Emetine for Viral Outbreaks (a.k.a. EVOLVE Antiviral Initiative)

Dengue fever is a mosquito-borne viral infection caused by the dengue virus (DENV), which belongs to the Flaviviridae family. It is transmitted primarily by Aedes aegypti and Aedes albopictus mosquitoes. Dengue is recognized as one of the top ten global public health threats, affecting an estimated 390 million people annually, with approximately 96 million cases manifesting clinically. Globally, dengue has seen a significant rise in incidence, with a 30-fold increase in the past 50 years. There is currently no antiviral agent proven to work against it. Dengue fever is endemic in Nepal with cyclical outbreaks. The country relies on supportive treatment. This often includes intravenous fluids and, in rare cases, steroids and organ support. Effective antiviral agents could significantly reduce the burden of dengue by preventing disease progression and reducing transmission.

In vitro and in vivo studies have suggested strong antiviral activity of emetine against SARS-CoV-2, dengue, Ebola, cytomegalovirus, and several other viruses. Low et al. had carefully demonstrated that emetine inhibited all four serotypes of DENV infection in cell lines by inhibiting the viral RNA synthesis or the viral protein translation pathway. In the past, emetine, an alkaloid extracted from ipecacuanha roots, has been widely used in the human treatment of amoebic dysentery, amoebic liver abscess, and several viruses such as herpes simplex, herpes zoster, influenza, hepatitis, and mumps. Because of cardiotoxicity (cardiac dysrhythmias), emetine was replaced by metronidazole. The toxicity was unequivocally associated with high-dose emetine (60 mg/day for 10 days to achieve an minimum inhibitory concentration (MIC) of 25 micromol (µM) against Entamoeba histolytica; however, the cardiovascular side-effects were minimal or none when emetine was used for various indications in low dose (<20 mg/day). The investigators have recently shown that by lowering the standard amoebicidal dose by a factor of 10, emetine can inhibit viral replication while avoiding cardiovascular toxicity.

Phase 1 and 2 studies have been previously carried out. The investigators' clinical trial to evaluate emetine against SARS-CoV-2 is currently approved by Johns Hopkins Medicine (JHM) Institutional Review Board (IRB) (IRB00283778) and is ongoing in Nepal. The investigators have enrolled a few patients in this trial and have not encountered any toxicity. Given the broad-spectrum antiviral activity of emetine, the investigators now plan to evaluate emetine's efficacy and safety in the treatment of symptomatic dengue fever in a clinical trial. The investigators hypothesize that emetine will be efficacious against dengue at low doses. By evaluating its efficacy against dengue, this research can directly inform treatment strategies for patients in over 100 countries, since about 50% of the global population is at risk of dengue fever. In the past, emetine was an essential World Health Organization (WHO)- and FDA-approved drug.

Inclusion criteria

• Age 18 to 65 years
• Admitted to the hospital
• Laboratory-confirmed infection with dengue virus within the last 5 days and preferably within the last 3 days. Testing for dengue virus using positive Nonstructural protein 1(NS1) strip assay or reverse-transcriptase polymerase chain reaction (RT-PCR)
• Having two or more clinical symptoms (fever, headache, retro-orbital pain, myalgia, arthralgia, rash, hemorrhagic manifestations, or leucopenia, gastrointestinal symptoms) with the onset of fever within 72 hours of presentation, and
• Able to provide voluntary informed consent and comply with all study procedures and visits.

Exclusion criteria

• Age ≥65 years
• Pregnant or breastfeeding
• Current or recent use of the study drug
• Known allergy to study drug
• Current or planned participation in another pharmacological interventional trial in the next 10 days
• Participants with known past history of dengue infection
• Participants on aspirin, anticoagulants, or with other conditions that might increase the risk of bleeding
• Participants on immunosuppressive agents, including long-term steroids
• Severe dengue as defined by the WHO 2009 revised case classification.
• Individuals with long-term immunosuppressive agents such as anti-cancer chemotherapy or radiation therapy within the past 6 months, or those on systemic corticosteroid therapy
• History of prior vaccination against dengue fever within one year.
• Patients who have recently used ayurvedic or herbal medications for dengue or any other conditions in the last 7 days (eg, Papaya leaf extract)