Hepatitis C virus (HCV) infection is the most common blood-borne virus in the United States. Several mono- and combination therapies have been approved by the US Food and Drug Administration for the treatment of HCV, but their routes of administration, dosing approaches, eras of introduction, and actual use in clinical practice and resulting effectiveness have not yet been reported.
The aim of this article was to characterize clinical use and virologic response (VR) of the HCV treatments interferon alfa-2b plus ribavirin (IFN + RBV) and peginterferon alfa-2b plus ribavirin (peg-IFN + RBV).
This retrospective chart review of office-based practices in theUnited States was conducted at 200 physicians' offices across the United States. We collected data concerning dosing patterns, VR (HCV RNA load, ≤1000 IU/mL or “negative” on polymerase chain reaction qualitative analysis), and adverse events (AEs) from the medical records of a geographically diverse sample of patients receiving treatment for chronic HCV infection in the United States from July 2001 to June 2002. For efficacy assessment, factors that were statistically different at baseline were adjusted using logistic regression. Providers also reviewed the medical records for symptoms or signs consistent with HCV treatment-related AEs.
Data from the records of 675 patients (423 men, 252 women; mean [SD] age of 45.5 [8.2] years; mean [SD] body weight, 80.8 [19.4] kg) were analyzed. At baseline, the IFN + RBV treatment group (330 patients) had significantly higher percentages of black patients (22.1% vs 15.7%; P = 0.032) and patients with hepatic disease based on clinician-reported cirrhosis and liver dysfunction (18.8% vs 9.9%; P < 0.001), and a significantly lower percentage of white patients (60.3% vs 69.6%; P = 0.012) compared with the peg-IFN + RBV treatment group (345 patients). The difference in log-transformed baseline HCV RNA loads between the 2 treatment groups in this study was <1 log unit. A significantly higher percentage of IFN + RBV-treated patients compared with peg-IFN + RBV-treated patients were prescribed HCV therapy on diagnosis (37.3% vs 29.9%; P = 0.041), and the mean (SD) duration of treatment was significantly different between the 2 treatment groups (52.5 [37.0] vs 27.5 [15.0] weeks; P < 0.001). Peg-IFN + RBV was associated with a higher rate of VR compared with IFN + RBV on univariate analysis (28.5% vs 17.5%; P = 0.018). Recommended doses of peg-IFN and higher-than-recommended doses of RBV were associated with an increased likelihood of VR. Higher-than-recommended doses of peg-IFN without a concomitant increase in RBV was not associated with an increased likelihood of VR. The incidences of the 3 most commonly reported AEs in the IFN + RSV group were significantly higher compared with those in the peg-IFN + RSV group: fatigue, 217 (65.8%) versus 185 (53.6%) patients (P = 0.001); depression, 147 (44.5%) versus 120 (34.8%) (P = 0.009); and anxiety, 87 (26.4%) versus 64 (18.6%) (P = 0.014). Nausea, however, was reported in a significantly higher number of patients in the peg-IFN group compared with the IFN + RBV group (74 [21.4%] vs 51 [15.5%]; P = 0.045). The frequencies of dose modification and treatment discontinuation due to AEs were similar between the 2 treatments and were similar to or less than those reported in other studies.
In this retrospective data analysis of US office-based practicesconcerning HCV treatment, clinicians were observed to prescribe IFN + RBV at doses that differ from recommendations in the product information (PI), as well as prescribe the RBV component of peg-IFN + RBV at doses that differed from PI recommendations. Although patients treated with peg-IFN + RBV appeared to achieve higher VR compared with those treated with IFN + RBV in our analysis of data from clinical practice, peg-IFN + RBV was associated with lower VR rates compared with those reported in clinical studies.
hepatitis C; pegylated interferon; interferon alfa-2b and ribavirin; ribavirin; dosing; outcomes
An essential task in a genomic analysis of a human disease is limiting the number of strongly associated genes when studying susceptibility to the disease. The goal of this study was to compare computational tools with and without feature selection for predicting osteoporosis outcome in Taiwanese women based on genetic factors such as single nucleotide polymorphisms (SNPs). To elucidate relationships between osteoporosis and SNPs in this population, three classification algorithms were applied: multilayer feedforward neural network (MFNN), naive Bayes, and logistic regression. A wrapper-based feature selection method was also used to identify a subset of major SNPs. Experimental results showed that the MFNN model with the wrapper-based approach was the best predictive model for inferring disease susceptibility based on the complex relationship between osteoporosis and SNPs in Taiwanese women. The findings suggest that patients and doctors can use the proposed tool to enhance decision making based on clinical factors such as SNP genotyping data.
Chronic hepatitis C (CHC) is a liver disease characterized by infection with the hepatitis C virus (HCV) persisting for more than six months. Patients with CHC often stop pursuing the pegylated interferon (peg-IFN) and ribavirin (RBV) treatment because of the high cost and associated adverse effects. Therefore, it is highly desirable, both clinically and economically, to establish the determinants of response to distinguish responders from nonresponders, and to predict the possible outcomes of the peg-IFN and RBV treatments. The aim of this study was to review recent data on the pharmacogenomics of the drug efficacy of IFN in CHC patients. Single nucleotide polymorphisms (SNPs) can be used to understand the relationship between genetic inheritance and IFN therapeutic response. In the recent advent of scientific research, the genome-wide association study (GWAS), which is an alternative to the candidate-gene approach, is widely utilized to examine hundreds of thousands of SNPs by high-throughput genotyping technologies. In addition to the candidate-gene approach, the GWAS approach has recently been employed to study the determinants of HCV’s response to therapy. Several recent findings have demonstrated that some SNPs in the interleukin 28B gene are closely associated with IFN responsiveness. These results promise to lead to mechanistic findings related to IFN responsiveness in this disease, and will probably have major contributions for individualized medicine and therapeutic decision making.
chronic hepatitis C; genome-wide association study; interferon; pharmacogenomics; ribavirin; single nucleotide polymorphisms
We aimed to compare the rates of sustained virologic response (SVR) achieved with peginterferon (PEG-IFN) alfa-2a and alfa-2b in combination with ribavinin (RBV) for chronic hepatitis C, using a large database of hepatitis cases to improve the generalizability of these results.
We identified patients with chronic hepatitis C who were treated with PEG-IFN alfa-2a or alfa-2b and RBV, from the Japanese Interferon Database, between December 2009 and April 2013. This database contains the medical records of IFN treatment collected from 36 prefectures in Japan. Multivariable logistic regression analysis was used to compare SVR rates obtained with PEG-IFN alfa-2a and alfa-2b, in combination with RBV.
A total of 16,349 patients were recorded in the Japanese Interferon Database. After application of the exclusion criteria, 12,706 patients (3,578 [1,710 males, 1,868 females] on PEG-IFN alfa-2a; and 9,128 [4,652 males, 4,476 females] on PEG-IFN alfa-2b) were included in this analysis. The SVR rate in the PEG-IFN alfa-2b group was 62.0%, as compared with a rate of 55.1% in the PEG-IFN alfa-2a group (crude odds ratio =1.31; 95% confidence interval [CI]: 1.23 to 1.44). There was no significant difference in the adjusted SVR rates between the two groups (adjusted odds ratio =0.96; 95% CI: 0.88 to 1.05). Similar proportions of adverse events were observed in the two groups, with the exception of thrombocytopenia, retinopathy, and anemia.
There was no significant difference in the SVR rates and safety profile between chronic hepatitis C patients treated with the PEG-IFN alfa-2a and alfa-2b.
sustained virologic response; HCV genotype; sustained virologic response; adverse events
AIM: To evaluate daclatasvir vs telaprevir, each combined with peginterferon alfa-2a/ribavirin (pegIFN/RBV), in treatment-naive hepatitis C virus (HCV) genotype (GT) 1-infected patients.
METHODS: In this phase 3, randomized, open-label, noninferiority study, 602 patients were randomly assigned (2:1) to daclatasvir vs telaprevir, stratified by IL28B rs12979860 host genotype (CC vs non-CC), cirrhosis status (compensated cirrhosis vs no cirrhosis), and HCV GT1 subtype (GT1a vs GT1b). Patients were selected by study inclusion criteria from a total of 793 enrolled patients. Patients received daclatasvir 60 mg once daily or telaprevir 750 mg 3 times daily plus pegIFN/RBV. Daclatasvir recipients received 24 wk of daclatasvir plus pegIFN/RBV; those without an extended rapid virologic response (eRVR; undetectable HCV-RNA at weeks 4 and 12) received an additional 24 wk of pegIFN/RBV. Telaprevir-treated patients received 12 wk of telaprevir plus pegIFN/RBV followed by 12 (with eRVR) or 36 (no eRVR) wk of pegIFN/RBV. The primary objective was to compare for noninferiority of sustained virologic response rates at posttreatment week 12 (SVR12) in GT1b-infected patients. Key secondary objectives were to demonstrate that the rates of anemia (hemoglobin < 10 g/dL) and rash-related events, through week 12, were lower with daclatasvir + pegIFN/RBV than with telaprevir + pegIFN/RBV among GT1b-infected patients. Resistance testing was performed using population-based sequencing of the NS5A region for all patients at baseline, and for patients with virologic failure or relapse and HCV-RNA ≥ 1000 IU/mL, to investigate any link between NS5A polymorphisms associated with daclatasvir resistance and virologic outcome.
RESULTS: Patient demographics and disease characteristics were generally balanced across treatment arms; however, there was a higher proportion of black/African Americans in the daclatasvir groups (6.0% and 8.2% in the GT1b and GT1a groups, respectively) than in the telaprevir groups (2.2% and 3.0%). Among GT1b-infected patients, daclatasvir plus pegIFN/RBV was noninferior to telaprevir plus pegIFN/RBV for SVR12 [85% (228/268) vs 81% (109/134); difference, 4.3% (95%CI: -3.3% to 11.9%)]. Anemia (hemoglobin < 10 g/dL) was significantly less frequent with daclatasvir than with telaprevir [difference, -29.1% (95%CI: -38.8% to -19.4%)]. Rash-related events were also less common with daclatasvir than with telaprevir, but the difference was not statistically significant. In GT1a-infected patients, SVR12 was 64.9% with daclatasvir and 69.7% with telaprevir. Among both daclatasvir and telaprevir treatment groups, across GT1b- or GT1a-infected patients, lower response rates were observed in patients with IL28B non-CC and cirrhosis - factors known to affect response to pegIFN/RBV. Consistent with these observations, a multivariate logistic regression analysis in GT1b-infected patients demonstrated that SVR12 was associated with IL28B host genotype (CC vs non-CC, P = 0.011) and cirrhosis status (absent vs present, P = 0.031). NS5A polymorphisms associated with daclatasvir resistance (at L28, R30, L31, or Y93) were observed in 17.3% of GT1b-infected patients at baseline; such variants did not appear to be absolute predictors of failure since 72.1% of these patients achieved SVR12 compared with 86.9% without these polymorphisms. Among GT1b-infected patients, treatment was completed by 85.4% (229/268) in the daclatasvir group, and by 85.1% (114/134) in the telaprevir group, and among GT1a-infected patients, by 67.2% (90/134) and 69.7% (46/66), respectively. Discontinuations (of all 3 agents) due to an AE were more frequent with telaprevir than with daclatasvir, whereas discontinuations due to lack of efficacy were more frequent with daclatasvir, due, in part, to differences in futility criteria.
CONCLUSION: Daclatasvir plus pegIFN/RBV demonstrated noninferiority to telaprevir plus pegIFN/RBV for SVR12 and was well-tolerated in treatment-naive GT1b-infected patients, supporting the use of daclatasvir with other direct-acting antivirals.
Direct-acting antiviral; Chronic hepatitis C; Daclatasvir; Genotype 1b; NS5A inhibitor; Liver disease
Background and purpose
Peginterferon Lambda was being developed as an alternative to alfa interferon for the treatment of chronic hepatitis C virus (HCV) infection. We compared peginterferon Lambda-1a plus ribavirin (Lambda/RBV) and Lambda/RBV plus daclatasvir (DCV; pangenotypic NS5A inhibitor) with peginterferon alfa-2a plus RBV (alfa/RBV) in treatment-naive patients with HCV genotype 2 or 3 infection.
In this multicenter, double-blind, phase 3 randomized controlled trial, patients were assigned 2:2:1 to receive 24 weeks of Lambda/RBV, 12 weeks of Lambda/RBV + DCV, or 24 weeks of alfa/RBV. The primary outcome measure was sustained virologic response at post-treatment Week 12 (SVR12).
Overall, 874 patients were treated: Lambda/RBV, n = 353; Lambda/RBV + DCV, n = 349; alfa/RBV, n = 172. Patients were 65 % white and 33 % Asian, 57 % male, with a mean age of 47 years; 52 % were infected with genotype 2 (6 % cirrhotic) and 48 % with genotype 3 (9 % cirrhotic). In the Lambda/RBV + DCV group, 83 % (95 % confidence interval [CI] 78.5, 86.5) achieved SVR12 (90 % genotype 2, 75 % genotype 3) whereas SVR12 was achieved by 68 % (95 % CI 63.1, 72.9) with Lambda/RBV (72 % genotype 2, 64 % genotype 3) and 73 % (95 % CI 66.6, 79.9) with peginterferon alfa/RBV (74 % genotype 2, 73 % genotype 3). Lambda/RBV + DCV was associated with lower incidences of flu-like symptoms, hematological abnormalities, and discontinuations due to adverse events compared with alfa/RBV.
The 12-week regimen of Lambda/RBV + DCV was superior to peginterferon alfa/RBV in the combined population of treatment-naive patients with genotype 2 or 3 infection, with an improved tolerability and safety profile compared with alfa/RBV.
Electronic supplementary material
The online version of this article (doi:10.1186/s40064-016-2920-z) contains supplementary material, which is available to authorized users.
Hepatitis C virus; Genotype 2; Genotype 3; Peginterferon lambda-1a; Peginterferon alfa-2a
A randomized, double-blind, multinational, phase 3 study was conducted comparing the efficacy and safety of peginterferon lambda-1a (Lambda)/ribavirin (RBV)/telaprevir (TVR) vs. peginterferon alfa-2a (Alfa)/RBV/TVR in patients with chronic hepatitis C virus (HCV) genotype-1 (GT-1) infection.
Patients (treatment-naïve or relapsers on prior Alfa/RBV treatment) were randomly assigned in a 2:1 ratio to receive Lambda/RBV/TVR or Alfa/RBV/TVR. Total duration of treatment was either 24 or 48 weeks (response-guided treatment), with TVR administered for the first 12 weeks. The primary endpoint was the proportion of patients who achieved a sustained virologic response at post treatment week 12 (SVR12), which was tested for noninferiority of Lambda/RBV/TVR.
A total of 838 patients were enrolled, and 617 were treated; 411 and 206 patients received Lambda/RBV/TVR and Alfa/RBV/TVR, respectively. The majority of patients were treatment-naïve, with HCV GT-1b and a high baseline viral load (≥800,000 IU/mL). Less than 10% of patients had cirrhosis (Lambda, 7.5%; Alfa, 6.8%). Lambda/RBV/TVR did not meet the criterion for noninferiority (lower bound of the treatment difference interval was -12.3%); the SVR12 in all patients (modified intent-to-treat) was 76.2% in the Lambda arm and 82.0% in the Alfa arm. Overall, the frequency of adverse events in each arm was comparable (Lambda, 91.7%; Alfa, 97.1%). As expected based on the safety profile of the 2 interferons, there were more hepatobiliary events observed in the Lambda arm and more hematologic events in the Alfa arm.
In this comparison of Lambda/RBV/TVR and Alfa/RBV/TVR in patients who were treatment-naïve or had relapsed on prior Alfa/RBV treatment, Lambda failed to demonstrate noninferiority based on SVR12 results. Treatment with Lambda/RBV/TVR was associated with a higher incidence of relapse. More patients discontinued Lambda/RBV/TVR treatment during the first 4 weeks of study treatment, mainly due to hepatobiliary-related events, and more Lambda patients were lost to follow-up.
Incident infections during treatment with peginterferon and ribavirin for chronic hepatitis C virus infection are associated with on-treatment lymphocytopenia, female sex, and baseline depression, but not with on-treatment neutropenia.
Background. Myelosuppression due to pegylated interferon (peg-IFN) is common during treatment for hepatitis C virus. The relationship between infection risk and decreases in leukocyte lines, however, is not well established. The objective of this analysis was to determine the incidence of and risk factors for infections during peg-IFN/ribavirin (RBV) therapy.
Methods. A total of 3070 treatment-naive, chronic hepatitis C genotype 1–infected patients were treated for up to 48 weeks with peg-IFN alfa-2b 1.5 µg/kg/week or 1 µg/kg/week, or peg-IFN alfa-2a 180 µg/week plus RBV. On-treatment leukocyte counts were obtained every 2–6 weeks. Dose reduction was required for a neutrophil count <0.75 × 109 cells/L, and treatment discontinuation was required for a neutrophil count <0.5 × 109 cells/L. Granulocyte colony-stimulating factor was prohibited. Data on infections were captured at each study visit and categorized according to MedDRA version 13.0.
Results. A total of 581 (19%) patients experienced moderate, severe, or life-threatening infections as assessed by the investigator; 648 (21%) patients had at least 1 neutrophil count <0.75 × 109 cells/L, but only 242 (8%) sustained an infection and had a neutrophil count <0.75 × 109 cells/L at any time while on treatment. Twelve patients had severe or life-threatening infection and grade 3/4 neutropenia, but only 4 had temporally related infections. In a multivariate logistic regression model, nadir lymphocyte count, history of depression, and female sex, but not nadir neutrophil count, were associated with moderate, severe, or life-threatening infection.
Conclusions. Nadir lymphocyte count, not nadir neutrophil count, was independently associated with moderate, severe, or life-threatening infections in the IDEAL study. Clinicians should be aware of their patients' absolute lymphocyte counts during peg-IFN/RBV therapy; peg-IFN dose reductions may be a consideration in patients with significant lymphocytopenia (<0.5 × 109 cells/L).
hepatitis C virus; lymphopenia; infections; neutropenia; interferon
Treatment of hepatitis C virus (HCV) infection with interferon (IFN) and ribavirin (RBV) is associated with adverse events, which may affect the patient's adherence to the treatment regimen and the treatment efficacy.
The aim of this study was to assess the sustained viral response (SVR) and interdependence between the haematological characteristics (leukocyte count, platelet count, and haemoglobin levels) in patients with chronic hepatitis C (CHC) infection during treatment with IFN and RBV.
Patients and Methods
We conducted a retrospective cohort study of 170 children with CHC infection who completed treatment with IFN-α and RBV. The children were divided into 2 groups: the first group (group I, n = 119) underwent a 48-week course of treatment with recombinant IFN α-2b (Intron A) at a dosage of 3 MU 3 times a week subcutaneously and RBV at a dosage of 15 mg/kg per day orally, and the second group (group II, n = 51) was administered pegylated IFN (peg-IFN)-α-2b (PegIntron) at a dosage of 1.5 μg/kg per week subcutaneously and RBV at a dosage of 15 mg/kg per day orally for 48 weeks. The dose of IFN was not adjusted but that of ribavirin was in 2 children from group II. Hematological growth factors and erythropoietin were not used. SVR was defined as undetectable serum HCV RNA 24 weeks after the end of treatment (study week 72). Serum HCV RNA was determined by performing polymerase chain reaction, and the HCV genotypes and hematological parameters were evaluated. Serum HCV RNA levels were analysed by descriptive statistics. Means and standard deviations were calculated for values collected at the baseline, on the 12th and 48th weeks during treatment, and after 24 weeks of untreated follow-up (study week 72).
Eighty-six (50%) of the 170 patients who underwent treatment achieved SVR: 62 (51%) out of 119 children from group I and 24 (47%) out of 51 from group II. The mean serum hemoglobin levels and leukocyte and platelet counts at week 12 were significantly lower than the baseline values in both responders and non-responders from both the groups (P < 0.05). In the responders in group I, the mean levels of serum hemoglobin after 24 weeks of treatment and at the end of therapy were significantly lower than the mean levels at baseline. In the group treated with peg-IFN-α-2b and RBV (group II), the mean serum hemoglobin levels at week 12 was lower in the responders than in the non-responders (P < 0.05). The decrease in the hemoglobin levels was associated with viral response. In both the responders and non-responders from both the groups, leukocyte counts decreased during treatment, and after 12 weeks, they were more significantly lower than the baseline value. The decrease was more marked in children treated with peg-IFN-α-2b + RBV (P < 0.05). After 12 weeks of treatment, the platelet count was low in children from group II who had achieved SVR.
A mild decrease in hemoglobin levels and leukocyte and platelet counts during treatment with IFN and RBV in children with CHC infection may be factors responsible for SVR induction.
Hepatitis C; Child; Therapeutics
Access to direct-acting antiviral agents (DAAs) is restricted in some settings; thus, the European Association for the Study of the Liver recommends dual peginterferon/ribavirin (PegIFN/RBV) therapy wherever DAAs are unavailable. HCV genotype (GT) 3 infection is now the most difficult genotype to eradicate and PegIFN/RBV remains an effective option. The goal of this study was to devise a simple predictive score to identify GT3 patients with a high probability of achieving a sustained virologic response (SVR) with PegIFN alfa-2a/RBV therapy.
Relationships between baseline characteristics and SVR were explored by multiple logistic regression models and used to develop a simple scoring system to predict SVR using data from 1239 treatment-naive GT3 patients who received PegIFN alfa-2a/RBV for 24 weeks in two large observational cohort studies.
The score was validated using a database of 473 patients. Scores were assigned for six factors as follows: age (years) (≤40: 2 points; >40 but ≤55: 1); bodyweight (kg) (<70: 2; ≥70 but <90: 1); no cirrhosis/transition to cirrhosis (2); ALT ≤2.5 x ULN (1); platelets (109/L) (>200: 2; ≥100 but <200: 1); HCV RNA (<400,000 IU/mL: 1). The points are summed to arrive at a score ranging from 0‒10 where higher scores indicate higher chances of SVR; 141, 123, 203, 249, 232, and 218 patients had total scores of 0‒4, 5, 6, 7, 8, and 9–10, respectively, among whom SVR rates were 45%, 62%, 72%, 76%, 84%, and 89%. Among 622 patients who had scores of 6‒10 and HCV RNA <50 IU/mL by treatment week 4 the SVR rate was 86% (532/622).
A simple baseline scoring system involving age, bodyweight, cirrhosis status, ALT level, platelet count and HCV RNA level can be used to identify treatment-naive Caucasian patients with HCV GT3 infection with a high probability of SVR with PegIFN alfa-2a/RBV therapy.
The impact of ribavirin (RBV) dosage on sustained virologic response (SVR) rates remains elusive in hepatitis C virus genotype 2 (HCV-2) rapid responders receiving 16 weeks of peginterferon (Peg-IFN) plus RBV. Treatment-naïve HCV-2 patients with rapid virologic response (RVR) received Peg-IFN alfa-2a 180 μg/week plus weight-based RBV (1,000 or 1,200 mg/day; cut-off body weight: 75 kg) for 6 weeks, and then randomly received Peg-IFN alfa-2a 180 μg/week plus weight-based (1,000 or 1,200 mg/day; n = 247) or flat-dose (800 mg/day; n = 246) RBV for additional 10 weeks. The primary endpoint was SVR24. Patients receiving weight-based and flat-dose RBV therapies had comparable SVR24 rates (93.5% versus 91.9%, P = 0.49). The risk differences (RDs) of SVR24 receiving weight-based and flat-dose RBV arms were 7.1% [95% CI: 0.7% to 13.6%] in males, and −5.8% [95% CI: −12.1% to 0.5%] in females (interaction P = 0.01). The SVR24 rate was higher in males receiving ≥13 mg/kg/day than those receiving <13 mg/kg/day (96.3% versus 85.1%, P = 0.001). In conclusion, Peg-IFN alfa-2a plus weight-based or flat-dose RBV for 16 weeks provides comparable SVR24 rates in treatment-naïve HCV-2 rapid responders. However, males should receive weight-based RBV to achieve a high SVR24 rate.
Over the last decade, the standard of care for the treatment of chronic hepatitis C has been the combination of pegylated-interferon-alfa (PEG-IFN) and ribavirin (RBV) which results in sustained virological response (SVR) rates of 75%-85% in patients with genotypes 2 or 3 but only of 40%-50% in patients with genotype 1. Currently, there are rapid and continuous developments of numerous new agents against hepatitis C virus (HCV), which are the focus of this review. Boceprevir and telaprevir, two first-generation NS3/4A HCV protease inhibitors, have been recently licensed in several countries around the world to be used in combination with PEG-IFN and RBV for the treatment of genotype 1 patients. Boceprevir or telaprevir based triple regimens, compared with the PEG-IFN/RBV combination, improve the SVR rates by 25%-31% in treatment-naïve genotype 1 patients, by 40%-64% in prior relapsers, by 33%-45% in prior partial responders and by 24%-28% in prior null responders. At the same time, the application of response-guided treatment algorithms according to the on-treatment virological response results in shortening of the total therapy duration to only 24 wk in 45%-55% of treatment-naïve patients. There are, however, several challenges with the use of the new triple combinations in genotype 1 patients, such as the need for immediate results of HCV RNA testing using sensitive quantitative assays, new and more frequent adverse events (anemia and dysgeusia for boceprevir; pruritus, rash and anemia for telaprevir), new drug interactions and increasing difficulties in compliance. Moreover, the SVR rates are still poor in very difficult to treat subgroups of genotype 1 patients, such as null responders with cirrhosis, while there is no benefit for patients who cannot tolerate PEG-IFN/RBV or who are infected with non-1 HCV genotype. Many newer anti-HCV agents of different classes and numerous combinations are currently under evaluation with encouraging results. Preliminary data suggest that the treatment of chronic HCV patients with well tolerated combinations of oral agents without PEG-IFN is feasible and may lead to a universal HCV cure over the next 5-10 years.
Chronic hepatitis C; Pegylated interferon; Ribavirin; Protease inhibitors; Nucleos(t)ide analogue inhibitors; Non-nucleos(t)ide analogue inhibitors; Hepatitis C virus polymerase; NS5A inhibitors; Cyclophilin inhibitors
Background & Aims
Intravenous silibinin (SIL) is a potent antiviral agent against hepatitis C virus (HCV) genotype-1. In this proof of concept case-study we tested: (i) whether interferon-alfa (IFN)-free treatment with SIL plus ribavirin (RBV) can achieve sustained virological response (SVR), (ii) whether SIL is safe and feasible for prolonged duration of treatment, and (iii) whether mathematical modeling of early on-treatment HCV kinetics can guide duration of therapy to achieve SVR.
A 44 year-old female HCV-(genotype-1)-infected patient who developed severe psychiatric adverse events to a previous course of pegIFN+RBV, initiated combination treatment with 1200 mg/day of SIL, 1200 mg/day of RBV and 6000 u/day vitamin D. Blood samples were collected frequently till week 4, thereafter every 1 to 12 weeks until the end of therapy. The standard-biphasic-mathematical model was used to predict the duration of therapy to achieve SVR.
Based on modeling the observed viral kinetics during the first 3 weeks of treatment, SVR was predicted to be achieved within 34 weeks of therapy. Provided with this information, the patient agreed to complete 34 weeks of treatment. IFN-free treatment with SIL+RBV was feasible, safe, and achieved SVR (week-33).
We report, for the first time, the use of real-time mathematical modeling of HCV kinetics to individualize duration of IFN-free therapy and to empower a patient to participate in shared decision making regarding length of treatment. SIL-based individualized therapy provides a treatment option for patients who do not respond to or cannot receive other HCV agents and should be further validated.
hepatitis C; silibinin; mathematical modeling; viral kinetics; sustained virological response; interferon-free treatment; individualized therapy
AIM: To study the efficacy and factors associated with a sustained virological response (SVR) in chronic hepatitis C (CHC) relapsing patients.
METHODS: Out of 1228 CHC patients treated with pegylated interferon (PEG-IFN) and ribavirin (RBV), 165 (13%) had a relapse. Among these, 62 patients were retreated with PEG-IFN-α2a or -α2b and RBV. Clinical, biological, virological and histological data were collected. Initial doses and treatment modifications were recorded. The efficacy of retreatment and predictive factors for SVR were analyzed.
RESULTS: An SVR was achieved in 42% of patients. SVR was higher in young (< 50 years) (61%) than old patients (27%) (P = 0.007), and in genotype 2 or 3 (57%) than in genotype 1 or 4 (28%) patients (P = 0.023). Prolonging therapy for at least 24 wk more than the previous course was associated with higher SVR rates (53% vs 28%, P = 0.04). Also, a better SVR rate was observed with RBV dose/body weight > 15.2 mg/kg per day (70% vs 35%, P = 0.04). In logistic regression, predictors of a response were age (P = 0.018), genotype (P = 0.048) and initial RBV dose/body weight (P = 0.022). None of the patients without a complete early virological response achieved an SVR (negative predictive value = 100%).
CONCLUSION: Retreatment with PEG-IFN/RBV is eff-ective in genotype 2 or 3 relapsers, especially in young patients. A high dose of RBV seems to be important for the retreatment response.
Chronic hepatitis C; Relapse; Retreatment; Ribavirin; Pegylated interferon
For patients infected with hepatitis C virus (HCV), the combination of the direct-acting antiviral agent telaprevir, pegylated-interferon alfa (Peg-IFN), and ribavirin (RBV) significantly increases the chances of sustained virologic response (SVR) over treatment with Peg-IFN and RBV alone. If patients do not achieve SVR with telaprevir-based treatment, their viral population is often significantly enriched with telaprevir-resistant variants at the end of treatment. We sought to quantify the evolutionary dynamics of these post-treatment resistant variant populations. Previous estimates of these dynamics were limited by analyzing only population sequence data (20% sensitivity, qualitative resistance information) from 388 patients enrolled in Phase 3 clinical studies. Here we add clonal sequence analysis (5% sensitivity, quantitative) for a subset of these patients. We developed a computational model which integrates both the qualitative and quantitative sequence data, and which forms a framework for future analyses of drug resistance. The model was qualified by showing that deep-sequence data (1% sensitivity) from a subset of these patients are consistent with model predictions. When determining the median time for viral populations to revert to 20% resistance in these patients, the model predicts 8.3 (95% CI: 7.6, 8.4) months versus 10.7 (9.9, 12.8) months estimated using solely population sequence data for genotype 1a, and 1.0 (0.0, 1.4) months versus 0.9 (0.0, 2.7) months for genotype 1b. For each individual patient, the time to revert to 20% resistance predicted by the model was typically comparable to or faster than that estimated using solely population sequence data. Furthermore, the model predicts a median of 11.0 and 2.1 months after treatment failure for viral populations to revert to 99% wild-type in patients with HCV genotypes 1a or 1b, respectively. Our modeling approach provides a framework for projecting accurate, quantitative assessment of HCV resistance dynamics from a data set consisting of largely qualitative information.
Hepatitis C virus (HCV) chronically infects approximately 170 million people worldwide. The goal of HCV treatment is viral eradication (sustained virologic response; SVR). Telaprevir directly inhibits viral replication by inhibiting the HCV protease, leading to high SVR rates when combined with pegylated-interferon alfa and ribavirin. Telaprevir-resistant variants may be detected in the subset of patients who do not achieve SVR with telaprevir. While the clinical impact of viral resistance is unknown, typically the telaprevir-sensitive virus re-emerges after the end of treatment due to competition between the telaprevir-sensitive and resistant variants. Previous estimates of these competition dynamics were obtained from population sequence data, which are qualitative and have a limited sensitivity of ∼20%. We sought to improve these estimates by combining these data with clonal sequence data, which are quantitative and have a sensitivity of ∼5%, and using quantitative modeling. The resulting model, which was verified with an independent data set, predicted that the median time for telaprevir-resistant variants to decline to less than 1% of the viral population was ≤1 year. Our modeling approach provides a framework for accurately projecting HCV resistance dynamics from a dataset consisting of largely qualitative information.
The aims of this phase III study were to assess the efficacy and safety of telaprevir in combination with peginterferon alfa-2b (PEG-IFN) and ribavirin (RBV) for difficult-to-treat patients who had not achieved sustained virological response (SVR) to prior regimens in Japan. The subjects were 109 relapsers (median age of 57.0 years) and 32 nonresponders (median age of 57.5 years) with hepatitis C virus genotype 1. Patients received telaprevir (750 mg every 8 h) for 12 weeks and PEG-IFN/RBV for 24 weeks. The SVR rates for relapsers and nonresponders were 88.1% (96/109) and 34.4% (11/32), respectively. Specified dose modifications of RBV that differed from that for the standard of care were introduced to alleviate anaemia. RBV dose reductions were used for 139 of the 141 patients. The SVR rates for relapsers did not depend on RBV dose reduction for 20–100% of the planned dose (SVR rates 87.5–100%, P < 0.05). Skin disorders were observed in 82.3% (116/141). Most of the skin disorders were controllable by anti-histamine and/or steroid ointments. The ratios of discontinuation of telaprevir only or of all the study drugs because of adverse events were 21.3% (30/141) and 16.3% (23/141), respectively. A frequent adverse event leading to discontinuation was anaemia. Telaprevir in combination with PEG-IFN/RBV led to a high SVR rate for relapsers and may offer a potential new therapy for nonresponders even with a shorter treatment period.
direct-acting antiviral; peginterferon; ribavirin; sustained virological response; treatment failure
Using an inclusive HCV treatment protocol that encourages prospective engagement in care, HIV-infected patients with and without ongoing barriers to care had similar chances of HCV sustained viral response irrespective of which HCV treatment regimen was used.
Background. Access to hepatitis C virus (HCV) medications for human immunodeficiency virus (HIV)-infected patients with ongoing barriers to care is restricted by healthcare payers in the absence of HCV treatment outcomes data in the era of direct-acting antivirals (DAA).
Methods. Retrospective analysis of HCV treatment outcomes using interferon (IFN)-free DAA regimens and an inclusive treatment protocol in an urban HIV clinic where ongoing barriers to care (drug or alcohol use, psychiatric disease, and/or unstable housing) are common. Then, using logistic regression analysis, we compared the proportion of HIV-infected patients who achieved HCV sustained viral response (SVR) in the pegylated-IFN plus ribavirin (PEG-IFN/RBV, 2008–2011), pegylated-IFN plus ribavirin and telaprevir (PEG-IFN/RBV/PI, 2011–2013), and IFN-free DAA therapy eras (2014). Results are displayed using forest plots.
Results. The proportion of patients who achieved HCV SVR in the PEG-IFN/RBV, PEG-IFN/RBV/PI, and IFN-free DAA therapy eras increased from 38.4% (95% confidence interval [CI], 23.2–53.7) and 48% (95% CI, 28.4–67.6) to 83.3% (95% CI, 70.0–96.7), respectively. Similar proportions of patients with ongoing barriers to care were treated during the PEG-IFN/RBV (25 of 39 [64%]), PEG-IFN/RBV/PI (14 of 25 [56%]), and IFN-free DAA (16 of 30 [53%]) eras. Hepatitis C virus SVR among patients with ongoing barriers to care improved from 40% (95% CI, 21–59) to 76.5% (95% CI, 56–97) in the PEG-IFN/RBV and IFN-free DAA eras, respectively. After stratification for factors associated with HCV SVR such as HCV genotype and cirrhosis, HCV SVR were similar in patients regardless of the presence of ongoing barriers to care.
Conclusions. Using IFN-free DAA and an inclusive HCV treatment protocol, 76.5% of HIV/HCV-treated patients with ongoing barriers to care achieved HCV SVR.
barriers to care; DAA; HCV; HIV
More than 50% of patients infected with chronic hepatitis C virus (HCV) do not respond to treatment with conventional interferon (IFN) combined with ribavirin (RBV). The aim of our study was to evaluate the effectiveness of retreatment with peginterferon alfa-2a or 2b (PEG-IFN 2a or 2b) concomitantly with RBV in patients with HCV genotype 2 and 3, which were non-responders or relapsers to initial treatment with IFN / RBV and to identify possible predictors of sustained virological response (SVR).
From September 2003 to March 2009 a cohort of 216 patients who had previously failed therapy with a regimen of standard interferon and ribavirin, were followed in a specialized service implemented in the Brazilian Unified Health System, Rio Grande do Sul. All patients were retreated with PEG-IFN 2a or 2b per week, associated with RBV, through oral route, with doses determined according to weight (1,000 mg if weight ≤ 75 Kg and 1,250 mg if ≥ 75 Kg) per day for 48 weeks. The HCV-RNA was tested by Polymerase Chain Reaction (PCR). Virological Response (VR) within 48 weeks and SVR in the 72 weeks was considered for evaluation of treatment efficacy. Analyses were performed in patients who received at least one dose of PEG-IFN.
The SVR rate for non-responders to previous treatment was 34.4% and for relapsers was 50% (p = 0.031). As predictive factors that contribute to improve SVR, were identified the age (p = 0.005), to be relapsers to previous treatment (p = 0.023) and present liver biopsy examination Metavir F0-F2 (p = 0.004). In assessing the safety profile, 51 patients (23.6%) discontinued treatment prematurely.
This alternative retreatment for patients who have failed prior therapies for anti-HCV, has demonstrated promising SVR rate, provided that it includes a careful selection of patients with predictors of response and adverse events monitored.
Hepatitis C; Retreatment; Peginterferon alpha; Ribavirin
Ribavirin (RBV) is an essential component of most current hepatitis C (HCV) treatment regimens and still standard of care in the combination with pegylated interferon (pegIFN) to treat chronic HCV in resource limited settings. Study results in HIV/HCV-coinfected patients are contradicting as to whether RBV concentration correlates with sustained virological response (SVR).
We included 262 HCV treatment naïve HIV/HCV-coinfected Swiss HIV Cohort Study (SHCS) participants treated with RBV and pegIFN between 01.01.2001-01.01.2010, 134 with HCV genotype (GT) 1/4, and 128 with GT 2/3 infections. RBV levels were measured retrospectively in stored plasma samples obtained between HCV treatment week 4 and end of therapy. Uni- and multivariable logistic regression analyses were used to evaluate the association between RBV concentration and SVR in GT 1/4 and GT 2/3 infections. The analyses were repeated stratified by treatment phase (week 4-12, 13-24, >24) and IL28B genotype (CC versus CT/TT).
SVR rates were 35.1% in GT 1/4 and 70.3% in GT 2/3 infections. Overall, median RBV concentration was 2.0 mg/L in GT 1/4, and 1.9 mg/L in GT 2/3, and did not change significantly across treatment phases. Patients with SVR had similar RBV concentrations compared to patients without SVR in both HCV genotype groups. SVR was not associated with RBV levels ≥2.0 mg/L (GT 1/4, OR 1.19 [0.5-2.86]; GT 2/3, 1.94 [0.78-4.80]) and ≥2.5 mg/L (GT 1/4, 1.56 [0.64-3.84]; GT 2/3 2.72 [0.85-8.73]), regardless of treatment phase, and IL28B genotype.
In HIV/HCV-coinfected patients treated with pegIFN/RBV, therapeutic drug monitoring of RBV concentrations does not enhance the chance of HCV cure, regardless of HCV genotype, treatment phase and IL28B genotype.
Pegylated (PEG)-interferon (IFN)-alfa-2a plus ribavirin (RBV) therapy for 24 weeks is now a standard treatment protocol for patients with hepatitis C virus (HCV) genotype 2. As RBV cannot be used in certain situations, we examined whether PEG-IFN-alfa-2a monotherapy for 24 weeks or less would be sufficient to obtain a sustained virological response (SVR) in patients infected with HCV genotype 2.
Forty-nine consecutive patients with HCV genotype 2 received PEG-IFN-alfa-2a (180 μg/week) subcutaneously without oral RBV for 8-64 weeks. HCV RNA level was determined by COBAS AMPLICOR HCV Test, v2.0.
HCV RNA was equal to or less than 100 KIU/mL (defined as low viral load) in 15 of 49 patients, and the remaining 34 had HCV RNA above 100 KIU/mL (defined as high viral load). All 15 patients with low viral load achieved rapid virological response (RVR; HCV RNA negative at week 4), and also achieved SVR with an average treatment duration of 17.1 weeks. The 34 patients with high viral load were treated for 33.7 weeks on average, and 19 of them (55.9%) achieved RVR. The SVR rates of these patients were significantly higher in those with RVR than without RVR (16/19 vs. 6/15 p = 0.0074).
PEG-IFN-alfa-2a monotherapy for 24 weeks or less might be sufficient to treat selected patients with HCV genotype 2, especially those with low viral load and becoming negative for HCV RNA by week 4 of treatment.
The combination of sofosbuvir (SOF), ribavirin (RBV) and peg-interferon-alfa-2a (peg-IFN-alfa-2a) as well as the combination of SOF and RBV for the treatment of patients infected with hepatitis c virus (HCV) has improved rates of sustained virological response (SVR) considerably in recent trials. However, there is only limited data concerning the efficacy and safety in a “real-life” cohort.
We analyzed a cohort of 119 patients with chronic HCV infection treated at four investigational sites in Germany. All patients received either a combination treatment of SOF, RBV and peg-IFN-alfa-2a or SOF and RBV.
The rates of SVR at 12 weeks after end of treatment (SVR 12) were as follows: Among 76 patients with genotype 1 infection the SVR 12 rate was 74 % (n = 56), among 14 patients with genotype 2 infection the SVR 12 rate was 79 % (n = 11), among 24 patients with genotype 3 infection the SVR 12 rate was 92 % (n = 22) and among 5 patients with genotype 4 infection the SVR 12 rate was 80 % (n = 4). Of all 26 patients with a relapse in our cohort, 69 % (n = 18) of these patients presented with liver cirrhosis and 58 % (n = 15) were treatment experienced. Notably, the level of HCV-RNA after 4 weeks of treatment was a significant predictor of treatment response in genotype 1 patients. Patients with HCV-RNA levels ≥ 12 IU ml-1 after 4 weeks of treatment achieved SVR 12 only in 30 % (n = 17/56, p < 0.0001) of cases and treatment response was even lower with SVR 12 of 25 % (n = 5/20, p = 0.0016) in the subgroup of patients with cirrhosis.
We observed a high rate of SVR 12 with SOF-based treatment regimes, however probably due to the high number of patients with liver cirrhosis and prior treatment experience, treatment response rates were lower than in previously published trials. In genotype 1 patients the analysis of early virological response may predict treatment response in SOF-based combination therapies.
Treatment with pegylated interferon alpha-2b (PEGIFN) plus ribavirin (RBV) is standard therapy for patients with chronic hepatitis C. Although the effectiveness, patients with high titres of group Ib hepatitis C virus (HCV) respond poorly compared to other genotypes. At present, we cannot predict the effect in an individual. Previous studies have used traditional statistical analysis by assuming a linear relationship between clinical features, but most phenomena in the clinical situation are not linearly related. The aim of this study is to predict the effect of PEG IFN plus RBV therapy on an individual patient level using an artificial neural network system (ANN). 156 patients with HCV group 1b from multiple centres were treated with PEGIFN (1.5 µg/kg) plus RBV (400–1000 mg) for 48 weeks. Data on the patients' demographics, laboratory tests, PEGIFN, and RBV doses, early viral responses (EVR), and sustained viral responses were collected. Clinical data were randomly divided into training data set and validation data set and analyzed using multiple logistic regression analysis (MLRs) and ANN to predict individual outcomes. The sensitivities of predictive expression were 0.45 for the MLRs models and 0.82 for the ANNs and specificities were 0.55 for the MLR and 0.88 for the ANN. Non-linear relation analysis showed that EVR, serum creatinine, initial dose of Ribavirin, gender and age were important predictive factors, suggesting non-linearly related to outcome. In conclusion, ANN was more accurate than MLRs in predicting the outcome of PEGIFN plus RBV therapy in patients with group 1b HCV.
Genetic variation around interleukin-28B (IL28B), encoding IFN-λ3, predict non-responders to pegylated interferon-α/ribavirin (Peg-IFN/RBV) therapy in chronic hepatitis C (CHC). However, it remains unclear the expression and the role of IL28B itself. The aim of this study is to develop easy and useful methods for the prediction of treatment outcomes.
The mRNA and protein levels of IFN-λ3 induced by ex vivo stimulation of peripheral blood mononuclear cells (PBMC) or magnetically selected dendritic cells (DCs) with toll-like receptor agonists (TLR3; poly I:C, TLR7; R-837) were measured by the quantitative real-time polymerase chain reaction and our newly developed chemiluminescence enzyme immunoassays, respectively, and compared with the clinical data.
We found that BDCA-4+ plasmacytoid and BDCA-3+ myeloid DCs were the main producers of IFN-λs when stimulated with R-837 and poly I:C, respectively. Detectable levels of IFN-λs were inducible even in a small amount of PBMC, and IFN-λ3 was more robustly up-regulated by R-837 in PBMC of CHC patients with favorable genotype for the response to Peg-IFN/RBV (TT in rs8099917) than those with TG/GG. Importantly, the protein levels of IFN-λ3 induced by R-837 clearly differentiated the response to Peg-IFN/RBV treatment (p = 1.0 × 10−10), including cases that IL28B genotyping failed to predict the treatment response. The measurement of IFN-λ3 protein more accurately predicted treatment efficacies (95.7 %) than that of IL28B genotyping (65.2 %).
Genetic variations around IL28B basically affect IFN-λ3 production, but different amounts of IFN-λ3 protein determines the outcomes of Peg-IFN/RBV treatment. This study, for the first time, presents compelling evidence that IL28B confer a functional phenotype.
Electronic supplementary material
The online version of this article (doi:10.1007/s00535-013-0814-1) contains supplementary material, which is available to authorized users.
Chronic hepatitis C; IL28B; IFN-λ3; Peg-IFN/RBV
Two functional variants in the inosine triphosphatase (ITPA) gene causing inosine triphos-phatase (ITPase) deficiency protect against ribavirin (RBV)-induced hemolytic anemia and the need for RBV dose reduction in patients with genotype 1 hepatitis C virus (HCV). No data are available for genotype 2/3 HCV. We evaluated the association between the casual ITPA variants and on-treatment anemia in a well-characterized cohort of genotype 2/3 patients treated with variable-duration pegylated interferon alfa-2b (PEG-IFN-α2b) and RBV. Two hundred thirty-eight Caucasian patients were included in this retrospective study [185 (78%) with genotype 2 and 53 (22%) with genotype 3]. Patients were treated with PEG-IFN-α2b plus weight-based RBV (1000/1200 mg) for 12 (n = 109) or 24 weeks (n = 129). The ITPA polymorphisms rs1127354 and rs7270101 were genotyped, and an ITPase deficiency variable was defined that combined both ITPA variants according to their effect on ITPase activity. The primary endpoint was hemoglobin (Hb) reduction in week 4. We also considered Hb reduction over the course of therapy, the need for RBV dose modification, and the rate of sustained virological response (SVR). The ITPA variants were strongly and independently associated with protection from week 4 anemia (P = 10−6 for rs1127354 and P = 10−7 for rs7270101). Combining the variants into the ITPase deficiency variable increased the strength of association (P = 10−11). ITPase deficiency protected against anemia throughout treatment. ITPase deficiency was associated with a delayed time to an Hb level < 10 g/dL (hazard ratio = 0.25, 95% confidence interval = 0.08–0.84, P = 0.025) but not with the rate of RBV dose modification (required per protocol at Hb < 9.5 g/dL). There was no association between the ITPA variants and SVR.
Two ITPA variants were strongly associated with protection against treatment-related anemia in patients with genotype 2/3 HCV, but they did not decrease the need for RBV dose reduction or increase the rate of SVR.
Thyroid dysfunction (TD) is more likely to occur in patients with chronic hepatitis C (CHC) and is particularly associated with interferon (IFN) treatment. The purpose of this study was to investigate the incidence, outcomes, and risk factors for TD during pegylated interferon (PEG-IFN) and ribavirin (RBV) combined therapy in patients with CHC.
A total of 242 euthyroid patients with CHC treated with PEG-IFN/RBV were included. Thyroid function and autoantibodies were measured at baseline, and virologic response and thyroid function were assessed every 3 months during therapy.
TD developed in 67 patients (27.7%) during the PEG-IFN/RBV treatment. The types of TD were subclinical hypothyroidism (50.7%), hypothyroidism (14.9%), thyroiditis (11.9%), subclinical hyperthyroidism (10.4%), and hyperthyroidism (10.4%). Most of the patients with TD recovered spontaneously; however, seven patients (10.4%) needed thyroid treatment. The sustained virological response rate was higher in patients with TD than those without (65.7% vs. 49.1%, p = 0.02). Baseline thyroid stimulating hormone (TSH) concentrations (odds ratio [OR], 2.09; 95% confidence interval [CI], 1.96 to 8.77; p < 0.001), presence of the thyroid peroxidase antibody (OR, 8.81; 95% CI, 1.74 to 44.6; p = 0.009), and PEG-IFNα-2b (OR, 3.01; 95% CI, 1.43 to 6.39; p = 0.004) were independent risk factors for the development of TD.
TD developed in 27.7% of patients with CHC during PEG-IFN/RBV treatment, and 10.4% of these patients needed thyroid treatment. TD is associated with a favorable virologic response to PEG-IFN/RBV. Assessment of TSH and thyroid autoantibodies at baseline and close monitoring of thyroid function during PEG-IFN/RBV therapy are necessary for early detection and management of IFN-induced TD.
Hepatitis C, chronic; Thyroid diseases; Interferons; Incidence; Risk factors