West Africa Ebola Outbreak 2013-2014: Disease, Treatments, and Global Impact

Jill E. Weatherhead, MD; Laila Woc-Colburn, MD

Disclosures

February 03, 2015

In This Article

Therapeutic Options for EVD

Currently, the treatment for suspected or documented EVD is primarily supportive and involves intravenous fluid administration, which is essential to manage endothelial damage and vascular leakage. Patients may have severe gastrointestinal fluid loss, leading to hypovolemic shock, as well as severe electrolyte disturbances. Replacement of fluids and electrolytes, treatment of concurrent infections, and maintaining hemodynamic stability are first-line supportive therapies for all patients with EVD.

No other therapy for the treatment of Ebola infection or postexposure prophylaxis has been approved by the US Food and Drug Administration.[2] However, several therapies under experimental review seem promising. Structural proteins, including nucleoproteins, virion proteins VP-30 and VP35, RNA polymerase, matrix proteins VP40 and VP23, and glycoproteins, have all been targets for new drug development.[3]

ZMapp™ is a combination of three humanized monoclonal antibodies targeting Ebola virus glycoprotein, manufactured in tobacco plants.[1,10] ZMapp is currently in early-phase development and has been used in emergency cases under a compassionate use protocol.[10] It is administered intravenously; unfortunately, the dosing in humans is currently unknown. A study in macaque monkeys showed efficacy of 50 mg/kg per day every 3 days for three doses.[1] ZMapp has several limitations, including lack of data on safety and efficacy, difficulty with transport (it requires freezing, owing to instability), and inability to scale up production after an exhausted supply.[1,2]

Brincidofovir is an orally available lipid conjugate of cidofovir, a nucleotide analog, that allows high intracellular levels of cidofovir and minimal systemic effects.[1,2] It has previously been approved and is under further investigation in phase 3 trials for such DNA viruses as cytomegalovirus and adenovirus.[1,2] It has been implemented in emergency use in patients with Ebola after showing positive in vitro results against Ebola virus.[2] In clinical trials to treat DNA viruses, the drug has been shown to have a long half-life, requiring only twice-weekly dosing, and it has few side effects, which include gastrointestinal symptoms.[1] The current dosing and safety profile for use in treatment of Ebola are lacking.[1]

Favipiravir (T-705) is an oral nucleotide analog converted to an active metabolite that inhibits viral RNA-dependent RNA polymerase.[1,10] In previous studies, it has demonstrated activity against arenaviruses and bunyaviruses, as well as shown efficacy in treating Ebola virus infections in cell culture and small animal models.[1] Dosing for treatment of influenza has been documented to be 300 mg/kg/day in two divided doses for 14 days; however, treatment dosing may be higher for EVD.[1,10] Dosing regimens for EVD treatment are currently under investigation in nonhuman primate models.[1,10] After recent late-stage studies using T-705 for other viruses, including influenza, supplies are readily available.[10]

TKM-Ebola is a small interfering RNA molecule that blocks expression of two viral replication genes, affecting production of Ebola surface proteins. It is administered intravenously and is currently in early clinical trials.[1,2,10] At this time, safety and efficacy data are limited. However, during previous phase 1 studies, development had been suspended as a result of cytokine elevation.[1] Given the recent epidemic, phase 1 studies have again commenced, and emergency use has been authorized for Ebola infection.[1,2]

Medications that are currently under review but with fewer ongoing studies include BCX-4430 and lamivudine. BCX-4430 is a broad-spectrum nucleoside analog of adenosine, phosphorylated into a triphosphate intracellularly, which has demonstrated efficacy in treating Ebola.[1] BCX-4430 is not incorporated into mammalian RNA or DNA and indirectly inhibits RNA polymerase activity.[1] No studies of BCX-4430 have been conducted in nonhuman primate models.[1]

Lamivudine, a cytosine analog used as an antiretroviral treatment for HIV and hepatitis B virus infection, inhibits HIV reverse transcription. The mechanism of action of lamivudine for treatment of Ebola virus is unclear, and current in vitro studies on lamivudine for Ebola virus are pending.[1]

Transfusion therapy entails treating Ebola-infected patients with convalescent whole blood or plasma obtained from previously infected individuals. Blood products that are positive for IgG Ebola virus antibodies and negative for Ebola virus antigen can be used to treat an infected patient.[1] Unfortunately, many limitations exist in the use of transfusion medicine in the current epidemic; these include a short supply, difficulty with safe blood screening (eg, finding matched blood types between donor and recipients), and safe collection and storage of samples.[1,2]

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