Unexplained liver enzyme increases in patients with HIV could be due to hepatitis E virus: screening recommended

Infection with hepatitis E virus should be considered as a possible cause of unexplained elevations in liver enzymes in HIV-positive patients, Swiss investigators suggest in Emerging Infectious Diseases.

Approximately 3% of patients with persistently elevated alanine aminotransferase (ALT) levels had antibodies to hepatitis E. None of these patients were co-infected with either hepatitis B or hepatitis C.

Screening for hepatitis E RNA found evidence of the infection in two patients with very low CD4 cell counts.

The study was undertaken because unexplained elevations in liver enzyme levels are common in patients with HIV.

Hepatitis E infection originates in pigs and a major mode of transmission in Europe and North America is via contaminated meat. It is also transmitted through faecal-oral contact, for example, in contaminated water.

The virus can cause disturbances in liver function and tends to lead to short-term illness with the same pattern of symptoms as hepatitis A before the virus is cleared. However in some people hepatitis E infection may lead to acute liver failure.This risk appears highest in pregnant women.

Cases of the infection have been detected in HIV-positive individuals.

Investigators from the Swiss HIV Cohort Study wanted to see if hepatitis E infection was the cause for persistent elevations in ALT levels.

To be eligible for the study, patients were required to have two consecutive ALT measurements above 60 iu/l. Individuals with hepatitis B or hepatitis C were excluded.

Blood samples were tested for antibodies to hepatitis E and for hepatitis E RNA.

A total of 735 patients met the inclusion criteria and were included in the investigators’ analysis.

A total of 19 patients (2.6%) had antibodies to hepatitis E virus. The co-infection was associated with female sex (p = 0.059) and Asian origin (p = 0.007).

There was no evidence that age, HIV risk group, lowest ever CD4 cell count, HIV viral load, body mass index, or ALT values.

However, after adjustment for age and sex, the investigators found that patients with a CD4 cell count between 100 and 350 cells/mm³ were 4.7 times more likely to have hepatitis E antibodies than individuals with a CD4 cell count below 100 cells/mm³ (OR = 4.68; 95% CI, 1.26-17.29; p = 0.02).

Duration of ALT elevation was also associated with hepatitis E co-infection (OR = 1.01; 95% CI, 1.00-1.002; p = 0.02).

In 16 of the 19 co-infected patients, additional blood samples obtained a median of 6.6 months before the first ALT elevation were available. Seroconversion from a previous hepatitis E test was found in five patients (31%).

One of the patients with antibodies to the infection also had evidence of hepatitis E RNA . The virus was detected over a 24-month period, even though the individual was hepatitis E antibody-negative for half this period. The patient was a 46-year-old gay man who was diagnosed with HIV in June 2001. He started antiretroviral therapy with a CD4 cell count of only 34 cells/mm³. At this time his ALT level was normal, but increased one month later. He was positive for hepatitis E’s genetic material between August 2001 and December 2004. However, this was no longer detectable after his CD4 cell count reached 83 cells/mm³. His liver function normalised six months later, after his CD4 cell count had increased to above 100 cells/mm³.

The investigators were concerned that hepatitis E antibody tests may perform less well in patients with severe immune suppression.  Therefore blood samples from 53 hepatitis E virus antibody-negative patients with a low CD4 cell count (below 150 cells/mm³) were retested for hepatitis E viral load.

The virus’s genetic material was detected in one patient, a 59-year-old gay man who started antiretroviral therapy in October 1996 when his CD4 cell count was 140 cells/mm³. Despite HIV therapy, his CD4 cell count remained below 250 cells/mm³ for the next twelve years. He had hepatitis E RNA testing between March 2002 and April 2008. The virus’s genetic material was identified from 2005 to 2006.

“Taken together, our results suggest that serologic screening alone may be insufficient to diagnose hepatitis E virus infection in HIV-infected patients with very low CD4 count because seroconversion may be delayed or not occur,” comment the investigators.

Even though the prevalence of hepatitis E infection was low, the authors conclude, “when investigating unexplained, elevated ALT level in HIV-infected patients, we propose that hepatitis E virus infection should be considered.”