Chronic hepatitis E in HIV/HBV coinfected patient (2017)

Hepatitis E virus (HEV) infection is an emerging zoonotic infection in developed countries. Data suggest that HEV is endemic in France [1]. In addition to hepatitis, HEV has been associated with neurological impairments particularly Guillain-Barré syndrome, neuralgic amyotrophy, and encephalitis [2]. Chronically persisting viremia is a rare event mainly restricted to profound immunosuppression, including HIV-infected patients with a CD4+ cell count below 200/μl, with a risk of cirrhosis within less than 3 years [3]. Recently, sofosbuvir was shown to inhibit HEV genotype 3 replication in vitro (inhibitory concentration 50% = 635 ng/ml, versus 7–58 ng/ml for HCV), with an additive effect with ribavirin [4]. We report the failure of sofosbuvir/ribavirin to treat a chronic HEV infection in an HIV/HBV coinfected patient with severe immunosuppression. A 59-year-old Caucasian man infected with HIV since 1987, with a past history of pneumocystis, cerebral toxoplasmosis, hepatitis B (virologically suppressed), diabetes mellitus, regenerative nodular hyperplasia of the liver associated with portal hypertension and grade 2 oesophageal varices, was admitted in February 2015 for paraplegia. He had been exposed to antiretroviral drugs since 1991 and received at entry tenofovir/emtricitabine/etravirine/raltegravir. Despite more than 3 years of HIV replication suppression, CD4+ cell count remained below 100/μl. HEV genotype 3i was detected in 2011 without a recognized source of infection. No neurologic disorder was detected then. In total, 50 months of ribavirin (1000 mg/day, great observance) had failed to cure HEV. Since September 2013, the patient had been presenting a progressive gait disturbance, bladder dysfunction, and disability in walking. In March 2015, neurological examination disclosed a spastic paraplegia, lower limb hyper-reflexia, and bilateral positive Hoffmann and Babinski signs. There was a loss of joint position and vibration sensation in both lower limbs. He had slowed thinking, mild cognitive impairment with temporospatial disorientation and short-term memory disturbances. Brain MRI showed left hemispheric white matter and corpus callosum hypersignals in fluid-attenuated inversion recovery and diffusion, of ischaemic origin, consistent with vasculitis, and sequellae of cerebral toxoplasmosis in the right hemispheric white matter, basal ganglia, and bilateral cerebellar hemispheres without gadolinium enhancement. At that time, cerebrospinal fluid analysis was normal, negative for all pathogens (including HIV), except for HEV (3.2 log10 copies/ml). HEV plasma viral load was 3.6 log10 copies/ml. All other causes of neurologic deficit were eliminated. Fibrotest was compatible with liver cirrhosis (A3F4), the α-foeto protein was 51.6 mg/l (normal <7) and Meld score was 7. In relation to a diagnosis of chronic HEV infection associated with neurological injury, the patient was treated with Peginterferon α 2a/ribavirin (1000 mg/day) after IV immunoglobulins during 3 months with failure despite an initial decrease of viral load (Fig. 1). Sequencing of the polymerase encoding gene revealed a G1634R substitution, described as increasing in-vitro HEV replicative capacity [5]. In December 2015, sofosbuvir/ribavirin (400 mg/1000 mg/day; unlabeled use) was introduced for 12 weeks. A decrease in HEV viral load (VL) was observed during the first weeks but then viral load plateaued and eventually led to failure with an ascension of VL after treatment cessation (Fig. 1), whereas plasma and cerebrospinal fluid concentrations of drugs were consistent with the daily doses. The magnitude of VL decrease under sofosbuvir and ribavirin was around the same compared to under ribavirin alone. As with previous treatments, there was no improvement of neurological impairments. From 2015, a decrease of visual acuity has progressed to near cortical blindness within 1 year. Brain MRI in August 2016 showed hypersignal of splenium and occipital lobe worsening with involvement of the bilateral optic radiation linked to a vasculopathy.Fig. 1: Evolution of HEV viral load and ALT.The case shows an initial response of HEV to sofosbuvir/ribavirin that did not lead to complete viral clearance. After 12 weeks, the regimen failed to cure persistent HEV infection in a context of cirrhosis and neurological disease. Severe immunosuppression and the G1634R substitution probably played a role in the lack of viral clearance. More clinical data on the efficacy of sofosbuvir in HEV infection are necessary. Optimal treatments for chronic HEV infection in severely immunocompromised patients still need to be defined. Acknowledgements We thank C.K., V.P., S.D., M.J., and R.C. for following the patient. The virological tests were performed by E.V., V.T., and S.A.; the concentrations of drugs by G.P. and the sequencing of the polymerase encoding gene by A-M.R-A. The study was written by V.P., E.T., and S.D., and checked by all the authors. We are grateful to V.M. and T.P. for their advice. Conflicts of interest There are no conflicts of interest.