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 co-infected with HIV may also nearly double the risk of death in patients taking antiretroviral therapy.

A study from Poland found that patients with the so-called 'CC' variant of mutation site rs 1979860 of the IL28B gene were 80% more likely to die during follow-up than patients with the other two possible variants, CT and TT (the letters refer to the particular bases, cytosine and thymine, at that point in the DNA molecule).

Interleukin (IL)28B is also called lambda interferon and is one of the family of natural immune modulators and virus-fighting chemicals produced by the body. Synthetic alpha 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 hepatitis C and not HIV who possessed the CC variant of the IL28B gene were much more likely both to clear hepatitis C from the body and to achieve a sustained viral response (SVR) in hepatitis C treatment. In initial studies, having the gene conferred a sevenfold improvement in treatment response in mono-infected people. The difference was not so dramatic in people co-infected 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 hepatitis C 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 responses 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 took longitudinal data on mortality in 484 patients, 84% of whom started antiretroviral therapy during the follow-up period (which followed people up to ten years) and did a genotype test on stored blood samples.

They found that 202 (42%) of patients had the CC variant, a figure consistent with other studies, 46% the CT variant and 12% the TT variant. There was no statistically significant association between any patient characteristic and their genotype, though there was a tendency for patients with CC to have had a higher CD4 nadir (lowest-ever CD4 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 (23%) of patients with the CC variant dying during the follow-up period compared with 38 (13.5%) of patients with CT or TT.

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

In multivariate analysis, the only patient characteristics significantly associated with mortality were female sex (women were 64% less likely to die than men) and CC genotype (people with it 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 people with IL28B CC 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 were unable to establish a difference between patients with CC variant and others.

One interesting fact is that despite being associated with higher levels of HIV treatment success, the CC gene variant is also associated with a higher HCV viral load and a higher risk of liver cirrhosis in people that don't clear infection. This suggests that the kind of lambda interferon you have might modulate inflammatory processes that, as we are familiar with in HIV, cause tissue damage and disease through immune overstimulation. But why, if the Polish study's findings are replicated, it only makes a difference in patients on antiretroviral therapy remains unexplained.

Parczewski M et al. IL28B gene polymorphisms and all-cause mortality in HIV infected patients. Thirteenth European AIDS conference, Belgrade. Abstract PS2/3. 2011.