Hepatitis E Virus Quasispecies and the Outcome of Acute Hepatitis E in Solid-Organ Transplant Patients

Abstract

c Hepatitis E virus (HEV) infections are responsible for chronic hepatitis in immunocompromised patients, and this can evolve to cirrhosis. Like all RNA viruses, HEV exists as a mixture of heterogeneous viruses defining quasispecies. The relationship between the genetic heterogeneity described as a quasispecies, cytokine secretion, and the outcome of acute hepatitis in immunocompromised patients remains to be elucidated. We cloned and sequenced the region encoding the M and P capsid domains of HEV from eight solid-organ transplant (SOT) patients with acute HEV infection who subsequently cleared the virus and from eight SOT patients whose infection became chronic. We analyzed the cytokines and chemokines in the sera of these SOT patients by multianalyte profiling. The nucleotide sequence entropy and genetic distances were greater in patients whose infections became chronic. A lower K a /K s ratio was associated with the persistence of HEV. The patients who developed chronic infection had lower serum concentrations of interleukin-1 (IL-1) receptor antagonist and soluble IL-2 receptor. Increased concentrations of the chemokines implicated in leukocyte recruitment to the liver were associated with persistent infection. Those patients with chronic HEV infection and progressing liver fibrosis had less quasispecies diversification during the first year than patients without liver fibrosis progression. Great quasispecies heterogeneity, a weak inflammatory response, and high serum concentrations of the chemokines involved in leukocyte recruitment to the liver in the acute phase were associated with persistent HEV infection. Slow quasispecies diversification during the first year was associated with rapidly developing liver fibrosis.

Chronic Hepatitis E Resolved by Reduced Immunosuppression in Pediatric Kidney Transplant Patients

“…1 When unnoticed or left untreated, chronic HEV infection may rapidly lead to cirrhosis. 6,[12][13][14][15] Fortunately, chronic HEV infection can be successfully treated, for example by modest decreases in immunosuppression. Of course, this approach may lead to rejection of the organ transplant.…”

Chronic Hepatitis E Virus Infection and Treatment

“…40 Slow HEV quasispecies diversification during the first year after infection has been associated with rapidly developing liver fibrosis. 51 …”

“…52,53 Patients who developed chronic infection also have lower serum concentrations of the IL-1 receptor antagonist and the IL-2 receptor during acute phases of HEV infection compared to patients with resolving hepatitis. 51 Increased serum concentrations of the chemokines implicated in leukocyte recruitment to the liver, such as RANTES, MIP-1b, MCP-1, and CXCL8, have been associated with persistent infection. 51 In a large multicenter study, the use of tacrolimus (compared to cyclosporine A) and a low platelet count were the only two independent predictive factors for chronic hepatitis E in patients with a SOT.…”

“…51 Increased serum concentrations of the chemokines implicated in leukocyte recruitment to the liver, such as RANTES, MIP-1b, MCP-1, and CXCL8, have been associated with persistent infection. 51 In a large multicenter study, the use of tacrolimus (compared to cyclosporine A) and a low platelet count were the only two independent predictive factors for chronic hepatitis E in patients with a SOT. 49 Pischke et al 12 found that the use of mycophenolate mofetil was associated with HEV clearance in heart transplant patients, although this data needs to be confirmed.…”

“…In addition, with acute phase HEV infection, a large heterogeneity of quasispecies has been observed in patients with persistent HEV compared to patients with resolving hepatitis. 51 …”