Achievement Of Rapid Virological Response Research Articles

Impact of hepatitis C virus core mutations on the response to interferon-based treatment in chronic hepatitis C.

AIMTo determine whether hepatitis C virus (HCV) core substitutions play a role in the response to interferon-based treatment in Caucasian patients.METHODSOne hundred eight HCV chronically infected patients initiating treatment with pegylated IFN plus ribavirin for 48 wk were tested for baseline substitutions at codons 70 and 91 of the viral core protein (BigDye Terminator vers.3.1, Applied Biosystems,) and for genetic polymorphisms in host IL28B gene rs12979860 (Custom TaqMan 5' allelic discrimination assay; Applied Biosystems).RESULTSOf the patients, all were infected with HCV genotype 1b, 44.4% had low baseline HCV viral load, and 37.9% had mild/moderate fibrosis. Only 38.9% achieved therapeutic success, defined as sustained virological response (SVR). Eighty-eight percent of the patients presented at least one substitution at core position 70 (R70Q/H) or/and position 91 (L91M). The favorable IL28B CC polymorphism was detected in only 17.6% of the patients. In the univariate analysis, young age (P < 0.001), urban residence (P = 0.004), IL28B CC genotype (P < 0.001), absence of core mutations (P = 0.005), achievement of rapid virologic response (P < 0.001) and early virological response (P < 0.001) were significantly correlated with SVR. A multivariate analysis revealed three independent predictors of therapeutic success: young age (P < 0.001), absence of core substitutions (P = 0.04) and IL28B CC genotype (P < 0.001); the model correctly classified 75.9% of SVR cases with a positive predictive value of 80.7%.CONCLUSIONHCV core mutations can help distinguish between patients who can still benefit from the affordable IFN-based therapy from those who must be treated with DAAs to prevent the evolution towards end-stage liver disease.

Evaluation of Simeprevir-Based Triple Therapy Using Pegylated-Interferon-α and Ribavirin in Patients With Hepatitis C Virus Genotype-1b Infection

Introduction: Pegylated-interferon-alfa(PEG) plus ribavirin(RBV) regimens were the standard of care in patients with hepatitis C virus(HCV) infection, but the sustained virological response(SVR; undetectable HCV-RNA) was not satisfactory in those with HCV-genotype-1b infection. Telaprevir(TLV; HCV NS3/4A protease inhibitor)-based triple therapy improved efficacy in such cases. However, adverse events(AEs) of TLV should be noted as well. In this study, efficacy and safety of simeprevir(SMV; the second generation of HCV NS3/4A protease inhibitor)-based triple-therapy using PEG/RBV were assessed in those with HCV-genotype-1b infection. Methods: Thirty-seven patients with high-load-1b HCV undergoing SMV-based triple-therapy were enrolled (male/female 19/18, age 61.6±11.4, FIB4-index 2.2±1.0). The population consists of treatmentnaïve( 11) and -experienced patients (prior relapsers(13), non-responders(11) or discontinuers(2) to IFN-based therapy). The genotypes of IL28B polymorphism were TT(22), TG(14) and GG(1), respectively. Twelve-week SMV-based triple-combination-therapy was followed by 12-week PEG/RBV therapy. The efficacy(rapid virological response(RVR); undetectable HCV-RNA 4 weeks after initiation of triple therapy, SVR12; undetectable HCV-RNA 12 weeks after the last treatment) as well as safety(including AEs) was assessed. Results: Serum HCV-RNA(LIU/mL) at baseline, weeks1, 2, 3, 4, 12 and 24 was 6.6±0.7, 1.7±0.8, 1.1±0.9, 0.5±0.9, 0.4±1.0, 0.2±1.0 and 0.1±0.3, respectively. HCV-negativity at weeks1, 2, 3, 4, 8 and 12 was 8.1%, 29.7%, 67.6%, 75.7%, 89.2 and 91.9%, respectively. RVR/SVR12 was 75.7% (28/37)/75.7% (28/37), respectively. In the univariate analysis, factors significantly associated with SVR12 were prior relapsers to IFN-based therapy or treatment-naïve, IL28B polymorphism with genotype TT, achievement of RVR, and PEG adherence over 70%, respectively. In the multivariate analysis, the factor significantly associated with SVR12 was prior relapsers to IFN-based therapy or treatment-naïve. Regarding safety, AEs with more than grade-3 such as neutrocytopenia and elevation of bilirubin and ALT observed during treatment were not clinically significant enough to affect therapeutic process. Two patients discontinued therapy because of depression probably due to PEG. At least, addition of SMV to conventional PEG/RBV caused no more additional clinically meaningful AEs. Conclusion: Although SMV-based triple-therapy using PEG/RBV could be feasible in patients with HCV-genotype-1b infection, efficacy could not be expected in prior non-responders to the conventional IFN-based therapy.

Sustained Virological Response Rates to Antiviral Therapy in Genotype 1 and 3 Chronic Hepatitis C Patients: A Study from North India

In India, both genotype 3 and 1 are predominant genotypes in patients with chronic hepatitis C (CHC). However, there is scanty data on sustained viral response (SVR) rate with conventionally recommended dual therapy with PEG-IFN and ribavirin. In this retrospective study, consecutive patients of CHC of genotypes 1 and 3, attending the single unit of Gastroenterology of our hospital, who received PEG-IFN and ribavirin therapy, were included. Patients who had co-infection with HIV or HBV were excluded. A total of 114 patients were included in the study median age 44 (15-72) years, 79% males. Most common presentation was with chronic hepatitis, while 10 (9%) patients had compensated cirrhosis. Nine (8%) patients had associated diabetes, 16 (14%) patients gave history of significant alcohol abuse. The median baseline HCV RNA level was 3.0×10(5) (1.7×10(3)-1.8×10(7))IU/mL. The most common genotype was 3 (75%) followed by genotype 1 (25%). 70% patients received PegIFN-α2a (median dose 180MIU/wk) and 30% patients received PegIFN-α2b (median dose 80MIU/wk). The median ribavirin dose was 800 (range 800-1200)mg. SVR in genotype 1 was 64% (18/28) while SVR in genotype 3 was 73% (63/86). The factors predicting SVR on univariate analysis were a lower baseline HCV RNA level (less than 3.0×10(5)), higher hemoglobin level>11.8g/dl, and achievement of rapid virological response (RVR), early virological response (EVR) and end of treatment response (ETR). In multivariate analysis the only baseline factor found independently correlating with SVR was low HCV RNA level (<3.0×10(5)IU/mL) (P=0.003). In north India, HCV genotype 3 has a SVR rate of 73%, which is comparable to genotype 1 with SVR rate of 64% when treated with PEG-IFN and ribavirin therapy. A baseline HCV RNA level lower than 3.0×10(5) best predicts SVR in addition to achievement of RVR, EVR or ETR.

Factors associated with sustained virological response in 24‐week telaprevir‐based triple therapy for chronic hepatitis C genotype 1b patients with the IL28B minor genotype

Single nucleotide polymorphisms (SNP) near the interleukin-28B (IL28B) gene affect the outcome of 24-week telaprevir-based triple therapy with telaprevir, pegylated interferon-α and ribavirin for chronic hepatitis C virus (HCV) genotype 1b patients. We aimed to identify factors associated with treatment outcomes in patients with the unfavorable minor IL28B SNP genotype, who have poor response to combination therapy. Pretreatment and on-treatment factors associated with sustained virological response (SVR) for 24-week telaprevir-based triple therapy were analyzed using multiple logistic regression analysis in 106 HCV genotype 1b patients with the minor IL28B SNP rs8099917 genotype (non-TT). Of the 106 non-TT patients, 62 (58.5%) achieved SVR. Of the 44 remaining patients, 22 experienced relapse, 13 experienced viral breakthrough and nine were non-responders. Pretreatment factors such as treatment-naïve/prior treatment response (P = 0.0041), high fasting serum low-density lipoprotein cholesterol (LDL-C) concentration (P = 0.0068) and low serum HCV RNA levels (P = 0.0088) were significantly and independently associated with SVR. On-treatment factors such as achievement of rapid virological response (RVR) were significantly and independently associated with SVR (P = 0.0001). For both pre- and on-treatment factors, treatment-naïve/prior treatment response (P = 0.0018), low pretreatment serum fasting LDL-C (P = 0.0062) and achieving RVR (P = 0.0021) were significantly and independently associated with SVR. In HCV genotype 1b patients with the minor IL28B SNP rs8099917 genotype, evaluating prior treatment response and achieving RVR and pretreatment serum fasting LDL-C concentrations were useful for predicting SVR achievement after 24-week telaprevir-based triple therapy.

Telaprevir or boceprevir triple therapy in patients with chronic hepatitis C and varying severity of cirrhosis

Risks and benefits of protease inhibitor (PI) (telaprevir or boceprevir) triple therapy in hepatitis C virus (HCV)-infected patients with mildly decompensated cirrhosis, including those wait-listed for liver transplantation (LT), are incompletely known. To assess virological responses and safety of PI triple therapy in patients with mildly decompensated Child-Pugh (CP) CP ≥6 vs. compensated (CP = 5) cirrhosis. Multicentre cohort of 160 adults with cirrhosis treated with peginterferon/ribavirin (peg-IFN/RBV) plus telaprevir (69%) or boceprevir (31%), comparing outcomes between those with CP = 5 and CP ≥6. Patients, 47% with CP ≥6 cirrhosis (CP range 6-10), received PI triple therapy for a targeted duration of 48 weeks. The cohort was median age 59 years, 32% female, 59% genotype 1a, 35% previous null/partial responders. Sustained virological response at 12 weeks (SVR12) was achieved by 35% of patients with CP ≥6 vs. 54% of those with CP = 5 (P = 0.02). CP = 5, achievement of rapid virological response and genotype 1b/other, independently predicted SVR12. Compared to those with CP = 5, patients with CP ≥6 had more peg-IFN dose reductions, eltrombopag use, transfusions and hospitalisations to manage adverse events (all P < 0.05). Overall, 67 (42%) discontinued treatment early. Nine wait-listed patients were treated for a median of 97 days (IQR 60-160) prior to liver transplantation and five achieved post-LT SVR. In the presence of mild decompensation (Child-Pugh ≥6), SVR12 rates with protease inhibitor triple therapy are significantly reduced and adverse events increased. Thus, treatment with protease inhibitor triple therapy, if judged as necessary, should be undertaken with close monitoring and awareness of the significant risks.

Vitamin D Levels and Il28B Polymorphisms are Related to Rapid Virological Response to Standard of Care in Genotype 1 Chronic Hepatitis C

Genotype 1 (G1) chronic hepatitis C (CHC) patients achieving a rapid virological response (RVR) on pegylated interferon (PEG-IFN) plus ribavirin have a high chance of sustained virological response (SVR), influenced by IL28B status, viral load, fibrosis and insulin resistance. We assessed whether 25-hydroxyvitamin D (25[OH]D) serum levels are linked to RVR and can be used together with IL28B to construct a pretreatment model to predict RVR. A total of 117 consecutive patients with G1 CHC were evaluated by biopsy and anthropometric and metabolic measurements. 25(OH)D serum levels were measured by HPLC. IL28B rs12979860 and rs8099917 polymorphisms were also evaluated. All patients underwent antiviral therapy with PEG-IFN-α2a plus ribavirin. HCV RNA was assessed at baseline, week 4, week 12, at the end of therapy and after 6 months of follow-up. Mean ±SD 25(OH)D serum levels were 26.3 ±10.6 μg/l (range 8.0-58.0) and 31 (26.5%) patients had the rs12979860 CC polymorphism. RVR was achieved in 35 (29.9%) patients, and 32 (91.4%) of them had an SVR, compared to 26 of 82 (31.7%) without RVR. The rs12979860 CC polymorphism (OR 4.575, 95% CI 1.761, 11.889; P=0.002) and higher 25(OH)D levels (OR 1.055, 95% CI 1.010, 1.101; P=0.01) were independently associated with the achievement of RVR by multivariate analysis. The likelihood of RVR progressively increased from patients in the worst class (vitamin D<26.8 μg/l and TT/TC polymorphism; RVR 14.2%), to those with only one positive predictor (RVR 29.7% and 37.5%), and to those in the best class (vitamin D≥26.8 μg/l and rs12979860 CC polymorphism; RVR 73.3%). In patients with G1 CHC, 25(OH)D serum levels and IL28B status are independently associated with the likelihood to achieve RVR and SVR. When incorporated into a pretreatment predictive model they can assist in further discriminating patients with a high likelihood of achieving RVR and SVR.

Evaluation of prognostic factors for Peg Interferon alfa-2b plus ribavirin treatment on HCV infected patients in Pakistan

The effective standard therapeutic regimen for patients with chronic hepatitis C is pegylated interferon plus ribavirin. The efficacy of treatment in chronic hepatitis C is defined as absence of detectable virus at six months after treatment. Analysis of patient dependent and virus related factors that enable us to predict the response to antiviral treatment is very important. We prospectively studied 403 patients who received PEG-IFN alpha-2b 1.5μg/kg/body weight plus ribavirin. Treatment was administrated for 24 weeks and 48 weeks for hepatitis C virus (HCV) genotypes 3 and 1, respectively. Out of 403 treated patients, 301 patients (74.7%) showed a sustained virologic response (SVR). Seven variables (age, sex, ethnic group, pretreatment viral load, HCV genotyping and pretreatment ALT) were chosen as possible predictors of SVR and were analysed by means of univariable and multivariable logistic regression analysis. Five variables were statistically significant (p<0.005) on univariable analysis: age, ethnic group, pretreatment viral load, response rate at week 4, and HCV genotype. In multivariable analysis independent factors associated with SVR were low pretreatment viral load (1.97; 95%CI, 1.06–3.66; p=0.03) and attainment of rapid virological response (RVR) (7.19; 95%CI, 4.15–12.45; p<0.001).Our findings support the association between viral load and SVR to PEG-IFN-alpha-2b plus ribavirin therapy. No achievement of RVR is an unfavorable marker for SVR. These findings suggest that all patients considered for treatment should have quantification of serum HCV RNA levels. The result can be used to counsel patients on the likelihood of achieving SVR and may influence the patient's decision on treatment. Future studies should confirm and explore this observation in other ethnic groups and in relation to HCV genotypes 1 and 3.

Role of interleukin-28B polymorphisms in the treatment of hepatitis C virus genotype 2 infection in Asian patients

Genome-wide association studies have linked single nucleotide polymorphisms (SNPs) near the interleukin-28B gene to the hepatitis C virus genotype 1 (HCV-1) response to peginterferon/ribavirin treatment. We aimed to explore the impact on the treatment outcomes of Asian HCV-2 patients. We determined rs8105790, rs8099917, rs4803219, and rs10853728 to be candidate SNPs in 482 Asian HCV-2 patients treated with the standard of care. Because the first three SNPs were in very strong linkage disequilibrium with one another (r2 = 0.94-0.96), rs8099917 and rs10853728 were selected for an analysis of their influence on the achievement of rapid virological response [RVR; seronegativity for hepatitis C virus (HCV) RNA in treatment week 4] and sustained virological response (SVR; seronegativity for HCV RNA throughout 24 weeks of posttreatment follow-up). The rs10853728 genotype did not predict RVR or SVR in HCV-2 patients. However, patients with the rs8099917 TT genotype, in comparison with patients with GT/GG genotypes, had a significantly higher rate of achieving RVR (85.2% versus 72.0%, P = 0.017) but did have not a significantly higher rate of achieving SVR (89.4% versus 86.0%). Multivariate analysis revealed that a baseline HCV viral load <400,000 IU/mL was the strongest predictor of RVR [odds ratio (OR) = 4.27, 95% confidence interval (CI) = 2.31-7.87, P < 0.001], and this was followed by advanced liver fibrosis (OR = 0.28, 95% CI = 0.15-0.53, P < 0.001), the carriage of the rs8099917 TT genotype (OR = 3.10, 95% CI = 1.34-7.21, P = 0.008), and the pretreatment level of aspartate aminotransferase (OR = 0.996, 95% CI = 0.99-1.00, P = 0.04). Nevertheless, the achievement of RVR was the single predictor of SVR with an OR of 19.37 (95% CI = 8.89-42.23, P < 0.001), whereas the rs8099917 genotypes played no role in achieving SVR with or without RVR. The rs8099917 TT genotype is significantly independently predictive of RVR, which is the single best predictor of SVR, in Asian HCV-2 patients.

Influence of a Single Nucleotide Polymorphism at the Main Ribavirin Transporter Gene on the Rapid Virological Response to Pegylated Interferon–Ribavirin Therapy in Patients with Chronic Hepatitis C Virus Infection

The equilibrative nucleoside transporter 1 (ENT1) is the main protein involved in ribavirin cellular uptake. Polymorphisms at the ENT1 gene may influence ribavirin activity as part of hepatitis C virus (HCV) therapy. A retrospective study was conducted in 109 human immunodeficiency virus (HIV)-infected patients who were infected with HCV genotypes 1 or 4 who had received pegylated interferon (pegIFN)-ribavirin. Single nucleotide polymorphisms (SNPs) at the ENT1 gene were examined using TaqMan 5'-nuclease assays. In the study population, allelic frequencies at rs760370 were as follows: A3 (43 [39%] of 109 patients), AG (50 [46%] of 109 patients), and GG (16 [15%] of 109 patients). Achievement of rapid virological response was more frequent in GG carriers than in AA/AG carriers (50% vs 17%, respectively; P = .007). In multivariate analysis, the GG genotype (odds ratio [OR], 15.9; 95% confidence interval [CI], 2.8-92.2; P < .002), a baseline serum HCV-RNA level <600,000 IU/mL (OR, 45.7; 95% CI, 8.7-240.5; P <.001) and a serum ribavirin trough concentration >2.5 μg/mL (OR, 4.8; 95% CI, 1.3-17.1; P < .016) were associated with rapid virological response. When 2 or more of these factors were present, positive and negative predictive values of rapid virological response were 65% and 91%, respectively. In summary, a SNP rs760370A→G at the ENT1 gene influences the chance of rapid virological response to pegIFN-ribavirin therapy in HIV-infected patients with chronic HCV infection due to HCV genotypes 1 or 4, most likely modulating intracellular ribavirin exposure within hepatocytes.

New Drug Targets for Hepatitis C and Other Flaviviridae Viruses

The Flaviviridae family comprises the genus Flavivirus, Hepacivirus and Pestivirus. These viruses are responsible for considerable human and animal disease and mortality worldwide. Flaviviruses cause a range of acute febrile illnesses along with encephalitic or haemorrhagic diseases. Chronic hepatitis C virus (HCV) infection is the most important hepacivirus human disease and remains a global health threat with nearly 200 million carriers worldwide. Current treatment consists in the use of peginterferon alfa (pegIFN) plus ribavirin (RBV) for 24 to 72 weeks, depending on HCV genotype, baseline viral load and the achievement of rapid virological response during therapy. However, current hepatitis C therapy fails to eradicate HCV in nearly half of treated patients and is hampered by relatively serious adverse events. No effective antiviral therapy is currently available for the treatment of flaviviruses or pestiviruses. Following the relative success of antiretroviral therapy against HIV infection, rapid progresses have been made in the development of specifically targeted antiviral therapies against HCV (STAT-C) and other Flaviviridae agents. Drug discovery for HCV is currently particularly exciting, since inhibitors of the HCV serine protease and the RNA-dependent RNA polymerase have recently entered the late stages of clinical development.

Role of rapid virological response in prediction of sustained virological response to Peg‐IFN plus ribavirin in HCV / HIV co‐infected individuals

The objective of the study was to evaluate the role of rapid virological response (RVR) in predicting sustained virological response (SVR) rates to hepatitis C virus (HCV) therapy. 65 HIV / HCV co-infected patients commenced HCV treatment per protocol. HIV / HCV patients with a mean CD4 count of 502 were treated for 24-48 weeks depending on genotype. Virological response was assessed at weeks 4 (RVR), 12 [early virological response (EVR)], 24, at end of treatment (EOTR) and 24 weeks post-completion of treatment (SVR). Primary end-point was defined as undetectable HCV RNA at 24 weeks post-treatment completion. Fifty-five per cent of co-infected patients were on highly active anti-retroviral therapy. A majority of patient group were male. 60% of HIV / HCV patients achieved SVR (35% genotype 1 / 4; 77% genotype 2 / 3). 24 HIV / HCV patients achieved undetectable HCV levels compared with baseline by week 4. The positive predictive value (PPV) of RVR at week 4 for subsequent SVR in HIV-HCV co-infected patients was 100%; the negative predictive value (NPV) was 57%. Significant variables associated with SVR were: (i) lower median pre-treatment HCV viral load, (ii) genotype 2 / 3 disease and (iii) achievement of RVR. Independent variables associated with RVR were low pre-treatment HCV viral load and genotype 2 / 3 disease. Achievement of RVR, a negative HCV-PCR, at week 4 of treatment is predictive of SVR in this cohort of patients. This may be used to guide optimal treatment duration in patient groups. More significantly, the data serve to highlight the subgroup of patients who, on achieving RVR, should be actively supported to complete HCV treatment with full dose therapy, especially patients co-infected with G2 / 3 disease for whom 6 months' full dose therapy may be sufficient to obtain a SVR.