Early Virological Response Research Articles

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.

Effectiveness and Safety of Sofosbuvir in Treatment-NäiveChildren with Hepatitis C Infection.

To determine the effectiveness and safety of Sofosbuvir and Ribavirin combination in treatment-näivechildren with HCV infection. An experimental study. Gastroentrology, Hepatology Department, The Children's Hospital and The Institute of Child Health, Lahore, from January to December 2016. HCV PCR positive treatment-näivepatients, 5 to 18 years of age, were enrolled by consecutive nonprobability sampling. Clinical features and investigations including complete blood count, bilirubin, ALT, PTand HCV genotyping were done. All patients were started on Sofosbuvir 400 mg once daily and Ribavirin 10-15 mg/kg/day. Patients were followed on 4-weekly basis. PCR was done after 4 weeks; if positive then again at 12 weeks. End of treatment and 12 weeks post treatment PCR was done in all patients. Total duration of therapy was 24 weeks. Computer program SPSS version 20 was used for data analysis. Atotal of 35 patients with mean age of 10.24 ±2.80 years, including 22 boys (62.86%), and 13 girls (37.14%) were included. The most common HCV genotype was genotype 3 encountered in 27 (77.15%), followed by genotype 1 in 6 (17.14%), while 2 (5.71%) patients were untypable. Thirty (85.71%) patients achieved rapid virological response while the rest 5 (14.28%) had early virological response. End-of-treatment PCR was negative in all patients. SVR was achieved by 34 (97.14%) patients. The treatment was well tolerated. Headache was observed in 8 (22.86%) patients, which improved spontaneously. Sofosbuvir and Ribavirin combination is highly effective in HCV genotypes 1 and 3 with no major undesirable short-term side effects.

Predictive value of platelet to lymphocyte ratio for early virological response in patients with genotype C hepatitis B virus infection who were treated with Entecavir

Objective To investigate the prognostic value of platelet to lymphocyte ratio (PLR) for early virological response in Entecavir (ETV)-treated chronic hepatitis B (CHB) patients with genotype C infection. Methods Ninety-one genotype C CHB patients with HBV DNA≥1×105 copies/mL were treated with ETV (0.5 mg/d) for 10—13 days. The correlation between PLR and viral load decline was evaluated by Pearson or Spearman′s rank correlation coefficient. Stepwise linear regression analysis was used to establish the prediction model of virological response. Receiver operating characteristic (ROC) curves were used to evaluate the predictive value of PLR for early virological response in ETV-treated patients with genotype C hepatitis B virus (HBV) infection. Results After 10—13 days of ETV treatment, HBV DNA decreased ≥1×lg copies/mL from baseline in 89 cases of the 91 patients, while HBV DNA declined ≥2×lg copies/mL in 65 patients and 4 patients achieved HBV DNA<500 copies/mL. HBV DNA decline was positively correlated with baseline PLR levels (r=0.235 09, P<0.05). After adjustment for age, gender, Hepatitis B e Antigen (HBeAg), and treatment days, HBV DNA decline was still positively correlated with baseline PLR levels (r=0.220 26, P<0.05). Area under curve (AUC) of prediction model including age , baseline aspartate transaminase (AST) and HBV DNA was 0.759 (95% CI : 0.660—0.859, P<0.01). After adding PLR to the prediction model, the AUC was 0.780 (95% CI: 0.685—0.875, P<0.01). Conclusions PLR is predictive to early virological response in ETV-treated CHB patients with genotype C infection. Higher baseline PLR level indicates a better virological response. PLR monitoring should be recommended in CHB patients with antiviral treatment in clinical practice. Key words: Hepatitis B, chronic; HBV DNA; Entecavir; Forecasting; PLR

Pegylated interferon plus ribavirin combination therapy in postliver transplant recipients with recurrent hepatitis C virus infection

Posttransplant hepatitis C virus (HCV) recurrence is universal in chronic hepatitis C recipients. Antiviral therapy is suggested after liver transplant to halt disease progression. Pegylated interferon plus ribavirin therapy remains the standard of care in many areas where direct antiviral agents are poorly accessible. This study aimed to assess the treatment efficacy and safety of the regimen for Taiwanese patients with post-transplant HCV recurrence. Nine patients with HCV recurrence postliver transplantation were allocated. Patients received either pegylated interferon α-2a 180 μg/wk or pegylated interferon α-2b 1.5 mg/kg/wk plus ribavirin for 24–48 weeks. The primary endpoint was the achievement of sustained virological response (SVR), defined as undetectable HCV RNA throughout 6 months of follow-up after the end of treatment. The safety profiles were also documented. The rates of rapid virological response, early virological response, end-of-treatment virological response, and SVR were 33%, 63%, 75%, and 56% respectively. Of the four patients who failed antiviral treatment, the treatment responses were nonresponse (n = 1), loss of follow-up (n = 1), and relapse (n = 2). Three patients terminated therapy early due to severe adverse events, including severe anemia, intra-abdomen infection, and hepatocellular carcinoma recurrence. One of the three patients who terminated treatment early at Week 6 experienced rapid virological response followed by SVR. Pegylated interferon/ribavirin combination allowed a chance for cure with a fair SVR rate in Taiwanese chronic hepatitis C patients postliver transplantation. Early identification of side effects and careful monitoring during therapy might enhance the treatment efficacy.

The effects of interleukin-28B gene polymorphisms on antiviral treatment response in patients with chronic hepatitis C

Objective To investigate the relationship between interleukin (IL)-28B gene polymorphisms (rs12979860 and rs8099917) and treatment response in patients with chronic hepatitis C in China. Methods Taqman probes single nucleotide polymorphism genotyping methods were used to detect the genotypes of rs12979860 (C/T) and rs8099917 (T/G) located at IL-28B gene in 105 included patients. The patients were treated with standard doses of pegylated interferon plus ribavirin and were followed up regularly for therapeutic response and adverse reaction. The relationship between IL-28B gene polymorphism and antiviral treatment response of patients were analyzed. Categorical data were analyzed using Pearson chi-square test or Fisher exact test. Results Totally 105 cases were included in our study and 2 cases lost to follow-up because of moving away. Eight-one cases (78.6%) of the remaining 103 patients were CC/TT genotype (CC/TT group) at rs12979860 and rs8099917, 19 cases (18.4%) were CT/TG (CT/TG group) and 3 cases (2.9%)were TT/TG (TT/TG group). No other genotypes were detected and linkage disequilibrium was discovered at the two polymorphism loci (r2=0.11). After 4 weeks of treatment, 35 cases (43.2%) in CC/TT group, 3 cases (15.8%) in CT/TG group and non in TT/TG group achieved rapid virological response (RVR). There were statistically significant differences among three groups (P=0.033). After 12 weeks of treatment, 45 cases (55.6%) in CC/TT group, 6 cases (31.6%) in CT/TG group and none in TT/TG group achieved early virological response (EVR). There were statistically significant differences among three groups (P=0.025). At the end of the treatment, 68 cases (83.9%) in CC/TT group, 10 cases (52.6%) in CT/TG group and only 1 case (33.3%) in TT/TG group achieved end-of-treatment response (ETR). There were significant statistical differences among the three groups (P=0.003). After 24 weeks of follow-up, 62 cases (76.5%) in CC/TT group, 9 cases (47.4%) in CT/TG group and 1 case (33.3%) in TT/TG group achieved sustained virological response (SVR). There were statistically significant differences among the three groups (P=0.014). One hundred and one cases in CC/TT group developed adverse events, among them 19 cases needed clinical treatment. There were 43 cases in CT/TG group developed adverse events and 9 cases needed treatment. Seven cases in TT/TG group developed adverse events and only 1 case needed treatment. There were no statistically significant difference among three groups (χ2=0.139, P>0.05). Conclusions The genotype of rs12979860 (C/T) and rs8099917 (T/G) at IL-28B gene could affect the treatment response in patients with chronic hepatitis C. RVR and SVR are higher in patients with genotype CC/TT, which might help to guide HCV treatment. Key words: Interleukin-28B; Hepatitis C, chronic; Polymorphism, single nucleotide; Antiviral response

Effectiveness of Sofosbuvir and Ribavirin for Eradicating Hepatitis C Virus in Renal Transplant Recipients in Pakistan: Where Resources Are Scarce.

Although direct-acting antiviral agents have revolutionized hepatitis C virus treatment, these novel agents are not widely available in the developing world. Further, no treatment recommendation for renal transplant recipients includes these agents. We aimed to evaluate the effectiveness of sofosbuvir and ribavirin, the only direct-acting antiviral agents available in Pakistan, in renal transplant recipients. All renal transplant recipients receiving sofosbuvir and ribavirin from August 2015 to March 2016 were enrolled in the study. Patients' demographics and baseline laboratory parameters were collected. Rapid virologic response, early virologic response, end-of-treatment response, and sustained virologic response at 12 and 24 weeks were analyzed. Statistical analyses were performed using IBM SPSS Statistics software, version 20.0. Of the 37 renal transplant recipients, the mean age was 37.2 ± 10.7 years and the majority (33 [89.2% ]) were men. Twenty-five patients were treatment naive; of the remaining 12 patients, 10 were responders, 2 were nonresponders, and 5 were relapsers to pretransplant hepatitis C treatment. The genotype most commonly seen posttransplant was genotype 1 (56.8%). Rapid virologic response was achieved in 33 patients (89.2%). Early virologic response, end-oftreatment response, and sustained virologic response at 12 weeks were achieved in all 37 patients (100%). Until the time of data collection, 14 patients had achieved a sustained virologic response at 24 weeks. No complications were noted during therapy. In 2 of 4 patients who developed decompensated cirrhosis, treatment led to the resolution of ascites. Sofosbuvir and ribavirin are well tolerated and effective in renal transplant recipients for eradicating hepatitis C virus. Their effectiveness is not limited to renal transplant recipients with genotypes 1, 2, 3, and 4 but also extends to those with mixed genotype (in this study, genotypes 1 and 3).

Treatment of HCV in renal transplant patients with peginterferon and ribavirin: long-term follow-up.

In addition to the observation of an increased viremia among patients with chronic hepatitis C virus (HCV) infection who undergo renal transplantation, fibrosis and necroinflammatory activity have been noted to worsen comparing pre- and post-renal transplantation liver biopsies in some of these patients. Apart from the reported reduced patient and allograft survival rates, post-transplant diabetes mellitus, de novo glomerulonephritis, and an increased overall risk of infection have been observed. However, antiviral therapy for HCV is generally considered contraindicated among patients with solid organ transplants, with the main worry being the risk of acute rejection in relation to the use of interferon. We reported the long-term outcome of four renal transplant patients with chronic HCV infection who received peginterferon-based therapy. We collected the long-term follow-up data of four patients who completed the therapy with peginterferon in combination with ribavirin. Two of them had renal impairment at baseline. With treatment, they had a significant improvement in terms of serum liver transaminase level, and two patients achieved the early virological response and the other two rapid virological response. All four patients achieved sustained virological response, with neither HCV flare up nor renal dysfunction during follow-up for a mean duration of 74.3months after therapy. These results suggest that sustained HCV virological response may be achieved without allograft dysfunction, in selected renal transplant patients using a peginterferon-based therapy.

Evaluation of Temporal Virological Responses to Interferon-α-2b plus Ribavirin among Genotype 3a Hepatitis C Virus-Infected Patients

Objectives: The present study aimed to examine the impact of rapid virological response (RVR) and early virological response (EVR) on sustained virological response (SVR) in chronic hepatitis C genotype 3a individuals. Methods: The patients were given antiviral therapy with IFN-α-2b, 3 million units 3 times a week and 800-1,200 mg of ribavirin daily adjusted to the patient's body weight (<60 kg 800 mg day−¹, and >60 kg 1,200 day−¹). The patients received this combination therapy for 24 weeks. The patients were evaluated for their viral load at week 4, 12, and 24 using RT-PCR. Results: Out of 1,471 patients, 43.3% showed a negative viral load in week 4, demonstrating RVR, whereas 56.6% maintained a high viral load. These were further separated based on viral reduction in their plasma: either negative for HCV-RNA at week 12 (n = 575), manifesting EVR, or showing a 2-log reduction in HCV viral load classified as partial EVR (PEVR; n = 259). The PEVR response was less (29.7%) compared with RVR (85.9%) and EVR (69.0%), although nonresponders were found in both groups. Conclusions: Individuals incompliant with their treatment who have a higher RVR significantly influence their SVR towards a better remission that can be treated within a short duration with standard treatment.

EFFICACY AND SAFETY OF THE COMBINATION OF RIBAVIRIN AND PEGYLATED INTERFERON ALFA-2A IN PATIENTS WITH CHRONIC HEPATITIS C: THE RESULTS OF TWO MULTICENTER, PROSPECTIVE, OPEN, NON-COMPARATIVE CLINICAL TRIALS

Aim. Study of efficacy and safety of ribavirin in combination to pegylated interferon α-2a (PegIFN- α-2a) within combined mode of treatment of patients with chronic hepatitis C (CHC) including patients with compensated cirrhosis and and HIV coinfection were conducted. Material and methods. Two open prospective multicenter, non-comparative clinical trials ML16709 NCT00922779 and ML27851 «Standart» (NCT01609049) were conducted. 6661 and 1496 patients with CHC were included accordingly. All were administrated combined therapy: ribavirin and PegIFN- α-2a. Patients with HCV genotype 1 received prescribing treatment for at least 12 but not more than 48 weeks, patients with HCV genotypes 2 and 3 – for at least 12 but not more than 24 weeks. The efficacy analysis included determining the frequency of achieving a rapid virologic response (BVO), an early virologic response (RVO), a virologic response at the end of therapy, and a sustained virologic response (SVR). The safety endpoints were assessed on data of all adverse events (AEs), serious adverse events (SNP), and clinical laboratory findings. Results. At 24 weeks SVR frequency was 43.4% in the subgroup of patients with HCV genotype 1 in the ML16709 study and 72,0% in the ML27851 study; 58,9% and 89,3% in the subgroup of patients with HCV genotypes 2 and 3 accordingly. In the ML27851 study proportion of patients with BVO was 46,8% in patients with HCV genotype 1 and 86,0% in patients with a different HCV genotype. RVO frequency was 37,4% in the subgroup of patients with HCV genotype 1 in the ML16709 study and 90,1% in the ML27851 study; 79,7% and 97,4% in a subgroup of patients with HCV genotypes 2 and 3 accordingly. The proportion of patients with virologic response at the end of therapy was 44,6% in the ML16709 study and 86.7% in the ML27851 study; in a subgroup of patients with genotypes 2 and 3, 73.8% and 97.6%, accordingly. In the ML16709 study 5887 AEs were registered, including 5812 (99%) of non-serious AEs and 75 serious AEs. In the ML27851 study 2557 non-serious AEs occurred in 822 (54.95%) patients. 49 serious AEs were registered in 39 patients (2.6%). Conclusion. The results of studies ML16709 and ML27851 confirm the efficacy and safety of treatment with ribavirin plus peginterferon alfa-2a in patients with chronic hepatitis C. The registered AEs profile is representative of pegylated interferons and ribavirin combination.

Telbivudine therapy for chronic hepatitis B: A journey to identify super-responders and to optimize treatment using the roadmap model.

Hepatitis B virus (HBV) infection is one of the most serious health problems worldwide with a high risk for cirrhosis and liver cancer. Several antiviral agents have been approved for the treatment of chronic hepatitis B, leading to a rapid reduction in HBV DNA and normalization of serum alanine aminotransferase levels. Telbivudine, a potent inhibitor of HBV replication, has been shown to be well tolerated. Because of the emergence of drug resistance, optimization strategies for telbivudine therapy have been shown to improve patient responses. Optimal baseline characteristics in so-called super-responders have been used to predict the virological response. Baseline HBV DNA levels < 9 log10 copies/mL (2 × 108 IU/mL) or alanine aminotransferase levels of more than or equal to twofold the upper limit of normal in HBeAg-positive patients and HBV DNA < 7 log10 copies/mL (2 × 106 IU/mL) in HBeAg-negative patients were strong predictors for virological response. In addition, the roadmap model, based on early virological response at week 24 of therapy, is considered as a powerful tool to identify patients at risk of treatment failure (HBV DNA ≥ 300 copies/mL, i.e. 60 IU/mL) and to reduce the risk of antiviral resistance. When considering pre-treatment characteristics and on-treatment responses, telbivudine may provide physicians with a wide choice of options to effectively treat patients with chronic hepatitis B, especially those with or at risk of renal impairment, or women of childbearing age.

Telaprevir combination therapy in patients infected with hepatitis C virus genotype 4

Background: The sustained virological response (SVR) rate for genotype 4 (G4) HCV-infected patients after pegylated interferon (PegIFN) and ribavirin (RBV) treatment is approximately 60%. We aimed to investigate the efficacy and safety of telaprevir (TVR) in combination with PegIFN and RBV in patients infected with G4 HCV who were previously treated with PegIFN/RBV and failed to achieve SVR. Material and Methods: The study included 10 patients: two prior relapsers, two prior partial responders, and six prior null responders to PegIFN/RBV treatment. The patients were given TVR/PegIFN/RBV for 12 weeks, followed by a 12-36 weeks PegIFN/RBV treatment. Rapid virological response (RVR), early virological response (EVR), extended rapid virological response (eRVR), SVR, and side effects of therapy were evaluated. Results: The mean age of the patients was 48.90±12.52 years and seven were female. All of HCV isolates were typed as 4d. Interleukin (IL) 28B genotype was found CT in seven patients and two patients had cirrhosis. Treatment was stopped within four weeks because of the side effects in two patients. Three of the remaining eight patients (37.5%) achived HVR, RVR, and eHVR. SVR was obtained in two of these patients, but one patient relapsed. SVR rates were 25% in all patients. Conclusion: TVR combination therapy had limited antiviral activity in this patient population. Further investigation of TVR combination therapy in patients with HCV G4 infection is warranted.

Positive and Negative Predictive Factors for Treatment Response in Patients with Chronic Viral C Hepatitis.

ABSTRACT: More than 200 million people worldwide are infected with hepatitis C virus. In the United States, suggested estimates are that more than 5 million people live with HCV. The purpose of this paper is to identify, within the Southwestern Romanian population, host factors associated with the response to Pegylated Interferon and Ribavirin treatment for Hepatitis C virus infection. We investigated several factors and their correlation to sustained virological response. The study included 267 patients diagnosed with chronic Hepatitis C between 2013 and 2016, treated with Pegylated Interferon and Ribavirin in the 2nd Medical Department of the Emergency County Hospital Craiova. From the 267 patients included in this study, 149 (55,81%) achieved sustained virological response during the 48 weeks of treatment. Several factors were taken in consideration regarding the treatment response. Positive predictive factors for achieving sustained virological response were: the female gender (35,96%), Low Viral Load at the beginning of treatment, Early Virological Response 75 (28,09%), Rapid Virologic Response133 (49,81%), and stage of fibrosis, with Stage F1 having the highest rate of Sustained Virological Response during double therapy 81 (30,34%). Although at the present time a number of more effective antiviral products have been approved for the treatment of viral hepatitis C, in our country the standard of treatment remains with PegInterferon and Ribavirin therapy. Multiple clinical and paraclinical tools can identify patients with a high chance of responding to treatment, or those who, during treatment, do not meet the criteria for prolonging therapy.

Early virological response to HIV treatment: can we predict who is likely to experience subsequent treatment failure? Results from an observational cohort study, London, UK

Early virological response to HIV treatment: can we predict who is likely to experience subsequent treatment failure? Results from an observational cohort study, London, UK

Early virological response to HIV treatment: can we predict who is likely to experience subsequent treatment failure? Results from an observational cohort study, London, UK.

Introduction: For people living with HIV, the first antiretroviral treatment (ART) regimen offers the best chance for a good virological response. Early identification of those unlikely to respond to first-line ART could enable timely intervention and increase chances of a good initial treatment response. In this study we assess the extent to which the HIV RNA viral load (VL) at 1 and 3 months is predictive of first-line treatment outcome at 6 months.Methods: All previously ART-naive individuals starting ART at two London centres since 2000 with baseline (−180 to 3 days) VL >500 c/mL had a VL measurement between 6 and 12 months after starting ART, and at least one at month 1 (4–60 days) or month 3 (61–120 days) were included. Lack of treatment response was defined as (i) VL >200 copies/mL at 6 months or (ii) VL >200 copies/mL at 6 months or simultaneous switch in drugs from at least two different drug classes before 6 months. The association with VL measurements at 1 and 3 months post-ART; change from pre-ART in these values; and CD4 count measurements at 1 and 3 months were assessed using logistic regression models. The relative fit of the models was compared using the Akaike information criterion (AIC).Results: A total of 198 out of 3258 individuals (6%) experienced lack of treatment response at 6 months (definition i), increasing to 511 (16%) for definition (ii). Those with a 1-month (day 4–60 window) VL of <1000, 1000–9999, 10,000–99,999 and >100,000 copies/ml had a 4%, 8%, 23% and 24% chance, respectively, of subsequently experiencing treatment non-response at 6 months (definition (i)). When considering the 3-month (day 61–120 window) VL, the chances of subsequently experiencing treatment non-response were, respectively, 3%, 25%, 67% and 75%. Results were similar for definition (ii).Conclusions: Whilst 3-month VL provides good discrimination between low and high risk of treatment failure, 1-month VL does not. Presence of a VL >10,000 copies/ml after 3 months of ART is a cutoff above which individuals are at a sufficiently higher risk of non-response that they may be considered for intervention.

Prevalence rate and prognostic value of the IL-28 gene polymorphism in hepatitis C patients in the Krasnodar territory

Objective. The study of the prevalence rate of the IL-28B genotype polymorphism in chronic hepatitis C (CHC) patients in the Krasnodar territory for the prediction of the effectiveness of various schemes of antiviral therapy. Materials and methods. There was executed the determination of single nucleotide polymorphisms (SNP) at loci rs8099917 and rs12979860 of the IL-28B gene in 833 CHC genotype 1 patients, aged of from 18 to 73 years, living in the Krasnodar Territory. In 260 cases the viral load has been determined. For genotyping IL-28B there was used the method of allele-specific PCR test system «AmpliSens Genoskrin IL28B-FL» in a amplifier with system of detection offluorescent signal in real-time mode “Rotor-Gene Q” (“Qiagen”, Germany). The investigation of the marker rs12979860 study was performed in combination with the marker rs8099917. Combinations of genotypic variants SNPIL-28B were compared with the rate of early virological response (EVR) and Sustained Virological Response (SVR) under antiviral therapy comprised of two components IFN/ ribavirin (20) andPEG-IFN/ribavirin (68 patients), as well as the "triple therapy": PEG-IFN/RBV/inhibitorsprotease 1 and 2 generations (16 cases). Results and discussion. In the Krasnodar territory in CHC genotype 1 patients there is prevailed heterozygous variant rs12979860 CTIL-28B (58.3%), potentially unfavorable in the prescription of "double" therapy. The detection rate of the protective allele CC is 2.1 times less often (27.7%). In the rs8099917 locus there is dominatedfavorable TTgenotype (53.4%), slightly exceeding the frequency of heterozygous risk genotype GT (41.2%). The frequency of combinations of various protective genotypes (CC+CT), less favorable (CT+TT), the most unfavorable for the prognosis (CT+GT) for two interleukin 28B gene loci is about the same accounting of from 26.3 to 32%. Patients with protective CC+TT alleles had the significantly higher viral load if compared with a group of patients with unfavorable TT+GG homozygotes. In the treatment of CHC patients with genotype CC+CT in investigated loci (rs12979860 and rs8099917) according to such schemes as IFN/RBV and Peg-IFN/RBV, EVR was observed in 100% and SvR - in 89.4-849% ofpatients respectively. The combination of CT+TT alleles of the IL28B gene significantly reduced the effectiveness of treatment of PEG-IFN/RBV to 50%; in this process a combination of CT+GT heterozygotes has the highest proportion while SVR does not exceed 33.3%."Triple" therapy with PEG-IFN/RBV/ protease inhibitors of 1st and 2nd generations eliminates the significance of the combination of unfavorable genotypes SNP of the interleukin 28B gene, allowing to achieve EVR in all the patients with the absence of protective alleles CC+TT, SVR - in 85.7% of cases. Conclusion. In choosing treatment regimens for CHC genotype 1 patients the differentiated approach is appropriate, with taking into account the favorable and unfavorable combinations of genotypic variants of the IL28B gene concerning rs12979860 and rs8099917. In patients with the presence ofprotective alleles CC+TT on these loci, a "double" combination therapy by as pegylated as well standard interferon preparations with ribavirin is highly effective and may be preferred; in the combination of less favorable alleles CT+TT, and particularly unfavorable heterozygotes CT+GT ofIL-28B gene, it is advisable to use a "triple" therapy with PEG-IFN/RBV/protease inhibitors of 1st and 2nd generations or non-interferon regimens. The study of the distribution of SNP genotypes of IL28B genes and their combinations in CHC patients C allowed to evaluate rationally the need of that cohort ofpatients for various, including expensive non-interferon, therapy schemes.

Tolerability and efficacy of pegylated consensus interferon-α in the treatment of chronic hepatitis C.

This study aimed to explore and evaluate the tolerability and antiviral activity of pegylated recombinant human consensus interferon-α (PEG-CIFN) in adults with hepatitis C virus (HCV) infection. A total of 48 adult subjects chronically infected with HCV were divided into five groups, which were treated separately with PEG-CIFN 1.0 µg/kg (n=10), 1.5 µg/kg (n=10), 2.0 µg/kg (n=9) or 3.0 µg/kg (n=10), or pegylated IFN α-2a (Pegasys) 180 µg (n=9) as controls. Symptoms were observed and laboratory results collected to monitor adverse reactions, adjust drug dosage and evaluate tolerability. The thrombocytopenic effects in all PEG-CIFN dose groups were less than that of pegylated IFN α-2a (at week 14, P<0.05). The rapid virologic response of the PEG-CIFN 1.5, 2.0 and 3.0 µg/kg groups and the pegylated IFN α-2a group were significantly higher than that of the PEG-CIFN 1.0 µg/kg group (P<0.05). Patients who had HCV genotype 1b infections had relatively high responses. The early virologic response of the PEG-CIFN 1.0, 1.5 and 2.0 µg/kg groups and the pegylated IFN α-2a group were 30, 90, 88.8 and 88.8% respectively. PEG-CIFN is well tolerated, and was found to have dose-dependent effectiveness in subjects with chronic hepatitis C. Virological response rates between PEG-CIFN 1.5 or 2.0 µg/kg, and pegylated IFNα-2a were similar, and not significantly different. It is concluded that 1.5 µg/kg PEG-CIFN may be the clinically recommended dose. PEG-CIFN is superior to pegylated IFN α-2a in maintaining platelet levels.

First Week HCV RNA Level Under the Pegylated Interferon and Ribavirin Treatment Predicts Sustained Virological Response

This study was planned to investigate whether the decrease in the hepatitis C virus (HCV) RNA levels at the first week of combined pegylated interferon and ribavirin treatment of naive genotype 1 patients with HCV was predicting sustained virologic response (SVR). Fifty-two patients were enrolled into the study. HCV RNA levels were measured at the baseline, first, fourth, and 12th weeks of treatment. Thirty-four patients achieved SVR, which basal, first week, and fourth week HCV RNA levels were log 5.57, log 3.65, and log 1.92, respectively. Eighteen patients could not achieve SVR, which basal, first week, and fourth week HCV RNA levels were log 6.22, log 5.45, and log 3.84, respectively (P < 0.05). Patients were distributed in 2 groups according to the amount of decrease in HCV RNA levels at the first week as less or more than 1.5 log. There were 20 patients with ≥1.5 log decrease in the HCV RNA levels at the first week. They were named as patients with very rapid virologic response (VRVR). All patients (100%) with VRVR were achieved SVR. In only 14 (44%) of the 32 patients without VRVR, SVR was achieved. In 16 (84%) of the 19 patients with rapid virologic response and 33 (79%) of the 42 patients with early virologic response, SVR was achieved. A ≥1.5 log decrease (VRVR) in HCV RNA levels of patients with HCV at the first week of combined pegylated interferon and ribavirin treatment predicts SVR very strongly.

Efficacy and safety of daclatasvir plus asunaprevir therapy for chronic hepatitis C patients with renal dysfunction.

Chronic hepatitis C virus (HCV) infection is associated with renal dysfunction. Daclatasvir and asunaprevir combination therapy showed a high virological response for genotype 1 chronic HCV-infected patients with renal dysfunction on hemodialysis. However, the safety and efficacy of the therapy for patients with renal dysfunction who are not on hemodialysis are not well-known. In total, 147 patients with chronic HCV genotype 1 infection were treated with 24 weeks of daclatasvir plus asunaprevir therapy. Among these patients, 126 had normal renal function (estimated glomerular filtration rate [eGFR] ≥ 50 ml/min/1.73 m2 ) and 21 had renal dysfunction (eGFR < 50 ml/min/1.73 m2 ). Plasma concentrations of daclatasvir and asunaprevir after 5 days of treatment were the same in the normal renal function and renal dysfunction groups. Early virological response (4, 8, 48, 96, and 168 hr after the start of the therapy) was similar between the two groups. End-of-treatment response was achieved in 122 (96.8%) and 20 (95.2%) patients with normal renal function and with renal dysfunction, respectively, and sustained virological response was achieved in 119 (94.4%) and 20 (95.2%) patients. The frequency of adverse events was also comparable between the two groups. Treatment discontinuation due to adverse events was required for only one patient in each group. Renal function did not change either during or after treatment in both groups. In conclusion, renal function is unlikely to have a significant impact on blood kinetics of daclatasvir and asunaprevir. This combination therapy was effective and safe for patients without hemodialysis. J. Med. Virol. 89:665-671, 2017. © 2016 Wiley Periodicals, Inc.

Assessment of the Response to Treatment in Patients with the Hepatitis C Virus Infection: A Quantitative Study by Focusing on Virologic and Biochemical Responses

Objectives: The main goal of the treatment of the hepatitis C virus (HCV) infection is reduction and elimination of viruses as well as achieving high sustained viral response (SVR). The present study aimed to assess response to treatment of HCV infection by focusing on virological and biochemical aspects. Methods: This study was performed in Hamadan, Iran on HCV infected patients who were referred between 2009 and 2013. All participants were under the treatment with Pegylated Interferon (PEG-IFN) and Ribavirin (RBV). The duration of treatment varied based on the HCV genotype as 24 weeks for genotypes 2 and 3, and 48 weeks for other genotypes. Results: Of the 186 patients with HCV infection, 52.8% had a genotype of 3a and 35.6% had a genotype of 1a/b. Three months after treatment, 75 patients were willing to do quantitative PCR and early virologic response was observed in 58 cases (78.4%). Also, 112 patients were assessed after completing the treatment (75 patients in 24 weeks and 37 patients in 48 weeks treatment protocol) and the end-of-treatment response (ETR) was 94.7% and 86.5% respectively. Amongst the 103 patients with ETR, 76 were followed up six months after treatment and the PCR was negative in 71 cases (SVR = 93.4). With the progress and completion of the treatment, improvement is observed in liver function tests. Conclusions: Even with the introduction of new drugs and interferon free protocols in treatment of hepatitis C infection it seems that the IFN-based treatment is still used in low/middle income countries for treatment-naive patients with HCV genotype 3.

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.