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EACS 2011: IL28B Gene Variant that Helps Hepatitis C Treatment May Hinder HIV Treatment


A common variant in a gene that doubles the chance of hepatitis C treatment working in people coinfected with HIV may also nearly double the risk of death in patients taking antiretroviral therapy (ART), according to a report at the 13th European AIDS Conference (EACS 2011) last week in Belgrade.

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A study from Poland found that patients with the so-called CC variant of mutation site rs1979860 of the IL28B gene were 80% more likely to die during follow-up than patients with the other 2 possible variants, CT and TT (the letters refer to the particular bases, cytosine and thymine, at that point in the DNA molecule).

Interleukin 28B (IL28B), also called lambda interferon, is one of the family of natural immune modulators and virus-fighting chemicals produced by the body. Synthetic alfa interferon (in its more potent pegylated form) is standard therapy for hepatitis C, and lambda interferon has already been found to produce similar results with fewer side effects as hepatitis C treatment.

In 2009 scientists found that patients infected with HCV and not HIV who carried the CC variant of the IL28B gene were much more likely both to clear HCV from the body and to achieve sustained virological response (SVR) to hepatitis C treatment.

In initial studies, having the gene conferred a 7-fold improvement in treatment response in HCV monoinfected people. The difference was not so dramatic in people coinfected with HIV; they were not more likely to clear their infection, but the CC variant still doubled the likelihood of treatment success, at least in patients with HCV genotypes 1 and 4, the hardest to treat. Tests for the IL28B gene have now been included in some hepatitis C pre-treatment assays.

Researchers from the Pomeranian Medical University in Szczecin, Poland, decided to see if any IL28B variant was associated with response to HIV therapy, anticipating, as presenter Milosz Parczewski told the conference, that the CC variant might have similarly beneficial effects.

They found the opposite. The researchers collected longitudinal data on mortality for 484 patients, 84% of whom started antiretroviral therapy during the follow-up period (up to 10 years) and did a genotype test on stored blood samples.

They found that 202 patients (42%) had the CC variant, a figure consistent with other studies; 46% had the CT variant and 12% had the TT variant. There was no statistically significant association between any patient characteristic and their IL28B pattern, though there was a tendency for patients with CC to have had a higher CD4 nadir (lowest-ever CD4 cell count).

During the follow-up period, there were 84 deaths (approximately 17% of patients), 55 of them due to AIDS-related conditions and 29 not.

There were proportionately more deaths in patients with the CC genotype, with 46 patients (23%) with the CC variant dying during the follow-up period compared with 38 patients (14%) with CT or TT.

There was no difference at all in the death rate of patients who were not taking antiretroviral therapy, but the mortality rates started to differ as soon as patients started combination HIV therapy. In a univariate analysis, patients on HIV therapy with the CC variant were 1.8 times more likely to die than those with the CT or TT variants, and this was statistically significant (P = 0.029).

In a multivariate analysis, the only patient characteristics significantly associated with mortality were female sex (women were 64% less likely to die than men) and CC gene pattern (people with CC were 74% more likely to die; P = 0.048). In addition, people with a baseline CD4 count of less than 100 cells/mm3 were 80% more likely to die, though this just missed statistical significance (P = 0.051).

Why might HIV positive people on ART with the IL28B CC pattern be more likely to die? The Polish researchers found that people with the minority TT variant had a slightly lower baseline HIV viral load and higher highest-ever CD4 count, but they were unable to establish a difference between patients with the CC variant and others.

One interesting fact is that despite being associated with a higher degree of HIV treatment success, the CC gene variant is also associated with higher HCV viral load and higher risk of liver cirrhosis in people who do not clear the infection.

This suggests that the kind of lambda interferon might modulate inflammatory processes that -- as has been seen with HIV -- can cause tissue damage and disease through immune over-stimulation. But why, if the Polish study's findings are replicated, it only makes a difference for patients on antiretroviral therapy remains unexplained.

Investigator affiliations: Pomeranian Medical University, Department of Infectious Diseases and Hepatology, Szczecin, Poland; Regional Hospital of Szczecin, Department of Infectious Diseases, Szczecin, Poland.



M Parczewski, D Bander, M Leszczyszyn-Pynkaet al. IL28B Gene Polymorphisms and All-Cause Mortality in HIV Infected Patients. 13th European AIDS Conference (EACS 2011). Belgrade, October 12-15, 2011. Abstract PS2/3.