Katja Wolthers (Amsterdam University Medical Center)

Summary of presentation:
Aim: In immunocompromised patients, enteroviruses (EVs) can lead to severe chronic infections. FDA approved broad-spectrum antivirals were explored as treatment options for EVs by off-label treatment in immunodeficient patients and by in vitro testing.
Methods: Five patients with severe chronic enterovirus-induced disease were treated with a 5-10 day course of Remdesivir (RDV) or Molnupiravir (MPV). Our newly developed human organoid co-culture with intestinal epithelium, fibroblasts and dendritic cells was used for in vitro antiviral testing of RDV, 2′-C-Methylcytidine (2CMC), MPV and favipiravir (FVP) against EV-A71 and/or EV-C Coxsackievirus A1 (CVA1), along with conventional cell-lines.
Results: Three immunocompromised patients with severe chronic enterovirus diarrhea infected with the rare EV-Cs Coxsackievirus A1 (CVA1) and CVA19 were treated with RDV. Treatment was successful in one patient, verified by clinical improvement and eradication of CVA19 RNA. In two patients, symptoms persisted and EV RNA remained detectable in stool after treatment. One patient, co-infected with CVA1 and norovirus, cleared CVA1 spontaneously. However, while symptoms gradually improved after MPV treatment, NoV RNA remained. One patient developed acute hearing loss and severe progressive limb weakness after rituximab and was diagnosed with an echo7 infection. RDV treatment was successful with undetectable EV RNA and neurological improvement. In vitro antiviral testing with EV-A71 and CVA1 in cell-lines demonstrated that RDV and 2CMC were effective at clinically relevant concentrations; however, they showed only modest viral load reductions in gut organoids. In contrast, MPV and FVP significantly inhibited viral replication in gut organoids.
Conclusions: Broad-spectrum antivirals may be effective treatment for severe virus infections but its efficacy might be patient-related. Antiviral efficacy in our organotypic model is more in line with the different responses seen in patient than testing in cell lines. Generation of patient-derived organoids is a promising next step towards a personalized medicine approach for determining antiviral drug efficacy.