Complete Early Virological Response Research Articles

Correlation of CD81 and SCARB1 polymorphisms on virological responses in Iranian patients with chronic hepatitis C virus genotype 1

The cluster of differentiation 81 (CD81) and scavenger receptor class B member 1 (SCARB1) plays an important role in the entry of hepatitis C virus (HCV). We assessed the correlation of five single nucleotide polymorphisms (SNPs) of CD81 (rs800136, rs2651842, rs2522012, rs800146, and rs708564) and SCARB1 rs10846744 polymorphisms with treatment responses in 395 treatment-naïve patients with chronic HCV (CHC) genotype 1 treated with pegylated interferon-α and ribavirin (pegIFN-α/RBV). The frequency of rapid virologic response (RVR), complete early virologic response (cEVR) and sustained virologic response (SVR) were 57.2%, 55.2%, and 58.2%, respectively. RVR, cEVR, and SVR were significantly associated with CD81 rs800136 (CC), CD81 rs2651842 (AA), CD81 rs708564 (TT), and SCARB1 rs10846744 (CC). High rates of RVR, cEVR, and SVR were reported for the CD81 rs800136 (CC), CD81 rs2651842 (AA), and CD81 rs708564 (TT) genotypes when correlated with higher levels of low-density lipoprotein (LDL) and lower levels of high-density lipoprotein (HDL) as well as lower levels of HDL and LDL in the SCARB1 rs10846744 (CC) genotype. In addition, patients with GG genotype had higher fasting blood glucose (FBS) level than those with CC genotype. In conclusion, CD81 and SCARB1 SNPs may serve as powerful predictor factors for treatment responses in CHC patients, and this effect is correlated with serum lipoprotein and FBS levels.

Discussion on optimal duration of pegylated interferon α combined with ribavirin for chronic hepatitis C in HIV-infected patients

Objective: To investigate the optimal duration of pegylated-alpha interferon (Peg-INFα) combined with ribavirin (RBV) in treating chronic hepatitis C infection in human immunodeficiency virus (HIV)-infected patients. Methods: A multicenter prospective study was conducted. The study subjects were divided into two groups; HIV/HCV co-infections (Group A, n = 158) and control with HCV-monoinfections (Group B, n = 60). All recruited patients received standard Peg-INFα plus RBV therapy. Group A was divided into 3 subgroups according to CD4(+) cell counts: A1 subgroup, 79 cases, CD4(+) counts > 350 cells /μl, who received anti-HCV before combination antiretroviral therapy(cART); A2 subgroup, 45 cases, CD4(+) counts between 200 and 350 cells/μl, who did not start anti-HCV until they could tolerate cART well; A3 subgroup, 34 cases, CD4(+) counts < 200 cells /μl, cART was administered first, and anti-HCV therapy was started when CD4(+) counts > 200 cells/μl. The anti-HCV efficacy of two groups and 3 subgroups were compared. Statistical analysis for normal distribution and homogeneity of variance data was calculated by t-test and the counting data was analyzed by χ (2) test. The Mann-Whitney U test was used for non-normal data. A one-way analysis of variance (ANOVA) was used for the comparison of multiple groups, followed by SNK method. Multiple independent samples were used for non-parametric tests. Results: There was no significant difference in age and baseline HCV RNA levels between groups and subgroups (P > 0.05). By an intent-to-treat (ITT) analysis, in Group A, the ratio of complete early virological response (cEVR) rate was 75.3% (119/158), the ratio of end of treatment virological response (eTVR) rate was 68.4% (108/158), and the ratio of sustained virological response (SVR) rate was 48.7% (77/158); in Group B, the ratio of cEVR rate was 93.3% (56/60), the ratio of eTVR rate was 90.0% (54/60), and the ratio of SVR rate was 71.7% (43/60); The therapeutic index of Group A were lower than those of Group B (P≤0.05). By per-protocol (PP) analysis, the ratio of cEVR rate in Group A [75.2% (88/112)] was still lower than that in Group B [93.3% (56/60)], but no significant differences were found in the ratio of eTVR rate and SVR rate between 2 groups (P > 0.05). Comparing the efficacy of subgroups (A1, A2 and A3) by ITT analysis, the ratios of cEVR rate were respectively 78.5% (62/79), 75.6% (34/45) and 67.6% (23/34); the ratios of eTVR rate were respectively 68.4%(54/79), 80.0%(36/45)and 52.9%(18/34); and the ratios of SVR rate were respectively 41.8%(33/79), 64.4%(29/45)and 44.1%(15/34). The ratio of eTVR in subgroup A2 was obviously higher than that in subgroup A3 and the ratio of SVR in subgroup A2 was statistically higher than that of subgroup A1(P≤0.05). However, by PP analysis, no significant differences of the therapeutic indexes were found among the respective subgroups (P > 0.05). Conclusion: HIV-HCV co-infected patients would have better anti-HCV efficacy with Peg-INFα-2a plus RBV than HCV- monoinfected patients. The best time for initiating anti-HCV therapy in HIV-HCV co-infected patients is when CD4(+) counts 200 cells/ μl.

The treatment outcome and impact on blood transfusion demand of Peg-interferon/ribavirin in thalassemic patients with chronic hepatitis C.

Hepatitis C virus (HCV) prevails in patients with thalassemia. We aimed to investigate the efficacy, safety, and impact on red blood cells (RBC) transfusion demand of pegylated interferon (Peg-IFN)/ribavirin therapy in thalassemic patients with HCV. This retrospective study included 18 thalassemic patients (16 with HCV-1b, one HCV-1b/2b, and one HCV-2b) and 54 consecutive sex- and genotype-matched controls. Patients with HCV-2, or HCV-1 or mixed HCV-1/2 with lower viral loads plus rapid virological response (RVR) received 24-week Peg-IFN/ribavirin; whereas HCV-1 or mixed HCV-1/2 with higher viral loads or without RVR received 48-week regimens. The rates of RVR, complete early virological response, and sustained virological response (SVR) in thalassemic patients were 72.2% (13/18), 94.1% (16/17), and 77.8% (14/18), which resembled those of controls (63.0%, 94.4%, and 81.5%, respectively). RVR was the only significant factor associated with SVR in thalassemic group, and was the strongest predictor for SVR among both groups (OR/95% CI=14.7/2.20-98.6), followed by male gender and lower viral loads. More proportion of interleukin-28B-TT carriage were observed among thalassemic patients with SVR versus non-SVR (78.6% vs. 50.0%). Thalassemic patients experienced significantly less 80/80/80 adherence, more ribavirin reduction and serious adverse events than controls. Notably, there was a decreased post-treatment RBC transfusion demand versus baseline in thalassemic patients with SVR (5.21 vs. 5.64units/month, p=0.05), but not in those without SVR (6.33 vs. 6.56units/month, p=0.54). Peg-IFN/ribavirin was effective and tolerable for thalassemic HCV patients. Successful antiviral therapy might have extra benefit of reducing the post-treatment transfusion demand.

Effect of IL15 rs10833 and SCARB1 rs10846744 on virologic responses in chronic hepatitis C patients treated with pegylated interferon-α and ribavirin

The scavenger receptor type B class I (SCARBI) is known to be involved in the entry of hepatitis C virus (HCV) into the host, while interleukin-15 (IL15) is an important cytokine in both the innate and acquired immune responses against HCV infection. We investigated the association of IL15 rs10833 or SCARB1 rs10846744 polymorphisms with treatment responses in patients with chronic HCV (CHC). SCARB1 rs10846744 and IL15 rs10833 were identified in 365 treatment-naïve CHC patients through genotyping by TaqMan® Real-Time PCR and PCR-restriction fragment length polymorphism (RFLP), respectively. Of these 365 CHC treatment-naïve patients, rapid virological response (RVR), complete early virological response (cEVR), and sustained virological response (SVR) were observed in 53.2%, 76.4%, and 66.0% of the patients, respectively. Multivariate logistic regression analysis revealed that RVR was associated with sex (P=0.016), aspartate aminotransferase (AST) (P=0.026), IL15 rs10833 (AA) genotype (P<0.001), and SCARB1 rs10846744 (CC) genotype (P<0.001), while there was a relationship between alanine aminotransferase (ALT) (P=0.013) and IL15 rs10833 (AA) genotype (P<0.001) with cEVR. Age (<40years) (P=0.001), AST (P=0.029), ALP (P=0.028), HCV genotypes (P=0.005), HCV viral load (P=0.026), IL15 rs10833 (AA) genotype (P<0.001), and SCARB1 rs10846744 (CC) genotype (P=0.001) were strongly associated with SVR. In conclusion, the SCARB1 rs10846744 (CC) and IL15 rs10833 (AA) genotypes can be considered as powerful predictors of treatment responses in CHC patients treated with an interferon-based therapy.

The impact of genetic variation in IL28B, IFNL4 and HLA genes on treatment responses against chronic hepatitis C virus infection

Single nucleotide polymorphisms (SNPs) near the interleukin-28B (IL28B), interferon lambda 4 (IFNL4) and the human leukocyte antigen (HLA) gene are associated with treatment responses in patients with chronic hepatitis C (CHC) virus infection treated with pegylated interferon-α and ribavirin (pegIFN-α/RBV). We compared the role of IL28B SNPs (rs12979860, rs12980275, and rs8099917), IFNL4 ss469415590 and HLA rs4273729 with treatment outcomes in patients with CHC virus. A total of 520 Iranian patients with CHC infection were enrolled. SNPs in IL28B, IFNL4 ss469415590 and HLA rs4273729 were genotyped by PCR-restriction fragment length polymorphism, TaqMan® Real-Time PCR and direct sequence. Out of 520 CHC treatment-naive patients, 42.9% were infected with HCV-1a, 15.4% with HCV-1b, 9.8% with HCV-2, and 31.9% with HCV-3a. Rapid virologic response (RVR), complete early virologic response (cEVR), and sustained virologic response (SVR) were 53.3%, 73.8%, and 66.7%, respectively. Multivariate logistic regression analysis showed that IL28B rs12980275 and IFNL4 ss469415590 in all HCV genotypes were associated with RVR. In addition, IL28B rs12979860 and RVR in all HCV genotypes and IL28B rs12980275, IFNL4 ss469415590, and HLA rs4273729 in HCV subtypes 1a, 1b, and 3a correlated with cEVR. In patient's achieving-SVR, IL28B rs12980275, and RVR in all HCV genotypes and IL28B rs12979860, IFNL4 ss469415590, and HLA rs4273729 in HCV subtypes 1a, 1b, and 3a were the powerful predictor factors. As the first report of its kind published in Iran, we indicated that beside IL28B SNPs and HLA rs4273729, IFNL4 ss469415590 was a powerful predictor factor for RVR, cEVR and SVR. Genotyping these SNPs may be a helpful priority in the treatment of patients with HCV infection, especially in countries where access to triple or double therapy with a viral protease inhibitor is limited.

EGFR rs11506105 and IFNL3 SNPs but not rs8099917 are strongly associated with treatment responses in Iranian patients with chronic hepatitis C

Interferon lambda 3 (IFNL3) and epidermal growth factor receptor (EGFR) single nucleotide polymorphisms (SNPs) may play a key role in the spontaneous clearance of hepatitis C virus (HCV) and treatment responses. The aim of this study was to evaluate the effect of IFNL3 SNPs and EGFR rs11506105 on treatment outcomes in patients with chronic HCV (CHC). IFNL3 SNPs and EGFR rs11506105 were genotyped by PCR-restriction fragment length polymorphism and PCR-sequencing, respectively, in 235 naïve patients with CHC infection. The frequency of rapid virologic response (RVR), complete early virologic response (cEVR) and sustained virologic response (SVR) were 52.3%, 76.2% and 64.7% respectively. The results of this study showed that RVR was associated with ALT (P=0.015), AST (P=0.020), IFNL3 rs12979860 (CC) (P=0.043), rs12980275 (AA) (P=1 × 10-4), and EGFR rs11506105 (AA) (P=0.010), and IFNL3 rs12979860 (CC) (P=0.048), rs12980275 (AA) (P=0.022), and EGFR rs11506105 (AA) (P=0.006) were correlated with cEVR. HCV genotype (P=0.007), IFNL3 rs12979860 (CC) (P=0.023), IFNL3 rs12980275 (AA) (P=1 × 10-4), EGFR rs11506105 (AA) (P=0.005), RVR (P=1 × 10-4), and cEVR (P=0.003) were significant predictors for SVR. These results, for the first time, revealed that beside IFNL3 SNPs, EGFR rs11506105 is strongly associated with RVR, cEVR and SVR. EGFR rs11506105 besides IFNL3 SNPs could predict treatment responses in CHC patients.

IL28B rs12980275 and HLA rs4273729 genotypes as a powerful predictor factor for rapid, early, and sustained virologic response in patients with chronic hepatitis C.

Single-nucleotide polymorphisms (SNPs) in the Interleukin-28B (IL28B) gene and rs4273729 in the human leukocyte antigen (HLA) gene in chronic hepatitis C (CHC) virus infection are important for predicting treatment outcome. In this study, the distribution of IL28B SNPs (rs12979860 and rs12980275) and HLA rs4273729 in rapid virologic response (RVR), complete early virologic response (cEVR) and sustained virologic response (SVR) in HCV Iranian patients with CHC virus infection was assessed. IL28B genotyping and rs4273729 were performed using the amplification refractory mutation system (ARMS)-PCR and direct sequencing in 190 CHC virus infections, respectively. RVR, cEVR, and SVR were 53.2%, 78.9%, and 65.8%, respectively. Multivariate regression analysis demonstrated that the responses significantly predicted SVR in patients with age<40years (p=0.008), HCV genotypes (p=0.032), IL28B rs12979860 CC genotype (p<0.001), rs12980275 AA genotype (p<0.001), rs4273729 GG genotype (p<0.001), RVR (p<0.001) and cEVR (p=0.024). Three critical predictor factors based on RVR response were rs12979860 CC genotype (p=0.033), rs12980275 AA genotype (p<0.001) and rs4273729 GG genotype (p<0.001), while rs12980275 AA (p=0.003) and rs4273729 GG genotypes (p<0.001) predicted cEVR. For the first time in Iran, these results revealed that the rs12980275 and HLA rs4273729 are important for the treatment of CHC infection. These findings may help predict responses to CHC infection treatment and reduce the cost and side effects of therapy.

Dynamics of PBMC gene expression in hepatitis C virus genotype 1-infected patients during combined peginterferon/ribavirin therapy.

Hepatitis C virus (HCV) can replicate in peripheral blood mononuclear cells (PBMCs), which can produce interferon to defend against virus infection. We hypothesized that dynamic gene expression in PBMCs might impact the treatment efficacy of peginterferon/ribavirin in HCV patients. PBMCs were collected at baseline, 1st week and 4th week of treatment from 27 chronic HCV-1 patients with 48-week peginterferon/ribavirin therapy (screening dataset n = 7; validation dataset n = 20). A sustained virologic response (SVR) was defined as undetectable HCV RNA throughout the 24 weeks after end-of-treatment. A complete early virologic response (cEVR) was defined as negative HCV RNA at treatment week 12. Forty-three differentially expressed genes identified by Affymetrix microarray were validated by quantitative polymerase chain reaction. Thirteen genes at week 1 and 24 genes at week 4 were upregulated in the SVR group compared with the non-SVR group. We selected 8 target genes (RSAD2, LOC26010, HERC5, HERC6, IFI44, SERPING1, IFITM3, and DDX60) at week 1 as the major components of the predictive model. This predictive model reliably stratified the responders and non-responders at week 1 (AUC = 0.89, p = 0.007 for SVR; AUC = 0.95, p = 0.003 for cEVR), especially among patients carrying the IL28B rs8099917 TT genotype (AUC = 0.89, p = 0.02 for SVR; AUC = 1.0, p = 0.008 for cEVR). The performance of this predictive model was superior to traditional predictors, including the rapid virologic response, viral load and IL28B genotype.

Effects of Pegylated Interferon/Ribavirin on Bone Turnover Markers in HIV/Hepatitis C Virus-Coinfected Patients.

HIV/hepatitis C virus (HCV) patients have a 3-fold increased fracture incidence compared to uninfected patients. The impact of HCV therapy on bone health is unclear. We evaluated bone turnover markers (BTM) in well-controlled (HIV RNA <50 copies/ml) HIV/HCV-coinfected patients who received pegylated interferon-α and ribavirin (PEG-IFN/RBV) in ACTG trial A5178. Early virologic responders (EVR: ≥2 log HCV RNA drop at week 12) continued PEG-IFN/RBV and non-EVRs were randomized to continuation of PEG-IFN alone or observation. We assessed changes in C-terminal telopeptide of type 1 collagen (CTX; bone resorption marker) and procollagen type I intact N-terminal propeptide (P1NP; bone formation marker), and whether BTM changes were associated with EVR, complete early virologic response (cEVR: HCV RNA <600 IU/ml at week 12), or PEG-IFN treatment. A total of 192 subjects were included. After 12 weeks of PEG-IFN/RBV, CTX and P1NP decreased: −120 pg/ml and −8.48 μg/liter, respectively (both p < 0.0001). CTX declines were greater in cEVR (N = 91; vs. non-cEVR (N = 101; p = 0.003). From week 12 to 24, CTX declines were sustained among EVR patients who continued PEG-IFN/RBV (p = 0.027 vs. non-EVR) and among non-EVR patients who continued PEG-IFN alone (p = 0.022 vs. Observation). Median decreases of P1NP in EVR vs. non-EVR were similar at weeks 12 and 24. PEG-IFN-based therapy for chronic HCV markedly reduces bone turnover. It is unclear whether this is a direct IFN effect or a result of HCV viral clearance, or whether they will result in improved bone mineral density. Further studies with IFN-free regimens should explore these questions.

Clinical efficacy of pegylated interferon in patients co-infected with HIV and HCV who failed standard interferon therapy

To investigate the efficacy and safety of pegylated interferon-alpha (PEG-INF-α) combined with ribavirin in patients co-infected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) who failed prior standard interferon therapy. A prospective study was performed to analyze HCV RNA load, liver function, and CD4+ count at weeks 0 (baseline), 12, 24, and 48 of treatment and at 24 weeks after drug discontinuation in 20 patients co-infected with HIV and HCV who failed standard interferon therapy and were then treated with PEG-INF-αand ribavirin. Among the 20 patients, 14 were infected with HCV genotype 1b, 3 with HCV genotype 2a, and 3 failed sequencing. At baseline, the mean CD4(+)count, mean CD8(+)count, and mean CD4(+)/CD8(+)ratio were 406.45 ± 210.83 cells/ml, 1 076.45 ± 716.18 cells /ml, and 0.43 ± 0.17, respectively; the mean HCV RNA load was 6.01 ± 1.13 log10IU/ml; 12 patients (60%) had abnormal liver function. A total of 14 patients (70%) achieved complete early virologic response, 15 (75%) achieved end-of-treatment virologic response, 7 (35%) achieved sustained virologic response (SVR), and 8 (40%) experienced recurrence. The incidence rate of drug-related adverse events during the treatment was 50% (10/20); no serious adverse events occurred, and no patient withdrew from the treatment due to adverse events. At week 48, both CD4(+)and CD8(+)counts of all patients declined significantly compared with the baseline values (P= 0.001 and 0.001), but the CD4(+)/CD8(+)ratio increased significantly (P= 0.032). The SVR group had a significantly lower mean baseline HCV RNA load than the non-SVR group (4.95 ± 1.18 log10IU/ml vs 6.59 ± 0.53 log10IU/ml,t= 3.49,P= 0.009). In the patients co-infected with HIV and HCV who failed standard interferon therapy, PEG-INF-αcombined with ribavirin has good efficacy and safety, and the patients with a low baseline HCV RNA load are more likely to achieve SVR.

Study of prevalence and effects of insulin resistance in patients with chronic hepatitis C genotype 4.

There is strong epidemiological evidence linking hepatitis C virus (HCV) infection and diabetes. Our aim was to evaluate the prevalence of insulin resistance in Egyptian patients with chronic HCV genotype 4 infection, to assess factors associated with insulin resistance and to test the impact of insulin resistance on outcomes of treatment with pegylated interferon/ribavirin. Insulin resistance [homeostasis model assessmentinsulin resistance (HOMA-IR) score > 3.0] was detected in 31 of 100 nondiabetic patients. The relationship between elevated HOMA-IR and baseline viral load and degree of fibrosis was statistically significant (r = 0.218 and r = 0.223). Follow-up of patients with complete early virological response until the end of treatment showed a statistically significant decrease in HOMA-IR score. Out of 29 liver tissue sections examined, 14 had a low level of expression of insulin receptor type 1 by immunohistochemical studies. This study confirms that insulin resistance affects treatment outcome, and thus HOMA-IR testing before initiation of therapy may be a cost-effective tool.

Evaluation of fluvastatin in combination with the standard of care therapy (PEG-IFN/Ribavirin) in Egyptian patients with hepatitis C virus.

Cholesterol biosynthesis suppresses the replication of HCV-1b replicons, thus influencing hepatitis C virus (HCV) natural history. This study aimed at comparing the efficacy and safety of fluvastatin (FLV) as an adjuvant therapy to the standard of care (SOC) therapy, i.e., pegylated interferon (PEG-IFN) and ribavirin, for the treatment of HCV patients. Sixty HCV patients were enrolled and allocated to either group I, who received the triple therapy (fluvastatin + SOC), or group II, who received SOC; the duration for both treatments was 48 weeks. All patients were subjected to pretreatment liver biopsy and monthly biochemical tests (liver profile, CBC), and quantitative HCV-RNA test was performed at weeks 0, 4, 12, 48, and 72. All virological responses were higher in group I than in group II, with no statistical difference. Group I showed no manifestations of hepatotoxicity. Fluvastatin yielded a borderline, significantly higher complete early virological response than SOC; therefore, it is a safe adjuvant to the SOC therapy.

Early Viral Response Predicts the Efficacy of Antiviral Triple Therapy with Simeprevir, Peg-Interferon and Ribavirin in Patients Infected with Hepatitis C Virus Genotype 1

Objectives: Triple therapy using peg-interferon, ribavirin and simeprevir (PEG-IFN/RBV/SMV) has reportedly resulted in high-sustained virological response (SVR) rates in patients with chronic hepatitis C (CHC), especially in naïve cases and relapsers to prior PEG-IFN/RBV therapy. Here, we retrospectively analyzed the antiviral response associated with a triple regimen, in the context of early reduction of viral load during treatment. Methods: Forty-six CHC patients with HCV genotype 1b were treated with PEG-IFN/RBV/SMV triple therapy: 20 were naïve cases, 12 were relapsers and 14 were non-responders to prior PEG-IFN/RBV therapy. We evaluated rapid virological response (RVR), complete early virological response (EVR), viral clearance at the end of the treatment (EOT) and at 12 weeks after the EOT (SVR12). In addition, we quantified the serum HCV-RNA on the 1st day and the 7th day after initiating treatment. Results: Multivariate analysis revealed that response to prior treatment was identified as an independent factor for achieving SVR12 after triple therapy (p = 0.0005). The achievement of serum HCV-RNA <2 log₁₀ IU/ml on day 7, RVR, EVR and EOT were associated with SVR12 (p = 0.0050, p = 0.0002, p = 0.0009 and p = 0.0002, respectively). Conclusions: Rapid decline of HCV is a predictive factor for the achievement of SVR12, even in antiviral triple therapy with PEG-IFN/RBV/SMV. An extended treatment period should be applied for patients who show detectable serum HCV-RNA at week 4.

Effect of Peginterferon or Ribavirin Dosing on Efficacy of Therapy With Telaprevir in Treatment-Experienced Patients With Chronic Hepatitis C and Advanced Liver Fibrosis

We investigated the safety, efficacy, and impact of ribavirin and peginterferon dose reduction on complete early virologic response and sustained virologic response (SVR) to triple therapy with telaprevir in treatment-experienced patients with advanced liver fibrosis.Treatment was initiated for 211 patients who failed treatment with peginterferon and ribavirin, with bridging fibrosis (F3, n = 68) or cirrhosis (F4, n = 143), including 103 (49%) null-responders (NR), 30 (14%) partial responders (PR), and 78 (37%) relapsers (REL). Impaired liver function (ILF) platelets <100,000/mm3 or albumin <35 g/L were present in 40 patients. The distribution of hepatitis C virus subtypes was: 1a, 1b, or 1, with undetermined subtype for 10 (5%), 187 (89%), and 14 (6%) patients, respectively. Treatment was started with peginterferon alpha-2a or alpha-2b, ribavirin, and telaprevir at standard doses.The overall SVR24 rate was 56% and was lower in cirrhotic patients (NR: 35%, PR: 40%, and REL: 63%, respectively) than in patients with bridging fibrosis (NR: 50%, PR: 75%, and REL: 75%, respectively). The lowest probability of SVR24 was in NRs with ILF (26%). The SVR24 rate significantly decreased in NRs receiving <60% vs >60% of the total ribavirin dose (23% vs 44%, respectively) or <80% vs >80% of the total ribavirin dose (33% vs 48%, respectively). A significant SVR24 decrease was noted subsequent to a total peginterferon dose reduction, both when comparing patients who received <60% vs >60% of the total dose (NR: 0% vs 44%; REL: 33% vs 68%) and patients who received <80% vs >80% of the total dose (NR: 17% vs 50%; REL: 46% vs 71%).Serious adverse events were observed in 31 patients (15%). Deaths occurred in 4 patients. All of the deceased subjects were cirrhotic members of the ILF (baseline serum albumin level <35 g/L and/or platelet count <100,000/mm3) group.Ribavirin dose reduction did not affect efficacy in REL but did in NR. Peginterferon dose reduction decreased the SVR24 rate for all groups, particularly in prior NR. ILF increased the risk of fatal complications with a low probability to achieve SVR24. One solution might be to provide wide and early access to novel, efficient, and safe interferon-free combinations to treatment-experienced patients, particularly those with liver cirrhosis.

The efficacy and prognostic predictors of different treatment courses with pegylated interferon α-2a and ribavirin combination in recurrent chronic hepatitis C patients

To study the efficacy and outcome predictors of combined re-treatment with pegylated interferon (Peg-IFN) α-2a and ribavirin in recurrent chronic hepatitis C (CHC) patients. A multicenter, prospective, randomized trial was designed. A total of 125 recurrent CHC patients were recruited in 16 clinical centers and randomly assigned into two groups: one was Peg-IFNα-2a combined with ribavirin for 48 weeks (group A) and the other the same combination for 72 weeks (group B). HCV RNA levels in patients' serum were detected at baseline, week 4, 12, 24, 48, 72 (group B) after treatment initiation, and 24 weeks after treatment. Of all the 90 patients who completed treatment and 24 weeks follow-up, 80.0% achieved sustained virological response (SVR) yet 12.2% relapsed. There was no significant difference between two groups. The SVR rate in patients previously treated with interferon alone was higher than that in patients with interferon plus ribavirin (92.6% vs 74.6%), but the difference was of no statistical significance (P = 0.05). Moreover, patients previously treated with common interferon (c-IFN) showed a higher SVR rate than patients with Peg-IFN (84.7% vs 71.0%, P > 0.05). The positive predictive value (PV) of rapid virological response (RVR) and complete early virological response for SVR was 92.3% and 86.4% respectively, and the negative PV of RVR, early virological response and delayed virological response for SVR was 36.8%, 66.7% and 100.0% respectively. Overall, 62.1% patients reported adverse events (AEs) and 1.6% patients were severe AEs. A high SVR rate has been achieved in recurrent CHC patients who were retreated with Peg-IFNα-2a and ribavirin for 48 weeks. Better SVR cannot be achieved in spite of a prolonged course of 72 weeks. Early virological response at week 12 was the most important predictor for SVR.

High sustained virological response to optimized therapy for refractory chronic hepatitis C treatment-na(i)ve patients: a multicenter randomized study

To perform a prospective,multicenter,open,randomized study to determine a treatment regimen for treatment-naive patients with refractory chronic hepatitis C (RHC) using the predictive value (PV) of early virological response (EVR). A total of 438 patients from 18 hospitals were recruited between December 2008 and December 2010 and administered peg-interferon/ribavirin treatment for 12 weeks. Patients who achieved complete EVR (cEVR) were assigned to group A for a 48-week course of treatment, while patients without cEVR were randomly allocated to either group B 1 for a 72-week course of treatment or to group B2 for a 96-week course of treatment. Serum hepatitis C virus RNA levels at baseline,treatment weeks 4, 12 and 24, end of treatment, and post-treatment week 24 were measured and used to evaluate the efficiency of therapy. The overall sustained virological response (SVR) rate was 85.1%. In all, 91.0% of patients achieved cEVR and were assigned to group A, which had an SVR rate of 90.8%. There was no statistically significant difference in the SVR rates of groups B1 and B2 (29.4% vs. 25.0%, P more than 0.05). The positive PV of rapid virological response (RVR), cEVR and delayed virological response (DVR) for SVR was 93.4%, 90.8% and 77.8% respectively, and the negative PV of RVR, EVR and DVR for SVR was 28.0%, 93.3% and 100% respectively. Overall, 66.9% of the patients experienced adverse events (AEs), but only 1.9% of patients experienced sevcre AEs. The majority of Chinese RHC treatmentna(i)ve patients (91.0%) can achieve cEVR and a high SVR rate with a low rate of severe AEs using the cEVR guided personal treatment regimen.

Baseline factors associated with treatment response in patients infected with hepatitis C virus 1b by stratification of IL28B polymorphisms.

Although the single-nucleotide polymorphism (SNP) rs12979860 in the IL28B gene is a better predictor of sustained virological response to treatment of chronic hepatitis C (CHC) than other baseline factors, some CHC patients with the favorable C allele cannot achieve a sustained virological response when treated with peginterferon plus ribavirin. The aim of this study was to examine baseline factors as predictors of rapid virological response (RVR) and complete early virological response (cEVR) to peginterferon alfa-2a plus ribavirin treatment in Chinese CHC patients with hepatitis C virus (HCV) genotype 1b, with emphasis on the difference between the rs129860 CC and CT/TT genotypes. A total of 337 treatment-naïve patients participated in this study. All patients were treated with peginterferon alfa-2a plus ribavirin at standard dosage. Serum samples from all patients were collected at baseline, week 4, and week 12 for testing of laboratory parameters, and IL28B genotypes were determined. Multivariate analysis showed that among rs12979860 CC genotype patients, glucose level and aspartate amino transferase (AST) activity were inversely associated with RVR, while abnormal platelet count and allergy inversely associated with cEVR. Among rs12979860 CT genotype patients, age below 40years and short infection duration were associated with RVR, while age below 40years, short infection duration, high body mass index (BMI), and no history of allergies were associated with cEVR. The baseline factors associated with the response to CHC treatment may depend on the IL28B genotype. Refinement of the baseline predictors based on IL28B genotypes may be useful for management of HCV infection.

Response-Guided Therapy for Hepatitis C Virus Recurrence Based on Early Protocol Biopsy after Liver Transplantation.

Hepatitis C virus (HCV) recurrence after liver transplantation (LT) is universal and progressive. Here, we report recent results of response-guided therapy for HCV recurrence based on early protocol biopsy after LT. We reviewed patients who underwent LT for HCV related liver disease between 2010 and 2012. Protocol biopsies were performed at 3, 6, and 12 months after LT in HCV recurrence (positive HCV-RNA). For any degree of fibrosis, ≥ moderate inflammation on histology or HCV hepatitis accompanying with abnormal liver function, we treated with pegylated interferon and ribavirin. We adjusted treatment period according to individual response to treatment. Among 41 HCV related recipients, 25 (61.0%) who underwent protocol biopsies more than once were enrolled in this study. The mean follow-up time was 43.1 (range, 23-55) months after LT. Genotype 1 and 2 showed in 56.0% and 36.0% patients, respectively. Of the 25 patients, 20 (80.0%) started HCV treatment after LT. Rapid or early virological response was observed in 20 (100%) patients. Fifteen (75.0%) patients finished the treatment with end-of-treatment response. Sustained virological response (SVR) was in 11 (55.0%) patients, including 5 (41.7%) of 12 genotype 1 and 6 (75.0%) of 8 non-genotype 1 (P = 0.197). Only rapid or complete early virological response was a significant predictor for HCV treatment response after LT (100% in SVR group vs. 55.6% in non-SVR group, P = 0.026). Overall 3-yr survival rate was 100%. In conclusion, response-guided therapy for HCV recurrence based on early protocol biopsy after LT shows encouraging results.

Alisporivir with peginterferon/ribavirin in patients with chronic hepatitis C genotype 1 infection who failed to respond to or relapsed after prior interferon-based therapy: FUNDAMENTAL, a Phase II trial.

Alisporivir (ALV) is an oral, investigational host-targeting agent, with pangenotypic activity against hepatitis C virus (HCV). This randomized, double-blind, placebo-controlled, Phase II study explored the efficacy and safety of ALV with peginterferon-α2a/ribavirin (PR) in patients with chronic HCV genotype 1 infection in whom prior PR had failed (43% relapsers, 34% null responders and 23% partial responders). Four-hundred-and-fifty-nine patients were randomized (1:1:1:1) to ALV 600 mg once daily (QD), ALV 800 mg QD, ALV 400 twice daily (BID) or placebo plus PR for 48 weeks. When the global ALV trial programme was put on clinical hold, all patients in this study had received ≥31 weeks of randomized treatment; patients completed 48 weeks on PR alone. All ALV groups demonstrated superior rates of complete early virologic response (cEVR; primary endpoint) vs PR alone (P ≤ 0.0131), with highest cEVR rate seen with ALV 400 mg BID (74% vs 36% with PR alone; P < 0.0001). Respective SVR12 rates (key secondary endpoint) were 65% vs 26% in prior relapsers, 63% vs 5% in partial responders and 68% vs 3% in null responders. In patients who received >40 weeks of randomized treatment, the SVR12 rate was 89% for ALV 400 mg BID vs 30% for PR alone (P = 0.0053). Rates of viral breakthrough and relapse were lowest with ALV 400 mg BID. One case of pancreatitis (fully recovered) occurred with ALV/PR. Common AEs were headache, fatigue, anaemia, neutropenia and nausea. Hypertension was infrequent, but more common with ALV. ALV merits further investigation in interferon-free regimens in combination with direct-acting antiviral agents.

Advanced hepatic fibrosis and steatosis are associated with persistent alanine aminotransferase elevation in chronic hepatitis C patients negative for hepatitis C virus RNA during pegylated interferon plus ribavirin therapy.

Clinical implications of persistent alanine aminotransferase (ALT) elevation and associated factors in chronic hepatitis C (CHC) patients who achieved undetectable hepatitis C virus (HCV) RNA during pegylated interferon plus ribavirin (peg-IFN/RBV) therapy remain unknown. A total of 1113 CHC patients with undetectable HCV RNA during peg-IFN/RBV therapy were enrolled. Baseline characteristics associated with persistent on-treatment ALT elevation (POAE), and its impact on treatment outcomes, were investigated. Of 1113 CHC patients, 254 (22.8%) had POAE. Among patients with HCV genotype 1 (HCV-1) who had complete early virologic response (EVR) and received 48 weeks of therapy, patients with POAE had a lower rate of sustained virologic response (SVR) than those without POAE (44.1% vs 74.0%; P = .0002). Multivariate analyses showed that body mass index ≥ 27 kg/m(2), ALT level ≥3 times the upper limit of normal, aspartate aminotransferase to platelet ratio index score ≥1.5, hepatic fibrosis ≥F3, and hepatic steatosis ≥S2 were independent factors associated with POAE after viral clearance. POAE is common in CHC patients during therapy. HCV-1 patients with POAE have a lower SVR rate to 48-week therapy if they achieve complete EVR. Advanced hepatic fibrosis, obesity, and steatosis are factors associated with POAE in these patients.