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Ebola Virus Disease and Clinical Care Part III: Experimental Treatments and Vaccine

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Ebola Virus Disease and Clinical Care Part III: Experimental Treatments and Vaccine Ebola Virus Disease and Clinical Care Part III: Experimental Treatments and Vaccine This lecture is part three of the Ebola Virus Disease and Clinical Care lectures. Preparing Healthcare Workers to Work in Ebola Treatment Units (ETU) in Africa This brief lecture will review current standards of care and Ebola Virus Disease and Clinical Care provide basic information on experimental treatments and Part III: Experimental Treatments and vaccines. Some of these have already been used to treat or Vaccines prevent Ebola virus disease (EVD), while others are in the pipeline. At this time, none of these are approved by the U.S. This presentation is current as of December, 2014. This presentation contains materials from Centers for Disease Control and Food and Drug Administration (FDA), and none have had more Prevention (CDC), Médecins Sans Frontières (MSF), and World Health Organization (WHO). than very early and limited testing in humans. Developments U.S.U.S. Department Department of ofHealth Health and and Human Human Services Services CentersCenters for for Disease Disease Control Control and and Prevention Prevention in the field are moving rapidly. If you have questions about the version 12.03.2014 use of such treatments or vaccines for exposed or ill healthcare workers, your sponsoring organization can provide information regarding their policies and procedures. NOTE: Information in this presentation will change regularly. Current and updated information can be found at: www.clinicaltrials.gov The learning objectives for this lecture are to: Learning Objectives Recognize supportive care is a cornerstone of ▶ Recognize supportive care is a cornerstone of clinical clinical management for patients with Ebola Understand the types of supportive care used in management for patients with Ebola caring for patients with Ebola ▶ Understand the role of current investigational Understand the types of supportive care used in caring for therapies and vaccines for the treatment of, or patients with Ebola prophylaxis against, Ebola virus disease (EVD) ▶ Understand the role of current investigational therapies and vaccines for the treatment of, or prophylaxis against, Ebola virus disease This presentation contains materials from CDC, MSF, and WHO 2 113 Course Lectures and Scripts > Ebola Virus Disease and Clinical Care Part III Clinical Management of EVD As has been presented earlier in this course, a cornerstone Supportive, but Aggressive of Ebola management is supportive care. However, this care Hypovolemia +/- sepsis physiology . Aggressive IV fluid resuscitation should be aggressive. Ringer’s lactate is preferred solution . Médecins Sans Frontières (MSF) advocates oral rehydration salts solution (ORS) Patients will often have hypovolemia due to substantial Electrolyte abnormalities (from GI losses) . Oral rehydration salts gastrointestinal fluid losses, and later may develop capillary . Ringer’s lactate preferred . + ++ - Normal saline with K , Mg , glucose, HCO3 leak, and exhibit a sepsis-like physiology. They might respond Symptomatic management of fever, nausea, vomiting, diarrhea, seizures, myalgia, abdominal pain well to aggressive IV fluid resuscitation. However, caution Consider empirical therapy should be exercised so that aggressive fluid resuscitation does . Antibiotics for possible bacterial infections . Antimalarials not result in pulmonary edema. Because intravenous catheter This presentation contains materials from CDC, MSF, and WHO 3 placement and maintenance entails risk to the healthcare worker, some ETUs, at times when high patient census or low staffing levels make use of IV fluids riskier, prefer to use oral rehydration solution (ORS). If your ETU uses IV fluid resuscitation, the intravenous catheter should be placed as soon as need for intravenous hydration has been identified. Catching up with fluid is difficult. IV catheter placement may require additional clinical staff to assist the patient and minimize risks. Fluid requirements by mouth are an excellent alternative. But patients can often be too weak or nauseated to take in enough fluid. It should be assumed electrolytes are being lost even in the absence of lab testing. Therefore, electrolyte abnormalities from vomiting and diarrheal losses should be replaced. Options include: ▶ Oral rehydration solution ▶ Intravenous fluid, with Ringer’s lactate. This is a preferred IV solution because of the presence of potassium and lactate ▶ Normal saline can be supplemented with Potassium (K+), Magnesium (Mg++), glucose, or Bicarbonate (HCO3-) Healthcare workers should provide symptomatic management of fever, nausea, vomiting, diarrhea, seizures, myalgia, or abdominal pain. Most ETUs provide empirical therapy for other infections that can complicate EVD, including broad spectrum antibiotics for possible bacterial infections and antimalarials. 114 Course Lectures and Scripts > Ebola Virus Disease and Clinical Care Part III There are currently no approved Ebola-specific prophylaxis or Investigational Therapies treatments that have proven to be effective. No approved Ebola virus-specific prophylaxis or treatment Some non-human primate data have been used to identify . Some non-human primate (NHP) data . Limited human clinical trial data (Phase I trials ongoing) potentially effective Ebola treatments, but data are limited, and • Therapeutic medications o Convalescent plasma and whole blood human clinical trial data are extremely limited. However, Phase o ZMapp—monoclonal antibody cocktail (Mapp Bio) o TKM-Ebola—small interfering RNA therapeutic (Tekmira) I trials are ongoing. o Brincidofovir – nucleotide analog (Chimerix) o Favipiravir – RNA-dependent RNA polymerase inhibitor (Toyama) . Vaccines On this slide you can see listed a few of the investigational . Limited availability of these study products therapies or vaccines you might hear about. We go into more detail on several of these in subsequent slides. Therapeutic This presentation contains materials from CDC, MSF, and WHO 4 interventions that have been tried during the current Ebola epidemic include: ▶ Convalescent plasma and whole blood ▶ ZMapp, a monoclonal antibody cocktail by Mapp Bio ▶ TKM-Ebola, a small interfering RNA therapeutic by Tekmira ▶ Brincidofovir – a nucleotide analog (Chimerix) ▶ Favipiravir – an RNA-dependent RNA polymerase inhibitor (Toyama) Several candidate Ebola vaccines are in the early stages of development and show some promise. At this time, availability of these study products is very limited and they are only used under an investigational protocol. 115 Course Lectures and Scripts > Ebola Virus Disease and Clinical Care Part III Investigational Therapies Convalescent blood products have been used to treat severe Convalescent blood products viral diseases, including EVD. Ebola survivors may have high . Variable in vivo data in NHP1 titers of antibodies against the virus that might provide some . Seven of eight patients who received convalescent plasma survived in one outbreak in 19952 protection for persons currently infected. The World Health • Unable to assess efficacy (not formally studied) Organization (WHO) indicated this approach was reasonable . Risks to try in the absence of any other specific therapy, and such • Transmission of bloodborne pathogens • Transfusion-related Acute Lung Injury (TRALI) • Possible Ab-dependent enhancement of Ebola pathogenesis blood products could be collected and made available in affected countries. However, in vivo data on effectiveness of . Clinical trials of convalescent plasma treatment currently being conducted in Africa convalescent plasma in non-human primates (NHP) have 1Jarhling, P et al. JID 2007 S400 2 Mupapa, K et al. JID 1999 S18 been inconsistent. In humans, seven of eight patients who This presentation contains materials from CDC, MSF, and WHO 5 received convalescent plasma survived in one outbreak in 1995. However, because the blood products were administered to patients later in the clinical course who seemed to be improving, the effectiveness could not be adequately assessed. However, there are potential risks to using this therapy, including: ▶ Transmission of bloodborne pathogens, ▶ Transfusion-related acute lung injury (TRALI), and ▶ Possible antibody-dependent ehancement (ADE) of Ebola virus pathogenesis. In short, it is unclear if convalescent whole blood or plasma provides any specific benefit for treatment of EVD. Clinical trials of convalescent plasma treatment for EVD are currently being conducted in Africa. Investigational Therapies ZMapp is a mix of three human-mouse monoclonal antibodies ZMapp produced in tobacco plant cells. The antibodies bind to Ebola . Cocktail of three chimeric human-mouse monoclonal antibodies virus proteins and render the virus less able to infect cells produced in tobacco plants1-3 . ZMapp completely protected non-human primates when in mammals. In NHPs, ZMapp completely protected rhesus treatment was initiated up to five days post exposure1 . Patients have been treated on compassionate grounds macaques when treatment was initiated up to five days post . No drug currently available exposure. Patients have been treated on compassionate . Phase I clinical trials (assessing safety) planned for 2015, followed by efficacy study grounds but a formal efficacy study has not been completed. ZMapp is administered by IV. Production capacity is very 1Olinger, GG et al. PNAS 2012 2 Dye, JM et al. PNAS 2012 3 Qiu, X et al. Sci Transl Med 2013 limited, and there is no current supply. Phase I clinical
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