Role of nucleoside transporters SLC28A2/3 and SLC29A1/2 genetics in ribavirin therapy

Article · February 2011with71 Reads
DOI: 10.1097/FPC.0b013e32834412e7 · Source: PubMed
The standard of hepatitis C antiviral therapy combines pegylated interferon-α with ribavirin. This polar guanosine analog improves the sustained virological response (SVR) rates, but may induce hemolytic anemia. As its pharmacokinetics depend on facilitated transmembrane transport, we assessed whether variants in genes that code for concentrative (concentrative nucleoside transporters 2 and 3 coded by SLC28A2 and SLC28A3, respectively) and equilibrative nucleoside transporters (equilibrative nucleoside transporters 1 and 2 coded by SLC29A1 and SLC29A2, respectively) are associated with the therapy response and side effects. Patients (n=169) chronically infected with the hepatitis C virus genotype 1, treated with standard doses of pegylated interferon-α and weight-based doses of ribavirin for up to 48 weeks, were genotyped for 21 variants in nucleoside transporter genes SLC28A2, SLC28A3, SLC29A1, and SLC29A2, selected to include reported functional variants and to span the complete gene loci. The presence or absence of a SVR (n=169) and a relevant decrease (>3 g/dl, n=115) in blood hemoglobin were associated with the genotypes. The variant SLC28A3 haplotype rs10868138G/rs56350726T (allelic frequency 0.074) was associated with a lower incidence (35.5%) of relevant decreases (>3 g/dl) in blood hemoglobin than in noncarriers (64.3%; P=0.024, n=115). This protection against hemolytic anemia was not associated with decreased SVR rates (n=169). A genetic variant in SCL28A3 coding for the concentrative nucleoside transporter 3 protects patients with chronic hepatitis C against hemolytic anemia without affecting SVR in hepatitis C virus genotype 1.
  • [Show abstract] [Hide abstract] ABSTRACT: Advances in hepatitis C pharmacogenomics identified modulations of a sustained virologic response (SVR) by frequent IL28B gene variants and of ribavirin-induced hemolysis by frequent ITPA gene variants. These associations have been widely reproduced in various ethnicities, clinical settings and hepatitis C viral genotypes. The IL28B minor alleles rs8099917G, rs12979860T and rs12980275G have been associated with non-SVR whereas the ITPA minor alleles rs1127354A and rs7270101C were associated with less hemolytic side effects, an effect also attributed to a nucleoside transporter gene SLC28A3 rs10868138G/rs56350726T haplotype. The significance levels of these associations, especially in genome-wide studies, were very high. We nevertheless tested how good clinical outcomes of peginterferon α/ribavirin therapy, such as SVR or hemolytic side effects, were predicted by these variants. An analysis in an example dataset of 115 patients revealed that the prediction of non-SVR or hemolysis by single variants was often only slightly better than guessing. Using combinations of IL28B variants provided a higher accuracy (64.5%) of predicting non-SVR than with single IL28B variants (accuracy 60-63%). Similarly, a decline in blood hemoglobin by ≥3 g/dl could be better predicted at an accuracy of 70% (10% better than guessing) with a combination of an ITPA variant with a nucleoside transporter gene (SLC28A3) haplotype. Thus, genotyping information about single IL28B or ITPA variants is reproducibly and statistically significantly associated with hepatitis C therapy outcomes; however, the clinical predictive utility of single variants can be increased by combinations of genotypes.
    Full-text · Article · Dec 2011
  • [Show abstract] [Hide abstract] ABSTRACT: Insufficiently treated hepatitis C virus (HCV) infection remains a major healthcare issue. Individual therapy responses vary considerably from spontaneous clearing of the virus to lethal conditions. Host genetics currently receives a major scientific and clinical interest as an important source of interindividual variability in treatment. Mainly the associations of interleukin 28B gene (IL28B) variants with decreased HCV clearance under standard therapy are considered as "state of the art" of hepatitis C pharmacogenetics. However, a search in PubMed identified 41 genes reportedly modulating the individual therapy response, e.g., genes coding for major histocompatibility complex (HLA), the tumor necrosis factor (TNF), interleukin 10 (IL10), other interferon coding genes than IL28B (e.g., IFNAR1, IFNAR2, IFNG), several components of downstream interferon signaling as well as genes modulating side effects of current anti-HCV therapeutics (e.g., SLC28A3, ITPA involved in ribavirin associated hemolytic effects or SLC6A4 and HTR1A involved in serotonin associated psychiatric side effects). Applying knowledge discovery methods from the area of data mining and machine-learning to this comprehensive set of HCV therapy modulating genes, relating the HCV genes to the world wide knowledge on genes given in the form of the Gene Ontology (GO) knowledge base, found that the relevant genes belong to the GO subcategories of "inflammatory response" and "immune response" and "response to virus". This complex approaches to the pharmacogenomics of HCV may serve to identify future candidates for a personalization of HCV therapy and structured approach to possible new therapeutic targets for the control of hepatitis C virus.
    Full-text · Article · Mar 2012
  • [Show abstract] [Hide abstract] ABSTRACT: Ribavirin has been used as an antiviral agent for several decades. Although it has activity against numerous viruses, its major use clinically has been in the treatment of respiratory syncytial virus in paediatric patients and chronic HCV infection in both children and adults. This review highlights the clinical application and mechanism of action of ribavirin and discusses the future role of ribavirin in treatment of HCV where there are intense research efforts to improve therapy.
    Article · May 2012
  • [Show abstract] [Hide abstract] ABSTRACT: Drug-induced haemolytic anaemia is a rare adverse effect. Drugs implicated include β-lactam antibiotics, co-trimoxazole, ciprofloxacin, fludarabine, lorazepam and diclofenac. Men with G6PD deficiency are at greater risk of developing drug-induced haemolytic anaemia with a greater range of drugs.
    Article · Oct 2012
  • [Show abstract] [Hide abstract] ABSTRACT: To construct formulae for predicting the likelihood of ribavirin-induced anemia in pegylated interferon α plus ribavirin for chronic hepatitis C. Five hundred and sixty-one Japanese patients with hepatitis C virus genotype 1b who had received combination treatment were enrolled and assigned randomly to the derivation and confirmatory groups. Single nucleotide polymorphisms at or nearby ITPA were genotyped by real-time detection polymerase chain reaction. Factors influencing significant anemia (hemoglobin concentration < 10.0 g/dL at week 4 of treatment) and significant hemoglobin decline (declining concentrations > 3.0 g/dL at week 4) were analyzed using multiple regression analyses. Prediction formulae were constructed by significantly independent factors. Multivariate analysis for the derivation group identified four independent factors associated with significant hemoglobin decline: hemoglobin decline at week 2 [P = 3.29 × 10(-17), odds ratio (OR) = 7.54 (g/dL)], estimated glomerular filtration rate [P = 2.16 × 10(-4), OR = 0.962 (mL/min/1.73 m(2))], rs1127354 (P = 5.75 × 10(-4), OR = 10.94) and baseline hemoglobin [P = 7.86 × 10(-4), OR = 1.50 (g/dL)]. Using the model constructed by these factors, positive and negative predictive values and predictive accuracy were 79.8%, 88.8% and 86.2%, respectively. For the confirmatory group, they were 83.3%, 91.0% and 88.3%. These factors were closely correlated with significant anemia. However, the model could not be constructed, because no patients with rs1127354 minor genotype CA/AA had significant anemia. Reliable formulae for predicting the likelihood of ribavirin-induced anemia were constructed. Such modeling may be useful in developing individual tailoring and optimization of ribavirin dosage.
    Full-text · Article · Nov 2012
  • [Show abstract] [Hide abstract] ABSTRACT: Background & aims: In the last decade, pegylated interferon-α (PegIFN-α) plus ribavirin (RBV) was the standard treatment of chronic hepatitis C for genotype 1, and it remains the standard for genotypes 2 and 3. Recent studies reported associations between RBV-induced anemia and genetic polymorphisms of concentrative nucleoside transporters such as CNT3 (encoded by SLC28A3) and inosine triphosphatase (encoded by ITPA). We aimed at studying genetic determinants of RBV kinetics, efficacy and treatment-associated anemia. Methods: We included 216 patients from two Swiss study cohorts (61% HCV genotype 1, 39% genotypes 2 or 3). Patients were analyzed for SLC28A2 single nucleotide polymorphism (SNP) rs11854484, SLC28A3 rs56350726, and SLC28A3 rs10868138 as well as ITPA SNPs rs1127354 and rs7270101, and followed for treatment-associated hemoglobin changes and sustained virological response (SVR). In 67 patients, RBV serum levels were additionally measured during treatment. Results: Patients with SLC28A2 rs11854484 genotype TT had higher dosage- and body weight-adjusted RBV levels than those with genotypes TC or CC (p=0.02 and p=0.06 at weeks 4 and 8, respectively). ITPA SNP rs1127354 was associated with hemoglobin drop ≥3 g/dl during treatment, in genotype (relative risk (RR)=2.1, 95% CI 1.3-3.5) as well as allelic analyses (RR=2.0, 95%CI 1.2-3.4). SLC28A3 rs56350726 was associated with SVR in genotype (RR=2.2; 95% CI 1.1-4.3) as well as allelic analyses (RR=2.0, 95% CI 1.1-3.4). Conclusions: The newly identified association between RBV serum levels and SLC28A2 rs11854484 genotype, as well as the replicated association of ITPA and SLC28A3 genetic polymorphisms with RBV-induced anemia and treatment response, may support individualized treatment of chronic hepatitis C and warrant further investigation in larger studies.
    Full-text · Article · Nov 2012
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