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1.  ITPA Gene Polymorphisms Significantly Affect Hemoglobin Decline and Treatment Outcomes in Patients Coinfected With HIV and HCV 
Journal of medical virology  2012;84(7):1106-1114.
Published studies have described a strong association with a single-nucleotide polymorphism (SNP) in the inosine triphosphate pyrophosphatase (ITPA) gene and ribavirin (RBV)-induced hemolytic anemia in HCV-infected patients receiving pegylated interferon (pegIFN) and RBV. This study sought to evaluate the effect of these polymorphisms on anemia, hemoglobin reduction, HCV kinetics, and treatment outcomes. Sixty-three patients coinfected with HIV and HCV and 58 patients infected with HCV only were treated with pegIFN/RBV were genotyped using the ABI Taq-Man allelic discrimination kit for the 2 ITPA SNP variants rs1127354 and rs7270101. A composite variable of ITPA deficiency using both SNPs was created as previously reported. Statistical analysis was performed using Mann-Whitney test or Chi square/Fishers exact test for categorical data and mixed model analysis for multiple variables. Thirty-five patients (30%) were predicted to have reduced ITPA activity. ITPA deficiency was found to be protective against the development of hemoglobin reduction >3 g/dl over the course of treatment. The rates of hemoglobin reduction >3 g/dl decreased in correlation with the severity of ITPA deficiency. ITPA deficiency was associated with slower hemoglobin decline early in treatment (week 4, P = 0.020) and rapid virologic response (RVR) at week 4 (P = 0.017) in patients coinfected with HIV and HCV. ITPA polymorphisms are associated with hemoglobin decline and in patients coinfected with HIV and HCV it is also associated with early virologic outcomes. Determination of ITPA polymorphisms may allow prediction of RBV-induced anemia and earlier initiation of supportive care to ensure optimal therapeutic outcomes.
PMCID: PMC3518921  PMID: 22585729
ribavirin-induced hemolytic anemia; ITPA; HIV/HCV; pharmacogenomics
2.  Limited Utility of ITPA Deficiency to Predict Early Anemia in HCV Patients with Advanced Fibrosis Receiving Telaprevir 
PLoS ONE  2014;9(4):e95881.
Severe anemia is a common side effect of Pegylated Interferon + Ribavirin (PR) and Telaprevir (TVR) in hepatitis C virus (HCV) genotype 1 patients with advanced fibrosis or cirrhosis (F3–F4). Inosine triphosphatase (ITPA) genetic variants are associated with RBV- induced anemia and dose reduction.
To test the association of ITPA polymorphisms rs1127354 and rs7270101 with hemoglobin (Hb) decline, need for RBV dose reduction (RBV DR), erythropoietin (EPO) support and blood transfusions during the first 12 weeks of TVR triple therapy.
Materials and Methods
69 consecutive HCV-1 patients (mean age 57 years) with F3-F4 who received PR and TVR were genotyped for ITPA polymorphisms rs1127354 and rs7270101. Estimated ITPA deficiency was graded on severity (0–3, no deficiency/mild/moderate/severe).
ITPA deficiency was absent in 48 patients (70%), mild in 12 (17%) and moderate in 9 patients (13%). Mean week 4 Hb decline was higher in non ITPA deficient patients (3,85 g/dL) than in mildly or moderately ITPA deficient patients (3,07 g/dL and 1,67 g/dL, p<0.0001). Grade 3–4 anemia developed in 81% non ITPA deficient patients versus 67% mild deficient and 55% moderate deficient patients (p = ns). Grade of ITPA deficiency was not associated with RbvDR (no deficiency: 60%, mild: 58%, moderate: 67%; p = ns), EPO use (no deficiency: 65%, mild: 58%, moderate:56%; p = ns) or need for blood transfusion (no deficiency: 27%, mild: 17%, moderate: 33%; p = ns).
In patients with F3–F4 chronic hepatitis C receiving TVR based therapy, ITPA genotype does not impact on the management of early anemia.
PMCID: PMC3997406  PMID: 24760000
3.  Association of ITPA Gene Polymorphisms and the Risk of Ribavirin-Induced Anemia in HIV/Hepatitis C Virus (HCV)-Coinfected Patients Receiving HCV Combination Therapy 
Polymorphisms of the ITPA gene have been associated with anemia during combination therapy in hepatitis C virus (HCV)-monoinfected patients. Our aim was to confirm this association in HIV/HCV-coinfected patients. In this prospective, observational study, 73 HIV/HCV-coinfected patients treated with pegylated interferon plus ribavirin (RBV) were enrolled. Two single nucleotide polymorphisms within or adjacent to the ITPA gene (rs1127354 and rs7270101) were genotyped. The associations between the ITPA genotype and anemia or treatment outcome were examined. Fifty-nine patients (80.8%) had CC at rs1127354, whereas 14 (19.2%) had a CA/AA ITPA genotype. Percent decreases from baseline hemoglobin level were significantly greater in patients with the CC genotype than in those with the CA/AA genotype at week 4 (P = 0.0003), week 12 (P < 0.0001), and week 36 (P = 0.0102) but not at the end of treatment. RBV dose reduction was more often needed in patients with the CC genotype than in those with the CA/AA genotype (odds ratio [OR] = 11.81; 95% confidence interval [CI] = 1.45 to 256.17; P = 0.0039), as was erythropoietin therapy (OR = 8.28; 95% CI = 1.04 to 371.12; P = 0.0057). Risk factors independently associated with percent hemoglobin nadir decrease were RBV dose reduction (OR = 11.72; 95% CI = 6.82 to 16.63; P < 0.001), baseline hemoglobin (OR = 1.69; 95% CI = 0.23 to 3.15; P = 0.024), and body mass index (OR = −0.7; 95% CI = −1.43 to 0.03; P = 0.061). ITPA polymorphism was not an independent predictor of sustained virological response. Polymorphisms at rs1127354 in the ITPA gene influence hemoglobin levels during combination HCV therapy and the need for RBV dose reduction and erythropoietin use in HIV/HCV-coinfected patients.
PMCID: PMC3370811  PMID: 22430973
4.  Variants in the ITPA Gene Protect Against Ribavirin-Induced Hemolytic Anemia in HIV/HCV-Coinfected Patients With All HCV Genotypes 
The Journal of Infectious Diseases  2011;205(3):376-383.
Background. A recent genome-wide association study reported a strong association with a single-nucleotide polymorphism (SNP) in the inosine triphosphate (ITPA) gene and hemolytic anemia in patients infected with hepatitis C virus (HCV) receiving pegylated interferon and ribavirin. We investigate these polymorphisms in a cohort of human immunodeficiency virus (HIV)/HCV–coinfected patients.
Methods. DNA was available for 161 patients with validated outcomes. We analyzed the association between the variants and week 4 hemoglobin reduction. Anemia over the course of therapy, ribavirin (RBV) dose reduction, serum RBV level, and rapid virological response (RVR) and sustained virological response (SVR) were also investigated. Using a candidate gene approach, ITPA variants rs1127354 and rs7270101 were tested using the ABI TaqMan kit. Multivariable models were used to identify predictors of anemia.
Results. A significant minority (33%) of patients were predicted to have reduced ITPase activity. The minor allele of each variant was associated with protection against week 4 anemia. In multivariable models only the genetic variants, creatinine, and zidovudine exposure remained significant. ITPase deficiency was not associated with RBV-dose reduction, RVR, or SVR.
Conclusions. This study confirms that polymorphisms in the ITPA gene are associated with protection from RBV-induced anemia in HIV/HCV-coinfected patients but not improved clinical outcomes.
PMCID: PMC3283113  PMID: 22158703
5.  The Impact of Inosine Triphosphatase Variants on Hemoglobin Level and Sustained Virologic Response of Chronic Hepatitis C in Korean 
Journal of Korean Medical Science  2013;28(8):1213-1219.
Two variants of the inosine triphosphatase (ITPA: rs1127354, rs7270101) gene cause ITPA deficiency and protect against the hemolytic toxicity of ribavirin. We investigated the clinical significance of ITPA variants in Korean patients treated with pegylated interferon (PEG-IFN) plus ribavirin. Of the 133 patients, 108 were CC and 25 were non-CC at rs1127354 (groups A and B, respectively). On the other hand, at rs7270101 all 133 were AA. The mean values of Hemoglobin (Hgb) after 4, 8, and 12 weeks of treatment in groups A and B were 12.2 and 14.0, 11.8 and 13.2, and 11.5 and 12.9, respectively (P=0.001, 0.036, 0.036). Sustained virologic response (SVR) was achieved in 67.8% (40/59) of genotype 1 patients and in 75% (27/36) of non-genotype 1 patients. Regarding ITPA variants, SVR was achieved by 66% and 80% of genotype 1 (P=0.282), and by 78% and 71% (P=0.726) of non-genotype 1. SVR was not significantly different in groups A and B. In conclusion, non-CC at rs1127354 without involvement of rs7270101 is strongly associated with protection from ribavirin-induced anemia, however, ITPA genotype is not associated with SVR.
PMCID: PMC3744711  PMID: 23960450
Hepatitis C, Chronic; Ribavirin; Anemia; ITPA; IL28B
6.  Roles of ITPA and IL28B Genotypes in Chronic Hepatitis C Patients Treated with Peginterferon Plus Ribavirin  
Viruses  2012;4(8):1264-1278.
It has been reported that inosine triphosphatase (ITPA) gene variants protect against ribavirin-induced anemia in patients treated for chronic hepatitis C. IL28B variants also influence the treatment response of peginterferon plus ribavirin treatment in these patients. In the present study, we examined how ITPA and IL28B genotypes have clinical impacts on treatment-induced hematotoxicities and treatment response in HCV-infected patients treated with peginterferon plus ribavirin. ITPA genotypes (rs1127354 and rs6051702) and IL28B genotype (rs8099917) were determined by TaqMan SNP assay. We compared clinical background, treatment course and treatment response in terms of these genotypes. Only IL28B rs8099917 major type could predict sustained virological response. ITPA rs1127354 major type leads to significantly greater ribavirin-induced anemia than ITPA rs1127354 minor type between days 0 and 84. We noticed that IL28B rs8099917 minor genotype was associated with higher reduction of neutrophils and platelets. ITPA rs1127354 is useful for the prediction of ribavirin-induced anemia in the early phase after the commencement of peginterferon plus ribavirin treatment and IL28B rs8099917 is useful for the prediction of sustained virological response. Use of the combination of these two genotypes could lead to safe and effective treatment of chronic hepatitis C patients.
PMCID: PMC3446761  PMID: 23012624
Anemia; HCV; IL28B; ITPA; SNP; sustained virological response
7.  Variants in the ITPA Gene Protect Against Ribavirin-Induced Hemolytic Anemia and Decrease the Need for Ribavirin Dose Reduction 
Gastroenterology  2010;139(4):1181-1189.
In a genome-wide association study of patients being treated for chronic hepatitis C, 2 functional variants in ITPA that cause inosine triphosphatase (ITPase) deficiency were shown to protect against ribavirin (RBV)-induced hemolytic anemia during early stages of treatment. We aimed to replicate this finding in an independent cohort from the Study of Viral Resistance to Antiviral Therapy of Chronic Hepatitis C and to investigate the effects of these variants beyond week 4.
Genetic material was available from 318 patients. The ITPA variants, rs1127354 (exon 2, P32T) and rs7270101 (intron 2, splice altering), were genotyped and tested for association with hemoglobin (Hb) reduction at week 4. An ITPase deficiency variable was defined that combined both ITPA variants according to documented effect on ITPase activity. We investigated the impact of ITPA variants on Hb levels over the course of therapy and on the need for RBV dose reduction.
The final analysis included 304 patients with genotype 1 hepatitis C virus (167 white patients and 137 black patients). The polymorphisms rs1127354 and rs7270101 were associated with Hb reduction at week 4 (P = 3.1 × 10−13 and 1.3 × 10−3, respectively). The minor alleles of each variant protected against Hb reduction. Combining the variants into the ITPase deficiency variable strengthened the association (P = 2.4 × 10−18). The ITPase deficiency variable was associated with lower rates of anemia over the entire treatment period (48 weeks), as well as a lower rate of anemia-related RBV dose reduction (hazard ratio, 0.52; P = .0037). No association with sustained virological response was observed.
Two polymorphisms that cause ITPase deficiency are strongly associated with protection from RBV-induced hemolytic anemia and decrease the need for RBV dose reduction.
PMCID: PMC3086671  PMID: 20547162
Pharmacogenomics; Genome-Wide Association Study; Polymorphism; Single Nucleotide Polymorphism; HCV; Adverse Event
8.  Pre-treatment role of inosine triphosphate pyrophosphatase polymorphism for predicting anemia in Egyptian hepatitis C virus patients 
AIM: To investigate and clarify, for the first time, the role of inosine triphosphate pyrophosphatase (ITPA) polymorphism in Egyptian chronic hepatitis C virus (HCV) patients.
METHODS:The human genomic DNA of all patients was extracted from peripheral blood cells in order to determine the single nucleotide polymorphism (SNP) of ITPA (rs1127354). SNP genotyping was performed by real time polymerase chain reaction (PCR, ABI TaqMan allelic discrimination kit) for 102 treatment-naive Egyptian patients with chronic HCV. All patients had no evidence of cardiovascular or renal diseases. They received a combination treatment of pegylated interferon α (PEG-IFNα) as a weekly subcutaneous dose plus an oral weight-adjusted dose of ribavirin (RBV). The majority received PEG-IFNα2a (70.6%) while 29.4% received PEG-IFNα2b. The planned duration of treatment was 24-48 wk according to the viral kinetics throughout the course of treatment. Pre-treatment liver biopsy was done for each patient for evaluation of fibrosis stage and liver disease activity. The basal viral load level was detected quantitatively by real time PCR while viral load throughout the treatment course was performed qualitatively by COBAS TaqMan assay.
RESULTS: Ninety-three patients (91.2%) had ITPA SNP CC genotype and 9 (8.8%) had non-CC genotype (CA and AA). The percentage of hemoglobin (Hb) decline was higher for CC patients than for non-CC patients, particularly at weeks 4 and 8 (P = 0.047 and 0.034, respectively). During the first 12 wk of treatment, CC patients had significantly more Hb decline > 3 g/dL than non-CC patients: 64.5% vs 22.2% at weeks 8 and 12, respectively, (P = 0.024 and 0.038). Reduction of the amount of the planned RBV dose was significantly higher for CC patients than non-CC patients during the first 12 wk (18% ± 12.1% vs 8.5% ± 10.2%, P = 0.021). The percentage of CC patients with RBV dose reduction was significantly greater than that of non-CC patients (77.4% vs 44.4%, P = 0.044). Multivariate analysis identified only the percentage of RBV dose as a predictor for Hb decline. Platelet decline was significantly higher in non-CC patients than CC patients at weeks 12, 24 and 48 (P = 0.018, 0.009 and 0.026, respectively).
CONCLUSION: Rs1127354 ITPA polymorphism plays a decisive role in protecting against treatment-induced anemia and the need for RBV dose reduction in Egyptian HCV patients.
PMCID: PMC3602498  PMID: 23538996
Anemia; Dose reduction; Hepatitis C; Inosine triphosphate; Ribavirin; Rs1127354
9.  Erythropoietin rs1617640 G allele associates with an attenuated rise of serum erythropoietin and a marked decline of hemoglobin in hepatitis C patients undergoing antiviral therapy 
BMC Infectious Diseases  2014;14(1):503.
A decline in hemoglobin (Hb) concentration during antiviral therapy in chronic hepatitis C (CHC) is a serious side effect. It may compel to dose reduction or even termination of antiviral treatment. The activation of erythropoietin (EPO) synthesis as a physiological response to anemia and its relation to a genetic variation within the EPO gene has not been evaluated yet.
Data of 348 CHC patients were reviewed retrospectively. Samples were genotyped for EPO rs1617640 and inosine triphosphatase (ITPA) rs1127354. Serum EPO concentrations were determined before and during therapy. Primary endpoints were set as Hb decline >3 g/dl at weeks 4 and 12.
EPO rs1617640 G homozygotes showed a significantly lower rise of serum EPO level over time than T allele carriers (p < 0.001). The cumulative frequency of a significant Hb reduction added up to 40%. Multivariate analysis revealed that besides age, ribavirin starting dose and baseline Hb also EPO rs1617640 G homozygosity associates with Hb reduction at week 4 (p = 0.025) and 12 (p = 0.029), while ITPA C homozygotes are at risk for Hb decline particularly early during treatment. Furthermore, EPO rs1617640 G homozygotes were more frequently in need for blood transfusion, epoetin-α supplementation, or ribavirin dose reduction (p < 0.001).
Our data suggest that EPO rs1617640 genotype, the rise of serum EPO concentration as well as ITPA rs1127354 genotype are promising parameters to evaluate the Hb decline during antiviral therapy. A rational adjustment of therapy with epoetin-α supplementation might prevent serious adverse events or the need to terminate treatment.
PMCID: PMC4175618  PMID: 25227310
Anemia; Chronic hepatitis C virus infection; Ribavirin; EPO promoter polymorphism rs1617640; ITPA rs1127354
10.  IL28B But Not ITPA Polymorphism Is Predictive of Response to Pegylated Interferon, Ribavirin, and Telaprevir Triple Therapy in Patients With Genotype 1 Hepatitis C 
Background. Pegylated interferon, ribavirin, and telaprevir triple therapy is a new strategy expected to eradicate the hepatitis C virus (HCV) even in patients infected with difficult-to-treat genotype 1 strains, although adverse effects, such as anemia and rash, are frequent.
Methods. We assessed efficacy and predictive factors for sustained virological response (SVR) for triple therapy in 94 Japanese patients with HCV genotype 1. We included recently identified predictive factors, such as IL28B and ITPA polymorphism, and substitutions in the HCV core and NS5A proteins.
Results. Patients treated with triple therapy achieved comparatively high SVR rates (73%), especially among treatment-naive patients (80%). Of note, however, patients who experienced relapse during prior pegylated interferon plus ribavirin combination therapy were highly likely to achieve SVR while receiving triple therapy (93%); conversely, prior nonresponders were much less likely to respond to triple therapy (32%). In addition to prior treatment response, IL28B SNP genotype and rapid viral response were significant independent predictors for SVR. Patients with the anemia-susceptible ITPA SNP rs1127354 genotype typically required ribavirin dose reduction earlier than did patients with other genotypes.
Conclusions. Analysis of predictive factors identified IL28B SNP, rapid viral response, and transient response to previous therapy as significant independent predictors of SVR after triple therapy.
PMCID: PMC3307155  PMID: 21628662
11.  Genome-wide association study of interferon-related cytopenia in chronic hepatitis C patients 
Journal of hepatology  2011;56(2):313-319.
Background & Aims
Interferon-alfa (IFN)-related cytopenias are common and may be dose-limiting. We performed a genome wide association study on a well-characterized genotype 1 HCV cohort to identify genetic determinants of peginterferon-α (peg-IFN)-related thrombocytopenia, neutropenia, and leukopenia.
1604/3070 patients in the IDEAL study consented to genetic testing. Trial inclusion criteria included a platelet (Pl) count ≥80 × 109/L and an absolute neutrophil count (ANC) ≥ 1500/mm3. Samples were genotyped using the Illumina Human610-quad BeadChip. The primary analyses focused on the genetic determinants of quantitative change in cell counts (Pl, ANC, lymphocytes, monocytes, eosinophils, and basophils) at week 4 in patients >80% adherent to therapy (n = 1294).
6 SNPs on chromosome 20 were positively associated with Pl reduction (top SNP rs965469, p = 10−10). These tag SNPs are in high linkage disequilibrium with 2 functional variants in the ITPA gene, rs1127354 and rs7270101, that cause ITPase deficiency and protect against ribavirin (RBV)-induced hemolytic anemia (HA). rs1127354 and rs7270101 showed strong independent associations with Pl reduction (p = 10−12, p = 10−7) and entirely explained the genome-wide significant associations. We believe this is an example of an indirect genetic association due to a reactive thrombocytosis to RBV-induced anemia: Hb decline was inversely correlated with Pl reduction (r = −0.28, p = 10−17) and Hb change largely attenuated the association between the ITPA variants and Pl reduction in regression models. No common genetic variants were associated with pegIFN-induced neutropenia or leucopenia.
Two ITPA variants were associated with thrombocytopenia; this was largely explained by a thrombocytotic response to RBV-induced HA attenuating IFN-related thrombocytopenia. No genetic determinants of pegIFN-induced neutropenia were identified.
PMCID: PMC3634361  PMID: 21703177
GWAS; ITPA; Thrombocytopenia; Hepatitis C; Neutropenia; IL28B
12.  Ribavirin-Induced Anemia in Hepatitis C Virus Patients Undergoing Combination Therapy 
PLoS Computational Biology  2011;7(2):e1001072.
The current standard of care for hepatitis C virus (HCV) infection – combination therapy with pegylated interferon and ribavirin – elicits sustained responses in only ∼50% of the patients treated. No alternatives exist for patients who do not respond to combination therapy. Addition of ribavirin substantially improves response rates to interferon and lowers relapse rates following the cessation of therapy, suggesting that increasing ribavirin exposure may further improve treatment response. A key limitation, however, is the toxic side-effect of ribavirin, hemolytic anemia, which often necessitates a reduction of ribavirin dosage and compromises treatment response. Maximizing treatment response thus requires striking a balance between the antiviral and hemolytic activities of ribavirin. Current models of viral kinetics describe the enhancement of treatment response due to ribavirin. Ribavirin-induced anemia, however, remains poorly understood and precludes rational optimization of combination therapy. Here, we develop a new mathematical model of the population dynamics of erythrocytes that quantitatively describes ribavirin-induced anemia in HCV patients. Based on the assumption that ribavirin accumulation decreases erythrocyte lifespan in a dose-dependent manner, model predictions capture several independent experimental observations of the accumulation of ribavirin in erythrocytes and the resulting decline of hemoglobin in HCV patients undergoing combination therapy, estimate the reduced erythrocyte lifespan during therapy, and describe inter-patient variations in the severity of ribavirin-induced anemia. Further, model predictions estimate the threshold ribavirin exposure beyond which anemia becomes intolerable and suggest guidelines for the usage of growth hormones, such as erythropoietin, that stimulate erythrocyte production and avert the reduction of ribavirin dosage, thereby improving treatment response. Our model thus facilitates, in conjunction with models of viral kinetics, the rational identification of treatment protocols that maximize treatment response while curtailing side effects.
Author Summary
The treatment of HCV infection poses a major global health-care challenge today. The current standard of care, combination therapy with interferon and ribavirin, works in only about half of the patients treated. Because no alternatives are available yet for patients in whom combination therapy fails, identifying ways to improve response to combination therapy is critical. Increasing exposure to ribavirin does improve response but is associated with the severe side-effect, anemia. One way to maximize treatment response therefore is to increase ribavirin exposure to levels just below where anemia becomes intolerable. A second way is to supplement combination therapy with growth hormones, such as erythropoietin, that increase the production of red blood cells (erythrocytes) and compensate for ribavirin-induced anemia. Rational optimization of combination therapy thus relies on a quantitative description of ribavirin-induced anemia, which is currently lacking. Here, we develop a model of the population dynamics of erythrocytes in individuals exposed to ribavirin that quantitatively describes ribavirin-induced anemia. Model predictions capture several independent observations of ribavirin-induced anemia in HCV patients undergoing combination therapy, estimate the threshold ribavirin exposure beyond which anemia becomes intolerable, suggest guidelines for the usage of growth hormones, and facilitate rational optimization of therapy.
PMCID: PMC3033369  PMID: 21304937
13.  Early Predictors of Anemia in Patients with Hepatitis C Genotype 1 Treated with Peginterferon alfa-2a (40KD) plus Ribavirin 
Adherence to ribavirin is one factor that is critically important in the treatment of hepatitis C virus infection. However, ribavirin can be associated with clinically significant hemolytic anemia resulting in dose modifications in up to one-quarter of patients. Currently, baseline predictors of considerable anemia are not sufficiently discriminating for routine therapeutic intervention. The objective of this analysis was to elucidate baseline and on-treatment factors predictive of a considerable hemoglobin drop at week 4.
Multiple logistic regression analysis was used to explore possible predictors for considerable hemoglobin decline (≥2.5 g/dL) at week 4 among patients receiving peginterferon alfa-2a (40KD) and ribavirin (1000/1200 mg/day).
A total of 555 patients were included in this analysis. At week 4, 236 patients exhibited a ≥2.5 g/dL decrease in hemoglobin. By regression analysis the most important independent variables associated with a decrease in hemoglobin of ≥2.5 g/dL were baseline creatinine clearance (p=0.0003) and a rapid decline in hemoglobin of ≥1.5 g/dL at week 2 (p<0.0001). Considerable hemoglobin decreases at week 4 were also significantly associated with early ribavirin dose reductions and a lower cumulative daily dose of ribavirin.
Patients with impaired renal function may be at an increased risk of ribavirin-related anemia and should be monitored accordingly. Furthermore, a hemoglobin drop of ≥1.5 g/dL by week 2 was an excellent early predictor for subsequent considerable hemoglobin decreases and might be used to identify candidates for early intervention against anemia in order to help maintain ribavirin dosing and avoid suboptimal exposure.
PMCID: PMC2752675  PMID: 18796095
HCV; PEGASYS; pegylated interferon; safety; hemoglobin
14.  Association of ITPA polymorphism with outcomes of peginterferon-α plus ribavirin combination therapy 
AIM: To analyzed the association between inosine triphosphatase (ITPA) (rs1127354) genotypes and sustained virological response (SVR) rates in peginterferon (Peg-IFN)α + ribavirin (RBV) treatment.
METHODS: Patients who underwent Peg-IFNα + RBV combination therapy were enrolled (n = 120) and they had no history of other IFN-based treatments. Variation in hemoglobin levels during therapy, cumulative reduction of RBV dose, frequency of treatment withdrawal, and SVR rates were investigated in each ITPA genotype.
RESULTS: In patients with ITPA CC genotype, hemoglobin decline was significantly greater and the percentage of patients in whom total RBV dose was < 60% of standard and/or treatment was withdrawn was significantly higher compared with CA/AA genotype. However, SVR rates were equivalent between CC and CA/AA genotypes, and within a subset of patients with Interleukin 28B (IL28B) (rs8099917) TT genotype, SVR rates tended to be higher in patients with ITPA CC genotype, although the difference was not significant.
CONCLUSION: ITPA CC genotype was a disadvantageous factor for Peg-IFNα + RBV treatment in relation to completion rates and RBV dose. However, CC genotype was not inferior to CA/AA genotype for SVR rates. When full-length treatment is accomplished, it is plausible that more SVR is achieved in patients with ITPA CC variant, especially in a background of IL28B TT genotype.
PMCID: PMC3729868  PMID: 23919217
Chronic hepatitis C; Interleukin 28B; Inosine triphosphatase; Peginterferon; Ribavirin
15.  Effect of laparoscopic splenectomy in patients with Hepatitis C and cirrhosis carrying IL28B minor genotype 
BMC Gastroenterology  2012;12:158.
IL28B and ITPA genetic variants are associated with the outcome of pegylated-interferon and ribavirin (PEG-IFN/RBV) therapy. However, the significance of these genetic variants in cirrhotic patients following splenectomy has not been determined.
Thirty-seven patients with HCV-induced cirrhosis who underwent laparoscopic splenectomy (Spx group) and 90 who did not (non-Spx group) were genotyped for IL28B and ITPA. The outcome or adverse effects were compared in each group. Interferon-stimulated gene 15 (ISG15) and protein kinase R expression in the spleen was measured using total RNA extracted from exenterate spleen.
Sustained virological response (SVR) rate was higher in patients carrying IL28B major genotype following splenectomy (50% vs 27.3%) and in patients carrying minor genotype in the Spx group compared to non-Spx group (27.3% vs 3.6%, P < 0.05). Pretreatment splenic ISG expression was higher in patients carrying IL28B major. There was no difference in progression of anemia or thrombocytopenia between patients carrying each ITPA genotype in the Spx group. Although splenectomy did not increase hemoglobin (Hb) level, Hb decline tended to be greater in the non-Spx group. In contrast, splenectomy significantly increased platelet count (61.1 × 103/μl vs 168.7 × 103/μl, P < 0.01), which was maintained during the course of PEG-IFN/RBV therapy.
IL28B genetic variants correlated with response to PEG-IFN/RBV following splenectomy. Splenectomy improved SVR rate among patients carrying IL28B minor genotype and protected against anemia and thrombocytopenia during the course of PEG-IFN/RBV therapy regardless of ITPA genotype.
PMCID: PMC3503804  PMID: 23145809
IL28B; ITPA; Splenectomy; Liver cirrhosis
16.  Pharmacogenetics of Efficacy and Safety of HCV Treatment in HCV-HIV Coinfected Patients: Significant Associations with IL28B and SOCS3 Gene Variants 
PLoS ONE  2012;7(11):e47725.
Background and Aims
This was a safety and efficacy pharmacogenetic study of a previously performed randomized trial which compared the effectiveness of treatment of hepatitis C virus infection with pegylated interferon alpha (pegIFNα) 2a vs. 2b, both with ribavirin, for 48 weeks, in HCV-HIV coinfected patients.
The study groups were made of 99 patients (efficacy pharmacogenetic substudy) and of 114 patients (safety pharmacogenetic substudy). Polymorphisms in the following candidate genes IL28B, IL6, IL10, TNFα, IFNγ, CCL5, MxA, OAS1, SOCS3, CTLA4 and ITPA were assessed. Genotyping was carried out using Sequenom iPLEX-Gold, a single-base extension polymerase chain reaction. Efficacy end-points assessed were: rapid, early and sustained virological response (RVR, EVR and SVR, respectively). Safety end-points assessed were: anemia, neutropenia, thrombocytopenia, flu-like syndrome, gastrointestinal disturbances and depression. Chi square test, Student's T test, Mann-Whitney U test and logistic regression were used for statistic analyses.
As efficacy is concerned, IL28B and CTLA4 gene polymorphisms were associated with RVR (p<0.05 for both comparisons). Nevertheless, only polymorphism in the IL28B gene was associated with SVR (p = 0.004). In the multivariate analysis, the only gene independently associated with SVR was IL28B (OR 2.61, 95%CI 1.2–5.6, p = 0.01). With respect to safety, there were no significant associations between flu-like syndrome or depression and the genetic variants studied. Gastrointestinal disturbances were associated with ITPA gene polymorphism (p = 0.04). Anemia was associated with OAS1 and CTLA4 gene polymorphisms (p = 0.049 and p = 0.045, respectively), neutropenia and thromobocytopenia were associated with SOCS3 gene polymorphism (p = 0.02 and p = 0.002, respectively). In the multivariate analysis, the associations of the SOCS3 gene polymorphism with neutropenia (OR 0.26, 95%CI 0.09–0.75, p = 0.01) and thrombocytopenia (OR 0.07, 95%CI 0.008–0.57, p = 0.01) remained significant.
In HCV-HIV coinfected patients treated with PegIFNα and ribavirin, SVR is associated with IL28B rs8099917 polymorphism. HCV treatment-induced neutropenia and thrombocytopenia are associated with SOCS3 rs4969170 polymorphism.
PMCID: PMC3487790  PMID: 23133602
17.  Increased Microerythrocyte Count in Homozygous α+-Thalassaemia Contributes to Protection against Severe Malarial Anaemia 
PLoS Medicine  2008;5(3):e56.
The heritable haemoglobinopathy α+-thalassaemia is caused by the reduced synthesis of α-globin chains that form part of normal adult haemoglobin (Hb). Individuals homozygous for α+-thalassaemia have microcytosis and an increased erythrocyte count. α+-Thalassaemia homozygosity confers considerable protection against severe malaria, including severe malarial anaemia (SMA) (Hb concentration < 50 g/l), but does not influence parasite count. We tested the hypothesis that the erythrocyte indices associated with α+-thalassaemia homozygosity provide a haematological benefit during acute malaria.
Methods and Findings
Data from children living on the north coast of Papua New Guinea who had participated in a case-control study of the protection afforded by α+-thalassaemia against severe malaria were reanalysed to assess the genotype-specific reduction in erythrocyte count and Hb levels associated with acute malarial disease. We observed a reduction in median erythrocyte count of ∼1.5 × 1012/l in all children with acute falciparum malaria relative to values in community children (p < 0.001). We developed a simple mathematical model of the linear relationship between Hb concentration and erythrocyte count. This model predicted that children homozygous for α+-thalassaemia lose less Hb than children of normal genotype for a reduction in erythrocyte count of >1.1 × 1012/l as a result of the reduced mean cell Hb in homozygous α+-thalassaemia. In addition, children homozygous for α+-thalassaemia require a 10% greater reduction in erythrocyte count than children of normal genotype (p = 0.02) for Hb concentration to fall to 50 g/l, the cutoff for SMA. We estimated that the haematological profile in children homozygous for α+-thalassaemia reduces the risk of SMA during acute malaria compared to children of normal genotype (relative risk 0.52; 95% confidence interval [CI] 0.24–1.12, p = 0.09).
The increased erythrocyte count and microcytosis in children homozygous for α+-thalassaemia may contribute substantially to their protection against SMA. A lower concentration of Hb per erythrocyte and a larger population of erythrocytes may be a biologically advantageous strategy against the significant reduction in erythrocyte count that occurs during acute infection with the malaria parasite Plasmodium falciparum. This haematological profile may reduce the risk of anaemia by other Plasmodium species, as well as other causes of anaemia. Other host polymorphisms that induce an increased erythrocyte count and microcytosis may confer a similar advantage.
Karen Day and colleagues show that increased microcytic erythrocyte count may contribute substantially to the protection of α+-thalassaemia-homozygous children against severe malaria anaemia.
Editors' Summary
Mutations (changes in the DNA that encodes proteins) continually arise within human populations. Harmful mutations that affect an individual's ability to reproduce usually disappear, but most other mutations persist at a low frequency. Some mutations, however, protect their human carriers against specific disease-causing organisms, and consequently occur at high frequencies in human populations that live in places where these organisms are common. For example, the inherited blood disorder α+-thalassemia, which is common in Africa and Southeast Asia, provides protection against malaria, a parasitic disease that occurs in tropical and subtropical parts of the world. α+-Thalassemia is caused by the loss of one or more of the genes that encode the α chains of hemoglobin, the red blood cell (erythrocyte) protein that carries oxygen around the body. These α chains are normally encoded by four genes, two on each Chromosome 16 (all chromosomes come in pairs). People with heterozygous α+-thalassemia lack one copy of the α chain gene and have a –α/αα genotype (genetic makeup). People with homozygous α+-thalassemia lack one copy of the gene on each chromosome (they have a –α/–α genotype) and have mild “microcytic anemia,” a condition characterized by increased numbers of abnormally small erythrocytes (microcytosis) that contain reduced amounts of hemoglobin.
Why Was This Study Done?
Paradoxically, although homozygous α+-thalassemia causes mild anemia, it provides protection against severe malarial anemia, a potentially fatal complication of malaria. Malaria parasites cause anemia because they multiply inside erythrocytes and rupture them. Scientists originally thought that α+-thalassemia protects against malaria by interfering with the parasite's ability to infect erythrocytes, but the evidence collected so far does not support this hypothesis. In this study, therefore, the researchers have investigated whether the microcytosis and increased erythrocyte count associated with α+-thalassemia might be responsible for the protection that this blood disorder provides against severe malarial anemia. Specifically, they asked whether this hematological (blood) profile protects against severe malarial anemia because people with the –α/–α genotype lose less hemoglobin for a given degree of malaria-induced erythrocyte loss than do those with the normal genotype.
What Did the Researchers Do and Find?
A study done in the mid 1990s in children living on the north coast of Papua New Guinea (where 68% of the population has α+-thalassemia) showed that homozygous α+-thalassemia protects against severe malaria. To investigate why, the researchers re-analyzed the genotype-specific reduction in erythrocyte counts and hemoglobin levels associated with acute malarial disease in these children and developed a simple mathematical model to predict hemoglobin levels after malaria infection. They found that when malarial infection reduced the number of erythrocytes per liter of blood by more than 1.1 × 1012 (the average measured loss of erythrocytes in this population because of malaria was 1.5 × 1012 per liter), children with homozygous α+-thalassemia lost less hemoglobin than did those with the normal genotype. Furthermore, children with homozygous α+-thalassemia needed a 10% greater reduction in their red blood cell count than children with the normal genotype for their hemoglobin levels to fall below the value that defines severe malarial anemia.
What Do These Findings Mean?
These findings suggest that the increased number of abnormally small erythrocytes associated with homozygous α+-thalassemia might be responsible for the protection against severe malarial anemia that this blood disorder provides, because more erythrocytes have to be destroyed by the parasite to reduce hemoglobin concentrations to a dangerous level than in people with the normal genotype. In other words, a lower concentration of hemoglobin per erythrocyte coupled with a larger population of erythrocytes might be advantageous in the face of the large reduction in erythrocyte numbers caused by infection with malaria parasites. The researchers note that their study population was infected with only one type of malaria parasite (Plasmodium falciparum), but speculate that the hematological profile associated with α+-thalassemia might also prevent other Plasmodium species causing anemia. Futhermore, they suggest, other mutations that increase the erythrocyte count and cause microcytosis might protect against severe malaria anemia in a similar fashion.
Additional Information.
Please access these Web sites via the online version of this summary at
The MedlinePlus encyclopedia contains pages on thalassemia and on malaria (in English and Spanish)
Detailed information is available on thalassemia (including useful links to other resources) from the US National Heart Lung and Blood Institute, from the US National Human Genome Research Institute, from the Cooley's Anemia Foundation, and from MedlinePlus
The US Centers for Disease Control and Prevention provide information on malaria (in English and Spanish)
Information is also available from the World Health Organization on malaria (in English, Spanish, French, Russian, Arabic, and Chinese)
PMCID: PMC2267813  PMID: 18351796
18.  Predictors of consent to pharmacogenomics testing in the IDEAL study 
Pharmacogenetics and genomics  2013;23(11):619-623.
Pharmacogenomic (PG) testing is important in developing individualized therapeutic approaches. In the phase 3 IDEAL clinical trial, a subset of patients receiving peginterferon and ribavirin for treatment of chronic hepatitis C agreed to provide blood samples for genetic testing. Genome-wide association studies subsequently identified associations between IL28B polymorphism and sustained virologic response, and ITPA polymorphism and ribavirin-associated anemia.
To characterize the groups of patients who accepted or declined PG testing in the IDEAL study.
Clinical and demographic factors and treatment outcomes were compared at all sites that had approved PG testing. Differences between patients who consented to and declined PG testing were analyzed using Student t and chi-square tests.
In total, 109 of 118 sites participated in the PG sub-study, and 1674 of 2949 (57%) patients enrolled at these sites consented to PG testing. More patients treated in academic medical centers than in community centers (60% vs. 52%, P < 0.001) provided consent. More males than females (58% vs. 54%, P = 0.04) consented to PG testing. There was no significant difference in PG participation between patients from different racial groups, including whites and African Americans (58% vs. 54%, P = 0.07). Treatment outcomes were also similar according to PG participation.
In the IDEAL study, patient consent to PG testing did not introduce selection bias. Treatment at an academic center and male gender were associated with higher rates of PG testing consent. Efficacy and safety outcomes were similar in patients who accepted and declined PG testing.
PMCID: PMC3951733  PMID: 24061202
pharmacogenomics; hepatitis C; peginterferon; ribavirin
19.  Optimum Ribavirin Exposure Overcomes Racial Disparity in Efficacy of Peginterferon and Ribavirin Treatment for Hepatitis C Genotype 1 
Peginterferon and ribavirin treatment is less effective for hepatitis C virus (HCV) genotype 1 infections in African Americans (AA) compared with Caucasian Americans (CA). Host genetic variability near the interleukin-28B (IL28B) gene locus is partly responsible. We investigated the relationship between ribavirin drug exposure and week 24 and 72 (sustained virologic response, SVR) responses (undetected serum HCV RNA) in 71 AA and 74 CA with HCV genotype 1 who received >90 % of the prescribed peginterferon and weight-based ribavirin (1,000 or 1,200 mg per day) from week 1 to 24.
Ribavirin plasma levels were measured at weeks 1, 2, 4, 8, 12 and 24; ribavirin area under the concentration vs. time curve (AUC) was calculated using the linear trapezoidal rule.
Compared with CA, AA had lower week 24 (WK24VR) (57.8 vs. 78.1; P < 0.05) and week 72 (SVR) (36.6 % vs 54.8 %; P < 0.05) response rates. AA also had significantly lower ribavirin exposure (AUC) from week 1 to 12 (P < 0.05). Ribavirin exposures ≥ 4,065 and ≥ 4,480 ng/ml/day in the first week (AUC0–7) were thresholds for WK24VR and SVR in receiver-operating characteristic curve analyses. AA were less likely to have a threshold ribavirin AUC0–7 level than CA (P < 0.05). There were no significant racial differences in WK24VR (AA: 77 vs. CA: 84 %) and SVR (AA: 52 vs. CA: 60 %) rates in patients who met the ribavirin AUC0–7 thresholds. Ribavirin AUC0–7 predicted WK24VR and SVR independently of IL28B single-nucleotide polymorphism rs12979860 genotype. Yet, achieving threshold AUC0–7 levels increased response rates primarily in AA with the less favorable non-C/C genotypes.
Standard weight-based dosing leads to suboptimal ribavirin exposure in AA and contributes to the racial disparity in peginterferon and ribavirin treatment efficacy for HCV genotype 1.
PMCID: PMC3718255  PMID: 23090351
20.  Does a rapid decline in the hematological and biochemical parameters induced by interferon and ribavirin combination therapy for the hepatitis C virus predict a sustained viral response? 
To analyze whether rapid myelosuppression and a decrease in alanine aminotransferase (ALT) induced by standard interferon (IFN) and ribavirin (RBV) combination therapy predict a sustained viral response (SVR) in hepatitis C virus patients.
Data from 111 patients (mean age 48.1 years) with chronic hepatitis C virus were retrospectively analyzed. All patients were treated with the same initial doses of IFN and RBV combination therapy. The following laboratory values were measured at baseline, and then at weeks 2, 4, 8, 12 and 24 of treatment: hemoglobin, white blood cells (WBCs), neutrophils, platelets and ALT. A delta value was then calculated for each interval from baseline (baseline values minus two weeks, etc). The delta value of each variable was then compared between the responders and nonresponders using Wilcoxon’s signed rank test.
Sixty patients (54%) achieved an SVR. There were no significant differences between the responder and nonresponder groups for baseline variables. The delta value of ALT was the only significant marker in the prediction of an SVR. The mean ± SD delta values for the ALT at week 2 of treatment were 71±92 U/L and 44±85 U/L for the responders and nonresponders, respectively (P<0.0046). At week 4, the values were 101±96 U/L and 84±100 U/L for the responders and nonresponders, respectively (P<0.0154). The decline was then calculated for the ALT as a percentage decrease from baseline: at weeks 2 and 4, the decreases were 64% and 66%, respectively, for the responders, and 43% and 41%, respectively, for the nonresponders. At week 2, the delta values for WBC count were found to be significant in predicting failure to achieve an SVR, with mean ± SD delta values of 0.85× 109/L±1.48× 109/L and 1.53× 109/L±2.16× 109/L for the responders and nonresponders, respectively (P<0.0173). The same trend emerged at two weeks for neutrophils: 0.72× 109/L±1.33× 109/L for the responders and 1.02× 109/L±1.20× 109/L for the nonresponders (P<0.0150). The delta values were insignificant for hemoglobin, lowest hemoglobin values and platelets.
The decline rates of ALT from baseline to week 2 and 4 of IFN and RBV combination therapy are good predictors of an SVR. A significant drop in WBC and neutrophil values is a predictor of failure to achieve an SVR. The hemoglobin, platelets and lowest hemoglobin values failed to predict an SVR.
PMCID: PMC2659134  PMID: 18299740
ALT; Biochemistry; Hepatitis C; Interferon; Myelosuppression; Ribavirin
21.  The Ribavirin Analog ICN 17261 Demonstrates Reduced Toxicity and Antiviral Effects with Retention of both Immunomodulatory Activity and Reduction of Hepatitis-Induced Serum Alanine Aminotransferase Levels 
The demonstrated utility of the nucleoside analog ribavirin in the treatment of certain viral diseases can be ascribed to its multiple distinct properties. These properties may vary in relative importance in differing viral disease conditions and include the direct inhibition of viral replication, the promotion of T-cell-mediated immune responses via an enhanced type 1 cytokine response, and a reduction of circulating alanine aminotransferase (ALT) levels associated with hepatic injury. Ribavirin also has certain known toxicities, including the induction of anemia upon chronic administration. To determine if all these properties are linked, we compared the d-nucleoside ribavirin to its l-enantiomer (ICN 17261) with regard to these properties. Strong similarities were seen for these two compounds with respect to induction of type 1 cytokine bias in vitro, enhancement of type 1 cytokine responses in vivo, and the reduction of serum ALT levels in a murine hepatitis model. In contrast, ICN 17261 had no in vitro antiviral activity against a panel of RNA and DNA viruses, while ribavirin exhibited its characteristic activity profile. Importantly, the preliminary in vivo toxicology profile of ICN 17261 is significantly more favorable than that of ribavirin. Administration of 180 mg of ICN 17261 per kg of body weight to rats by oral gavage for 4 weeks generated substantial serum levels of drug but no observable clinical pathology, whereas equivalent doses of ribavirin induced a significant anemia and leukopenia. Thus, structural modification of ribavirin can dissociate its immunomodulatory properties from its antiviral and toxicologic properties, resulting in a compound (ICN 17261) with interesting therapeutic potential.
PMCID: PMC89855  PMID: 10770762
22.  Increased Duration of Dual Pegylated Interferon and Ribavirin Therapy for Genotype 1 Hepatitis C Post-liver Transplantation Increases Sustained Virologic Response: A Retrospective Review 
In patients with advanced post-transplant hepatitis C virus (HCV) recurrence, antiviral treatment (AVT) with interferon and ribavirin is indicated to prevent graft failure. The aim of this study was to determine and report Canadian data with respect to the safety, efficacy, and spontaneous virologic response (SVR) predictors of AVT among transplanted patients with HCV recurrence.
Patients and Methods:
A retrospective chart review was performed on patients transplanted in London, Ontario and Edmonton, Alberta from 2002 to 2012 who were treated for HCV. Demographic, medical, and treatment information was collected and analyzed.
A total of 85 patients with HCV received pegylated interferon with ribavirin post-liver transplantation and 28 of the 65 patients (43%) with genotype 1 achieved SVR. Of the patients having genotype 1 HCV who achieved SVR, there was a significantly lower stage of fibrosis (1.37 ± 0.88 vs. 1.89 ± 0.96; P = 0.03), increased ribavirin dose (total daily dose 1057 ± 230 vs. 856 ± 399 mg; P = 0.02), increased rapid virologic response (RVR) (6/27 vs. 0/31; P = 0.05), increased early virologic response (EVR) (28/28 vs. 18/35; P = 0.006), and longer duration of therapy (54.7 ± 13.4 weeks vs. 40.2 ± 18.7; P = 0.001). A logistic regression model using gender, age, RVR, EVR, anemia, duration of therapy, viral load, years’ post-transplant, and type of organ (donation after cardiac death vs. donation after brain death) significantly predicted SVR (P < 0.001), with duration of therapy having a significant odds ratio of 1.078 (P = 0.007).
This study identified factors that predict SVR in HCV-positive patients who received dual therapy post-transplantation. Extending therapy from 48 weeks to 72 weeks of dual therapy is associated with increased SVR rates. Future studies examining the role of extended therapy are needed to confirm these findings, since the current study is a retrospective one.
PMCID: PMC3793474  PMID: 24045596
Hepatitis C virus; liver transplant; retrospective study
23.  Predicting the Outcomes of Combination Therapy in Patients With Chronic Hepatitis C Using Artificial Neural Network 
Hepatitis Monthly  2014;14(6):e17028.
Treatment with Peginterferon Alpha-2b plus Ribavirin is the current standard therapy for chronic hepatitis C (CHC). However, many host related and viral parameters are associated with different outcomes of combination therapy.
The aim of this study was to develop an artificial neural network (ANN) model to predetermine individual responses to therapy based on patient’s demographics and laboratory data.
Patients and Methods:
This case-control study was conducted in Tehran, Iran, on 139 patients divided into sustained virologic response (SVR) (n = 50), relapse (n = 50) and non-response (n = 39) groups according to their response to combination therapy for 48 weeks. The ANN was trained 300 times (epochs) using clinical data. To test the ANN performance, the part of data that was selected randomly and not used in training process was entered to the ANN and the outputs were compared with real data.
Hemoglobin (P < 0.001), cholesterol (P = 0.001) and IL-28b genotype (P = 0.002) values had significant differences between the three groups. Significant predictive factor(s) for each group were hemoglobin for SVR (OR: 1.517; 95% CI: 1.233-1.868; P < 0.001), IL-28b genotype for relapse (OR: 0.577; 95% CI: 0.339-0.981; P = 0.041) and hemoglobin (OR: 0.824; 95% CI: 0.693-0.980; P = 0.017) and IL-28b genotype (OR: 2.584; 95% CI: 1.430-4.668;P = 0.001) for non-response. The accuracy of ANN to predict SVR, relapse and non-response were 93%, 90%, and 90%, respectively.
Using baseline laboratory data and host characteristics, ANN has been shown as an accurate model to predict treatment outcome, which can lead to appropriate decision making and decrease the frequency of ineffective treatment in patients with chronic hepatitis C virus (HCV) infection.
PMCID: PMC4071357  PMID: 24976838
Cholesterol; Hepatitis C, Chronic; Hemoglobin; IL28B Protein, Human; Peginterferon Alfa-2b; Ribavirin
24.  Boceprevir for Previously Treated Chronic HCV Genotype 1 Infection 
The New England journal of medicine  2011;364(13):1207-1217.
In patients with chronic infection with hepatitis C virus (HCV) genotype 1 who do not have a sustained response to therapy with peginterferon–ribavirin, outcomes after retreatment are suboptimal. Boceprevir, a protease inhibitor that binds to the HCV nonstructural 3 (NS3) active site, has been suggested as an additional treatment.
To assess the effect of the combination of boceprevir and peginterferon–ribavirin for retreatment of patients with chronic HCV genotype 1 infection, we randomly assigned patients (in a 1:2:2 ratio) to one of three groups. In all three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (control group) received placebo plus peginterferon–ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon–ribavirin for 32 weeks, and patients with a detectable HCV RNA level at week 8 received placebo plus peginterferon–ribavirin for an additional 12 weeks; and group 3 received boceprevir plus peginterferon–ribavirin for 44 weeks.
A total of 403 patients were treated. The rate of sustained virologic response was significantly higher in the two boceprevir groups (group 2, 59%; group 3, 66%) than in the control group (21%, P<0.001). Among patients with an undetectable HCV RNA level at week 8, the rate of sustained virologic response was 86% after 32 weeks of triple therapy and 88% after 44 weeks of triple therapy. Among the 102 patients with a decrease in the HCV RNA level of less than 1 log10 IU per milliliter at treatment week 4, the rates of sustained virologic response were 0%, 33%, and 34% in groups 1, 2, and 3, respectively. Anemia was significantly more common in the boceprevir groups than in the control group, and erythropoietin was administered in 41 to 46% of boceprevir-treated patients and 21% of controls.
The addition of boceprevir to peginterferon–ribavirin resulted in significantly higher rates of sustained virologic response in previously treated patients with chronic HCV genotype 1 infection, as compared with peginterferon–ribavirin alone.
PMCID: PMC3153125  PMID: 21449784
25.  Effect of Ribavirin Alone or Combined with Silymarin on Carbon Tetrachloride Induced Hepatic Damage in Rats 
Drug Target Insights  2007;2:19-27.
The effect of the antiviral agent ribavirin given alone or in combination with silymarin on the development of liver injury induced in rats with carbon tetrachloride (CCl4; 2.8 ml/kg followed by 1.4 ml/kg after one week) was studied. Ribavirin at three dose levels (30, 60 or 90 mg/kg), silymarin (25 mg/kg) or combination of ribavirin (60 mg/kg) and silymarin (25 mg/kg) was administered once daily orally for 14 days, starting at time of administration of CCl4. The administration of ribavirin decreased the elevations in serum alanine aminotransferase (ALT) by 78.5, 82.1, 75.1%, aspartate aminotransferase (AST) 47.5, 37.4, 38.8%, and alkaline phosphatase (ALP) by 23.4, 16, 21.6%, respectively and also pre-vented the development of hepatic necrosis caused by CCl4. In comparison, the elevated serum ALT, AST and ALP levels decreased to 43.3%, 46%, and 37.5% of controls, respectively by silymarin. When silymarin was combined with ribavirin, the serum activities of AST and ALP were further decreased, indicating a beneficial additive effect. Morphometric analysis indicated significant reduction in the area of necrosis and fibrosis on ribavirin treatment and this was further reduced after the addition of silymarin. Metabolic pertuberations caused by CCl4 as reflected in a decrease in intracellular protein content in hepatocytes were improved by ribavirin monotherapy and to higher extent by combined silymarin and ribavirin therapy. Proliferating cell nuclear antigen was reduced in nuclei of hepatocytes by ribavirin montherapy or the combination of ribavirin and silymarin compared with CCl4-control group. The study demonstrates that ribavirin treatment in the model of CCl4-induced liver injury results in less liver damage. Results also indicate that the combined application of ribavirin and sily-marin is likely to be a useful additive in reducing liver injury.
PMCID: PMC3155230  PMID: 21901059
Ribavirin; silymarin; carbon tetrachloride; liver injury; rat

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