Immune reconstitution hepatitis E: a neglected complication of antiretroviral therapy in Africa?
Andersson, Monique I.a; Preiser, Wolfganga; Maponga, Tongai G.a; Heys, Izakb; Taljaard, Jantjie J.b; van Rensburg, Christoc; Tedder, Richard S.d; Ijaz, Samreend
aDivision of Medical Virology, Department of Pathology, University of Stellenbosch/National Health Laboratory Service Tygerberg
bDivision of Infectious Diseases
cDivision of Gastroenterology and Hepatology, Department of Medicine, University of Stellenbosch/Tygerberg Hospital, South Africa
dBlood Borne Viruses Unit, Virus Reference Department, Microbiology Services Division, Health Protection Agency, Colindale, London, UK.
Correspondence to Dr Monique I. Andersson, Division of Medical Virology, Department of Pathology, Faculty of Medicine and Health Sciences, Stellenbosch University, P.O. Box 19063, Tygerberg Campus, 7505, South Africa. E-mail: firstname.lastname@example.org
Received 28 September, 2012
Accepted 5 October, 2012
Hepatitis E virus (HEV) is a major cause of enterically transmitted hepatitis in resource-poor settings  and occurs sporadically in resource-rich settings, where it is zoonotic in origin . Chronic HEV infection may occur in immunocompromised patients. We describe a case of chronic infection in an HIV-infected patient in Cape Town, South Africa, who presented with persistently raised liver transaminases after starting antiretroviral therapy (ART).
A 42-year-old HIV-infected male commenced ART in March 2010, with a CD4 cell count nadir of 37 cells/μl. Five months into a combination of stavudine, lamivudine and efavirenz, stavudine was switched to tenofovir because of peripheral neuropathy. His HIV viral load remained below 400 copies/ml from June 2010. Persistently raised transaminases from the time of commencing ART (Fig. 1) led to a specialist review in January 2012. He reported only social alcohol use of below 5 units/week for the previous 2 years and denied any other drug or herbal medicine use. His home was a brick house with running water and sanitation. He had neither family history of liver disease, nor exposure to anyone who was jaundiced. Clinically he was well, not jaundiced and had no stigmata of chronic liver disease. The ultrasound scan of his abdomen was unremarkable. He was seronegative for hepatitis A and C virus antibodies and hepatitis B surface antigen but anti-HBc-seropositive with an anti-HBs level above 100 IU/ml. His autoimmune screen was negative.
His serum tested positive for IgG and IgM antibodies to HEV by an ELISA (Fortress Diagnostics, Dublin) and for HEV RNA by RT-PCR  (61 600 GEq/ml), as did a stored sample taken 8 months previously, with a CD4 cell count between 60 and 235 cells/μl. A sample taken 11 months prior to starting ART was HEV IgM and IgG-negative, but RNA-positive. Sequence analysis of a 300-bp region of open reading frame 2 revealed a genotype 3 virus clustering with European and Japanese strains. By March 2012, with a CD4 cell count of 324 cells/μl and a fully suppressed HIV viral load, his transaminases had normalized and his serum became negative for HEV RNA. He continues on ART with no evidence of chronic liver disease.
The observation of chronic HEV infection in an HIV-infected individual that cleared with immune reconstitution due to ART is important for several reasons: it is the first well documented case of HEV disease in South Africa; it is the first description of human HEV genotype 3 infection from South Africa; and whereas cases of chronic HEV infection in HIV-infected patients have been described elsewhere, this is the first such case in our region with its high prevalence of HIV. In this case we have shown an immune reconstitution hepatitis with CD4 recovery, seroconversion and clearance of HEV RNA.
HEV outbreaks in Africa have been linked to genotype 2 [4,5]. The HEV sequence from our patient, however, clustered closely with genotype 3 sequences from Europe and Japan. Although the source of this infection is unclear, genotype 3 and 4 viruses have been found in domestic pigs in Central  and South Africa (sequence submission to GenBank, acc. no. AY621664). Domestic pigs were introduced to South Africa from Europe and therefore the presence of HEV genotype 3 is plausible, implying the importation of the virus into South Africa along with the pigs.
Chronic HEV infection, defined as HEV RNA positivity in stool or serum persisting for more than 6 months, has been described in solid organ transplant recipients and so far 14 HIV-infected patients . About 30% of transplant recipients will clear chronic HEV infection with a reduction of iatrogenic immunosuppression . It is likely that ART-induced immune reconstitution might likewise induce HEV clearance in HIV patients. However, this may cause immune reconstitution hepatitis. Whereas well known for HBV and HCV co-infection, this has not previously been described for HEV.
The incidence of HEV infection in HIV-infected patients in the developed world is thought to be low [8,9], but it is unknown for Africa. An anti-HEV seroprevalence of 10% reported from South Africa in the mid-1990s was based on poorly performing assays ; no more recent data are available.
The differential diagnosis of HIV patients with elevated transaminases in sub-Saharan Africa is wide and includes drug effects, traditional remedies, alcohol, chronic viral hepatitis, sepsis, tuberculosis and immune reconstitution syndrome. We suggest that all patients presenting with jaundice and/or raised transaminases with no other obvious cause should be tested for HEV infection using genomic assays rather than relying solely on serology. Further studies are needed to define the epidemiology of HEV in sub-Saharan Africa. This is particularly germane in the context of the HIV epidemic.
We thank Professor Susan Engelbrecht for assistance with the phylogenetic analysis.
Conflicts of interest
This work was funded in part by the Wellcome Trust. There are no conflicts of interest.
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