. Challenges; Summary and conclusion
  • 28:27
    5. Q and A sessio

Improving Communication and Collaboration: the UNAIDS Perspective


Luiz Loures (UNAIDS)
  • 00:01
    1. Introduction
  • 07:40
    2. Progress 2001-2011
  • 14:50
    3. New partnerships; Estimations of incidence
  • 25:48
    4. Innovation; Community support
  • 35:56
    5. Investments
  • 39:05
    6. Q and A sessio

Using the Tools We Have Today to Drive the Epidemic to Zero


Robert R. Redfield (University of Maryland School of Medicine)
  • 00:01
    1. Introduction, history, and overview
  • 08:45
    2. The HIV epidemic in Baltimore; The JACQUES Initiative
  • 16:39
    3. Sustained linkage to care; Ending the epidemic in the U.S.; Conclusion
  • 22:38
    4. Q and A sessio

Antiviral Therapy to Prevent HIV


Myron S. Cohen (The University of North Carolina at Chapel Hill)
  • 00:01
    1. Introduction; The efficiency of transmission
  • 06:12
    2. Prevention opportunities
  • 12:10
    3. The HPTN 052 Study
  • 21:50
    4. Aspiration meets reality; Glimmers of hope; Conclusion
  • 27:10
    5. Q and A sessio

Vaccine Update: Africa and Thailand


Nelson L. Michael (Walter Reed Army Institute of Research)
  • 00:01
    1. Introduction and overview
  • 03:40
    2. RV144 study
  • 12:31
    3. IgG3 study; Sieve analysis of V1V2
  • 18:33
    4. Correlates of infection risk; Towards a globally effective vaccine
  • 26:37
    5. Ad26-MVA-Protein; Conclusion
  • 27:12
    6. Q and A sessio

Treatment as Prevention: the BC Experience


Julio Montaner (BC Centre for Excellence in HIV/AIDS, Canada)
  • 00:01
    1. Introduction and history; HIV incidence among injection drug users
  • 10:04
    2. The Vancouver Supervised Injecting Facility; HAART coverage in BC
  • 16:40
    3. Using Cascade of Care data; Summary and conclusion
  • 19:53
    4. Q and A sessio

Violence, Trafficking, and HIV Transmission: a Public Health Perspective


Michele R. Decker (Johns Hopkins Bloomberg School of Public Health)
  • 00:01
    1. Introduction and overview
  • 05:45
    2. Sex workers as a vector of disease transmission; Findings from Russia
  • 12:13
    3. Sex trafficking and STI/HIV risk; Dialogue on trafficking and sex work
  • 20:37
    4. HIV epidemic impact of reducing violence against FSWs; Summary and conclusion
  • 25:15
    5. Q and A sessio

When Gender and Conflict Collide


Annie Sparrow (Mount Sinai Global Health)
  • 00:01
    1. Introduction; Rape in conflict and HIV
  • 07:15
    2. Kenyan property law; Child marriage and genital mutilation
  • 20:04
    3. The effects of armed conflict; Conclusion
  • 37:00
    4. Q and A sessio

Panel Discussion


Moderator: Jerome H. Kim (Walter Reed Army Institute of Research)
  • 00:01
    1. Structural violence; Addressing key populations; Funding
  • 10:02
    2. Vaccine development; Treatment access; Choices going forward
  • 21:55
    3. Social and political impediments to treatment
  • 33:42
    4. The larger context; Cost benefit analysis; Concluding thought

Journal Articles and Reports

Improving communication and collaboration

Centers for Disease Control and Prevention. Diagnoses of HIV Infection in the United States and Dependent Areas, 2011.HIV Surveillance Report. 2011 (23).

Decroo T, Telfer B, Biot M, et al. Distribution of antiretroviral treatment through self-forming groups of patients in Tete Province, Mozambique. J Acquir Immune Defic Syndr. 2011;56(2):e39-44.

Fox MP, Rosen S. Patient retention in antiretroviral therapy programs up to three years on treatment in sub-Saharan Africa, 2007–2009: systematic review. Trop Med Int Health. 2010;15 Suppl 1:1-15.

Hall HI, Song R, Rhodes P, et al. Estimation of HIV incidence in the United States. JAMA. 2008;300(5):520-9.

Joint United Nations Programme on HIV/AIDS (UNAIDS). UNAIDS report on the Global AIDS Epidemic. 2012.

Lucas GM, Chaisson RE, Moore RD. Survival in an urban HIV-1 clinic in the era of highly active antiretroviral therapy: a 5-year cohort study. J Acquir Immune Defic Syndr. 2003;33(3):321-8.

Mignano JL, Spencer DE. The JACQUES Initiative Comprehensive Testing and Outreach Model. Abstract and poster presented at the 2010 Ryan White Grantee Meeting/13th Annual Clinical Update, Washington DC. August 23–26, 2010. Poster Number RYP 629.

Sullivan PS, Hamouda O, Delpech V, et al. Reemergence of the HIV epidemic among men who have sex with men in North America, Western Europe, and Australia, 1996–2005. Ann Epidemiol. 2009;19(6):423-31.

Towards zero new HIV infections and zero AIDS-related deaths

Balazs AB, Chen J, Hong CM, et al. Antibody-based protection against HIV infection by vectored immunoprophylaxis. Nature. 2011;481(7379):81-4.

Beddows S, Franti M, Dey AK, et al. A comparative immunogenicity study in rabbits of disulfide-stabilized, proteolytically cleaved, soluble trimeric human immunodeficiency virus type 1 gp140, trimeric cleavage-defective gp140 and monomeric gp120. Virology. 2007;360(2):329-40.

Beddows S, Schülke N, Kirschner M, et al. Evaluating the immunogenicity of a disulfide-stabilized, cleaved, trimeric form of the envelope glycoprotein complex of human immunodeficiency virus type 1. J Virol. 2005;79(14):8812-27.

Binley JM, Sanders RW, Clas B, et al. A recombinant human immunodeficiency virus type 1 envelope glycoprotein complex stabilized by an intermolecular disulfide bond between the gp120 and gp41 subunits is an antigenic mimic of the trimeric virion-associated structure. J Virol. 2000;74:627-643.

Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med. 2011;365:493-505.

Cohen MS, Hellmann N, Levy JA, et al. The spread, treatment, and prevention of HIV-1: evolution of a global pandemic. J Clin Invest. 2008;118(4):1244-54.

Cohen MS, McCauley M, Gamble TR. HIV treatment as prevention and HPTN 052. Curr Opin HIV AIDS. 2012;7:99-105.

Cohen MS, McCauley M, Sugarman J. Establishing HIV treatment as prevention in the HIV Prevention Trials Network 052 randomized trial: an ethical odyssey. Clin Trials. 2012;9:340-7.

Dey AK, David KB, Lu M, Moore JP. Biochemical and biophysical comparison of cleaved and uncleaved soluble, trimeric HIV-1 envelope glycoproteins. Virol. 2009;385:275-281.

Eshleman SH, Hudelson SE, Redd AD, et al. Analysis of genetic linkage of HIV from couples enrolled in the HIV Prevention Trials Network 052 trial. J Infect Dis. 2011;204:1918-26.

Haim H, Salas I, Sodroski J. Proteolytic processing of the human immunodeficiency virus envelope glycoprotein precursor decreases conformational flexibility. J Virol. 2013;87:1884-89.

Haynes BF, Gilbert PB, McElrath MJ, et al. Immune-correlates analysis of an HIV-1 vaccine efficacy trial. N Engl J Med. 2012;366(14):1275-86.

Herrera C, Klasse PJ, Michael E, et al. The impact of envelope glycoprotein cleavage on the antigenicity, infectivity, and neutralization sensitivity of Env-pseudotyped human immunodeficiency virus type 1 particles. Virol. 2005;338:154-172.

Julien JP, Lee JH, Cupo A, et al. Asymmetric recognition of the HIV-1 trimer by broadly neutralizing antibody PG9. Proc Natl Acad Sci U S A. 2013;110(11):4351-6.

Julien JP, Lee PS, Wilson IA. Structural insights into key sites of vulnerability on HIV-1 Env and influenza HA. Immunol Rev. 2012;250(1):180-98.

Letvin NL, Rao SS, Montefiori DC, et al. Immune and Genetic Correlates of Vaccine Protection Against Mucosal Infection by SIV in Monkeys. Sci Transl Med. 2011;3(81):81ra36.

Li Y, O'Dell S, Wilson R, et al. HIV-1 neutralizing antibodies display dual recognition of the primary and coreceptor binding sites and preferential binding to fully cleaved envelope glycoproteins. J Virol. 2012;86(20):11231-41.

Mathew GD, Qualtiere LF, Neel HB 3rd, Pearson GR. IgA antibody, antibody-dependent cellular cytotoxicity and prognosis in patients with nasopharyngeal carcinoma. Int J Cancer. 1981;27(2):175-80.

Nikolova EB, Russell MW. Dual function of human IgA antibodies: inhibition of phagocytosis in circulating neutrophils and enhancement of responses in IL-8-stimulated cells. J Leukoc Biol. 1995;57(6):875-82.

Pancera M, Wyatt R. Selective recognition of oligomeric HIV-1 primary isolate envelope glycoproteins by potently neutralizing ligands requires efficient precursor cleavage. Virol. 2005:332;145-156.

Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, et al. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N Engl J Med. 2009;361(23):2209-20.

Rolland M, Edlefsen PT, Larsen BB, et al. Increased HIV-1 vaccine efficacy against viruses with genetic signatures in Env V2. Nature. 2012;490(7420):417-20.

Sanders RW, Vesanen M, Schuelke N, et al. Stabilization of the soluble, cleaved, trimeric form of the envelope glycoprotein complex of human immunodeficiency virus type 1. J Virol. 2002;76(17):8875-89.

Si Z, Phan N, Kiprilov E, Sodroski J. Effects of HIV type 1 envelope glycoprotein proteolytic processing on antigenicity. AIDS Res Hum Retro. 2003;19:217-226.

Smith MK, Powers KA, Muessig KE, et al. HIV treatment as prevention: the utility and limitations of ecological observation. PLoS Med. 2012;9(7):e1001260.

Tanser F, Bärnighausen T, Grapsa E, et al. High coverage of ART associated with decline in risk of HIV acquisition in rural KwaZulu-Natal, South Africa. Science. 2013;339(6122):966-71.

Tran EE, Borgnia MJ, Kuybeda O, et al. Structural mechanism of trimeric HIV-1 envelope glycoprotein activation. PLoS Pathog. 2012;8(7):e1002797.

Zak DE, Aderem A. Overcoming limitations in the systems vaccinology approach: a pathway for accelerated HIV vaccine development. Curr Opin HIV AIDS. 2012;7(1):58-63.

Translating science into action

Baral S, Beyrer C, Muessig K, et al. Burden of HIV among female sex workers in low-income and middle-income countries: a systematic review and meta-analysis. Lancet Infect Dis. 2012;12(7):538-49.

Decker MR, McCauley HL, Phuengsamran D, et al. Sex trafficking, sexual risk, sexually transmitted infection and reproductive health among female sex workers in Thailand. J Epidemiol Community Health. 2011;65(4):334-9.

Decker MR, McCauley HL, Phuengsamran D, et al. Violence victimization, sexual risk and sexually transmitted infection symptoms among female sex workers in Thailand. Sex Transm Infect. 2010;86(3):236-40.

Decker MR, Seage GR 3rd, Hemenway D, et al. Intimate partner violence functions as both a risk marker and risk factor for women's HIV infection: findings from Indian husband-wife dyads. J Acquir Immune Defic Syndr. 2009;51(5):593-600.

Decker MR, Seage GR 3rd, Hemenway D, et al. Intimate partner violence perpetration, standard and gendered STI/HIV risk behavior, and STI/HIV diagnosis among a clinic-based sample of men. Sex Transm Infect. 2009;85(7):555-60.

Decker MR, Wirtz AL, Baral SD, et al. Injection drug use, sexual risk, violence and STI/HIV among Moscow female sex workers. Sex Transm Infect. 2012;88(4):278-83.

Decker MR, Wirtz AL, Pretorius CS, et al. Estimating the impact of reducing violence against female sex workers on HIV epidemics in Kenya and Ukraine: a policy modeling exercise. Am J Reprod Immunol. 2013;69(Suppl 1):122-32.

Dunkle KL, Decker MR. Gender-based violence and HIV: reviewing the evidence for links and causal pathways in the general population and high-risk groups. Am J Reprod Immunol. 2013;69 Suppl 1:20-6.

Falb KL, McCauley HL, Decker MR, et al. Trafficking mechanisms and HIV status among sex-trafficking survivors in Calcutta, India. Int J Gynaecol Obstet. 2011;113(1):86-7.

Gardner EM, McLees MP, Steiner JF, et al. The spectrum of engagement in HIV care and its relevance to test-and-treat strategies for prevention of HIV infection. Clin Infect Dis. 2011;52(6):793-800.

Gupta J, Raj A, Decker MR, et al. HIV vulnerabilities of sex-trafficked Indian women and girls. Int J Gynaecol Obstet. 2009;107(1):30-4.

Human Security Report Project. Human Security Report 2012.

Montaner JS, Lima VD, Barrios R, et al. Association of highly active antiretroviral therapy coverage, population viral load, and yearly new HIV diagnoses in British Columbia, Canada: a population-based study. Lancet. 2010;376(9740):532-9.

Shannon K, Kerr T, Strathdee SA, et al. Prevalence and structural correlates of gender based violence among a prospective cohort of female sex workers. BMJ. 2009;339:b2939.

Silverman JG, Decker MR, Saggurti N, et al. Intimate partner violence and HIV infection among married Indian women. JAMA. 2008;300(6):703-10.

Silverman JG, Raj A, Cheng DM, et al. Sex trafficking and initiation-related violence, alcohol use, and HIV risk among HIV-infected female sex workers in Mumbai, India. J Infect Dis. 2011;204 Suppl 5:S1229-34.

When To Start Consortium, Sterne JA, May M, et al. Timing of initiation of antiretroviral therapy in AIDS-free HIV-1-infected patients: a collaborative analysis of 18 HIV cohort studies. Lancet. 2009;373(9672):1352-63.

Organizers

Jerome H. Kim, MD

Walter Reed Army Institute of Research
e-mail | website | publications

Jerome H. Kim is the principal deputy and chief at the Laboratory of Molecular Virology and Pathogenesis at the U.S. Military HIV Research Program (MHRP) and is the HIV Vaccines Project manager for the U.S. Army Medical Materiel Development Activity. Kim, a colonel in the United States Army Medical Corps, was the product manager for the RV144 Vaccine Trial while serving as the chief of the Department of Retrovirology in the U.S. Army Medical Component at the Armed Forces Research Institute of Medical Sciences in Bangkok, Thailand. Kim's research interests include HIV molecular epidemiology, host genetics, and HIV vaccine development. He graduated from Yale University School of Medicine and completed his training in internal medicine and a fellowship in infectious diseases at Duke University Medical Center.

Yegor Voronin, PhD

Global HIV Vaccine Enterprise
e-mail | website | publications

Yegor Voronin is a senior science officer at the secretariat of the Global HIV Vaccine Enterprise, an alliance of organizations dedicated to accelerating the development of preventive HIV vaccines. He oversees the Timely Topics in HIV Vaccines program, which brings experts together to identify and address the most pressing strategic needs of HIV vaccine research and development. Voronin has spent nearly 15 years in HIV research. He began his work at West Virginia University and the National Cancer Institute, studying the molecular details of the reverse transcription process. He then moved on to the Fred Hutchinson Cancer Research Center, where he studied population genetics and mechanisms of evolution of HIV. Voronin holds a Master's degree in molecular biology from the Novosibirsk State University in Russia and a PhD in biochemistry from West Virginia University.

Jennifer Henry, PhD

The New York Academy of Sciences
e-mail

Jennifer Henry is the director of Life Sciences at the New York Academy of Sciences. Henry joined the Academy in 2009, before which she was a publishing manager in the Academic Journals division at Nature Publishing Group. She also has eight years of direct editorial experience as editor of Functional Plant Biology for CSIRO Publishing in Australia. She received her PhD in plant molecular biology from the University of Melbourne, specializing in the genetic engineering of transgenic crops. As director of Life Sciences, she is responsible for developing scientific symposia across a range of life sciences, including biochemical pharmacology, neuroscience, systems biology, genome integrity, infectious diseases and microbiology. She also generates alliances with organizations interested in developing programmatic content.


Speakers

Myron S. Cohen, MD

The University of North Carolina at Chapel Hill
e-mail | website | publications

Myron S. Cohen is the J. Herbert Bate Distinguished Professor of Medicine, Microbiology and Immunology and Public Health at the University of North Carolina at Chapel Hill. He received his MD from Rush Medical College, completed internal medicine training at the University of Michigan, and completed an infectious disease fellowship at Yale University. Cohen serves as the director of the Division of Infectious Disease and the Institute for Global Health and Infectious Disease and as associate vice chancellor for global health at UNC. He is a co-principal investigator of the NIH HIV Prevention Trials Network (HPTN). His research focuses on the transmission and prevention of HIV. He helped to develop laboratory methods to measure HIV in genital secretions, as well as to detect the best antiviral agents to reduce replication of HIV in these compartments. Cohen is the architect and principal investigator of the multinational HPTN 052 trial, which has demonstrated that antiretroviral treatment prevents the sexual transmission of HIV-1. This work was recognized by Science Magazine as the Breakthrough of the Year in 2011.

Michele R. Decker, ScD, MPH

Johns Hopkins Bloomberg School of Public Health
e-mail | website | publications

Michele R. Decker is an assistant professor in the Department of Population, Family and Reproductive Health at the Johns Hopkins Bloomberg School of Public Health, where she also directs the Women's Health program at the Center for Public Health and Human Rights. A social epidemiologist by training, Decker focuses her research on gender violence—sexual assault, intimate partner violence, and sex trafficking—and its implications for HIV and other aspects of sexual and reproductive health, especially in marginalized populations, including urban women, adolescents, and those involved in transactional sex or sex work. She is currently developing clinic-based interventions to mitigate the health consequences of violence, as well as primary mixed-methods research strategies to understand the mechanisms by which violence influences sexual health and HIV risk.

Luiz Loures, MD, MPH

UNAIDS
e-mail | website | publications

Luiz Loures is the deputy executive director of programme of the Joint United Nations Programme on HIV/AIDS (UNAIDS) and assistant secretary-general of the United Nations. Loures leads UNAIDS efforts to support countries in meeting the 2015 global AIDS targets and establishing a sustainable response to AIDS. Loures is a medical doctor with nearly 30 years of experience in the AIDS response. His work ranges from providing medical care to people living with HIV in the early days of the epidemic to helping to develop a global policy framework. Loures received his MD at the Federal University of Minas Gerais in Brazil, specializing in critical care. He also holds an MPH from the University of California, Berkeley.

Mary A. Marovich, MD

National Institute of Allergy and Infectious Diseases, NIH
e-mail | website | publications

Mary A. Marovich is the director of the Vaccine Research Program in the Division of AIDS at the National Institute of Allergy and Infectious Diseases, NIH, where she leads clinical and preclinical research on HIV vaccines. Marovich previously served in the U.S. Military HIV Research Program as chief of vaccine research and development and as chair of the Walter Reed Army Institute of Research Institutional Review Board. Marovich holds an MD from Loyola University of Chicago–Maywood and completed a residency in internal medicine and clinical infectious disease training at the University of Colorado. She also holds a diploma in tropical medicine and hygiene from the Royal College of Physicians and Surgeons at London School of Tropical Medicine and Hygiene, UK. She is an associate professor of medicine in the Department of Medicine at the Uniformed Services University.

Nelson L. Michael, MD, PhD

Walter Reed Army Institute of Research
e-mail | website | publications

Nelson L. Michael is the director of the U.S. Military HIV Research Program (MHRP) at the Walter Reed Army Institute of Research, an international HIV vaccine research program that integrates HIV/AIDS prevention, care, and treatment. His career has focused on developing an effective HIV vaccine to protect U.S. and Allied Armed Services and to reduce the global impact of the disease. The program has seven research centers in the U.S., Africa, and Asia, and conducts HIV discovery research, cohort studies, vaccine trials, and therapeutic investigations. Michael guided MHRP through the completion of the RV144 HIV vaccine study in Thailand, which provided the first demonstration that a preventive HIV vaccine is possible. More recently, he helped lead a study on a new vaccine regimen that partially protected monkeys from HIV-like infection. This research also identified factors associated with HIV prevention and control and identified new HIV vaccine candidates to test in human clinical trials for both prevention and therapeutic applications.

Julio Montaner, MD

BC Centre for Excellence in HIV/AIDS, Canada
e-mail | website | publications

Julio Montaner is a professor and head of the Division of AIDS at the University of British Columbia (UBC). He is also the UBC and St. Paul's Hospital Foundation chair in AIDS research, as well as the director of the BC Centre for Excellence in HIV/AIDS. He was the president of the International AIDS Society from 2008 to 2010. He played a key role in establishing the efficacy of NNRTI-based highly active antiretroviral therapy (HAART) and, more recently, of HAART as prevention. His research interests include HAART as prevention, optimal use of HAART, salvage therapy, and new antiretrovirals, as well as hard-to-reach populations, treatment as prevention of viral hepatitis, and addiction management. He holds and MD from University of Buenos Aires in Argentina, received an honorary doctor of science degree from Simon Fraser University in Canada, and is the recipient of numerous awards for his contributions to the field of HIV/AIDS.

John P. Moore, PhD

Weill Cornell Medical College
e-mail | website | publications

John P. Moore is a tenured professor of microbiology and immunology at Weill Cornell Medical College. He holds MA, MPhil, and PhD degrees from Cambridge University, UK; he worked there, at the University of Glasgow, and at the Chester Beatty Laboratories in London before joining the medical college in 2000. He was previously an Elizabeth Glaser Scientist of the Pediatric AIDS Foundation and has held an unrestricted grant for infectious disease research from the Bristol-Myers Squibb Foundation and a Merit Award from NIAID. He is an editorial board member for several journals and has served on study sections and committees for the NIH and charities. His research focuses on understanding HIV-1 entry into cells and how to inhibit it with specific drug candidates and antibodies, designing envelope glycoprotein trimers for neutralizing antibody induction and structural studies and understanding HIV-1 resistance under selection by CCR5 inhibitors.

Robert R. Redfield, MD

University of Maryland School of Medicine
e-mail | website | publications

Robert R. Redfield holds an MD from Georgetown University and completed internal medicine and infectious diseases training at Walter Reed Army Medical Center and Walter Army Institute of Research. He was the founding director of the Department of Retroviral Research in the Military's HIV Research Program, retiring after 20 years of service in the U.S. Army Medical Corps to co-found the University of Maryland's Institute of Human Virology (IHV). He is a professor of medicine, a professor of microbiology and immunology, and chief of infectious diseases at the university, and is the director of the Division of Clinical Care and Research at the IHV. Redfield made several important early contributions to our understanding of HIV, including demonstrating the importance of heterosexual transmission and developing the Walter Reed staging system for HIV infection. His research focuses on novel biological approaches to treating chronic viral pathogens, particularly targeting host-cell pathways and host-directed immunity. Redfield oversees a clinical program in the Baltimore/Washington DC region, leads USG-funded global care and treatment programs, and directs post-graduate medical education programs in five African and two Caribbean countries.

Magdalena Sobieszczyk, MD, MPH

Columbia University Medical Center
e-mail | website | publications

Magdalena Sobieszczyk is an assistant professor of clinical medicine in the Infectious Diseases Division at Columbia University College of Physicians and Surgeons. She is an investigator in the NIH-sponsored HIV Vaccine Trials Network (HVTN), a multicenter organization that works to develop an effective preventive HIV vaccine; an investigator in the AIDS Clinical Trials Group; and the associate director of the NYC HIV Vaccine Unit. Her research focuses on developing, testing, and implementing biomedical strategies to prevent HIV. She has been involved in several HIV vaccine protocols, including serving as the co-chair of HVTN 505. Sobieszczyk is also the protocol chair of HVTN 802, a longitudinal observational study to evaluate the virological, immunological, and clinical course of HIV infection among participants in advanced phase HIV vaccine trials. Sobieszczyk completed an internal medicine residency and a fellowship in infectious diseases at Columbia University College of Physicians and Surgeons and holds an MPH from the university's Mailman School of Public Health.

Annie Sparrow, MD, MPH

Mount Sinai Global Health
website

Annie Sparrow is assistant professor and deputy director of the Human Rights Program in the Department of Global Health at Mount Sinai, where she teaches human rights and humanitarian aid in complex emergencies. Sparrow practiced pediatric intensive care before switching her focus to public health after working briefly in Taliban-controlled Afghanistan. She served as a lead public advocate for refugees detained in punitive conditions in Australia and worked in remote Aboriginal communities. She obtained an MPH from Harvard University and then joined Human Rights Watch, where she focused on HIV and sexual violence in conflict, mainly in Sudan and Chad. On one trip to Darfur, she gave displaced children crayons and paper; the pictures they drew about the atrocities they had witnessed and escaped became the much-acclaimed "Darfur Drawings," an exhibit that traveled widely and was used by the International Criminal Court as evidence of systematic war crimes by the Sudanese government. Sparrow spent several years in Kenya working in various complex humanitarian emergencies for the Emergency Response Team of Catholic Relief Services. She also spent a year as director of UNICEF's Malaria Program in Somalia for the Global Fund against AIDS, Tuberculosis and Malaria.


Panelists

Chris Collins

amfAR, The Foundation for AIDS Research
e-mail | website

Chris Collins is the vice president and director of public policy at amfAR, The Foundation for AIDS Research. He holds a Master's degree in public policy from the Kennedy School of Government at Harvard University. He authored Improving Outcomes: Blueprint for a National AIDS Plan for the United States and subsequently helped to organize the development of a U.S. National HIV/AIDS Strategy. He also coordinated the Global HIV Prevention Working Group as a consultant with the Bill & Melinda Gates Foundation and oversaw production of the Missing the Target reports for the International Treatment Preparedness Coalition (ITPC). Collins is a co-founder of the AIDS Vaccine Advocacy Coalition (AVAC). As an appropriations associate for Rep. Nancy Pelosi, he developed the first Congressional legislation designed to provide incentives for the development and delivery of vaccines against AIDS, malaria, and tuberculosis.

Tim Horn

Treatment Action Group
e-mail | website

Tim Horn is the HIV project director at the Treatment Action Group (TAG), a New York-based independent research and policy think tank advocating for better treatment, a vaccine, and a cure for AIDS. He is the former editor-in-chief of AIDSmeds.com, an educational portal for people living with HIV/AIDS, and the former executive editor of the PRN Notebook, a quarterly journal for HIV-treating clinicians. He previously worked for the Foundation for AIDS Research (amfAR), the AIDS Treatment Data Network, and the PWA Health Group. He has been living with HIV since 1992.

Rick King, PhD

International AIDS Vaccine Initiative
e-mail | website | publications

Rick King is the vice president of vaccine design at the International AIDS Vaccine Initiative, overseeing a comprehensive AIDS vaccine discovery program. King received his PhD in biochemistry from Johns Hopkins University and completed postdoctoral research at the National Cancer Institute, where he discovered a molecular abnormality that occurs with certain breast cancers. King was previously an associate professor in the Department of Biochemistry at the Lombardi Cancer Research Center and the senior vice president of research at GenVec Inc, where he led efforts to identify, select, and advance products for cancer, ocular, and infectious disease applications, leading to therapeutics currently in clinical trials.

Daniel Tietz, RN, JD

AIDS Community Research Initiative of America
e-mail | website

Daniel Tietz is executive director of the AIDS Community Research Initiative of America (ACRIA), where he has expanded research activities and consulting services and focused on science-based public policy initiatives. With the creation of the ACRIA Center on HIV & Aging, Tietz guided the organization to become an international leader in research on and responses to the needs of older adults with and at risk for HIV. A registered nurse and lawyer, Tietz previously worked for the Coalition for the Homeless, the Day Treatment and Residential Services at Housing Works, and the Postgraduate Center for Mental Health. Tietz has long-advocated on behalf of LGBT rights and social justice issues through independent political activity, including campaign management.

Mitchell Warren

AIDS Vaccine Advocacy Coalition
e-mail | website

Mitchell Warren is the executive director of the AIDS Vaccine Advocacy Coalition(AVAC), an international nongovernmental organization that uses education, policy analysis, advocacy, and a network of global collaborations to accelerate HIV prevention options. He previously worked for the International AIDS Vaccine Initiative and the Female Health Company. Warren also spent six years at Population Services International (PSI) designing and implementing social marketing, communications, and health promotion in Africa, Asia, and Europe. He is a member of several working groups and advisory boards, including the Global HIV Prevention Working Group, the WHO–UNAIDS HIV Vaccine Advisory Committee, and the NIH's Office of AIDS Research Advisory Council and AIDS Research Advisory Committee, NIAID.

Jane Waterman

International AIDS Vaccine Initiative
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Jane Waterman guides the International AIDS Vaccine Initiative's (IAVI) advocacy, policy, resource mobilization, communications, and media relations programs. She was previously on the senior management team of the International HIV/AIDS Alliance, a global network that provides financial and technical support to community organizations in more than 40 countries. She was head of resource mobilization at the International Planned Parenthood Federation and spent time in sub-Saharan Africa, initially as a VSO volunteer and then with the British Council. Waterman holds a Master's degree in Gender and Development, a postgraduate certificate in education, and a certificate in fundraising management. She is a graduate of the United Kingdom Cabinet Office/Henley Business School Top Management program.


Michael Linde

Michael Linde is a Denver-based medical writer. He specializes in HIV/AIDS, but has also written about diverse medical and scientific topics, including health care delivery, oncology, diabetes, neurology, urology, end of life care, and immunology. He holds an MS is in biochemistry and molecular biology from University of Southern California and is a PhD candidate in immunology at Johns Hopkins University.

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Supported by educational grants from Gilead Sciences Inc, Janssen Therapeutics, Division of Janssen Products, LP and Merck Sharp & Dohme Corp, a subsidiary of Merck & Co Inc.

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According to UNAIDS, approximately 34 million people live with human immunodeficiency virus (HIV); thus, ending the epidemic is both a top global priority and a massive undertaking. Sub-Saharan Africa remains the most severely affected region, accounting for almost seven in ten cases of HIV. Asia also bears a significant HIV burden: at the end of 2011 approximately 5 million people in the region were infected.

While the number of new infections has declined in recent years, the prevalence of HIV continues to rise worldwide. The face of the disease varies by region. In the United States, HIV incidence has remained stable but disease demographics have changed: new HIV infections are more commonly reported among older adults, nonwhites, and young men who have sex with men (MSM). Globally, HIV prevalence tends to be low among the general population, but can be high among at-risk populations, such as injection drug users and sex workers. These people often have limited access to treatment and prevention tools and may have compromised sexual negotiation; this lack of agency contributes to the spread of HIV, so addressing human rights and improving access to treatment are important to prevention campaigns.

Researchers and policy makers aim to eliminate HIV/AIDS by achieving the UNIAIDS three zeros goals: zero new HIV deaths, zero new HIV infections, and zero discrimination against people living with HIV. This will require advances in science, implementation, and policy. Preventing new infections relies on the development of vaccines and microbicides that inhibit viral transmission; eliminating new infections requires widespread access to new treatments, such as pre-exposure prophylaxis (PrEP), post-exposure prophylaxis (PEP), and treatment as prevention (TasP).

The potential impact of a preventative vaccine on HIV incidence. (Image courtesy of Nelson L. Michael)

Many approaches have been developed to reach at risk-populations, from awareness campaigns in the U.S. focused on young MSM to ambitious testing programs in South Africa. Without such initiatives, it is likely that efforts to stop the spread of HIV will be unsuccessful. It is important to ensure equal access to health services and preventative therapies. Structural violence and its associated lack of agency must also be addressed.

Achieving the three zeros will only be feasible through communication and collaboration among scientists, policy makers, advocates, and members of at-risk populations. It will also require significant, continued funding and the political and social will to enact measures to combat, and hopefully eliminate, the HIV epidemic on a global scale.

Speakers:
Mary A. Marovich, National Institute of Allergy and Infectious Diseases, NIH
Luiz Loures, UNAIDS
Robert R. Redfield, University of Maryland School of Medicine

Highlights

  • The global scale of the HIV epidemic makes effective communication critical to prevention efforts.
  • In the U.S. there is a need to improve diagnosis rates, linkage and retention in HIV care, and treatment strategies, as well as to develop a preventive HIV vaccine and long-term solutions for new infections.
  • The National Institutes of Heath supports initiatives that foster collaboration between organizations working to decrease HIV transmission.

Improving communication and collaboration—the NIH perspective

The National Institutes of Health (NIH) encourages organizations to work collaboratively to decrease HIV transmission rates. Mary A. Marovich from the National Institute of Allergy and Infectious Diseases (NIAID) explained that this approach relies on establishing communication, trust, and respect; clear goals; leadership and consensus; and mutual motivation. NIH-supported multidisciplinary programs facilitate knowledge acquisition and economies of space, equipment, and effort. Their programs range from big-science projects to consortia and public–private partnerships.

HIV/AIDS vaccine development is a top priority at NIAID. Their vaccine research program has three branches: preclinical research and discovery, vaccine translational research, and vaccine clinical research. The NIH supports the Duke Center for HIV/AIDS Vaccine Immunology & Immunogen Discovery (CHAVI-ID), which investigates immune responses that prevent or contain HIV to generate immunogen constructs that will induce HIV protection. CHAVI-ID has east- and west-coast groups with cooperative agreements to coordinate their efforts, a flexible leadership team that directs the focus of their programs, a cohesive project structure, and an external scientific advisory board. The B-cell biology programs, another initiative, support B-cell research aiming to produce broadly protective antibody responses to HIV. Similarly, the B-cell Immunology Partnership Program for HIV Vaccine Discovery fosters networking between B-cell immunologists and HIV vaccinologists to inform vaccine discovery and immunization strategies.

The Consortia for AIDS Vaccine Research in Nonhuman Primates at Emory University and Beth Israel Deaconess Medical Center at Harvard University is funded by the NIH to study mucosal viral infection and immune responses to vaccines in Rhesus macaques. The organizations involved share resources to mitigate availability- and cost-limitations, and use sophisticated high-throughput technologies such as systems biology approaches to analyze and report data.

The NIH-funded pox-protein public–private partnership (P5) is another large-scale project with contributions from many partner organizations. P5 was developed as a follow-up to the RV144 trial in Thailand. It aims to extend that trial to other high-HIV-incidence populations, addressing specific regional health needs and creating models that can be expanded globally. Work is underway to improve RV144 vaccine efficacy (VE) in high-risk MSM in Thailand to greater than 50%, with an ALVAC + gp120/adjuvant, and to increase VE in high-risk heterosexuals in southern Africa, using a new DNA/NYVAC vaccination strategy.

The public health impact and regional relevance of the P5 research and licensure strategy. (Image courtesy of Mary A. Marovich)

A significant challenge raised by large-scale collaborations is the implementation of coordinated, rapid, consistent messaging across both scientific and community forums. This is especially critical when a vaccine trial is discontinued, as in the HVTN 505 trial, since discontinuation needs to occur immediately to protect participants.

Improving communication and collaboration—the UNAIDS perspective

Luiz Loures from UNAIDS believes it is possible to move toward the end of HIV. He noted that HIV incidence decreased by about 700 000 worldwide between 2001 and 2011, with much of this progress achieved in Africa, and that there were half a million fewer HIV-associated deaths in 2011 than in 2005. While the first decade in the HIV epidemic was difficult, the second decade saw the introduction of life-saving treatment and global mobilization. The corresponding exponential growth in awareness and funding has helped to lower incidence and mortality rates. Loures asserted that HIV funding should be guided by a real-world view of the epidemic; only by accounting for how the virus spreads and who it affects can we take the correct steps to intervene.

To achieve the end of HIV/AIDS, we need definite endpoints and timeframes. These objectives will differ among populations; for example, ending mother-to-child HIV transmission may be possible relatively soon as a result of significant advances in vertical transmission reduction, while ending injection-drug-use HIV transmission will probably take longer. Partnerships should incorporate community support and work towards focused, evidence-based, and innovative goals that address human rights issues and investment resources wisely. There is a need to focus on HIV hot spots, particularly in developed-world populations, such as among young MSM.

The importance of community involvement in HIV treatment. (Image courtesy of Luiz Loures)


 

Case study: using tools we have to drive the epidemic to zero

According to Robert R. Redfield from the University of Maryland School of Medicine, the response to HIV should be informed by successful initiatives from past epidemics, such as the Stop Syphilis campaign headed by U.S. Surgeon General Thomas Parran in the 1930s. That campaign recommended that syphilis testing be a part of standard medical care, and a positive test result was followed with continuous, intensive, and persistent treatment. In HIV programs, a disconnect between diagnosis and care has contributed to the epidemic.

Redfield presented a case study of current approaches to treating HIV in inner cities. Maryland has the highest HIV incidence of any state, with most infections occurring in Baltimore and Washington DC. HIV incidence has decreased among injection drug users (IDUs) but has increased among MSM. While fragmented care and poor treatment rates are common across the U.S., this trend is especially chronic in Maryland, where only one in five HIV-positive people were virologically suppressed in 2011, an increase from 2010. This low rate is particularly surprising in the Baltimore region, where there are many physicians and medical care should be easily accessible.

The University of Maryland has created the JACQUES Initiative (Joint AIDS Community-wide Quest for Unique and Effective Treatment Strategies), designed for and by the community, to integrate care and improve the continuum from testing to treatment and retention. Patients who test HIV positive are immediately linked to care with same-day appointments. The program focuses on early diagnosis—expanding routine HIV testing in clinical settings, community programs, and faith-based sites—and on changing practice standards for the next generation of health care professionals. The program follows a hub-and-spoke model, with core components including primary care, case management, pharmacy, and education, as well as connections to other programs, such as community services, dentistry, and testing initiatives.

The integrated care-delivery model for the JACQUES initiative in Maryland. (Image courtesy of Robert R. Redfield)

The initiative is integrated with the Connect 2 Care (C2C) program, a five-day no-appointment-necessary clinic linking people living with HIV to care. In the C2C program, almost 85% of those who test positive for HIV attend one care appointment and 97.5% of those patients attend at least a second appointment.

This program is a model for other U.S. cities. Improvements in the continuum of care can reduce HIV incidence; new care-delivery models, coupled with regionally prioritized replication, will be a "linchpin to success," according to Redfield. He believes that increased HIV-diagnosis rates, improved linkage and retention in care, effective treatment, and research supporting vaccine development and long-term solutions, combined with sufficient funding, political will, and leadership, will make it possible to eliminate new HIV infections in the U.S. in the next seven years.

Speakers:
Myron S. Cohen, The University of North Carolina at Chapel Hill
John P. Moore, Weill Cornell Medical College
Magdalena Sobieszczyk, Columbia University Medical Center
Nelson L. Michael, Walter Reed Army Institute of Research

Highlights

  • Prevention efforts include behavioral, barrier, and pharmaceutical interventions, but the best approach would be a highly effective preventative vaccine.
  • Recent studies show that HIV transmission can be reduced by treating people who are HIV-positive.
  • Vaccine research has yielded new insight into which immunogen strategies are likely to be viable, but a vaccine candidate with sufficient efficacy has yet to be developed.

Antiretroviral treatment for the prevention of HIV transmission

The rate at which an infectious disease spreads is determined by transmission efficiency, duration of infectiousness, and the number of people exposed. The commonly cited rate of infection for HIV is 1/1000 episodes of exposure. Myron S. Cohen from the University of North Carolina at Chapel Hill reported that this is probably an underestimate of the true infection rate.

A number of factors can amplify HIV transmission: some increase infectiousness (such as blood viral load, genital tract viral load, inflammatory STDs, and viral clade); others increase susceptibility (such as genital ulcers, inflammatory STDs, cytokine profile, lack of circumcision, cervical ectopy, and HLA haplotype). Acute infection, characterized by a very high viral load following the initial infection, appears to increase infectiousness. Preventative measures that focus on reducing transmission by decreasing infectiousness or susceptibility are often classified by their target: people who are unexposed, exposed (pre-coital/coital or post-coital), or infected.

Four opportunities to prevent HIV transmission. (Image courtesy of Myron S. Cohen)

The first goal is to help unexposed people remain HIV-negative. Circumcision, barrier protection, microbicides, and STD-reduction programs help prevent viral transmission. Pre-exposure prophylaxis (PrEP), which involves taking antiretroviral therapy (ART) before a potential exposure, has recently been shown to reduce transmission. However, PrEP medications must be taken close to the time of exposure, which may not be practical. Thus, there is a need for alternative PrEP methods, such as novel deliveries with longer-lasting effects. Researchers have raised concerns about using PrEP medications, which are also the first-line of treatment for HIV infection, because of the risk of developing resistance. An alternative to PrEP is post-exposure prophylaxis (PEP), but this similarly requires rapid initiation. The best option to prevent transmission would be an effective HIV vaccine.

One of the more recent strategies is treatment as prevention. Antiretrovirals can reduce viral load, and thus the risk of transmitting the virus to uninfected partners. The HPTN 052 study evaluates whether active antiretroviral treatment among stable, healthy, serodiscordant, sexually active couples reduces the HIV transmission rate. The ongoing 11-year study has provided HIV-prevention counseling to over 17 000 serodiscordant couples around the world. Results show that there are significantly fewer transmission events when the HIV-positive partner initiates ART early. In cases of transmission, the study uses viral genotyping to link infections and confirm the source of the infection as the HIV-positive partner. The results, demonstrating that viral suppression can reduce HIV transmission at the population level, were named the Science Breakthrough of the Year in 2011. The study is now investigating the durability of the prevention benefit and the consequences of delayed ART.

HIV transmission tends to occur in clusters, so targeting viral load within these clusters may impact transmission rates. In KwaZulu-Natal, South Africa, individual HIV acquisition risk was significantly lower in communities with more than 40% of infected individuals on ART. Cohen asserted that large-scale use of treatment as prevention could serve as a bridge to lower infection rates until there are simpler prevention methods, such as a preventative vaccine or a cure for HIV. Effective implementation is labor-intensive, but this study is cause for optimism.

Next-generation, soluble, cleaved HIV-1 Env trimers for vaccine and structural studies

A successful preventative vaccine is likely to require broadly neutralizing antibodies (bNAbs) against the HIV envelope glycoprotein (Env). Neutralizing antibodies are antibodies that effectively target HIV and prevent viral entry, while non-neutralizing antibodies may bind the virus, but do not confer immunological protection. Env is a trimer in its natural state, and any recombinant protein used to generate bnAbs should maintain this structure in some capacity. John P. Moore from Weill Cornell Medical College explained that one recombinant construct induces protein stability by introducing a disulfide bond to link the gp120 and gp41 components of the Env protein and adding a mutation in the gp41 protein. The construct also has a modification to ensure efficient furin cleavage and to reduce protein aggregation, which are important for generating a protein that mimics the native viral spike. The resulting recombinant protein (named SOSIP gp140 trimers) exposes neutralizing epitopes, occludes most non-neutralizing epitopes, efficiently binds CD4 and CCR5 (the receptor and one co-receptor for HIV), and is more immunogenic than prior vaccine candidates based on monomeric gp120 constructs.

The third generation of the recombinant protein (BG505 SOSIP.664 gp140) is based upon a subtype A T/F virus that was flagged by the International AIDS Vaccine Initiative in an in silico screen based on antigenicity predictions. These trimmers are highly stable and can induce the generation of neutralizing antibodies, as assessed by surface plasmon resonance, isothermal calolimitry, and electron micrographs. While no soluble gp140 trimer may ever exactly mimic the native, virion-associated functional spike (the complex of proteins HIV uses to access the cell), in this study most of the gp120 bNAb epitopes were exposed, while gp41 non-neutralizing epitopes were occluded. There is a strong correlation between trimer binding and virus neutralization, assessed by ELISA; however, as antigenicity, or the ability to elicit antibody production, does not predict immunogenicity, animal studies are needed to confirm how the construct performs as an immunogen. Production scale-up and additional studies are underway.

HVTN 505 clinical trial results

The HVTN 505 study investigated the vaccine efficacy (VE) of the VRC's multiclade, multigene DNA/rAd5 prime/boost vaccine regimen in MSM and male-to-female transgendered people who have sex with men. Magda Sobieszczyk from Columbia University Medical Center, a member of the HTVN 505 study team, presented the results from the trial, which was conducted in 18 U.S. cities and included 2500 participants.

The VRC DNA/rAd5 regimen is designed to elicit HIV-specific, balanced, multifunctional CD4 and CD8 responses and binding antibodies to HIV envelopes A, B, and C. Preclinical data supported regimen safety, immunogenicity, and potential for VE. The trial had two primary endpoints: HIV acquisition and viral load set point. The study began enrollment in 2009; from 2010 to 2013, the Data Safety and Monitoring Board (DSMB) reviewed interim data on study status, receipts of the vaccination, retention, safety, data management quality, PrEP/PEP use, HIV infections, VL, CD4 T-cell counts, ART initiation, and operational futility. In April 2013, after the first planned review of VE futility, the DSMB determined that the study had reached pre-defined terms for VE and viral load set-point futility (<50% VE and a <1 log10 decrease in HIV RNA set-point, respectively), and the trial was stopped.

At this point, 1244 volunteers had received placebo and 1250 volunteers had received vaccine. There was a median follow-up of 15 months and 64% of the total person-years of follow-up between entry and month 24 had been completed. The vaccine was safe compared to placebo—all adverse events in the vaccination arm were judged to be unrelated to the vaccine, except for one severe viral infection. However, at the DSMB review there were 72 reported HIV infections, 31 in the placebo group and 41 in the vaccination group. (Since the DSMB meeting, one additional placebo group infection was reported.) Thus, the study group concluded that the VRC DNA prime/rAd5 boost vaccine regimen neither reduced HIV acquisition nor decreased post-acquisition viral load.

Although the trial reached efficacy futility, it was successful in meeting accrual requirements, achieving high retention rates, and implementing rapid discontinuation protocols. The study was well conducted, with balance between arms, a high proportion of fully vaccinated participants, and excellent data quality. While the results are disappointing, the primary question—vaccine efficacy—was definitively answered at the earliest possible time.

Vaccine update: Africa and Thailand

A preventative vaccine with even modest VE has the potential to save millions of lives. As Nelson L. Michael from Walter Reed Army Institute of Research explained, a vaccine with just 50% efficacy administered to 30% of the population in low- and middle-income countries could avert almost 20% of all HIV infections. While just a handful of vaccine concepts have been investigated, each trial advances vaccine development.

Prior HIV preventative vaccine trials and their key conclusions. (Image courtesy of Nelson L. Michael)

The RV144 trial showed an early VE of 60%, but this waned to 31% over time. The vaccine had no effect on post-infection CD4 T-cell counts or viral load. Notably, 90% of the breakthrough viruses—which were able to establish infection—were variant CRF01_AE. Antibody responses were correlated with infection risk, which increased with serum IgA antibodies binding to the viral envelope and decreased with IgG binding to the gp120-V1-V2 domain. Further studies suggest that the V2 region of the gp120 domain is the most important region for antibodies to bind to for immunity. The IgA correlation may be explained by inhibition of IgG-induced phagocytosis or IgG-mediated complement-dependent bacteriolysis. In addition, a serum IgA antibody blocked IgG-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) in a dose-dependent manner in vitro. Thus, a fraction of RV144 volunteers elicited IgA specificities capable of inhibiting IgG and NK-mediated ADCC. It is important to note that these are serum IgA antibodies and that mucosal responses to RV144 may differ. A follow-up study to the RV144 data also determined that V1/V2 IgG3 antibody subtype responses correlate with a significantly decreased risk of infection.

Further analysis supports the importance of the gp120 V2 region. A comparison of the sequences of viruses that infect participants receiving RV144 vaccine versus placebo revealed that mutations within the V2 region were associated with vaccine efficacy. However, while these data are valuable for future vaccine design, the gp120 V2 region may not be a significant marker in new vaccines because different vaccines for the same pathogen can have different correlates of risk and protection.

The P5 partnership is building on the RV144 trial, with several research projects designed to advance and ultimately license HIV pox-protein vaccine candidates, including the ALVAC and NYVAC vectors that have the potential to achieve a broad public health impact. It is investigating ALVAC vaccines in high-risk MSM in Thailand and high-risk heterosexuals in southern Africa. The group is also studying a NYVAC/DNA vaccine strategy among high-risk heterosexuals.

Vaccination trials using Ad5 adenovirus vectors have failed to show adequate VE to date, but other adenovirus vectors may elicit different immune responses which may increase VE. In a monkey model, an Ad26/MVA (modified vaccinia virus Ankara) strategy resulted in significant control of viremia for some Rhesus macaques. In humans, different adenoviruses result in very different gene expression profiles in the host, so there is a rationale for continuing with Ad26-based strategies despite the failure of the Ad5 vector in the HTVN 505 trial. There are significant biological differences between Ad5 and Ad26, including cellular receptor usage, tropism, gene expression profile, innate immune profile, adaptive immune phenotype, and seroepidemiology. While DNA/Ad5 and Ad5 vaccines fail to protect against SIVmac251 challenges in non-human primates, Ad26/MVA and Ad26/protein vaccines offer substantial protection. The leading hypothesis for the failure of Ad5 vectors is that they activate CD4 cells at mucosal surfaces; it has been demonstrated that this does not occur with Ad26 vectors in humans, and clinical vaccine development using Ad26 vectors is underway.

Speakers:
Julio Montaner, BC Centre for Excellence in HIV/AIDS, Canada
Michele R. Decker, Johns Hopkins Bloomberg School of Public Health
Annie Sparrow, Mount Sinai Global Health
 
Moderator:
Jerome H. Kim, Walter Reed Army Institute of Research
 
Panelists:
Chris Collins, amfAR, The Foundation for AIDS Research
Tim Horn, Treatment Action Group
Rick King, International Aids Vaccine Initiative
Daniel Tietz, AIDS Community Research Initiative of America
Mitchell Warren, AIDS Vaccine Advocacy Coalition
Jane Waterman, International Aids Vaccine Initiative

Highlights

  • Treatment as prevention, coupled with other strategies, has led to a significant decrease in new HIV infections in British Columbia; this model may be useful for other regions with high HIV-transmission rates.
  • There is a need to specifically address at-risk populations, including commercial sex workers and other populations with a lack of agency.
  • HIV prevention efforts for these at-risk populations will only be successful if accompanying violence and structural barriers are addressed.

Implementing treatment as prevention—the key to an AIDS- and HIV-free generation

Julio Montaner from the BC Centre for Excellence in HIV/AIDS reported that he was skeptical about non-nucleoside reverse transcriptase inhibitors when antiretroviral therapy was first developed in the 1990s. But the treatment has been successful, and since the advent of combination therapy and PCR analysis of HIV RNA in 1998, it has been possible to suppress viremia to undetectable levels. HIV-associated mortality has decreased, and recent data indicate that this therapy can also be used as a preventative approach.

Treatment that suppresses viral load to undetectable levels limits the transmission of HIV. Used on a large scale, the treatment-as-prevention (TasP) strategy seeks to decrease the viral load in a community and thereby decrease transmission. In Vancouver the HIV incidence among IDUs has decreased as a result of increased virologic suppression: data from 2011 indicate that HIV incidence decreased by 74% for each log decline in community plasma viral load from 1997. Additionally, a separate model indicates that HIV incidence decreased by 5% (3%–8%) for each 1% increase in the proportion of patients receiving HAART.

Prevention involves more than simply taking medication; it should also include other efforts, such as using safe injecting tools and "shooting galleries," said Montaner. TasP programs and projects such as InSite, which provides clean injection galleries, have decreased the number of new AIDS cases reported in British Columbia by more than 80% since combination ART was introduced. New HIV diagnoses fell to 238 in 2012, from almost 700 in 1996. Among IDUs, new HIV diagnoses fell from almost 400 in 1996 to 29 in 2012. The number of patients on HAART increased from less than 1000 to almost 6500, and the rate of treatment resistance decreased, in part because of improved treatment options.

HAART and HIV incidence in British Columbia. (Image courtesy of Julio Montaner)

This decline in HIV incidence has other beneficial effects, including significantly lower tuberculosis rates in the HIV-positive population and a reduction of more than 90% in all-cause mortality among people living with HIV. There are very few people with high HIV RNA levels in British Columbia, but there is still a need for treatment and prevention efforts targeted to high-risk populations. Facilitated access to testing and care is essential to fully capitalize on the promise of TasP. Montaner concluded that progress will be hindered if programs do not embrace all affected populations, including IDUs. Persistently high levels of stigma, discrimination, and criminalization must be addressed.

Violence, trafficking, and HIV transmission: a public health perspective

Michele R. Decker from Johns Hopkins Bloomberg School of Public Health discussed the intersection between human rights and public health and the important role it plays in HIV-elimination efforts. Violence against women is associated with increased rates of HIV and sexually transmitted infections, often as a result of compromised sexual negotiation, in which women are unable to refuse sex or certain kinds of sex; compromised condom negotiation; and a greater infection risk from male perpetrators, who may be engaged in high-risk sexual behavior.

A meta-analysis found that female sex workers (FSWs) have a disproportionately high HIV burden—approximately 11 times that of other women of reproductive age. While the historical focus of studies on FSWs has been on sex work as a transmission vector, there are also gender-based vulnerabilities that may promote increased risks for HIV and STI transmission.

It is important to understand physical and sexual victimization within the context of commercial sex work. Client violence, which is often related to condom and sexual negotiation, can be severe. Abuse may also be perpetrated by pimps or managers. FSWs often have limited ability to address violence because of power imbalances and a lack of attention from police authorities. These factors create a climate of disempowerment, affecting condom use, increasing FSW vulnerability, and undermining access to testing and treatment services.

Addressing sex trafficking is central to reducing HIV transmission. The United Nations Palermo Protocol defines sex trafficking as entry to commercial sex work via force, fraud, or coercion, or commercial sex work by individuals under age 18. Broadly defined, sex trafficking is forced or coerced migration within or across national borders for the purpose of sexual exploitation. Sex trafficking victims have compromised access to prevention, testing, and treatment, in part because they are isolated, dependent, and unable to travel freely. HIV prevalence among sex trafficking survivors is high: a 2007 study in Mumbai found that 22.9% were HIV-positive; a 2006 study in Nepal found that 37.2% were HIV-positive. In Mumbai, younger age was a predictor of longer brothel duration, which was in turn a predictor of HIV status. In Nepal, the HIV-infection rate was 3-times higher for girls under age 18, with an HIV prevalence of almost 60% among those 14 years old and younger.

Limited data exist on sex trafficking; it is difficult to assess its prevalence. Conditions of entry to sex work are not well described and the research base for these studies is increasingly fragmented. However, it is clear that those who enter sex work through trafficking have a high risk for HIV infection. Trafficked FSWs also have higher rates of violence perpetrated against them.

Increased relative risks for HIV risk factors among trafficked female sex workers in Thailand compared to non-trafficked female sex workers. (Image courtesy of Michele R. Decker)

Few sex workers identify as trafficked, so strategies must be inclusive to all FSWs. Categorizing victims as "worthy" or "unworthy" marginalizes the need to address violence against FSWs who have not been trafficked. Modeling studies indicate that violence-reduction initiatives among FSWs could substantially reduce the rate of new infections. This requires trauma-informed care to address risks beyond patients' control and better law enforcement to hold perpetrators accountable.

When gender and conflict collide: the role of sexual violence and other human rights violations in conflict on HIV transmission

Data on the relationship between HIV transmission and structural violence is sparse, but the issue needs attention, said Annie Sparrow from Mount Sinai Global Health. Gender-based structural violence includes, among other things, female circumcision, lack of property or citizenship rights, rape, and sex trafficking. It creates a lack of agency among victims, with negative impacts on health; for example, on the health of the bride in child marriage. In Rwanda HIV incidence is higher among younger brides. In Uganda HIV-positive women aged 13 to 19 are twice as likely to be married. This correlation between younger age and HIV status may result from a combined lack of agency and an immature genital tract. Adolescent transmission can be increased by rape, coercion, transactional sex, prostitution, date-rape, child marriage, dowry crimes, and trafficking. Many of these factors are also involved in HIV transmission among older women. All have contributed to the "feminization" of HIV, a pattern of increased incidence among women, fueled by discrimination, marginalization, stigmatization, and human rights violations. As a result, the majority of HIV-associated deaths in Africa by 2020 will be among women and girls.

Conflict can create conditions for gender-based vulnerabilities. Women are vulnerable during the conflict, while fleeing conflict, and during asylum, repatriations, and reintegration. Rape may be used as a weapon, and women can continue to be vulnerable while displaced, particularly if they are separated from family. Notably, sub-Saharan Africa has both the highest HIV rates and the most attacks on civilians. This region is not alone in one-sided violence, however. In the fight against HIV/AIDS there are two epidemics to challenge: the HIV epidemic and the gender-based violence epidemic.

Sexual violence in conflict. (Image courtesy of Annie Sparrow)


 

Panel discussion

A panel discussion moderated by Jerome H. Kim from Walter Reed Army Institute of Research looked at what needs to be done in the context of structural and behavioral violence to reach the three zeros of HIV. Two questions that need to be answered are: what violence is occurring and who is culpable? Structural violence creates instability and a climate of disempowerment, which undermines efforts to reduce HIV transmission. Alleviating barriers to care is one way to reduce structural violence.

Those most at risk for HIV, including MSM, IDUs, and commercial sex workers, are frequently victims of structural violence. Thus, HIV-prevention programs may face increased barriers to reaching these populations. Funding is often lacking for these groups, even when it is allocated to them. Furthermore, funding for many programs has shrunk in the current economic climate. In the U.S., many at-risk populations lack access to HIV care. Medicaid does not always cover medication for HIV patients and those at risk for HIV.

If a highly effective preventative vaccine is developed but is not available to at-risk populations its efficacy will be significantly diminished. The challenge is to translate new science into progress within communities. Public health approaches such as needle exchange programs may be limited by local laws and customs. It is important to work within these systems to effect change. Community involvement is critical and working with other health care aid programs outside HIV-specific care will help to increase and expand uptake.

To advance prevention initiatives, continued funding is needed. Interested parties can become funding advocates, and funding should be spent on initiatives that show the greatest benefits. Cost–benefit analyses help to focus efforts and funding to these programs.

How can scientists coordinate translational research to help reduce the spread of HIV?

Which tools and strategies offer the most cost-effective means to address HIV transmission on a global scale? How can adequate funding for these strategies be secured?

Which protein structures elicit the best broadly neutralizing antibodies against HIV without eliciting non-neutralizing antibody responses?

How can programs effect change in populations that are most at risk for HIV infection?

How should structural violence barriers be addressed among at-risk populations with a lack of agency?

How should available tools be utilized to decrease HIV transmission?