KIR Genotypes Impact Progression to Hepatocellular Carcinoma in Patients with Chronic Hepatitis C Infection
Waleed AbdelmaguidDoha MaherMohamed KohlaSameera EzzatInas MoazWael Abdel-MageedKhalil El-HalfawyMohamed H. Abdel‐Rahman
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In Egypt, hepatocellular carcinoma (HCC) is the most prevalent cancer in men and the second most prevalent cancer in women. In addition, Egypt has one of the highest prevalences of hepatitis C infection in the world. The aim of the present work was to study the potential role of the 16 KIR genes in the outcome of individuals with chronic hepatitis C virus (HCV) infection in Egypt. The study was carried out under an IRB-approved protocol. Sequence-Specific-Primer-PCR (SSP-PCR) was used for KIR genotyping of germline DNA extracted from peripheral blood leukocytes or from the non-tumor liver of 83 HCC patients, 100 patients with chronic HCV infection without HCC, and 120 matched healthy controls. Out of the 83 HCC patients, only 7 (8.4%) were treated by interferon and/or interferon Ribavirin combination, while for the remaining patients 50 (60.2%) received no prior HCV therapy and 26 (31.3%) were treated with direct-acting antiviral (DAA). Our results showed that KIR haplotype AA that contains more inhibitory KIR genes and fewer activating genes was observed with a significantly lower frequency in HCC patients (6/83, 7.2%) compared to chronic HCV (27/100, 27.0%) (p = 0.0005, OR = 0.21 [0.08–0.53]) and healthy controls (29/119, 24.4%) (p = 0.001, OR = 0.24 [0.09–0.61]). In addition, the frequency of genotype 6 (G6) which contains all the KIR genes was significantly high in the HCC patients (16/83, 19.3%) compared to chronic HCV (8/100, 8.0%) (p = 0.02, OR = 2.7 [1.11–6.79]) and healthy controls (8/119, 6.7%) (p = 0.006, OR = 3.31 [1.35–8.16]). Activating KIR genes 2DS1 and 3DS1 were significantly higher in HCC patients (48/83, 57.83% and 45/83, 54.22%) compared to the chronic HCV patients (36/100, 36% and 34/100, 34%), p = 0.028, 0.027, respectively. Our results are contrary to a prior work on HCC from patients with HCV who were mostly treated by interferon-based therapies. In conclusion, KIR haplotype AA has an important role in host defense against HCC progression especially in patients treated by DAA, suggesting an important role of the KIR genotype status on the outcome of chronic HCV infection.Keywords:
Liver Cancer
Hepatitis C
Peginterferon alfa-2a
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Hepatitis C
Interferon alfa
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Ribavirin, once a staple of hepatitis C treatment, has significant drawbacks, including treatment-limiting side effects, the requirement for intensive laboratory monitoring, the need for frequent dose adjustments, and teratogenicity. These factors make it difficult to escalate ribavirin-based HCV treatment to most infected patients globally. Most studies have shown comparable response rates between ribavirin-inclusive and ribavirin-sparing regimens in uncomplicated patient populations. However, ribavirin is still used in the management of patients who have failed previous therapy as well as those with decompensated liver disease. In this review, we explore the evidence supporting the use of ribavirin in the current climate of hepatitis C treatment with oral combination direct-acting antiviral agents.
Hepatitis C
Limiting
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Objective: To assess the efficacy of combination therapy of Conventional interferon alpha-2b plus ribavirin in patients of chronic hepatitis C.
Methods: Records of 65 patients (43 males and 22 females) of chronic hepatitis C treated with combination therapy of interferon alpha-2b plus ribavirin from January 2003 to December 2003 were analyzed for base-line parameters, response rates and any adverse effects.
Results: End-treatment response was found in 86.04% male patients and 86.36% female patients. Sustained response was found in 81.39% male patients and 86.36% female patients.
Conclusions: The study shows that conventional interferon plus ribavirin combination therapy remains an effective therapy in the treatment of chronic hepatitis C naive patients in our set-up. (Rawal Med J 2005;30:9-11).
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Peginterferon alfa-2a
Interferon alfa
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Ribavirin is used as a component of combination therapies for the treatment of chronic hepatitis C virus (HCV) infection together with pegylated interferon and/or direct-acting antiviral drugs. Its mechanism of action, however, is not clear. Direct antiviral activity and immunomodulatory functions have been implicated. Plasmacytoid dendritic cells (pDCs) are the principal source of type 1 interferon during viral infection. The interaction of pDCs with HCV-infected hepatocytes is the subject of intense recent investigation, but the effect of ribavirin on pDC activation has not been evaluated. In this study we showed that ribavirin augments toll-like receptors 7 and 9-mediated IFNα/β expression from pDCs and up-regulated numerous interferon-stimulated genes. Using the H77S.3 HCV infection and replication system, we showed that ribavirin enhanced the ability of activated pDCs to inhibit HCV replication, correlated with elevated induction of IFNα. Our findings provide novel evidence that ribavirin contributes to HCV inhibition by augmenting pDCs-derived type 1 IFN production.
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TLR7
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Background/Aims Ribavirin significantly enhances the antiviral response of interferon-α (IFN-α) against Hepatitis C virus (HCV), but the underlying mechanisms remain poorly understood. Recently, p53 has been identified as an important factor involving the suppression of HCV replication in hepatocytes. We, therefore, decided to investigate whether and how ribavirin inhibits the replication of HCV by promoting the activity of p53. Methods HepG2 and HCV replicons (JFH1/HepG2) were utilized to study the relationship between ribavirin and p53. The effect of ribavirin on cell cycles was analyzed by flow cytometry. The activation of p53 and the signaling pathways were determined using immunoblotting. By knocking down ERK1/ERK2 and p53 utilizing RNA interference strategy, we further assessed the role of ERK1/2 and p53 in the suppression of HCV replication by ribavirin in a HCV replicon system. Results Using HepG2 and HCV replicons, we demonstrated that ribavirin caused the cell cycle arrest at G1 phase and stabilized and activated p53, which was associated with the antiviral activity of ribavirin. Compared to either ribavirin or IFN-α alone, ribavirin plus IFN-α resulted in greater p53 activation and HCV suppression. We further identified ERK1/2 that linked ribavirin signals to p53 activation. More importantly, knockdown of ERK1/2 and p53 partially mitigated the inhibitory effects of ribavirin on the HCV replication, indicating that ERK1/2-p53 pathway was involved in the anti-HCV effects of ribavirin. Conclusion Ribavirin stimulates ERK1/2 and subsequently promotes p53 activity which at least partly contributes to the enhanced antiviral response of IFN-α plus ribavirin against HCV.
Replicon
Hepatitis C
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Peginterferon alfa-2a
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Hepatitis C is a worldwide problem that frequently results in end-stage liver disease and its complications. Treatment for hepatitis C virus (HCV) has been rather ineffective but several recent studies have clarified the role of interferon and ribavirin therapy. In line with therapeutic progress in HIV infection, hepatitis C is now entering the era of multidrug antiviral therapy. Ribavirin is an orally active synthetic guanosine analogue with theoretical antiviral and immunomodulatory actions. In this review we have evaluated the role of interferon and ribavirin in treatment-naive patients, relapsers and non-responders. In naive patients the combination results in improved end-of-treatment and sustained response rates, with an overall 41% sustained virological response rate in patients treated for 48 weeks. Therapeutic benefit also extends to the traditionally difficult to treat patients (genotype 1, high vital load and advanced fibrosis). The addition of ribavirin to interferon has also resulted in an increased toxicity profile, which has made therapy more difficult for both the patient and managing physician. However, the significant improvement in response rates for all patients makes combination therapy the most appropriate choice as the first-line therapy for suitable patients with chronic viral hepatitis C. Appropriate management with interferon and ribavirin includes assessing the patient's HCV genotype to determine the optimal duration of therapy, assessing therapeutic efficacy by measuring HCV-RNA at 24 weeks and monitoring for the additional ribavirin side-effects.
Hepatitis C
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