Studying the Role of Programmed Cell Death-1 and Interleukin-28B Genetic Polymorphism in Treatment Outcome of HCV"

Abstract

Summary and conclusions C hronic hepatitis C is a worldwide resistant fatal problem, and represents a heavy burden in Egypt specifically. Egypt has long suffered from the curse of HCV with yearly 150,000-200,000 new infections mostly of genotype 4, a rare genotype in other parts of the world and thus receives less attention and studies than other frequent genotypes. The disease is frequently asymptomatic in its early stages, and becomes chronic in 70-80% of cases where years or decades may pass before affected individuals seek treatment. Clinicians have depended for years on PEG-IFN injections+ Ribavirin weight-based tablets as a mainstay of therapy for chronic HCV given for 24 or 48 weeks. The disappearance of HCV RNA from sera of patients after 6 months of stopping treatment is eventually associated in 99% of cases with treatment success. Despite the appearance of the new oral medications; DAAs, having better efficacy, shorter regimens, patient tolerability and convenience, yet, the extremely high cost, limited studies, possible resistance and relapse makes worldwide implementation a challenge. Moreover, in Egypt it is still advised that DAAs regimens be taken along with PEG-IFN+ RBV rendering it a backbone in the therapy and an economic option for patients incapable of paying for newer medications. However, since PEG-IFN/RBV is hampered by its long duration, the high burden of side effects, and failure of therapy in 40-60% of cases studies aiming to maximize use and regimen for this therapy are warranted. Several factors related to both the virus and the host and interplay between them, are emerging as possible effectors on treatment outcome or possible predictors for achieving SVR. One of the fields gaining growing interest especially among clinicians is how simple variations in host genetic SNPs could affect HCV therapeutic outcome. However, in Egypt well rounded, replicate studies taking into account different host and viral factors are still needed. Interleukin-28B, a gene involved in innate immunity and HCV virus elimination, has frequently been highlighted in the literature in the past few years as a strong predictor of HCV therapy outcome and a focus of much research. On the other hand, it had been declared as in sufficient for decision making on its own requiring other strong predictors. Co-inhibitory molecules as PD-1 and CTLA-4 are gaining wide attention and subsequently studied in areas pertaining to immunity, cancer and infectious diseases. Those molecules are associated with adaptive immunity and are among a family of receptors associated with T cells required for tolerance and proper immune regulation. However, in diseases as HCV they have been associated with T cell exhaustion and insufficient immune responses. Some SNPs associated with genes of these molecules have been suggested to affect their transcription and could be a reason for variable patient response to the disease and therapy. In this setting, this is the first study that aimed to analyze the role of IL28B (rs12979680), PD-1.3 (rs11568821) and CTLA-4 (rs231775) along with other potential viral and host clinical parameters collectively to predict SVR in HCV genotype 4 infected Egyptians in an attempt to eventually reach more accurate predictors of outcome would help clinicians optimize treatment plans and duration. In order to fulfil our aim, this study was conducted on 200 Egyptian subjects infected with chronic HCV and assigned to receive PEG-IFNα + RBV therapy and were divided according to response to treatment into the following two groups: a) Group I: SVR, included those who were HCV RNA negative 6 months post treatment and were 91 patients. b) Group II: NR, included those who failed to respond adequately to the treatment and were 109 patients. Patients were selected from those attending Yassin Abdulghafar hepatology center and Dr Nadia Al-Ansary center. They were diagnosed according to clinical and pathological investigations. For all subjects the following was done: 1) Routine pretreatment LFT's, AFP, TC, FBG, insulin, hematologic parameters, and viral load were measured. Calculation of BMI and HOMA-IR were also done. 2) Genetic SNPs were assessed by genotyping assays using real time PCR IL28B (rs12979680), PD-1.3 (rs11568821) and CTLA-4 (rs231775). Association of these factors with SVR was statistically examined and evaluated.