Cytokine and apoptosis gene polymorphisms influence the outcome of hepatitis C virus infection.

BACKGROUND: Hepatitis C virus (HCV) infection is thought to be chronic and the factors leading to viral clearance or persistence are poorly understood. This study was undertaken to investigate the possibility of a significant relationship between the spontaneous clearance or the persistence of hepatitis C virus (HCV) infection and cytokine and apoptosis gene polymorphisms in Tunisian patients on hemodialysis. METHODS: Polymorphisms of the genes IL-1 (-889 IL-1alpha, -511 and +3954 IL-1beta, IL-1Ra), IL-18 (-137 and -607), IL-12 (-1188) and Apo1/Fas (-670) were determined by PCR-RFLP, PCR-SSP and PCR-VNTR in 100 healthy blood donors and 100 patients infected with HCV and undergoing hemodialysis. The patients were classified into two groups: G1 consisted of 76 active chronic hepatitis patients (positive for HCV RNA) and G2 consisted of 24 hemodialysed patients who spontaneously eliminated the virus (negative for HCV RNA). RESULTS: The frequency of genotype association [-137GC/-607CA] IL-18 was higher in G2 (41.7%) than in G1 (15.8%) (P=0.008; OR=0.26; 95% CI, 0.10-0.73). We also found a higher frequency of the AA genotype of the Apo1/Fas gene in G2 (41.6%) than in G1 (17.5%) (P=0.026; OR=3.49; 95% CI, 1.13-10.69). Adjustment for known covariate factors (age, gender and genotype) confirmed these univariate findings and revealed that the genotype association GC-CA of the (-137 and -607) IL-18 gene and the AA genotype of the Apo1/Fas gene were associated with the clearance of HCV (P=0.041 and 0.017, respectively). CONCLUSION: The two genotypes GC-CA of the (-137 and -607) IL-18 polymorphism and the AA genotype of the Apo1/Fas gene influence the outcome of HCV infection in Tunisian patients on hemodialysis.

[Hepatitis C in kidney transplantation: comparative study between two Maghrebin centers: Casablanca and Tunis]. / L'hépatite virale C au cours de la transplantation rénale: étude comparative entre deux centres Maghrébins: Casablanca et Tunis.

BACKGROUND: Hepatitis viral C (HVC) is relatively frequent among kidney transplants. It is responsible for a morbid-mortality that compromises the results of transplantation in the medium and long term. AIM: To evaluate and to compare the prevalence of HVC, 172 kidney transplant adult patients were investigated in two Maghrebian centers at Casablanca (G1): 57 Moroccan patients and Tunisia (G2):.115 Tunisian patients. The impact of the HVC infection for a morbid-mortality was concerned only the Tunisian recipient patients: 20 kidney recipients having antibodies anti-VHC and positive HVC-RNA (Cases) which were matched in age, sex and date of the kidney graft, to 20 kidney transplant patients anti-HVC and VHCRNA negative (Controls). METHODS: The anti-VHC antibodies were detected by ELISA: Innogenetics and their positivity were confirmed by RIBAII. The ARN-VHC was analyzed by RT-PCR INNO-LiPA HCV II amplification of Innogenetics. RESULTS: The prevalence of hepatitis C is similar for the two groups: 19.3% among Moroccan kidney transplants and 20.9% among Tunisians. The infection by the HVC was often active and the detection of viral RNA was found in 91.7% of the G2 patients against 50% among G1 patients. The genotype 1b is the most prevalent; it is found in 59% of the patients. The frequency of HVC among our kidney transplant patients is particularly determined by the duration and the mode of dialysis. In fact, 22.1% of the patients treated by hemodialysis are VHC (+) against 5,6% patients treated by peritoneal dialysis. Also, the average duration of the dialysis is 58,8 months for HVC (+) patients against 33.5 months for HVC (-) (p<0.0001) patients. The frequency of the chronic rejection of the graft is higher in the G2, but it is similar in Tunisian patients with or without antibodies anti-HVC. In the G1, this frequency is statistically higher among positive HVC transplant patients compared to the negative HVC grafted patients (p<0.05). The case-control study emphasizes the frequency of the proteinuria, the renal insufficiency, the mellitensis diabetes and the polyglobulinemia among patients HCV (+); however the differences between the two groups remain statistically non significant. The total rate of the hospitalizations is 26 per 100 patients per year in the HCV (+) group against 17 for the HCV (-). The average duration of hospitalizations is 72 days among HCV (+) patients against 30.2 days for the controls (p<0.05). The averages of survival of the patients and of the controls were similar 11.6±5.6 years for transplant patient HCV (+) against 11.2±5.5 years for the controls. The actuarial curves of the patients were not different for the patients having antibodies anti-HCV positive or negative. CONCLUSION: The blood and nosocomial modes of contamination of HVC infection explain their higher frequency in this population at risk. The mortality and the morbidity of the renal transplant patients infected by the HCV seem to be higher compared to the uninfected patients. A further study by large population should be carried out to confirm these results.

Immunogenicity of antitumor necrosis factor therapy in patients with spondyloarthritis.

Objectives To evaluate the serum dosage of the biomedicine (DBM) and the incidence of antidrug antibody (ADA) against antitumor necrosis factor (TNF) in spondyloarthritis, and to demonstrate the influence of these parameters on the clinical efficiency. Methods We conducted a cross-sectional multicentric study including patients with spondylarthritis (SpA) under antiTNF (infliximab [INF], etanercept [ETA] and adalimumab [ADL]) for at least 6 months. A dosage of the ADA and DBM were practiced by the immuno-enzymatic essay. Result Seventy one patients were recruited. Disease modifying antirheumatic drugs (DMARDs) were associated with anti-TNF in 30%. ADA was positive in 54% for INF, 33% for ADL and 0% for ETA with a significant difference(p<0.0001). Immunogenicity was correlated to a bad therapeutic response (Bath Ankylosing Spondylitis Disease Activity Index [BASDAI]≥4)(p=0.04). The DBM was inversely correlated with the rate of ADA for patients treated with INF(p<0.0001) and ADL(p<0.0001). The DBM was also inversely correlated with BASDAI of INF(p=0.03) and ADL (p=0.01). ADA was significantly associated with an anterior switch of anti TNF(p=0.04), the use of INF(p=0.002), presence of coxitis(p=0.01) and higher body mass index (BMI)(p=0.007). DMARDs associated with anti TNF were not a protective factor for positive ADA. In a multivariate study, only INF and BMI were independent factors of positive ADA. Conclusion The ADA formation lowered the DBM and favored the therapeutic failure.

Natural evolution of hepatitis C virus infection in hemodialysis Tunisian patients and CTLA-4 SNP's.

AIM: To analyze the polymorphisms of CTLA-4 gene involved in the response against hepatitis C virus (HCV) infection. METHODS: We recruited 500 hemodialysed patients from several hemodialysis centers, all HCV-antibody positive, spread over different regions of Tunisia, as part of a national survey in 2008 conducted in the laboratory of immunology at the Charles Nicolle hospital Tunisia, classified into two groups G1 (PCR+) and G2 (PCR-) according to the presence or absence of viral RNA. Of these patients, 307 were followed prospectively on a viral molecular level over a period from 2002 to 2008, divided into two groups based on the persistence and viral clearance. PCR-RFLP was performed for the analysis of SNPs (+49) A/G and (+6230) G/A CTLA-4 for these 500 patients and 358 healthy controls. RESULTS: Analysis of clinical and virological characteristics of our cohort suggests a nosocomial infection in our hemodialysed patients with transfusion history as a primary risk factor and a predominance of genotype 1b. The haplotype analysis revealed an increase of frequencies of GG (+49)/(CT60) CTLA-4 in the entire patients group compared to controls (P = 0.0036 and OR = 1.42; 95%CI: 1.12-1.79, respectively). This haplotype is therefore associated with susceptibility to HCV infection. CONCLUSION: Our study suggests a possible role of CTLA-4 polymorphisms in the outcome of HCV infection in the Tunisian hemodialysed population.

Investigation of DNA sequence in the Basal core promoter, precore, and core regions of hepatitis B virus from Tunisia shows a shift in genotype prevalence.

BACKGROUND: In this study, we evaluated the prevalence of the most common mutations occurring in Enhancer II (EnhII), Basal Core Promoter (BCP), Precore (PC), and Core (C) regions of hepatitis B virus (HBV) genome. OBJECTIVES: We also investigated the correlation between HBV variants, their genotypes, and patients' HBe antigen (HBeAg: soluble shape of the capsid antigen) status. PATIENTS AND METHODS: We retrieved viral DNA from 40 serum samples of Tunisian patients positive for hepatitis B surface antigen (HBsAg) and HBV DNA, amplified the above mentioned regions using specific primers, and sequenced the corresponding PCR (polymerase chain reaction) products. For further analysis purpose, the patients were divided into two groups: Group1 including 34 HBeAg-negative patients and Group2 with 6 HBeAg-positive patients. RESULTS: Twenty-one patients (52.5%) showed PC G1896A mutation and 11 (27.5%) carried A1762T/G1764A double mutations. These mutations were more frequent in HBeAg-negative patients than that in HBeAg-positive ones. Indeed, 58.8% of patients bearing G1896A mutation were HBeAg-negative while 16.7% were positive. In patients bearing T1762/A1764 double mutation, 29.4% were positive and 16.7% were negative. In addition, the A1896 mutation was restricted to HBV isolates that had wild-type T1858, while C1858 was rather linked to the occurrence of T1762/A1764 mutation. Interestingly, this study revealed a high frequency of genotype E. This frequency was important as compared to that of genotype D known to be predominant in the country as delineated in previous studies. CONCLUSIONS: Previous results supported and showed that HBV strains present in Tunisia belonging to genotype D and, to a lesser extent, to genotype E, were prone to mutations in BCP/ PC regions. This observation was more obvious in HBV isolates from asymptomatic chronic carriers (AsC). The high mutational rates observed in our study might result from a mechanism of viral escape that plays an important role in the loss of HBeAg.