Autochthonous acute hepatitis E: treatment with sofosbuvir and ribavirin

Biliotti, Elisa; Franchi, Cristiana; Spaziante, Martina; Garbuglia, Anna Rosa; Volpicelli, Lorenzo; Palazzo, D.; Angelis, Maurizio De; Esvan, Rozenn; Taliani, Gloria

doi:10.1007/s15010-018-1168-7

Cited by 21 publications

(14 citation statements)

References 10 publications

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“…In both these studies where sofosbuvir had no effect on G1 HEV, the Sar55/S17/luc replicon, which harbors an insertion from the human ribosomal S17 protein within the hypervariable region, was utilized (37,62). This S17 insertion dramatically enhances replication levels (37) and, as such, likely renders it less susceptible to sofosbuvir inhibition than wildtype viruses and other replicons which lack this insertion, as previously observed with G1634R-associated ribavirin failure (63,64).…”

Section: Discussionmentioning

confidence: 61%

“…Clinically, sofosbuvir has been used in a few individual cases with or without ribavirin to treat HEV G3-infected patients with variable success (63,(65)(66)(67)(68), ranging from a reduction of HEV RNA to undetectable levels (63,66) to treatment failure or relapse following treatment (65,67,68). These mixed reports of efficacy have raised questions around the pursuit of sofosbuvir as an HEV antiviral (69), indicating that further work is required to ascertain its suitability as an anti-HEV therapeutic.…”

Section: Discussionmentioning

confidence: 99%

“…These mixed reports of efficacy have raised questions around the pursuit of sofosbuvir as an HEV antiviral (69), indicating that further work is required to ascertain its suitability as an anti-HEV therapeutic. Clinical treatment failure of sofosbuvir has been attributed to the HEV phylogenetic subtype, patient immune status (63), and presence of HEV RdRp mutations known to confer increased replication levels that cause ribavirin treatment failure, particularly G1634R (63,64).…”

Section: Discussionmentioning

confidence: 99%

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Antiviral Candidates for Treating Hepatitis E Virus Infection

Netzler

Tuipulotu

Vasudevan

et al. 2019

Antimicrob Agents Chemother

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Globally, hepatitis E virus (HEV) causes significant morbidity and mortality each year. Despite this burden, there are no specific antivirals available to treat HEV patients, and the only licensed vaccine is not available outside China. Ribavirin and alpha interferon are used to treat chronic HEV infections; however, severe side effects and treatment failure are commonly reported. Therefore, this study aimed to identify potential antivirals for further development to combat HEV infection. We selected 16 compounds from the nucleoside and nonnucleoside antiviral classes that range in developmental status from late preclinical to FDA approved and evaluated them as potential antivirals for HEV infection, using genotype 1 replicon luminescence studies and replicon RNA quantification. Two potent inhibitors of HEV replication included NITD008 (half-maximal effective concentration [EC50], 0.03 μM; half-maximal cytotoxic concentration [CC50], >100 μM) and GPC-N114 (EC50, 1.07 μM, CC50, >100 μM), and both drugs reduced replicon RNA levels in cell culture (>50% reduction with either 10 μM GPC-N114 or 2.50 μM NITD008). Furthermore, GPC-N114 and NITD008 were synergistic in combinational treatment (combination index, 0.4) against HEV replication, allowing for dose reduction indices of 20.42 and 8.82 at 50% inhibition, respectively. Sofosbuvir has previously exhibited mixed results against HEV as an antiviral, both in vitro and in a few clinical applications; however, in this study it was effective against the HEV genotype 1 replicon (EC50, 1.97 μM; CC50, >100 μM) and reduced replicon RNA levels (47.2% reduction at 10 μM). Together these studies indicate drug repurposing may be a promising pathway for development of antivirals against HEV infection.

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Section: Discussionmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Antiviral Candidates for Treating Hepatitis E Virus Infection

Netzler

Tuipulotu

Vasudevan

et al. 2019

Antimicrob Agents Chemother

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“…Sofosbuvir was shown to inhibit HEV Kernow-C1 replication in vitro and the combination with ribavirin even resulted in an additive effect [48]. However, there is not enough clinical data yet to estimate the effectivity in vivo due to few contradictory reports [49,50,51]. Recent reports suggest silvestrol as a drug candidate to treat HEV [52,53].…”

Section: Discussionmentioning

confidence: 99%

Isolation of Subtype 3c, 3e and 3f-Like Hepatitis E Virus Strains Stably Replicating to High Viral Loads in an Optimized Cell Culture System

Schemmerer¹,

Johne

Erl³

et al. 2019

Viruses

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The hepatitis E virus (HEV) is transmitted via the faecal–oral route in developing countries (genotypes 1 and 2) or through contaminated food and blood products worldwide (genotypes 3 and 4). In Europe, HEV subtypes 3c, 3e and 3f are predominant. HEV is the leading cause of acute hepatitis globally and immunocompromised patients are particularly at risk. Because of a lack of cell culture systems efficiently propagating wild-type viruses, research on HEV is mostly based on cell culture-adapted isolates carrying uncommon insertions in the hypervariable region (HVR). While optimizing the cell culture system using the cell culture-adapted HEV strain 47832c, we isolated three wild-type strains derived from clinical specimens representing the predominant spectrum of HEV in Europe. The novel isolates 14-16753 (3c), 14-22707 (3e) and 15-22016 (3f-like) replicate to high viral loads of 108, 109 and 106.5 HEV RNA copies/mL at 14 days post-inoculation, respectively. In addition, they could be kept as persistently infected cell cultures with constant high viral loads (~109 copies/mL) for more than a year. In contrast to the latest isolates 47832c, LBPR-0379 and Kernow-C1, the new isolates do not carry genome insertions in the HVR. Optimization of HEV cell culture identified amphotericin B, distinct salts and fetal calf serum (FCS) as important medium supplements. Overconfluent cell layers increased infectivity and virus production. PLC/PRF/5, HuH-7-Lunet BLR, A549 and HepG2/C3A supported replication with different efficiencies. The novel strains and optimized cell culture system may be useful for studies on the HEV life cycle, inactivation, specific drug and vaccine development.

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“…Moreover, it was administered as combination therapy with ribavirin in some ribavirin-resistant cases. Biliotti et al[ 137 ] showed the clearance of the HEV with sofosbuvir/ribavirin combination therapy in patients with acute HEV infection. In another study, combination therapy was reported to treat refractory HEV infection in an immunosuppressed individual[ 138 ].…”

Section: Promising Treatment Options For Ribavirin-resistant Hev Infementioning

confidence: 99%

Hepatitis E virus: Epidemiology, diagnosis, clinical manifestations, and treatment

Aslan

Balaban

2020

WJG

118

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The hepatitis E virus (HEV) is the fifth known form of viral hepatitis and was first recognized as the cause of an epidemic of unexplained acute hepatitis in the early 1980s. Globally, it is one of the most frequent causes of acute viral hepatitis. The majority of HEV infections are asymptomatic and lead to the spontaneous clearance of the virus. Among the eight different genotypes identified to date, HEV genotype 1 (HEV1), HEV2, HEV3, and HEV4 are the most frequent genotypes causing infections in humans. HEV1 and HEV2 are prevalent in developing regions and able to result in large-scale outbreaks originating from contaminated water supplies. They are also responsible for severe hepatitis in pregnant patients and infants. In contrast, HEV3 and HEV4 are zoonotic, and the transmission of these genotypes to humans occurs mainly through the fecal contamination of water and consumption of contaminated meat from infected animals. Their main reservoir is the pig, and they are mostly encountered in developed countries. The major risk groups for HEV infection and its ensuing adverse consequences are pregnant women, infants, older people, immunocompromised individuals, patients with underlying chronic liver diseases, and workers that come into close contact with HEV-infected animals. In the clinical perspective, HEV infections have diverse clinical manifestations including acute and self-limiting hepatitis, acute-on-chronic liver disease, chronic hepatitis, cirrhosis, and liver failure. Although HEV mainly results in acute self-limiting infection, chronic HEV infection may occur among immunocompromised patients ( e.g ., solid-organ transplant recipients). Additionally, HEV-associated extrahepatic manifestations involving various organs have been reported in the last decade, although the causal link for many of them still needs to be proven. Ribavirin and interferon-alpha are the most widely used agents for the treatment of HEV infections with a certain level of success. However, ribavirin is contraindicated in pregnant patients, and interferon-alpha cannot be used in most transplant recipients. Therefore, there is an urgent need for novel antiviral compounds that are safe and effective particularly for patients having contraindications for ribavirin or interferon-alpha and infected by the ribavirin-resistant HEV. In this review article, a literature search using PubMed and MEDLINE databases was performed, up to March 2020. Only the articles published in English were reviewed.

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Autochthonous acute hepatitis E: treatment with sofosbuvir and ribavirin

Abstract: In conclusion, although more data are required before firm conclusions could be drawn, the combination of sofosbuvir and ribavirin in not immunosuppressed patients with acute hepatitis E may be able to clear HEV infection.

Cited by 21 publications

References 10 publications

Antiviral Candidates for Treating Hepatitis E Virus Infection

Antiviral Candidates for Treating Hepatitis E Virus Infection

Isolation of Subtype 3c, 3e and 3f-Like Hepatitis E Virus Strains Stably Replicating to High Viral Loads in an Optimized Cell Culture System

Hepatitis E virus: Epidemiology, diagnosis, clinical manifestations, and treatment

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