Hepatitis E virus infection can cause rapid liver cirrhosis in people with HIV who have low CD4 cell counts

Treatment with ribavirin partially effective
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Infection with hepatitis E virus (HEV) can cause rapid liver fibrosis in people with HIV who have low CD4 cell counts, case reports published in the online edition of Clinical Infectious Diseases show. Spanish investigators reported two instances of HEV infection in gay men with HIV who had severe immunosuppression. Treatment with ribavirin monotherapy led to normalisation of liver function and temporary suppression of HEV replication.   

“Chronic HEV…can lead to cirrhosis within less than three years,” comment the authors. “In the setting of immunosuppressed HIV-infected patients with chronic hepatitis E, progression to cirrhosis may be even faster than that observed in HBV [hepatitis B virus] or HCV [hepatitis C virus]/HIV coinfection.”

Hepatitis E is a leading cause of acute hepatitis in resource-limited countries. Often there are no symptoms and the infection is usually cleared by the body’s natural defences. Most infections are caused by consumption of undercooked pork products.

Glossary

hepatitis E virus (HEV)

The hepatitis E virus is primarily transmitted through contaminated food and water, as well as human faeces. It may be passed on through rimming (oral-anal contact). The virus can be found in some animals and can sometimes be passed from the animal to humans (for example by eating undercooked meat). Chronic infection (over six months) with HEV is very rare.

ribonucleic acid (RNA)

The chemical structure that carries genetic instructions for protein synthesis. Although DNA is the primary genetic material of cells, RNA is the genetic material for some viruses like HIV.

 

detectable viral load

When viral load is detectable, this indicates that HIV is replicating in the body. If the person is taking HIV treatment but their viral load is detectable, the treatment is not working properly. There may still be a risk of HIV transmission to sexual partners.

cirrhosis

Severe fibrosis, or scarring of organs. The structure of the organs is altered, and their function diminished. The term cirrhosis is often used in relation to the liver. 

alanine aminotransferase (ALT)

An enzyme found primarily in the liver. Alanine aminotransferase may be measured as part of a liver function test. Abnormally high blood levels of ALT are a sign of liver inflammation or damage from infection or drugs.

Immunosuppression is a recognised risk factor for the persistence of HEV infection, and high rates of HEV/HIV co-infection have been reported in some countries. In Spain, between 2 and 7% of the general population have antibodies to HEV, and a similar prevalence has been observed in people with HIV.

Doctors in Spain were concerned by two cases of chronic HEV infection causing rapid liver damage involving people with HIV who had low CD4 cell counts.

The first case involved a 47-year-old gay man. He was diagnosed with HIV in 1995, at which time his CD4 cell count was just 17 cells/mm3. Antiretroviral therapy suppressed his viral load to undetectable levels, but his CD4 cell count remained persistently low, never rising to above 100 cells/mm3 in the early years of therapy and subsequently never increased above 200 cells/mm3.

In April 2008 monitoring of liver function revealed an ALT level of 482 iu/ml, well above the upper-limit of normal. Tests for hepatitis A, B and C were all negative. However, antibodies to hepatitis E were detected. The man’s liver function had normalised by January 2009 but again spiked one month later. Liver stiffness increased from 4.9 kPa in April 2006 to 17.1 kPa in April 2011, suggesting rapid onset liver cirrhosis. This was confirmed by liver biopsy, which revealed cirrhosis with significant steatosis (fatty liver). Screening tests for hepatitis A, B and C remained persistently negative, and the man reported only modest alcohol consumption.

Retrospective analysis of stored serum samples confirmed acute infection with HEV genotype-3 in March 2008. The patient initiated a 24-week course of ribavirin monotherapy (1200mg daily) in November 2011. Within one month, his liver enzymes had normalised, HEV RNA was suppressed to undetectable levels and antibodies to HEV were present. HEV viral load was undetectable at the end of therapy and three months later. Liver enzymes remained normal and liver stiffness declined to 14 kPa. However, in October 2012, HEV RNA was once again detectable in plasma.

The second case involved a 53-year-old gay man born in Cuba who had been resident in Spain since 1979. He was diagnosed with HIV in 1999 when his CD4 cell count was 19 cells/mm3. HIV therapy was immediately initiated, but the man frequently interrupted his treatment. In April 2006, when his CD4 cell count was 88 cells/mm3, a flare in ALT to 261 was recorded. Screening tests for hepatitis A, B and C were all negative.

A dramatic increase in liver stiffness from 6.7 kPa to 38.5 kPa was observed. An endoscopy revealed the presence of esophageal varices. Tests also showed the presence of HEV antibodies.

Stored serum samples were negative for HEV antibodies before the ALT spike, but positive thereafter. HEV RNA was intermittently detectable in blood and persistently detectable in faeces. Sequencing confirmed infection with HEV genotype-3. The infection was attributed to the consumption of homemade pork liver pâté manufactured by his relatives at their farm in northern Spain.

A 24-week course of ribavirin monotherapy (1000mg daily) was initiated in September 2011. By January 2012, HEV viral load was undetectable in both plasma and faeces. Liver function normalised, liver stiffness declined and the man’s CD4 cell count increased to 289 cells/mm3. Ten weeks after the end of treatment, HEV RNA was once again detectable in plasma, but had disappeared by October 2012.

“In the setting of HIV carriers, HEV-3 infection should be regarded as an opportunistic infection, since it appears to evolve differently in HIV infection,” comment the investigators. “A delay in the diagnosis of HEV infection and, as a result, in starting antiviral therapy, can lead to clinical complication and hazardous consequences for the patient.”

They conclude: “Screening for HEV in HIV-infected individuals presenting unexplained transaminase elevations or with hepatic fibrosis of unknown origin is warranted. A short course of ribavirin may temporarily control viral replication, however, optimal treatment regimens need to be defined.”

References

Neukam K et al. Chronic hepatitis E in HIV patients: rapid progression to cirrhosis and response to oral ribavirin. Clin Infect Dis, online edition, 2013.