Sébastien Lhomme

Ribavirin Therapy Inhibits Viral Replication on Patients With Chronic Hepatitis E Virus Infection

BACKGROUND & AIMS Hepatitis E virus (HEV) infection can evolve to chronic hepatitis in immunocompromised patients. Pegylated α-interferon can effectively treat chronic HEV infection after liver transplantation but is contraindicated for kidney transplantation. We assessed the antiviral effect of ribavirin monotherapy in patients with chronic HEV infection following kidney transplantation. METHODS In a pilot study performed at Toulouse University Hospital, 6 patients that received kidney transplants who were positive for HEV RNA (infected with HEV for 36.5 months; [range, 11-46 months]) were given ribavirin monotherapy for 3 months. Ribavirin was given at 600-800 mg/day in 2 separate doses, based on the patients ability to clear creatinine. RESULTS Median serum concentration of HEV RNA at baseline was 5.77 log copies/mL (range, 4.35-7.35 log copies/mL). Three months after ribavirin therapy commenced, HEV RNA was undetectable in serum samples from all patients. A sustained virologic response was observed in 4 patients; the other 2 patients relapsed at 1 and 2 months after ribavirin therapy ended. At the end of the study, all patients had normal levels of alanine and aspartate aminotransferase. Anemia was the main side effect caused by ribavirin therapy. CONCLUSIONS Ribavirin monotherapy inhibits the replication of HEV in vivo and might induce a sustained virological response in patients with chronic HEV infections. Further studies are required to determine the optimal duration of ribavirin therapy.

Hepatitis E Virus Strains in Rabbits and Evidence of a Closely Related Strain in Humans, France

The host range of HEV in Europe is expanding, and zoonotic transmission of HEV from rabbits is possible.

Hepatitis E Virus Infection without Reactivation in Solid-Organ Transplant Recipients, France

Infections with hepatitis E virus (HEV) in solid-organ transplant recipients can lead to chronic hepatitis. However, the incidence of de novo HEV infections after transplantation and risk for reactivation in patients with antibodies against HEV before transplantation are unknown. Pretransplant prevalence of these antibodies in 700 solid-organ transplant recipients at Toulouse University Hospital in France was 14.1%. We found no HEV reactivation among patients with antibodies against HEV at the first annual checkup or by measuring liver enzyme activities and HEV RNA. In contrast, we found 34 locally acquired HEV infections among patients with no antibodies against HEV, 47% of whom had a chronic infection, resulting in an incidence of 3.2/100 person-years. Independent risk factors for HEV infection were an age <52 years at transplantation and receiving a liver transplant. Effective prophylactic measures that include those for potential zoonotic infections should reduce the risk for HEV transmission in this population.

Hepatitis E Virus Reinfections in Solid-Organ-Transplant Recipients Can Evolve Into Chronic Infections

BACKGROUND Hepatitis E virus (HEV) infections are a major cause of acute hepatitis in developing and industrialized countries. Little is known about anti-HEV immunity in solid-organ recipients. METHODS We screened 263 solid-organ recipients for anti-HEV immunoglobulin G (IgG) at transplantation. They were followed up for 1 year and tested for HEV RNA and anti-HEV antibodies 1 year after transplantation and if their liver enzyme activities increased. RESULTS A total of 38.4% had anti-HEV IgG at transplantation. The mean concentrations (±SD) of anti-HEV IgG at transplantation (8 ± 17.5 U/mL) and 1 year later (6.4 ± 12.0 U/mL, P = .4) were similar. There were 3 de novo HEV infections during the 1-year follow-up among patients who were HEV seronegative before transplantation, giving an annual incidence of 2.1%. We also identified 3 HEV reinfections among patients who were seropositive before transplantation through detection of HEV RNA, for an annual incidence of 3.3%. Their anti-HEV IgG concentrations were 0.3, 2.1, and 6.2 World Health Organization (WHO) units/mL before transplantation. Reinfection of the patient with the lowest IgG concentration at transplantation had evolved to a chronic infection. CONCLUSIONS Low anti-HEV antibodies (<7 WHO units/mL) seemed not to protect solid-organ recipients. HEV reinfection in immunocompromised patients can lead to chronic infection, as in primary infections.

Hepatitis E Virus Infections in Blood Donors, France

We screened plasma samples (minipools of 96 samples, corresponding to 53,234 blood donations) from France that had been processed with solvent–detergent for hepatitis E virus RNA. The detection rate was 1 HEV-positive sample/2,218 blood donations. Most samples (22/24) from viremic donors were negative for IgG and IgM against HEV.

Genotype 3 Diversity and Quantification of Hepatitis E Virus RNA

ABSTRACT Genotype 3 hepatitis E viruses (HEVs) are distributed across the world and are now considered to be an emerging public health concern in industrialized countries. At least 10 genotype 3 subtypes have been identified in humans and animals worldwide. It was recently reported that the sensitivities of HEV RNA assays differ greatly. We have assessed the influence of genotype 3 diversity on the performances of two HEV RNA assays: one targeting the ORF3 gene and the other targeting the ORF2 gene. We tested a panel of 5 HEV-positive reference samples of genotypes 3a, 3b, 3c, 3e, and 3f at 10-fold serial dilutions. The HEV RNA concentrations obtained with both reverse transcription (RT)-PCRs were correlated, but the RT-PCR based on ORF2 underestimated the HEV RNA concentrations. The mean [ORF3 − ORF2] difference was 1.41 log copies/ml. We also tested 34 clinical specimens of genotypes 3c (n = 15), 3e (n = 4), and 3f (n = 15), representing the most prevalent subtypes in Europe. The mean [ORF3 − ORF2] differences were 1.41 log copies/ml for genotype 3c, 0.96 log copies/ml for genotype 3e, and 0.70 log copies/ml for genotype 3f. The bias between the 2 RT-PCR assays was significantly greater for genotype 3c than for genotype 3f (P = 0.007). We therefore recommend the use of an RT-PCR protocol based on ORF3 to quantify HEV RNA of genotype 3 strains.

Performance of anti-HEV assays for diagnosing acute hepatitis E in immunocompromised patients

Hepatitis E virus is an emerging concern in immunocompromised patients, who may become chronically infected. This prompted us to assess the performance of two anti-HEV IgG and IgM assays for diagnosing acute HEV infections. The specificities of the assays were estimated by testing samples from 2 to 3 year-old French children and blood donors and their sensitivities by testing 40 immunocompromised patients acutely infected. Both anti-HEV IgM assays were highly specific (99.6% and 100%). The sensitivity of the Adaltis was 87.5%, and that of Wantai was 85%. The specificities of anti-HEV IgG Wantai (97.8%) and Adaltis tests (89.5%, p=0.1) were similar but the Wantai test was more sensitive (45%) than the Adaltis test (15%, p<0.001). None of the samples was anti-HEV IgM negative and IgG positive. We conclude that these anti-HEV IgM assays performed well in immunosuppressed subjects with acute hepatitis E and can be used as first line virological tools. Testing for anti-HEV IgG and IgM simultaneously at the acute phase did not improve the diagnostic performance. In contrast, molecular detection of HEV RNA appears essential to exclude an HEV infection in patients who are negative for anti-HEV IgM and to assess the evolution of hepatitis E 3 months thereafter.

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

ABSTRACT 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 Ka /Ks 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.

Hepatitis E virus: Chronic infection, extra-hepatic manifestations, and treatment

Hepatitis E virus (HEV) infection is a worldwide disease. An improved understanding of the natural history of HEV infection has been achieved within the last decade. Several reservoirs and transmission modes have been identified. It is an underdiagnosed disease because of the use of low-sensitivity serological assays; however, diagnostics tools, including nucleic-acid tests, have improved. HEV infection is usually an acute self-limiting disease, but causes chronic infection with rapidly progressive cirrhosis in adult and pediatric organ-transplant-patients. HEV infection evolves to chronic hepatitis in nearly 60% of HEV-infection solid-organ-transplant patients. HEV can also cause extra-hepatic manifestations, such as neurological symptoms and kidney injury. Reducing immunosuppression in transplant patients can lead to HEV clearance in one-third of patients with chronic hepatitis. The use of anti-viral therapies, such as pegylated-interferon and ribavirin, has been found to efficaciously treat HEV infection.

High Proportion of Asymptomatic Infections in an Outbreak of Hepatitis E Associated With a Spit-Roasted Piglet, France, 2013

BACKGROUND On 11 December 2013, 3 clustered cases of hepatitis E were reported on a French coastal island. Individuals had taken part in a wedding meal that included a spit-roasted piglet. The piglet had been stuffed with a raw stuffing partly made from the liver. Investigations were carried out to identify the vehicle of contamination and evaluate the dispersion of the hepatitis E virus (HEV) in the environment. METHODS A questionnaire was administered to 98 wedding participants who were asked to give a blood sample. Cases were identified by reverse transcription-polymerase chain reaction and serological tests. A retrospective cohort study was conducted among 38 blood-sampled participants after the exclusion of 14 participants with evidence of past HEV infection. Relative risks (RR) and 95% confidence intervals were calculated based on food consumed at the wedding meal using univariate and multivariable Poisson regressions. Phylogenetic analyses were performed to compare the clinical HEV strains. Strains were detected in the liquid manure sampled at the farm where the piglet was born and in the untreated island wastewater. RESULTS Seventeen cases were identified, 70.6% were asymptomatic. Acute HEV infection was independently associated with piglet stuffing consumption (RR = 1.69 [1.04-2.73], P = .03). Of clinical strains from the index cases, veterinary and environmental HEV strains were identical. CONCLUSIONS Our investigation attributed this large HEV outbreak to the consumption of an undercooked pig liver-based stuffing. After infection, the cases became a temporary reservoir for HEV, which was detected in the islands untreated wastewater.