CROI 2016 Abstract eBook

Abstract Listing

Oral Abstracts

76LB A Randomized Controlled Trial of the Safety and Immunogenicity of Two Ebola Vaccines Fatorma Bolay ; for the Partnership for Research on EbolaVaccines in Liberia (PREVAIL 1)Team, Liberian Inst of BioMed Rsr–NIH Partnership, Bethesda, MD, USA Background: In November 2014, two candidate Ebola virus vaccines were in the late stages of phase 1 testing, the chimpanzee adenovirus 3 (ChZ) - based vaccine and the recombinant Vesicular Stomatitis virus (rVSVdeltaG-ZEBOV GP) - based vaccine. In order to rapidly evaluate these vaccines, a 28,170 subject randomized, placebo-controlled trial aimed at preventing Ebola virus disease (EVD) that included both vaccines was designed. As the number of new cases declined to a level that a phase 3 study was no longer feasible the study was converted to a 1,500 subject phase 2 safety and immunogenicity trial. Methods: Consenting volunteers ≥18 years were randomized to saline or one of the two experimental vaccines. Temperature > 38º C, history of EVD, pregnancy and breastfeeding were exclusions. Follow-up visits occurred at week 1, month 1, month 2 and then every 2 months thereafter through 12 months. Blood was collected for antibody measurements at baseline, week 1, month 1 and months 6 and 12. Chi-square tests were used to compare each vaccine versus the placebo group for injections site reactions, targeted symptoms, and antibody responses. Results: From February 2015 through April 2015, 1,500 volunteers were enrolled at Redemption Hospital in Monrovia, Liberia (500 per group). Median age was 30 years and 37% were women. 0.7% reported recent contact with a patient with Ebola; 4.6% reported working in a job that required contact with Ebola patients. The percentages of participants with positive serostatus for HIV and syphilis at baseline were 5.2% and 5.1%, respectively. Overall follow-up visit attendance has exceeded 98%. Differences with placebo in injection site reactions, targeted symptoms (headache, muscle pain, feverishness, fatigue) and lymphocyte counts were noted at week 1, but not month 1 for both vaccines. Antibodies, measured using the FANG ELISA assay for 50% of participants, show that 8% had an antibody response to Ebola at baseline. Excluding these individuals, an antibody response at month 1 was noted in >85% of participants in each of the vaccine arms and <10% of participants in the placebo arm (p<0.001) Conclusions: It is possible to conduct a well-designed, randomized, placebo-controlled trial in the middle of an epidemic outbreak. Both vaccines were demonstrated to be safe and immunogenic. A number of individuals without a known history of Ebola virus disease were found to have evidence of past infection with Ebola. The prevalence of HIV-1 in this cohort is higher than expected. 77LB PREVAIL II: A Randomized Controlled Trial of ZMapp™ in Acute Ebola Virus Infection Richard T. Davey ; for the Multi-National PREVAIL II StudyTeam, NIAID, Bethesda, MD, USA Background: Although there are currently no licensed treatments for Ebola virus disease (EVD), the triple monoclonal antibody cocktail ZMapp is one of the most promising immune-based approaches for treating EVD based upon non-human primate data. Given the changing patterns of morbidity and mortality for human EVD identified during the recent outbreak in West Africa, it was believed that the single most definitive means of determining the efficacy of such an intervention would be through performance of a randomized controlled trial (RCT) with a clinical endpoint. Methods: In a collaboration sponsored by the U.S. Department of Health and Human Services and involving the Ministries of Health of Sierra Leone, Guinea and Liberia, Mapp Biopharmaceuticals, Inserm, and academic medical centers in the U.S., consenting patients of any age diagnosed with EVD by polymerase chain reaction (PCR) between March- November 2015 were enrolled in the affected countries. Patients were randomized 1:1 to receive either optimized standard of care (oSOC, defined minimally as intravenous (iv) fluid resuscitation plus electrolyte monitoring) or oSOC plus three iv infusions of 50 mg/kg ZMapp spread three days apart. Patients were stratified by baseline Cycle Threshold (CT) value (≤22 vs. > 22) on PCR and by treatment site (U.S. vs. Liberia/Sierra Leone vs. Guinea [where favipiravir was part of oSOC]). The primary endpoint was mortality 28 days following randomization. An independent Data and Safety Monitoring Board (DSMB) reviewed interim results. Results: As of January 5, 2016, 72 patients were enrolled in the U.S. (n=1), Liberia (n=5), Sierra Leone (n=54), or Guinea (n=12). 30/72 (42%) and 42/72 (58%) had CT values ≤22 and >22, respectively, with an overall mean CT value of 23.9 at enrollment. The mean age of the enrolled cohort was 26.1 years: 55.6%were female. Only 6.9% had prior occupational exposure to persons with known EVD. The mean #days since symptom onset was 4.2. Overall mortality at 28 days was 21/72 (29.2%). Conclusions: In the only RCT of a putative therapeutic agent performed to date in the current crisis, 72 patients were randomized to receive either oSOC plus ZMapp versus oSOC alone over a 9 month period in the latter half of the 2014-15 EVD epidemic. Barring a resurgence of additional EVD cases and with DSMB concurrence, the study will be unblinded for safety and efficacy analyses on January 14, 2016, 42 days after the last confirmed EVD case in West Africa. 78 Progress in Gene Therapy for HIV Cure Paula M. Cannon , Univ of Southern California, Los Angeles, CA, USA A defining characteristic of the human immunodeficiency virus is its ability to permanently integrate into the genome of an infected cell. Since a subset of viruses become latent shortly after infection, a reservoir of HIV persists that is not impacted by antiretroviral therapy (ART), yet retains the ability to restart viremia should ART be discontinued. This viral trick creates a life-long requirement for ART in most individuals in order to maintain virologic control, and no cure. Latent HIV shares many of the characteristics of a genetic disease, so it was no coincidence that HIV became an early target for gene therapy. Despite the complexity of these procedures, the potential for long-lasting effects, especially if stem cells could be modified, was appealing when measured against life-long ART. Initial studies focused on the idea of protecting uninfected cells by adding anti-HIV factors, and early trials established a portfolio of anti-HIV candidates and safety, although they stopped far short of demonstrating efficacy. More recently, applications of gene therapy have been expanded to include consideration of a cure. However similar to ART, gene therapies aimed at simply protecting uninfected cells are not expected to impact the latent reservoir. Therefore approaches being considered combine transient drug treatments to ‘shock’ HIV awake with engineering HIV-specific immune cells that would deplete the infected cells so revealed. Other strategies under development are taking advantage of our deeper understanding of the biology of the host-virus interaction. Recent advances in genome editing based on targeted nucleases are allowing for the possibility of removing host dependency factors, such as the CCR5 coreceptor, or editing anti-viral restriction factors to shift the balance in favor of the host. Finally, the HIV genome itself is a tantalizing target for disruption, since nucleases can also be engineered to specifically recognize and disable this genetic parasite, if only the significant challenges of in vivo delivery could be met. Antiretroviral drugs have made extraordinary progress over the last 30 years, turning HIV into a chronic and medically managed disease, but they have reached a limit in the latent HIV reservoir. Gene, immune and cell-based therapies may yet prove to be part of the final push that is needed to achieve a cure. 79 HIV in Transgender Populations: Charted and UnchartedWaters Tonia C. Poteat , Johns Hopkins Univ, Baltimore, MD, USA A growing body of research has demonstrated the heavy and disproportionate burden of HIV among transgender populations around the world. Transgender women, in particular, face an estimated global HIV prevalence of 19%with 49 times the odds of infection compared to the general adult population. Research among transgender men is quite limited with prevalence estimates that range from 0 - 10%. Estimates of the absolute number of transgender people living with HIV are lacking; however, recent data suggest they make up a key minority of HIV-infected adults in care. This presentation will focus on what is known and not known about HIV and its drivers among transgender populations. Access to and utilization of exogenous hormone therapy and its impact on HIV risk as well as clinical implications for antiretroviral therapy will be discussed. What is known about the impact of genital reconstruction on HIV acquisition and transmission will be reviewed. We will examine the widespread use of illicit soft tissue fillers for body modification and their potential consequences for HIV disease progression. Relationships between stigma, sex work, and co-occurring syndemics of depression, victimization, substance use, and HIV will be described.

Oral Abstracts

30

CROI 2016