Circulating miRNA-192 and miR-29a as Disease Progression Biomarkers in Hepatitis C Patients with a Prevalence of HCV Genotype 3.

MicroRNAs miR-29a and miR-192 are involved in inflammatory and fibrotic processes of chronic liver disease, and circulating miR-29a is suggested to diagnose fibrosis progression due to hepatitis C virus (HCV) infection. This study aimed to evaluate the expression profile of circulating miR-192 and 29a in a patient cohort with a high frequency of HCV genotype-3. A total of 222 HCV blood samples were collected and serum were separated. Patients were classified into mild, moderate, and severe liver injury based on their Child-Turcotte-Pugh CTP score. RNA was isolated from the serum and used for quantitative real-time PCR. The HCV genotype-3 (62%) was the predominant HCV genotype. In HCV patients, the serum miR-192 and miR-29a levels were significantly upregulated in comparison to healthy controls (p = 0.0017 and p = 0.0001, respectively). The progression rate of miR-192 and 29a in the patient group with mild was highly upregulated compared to patients with moderate and severe hepatitis infection. The ROC curve of miR-192 and miR-29a of moderate liver disease had a significant diagnostic performance compared to the other HCV-infected groups. The increase in miR-29a and miR-192 serum levels was even slightly higher in patients with HCV genotype-3 than in non-genotype-3 patients. In conclusion, serum miR-192 and miR-29a levels significantly increased during the progression of chronic HCV infection. The marked upregulation in patients with HCV genotype-3 suggests them as potential biomarkers for hepatic disease, independently of the HCV genotype.

Hesperidin identified from Citrus extracts potently inhibits HCV genotype 3a NS3 protease.

BACKGROUND: Hepatitis C virus infection is the main cause of liver ailments across the globe. Several HCV genotypes have been identified in different parts of the world. Effective drugs for combating HCV infections are available but not affordable, particularly to infected individuals from resource-limited countries. Hence, cost-effective drugs need to be developed against important HCV drug targets. As Citrus fruits naturally contain bioactive compounds with antiviral activities, the current study was designed to identify antiviral inhibitors from Citrus fruit extracts against an important drug target, NS3 protease, of HCV genotype 3a which is found predominantly in South Asian countries. METHODS: The full-length NS3 protease alone and the NS3 protease domain in fusion with the cognate NS4A cofactor were expressed in Escherichia coli, and purified by chromatographic techniques. Using the purified protein as a drug target, Citrus extracts were evaluated in a FRET assay, and active ingredients, identified using ESI-MS/MS, were docked to observe the interaction with active site residues of NS3. The best interacting compound was further confirmed through the FRET assay as the inhibitor of NS3 protease. RESULTS: Fusion of the NS3 protease domain to the NS4A cofactor significantly improved the purification yield, and NS3-NS4A was functionally more active than the full-length NS3 alone. The purified protein (NS3-NS4A) was successfully employed in a validated FRET assay to evaluate 14 Citrus fruit extracts, revealing that the mesocarp extract of Citrus paradisi, and whole fruit extracts of C. sinesis, C. aurantinum, and C. reticulata significantly inhibited the protease activity of HCV NS3 protease (IC50 values of 5.79 ± 1.44 µg/mL, 37.19 ± 5.92 µg/mL, 42.62 ± 6.89 µg/mL, and 57.65 ± 3.81 µg/mL, respectively). Subsequent ESI-MSn analysis identified a flavonoid, hesperidin, abundantly present in all the afore-mentioned Citrus extracts. Importantly, docking studies suggested that hesperidin interacts with active site residues, and acts as a potent inhibitor of NS3 protease, exhibiting an IC50 value of 11.34 ± 3.83 µg/mL. CONCLUSIONS: A FRET assay was developed using NS3-NS4A protease, which was successfully utilized for the evaluation of Citrus fruit extracts. Hesperidin, a compound present in the Citrus extracts, was identified as the main flavonoid, which can serve as a cost-effective potent inhibitor of NS3 protease, and could be developed as a drug for antiviral therapy against HCV genotype 3a.

Sero-reactivity to three distinct regions within the hepatitis C virus alternative reading frame protein (ARFP/core+1) in patients with chronic HCV genotype-3 infection.

Hepatitis C virus (HCV) infection affects more than 71 million people worldwide. The disease slowly progresses to chronic, long-term liver injury which leads to hepatocellular carcinoma (HCC) in 5 % of infections. The alternative reading frame protein (ARFP/core+1) is encoded by a sequence overlapping the HCV core gene in the +1 reading frame. Its role in hepatitis C pathogenesis and the viral life cycle is unclear, although some observers have related its production to disease progression and the development of HCC. The aim of this study was to determine whether ARFP is immunogenic in patients with chronic HCV genotype 3 infection and to assess whether sero-reactivity is associated with disease progression, particularly to HCC. Immunogenic epitopes within the protein were predicted by a bioinformatics tool, and three -20 aa length-peptides (ARFP-P1, ARFP-P2 and ARFP-P3) were synthesized and used in an avidin-biotin ARFP/core+1 peptide ELISA. Serum samples from 50 patients with chronic HCV genotype 3 infection, 50 genotype-1 patients, 50 HBV patients and 110 healthy controls were tested. Sero-reactivity to the ARFP peptides was also tested and compared in 114 chronic HCV genotype-3 patients subdivided on the basis of disease severity into non-cirrhotic, cirrhotic and HCC groups. Chronic HCV genotype-3 patients showed noticeable rates of reactivity to ARFP and core peptides. Seropositivity rates were 58% for ARFP-P1, 47 % for ARFP-P2, 5.9 % for ARFP-P3 and 100 % for C22 peptides. There was no significant difference between these seroreactivities between HCV genotype-3 patients with HCC, and HCV genotype-3 patients with and without liver cirrhosis. Patients with chronic HCV genotype-3 infection frequently produce antibodies against ARFP/core+1 protein. ARFP peptide reactivity was not associated with disease severity in patients with HCV genotype-3. These results support the conclusion that ARFP/core+1 is produced during HCV infection, but they do not confirm that antibodies to ARFP can indicate HCV disease progression.

Hepatocellular carcinoma occurs frequently and early after treatment in HCV genotype 3 infected persons treated with DAA regimens.

BACKGROUND: There are conflicting data regarding the risk of hepatocellular carcinoma (HCC) after direct-acting antiviral agent (DAA) treatment. Risk of HCC in HCV genotype-3 infected persons after DAA therapy is not well known. METHODS: We prospectively studied HCV infected persons initiated on a DAA regimen between October 2014 and March 2017 at two centers in Pakistan. All persons were free of HCC at study initiation. HCC was confirmed based on characteristic CT scan findings. Patients were followed for 12 months after the completion of therapy. RESULTS: A total of 662 persons initiated treatment. Median age (IQR) was 50 (41, 57) years and 48.8% were male. At baseline, 49.4% were cirrhotic, 91% were genotype 3 and 91.9% attained SVR. Treatment regimens used were: Sofosbuvir (SOF)/ribavirin (RBV)/pegylated interferon (PEG-IFN), 25.2%; SOF/RBV, 62.4%; SOF/RBV/daclatasavir (DCV), 10.6%; SOF/DCV, 2.0%. Incident HCC was detected in 42 patients (12.8%) in the 12-month period after treatment completion and was exclusively observed in those with cirrhosis. In multivariable Cox regression analysis, SVR was associated with a reduction in HCC risk (HR, 95% CI: 0.35, 0.14,0.85). In Kaplan-Meier plots by treatment regimen, those treated with SOF/RBV, SOF/RBV/DCV, or SOF/DCV regimens had a shorter HCC-free survival compared with those treated with a SOF/RBV/PEG-IFN regimen. CONCLUSION: In a predominantly genotype 3 cohort, incident HCC occurred frequently and early after treatment completion, and exclusively in those with pre-treatment cirrhosis. SVR reduced the risk of HCC. Treating HCV infected persons before development of cirrhosis may reduce risk of HCC.

Developments in the treatment of HCV genotype 3 infection.

Introduction: Unlike other hepatitis C virus (HCV) genotypes (GTs), patients infected with GT3 are associated with an increased risk of accelerated liver disease progression. Although early immuno-modulator therapies yielded moderate sustained virologic response (SVR) rates, treatment of GT3 patients has proven more challenging in the era of direct-acting antivirals (DAAs). Areas covered: The review provides an overview of the evolution of therapies against GT3 since the approval of the first immunomodulatory agent nearly 30 years ago. Expert opinion: A greater choice of treatment options is now available for HCV GT3-infected patients. In treatment-naïve patients with or without compensated cirrhosis, SVR rates are comparably high approaching 100% irrespective of treatment option. For treatment-experienced patients, choosing the right therapy is important, especially for those with advanced liver disease. For the few patients who fail with multiple persistent highly resistant DAA substitutions, retreatment options are limited. Additional real-world treatment comparisons are required to confirm differences in SVR in these more difficult-to-treat patients. This also includes patients infected with GT3 subtypes such as GT3b where multiple DAA-resistant substitutions occur naturally. In the absence of new drugs with non-overlapping drug-resistant profiles, an interferon-based therapy may still be beneficial in select patient populations with high-level multiple DAA-resistant substitutions.

Effectiveness and safety of sofosbuvir/velpatasvir/voxilaprevir in patients with chronic hepatitis C previously treated with DAAs.

BACKGROUND & AIMS: Around 5% of patients with chronic hepatitis C virus (HCV) infection treated with direct-acting antiviral (DAA) agents do not achieve sustained virological response (SVR). The currently approved retreatment regimen for prior DAA failure is a combination of sofosbuvir, velpatasvir, and voxilaprevir (SOF/VEL/VOX), although there is little data on its use in clinical practice. The aim of this study was to analyse the effectiveness and safety of SOF/VEL/VOX in the real-world setting. METHODS: This was a prospective multicentre study assessing the efficacy of retreatment with SOF/VEL/VOX in patients who had experienced a prior DAA treatment failure. The primary endpoint was SVR 12 weeks after the completion of treatment (SVR12). Data on safety and tolerability were also recorded. RESULTS: A total of 137 patients were included: 75% men, 35% with liver cirrhosis. Most were infected with HCV genotype (GT) 1 or 3. The most common prior DAA combinations were sofosbuvir plus an NS5A inhibitor or ombitasvir/paritaprevir/r+dasabuvir. A total of 136 (99%) patients achieved undetectable HCV RNA at the end of treatment. Overall SVR12 was 95% in the 135 patients reaching this point. SVR12 was lower in patients with cirrhosis (89%, p = 0.05) and those with GT3 infection (80%, p <0.001). Patients with GT3 infection and cirrhosis had the lowest SVR12 rate (69%). Of the patients who did not achieve SVR12, 1 was reinfected and 7 experienced treatment failure (6 GT3, 1 GT1a). The presence of resistance-associated substitutions did not impact SVR12. Adverse effects were mild and non-specific. CONCLUSION: Real-world data show that SOF/VEL/VOX is an effective, safe rescue therapy for patients with prior DAA treatment failure despite the presence of resistance-associated substitutions. However, patients with liver cirrhosis infected by GT3 remain the most-difficult-to-treat group. LAY SUMMARY: Treatment with sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) for 12 weeks is the current recommendation for the 5% of patients infected with HCV who do not achieve eradication of the virus under treatment with direct-acting antivirals. In a Spanish cohort of 137 patients who failed a previous combination of direct-acting antivirals, a cure rate of 95% was achieved with SOF/VEL/VOX. Genotypic characteristics of the virus (genotype 3) and the presence of cirrhosis were factors that decreased the rate of cure. Treatment with SOF/VEL/VOX is an effective and safe rescue therapy due to its high efficacy and very good safety profile.

Geographic Distribution of HCV-GT3 Subtypes and Naturally Occurring Resistance Associated Substitutions.

BACKGROUND: Little is known about the frequency or geographic distributions of naturally occurring resistance-associated substitutions (RASs) in the nonstructural protein 5A (NS5A) domain of hepatitis-C virus (HCV) genotype-3 (GT-3) different subtypes. We investigated naturally occurring GT-3 RASs that confer resistance to NS5A inhibitors. METHODS: From a publicly accessible database, we retrieved 58 complete GT-3 genomes and an additional 731 worldwide NS5A sequences from patients infected with GT-3 that were naive to direct-acting antiviral treatment. RESULTS: We performed a phylogenetic analysis of NS5A domains in complete HCV genomes to determine more precisely HCV-GT-3 subtypes, based on commonly used target regions (e.g., 5'untranslated region and NS5B partial domain). Among 789 NS5A sequences, GT-3nonA subtypes were more prevalent in Asia than in other geographic regions (P<0.0001). The A30K RAS was detected more frequently in HCV GT3nonA (84.6%) than in GT-3A subtypes (0.8%), and the amino acid change was polymorphic in isolates from Asia. CONCLUSIONS: These results provided information on the accuracy of HCV-3 subtyping with a phylogenetic analysis of the NS5A domain with data from the Los Alamos HCV genome database. This information and the worldwide geographic distribution of RASs according to HCV GT-3 subtypes are crucial steps in meeting the challenges of treating HCV GT-3.

SVR 24 Achievement Two Weeks After a Tripled Dose of Daclatasvir in an HCV Genotype 3 Patient.

Directly-acting antivirals (DAA) have changed the chronic hepatitis C virus (HCV) infection therapeutic scenario allowing virus eradication in more than 95% of patients, independently from the genotype, with 12 to 24-week treatment regimens. We describe a 51-year-old Pakistani man with a chronic HCV-genotype 3 (GT3a) infection with moderate liver fibrosis, who achieved sustained virological response (SVR) 24 after a tripled dose of Daclatasvir (DCV) taken erroneously associated to Sofosbuvir (SOF). The patient had a concomitant intestinal TB infection whose treatment had been delayed in order to firstly eradicate HCV to reduce the liver toxicity of anti-mycobacterial drugs. Thanks to the cultural mediator support, we explained to the patient the correct posology of each drug to take during the day consisting of 12 week SOF (400 mg daily) plus DCV (60 mg daily) regimen. He returned 13 days after for a programmed visit and we were surprised to learn that he had taken 3 pills of DCV (180 mg/daily) instead of one, thus ending DCV assumption after only 9 days while SOF was taken correctly. He complained no symptoms. We immediately performed blood test that showed alteration of lactate dehydrogenase, creatine phosphokinase, and creatin kinase MB activity. At day 15 we stopped SOF closely monitoring the patient. Blood test alterations returned normal after one week of treatment suspension, HCV viremia remained suppressed after 4, 12 and 24 weeks proving HCV eradication. If confirmed, these data could suggest that higher doses of DCV, if tolerated, might be employed in short-time HCV-GT3 treatment.

Upregulated hepatic expression of mitochondrial PEPCK triggers initial gluconeogenic reactions in the HCV-3 patients.

OBJECTIVE: To identify the differential expression of candidate gluconeogenic genes which may initiate hepatitis C virus (HCV) related metabolic disorder during early stages of disease. METHODS: Patients of diverse age and sex, with positive HCV genotype 3 (HCV-3) RNA in serum and with no history of other related infections, co-infections, alcoholism, diabetes or chemotherapeutic treatments were considered for this study. Semi-quantitative reverse transcriptase PCR analysis and quantitative fold change analysis of the fresh liver biopsies of eight chronically infected HCV-3 patients and six healthy individuals were evaluated for three potential biomarkers involved in glucose homeostasis induction, namely mitochondrial phosphoenolpyruvate carboxykinase 2 (PCK2), glucose-6-phosphatase catalytic subunit (G6PC) and associated forkhead box protein 01 (FOXO1). RESULTS: Symptomatic evaluation, clinical history and blood test were conducted according to general disease prognosis procedures and reported here. Significantly upregulated expression of PCK2 independent of age, sex and viral infectivity levels in all HCV patients was observed, whereas no significant changes in the expression of G6PC and FOXO1 were found. CONCLUSIONS: PCK2 triggers initial gluconeogenic reactions which ultimately result in the accumulation of glycogen in the liver hepatocytes. We therefore suggest that the overproduction of PCK2 has important physiological role in the onset of metabolic disorder in the HCV-3 patients.

HCV genotype 3 and squamous cell carcinoma antigen (SCCA)-IgM are independently associated with histological features of NASH in HCV-infected patients.

Nonalcoholic steatohepatitis (NASH) enhances the risk of progressive liver disease. In chronic hepatitis C (CHC), liver steatosis is frequent, especially in genotype 3, but its clinical significance is debated. As squamous cell carcinoma antigen (SCCA)-IgM has been associated with advanced liver disease and risk of tumour development, we evaluated its occurrence in CHC and the possible relation with NASH at liver biopsy. Using a validated ELISA, serum SCCA-IgM was measured in 91 patients with CHC at the time of liver biopsy performed before antiviral treatment, at the end of treatment and 6 months thereafter, and in 93 HCV-negative patients with histological diagnosis of nonalcoholic fatty liver disease, as controls. SCCA-IgM was detected in 33% of CHC patients and in 4% of controls. This biomarker was found more elevated in CHC patients with histological NASH, and at multivariate analysis, SCCA-IgM and HCV genotype 3 were independently associated with NASH [OR (95% CI): 6.94 (1.21-40) and 27.02 (4.44-166.6)]. As predictors of NASH, HCV genotype 3 and SCCA-IgM had a specificity and a sensitivity of 97% and 44%, and of 95% and 27%, respectively. PPV and NPV were 80% and 86% for HCV genotype 3 vs 73% and 72% for SCCA-IgM. In patients with sustained virologic response to therapy, SCCA-IgM levels decreased significantly, while these remained unchanged in nonresponders. In conclusion, SCCA-IgM is detectable in one-third of patients with CHC and significantly correlates with histological NASH.

Polymorphism of the IL28B gene (rs8099917, rs12979860) and virological response of Pakistani hepatitis C virus genotype 3 patients to pegylated interferon therapy.

BACKGROUND: The gold standard treatment for chronic hepatitis C virus (HCV) infection is pegylated interferon (PEG-IFN) in combination with ribavirin. Most patients treated with PEG-IFN achieve a sustained virological response (SVR). However host genetic factors play a vital role in the spontaneous and treatment-induced clearance of HCV infection from these infected patients. In the current study, polymorphisms of IL28B (rs8099917 and rs12979860) were analyzed and their association with the virological response to PEG-IFN alpha treatment was determined. METHODS: One hundred and fifty HCV genotype 3 patients were assessed to study the correlation of IL28B with a therapeutic regimen of PEG-IFN alpha plus ribavirin. Twenty patients were excluded due to a refusal to participate in the study and 25 patients failed to meet the inclusion criteria. Of the 105 patients recruited, 49 (46.7%) were male and 56 (53.3%) were female. In order to determine single nucleotide polymorphisms of rs8099917 and rs12979860, the sample was amplified by PCR and then IL28B typing was carried out by restriction fragment length polymorphism (RFLP) followed by standard sequencing. RESULTS: We found three types of genotype in rs8099917 of IL28B: wild-type TT in 60.0% of patients, heterozygous GT minor genotype in 36.2%, and GG in 3.8%. The frequency of the CC genotype of rs12979860 was 54.3%, CT was 37.1%, and TT was 8.6%. Overall, SVR was achieved in 68.6% of patients. A higher SVR was achieved for patients with the favorable genotype CC of rs12979860, with 84.2% as compared to 56.4% and 22.2% for minor genotype CT and TT, respectively (p=0.0001). We did not find a significant association for SVR to antiviral treatment in patients with genotype TT (rs8099917) (71.9%, p=0.36). The rapid virological response (RVR) rate was significantly higher in patients with major genotype TT (88.9%, p=0.04). These results show that IL28B polymorphism is highly associated with SVR to therapy in the Pakistani population infected with HCV genotype 3. CONCLUSIONS: HCV-infected patients carrying homozygous C/C have a higher chance of SVR. In addition, patients who carry T/T (rs8099917) have a higher chance of RVR.

Exploratory trial of ombitasvir and ABT-450/r with or without ribavirin for HCV genotype 1, 2, and 3 infection.

OBJECTIVES: To examine the safety and efficacy of ombitasvir and ABT-450 with ritonavir (ABT-450/r) ± ribavirin (RBV) in treatment-naïve, non-cirrhotic adults with chronic HCV genotype 1-3 infection. METHODS: Patients in this open-label, exploratory, phase 2, multicenter study received ombitasvir (25 mg QD) and ABT-450/r (200/100 mg QD) ± RBV for 12 weeks. Primary efficacy endpoint was HCV RNA < lower limit of quantitation (LLOQ) from week 4 through 12. Sustained virologic response 12 weeks post-treatment (SVR12) was a secondary endpoint. RESULTS: Sixty-one patients were enrolled. Among genotype 1-, 2-, and 3-infected patients, respectively, HCV RNA was

Upregulated hepatic expression of mitochondrial PEPCK triggers initial gluconeogenic reactions in the HCV-3 patients

OBJECTIVE@#To identify the differential expression of candidate gluconeogenic genes which may initiate hepatitis C virus (HCV) related metabolic disorder during early stages of disease.@*METHODS@#Patients of diverse age and sex, with positive HCV genotype 3 (HCV-3) RNA in serum and with no history of other related infections, co-infections, alcoholism, diabetes or chemotherapeutic treatments were considered for this study. Semi-quantitative reverse transcriptase PCR analysis and quantitative fold change analysis of the fresh liver biopsies of eight chronically infected HCV-3 patients and six healthy individuals were evaluated for three potential biomarkers involved in glucose homeostasis induction, namely mitochondrial phosphoenolpyruvate carboxykinase 2 (PCK2), glucose-6-phosphatase catalytic subunit (G6PC) and associated forkhead box protein 01 (FOXO1).@*RESULTS@#Symptomatic evaluation, clinical history and blood test were conducted according to general disease prognosis procedures and reported here. Significantly upregulated expression of PCK2 independent of age, sex and viral infectivity levels in all HCV patients was observed, whereas no significant changes in the expression of G6PC and FOXO1 were found.@*CONCLUSIONS@#PCK2 triggers initial gluconeogenic reactions which ultimately result in the accumulation of glycogen in the liver hepatocytes. We therefore suggest that the overproduction of PCK2 has important physiological role in the onset of metabolic disorder in the HCV-3 patients.

Upregulated hepatic expression of mitochondrial PEPCK triggers initial gluconeogenic reactions in the HCV-3 patients

Objective: To identify the differential expression of candidate gluconeogenic genes which may initiate hepatitis C virus (HCV) related metabolic disorder during early stages of disease. Methods: Patients of diverse age and sex, with positive HCV genotype 3 (HCV-3) RNA in serum and with no history of other related infections, co-infections, alcoholism, diabetes or chemotherapeutic treatments were considered for this study. Semi-quantitative reverse transcriptase PCR analysis and quantitative fold change analysis of the fresh liver biopsies of eight chronically infected HCV-3 patients and six healthy individuals were evaluated for three potential biomarkers involved in glucose homeostasis induction, namely mitochondrial phosphoenolpyruvate carboxykinase 2 (PCK2), glucose-6-phosphatase catalytic subunit (G6PC) and associated forkhead box protein 01 (FOXO1). Results: Symptomatic evaluation, clinical history and blood test were conducted according to general disease prognosis procedures and reported here. Significantly upregulated expression of PCK2 independent of age, sex and viral infectivity levels in all HCV patients was observed, whereas no significant changes in the expression of G6PC and FOXO1 were found. Conclusions: PCK2 triggers initial gluconeogenic reactions which ultimately result in the accumulation of glycogen in the liver hepatocytes. We therefore suggest that the overproduction of PCK2 has important physiological role in the onset of metabolic disorder in the HCV-3 patients.

Upregulated hepatic expression of mitochondrial PEPCK triggers initial gluconeogenic reactions in the HCV-3 patients

Objective:To identify the differential expression of candidate gluconeogenic genes which may initiate hepatitis C virus (HCV) related metabolic disorder during early stages of disease. Methods:Patients of diverse age and sex, with positive HCV genotype 3 (HCV-3) RNA in serum and with no history of other related infections, co-infections, alcoholism, diabetes or chemotherapeutic treatments were considered for this study. Semi-quantitative reverse transcriptase PCR analysis and quantitative fold change analysis of the fresh liver biopsies of eight chronically infected HCV-3 patients and six healthy individuals were evaluated for three potential biomarkers involved in glucose homeostasis induction, namely mitochondrial phosphoenolpyruvate carboxykinase 2 (PCK2), glucose-6-phosphatase catalytic subunit (G6PC) and associated forkhead box protein 01 (FOXO1).Results:Symptomatic evaluation, clinical history and blood test were conducted according to general disease prognosis procedures and reported here. Significantly upregulated expression ofPCK2 independent of age, sex and viral infectivity levels in all HCV patients was observed, whereas no significant changes in the expression ofG6PC andFOXO1were found.Conclusions:PCK2 triggers initial gluconeogenic reactions which ultimately result in the accumulation of glycogen in the liver hepatocytes. We therefore suggest that the overproduction of PCK2 has important physiological role in the onset of metabolic disorder in the HCV-3 patients.

Rapid virological response tailors the duration of treatment in hepatitis C virus genotype 3 patients treated with pegylated interferon alfa-2a and ribavirin in Pakistan.

BACKGROUND: Rapid virological response (RVR) is now thought to be the strongest predictor of sustained virological response (SVR) in hepatitis C virus (HCV) patients undergoing antiviral therapy. It can be used as a guide to individualize treatment duration. The aim of this study was to assess the role of RVR in tailoring the duration of treatment. METHODS: Patients with HCV genotype 3 infections were enrolled and treated with pegylated interferon alfa-2a (PEG IFN alfa-2a) 180 µg/week and ribavirin. HCV RNA was analyzed at weeks 4, 12, 16, and 24. Treatment duration was individualized on the basis of RVR. Patients who achieved RVR and who were aged ≤ 40 years with a body mass index (BMI) ≤ 27 kg/m(2) received 16 weeks of treatment (group A). Patients who achieved RVR and were aged >40 years with a BMI >27 kg/m(2), aged >40 years with a BMI ≤ 27 kg/m(2), and aged ≤ 40 years with a BMI >27 kg/m(2) received 24 weeks of treatment (group B). Patients who did not achieve RVR but who achieved an early virological response (EVR; HCV PCR-negative or ≥ 2 log drop in HCV RNA at week 12) were treated with 24 weeks of therapy (group C). RESULTS: SVR was observed in 86% in group A, 82.2% in group B, and 46.8% in group C. A difference was observed in SVR for patients with and without RVR and receiving the standard duration of treatment (82.2% vs. 46.8%, p<0 .001). The results show that the rate of SVR is not inferior in those with RVR treated with 16 weeks of therapy compared to 24 weeks (86% vs. 82.2%, p=0.004). CONCLUSIONS: RVR is useful to individualize the duration of treatment and to predict the treatment outcome. A short treatment of 16 weeks is as effective as 24 weeks in HCV genotype 3 patients who achieve RVR, who have a low BMI, and are younger in age.