In the last few years, IL28B gene polymorphisms have been extensively studied in HCV genotype 1-infected patients because of their predictive role in the treatment outcome and possible association with disease progression [5
]. When studied in different ethnic populations, it has been shown that allele distributions of IL28B SNPs are different between races and ethnic backgrounds [14
]. This is thought to partially explain the difference in response rates to current antiviral therapy between races and different HCV genotypes. Our analysis of IL28B allele frequencies in HCV-G4 patients of Arab ethnicity showed that the CC allele of rs12979860 and the AA allele of rs12980275 were associated with a significantly higher SVR.
To our knowledge, only three other groups have investigated the effect of a single IL28B SNP, rs12979860, on response to therapy in monoinfected HCV-G4 patients. In one study, Asselah et al. [17
] investigated 82 HCV-G4 infected patients from three different ethnic groups: Egyptians, Europeans, and sub-Saharan Africans. The SVR rates were 81.8, 46.5, and 29.4 % for genotypes CC, CT, and TT, respectively. In another study from Austria, in which Egyptian HCV-G4 patients (n
= 47) were included, a retrospective evaluation of the impact of the same SNP rs12979860 on virological relapse was performed [18
]. The study showed that individuals with a CC genotype were more likely to achieve SVR than those who carried the T allele. In addition, relapse was uncommon in HCV-G4 patients who achieved a rapid virological response. Although consistent with the results in individuals infected with HCV-G1, the low number of patients prevented authors from drawing firm conclusions in the G4 infected cohort [18
]. This has also been confirmed in a recent study conducted on 103 HCV-G4 infected patients of European and North African ethnicity again showing a strong predictive role of rs12979860 polymorphism on SVR [19
Generally, the genetic polymorphisms near the IL28B gene are associated with the virological nonresponse (no relapse), indicating possible resistance to interferon. Although the number of relapsers in our study was very low (6.2 %), we reanalyzed the five IL28B SNPs in association with nonresponse (excluding relapse) and found that the results were not different from the data presented.
Our present study, on the other hand, has multiple strengths that build on the scarce body of knowledge in HCV-G4. First, it is comparatively the largest study in a HCV-G4 infected cohort, including 129 patients. Second, all patients belong to the same ethnic group, thereby helping to unify the independent effect of ethnicity on the response to therapy and allowing for a more clear examination of the role of the studied SNPs. It is worth noting that while previous studies in HCV-G4 patients were conducted in Egyptian patients, ours was a Saudi population (i.e., North African versus Arab ethnicity). Previous studies have shown that genotype distributions of SNP rs128979860 were different in different ethnic groups [14
]. In line with this, Asselah et al. [17
] also reported differential frequencies of the C allele of rs12979860 among the three ethnic groups in their study, i.e. 61.4, 54.7, and 31.0 %, for patients of Egyptian, European, and sub-Saharan African origin, respectively. In our present study population of Arab (Saudi) ethnicity, the C allele was observed in 64 %, being closer to what was reported in Egyptians previously. Nevertheless, a significant association between IL28B and SVR remained in each ethnic group, as reported by De Nicola et al. [19
]. Finally, unlike other studies, we investigated the association of all five previously reported IL28B SNPs, albeit in other HCV genotypes, with the treatment response. With this approach we identified the association of two SNPs, rs12979860 and rs12980275 (Table ), with a higher response in HCV-G4, of which the former has been confirmed in the multivariate analysis.
Despite these strengths, our present study has some limitations. Principally, we were unable to include the early viral kinetics in our present study because of a lack of complete data on rapid virological response in some patients. In addition, all patients underwent a 48-week treatment regimen and did not undergo the recently suggested extension of treatment duration to 72 weeks in slow virological responders. However, the vast majority of our patients were treated prior to the recommendations for modifying treatment duration were made.
In a recent expert panel recommendation on the management of HCV-G4, no sufficient evidence was available to make any solid recommendations regarding the use of IL28B testing in the management of patients infected with this genotype [4
]. Based on our present study, as well as the study by Asselah et al. [17
] and De Nicola et al. [19
], it is clear that IL28B plays a major role in predicting the response to antiviral therapy in HCV-G4 patients, similar to other genotypes, arguing for a need to incorporate IL28B testing in guideline recommendations. Further studies are needed to elucidate how this important tool can now be used in clinical practice. Clearly, its use in selecting patients for treatment, determining the potential dose and duration of therapy, opting for two versus three medications, and many other relevant clinical questions remain to be studied.