Can Helicobacter pylori be eradicated with high-dose proton pump inhibitor in extensive metabolizers with the CYP2C19 genotypic polymorphism?

Proton pump inhibitors (PPI) metabolism and pharmacokinetics are regulated by cytochrome P450 enzymes in the liver. Cytochrome P450 2C19 (CYP2C19) polymorphism plays an import role in the metabolism of PPIs. The three possible genotypes for CYP2C19 each has a distinct effect on the pharmacodynamics of PPIs. Homozygote extensive metabolizers (HomEM) are the most frequent genotype and have two wild-types (non-mutant) (*1/*1) alleles. HomEM is associated with increased enzyme activity, which increases the rate of PPI metabolism. Intragastric pH, which is required for eradication, is lowest in HomEM. In HomEMs, an insufficient increase in intragastric pH results in decreased anti-Helicobacter pylori (HP) efficacy of the antibiotics and, therefore, lower eradication rates. We determined whether the HP eradication rate would increase after high-dose PPI treatment of extensive PPI metabolizers who had been treated unsuccessfully with a standard PPI dose. In our report, increasing the PPI dosage in patients with genotype polymorphisms may be effective on eradication rates. Eradication rates are directly affected by CYP2C19 polymorphisms, and eradication treatments should be planned considering such genotypic polymorphisms. Hence, CYP2C19 genotyping prior to treatment may facilitate determination of the optimum PPI dose to improve the therapeutic outcome. However, further researches are required to confirm this hypothesis.

Steroid-refractory inflammatory bowel disease is a risk factor for CMV infection.

OBJECTIVE: Patients with inflammatory bowel disease (IBD) show increased the prevalence of cytomegalovirus (CMV) infection due to the severity of the disease and the immunosuppressive treatments they receive. The aim of this study was to determine the prevalence of CMV infection in IBD patients and identify the risk factors for CMV infection with different demographic characteristics in IBD patients. PATIENTS AND METHODS: We enrolled 85 patients diagnosed with IBD (43 with ulcerative colitis (UC) and 42 with Crohn's disease (CD)) in this prospective study. The clinical disease activities of UC and CD were assessed using Truelove-Witts and Crohn's disease activity index (CDAI). CMV infection was assessed by detection of DNA using real-time polymerase chain reaction (PCR) in blood samples and quantitative PCR in colonic biopsy specimens and by detection of inclusion bodies using hematoxylin-eosin staining. RESULTS: Thirteen patients with IBD exhibited concomitant CMV infection. CMV infection was not detected in any of the patients in remission. Viral loads measured in the colonic mucosa of infected patients ranged from 800-7000 genome copies/mL total extracted DNA. The mean serum CMV DNA level was 1694 ± 910 copies/mL (range: 800-3800). The rate of steroid resistance in CMV-positive cases was significantly higher than that in CMV-negative cases (p = 0.001). CD with acute exacerbation was a risk factor for CMV disease (p = 0.04). All of the CMV-positive patients received immunosuppressive treatments. CONCLUSIONS: CMV infection should be suspected in steroid-resistant UC and CD. Antiviral treatment improved the clinical outcome in steroid-resistant IBD cases with serum CMV DNA levels above 1000 copies/mL.

Effect of cytochrome P450 2C19 polymorphisms on the Helicobacter pylori eradication rate following two-week triple therapy with pantoprazole or rabeprazole.

OBJECTIVE: Cytochrome P450 2C19 (CYP2C19) polymorphisms play an important role in the metabolism of proton pump inhibitors. Rabeprazole is primarily metabolized via non-enzymatic pathways. In this study, we determined whether rabeprazole- and pantoprazole-based eradication treatments were influenced by CYP2C19 polymorphisms. PATIENTS AND METHODS: A total of 200 patients infected with Helicobacter pylori were treated with either 40 mg of pantoprazole or 20 mg of rabeprazole plus 500 mg of clarithromycin, 1000 mg of amoxicillin twice daily for 2 weeks. CYP2C19 genotype status was determined by Polymerase Chain Reaction (PCR)-restriction-fragment-length polymorphism. The genotypes of cytochrome P450 2C19 were classified as homozigote extensive metabolizer (HomEM), heterozigote metabolizer (HetEM) and poor metabolizer (PM). The CYP2C19 genotype of all patients, the effectiveness of the treatment, the effect of the genotypic polymorphism on the treatment were assessed. RESULTS: The frequencies of HotEM, HetEM, PM were 78%, 19.5% and 2.5%, respectively. 48% (n = 96) of the patients received treatment with rabeprazole and 52% (n = 104) with pantoprazole. The eradication rate was 64.7% for HomEM, 79.4% for HetEM, 100% for PM (p = 0.06). In HetEM, PM, are considered as a single group, the eradication rates were higher in patients with the HetEM and PM (HetEM+PM) genotypes than in those with the wild-type genotype (81.8 vs. 64.7% p = 0.031). Among the patients treated with rabeprazole, the eradication rates were significantly lower in those with the HomEM genotype than in those with the HetEM+PM genotypes (60% vs. 85.7% p = 0.023). CONCLUSIONS: The genotypic polymorphism is effective on the rate of eradication. Eradication treatment rate with rabeprazole is influenced by CYP2C19 genotype.

Treatment failure may lead to accelerated fibrosis progression in patients with chronic hepatitis C.

Chronic hepatitis C (CHC) patients with treatment failure (TF) remain at risk of continuing fibrosis progression. However, it has not been investigated whether there is an increased risk of accelerated fibrosis progression after failed interferon-based therapy. We aimed to investigate long-term influence of TF on fibrosis progression compared with untreated patients with CHC. We studied 125 patients with CHC who underwent paired liver biopsies from 1994 to 2012. Patients with advanced fibrosis were excluded from the analysis. Sixty-three patients had TF, and 62 patients were treatment-naïve (TN). Annual fibrosis progression rate (FPR) was calculated, and significant fibrosis progression (SFP) was defined as ≥ 2 stage increase in fibrosis during follow-up. Multiple regression analyses were performed to find out independent predictors of FPR and SFP. Demographic characteristics and duration between paired liver biopsies were similar in TF and TN groups. Baseline alanine aminotransferase and gamma-glutamyl transferase (GGT) levels (71 ± 31 vs 47 ± 22, P < 0.001 and 49 ± 39 vs 36 ± 28, P = 0.027, respectively), baseline mean fibrosis stage (2.2 ± 0.7 vs 1.9 ± 0.7, P = 0.018) and histologic activity index (6.3 ± 1.9 vs 4.3 ± 1.6, P < 0.001) were higher in the TF group compared with the TN group. In regression analyses, the strongest independent predictor of fibrosis progression was the GGT level (OR: 1.03, 95%CI 1.01-1.5, P < 0.001). Treatment experience (OR: 5.97, 95%CI 1.81-19.7, P = 0.003) also appeared as an independent predictor of both FPR and SFP. Failed interferon-based CHC treatment may lead to accelerated FPR in the long-term compared with the natural course.