CROI 2020 Abstract eBook

Abstract eBook

Oral Abstracts

to reason, therefore, that long-lived latently-infected cells may accumulate over the course of HIV infection and persist after ART is initiated. Indeed, many studies have demonstrated the persistence of latently-infected cells during ART and, it is believed that such cells carrying replication-competent proviruses, when activated, are the source of viral rebound when ART is interrupted. It was recently discovered that HIV infected T-cells can persist in vivo through cellular proliferation, which occurs both prior to and during ART. Several cases, thus far, have described highly expanded infected CD4+ T cell clones that were shown to be the source of persistent infectious viremia during ART. This talk will summarize emerging data from studies investigating HIV infected CD4+ T cell clones including their sites of HIV integration in blood and tissues both prior to and during ART, the fraction of HIV expressing cells within cell clones, including those carrying replication-competent proviruses, and explore new technologies for investigating HIV integration landscape and full-length proviral structures. Understanding the integration site landscape in cell clones that persist during ART will lead to a better understanding of the HIV reservoir, the nature of latency, and the sources of rebound viremia when ART is interrupted. SINGLE-CELL EPIGENETICS: COLORING IMMUNE CELLS WITH A RICH PALETTE OF HISTONE MARKS Alex J. Kuo , Stanford University, Stanford, CA, USA Chromatin-based epigenetic mechanisms govern diverse cellular and organismal phenotypes without DNA base alterations. Post-translational modifications of histone proteins, often referred to as histone marks, directly modulate chromatin dynamics and genome organization, adding additional complexity and plasticity to the relatively static genetic code. The harmonious orchestration of chromatin regulators is essential for hematopoiesis and immune system development, effective immune responses against foreign substances and pathogens, and immune tolerance to prevent damage to host tissues. Previously, we have leveraged highly multiplexed single-cell mass cytometry to characterize global histone modification profiles of various immune cells in the human immune system. This powerful analytic platform, which we term “Epigenetic landscape profiling using cytometry by Time- Of-Flight (EpiTOF)”, facilitates the discovery of histone marks preferentially enriched in selected immune cells. We identify immune cell subtype- and hematopoietic lineage-specific epigenetic patterns, which predict immune cell identity. Differential analysis between younger and older adults reveals increased epigenetic variation between individuals, and elevated cell-to-cell epigenetic variability between single cells with age. Analysis of a twin cohort further shows that these aging-related epigenetic alterations are driven predominantly by non-heritable influences. Recently, we have demonstrated how EpiTOF can be integrated with genomic methods to investigate chromatin dynamics (i.e. ChIP-seq, ATAC-seq), and combined with transcriptomic and functional analyses to gain a comprehensive understanding of how the immune system is regulated by chromatin-based mechanisms. Using this “systems epigenetics” approach, we have extensively characterized the biological significance of a histone mark involving histone H3 proteolytic cleavage in monocyte-to-macrophage differentiation. Our findings have marked implications for cellular fate determination, trained immunity, and human diseases with prominent monocyte and/or macrophage involvements. Together, EpiTOF provides a unique opportunity to interrogate epigenetic regulation of the immune system. We propose that a systems epigenetics approach will i) reveal how acute and chronic viral infection alters the host chromatin landscape; ii) uncover chromatin-based mechanisms by which host immune cells develop an effective defense against viruses, and iii) provide insights into the variability of anti-viral response between single cells and between individuals. PUTTING ANALYSIS INTO ANALYTICAL TREATMENT INTERRUPTIONS Lu (Summer) Zheng , Harvard T.H. Chan School of Public Health, Boston, MA, USA Analytic treatment interruption (ATI) is an essential component for HIV clinical trials assessing efficacy of interventions aimed at achieving HIV remission or virological control in the absence of antiretroviral or other treatments. With recent experiences of evaluating a variety of novel therapeutic interventions, including latency-reversing agents, therapeutic vaccines, and broadly neutralizing antibodies utilizing ATI, the design of treatment interruption studies has evolved towards shorter durations with more frequent monitoring and time to viral rebound as primary outcome measure. This talk will review and discuss the current practices of ATI studies on analytical approaches, design features related to the mechanism of action of the agents being

evaluated, including the selection of study outcomes, ART re-initiation criteria, using historical controls vs. placebo-controlled design, as well as ethical considerations. ADVANCING FROM PHASE II TO PHASE III: NAVIGATING THE LAND OF EXPECTATIONS Patrick Phillips , University of California San Francisco, San Francisco, CA, USA Mycobacteria tuberculosis kills more people every year than any other single pathogen, yet the first-line treatment regimen used globally has remained largely unchanged for 40 years. Shorter, safer, and more effective regimens are urgently needed to halt the epidemic. Clinical trials for new drugs to treat HIV depend on changes in HIV viral load as an established marker of infection and treatment response. In contrast, while several new TB drugs are in clinical development, the absence of a reliable surrogate endpoint hampers decisions about whether and when a new TB regimen is ready for confirmatory phase III evaluation. Further challenges include the necessity of determining the optimal combination and duration of therapy during phase II development alongside the limited funding for TB drug development and the allure of accelerated approval. In this workshop, I will talk about the burden of expectations and the latest developments in designing phase II trials to identify the best regimens to advance to phase III. I will talk about platform and other adaptive treatment- selection trial designs, the novel phase IIC design, designs to identify the optimal duration of therapy and the role of an internal control. I will also touch on challenges in TB prevention trials in the absence of a true marker of infection. In general, active-controlled noninferiority (NI) trials are considered when superiority trials, to an active control or placebo, are not possible due to ethical or other considerations. NI trials share some of the same biases as historically controlled trials because they rely on information external to the clinical trial. Food and Drug Administration (FDA) guidance states that NI designs are credible and appropriate only in situations in which the active control has shown a consistent effect (generally compared to placebo) in prior superiority trials conducted in a patient population similar to the population in the clinical investigation being planned. This is called the constancy assumption and allows for assay sensitivity in an NI trial. NI is met if the new intervention is 'not unacceptably worse' than the active control by a specified amount, the NI margin. The NI margin should be no larger than the effect the active control had in previous trials. Unless a placebo group is also included, NI trials depend on the assumption that the active control had its expected effect in the trial. From a regulatory perspective knowing the active control had its expected effect is necessary to ensure that a trial that concludes NI has identified a treatment that is superior to placebo. HIV treatment trials have successfully used NI trials for antiretroviral (ARV) drug development for many years; however, quantifying the treatment effect of each component of an ARV regimen has been challenging as drug regimens evolve, which can have consequences when designing an NI trial. HIV prevention research also illustrates the limitations of NI trial designs. Although collective data show that emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) can be highly efficacious at preventing HIV infection when taken as prescribed in uninfected individuals, the prophylactic effect has been highly variable over time and by population. Two trials that included FTC/TDF arms in cisgender women in Africa showed a lack of pre-exposure prophylaxis (PrEP) efficacy due to poor adherence. The lack of a consistent PrEP effect across trials in all populations invalidates a constancy assumption of FTC/TDF as an active control in an NI trial for some populations. Other types of trial designs using external controls might be more credible and appropriate than NI trials and are currently being explored. NONINFERIORITY COMPLEX Jeffrey Murray , FDA, Silver Spring, MD, USA The unprecedented nature of AIDS as a syndrome and a pandemic created unprecedented demands on clinical trials investigators and networks to creatively and meaningfully address the syndromic nature of AIDS, the complex etiology and pathogenesis of HIV infection, its associated opportunistic infections, coinfections, and malignant, end-organ, and neurologic sequelae, in diverse affected populations including men who have sex with men, drug users, sex workers, young people, infants, children, adolescents, pregnant women, and people grappling with multiple syndemics (opioids, viral hepatitis, sexually INCLUSION OF DIVERSE POPULATIONS IN TRIALS Mark Harrington , Treatment Action Group, New York, NY, USA

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CROI 2020