Coinfection

Larger Viral Decline during Hepatitis C Treatment in HIV/HCV Coinfected People with Favorable IL28B Pattern

HIV/HCV coinfected patients with the C/C IL28B gene pattern experience larger decreases in hepatitis C virus (HCV) levels during the first phase of viral decline after starting treatment with pegylated interferon plus ribavirin, and were more likely to achieve virological response, researchers reported in the December 19, 2010 advance online edition of the Journal of Acquired Immune Deficiency Syndromes. A similar effect was seen for second-phase viral decline in people with HCV genotype 1, but not genotype 3.

It is now well recognized that the pattern of genetic variations on chromosome 19 near the IL28B gene, which controls production of interferon lambda, is strongly associated with outcomes in people with hepatitis C. A single nucleotide polymorphism (SNP), or substitution of a single genetic building block, known as rs12979860 has been implicated most often.

This SNP has 2 natural variations -- dubbed "C" and "T" -- and each individual carries 2 copies, one from each parent. People with the C/C pattern are more likely to spontaneously clear HCV and respond better to interferon-based therapy than those with the C/T or T/T patterns. This association is strong in people with HCV alone. It has also been demonstrated, but may be weaker, in people with HIV/HCV coinfection.

In the present study, Evaldo Stanislau Affonso de Araoejo from the University of Sao Paulo in Brazil and colleagues examined the association between IL28B rs12979860 pattern and HCV kinetics (changes in virus levels) in this population during treatment with pegylated interferon plus ribavirin.

The analysis included 26 HIV/HCV coinfected patients from South America who were treated with pegylated interferon alfa-2a (Pegasys) and ribavirin. The researchers measured serum HCV RNA and interferon concentrations frequently during the first 12 weeks of therapy.

Results

• Black and white patients had a similar distribution of IL28B genetic variations (P = 0.5), in contrast with prior research suggesting that lower frequency of the favorable C/C pattern may help explain why blacks respond less well to interferon.
• The C/C gene pattern was over-represented among people with HCV genotype 3 compared with genotype 1 (P = 0.015).
• Among patients with HCV genotype 1 and genotype 3, first-phase viral decline immediately after starting therapy was larger -- and interferon effectiveness was greater -- in individuals with the C/C pattern compared with C/T or T/T.
• Among genotype 1 patients, the slower second-phase viral decline during days 2-29 was also larger, and infected cells were lost at a greater rate, in those with the C/C pattern.
• These associations were not observed, however, in people with HCV genotype 3.
• Rapid virological response (week 2) and complete early virological response (week 12) were significantly associated with the C/C gene pattern.
• 10 of 11 patients with C/T or T/T patterns failed to achieve sustained virological response (SVR), but the association between the C/C pattern and SVR did not reach statistical significance.

Overall, in HIV/HCV coinfected patients, the IL28B rs12979860 C/C gene pattern "was most strongly associated with a higher first-phase viral decline and greater average [pegyalted interferon] effectiveness during the first week of therapy," the study authors concluded. "These findings indicate that [pegyalted interferon] has greater efficacy in blocking HCV production/release in patients with the favorable IL28B CC-genotype."

They added that pharmacodynamic analysis showed that the IL28B C/C pattern "conferred increased sensitivity to [pegyalted interferon]," as shown by a lower EC50, or 50% effective concentration.

"These kinetic findings raise the possibility that the IL28B C/C genotype favorably affects viral response by augmenting [interferon lambda] mediated activation of the [interferon] signaling cascade, leading to increased effectiveness in blocking virion production/release," they explained. "Notably, as we approach a new era of combination therapy with [pegyalted interferon] and direct antiviral agents, a better understanding of factors associated with [pegyalted interferon]-related viral kinetics will provide the basis to develop optimal treatment strategies for HCV."

Investigator affiliations: University of Sao Paulo Hospital das Clinicas, Sao Paulo, Brazil; Department of Medicine, University of Illinois at Chicago, Chicago, IL; Bar Ilan University, Life Sciences Faculty, Ramat Gan, Israel.

1/11/10

Reference

ES Affonso de Araoejo, H Dahari, SJ Cotler, and others. Pharmacodynamics of PEG-IFN alpha-2a and HCV response as a function of IL28B polymorphism in HIV/HCV co-infected patients. Journal of Acquired Immune Deficiency Syndromes (Abstract). December 19, 2010 (Epub ahead of print).