Inosine triphosphatase polymorphisms and ribavirin pharmacokinetics as determinants of ribavirin-associate anemia in patients receiving standard anti-HCV treatment.

BACKGROUND: Functional variants of inosine triphosphatase (ITPA) were recently found to protect against ribavirin (RBV)-induced hemolytic anemia. However, no definitive data are yet available on the role of plasma RBV concentrations on hemoglobin (Hb) decrement. Moreover, no data have been published on the possible interplay between these 2 factors. METHODS: A retrospective analysis included 167 patients. The ITPA variants rs7270101 and rs1127354 were genotyped and tested using the χ test for association with Hb reduction at week 4. We also investigated, using multivariate logistic regression, the impact of RBV plasma exposure on Hb concentrations. RESULTS: Both single nucleotide polymorphisms were associated with Hb decrease. The carrier of at least 1 variant allele in the functional ITPA single nucleotide polymorphisms was associated with a lower decrement of Hb (-1.1 g/dL), as compared with patients without a variant allele (-2.75 g/dL; P = 4.09 × 10). RBV concentrations were not influenced by ITPA genotypes. A cut-off of 2.3 µg/mL of RBV was found to be associated with anemia (area-under-receiver operating characteristic = 0.630, sensitivity = 50.0%, and specificity = 69.5%, P = 0.008). In multivariate logistic regression analyses, the carrier of a variant allele (P = 0.005) and plasma RBV concentrations <2.3 µg/mL (P = 0.016) were independently associated with protection against clinically significant anemia at week 4. CONCLUSIONS: Although no direct relationship was found between ITPA polymorphisms and plasma RBV concentrations, both factors were shown to be significantly associated with anemia. A multivariate regression model based on ITPA genetic polymorphisms and RBV trough concentration was developed for predicting the risk of anemia. By relying upon these 2 variables, an individualized management of anemia seems to be feasible in recipients of pegylated interferon-RBV therapy.

Negative predictive value of IL28B, SLC28A2, and CYP27B1 SNPs and low RBV plasma exposure for therapeutic response to PEG/IFN-RBV treatment.

OBJECTIVES: The response rate to treatment of chronic hepatitis C virus-genotype 1 and 4 infections was recently found to be strongly influenced by many polymorphisms. The aim of our study was to carry out an integrated analysis of the effects of polymorphisms and ribavirin (RBV) plasma exposure on outcome. METHODS: The retrospective analysis included 174 patients. IL28B, CYP27B1, SLC29A1, SLC28A3, and SLC28A2 polymorphisms were genotyped and tested for association with sustained virological response. The impact of RBV plasma exposure during the first 3 months of therapy on outcome was also investigated. RESULTS: Considering patients infected by hepatitis C virus-1/4, 3 polymorphisms (IL28B rs8099917TT, CYP27B1 rs4646536TT, and CNT2 rs11854484TT) were associated with sustained virological response. The number of negative variant allele and low RBV exposure were correlated to percentage increasing to therapy failure, suggesting some degree of cumulative effect of the 4 factors. A cutoff of 2.5 µg/mL of RBV was found to be associated with outcome (area under ROC [AUROC] curve = 0.64, sensitivity = 55.0%, and specificity = 71.2%, P = 0.020). In multivariate logistic regression analyses, each variant allele and RBV plasma exposure cutoff were independently associated with outcome. CONCLUSIONS: In this study, we found that additional polymorphisms and RBV plasma exposure are also able to influence the achievement of response. Regardless of the magnitude of RBV pharmacokinetic exposure, the negative predictive value of the polymorphisms here investigated is much stronger than the positive one.

Incidence of type 2 diabetes mellitus and glucose abnormalities in patients with chronic hepatitis C infection by response to treatment: results of a cohort study.

BACKGROUND: Patients with chronic hepatitis C are at risk of developing type 2 diabetes mellitus (DM) and impaired fasting glucose (IFG), and this risk may increase among hepatitis C virus (HCV) patients not responding to an antiviral therapy. AIM: To compare the incidence of glucose abnormalities (IFG or DM) after an antiviral therapy between HCV+ patients with a long-term virological response (LTR) and nonresponders (NR; persistently positive HCV-RNA). METHODS: All 202 HCV+ patients without the baseline glucose abnormalities enrolled by our center in investigational trials or routinely treated with interferon (IFN)/peginterferon (Peg-IFN) (+/- ribavirin) from 1988 to 2001, with the available baseline sera stored at -80 degrees C, were considered. The baseline data included age, sex, body mass index (BMI), viral load, genotype, liver histologic staging and steatosis, glucose, and cholesterol. The homeostatic assessment of insulin resistance (HOMA-IR) was calculated in the baseline serum. The incidence of IFG or DM at the end of follow-up was compared between patients with LTR and NR. RESULTS: After a median follow-up of 8.0 yr (range 5-16), the cumulative risk of DM (N = 7) or IFG (N = 33) among the 202 HCV+ included patients was 16.9% (95% confidence interval [CI] 11.3-22.5). The 8-yr risk was not significantly lower between LTRs (14.5%) compared to NRs (18.8%) (hazard ratio [HR] 0.60, CI 0.30-1.20, P= 0.16). The HR adjusted for the baseline risk factors for DM and the predictors of a poor response (age, sex, HOMA-IR, BMI, family history of diabetes, HCV genotype 1, high viral load, cirrhosis, and steatosis) was 0.88 (CI 0.38-2.02, P= 0.76). Among other factors, those more associated to IFG-DM were an increasing age (P= 0.017), a higher BMI (P= 0.054), and a family history of DM (P= 0.065). CONCLUSIONS: After adjustment for several baseline risk factors, the incidence of glucose abnormalities was not significantly different between LTRs and NRs. Our data suggest that HCV clearance does not significantly reduce the risk of glucose intolerance.

Studies of therapy with thymosin alpha1 in combination with pegylated interferon alpha2a and ribavirin in nonresponder patients with chronic hepatitis C.

Despite the use of combination therapy with pegylated interferon alpha2a (peg-IFN-alpha2a) + Ribavirin, a large proportion of patients with chronic hepatitis C (CHC) remain unresponsive to treatment. Thymosin alpha 1 (Talpha1) is an immunomodulator, which displays immunological and antiviral activities against hepatitis C virus (HCV) in preclinical clinical settings. The purpose of this study was to evaluate the efficacy and safety of a triple combination therapy with peg-IFN-alpha2a + Ribavirin + Talpha1 in CHC patients who were nonresponders to a previous course with peg-IFN-alpha2a + Ribavarin. The primary endpoint is the rate of sustained virological response (SVR). We designed a phase 3, randomized, double-blind, multicenter, prospective, placebo controlled study. Patients meeting selection criteria were randomized centrally (through IVR system) to receive either peg-IFN-alpha2a 180 mcg s.c. once weekly + Ribavirin 1000-1200 mg p.o. daily + Talpha1 1.6 mg s.c. twice weekly for 24 weeks. Patients who remained HCV-RNA positive after 24 weeks stopped treatment and were considered nonresponders. HCV-RNA negative patients continued treatment up to week 48. All patients were followed up for 24 additional weeks after the end of treatment for the evaluation of the SVR. From December 2004 to November 2006, 638 patients were screened in 52 European sites. Preliminary blinded safety analysis suggests that both regimens are well tolerated. Efficacy evaluation will be available after the opening of this blinded phase 3 trial, planned for May 2008.

Real-world outcomes in patients with chronic hepatitis C: primary results of the PROBE study.

BACKGROUND: This large prospective multicentre cohort study aimed to improve knowledge of therapy for chronic hepatitis C (CHC) in real clinical practice. METHODS: A diverse population of adults with CHC including patients with comorbid conditions, laboratory abnormalities and demographic features [comorbidities or special populations (CSP)] who were under-represented or excluded from peginterferon registration studies was treated with peginterferon α-2a (40 kDa) or α-2b (12 kDa) plus ribavirin at the investigator's discretion. RESULTS: During the study, 5399 treatment-naive patients [2527 (46.8%) with CSP] received peginterferon α-2a (n=3513, 65.1%) or peginterferon α-2b (n=1886, 34.9%). The sustained virological response rate was 56.6% (3057/5399) overall, 59.7% (1716/2872) in patients without CSP and 53.1% (1341/2527) in patients with CSP. Significant predictors of sustained virological response included hepatitis C virus genotype 2 or 3 infection, absence of cirrhosis, hepatitis C virus RNA≤500 000 IU/ml, alanine transaminase quotient >3× the upper limit of normal, age ≤65 years, BMI<25 kg/m, at least 80% of the planned exposure to peginterferon and ribavirin and prescription of peginterferon α-2a. CONCLUSION: The results provide detailed information on the outcome of therapy for CHC in a diverse Italian population that included a large number of patients with CSP and provides an insight into the generalizability of the results obtained in the more restricted setting of randomized registration trials.

Triple therapy with first-generation protease inhibitors for patients with genotype 1 chronic hepatitis C: recommendations of the Italian association for the study of the liver (AISF).

The first-generation Protease Inhibitors Boceprevir and Telaprevir administered in triple therapy regimens with Peg-interferon alpha and Ribavirin have been proven effective in increasing the rate of Sustained Virological Response in both naive and treatment-experienced patients with chronic genotype-1 hepatitis C. However, at the individual level, the therapeutic advantage of triple therapy is highly variable and results from the combination of multiple factors related to the characteristics of patient, viral status and liver disease. The recommendations presented are promoted by the Italian Association for the Study of the Liver, with the aim to help the physician in the decision-making process as well as to manage patients during treatment with triple therapy.

IL28B polymorphism genotyping as predictor of rapid virologic response during interferon plus ribavirin treatment in hepatitis C virus genotype 1 patients.

AIM: To clarify the association of interleukin-28B (IL28B) single nucleotide polymorphisms (SNPs) with hepatitis C virus (HCV) viremia changes for assessment of interferon (IFN) response. METHODS: A cohort of 118 Caucasian treatment-naïve HCV-G1 infected patients, treated with pegylated-IFN alpha 2a or 2b associated with ribavirin (53 responders, 65 non-responders) during the period 2010-2012, were genotyped for IL28B SNPs rs12979860 C>T and rs8099917 T>G. Genotyping was performed by real-time allelic discrimination assay. Serum HCV RNA levels were assayed at 2, 4, 12, 24 and 48 wk during therapy. Correlation between IL28B genotypes and serum HCV RNA kinetics was investigated. Multivariable logistic regression analysis was performed to identify predictors of null-response. RESULTS: Twenty-six out of 118 patients (22%) had no HCV RNA decline ≥ 1 log IU/mL at therapy week 4 (null-responders). IL28B genotype was rs8099917 (G)/rs1297860 in 21/26 (80%) of null-responder patients. Using multivariate analysis, it was shown that the presence of the rs8099917 G allele was the best predictor of null-response (OR = 7.9, 95%CI: 1.99-31.18). The presence of at least one favorable genotype showed a positive predictive value of above 90% for HCV RNA reduction ≥ log at week 4. Analysis of the HCV RNA kinetics during 12 wk of therapy in patients with IL28B rs12979860 CT heterozygosis (n = 73), according to their rs8099917 status, showed that the viremia reduction was significantly different in patients carrying the rs8099917 G allele compared to those with favorable homozygosis. CONCLUSION: Our findings emphasize the association of the IL28B rs8099917 G allele with HCV. Genotyping for both IL28B SNPs is useful in clinical practice for thorough patient risk stratification based on IFN responsiveness.

Boceprevir is highly effective in treatment-experienced hepatitis C virus-positive genotype-1 menopausal women.

AIM: To investigate the safety/efficacy of Boceprevir-based triple therapy in hepatitis C virus (HCV)-G1 menopausal women who were historic relapsers, partial-responders and null-responders. METHODS: In this single-assignment, unblinded study, we treated fifty-six menopausal women with HCV-G1, 46% F3-F4, and previous PEG-α/RBV failure (7% null, 41% non-responder, and 52% relapser) with 4 wk lead-in with PEG-IFNα2b/RBV followed by PEG-IFNα2b/RBV+Boceprevir for 32 wk, with an additional 12 wk of PEG-IFN-α-2b/RBV if patients were HCV-RNA-positive by week 8. In previous null-responders, 44 wk of triple therapy was used. The primary objective of retreatment was to verify whether a sustained virological response (SVR) (HCV RNA undetectable at 24 wk of follow-up) rate of at least 20% could be obtained. The secondary objective was the evaluation of the percent of patients with negative HCV RNA at week 4 (RVR), 8 (RVR BOC), 12 (EVR), or at the end-of-treatment (ETR) that reached SVR. To assess the relationship between SVR and clinical and biochemical parameters, multiple logistic regression analysis was used. RESULTS: After lead-in, only two patients had RVR; HCV-RNA was unchanged in all but 62% who had ≤ 1 log10 decrease. After Boceprevir, HCV RNA became undetectable at week 8 in 32/56 (57.1%) and at week 12 in 41/56 (73.2%). Of these, 53.8% and 52.0%, respectively, achieved SVR. Overall, SVR was obtained in 25/56 (44.6%). SVR was achieved in 55% previous relapsers vs. 41% non-responders (P = 0.250), in 44% F0-F2 vs 54% F3-F4 (P = 0.488), and in 11/19 (57.9%) of patients with cirrhosis. At univariate analysis for baseline predictors of SVR, only previous response to antiviral therapy (OR = 2.662, 95%CI: 0.957-6.881, P = 0.043), was related with SVR. When considering "on treatment" factors, 1 log10 HCV RNA decline at week 4 (3.733, 95%CI: 1.676-12.658, P = 0.034) and achievement of RVR BOC (7.347, 95%CI: 2.156-25.035, P = 0.001) were significantly related with the SVR, although RVR BOC only (6.794, 95%CI: 1.596-21.644, P = 0.010) maintained significance at multivariate logistic regression analysis. Anemia and neutropenia were managed with Erythropoietin and Filgrastim supplementation, respectively. Only six patients discontinued therapy. CONCLUSION: Boceprevir obtained high SVR response independent of previous response, RVR or baseline fibrosis or cirrhosis. RVR BOC was the only independent predictor of SVR.

Durability of the response to peginterferon-α2b and ribavirin in patients with chronic hepatitis C: a cohort study in the routine clinical setting.

OBJECTIVES: To evaluate whether, in chronic hepatitis C-positive naive patients recruited in the routine clinical setting and treated with pegylated-interferon-α2b (Peg-IFN) and ribavirin (RBV), the sustained virologic response (SVR) is durable over the long term and whether it is associated with a decrease in liver complications and incidence of glucose abnormalities. PATIENTS AND METHODS: This was a prospective long-term follow-up study of 182 naive patients enrolled in 2001-2002 and treated with Peg-IFN and RBV and followed up to December 2010, with clinical, biochemical, and virological evaluations every 6-12 months. RESULTS: None of the 115 (63.2%) sustained responders showed late viremic relapse during the follow-up. SVR was better defined at 24 weeks (16/16 relapsers, 100%) than at 12 weeks after the end of therapy (14/16 relapsers, 87.5%). On multivariable analysis, viral genotype (odds ratio 0.16, 95% confidence interval 0.07-0.36, P=0.0001) and a greater than 20% RBV reduction (odds ratio 5.21, 95% confidence interval 1.54-17.67, P=0.008) predicted long-term response (LTR) independently. The incidence of cirrhosis was significantly higher among nonresponders (21.3%) compared with long-term responders (0.9%, P≤0.0001), but the risk of developing glucose abnormalities was not significantly reduced in long-term responders (hazard ratio 1.36, P=0.363). Hepatocellular carcinoma occurred only in three cases. CONCLUSION: SVR achieved in patients treated in the routine clinical setting with Peg-IFN and RBV is durable over the long term and LTR significantly reduces the risk of progression to cirrhosis; however, in a population with mild liver fibrosis, the clinical impact of LTR on the risk of glucose abnormalities seems negligible.

Short duration treatment in genotype 1 chronic hepatitis C patients with rapid virologic response to pegylated interferon plus ribavirin.

BACKGROUND: In patients with chronic hepatitis C, rapid HCV-RNA clearance under treatment might allow shorter treatment duration without modifying the sustained virological response (SVR) rate. This study evaluated the impact of rapid virological response (RVR) in HCV genotype 1b infection management. METHODS: In an open-label trial, 180 patients received standard doses of peginterferon alfa-2a plus ribavirin. Those with undetectable serum HCV-RNA at week 6 (RVR) received 24-week short-course treatment; patients with undetectable HCV-RNA at week 12 (early responders [ER]) received 48-week "standard of care" treatment; patients with positive HCV-RNA at week 12 (non-responders [NR]) stopped the treatment. Study end-point was to determine SVR rate at week 24. RESULTS: The following responses were observed: 24% RVR, 44% ER, 32% NR. Among RVR subjects, HCV-RNA baseline levels and age were significantly lower (P=0.038 and 0.035 respectively) than in non-RVR patients. At follow-up, 91% of RVR and 33% of ER patients achieved SVR. Among those with RVR, patients experiencing post-therapy relapse were older than those who achieved a SVR (P=0.028). CONCLUSIONS: Chronic HCV-1b patients, achieving RVR with a 24-week treatment regimen, attained excellent SVR rates. In a cost-effective therapeutic approach, all HCV-1b patients eligible for therapy may have a short duration therapy on the basis of RVR.

Pegylated interferon alpha-2b as monotherapy or in combination with ribavirin in chronic hepatitis delta.

Therapy of chronic hepatitis delta with standard interferon therapy has met with limited efficacy. This study was designed to examine the efficacy and safety of peginterferon with or without ribavirin. Thirty-eight serum hepatitis B surface antigen- and HDV RNA-positive patients with alanine aminotransferase (ALT) more than 1.5 times the upper normal limit received peginterferon alpha-2b (1.5 microg/kg) alone as monotherapy (n=16) or in combination with ribavirin (n=22), for 48 weeks. Thereafter, all the patients were maintained on peginterferon for 24 weeks and followed for 24 weeks off therapy. The primary end point studied was the virological and biochemical response at the end of follow-up. HDV RNA was determined by single or nested polymerase chain reaction assays. Twenty-seven patients (71%), 11 receiving monotherapy and 16 receiving the combination treatment, completed the follow-up. At the end of treatment, a virological response was observed in 3 of the patients treated with peginterferon (19%) and in 2 of the patients treated with combination therapy (9%), and a biochemical response was observed in 6 (37.5%) and 9 patients (41%), respectively. In nonresponders, ALT diminished from a mean of 174+/-53 to 86+/-41 IU/L. At the end of follow-up, serum HDV RNA was negative in 8 patients (21%), and a biochemical response was detected in 10 patients (26%). Treatment was discontinued in 25% of the patients, and dosing was modified in 58%. In conclusion, a prolonged course of peginterferon alpha-2b resulted in clearance of serum HDV RNA and ALT normalization in a fifth of patients with chronic hepatitis D, while ribavirin had no effect on the viral clearance rate. Overall tolerance of therapy was poor.