CROI 2017 Abstract e-Book

Abstract eBook

Oral Abstracts

143 IMMUNOGEN DESIGN TO INDUCE HIV NEUTRALIZING ANTIBODIES William R. Schief, Scripps Rsr Inst, La Jolla, CA, USA Abstract is available in the CROI mobile App. 144 STRUCTURAL STUDIES OF HIV NEUTRALIZING ANTIBODIES Andrew B. Ward, Scripps Rsr Inst, La Jolla, CA, USA

The HIV envelope glycoprotein (Env) trimer on the surface of the virus is the sole target of broadly neutralizing antibodies. Soluble, native-like Env trimers, particularly those of the SOSIP design, have recently been developed and enabled high-resolution structural studies as well as opportunities for protein subunit vaccination with bona fide trimers. A number of labs have ongoing or completed animal immunization studies using these trimers, and there is a planned human clinical trial. The SOSIP trimers typically induce strong autologous neutralizing antibody responses and monoclonal antibodies have been isolated. Here we will describe the structures of these monoclonal neutralizing antibodies in complex with SOSIP Env trimers in an effort to describe the spectrum of responses elicited by the large antigenic surface on the Env trimer. While some responses mirror those found in natural infection, some responses appear unique to the soluble Env trimer. This catalogue of responses serves as a basis for further immunogen design and as a comparator for the upcoming human clinical trial. 145 CLINICAL STUDIES WITH BROADLY NEUTRALIZING ANTIBODIES Michel Nussenzweig, Rockefeller Univ, New York, NY, USA Clinical Studies with Broadly Neutralizing Antibodies Michel C. Nussenzweig AIDS is a preventable disease. Nevertheless, according to UNAIDS, 2.1 million of individuals were infected with HIV-1 in 2015 worldwide. An effective vaccine is highly desirable. Most vaccines in clinical use today prevent infection because they elicit antibodies that block pathogen entry. Consistent with this general rule, studies in experimental animals have shown that broadly neutralizing antibodies to HIV-1 can prevent infection, suggesting that a vaccine that elicits such antibodies would be protective. However, despite significant efforts over the last 30 years, attempts to elicit broadly HIV-1 neutralizing antibodies by vaccination failed until recent experiments in genetically engineered mice were finally successful. Nevertheless, a small fraction of HIV-1-infected individuals develop antibodies that effectively neutralize the majority of existing HIV-1 isolates. Single cell antibody cloning methods revealed that this serum neutralizing activity is due to one or a combination of monoclonal antibodies that target different non-overlapping epitopes on the HIV-1 envelope spike. When passively transferred, many of these newly discovered antibodies protect against infection in humanized mice and macaques, even when present at very low concentrations. In addition, combinations of antibodies targeting non-overlapping epitopes can control active infection in humanized mice and macaques. Finally, when they are administered together with agents that induce viral transcription to activate latently infected cells, antibodies decrease the incidence of viral rebound from the latent reservoir in HIV-1-infected humanized mice. These preclinical findings have been extended to humans in phase 1 clinical trials of 2 antibodies that target non-overlapping epitopes 3BNC117 and 10-1074. The results of those trials will be discussed. 146 HIV-1 DRUG RESISTANCE IN RESOURCE-LIMITED SETTINGS Ravindra K. Gupta, Univ College London, London, UK Introduction: The global scale up of cART has now reached 17 million treated individuals, largely in LMICs. Antiretroviral therapy (ART) is pivotal for controlling HIV-1 infection through widescale treatment as prevention (TasP) and pre-exposure prophylaxis (PreP). Pre treatment drug resistance to NNRTI is associated with a 2-3 fold higher viral failure rate in both high and low income settings, and the clinical consequences can be severe where viral load monitoring is not available. Highly potent tenofovir containing regimens are increasingly being used to treat and prevent HIV. Data from clinical trials and cohorts in high-income settings using tenofovir combined with NNRTI have reported low prevalence of tenofovir resistance at viral failure, in stark contrast to LMICs where prevalence of K65R and NNRTI resistance is much higher following viral failure of first line, thought to be due to sub-optimal monitoring. Furthermore, viruses with K65R are fit in vivo, in contrast to observations in model systems. There is also emerging evidence from LMIC that drug resistance is higher in individuals who have been pre-treated, often with thymidine analogue based regimens. The result of this emergence of HIV DR is transmission to untreated individuals that has been increasing globally since ART scale up. Conclusions: Drug resistance emerges in a high proportion of patients following virological failure across LMIC regions and has led to rising transmitted drug resistance worldwide. Effective surveillance for transmission of drug resistance is critical. Effective point-of-care viral load monitoring and point-of-care resistance tests could mitigate emergence and spread of MDR strains that threaten control efforts. 147 LONG-ACTING ANTIRETROVIRAL THERAPY: A SHOT IN THE DARK OR A PARADIGM SHIFT? Charles W. Flexner, The Johns Hopkins Univ, Baltimore, MD, USA Long-acting and extended-release (LA/ER) formulations of antiretroviral drugs have the potential to revolutionize treatment and prevention. Formulations in current development run the gamut from oral products capable of delivering effective systemic anti-HIV drug concentrations for 7-14 days after a single dose, to implants capable of providing effective treatment for as long as 6, and possibly 12 or more months. These approaches are ideal for patients having difficulty with adherence, suffering from pill fatigue, or living in areas where the stigma of taking daily HIV pills is a concern. Other important applications include use in patients who cannot or will not take daily oral medication, including infants, children, and adolescents. Recent survey research suggests widespread popularity of switching to parenteral LA/ER treatment amongst those already taking daily oral combination ART. Two injectable LA formulations -- of rilpivirine and cabotegravir -- are in Phase 3 clinical testing, and several others have entered clinical development. Other candidates for LA/ER delivery include biologics and broadly neutralizing monoclonal antibodies. New approaches to developing a broader array of possible LA/ER products include prodrug approaches to modify existing ARV’s in order to make themmore amenable to nanoformulation. Physiologically-based pharmacokinetic (PBPK) modeling can be used to prioritize candidate formulations for further preclinical and clinical development, based on a better understanding of the fundamental principles governing drug release from an intramuscular depot or subcutaneous implant. Class-wide problems associated with LA/ER approaches include concerns about drug resistance, missed doses, coverage of the long tail of drug concentrations when treatment is stopped or switched, and what to do about drug interactions, pregnancy, and irreversible or long-lived side effects. Although the many drawbacks of LA/ER formulations will need to be addressed during clinical development, there is little doubt that these approaches to drug delivery are going to have a meaningful impact on the treatment and prevention of HIV and other infectious diseases. 148 SIMPLE ART: MORE COMPLEX THAN THOUGHT Jose R. Arribas, Hosp La Paz, Madrid, Spain Do we need to use the same type of ART regimens in an HIV-infected patient with a viral load of 550,000 HIV RNA copies/mL and a CD4 cell count of 75 cells/µL than in a patient who has been virologically suppressed for 7 years and has a current CD4 cell count of 750 cells/µL? Can we “simplify” the ART regimen in virologically suppressed patients? These questions have been a matter of research and controversy during the last two decades. Since at the present moment HIV infection needs to be treated for the entire life of the patient there is a strong motivation to use ART regimens that are as simple, efficacious and safe as possible. Numerous clinical trials have evaluated ART simplification in virologically suppressed patients. In many occasions, the new “simple” regimens have been very different from the regimens used in antiretroviral naïve patients with active viral replication. There have been multiple attempts to use regimens with less than three antiretroviral drugs: monotherapy with boosted protease inhibitors, dual therapy completely sparing nucleoside reverse transcriptase inhibitors (NRTIs), dual therapy sparing just one NRTI and dual therapy sparing both NRTIs and boosted protease inhibitors. In many occasions, results of these trials have produced unexpectedly disappointing results. For example, it is still unclear why potent ART regimens combining a boosted protease inhibitor and an integrase inhibitor have underperformed compared to triple therapy regimens that include two NRTIs. Even if the new simple regimen includes three antiretroviral drugs

Oral Abstracts

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CROI 2017