CROI 2018 Abstract eBook

Abstract eBook

Oral Abstracts

challenge to national health programs and donors. Eliminating all cells capable of producing HIV seems a near unattainable goal with current therapies and a more achievable goal may be HIV remission, i.e. the ability to control HIV after ART interruption to levels below detection. Individuals treated since acute HIV infection (AHI) achieve significantly smaller HIV reservoirs, preserved immune function and little viral escape and are therefore targeted for early intervention therapy studies in humans. Interventions to date include latency reversing agents, harnessing antibodies to induce HIV remission, enhancing CTL-mediated killing of infected cells, and gene editing. The SEARCH 010/RV254 study is a cohort of over 500 individuals, predominantly Thai MSM, treated with ART since the earliest stages of HIV infection (Fiebig I-IV). In this cohort, proof of concept studies with these very interventions, with the exception of gene editing, are taking place, followed by analytic treatment interruption (ATI). Thus far, these single intervention HIV remission studies have demonstrated viral load rebound from 9 days to 10 months after ATI, while ATI appeared safe. This presentation will review the results of these single HIV remission studies as representative of findings of the field to date, including effects of early ART, additional therapeutic interventions, and ATI on endpoints, including timing and magnitude of viral load rebound, and HIV reservoir size. Immune mechanisms associated with these dynamics, such as effector CD8+ T cells contributing to lower viral loads after ATI, will also be described, as will safety parameters associated with ATI including assessment for acute retroviral syndrome, de novo resistance mutations, and virological failure. Given the risks and uncertainties associated with these early stage trials, compounded by the complex concepts of cure and remission, it is critical that community participation and social science studies continue to inform the conduct of these trials. Andrew Prendergast , Queen Mary University of London, London, UK The infant gut undergoes major adaptation in response to genetic and environmental signals soon after birth and throughout infancy. Ontogeny of the intestinal epithelium, microbiota and mucosal immune system occur in tandem, are highly interdependent and are critical for healthy infant growth and development. Mothers and infants have a dynamic relationship during breastfeeding. It is becoming apparent that bi-directional signals between the mother-infant pair ensure that the infant’s nutritional needs are met, while shaping development of the infant gut, microbiota and immune system. Exclusive breastfeeding improves child survival and reduces HIV breast milk transmission, but the mechanisms underlying these benefits remain poorly understood. In developing countries, a spectrum of enteropathies leads to altered gut structure and function, and this may impact infant growth, development and risk of breast milk viral transmission. This talk will provide an overview of our current understanding of healthy gut development, discuss the adaptive changes that occur in response to breastfeeding and environmental exposures, and highlight the delicate balance between protection and vulnerability to breast milk transmission of HIV and other viruses conferred by the infant gut. Human T-cell Lymphotropic Virus type 1 (HTLV-1) is a human retrovirus that infects at least 5-10 million people worldwide mainly in highly endemic areas such as southern Japan, West/Central Africa, the Caribbean region, and parts of South America and Australo-Melanesia. HTLV-1 infection is mostly associated with two distinct types of diseases: a lymphoproliferation, the Adult T-cell Leukemia/Lymphoma (ATLL), and an inflammatory neurological disease, the tropical spastic paraparesis or HTLV-1 associated myelopathy (TSP/HAM). ATLL is one of the worst cancers with a median of survival of less than one year in the leukemic and lymphoma types. The virus preferentially infects CD4+ T cells, but CD8+ cells may also play an important role as reservoir in the host. Different modes of transmission have been identified for HTLV-1: 1/ sexual contact (mainly frommen to women); 2/ transfusion of contaminated blood; and 3/ frommother-to-child (MTCT) during prolonged breast-feeding. In each case, such a transmission involves the transfer of HTLV-1 infected body fluid cells (semen, blood, milk, respectively). In the case of MTCT, different studies indicate that infection during childhood is a major risk factor for the development of ATLL. Based on epidemiological, virological and experimental data, it is now clear that the rate of HTLV-1 MTCT increases with: 1) the duration of breast-feeding, 2) the HTLV-1 proviral load in blood and milk of the infected

mother and 3) the HTLV-1 antibody titers level in blood of the mother. However, the mechanisms of such a transmission remain largely unknown. For instance, the nature of the infected cells present in the milk, the anatomical sites of viral entry through the mucosa, the first cellular targets of infection, the role of anti- HTLV-1 antibodies present in breast milk, the role of other milk factors that may influence MTCT, as well as genetic bases of susceptibility for viral infection in children have not yet been completely addressed. As there is neither vaccination against HTLV-1 infection, nor therapeutic regimen to prevent HTLV-1 MTCT, the only way to act on such retroviral transmission should be to try refrain HTLV-1 seropositive mothers from breast-feeding. Such action, which is currently ongoing in several high endemic areas have been very successful, resulting in a huge reduction of HTLV-1 MTCT in some areas of Southern Japan and some Caribbean regions. Ameena Goga , South African Medical Research Council, Cape Town, South Africa Breastfeeding is a critical child survival strategy. Its importance for child health and survival beyond HIV has stood the test of rigorous research, even in high HIV prevalence settings. However, infants can acquire HIV infection through infected breastmilk. Following the implementation of Option B+ (lifelong triple antiretroviral therapy (ART) for pregnant and lactating women) to prevent mother to child HIV transmission, multiparous mothers are likely to conceive on ART, pregnant women are likely to initiate ART earlier in pregnancy and breastfeeding mothers should initiate ART during lactation. This earlier and increased antiretroviral use provides a platform for maternal HIV viral load suppression and for eliminating mother to child HIV transmission as a public health problem (MTCT). Eliminating MTCT is defined as less than five percent MTCT and ≤50 new paediatric HIV infections per 100 000 live births. This talk will synthesize current data and field-based experiences on the epidemiology, timing, virology and risk of breast milk HIV transmission including risks for mothers on ART, the role of post-exposure infant prophylaxis, the interplay between breastmilk intake and viral load suppression and dilemmas for resource poor settings, to answer the question: Can we eliminate breastmilk transmission of HIV? Data from Africa, where infectious diseases are the main contributors to infant and under-five morbidity and mortality, and breastfeeding is a key child survival strategy, suggest that maternal ART adherence is sub-optimal, fewmothers receive regular viral load monitoring and where viral suppression is known, 16-78% of people living with HIV are virally suppressed. This questions the feasibility of eliminating breastmilk MTCT in real-life resource-limited settings. Additionally, the percent MTCT yielded by different clinical trials of mothers on ART, ranges from 1.1% at 6 months to 0.6% at 12 months, and 1.4% at 18 months. Using clinic/facility-level data, MTCT percentages of 3.5% at 6-12 weeks, 4.1% at 18 months and 3.2% at 24 months have been described. With 4.1%MTCT, the EMTCT target will only be achieved if maternal HIV prevalence is <0.12%. This massive decline in maternal HIV prevalence is unlikely; thus combination strategies of maternal ART with support for ART adherence and maternal and / or infant passive or active vaccination may be the next holy grail. An estimated 1.5 million HIV-positive women become pregnant each year, 90% of whom live in regions where breastfeeding is WHO-recommended infant feeding option. Changes to WHO and national policies in recent years mean that an increasing number of infants are exposed to ART throughout pregnancy and breastfeeding. The clear benefit to the infant is the huge reduction in risk of HIV acquisition, from around 40% in the pre-ART era, through to less than 1% in clinical trials, even among breastfeeding populations. Less clear are the potential risks to the infant of long-term low dose ART exposure through breast milk. Potential risks include the development of HIV-drug resistance in the infant should HIV infection occur, and toxicities due to drug exposure. This talk will summarise the existing pharmacokinetic data regarding ART transfer into breast milk and to the breastfed HIV-negative infant, will summarise existing data regarding potential risk of HIV-drug resistance in the infant should transmission occur and will review available data regarding drug toxicity in the infant. Finally, current and future priorities for research and monitoring will be presented.

Oral Abstracts

54 CAN WE ELIMINATE BREASTMILK TRANSMISSION OF HIV?

52 THE INFANT GUT: A GREAT DEFENSE SYSTEM?

53 MOTHER-TO-CHILD TRANSMISSION OF HTLV-1 Antoine Gessain , Institut Pasteur, Paris, France

55 ART IN BREASTMILK: DEFINING THE RISK-BENEFIT RATIO Catriona Waitt , University of Liverpool, Liverpool, UK

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CROI 2018