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researchsquare; 2022.


Since the first reports of hepatitis of unknown aetiology occurring in UK children, over 1000 cases have been reported worldwide, including 268 cases in the UK, with the majority younger than 6 years old. Using genomic, proteomic and immunohistochemical methods, we undertook extensive investigation of 28 cases and 136 control subjects. In five cases who underwent liver transplantation, we detected high levels of adeno-associated virus 2 (AAV2) in the explanted livers. AAV2 was also detected at high levels in blood from 10/11 non-transplanted cases. Low levels of Adenovirus (HAdV) and Human Herpesvirus 6B (HHV-6B), both of which enable AAV2 lytic replication, were also found in the five explanted livers and blood from 15/17 and 6/9 respectively, of the 23 non-transplant cases tested. In contrast, AAV2 was detected at low titre in 6/100 whole bloods from child controls from cohorts with presence or absence of hepatitis and/or adenovirus infection. Our data show an association of AAV2 at high titre in blood or liver tissue, with unexplained hepatitis in children infected in the recent HAdV-F41 outbreak. We were unable to find evidence by electron microscopy, immunohistochemistry or proteomics of HAdV or AAV2 viral particles or proteins in explanted livers, suggesting that hepatic pathology is not due to direct lytic infection by either virus. The potential that AAV2, although not previously associated with disease, may, together with HAdV-F41 and/or HHV-6, be causally implicated in the outbreak of unexplained hepatitis, requires further investigation.

medrxiv; 2022.
Preprint in English | medRxiv | ID: ppzbmed-10.1101.2022.02.11.22270775


Background: Early antiviral treatment is effective for COVID-19 but currently available agents are expensive. Favipiravir is routinely used in many countries, but efficacy is unproven. Antiviral combinations have not been systematically studied. We aimed to evaluate the effect of favipiravir, lopinavir-ritonavir or the combination of both agents on SARS-CoV-2 viral load trajectory when administered early. Methods: We conducted a Phase 2, proof of principle, randomised, placebo-controlled, 2x2 factorial, double-blind trial of outpatients with early COVID-19 (within 7 days of symptom onset) at two sites in the United Kingdom. Participants were randomised using a centralised online process to receive: favipiravir (1800mg twice daily on Day 1 followed by 400mg four times daily on Days 2-7) plus lopinavir-ritonavir (400mg/100mg twice daily on Day 1, followed by 200mg/50mg four times daily on Days 2-7); favipiravir plus lopinavir-ritonavir placebo; lopinavir-ritonavir plus favipiravir placebo; or both placebos. The primary outcome was SARS-CoV-2 viral load at Day 5, accounting for baseline viral load. NCT04499677. Findings: Between 6 October 2020 and 4 November 2021, we recruited 240 participants. For the favipiravir+lopinavir-ritonavir, favipiravir+placebo, lopinavir-ritonavir+placebo and placebo-only arms, we recruited 61, 59, 60 and 60 participants and analysed 55, 56, 55 and 58 participants respectively who provided viral load measures at Day 1 and Day 5. In the primary analysis, the mean viral load in the favipiravir+placebo arm had decreased by 0.57 log10 (95% CI -1.21 to 0.07, p=0.08) and in the lopinavir-ritonavir+placebo arm by 0.18 log10 (95% CI -0.82 to 0.46, p=0.58) more than in the placebo arm at Day 5. There was no significant interaction between favipiravir and lopinavir-ritonavir (interaction coefficient term: 0.59 log10, 95% CI -0.32 to 1.50, p=0.20). More participants had undetectable virus at Day 5 in the favipiravir+placebo arm compared to placebo only (46.3% vs 26.9%, odds ratio (OR): 2.47, 95% CI 1.08 to 5.65; p=0.03). Adverse events were observed more frequently with lopinavir-ritonavir, mainly gastrointestinal disturbance. Favipiravir drug levels were lower in the combination arm than the favipiravir monotherapy arm. Interpretation: At the current doses, no treatment significantly reduced viral load in the primary analysis. Favipiravir requires further evaluation with consideration of dose escalation. Lopinavir-ritonavir administration was associated with lower plasma favipiravir concentrations.