The Three Zeros of Eliminating HIV / AIDS

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.

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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?