Gene associated with increased risk of cirrhosis for HIV/HCV-co-infected patients

Michael Carter
Published:
24 May 2011

A genetic mutation is associated with an increased risk of cirrhosis for patients co-infected with HIV and hepatitis C, according to Spanish research published in the June 1st edition of the Journal of Infectious Diseases.

Carriage of the IL28B gene was the single biggest risk factor for cirrhosis, possibly explained by its association with long-term disturbances in liver function.

Paradoxically, earlier research has shown that individuals who carry the gene are more likely to spontaneously clear hepatitis C infection and respond to interferon-based therapies.

Glossary

FibroScan

A non-invasive test, used instead of a biopsy, to measure the stiffness or elasticity of the liver using an ultrasound probe.

IL28B

An inherited gene which all individuals have. There are three genotypes of IL28B; these influence response to hepatitis C and its treatment. People with CC genotype are more likely to spontaneously clear acute infection or (during chronic infection) respond well to interferon-based treatment. The other two genotypes are known as CT and TT.

Indeed, it was this relationship between the gene and improved outcomes that prompted investigators in Madrid and Andalusia to carry out a retrospective study to assess the gene’s association with cirrhosis.

The study involved 304 co-infected patients.

FibroScan, a non-invasive test that assesses liver stiffness, was used to assess the patients’ fibrosis stage. In addition, blood tests were used to monitor patients for the presence of the IL28B gene, and to determine hepatitis C genotype, liver function, and HIV-related parameters.

Participants had a mean age of 43 years, 80% were male, 86% were former injecting drug users, and 19% had a history of alcohol abuse. None of the patients had received hepatitis C therapy.

Most patients (85%) were taking antiretroviral therapy, and 79% had an undetectable HIV viral load. The mean CD4 cell count was 552 cells/mm3.

Abnormal liver function was common, and 72% of patients had ALT levels above the upper limit of normal. Mean hepatitis C viral load was 6.12 log10 copies iu/ml, and 68% had a level above 600,000 copies iu/ml. The harder to treat hepatitis C genotypes (1 and 4) were present in 68% of patients.

Cirrhosis was diagnosed in 18% of individuals. However, none of the patients had decompensated liver disease.

The IL28B gene was present in 46% of patients. Patients carrying this gene had significantly lower mean CD4 cell counts (518 vs 581 cells/mm3; p = 0.04), and there was also a trend for them to have higher mean ALT levels (93 vs 82 iu/ml; p = 0.14). Moreover, in the five years before baseline analysis, mean ALT levels were significantly greater in the IL28B carriers than other patients (p = 0.01).

FibroScan tests showed that liver stiffness values were significantly greater in carriers of the gene (p < 0.05), and these patients were also significantly more likely to have cirrhosis than non-carriers of the gene (24 vs 13%, p = 0.01).

In addition, patients with cirrhosis were also significantly older (43 vs 41 years; p = 0.04), had longer duration of hepatitis C infection (25 vs 23 years; p = 0.03), and were marginally more likely to have a history of alcohol abuse (28 vs 17%; p = 0.06).

Regardless of the hepatitis C genotype with which a patient was infected, the IL28B gene was associated with a greater prevalence of cirrhosis  (genotype 1: 28 vs 15%, p = 0.04; genotype 3: 22 vs 6%, p = 0.04; genotype 4: 18 vs 15%).

Statistical analysis that controlled for potential confounders showed that carriage of the IL28B gene was the single most important risk factor for the development of cirrhosis (odds ratio [OR] = 2.32; 95% CI, 1.22 to 4.41; p = 0.01).

By contrast, the association with older age (p = 0.08) and prior alcohol abuse (p = 0.07) was only of borderline significance.

Further analysis showed that patients carrying the IL28B gene developed cirrhosis more frequently and within a shorter duration of time than other individuals (hazard ratio = 3.02; 95% CI, 1.24 to 7.39; p = 0.015).

“HIV-HCV-coinfected patients carrying the IL28B…genotype are at greater risk of developing liver cirrhosis,” conclude the investigators; “enhanced immune-mediated damage in the liver of chronically HCV-infected persons who harbour the genotype could hypothetically explain these findings.”

Reference

Barreiro P et al. Influence of interleukin-28B single nucleotide polymorphisms on progression to liver cirrhosis in human immunodeficiency virus-hepatitis C virus-coinfected patients receiving antiretroviral therapy. J Infect Dis 203: 1629-36, 2011 (click here for the free abstract).