SVR Rates and rs12979860 on Chromosome 19

In a GWAS, Ge et al. [Nature 2009] reported that a genetic polymorphism on chromosome 19, rs1297860, was strongly associated with SVR in all patient groups, with the Caucasian population sample showing overwhelming genomewide significance (p=1.06 × 10⁻²⁵) versus that seen in African-Americans (p=2.06 × 10⁻³). It is also known that the variants that are associated with SVR also influence natural clearance.

In patients with HCV genotypes 2 or 3 (n=341) who were treated with 12 or 24 weeks of pegIFN/RBV therapy, rs12979860 determined the first phase of viral elimination (p<0.001). In patients who were treated for 24 weeks, rs1279860 also predicted the rate of SVR (p=0.02), especially in those with high baseline hepatitis C virus ribonucleic acid (HCV RNA levels (p=0.02) or aged >45 years (p=0.01). Patients who carried the CC genotype had higher baseline HCV RNA levels (p<0.001). When treated for 12 weeks, they did not achieve SVR more often than those who were carrying CT or TT genotypes.

The results indicate that IL28B gene testing may identify HCV genotype 2 or 3 patients who could benefit from extended treatment [Lindh M et al. J Infect Dis 2011]. IL28B genotyping could also aid in PegIFN/RBV clinical decision-making and may be useful in the selection of candidates for triple therapy with PegIFNB/RBV plus direct-acting antiviral drugs [Marcias J et al. Curr Opin HIV AIDS 2011].

In a recent study of HCV, 4 patients who were treated with PegIFN/RBV, 49% achieved an SVR (88% in CC patients vs 37% in CT/TT patients; p<0.0001). CC patients had a rapid virologic response (RVR) more often than CT/TT patients (50% vs 23%; p=0.08), while also showing lower relapse rates (0% vs 36; p=0.0013). In non-RVR patients, SVR ratings were higher in CC than CT/TT patients (75% vs 23%; p=0.001). By logistic regression, the IL28B rs12979860 CC genotype was an independent predictor of SVR, with an odds ratio of 11.1 (95% CI, 3.04 to 40.57; p<0.0001) [De Nicola S et al. Hepatology 2011].

Looking for Answers in the Extremes: The CHAVI 014 Hemophilia Study

Translation of the genetic architecture of HCV into therapeutic opportunities has been slow [Thurs M et al. Semin Liver Dis 2011]. The specific mechanisms of how IL28B polymorphisms affect HCV suppression remain unknown, and how to incorporate current IL28B data into treatment algorithms with pegIFN and RBV is a matter of ongoing debate. However, new technology (eg, whole-genome sequencing) and searches at the extremes of disease transmission might provide new insights and knowledge.

The Center for HIV/AIDS Vaccine Immunology has been looking at a small cohort of hemophiliacs who had been exposed to HIV but remained uninfected despite receiving factor VIII concentrates that were derived from large pools of blood that was collected from donors, some of whom were infected with HIV.

The study, known as CHAV 014, set out to identify any key genetic determinants that might explain the apparent resistance of these exposed seronegatives (ESNs) to HIV. To date, whole-genome sequencing has failed to find any common genetic variants that are associated with HIV resistance among 393 non-HIV infected cases compared with 823 HIV-infected controls.

With the protective genes unlikely to be common ones, the search for much rarer genetic variants that may explain the ESNs' resistance to HIV infection is underway. In the past 2 years, researchers have identified close to 1000 rare variants of interest that might have contributed to protection against HIV acquisition in certain hemophiliacs.

According to Dr. Goldstein, the job now is to confirm genotypes of variants of interest by other techniques, sequence additional ESN and HIV-positive samples, and deep-sequence interesting genes. He concluded that there are sample and phenotype limitations in the study of infectious disease genomics. At the same time, natural variation offers a tremendous resource for leads into vaccine development and treatment.