CROI 2020 Abstract eBook

Abstract eBook

Oral Abstracts

T-cells, and other subsets, and review lead candidates for scalable delivery of these therapies, namely in resource-limited settings. First and foremost, any curative intervention must be at least as safe and feasible as lifelong ART. A careful examination of the fundamental aspects of cure in HIV-infected stem cell transplantation patients lays out a compelling road map towards a gene therapy-based strategy, focused on enhancing virus-specific immunity. One such strategy involves adoptively transferred T-cells, for example cells modified to express chimeric antigen receptors (CARs). CAR T-cells have enabled long- term remission in cancer and have recently shown similar promise for HIV-1. However, since the maximum time frame during which latently infected cells may reappear following ART interruption is unknown, curative interventions must assume the need for lifelong protection. Although T-cell immunotherapies currently display a superior safety profile, HSPC-derived therapies may offer persistent antiviral functions capable of recognizing recrudescent virus that appears months or years after removal of suppressive therapy. Finally, scalability is an essential facet for any cell and gene therapy approach and must be developed in parallel with “proof of principle” strategies that are frequently only applicable in developed nations. By investing heavily in viral vectors, nanoparticles, and other so-called in vivo delivery platforms that are portable, affordable, and can be administered without the need for costly biomedical infrastructure, we may yet achieve the high bar of permanent HIV remission in the absence of suppressive therapy. eCD4-Ig is an exceptionally broad HIV-1 entry inhibitor that uniquely neutralizes all of the 270 HIV-1, HIV-2 and SIV isolates it has been tested against, in every case with IC80 values < 10 µg/ml. eCD4-Ig’s breadth and potency derives from the fact that it closely and simultaneously mimics the HIV-1 receptor CD4 and the HIV-1 coreceptor. Consistent with this breadth, eCD4-Ig is much harder to escape than broadly neutralizing antibodies (bNAbs). To date full escape has not been observed either in cell culture or rhesus macaques and viruses which partially escape eCD4-Ig in both cases pay clear fitness costs. Adeno-associated virus (AAV)-expressed eCD4-Ig functions as an effective vaccine alternative, and protects rhesus macaques from repeated high-dose viral challenges with both SHIV-AD8 and SIVmac239. Unlike bNAbs and other multispecific antibody- like inhibitors, eCD4-Ig markedly improves the endogenous ADCC activity of patient sera. It does so by altering the conformation of HIV-1 Env, allowing otherwise dormant V3 and CD4i antibodies to bind Env. To determine whether eCD4-Ig could suppress an established infection, six SHIV-AD8-infected rhesus macaques were placed on combined anti-retroviral therapy (ART) 12 weeks after infection and inoculated with AAV-eCD4-Ig 42 to 50 weeks post-infection. ART was subsequently lifted and viral loads and eCD4-Ig concentrations where monitored for now two years. We observed that relatively low concentrations of AAV-expressed eCD4-Ig (3-19 µg/ml) prevent viral rebound of an established SHIV-AD8 infection after ART cessation all six macaques, albeit with sporadic viral ‘blips observed in most animals. Macaques “functionally cured” in this manner could provide an ideal platform to monitor the impact of latency- reversing agents on the reservoir of latently infected cells, and to determine if an entry inhibitor with potent ADCC activity can itself change the rate of reservoir decay. Stable HIV-1 remissions may also be appealing and useful to humans, for example limiting transmission from individuals who cannot or will not use conventional ART, enabling long-term drug holidays, and providing a backstop for an imperfect sterilizing cure. Efforts to increase the robustness and consistency of these functional cures will be described. WHO estimates 660,000 cases of mother-to-child transmission of syphilis (congenital syphilis) occurred in 2016, resulting in 350,000 adverse birth outcomes inclusive of over 200,000 stillbirths and neonatal deaths. By comparison, UNAIDS estimates approximately 180,000 new cases of HIV occurred in 2016 among children ages 0-14 years. Although over 90% of countries include screening of pregnant women for syphilis in national antenatal care guidance, efforts to ensure high screening coverage have seen limited improvement, resulting in static estimates of congenital syphilis in the setting of stable or increasing syphilis prevalence among general and high-risk populations of adults. In 2016, WHO estimated 66% coverage of syphilis

screening among pregnant women with an estimated global syphilis prevalence in this group of 0.69% (0.70% in 2012). In 2014, WHO launched the initiative “Elimination of Mother-to-Child Transmission of HIV and syphilis” (EMTCT). While 14 countries have been validated by WHO for this achievement, high burden countries in several regions are challenged to achieve the WHO EMTCT criteria of 95% coverage of antenatal care, syphilis testing and treatment of infected pregnant women with benzathine penicillin. Limited national prioritization and stakeholder engagement have resulted in lower coverage of syphilis screening as compared to HIV screening in pregnant women. Recent global shortages of benzathine penicillin have challenged treatment coverage as this medication is currently the only WHO-recommended treatment for pregnant women with syphilis. Newer technologies including rapid syphilis tests and rapid dual HIV/syphilis tests have offered the opportunity for same-visit testing and treatment of syphilis. The rapid dual HIV/syphilis test offers numerous advantages to separate tests and can be purchased at a similar price to that of a single HIV test. Implementation of the rapid dual HIV/syphilis tests can result in the immediate equalization of syphilis screening coverage to that of HIV among pregnant women. Studies to evaluate alternative treatment regimens for syphilis that could be appropriate for use in pregnant women are underway. 55 CHLAMYDIA AND GONORRHOEA IN PREGNANCY: SILENCE OF THE GERMS Nicola Low , University of Bern, Bern, Switzerland Sex causes pregnancy, HIV infection and bacterial sexually transmitted infections (STI). Every year, women aged 15-49 years will experience about 63.8 million new infections caused by Chlamydia trachomatis (chlamydia) and 37.1 million caused by Neisseria gonorrhoeae (gonorrhoea). These estimated incidence rates are highest in southern sub-Saharan Africa and Oceania regions and in women under 25 years. About 2.2 million women aged 15-24 years are living with HIV infection and they are at higher risk of chlamydia and gonorrhoea than HIV-uninfected women. Most of these infections are clinically silent and undiagnosed. The high prevalence of STI in pregnant women in some countries could pose risks to the fetus and newborn. Among pregnant women in South Africa, Botswana, Brazil, and Papua New Guinea, chlamydia prevalence of 10-20% has been observed, with gonorrhoea prevalence of 5-10% in South Africa and Papua New Guinea and 1-2% in Botswana and Brazil. Chlamydia and gonorrhoea, when transmitted during labour, can cause neonatal conjunctivitis and chlamydia can cause neonatal pneumonia. During pregnancy, chlamydia and gonorrhoea have also been associated with other adverse outcomes, including preterm birth, premature rupture of membranes, low birth weight and perinatal death. These associations are not consistent, however; they are subject to confounding and biases in selection and measurement. Chlamydia and gonorrhoea in pregnancy do not seem to increase the risk of HIV mother-to- child transmission. Further research is needed to understand the causal role of chlamydia and gonorrhoea at different stages of pregnancy, and to understand biological mechanisms and the role of other co-infections and interactions with the vaginal microbiota. To prevent adverse pregnancy outcomes, robust evaluation of interventions is needed. In a cluster-randomised trial in Rakai, Uganda, presumptive antimicrobial treatment versus syndromic management reduced infection prevalence and several adverse outcomes, but resulted in overtreatment. There are no completed randomised trials of antenatal screening for C. trachomatis and/or N. gonorrhoeae globally. Near-patient molecular diagnostics will make screening in low- and middle-income settings more feasible. A cluster crossover trial in Papua New Guinea comparing near-patient screening with syndromic management will end in December 2020 and planned trials in China, Ethiopia, and South Africa will add to the evidence base. 56 MOTHER-TO-CHILD TRANSMISSION OF HEPATITIS B: CAN IT BE ELIMINATED? Yusuke Shimakawa , Institut Pasteur, Paris, France Viral hepatitis, the 7th leading cause of death worldwide, is now integrated into the United Nations Sustainable Development Goals. Consequently, the WHO developed a global strategy to eliminate viral hepatitis as a public health threat by 2030, aiming to reduce the incidence of chronic infection with hepatitis B virus (HBV) by 90% and its mortality by 65%. To achieve these elimination goals, it is essential to prevent perinatal mother-to-child transmission (MTCT) of HBV. Compared to horizontal transmission, MTCT is associated with an increased risk of developing chronic HBV infection, and also with an elevated risk of liver disease progression in those who became a chronic carrier. Moreover, a

Oral Abstracts

53 TOWARD DURABLE CONTROL OF HIV-1 WITH eCD4-Ig Michael Farzan , The Scripps Research Institute, La Jolla, CA, USA

54 SYPHILIS CAUSES STILLBIRTH: PENICILLIN IS PREVENTION Melanie Taylor , WHO, Geneva, Switzerland

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CROI 2020