Hepatitis C Virus Infected Patients Research Articles

Association of TGF-\xdf1 polymorphisms and chronic hepatitis C infection: a Meta-analysis

BackgroundAlthough several researches have reported the connection between the transforming growth factor-beta 1 (TGF-β1) gene polymorphisms and chronic hepatitis C virus (HCV) infection, the conclusions of these studies were not always consistent. Here, this paper proposed a meta-analysis to evaluate whether the TGF-ß1 gene polymorphisms, −509C/T (rs1800469), codon 10 T/C (rs1982073) and codon 25G/C (rs1800471), were associated with chronic HCV infection.MethodsThe summary odds ratios (ORs) of chronic HCV infected patients and controls with all SNPs were obtained by adaptive fixed or random effect model. A series of statistical tools were employed to guarantee the accuracy of related pooling ORs, including the Hardy-Weinberg equilibrium (HWE) test, sensitivity analysis and publication bias test.ResultsThis paper analyzed 18 case-control studies in 17 articles which totally contains 2718 chronic HCV infection cases corresponding to 1964 controls. The results of the meta-analysis indicated that the −509C/T polymorphism effected an increased risk of chronic HCV infection in all gene models. More specifically by ethnicity stratification, the Egyptians shared the similar association with the above overall study. Moreover, the meta-fusion of healthy control studies showed that − 509 T allele carriers (TT + TA) had nearly 2.00 and 3.36 fold higher risk of chronic HCV infection in the total and Egyptian populations, respectively (OR = 2.004, 95% CI = 1.138–3.528, P = 0.016; OR = 3.363, 95% CI = 1.477–7.655, P = 0.004, respectively). However, our meta-analysis did not find any significant association between the codon 10 T/C or codon 25G/C polymorphisms and chronic HCV infection.ConclusionsOur results suggested that the TGF-ß1–509C/T polymorphism may effect an increased risk of chronic HCV infection, especially in Egyptian population.

Circulating microRNA-301 as a promising diagnostic biomarker of hepatitis C virus-related hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a serious consequence of persistent hepatitis C virus (HCV) infection and represents one of the most aggressive neoplasms globally. The implication of microRNA-301 (miR-301) in the initiation and progression of different types of cancers has been proved. We aimed to assess circulating microRNA-301 as possible biomarker for the early detection of HCC in patients with chronic HCV infection. miR-301 expression levels were estimated in plasma samples of 42 patients with newly diagnosed HCV-related HCC, 48 chronically HCV infected patients with liver cirrhosis and 40 healthy individuals by reverse transcription-quantitative polymerase chain reaction technique. In comparison with chronically HCV infected patients and healthy controls, miR-301 expression levels were significantly increased in HCC patients (P < 0.001). miR-301 levels distinguished HCC patients from chronic HCV patients, with area under the receiver-operating characteristic curve of 0.89 (95% CI 0.82-0.96), the sensitivity and the specificity were 78.57% and 89.58% respectively. Moreover, miR-301 levels were significantly linked with tumor size (P = 0.014), serum levels of alpha-fetoprotein (AFP) (P = 0.028) and Barcelona Clinic Liver Cancer (BCLC) score (P = 0.003). These results reveal that miR-301 can serve as a promising non-invasive biomarker for diagnosis of HCC in chronically HCV infected patients.

Prediction of HCV load using genotype, liver biomarkers, and clinical symptoms by a mathematical model in patients with HCV infection.

Hepatitis C virus (HCV) infection is a major public health problem with about 1.75 million new HCV cases and 71 million chronic HCV infections worldwide. The study aimed to evaluate clinical, serological, molecular, and liver markers to develop a mathematical predictive model for the quantification of the HCV viral load in chronic HCV infected patients. In this cross-sectional study, blood samples were taken from 249 recently diagnosed HCV-infected subjects and were tested for liver condition, viral genotype, and HCV RNA load. Receiver operating characteristics (ROC) curves and multiple linear regression analysis were used to predict the HCV-RNA load. Genotype 3 followed by genotype 1 were the most prevalent genotypes in Mashhad, Northeastern Iran. The maximum levels of viral load were detected in the mixed genotype group, and the lowest levels in the undetectable genotype group. The log of the HCV viral load was significantly associated with thrombocytopenia and higher serum levels of alanine transaminase (ALT). In addition, the log HCV RNA was significantly higher in patients with arthralgia, fatigue, fever, vomiting, or dizziness. Moreover, genotype 3 was significantly associated with icterus. A ROC curve analysis revealed that the best cut-off points for serum levels of aspartate aminotransferase (AST), ALT, and alkaline phosphatase (ALP) were >31, >34, and ≤246 IU/L, respectively. Sensitivity, specificity, and positive predictive values for AST were 87.7%, 84.36%, and 44.6%, for ALT they were 83.51%, 81.11%, and 36%, and for ALP were 72.06%, 42.81%, and 8.3%, respectively. A mathematical regression model was developed that could estimate the HCV-RNA load. Regression model: log viral load = 7.69 - 1.01 × G3 - 0.7 × G1 + 0.002 × ALT - 0.86 × fatigue.

Relation between microRNA‐21, transforming growth factor β and response to treatment among chronic hepatitis C patients

Persistence of hepatitis C virus(HCV) infection and response to antiviral therapy has been shown to be associated with inappropriate levels of cytokines and microRNAs (miRNAs). miRNA levels have been reported to fluctuate during treatment. Thus they could be useful predictors for responses to treatment among HCV infected patients, thereby reducing ineffective treatments. The current study aimed to investigate the relation between miRNA-21 expression profiles, transforming growth factor β (TGF-β) serum levels and response to treatment with the new direct antiviral drugs (sofosbuvir + daclatasvir ± ribavirin), among HCV infected Egyptian patients. This prospective study was conducted on 50 HCV infected patients (before and after treatment) and 20 healthy volunteers. miRNA expression profiles were determined by real-time polymerase chain reaction and TGF-β1 serum levels were measured by using enzyme-linked immunosorbent assay. There was a significant increase in serum albumin, platelets count and a significant decrease in liver enzymes, serum bilirubin, and prothrombin time after treatment. Significant reduction of viral load among HCV patients after receiving the treatment was reported. Concomitantly, there was an increase in the relative quantity of miRNA-21 (P = .001*) and serum levels of TGF-β1 ( P = .337) among HCV patients after receiving treatment. Nearly all responders to direct antiviral drugs showed increased levels of both miRNA-21 and TGF-β1. This may indicate an interplay between TGF-β1 and miRNA-21 during remission or progression of viral infection. Thus miRNA-21 could be used as promising serum biomarker, for assessment of antiviral treatment efficacy and improvement of fibrosis among chronically infected HCV patients.

The Investigation of Drug Resistance Substitutions in NS3 Protease Sequence of Hepatitis C Virus from Non-Responder Patients.

Background:Even with the fantastic successes of direct-acting antivirals (DAA) in the treatment of Hepatitis C Virus (HCV) infection, natural drug resistance remains a challenging obstacle for their impacts. The data regarding protease inhibitors (PIs) resistance in Iran population are limited. The aim of this study was to investigate the variations in NS3 protease of HCV from non-responder patients.Methods:In this cross-sectional study, 14 HCV infected patients with genotype 1(N=5) and 3(N=9) who have not responded to Interferon-related regime were enrolled from Liver Clinic, Shiraz. The NS3 protease region was amplified by Nested-PCR followed by product gel extraction. Besides, some amplified protease regions were cloned into a cloning vector to improve the sensitivity of mutation detection. Both crude and cloned sequences were then introduced into sequencing. The obtained sequences were compared with the NS3 reference sequences and analyzed by Geno2pheno available software to find possible substitutions. In the end, the phylogenetic tree was constructed. Results:Among variations responsible for PIs resistance, only one out of 14 (7%) sample who was infected with genotype 1a, harbored R117C+N174S double mutation, which causes reduced susceptibility to Telaprevir. Any another resistance mutation was not found among the studied population. The most frequent substitutions were determined as I52M(N=9), S102A(N=9), S166A(8) and V170I(8) for genotype 3a, and F147S/A(4) for genotype 1. However, some uncharacterized substitutions on scored position, including I132L(N=1), I170V(N=3) and N174S(N=2) were also determined among sequences. Phylogenetic analysis demonstrated that the protease region has enough power to correctly classify enrolled samples into relevant clusters on the tree. There were 2, 3 and 9 cases of sub-genotypes 1a, 1b, and 3a, respectively.Conclusion:A low frequency of PIs resistance mutations in our HCV infected population is a hopeful point of starting these drugs in HCV infected patients.

Subcutaneous, Ganglion and Pulmonary Sarcoidosis in a Patient with Chronic Hepatitis C Virus Infection

Abstract Chronic hepatitis C and sarcoidosis are both well-known diseases. Some studies support the hypothesis that the hepatitis C virus (HCV) may trigger sarcoidosis(1). We present a case of chronic hepatitis C, developing a silent lung systemic disease with subcutaneous and ganglionar nodules, ultimately proving to be sarcoidosis. The clinical picture is complicated by a hepatic nodule, challenging the treatment course. The unveiling of a sarcoidosis in a previously HCV infected patient may not be accidental, the course of infection could be influenced by systemic disease. The therapy of chronic hepatitis C in the context of sarcoidosis is very challenging and demands a careful monitoring(2).

Viral dynamics among HCV infected patients with different genotypes treated with genotypic specific or pan-genotypic direct-acting antiviral agent combinations.

BackgroundNew hepatitis C virus (HCV) therapies have improved efficacy, allowed pangenotypic applications, increased barriers to drug resistance and shortened therapy duration.MethodsPatients infected with different HCV genotypes were divided into two groups: group 1 included 169 patients receiving genotypic specific regimens (GSR), while group 2 included 186 patients receiving pan-genotypic regimens (PGR). Patient’s HCV RNA was quantified and sequenced.ResultsComparable sustained viral response (SVR) rates were observed in both GSR and PGR treated patients. Nevertheless, even if not significant, a greater proportion of non-detectable levels (NDL) of HCV RNA was observed in patients treated with PGR as compared with GSR. Overall, among patients in the GSR and PGR groups with residual viremia, 124/169 (73.4%) and 125/186 (67.2%) at four weeks, and 66/169 (39.1%) and 58/186 (31.2%) at eight weeks, achieved SVR. No difference was observed in the clinical outcome comparing patients in the GSR and PGR groups according to genotype. While, comparing patients between the two groups, the proportion of patients with NDL HCV RNA at four and eight weeks was higher in patients infected with genotype 1b treated with PGR (p=0.0015). A significantly higher number of patients infected with 1b had RASs at baseline (p=0.0001). In addition, the proportion of patients with treatment failure was higher in patients with RASs at baseline compared with those without (p=0.012). Overall, 2.5% patients failed to achieve SVR after DAA treatment.ConclusionA sharp HCV RNA decrease was observed in patients treated with both GSR and PGR. However, even if comparable, a slightly greater number of patients treated with PGR achieved NDL HCV RNA as compared with GSR. A significant difference was observed in patients with baseline RASs, both in relation to treatment failure and genotype. In conclusion, the use of new DAA combinations helps patients achieve a more rapid virologic response.

HIV and HCV augments inflammatory responses through increased TREM-1 expression and signaling in Kupffer and Myeloid cells.

Chronic infection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) affects an estimated 35 million and 75 million individuals worldwide, respectively. These viruses induce persistent inflammation which often drives the development or progression of organ-specific diseases and even cancer including Hepatocellular Carcinoma (HCC). In this study, we sought to examine inflammatory responses following HIV or HCV stimulation of macrophages or Kupffer cells (KCs), that may contribute to virus mediated inflammation and subsequent liver disease. KCs are liver-resident macrophages and reports have provided evidence that HIV can stimulate and infect them. In order to characterize HIV-intrinsic innate immune responses that may occur in the liver, we performed microarray analyses on KCs following HIV stimulation. Our data demonstrate that KCs upregulate several innate immune signaling pathways involved in inflammation, myeloid cell maturation, stellate cell activation, and Triggering Receptor Expressed on Myeloid cells 1 (TREM1) signaling. TREM1 is a member of the immunoglobulin superfamily of receptors and it is reported to be involved in systemic inflammatory responses due to its ability to amplify activation of host defense signaling pathways. Our data demonstrate that stimulation of KCs with HIV or HCV induces the upregulation of TREM1. Additionally, HIV viral proteins can upregulate expression of TREM1 mRNA through NF-кB signaling. Furthermore, activation of the TREM1 signaling pathway, with a targeted agonist, increased HIV or HCV-mediated inflammatory responses in macrophages due to enhanced activation of the ERK1/2 signaling cascade. Silencing TREM1 dampened inflammatory immune responses elicited by HIV or HCV stimulation. Finally, HIV and HCV infected patients exhibit higher expression and frequency of TREM1 and CD68 positive cells. Taken together, TREM1 induction by HIV contributes to chronic inflammation in the liver and targeting TREM1 signaling may be a therapeutic option to minimize HIV induced chronic inflammation.

Characterization of The Type of Response to Different HCV Antigens and Quantification of Viral Load in Newly Diagnosed Hepatocellular Carcinoma Patients

Background: Hepatitis C virus (HCV) is a blood born virus that is considered a major cause of chronic liver disease and hepatocellular carcinoma (HCC) worldwide. HCV is thought to induce HCC either indirectly or directly by the effect of its viral proteins on different host cell proteins and signaling pathways. Objective: The aim of the study was to characterize the type of response to different HCV antigens, quantify HCV viral load, transforming growth factor- beta and miRNA 122 in patients with newly diagnosed Hepatocellular Carcinoma. Patients and methods: This study was done on three groups: the first group consisted of 40 newly discovered hepatocellular carcinoma patients with HCV infection. The second group consisted of twenty HCV infected patients with other types of cancer (other than HCC). The third group consisted of 20 healthy individuals served as a control group. Serum was separated for detection of the four parameters. Results: TGF-β showed a very weak negative correlation with the miRNA 122 serum levels that is statistically non-significant. Results also showed that miRNA 122 may not be useful in differentiating between liver cirrhosis from HCC patients and it is associated with the severity of the disease rather than the viremia count. Conclusion: Study showed no correlation between the four investigated parameters (HCV antigens, HCV viral load, TGFβ- serum levels of miRNA 122) in an attempt for early diagnosis of HCV induced HCC.

Autoimmune and non-autoimmune thyroid dysfunction in HCV infected and HCV–HIV co-infected patients before and after interferon alpha therapy: A prospective study

IntroductionAutoimmune thyroid diseases are reported in no treated hepatitis C virus (HCV) infection. The standard interferon alpha (IFNα) treatment is associated with an increase of thyroid damage and dysfunction. The present cohort prospective study compared thyroid function and autoimmunity in HCV patients’ monoinfected and coinfected HCV–HIV at baseline, during and after IFNα therapy. MethodsWe studied 790 HCV infected patients: G1 (monoinfected HCV: N=580) and G2 (HCV–HIV coinfected: N=210). They were evaluated for thyroid function and thyroid tiroperoxidase antibodies (TPOAb) at baseline and 235 patients (G1: 183; G2: 52) post IFNα therapy.If thyroid dysfunction (TD) was diagnosed, they were reevaluated at 12 month after discontinuation to determine whether the TD was transitory or definitive. ResultsNo difference was found in the prevalence of TD at baseline in G1 (7.6%) and G2 (9%). However, monoinfected patients showed a higher prevalence of TPOAb positivity with a women preponderance in this group. There was no difference in TD between both groups during IFNα therapy (G1 23.5% vs G2 19.2%). In G1 the autoimmune TD was higher than in G2 (67.4% vs 30%, p=0.02). Autoimmune TD during IFNα tended to evolve to definitive hypothyroidism and non-autoimmune TD recovered euthyroidism after IFNα discontinuation. The presence of positive TPOAb (RR 3.55) and female gender (RR 2.4) were associated with the development of TD with IFNα therapy. ConclusionOur hypothesis is the importance of HCV in G1 and G2, combined with IFNα in triggering TD and TPOAb positivity, not described in other diseases’ applications.

Implications of soluble E-cadherin level of antiviral treatment in patients with chronic hepatitis C virus infection

Background and aimsSoluble E-cadherin (sE-cadherin) has been observed elevated in patients with various diseases, and implicated in the occurrence and development of those diseases. The implications of sE-cadherin in chronic hepatitis C virus (HCV) infection are still unclear. The purpose of this study is to explore the significance of sE-cadherin in chronic hepatitis C infection and the correlation with treatment response. Methods87 chronic HCV infected patients and 60 healthy subjects were enrolled in this study. Blood samples from patients receiving the combined treatment of pegylated interferon-a (Peg-IFN-α) with ribavirin (RBV) were collected before treatment, during 4th, 12th therapy weeks, end of the treatment, and 24 weeks post-therapy. Plasma sE-cadherin level was detected by enzyme-linked immunosorbent assay (ELISA) and the relationship between sE-cadherin and antiviral treatment outcome was analyzed. ResultsPlasma sE-cadherin concentrations of Chronic HCV infected patients were significantly higher than that of healthy controls. A strong correlation between sE-cadherin level and the HCV viral load, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and also glutamyl transpeptidase (GGT) level was detected. Chronic HCV infected patients achieving rapid virological response (RVR) and sustained virological response (SVR) had lower baseline sE-cadherin concentrations compared with the non-RVR and non-SVR groups respectively. Univariate and multivariate regression analyses suggested that baseline plasma sE-cadherin level was predictive of therapeutic effect in patients with chronic HCV infection. ConclusionBaseline sE-cadherin level could be considered as an independent predictor of SVR with Peg-IFN-α plus ribavirin therapy in the Chinese Han population chronic HCV infection patients. Effective antiviral therapy might restore sE-cadherin at physiological levels.

Successful treatment of HBV, HCV, & HEV, with 12-week long use of tenofovir, sofosbuvir, daclatasvir, and ribavirin: A case report

Hepatitis C virus (HCV) is the leading cause of morbidity and mortality worldwide. It causes both chronic and acute infections and it has been estimated that about 80% of HCV infected patients develop chronic HCV infection of which 15–30% develop liver complications specifically liver cirrhosis and hepatocellualar carcinoma (HCC). Interferon therapy was previously used standard of care therapy associated with poor efficacy in major proportion of HCV infected population whereas, the recent development of interferon-free therapy or direct-acting antiviral (DAA) drugs are able to achieve sustained virological response (SVR) in 95% of patients. These new drugs are still not properly explored and currently there is minimal clinical experience regarding an efficacious treatment option suitable for triple infection i.e, Hepatitis B virus (HBV), HCV, and Hepatitis E virus (HEV). Here, we suggest well-tolerated sofsobuvir-based treatment regimen in patient infected with HBV, HCV, and HEV. Twelve weeks long treatment with sofsobuvir, daclatasvir, ribavirin, and tenofovir resulted in sustained virological response (SVR) and cleared HBV, HCV, and HEV in diabetic and asthmatic patient.

PB1832 MATRIX CHEMOTHERAPY FOR PRIMARY CNS LYMHPOMA COMPLICATED WITH HCV INFECTION AND SUCCESSFUL ERADICATION OF BOTH DISEASES

Background:There is a well‐known connection between Hepatitis C virus (HCV) infection and B‐cell lymphomas (BCL). HCV infected patients have an increased risk of developing BCL. Hypothetically, lymphomagenesis can be induced by chronic antigen stimulation (analogous to Helicobacter pylori associated gastric marginal zone lymphoma) and/or a direct pro‐oncogenic effect of intracellular HCV proteins. Several studies have demonstrated that antiviral therapy may induce remission and improve prognosis of HCV‐associated lymphomas. On the other hand, HCV infection can cause sever complication during the immunochemotherapy and stem cell transplantation. These patients are at risk for HCV reactivation, accelerated liver disease progression, drug‐induced liver toxicity. Thus, HCV‐infected patients often suffer treatment delays, reduced dose intensity, and many times are excluded from bone marrow transplantation. Accordingly, there is some evidence of negative prognostic impact of HCV infection on survival.Aims:To draw attention to the HCV caused complications during lymphoma treatment.Methods:Here we present the case of a HCV‐infected patient with primary central nervous system (CNS) lymphoma complicated with HCV infection and review the relevant literature.Results:A 56‐year old woman with CNS lymphoma was treated with MATRIX (methotrexate, cytarabine, thiotepa, and rituximab). Initial serum serology showed reactivity to HBcAg and HCV. Polymerase chain reaction (PCR) detected no hepatits B virus DNA, however the copy number for hepatitis C virus (HCV) RNA was 104 850 000 IU/ml. She received HBV prophylaxis with lamivudine and subsequently entecavir against reactivation of HBV. After the 2nd cycle of chemotherapy her liver function tests became severely abnormal (AST: 514 U/L ALT: 264 U/L, ALP: 145 U/L, GGT: 1328 U/L, total Bi: 74.6 umol/L, conjugated Bi: 63.5 umol/L). The patient was asymptomatic regarding the lymphoma and in complete remission according to MRI scans. Further systemic chemotherapy had to be halted. The HBV DNA was still undetectable by PCR. Drug induced or mechanical cholestasis and the role of ongoing HCV infection was contemplated. The biliary tracts were not dilated on ultrasound scans. She had an ERCP with sphincterotomy and sofosbuvir plus ledipasvir plus ribavirin treatment for HCV was started. Meanwhile, intrathecal methotrexate therapy was administered 3‐weekly to bridge till next chemotherapy. The antiviral therapy was completed without any side effects and at 3 months, her HCV RNA PCR was negative with entirely normal liver function. The patient achieved sustained virological response. Two more cycles of MATRIX was delivered and an autologous stem cell transplantation with BCNU and thiothepa conditioning. Liver function remained normal ever since.Summary/Conclusion:This is a rare case where the role of HCV infection in liver damage during systemic chemotherapy is highly possible. We would like to draw attention to the liver vulnerability caused by chronic HCV infection. Nowadays HCV eradication is feasible with novel direct acting antiviral therapies, HCV‐infection should not contraindicate the adequate chemotherapy.

Discovery of velpatasvir (GS-5816): A potent pan-genotypic HCV NS5A inhibitor in the single-tablet regimens Vosevi® and Epclusa®.

Direct-acting antiviral inhibitors have revolutionized the treatment of hepatitis C virus (HCV) infected patients. Herein is described the discovery of velpatasvir (VEL, GS-5816), a potent pan-genotypic HCV NS5A inhibitor that is a component of the only approved pan-genotypic single-tablet regimens (STRs) for the cure of HCV infection. VEL combined with sofosbuvir (SOF) is Epclusa®, an STR with 98% cure-rates for genotype 1-6 HCV infected patients. Addition of the pan-genotypic HCV NS3/4A protease inhibitor voxilaprevir to SOF/VEL is the STR Vosevi®, which affords 97% cure-rates for genotype 1-6 HCV patients who have previously failed another treatment regimen.

Restoration of HCV-Specific Immune Responses with Antiviral Therapy: A Case for DAA Treatment in Acute HCV Infection.

Worldwide, 71 million individuals are chronically infected with Hepatitis C Virus (HCV). Chronic HCV infection can lead to potentially fatal outcomes including liver cirrhosis and hepatocellular carcinoma. HCV-specific immune responses play a major role in viral control and may explain why approximately 20% of infections are spontaneously cleared before the establishment of chronicity. Chronic infection, associated with prolonged antigen exposure, leads to immune exhaustion of HCV-specific T cells. These exhausted T cells are unable to control the viral infection. Before the introduction of direct acting antivirals (DAAs), interferon (IFN)-based therapies demonstrated successful clearance of viral infection in approximately 50% of treated patients. New effective and well-tolerated DAAs lead to a sustained virological response (SVR) in more than 95% of patients regardless of viral genotype. Researchers have investigated whether treatment, and the subsequent elimination of HCV antigen, can reverse this HCV-induced exhausted phenotype. Here we review literature exploring the restoration of HCV-specific immune responses following antiviral therapy, both IFN and DAA-based regimens. IFN treatment during acute HCV infection results in greater immune restoration than IFN treatment of chronically infected patients. Immune restoration data following DAA treatment in chronically HCV infected patients shows varied results but suggests that DAA treatment may lead to partial restoration that could be improved with earlier administration. Future research should investigate immune restoration following DAA therapies administered during acute HCV infection.

Molecular Epidemiology of Hepatitis C Virus Genotypes Among Chronically Infected Patients in Pakistan

Background: A number of studies on the distribution of hepatitis C virus (HCV) genotypes among the chronically HCV-infected people have reported different patterns from various geographical regions of Pakistan. A relatively large scale epidemiological study was needed in order to figure out the distribution pattern of HCV genotypes. Objectives: This research study was carried out to investigate the distribution pattern of hepatitis C virus genotypes in different geographical regions of Pakistan. Methods: In the current study, 5259 randomly selected patients with different genders, ethnicity, age groups, belonging to 24 geographical locations of Pakistan were included. Blood samples from patients with a positive history of active HCV infection were collected from various healthcare units from February 2016 to September 2018. Hepatitis C virus RNA was detected in serum samples by qualitative PCR and confirmed by real-time PCR. Hepatitis C virus genotyping analysis was performed by type specific PCR. Results: Our study revealed that out of 5259 HCV infected patients, HCV genotype 3a was the most frequent one (n = 4203, 79.9%) in all of the 24 regions of Pakistan, especially in Rawalpindi and Islamabad (Twin cities). Untypeable genotype (n = 415, 7.9%) was the second most frequent one after 3a followed by 3a3b co-infection (n = 355, 6.7%), 3b (n = 182, 3.5%), 2a (n = 92, 1.7%), 2b (n = 10, 0.2%), and 1b (n = 2, 0.03%). Interestingly, rarely detectable genotype 4 (n = 1, 0.01%) was also reported. The overall distribution pattern of HCV genotypes was the same in both the genders. Comparatively higher HCV chronic infection was reported among patientwith age group (41 - 55). Conclusions: Currently the existing distribution pattern of HCV genotypes in Pakistan is similar to slight variations in some regions. Comparative analysis of the HCV genotype distribution indicated that the dynamics of HCV genotypes has changed in different areas with the emergence of a relatively uniform pattern across the country.

Sofosbuvir-based regimen is safe and effective for hepatitis C infected patients with stage 4\u20135 chronic kidney disease: a systematic review and meta-analysis

BackgroundWhether sofosbuvir is suitable for hepatitis C virus (HCV) infected patients with severe renal impairment is inconclusive. This systematic review aims to evaluate the safety and effectiveness of SOF-based regimen in the setting of stage 4 and 5 chronic kidney disease (CKD).MethodsWe conducted a systematic literature search in PubMed, Web of Science, EMBASE and Google Scholar with searching strategy: (sofosbuvir OR Sovaldi OR Harvoni OR Epclusa OR Vosevi) AND (severe kidney impairment OR severe renal impairment OR end-stage renal disease OR dialysis OR renal failure OR ESRD OR renal insufficiency OR hepatorenal syndrome OR HRS). Sustained virological response (SVR12/24) rate and serious adverse event (SAE) rate with 95% confidence intervals were aggregated. Subgroup analysis was implemented to evaluate the impact of treatment strategy and patient characteristics.ResultsTwenty-one studies met inclusion criteria, totaling 717 HCV infected patients with CKD stage 4 or 5 (58.4% on dialysis). Pooled SVR12/24 was 97.1% (95% CI 93.9–99.3%), and SAE rate was 4.8% (95% CI 2.1–10.3%). There was no significant difference at SVR12/24 (97.1% vs 96.2%, p = 0.72) or SAE rate (8.8% vs 2.9%, p = 0.13) between subgroups applying full or decreased dose of sofosbuvir. Cirrhotic and non-cirrhotic patients achieved comparable sustained virological response (RR 0.93, 95% CI 0.85–1.02). Four studies reported eGFR/serum creatinine pre- and post- treatment, with no significant modification.ConclusionsOur study suggests SOF-based regimen might be used safely and effectively in patients living with HCV infection/stage 4–5 CKD, with normal and reduced dose of sofosbuvir. Prospective and well-controlled trials are needed to confirm these findings.Trial registrationPROSPERO CRD42018107440.

Structural Modification in Hepatitis C Virus Envelope Protein; Potential Viral Strategy Against Interferon Therapy

Interferons (IFNs) are the main part of the immune system as a defensive response to viral infection. The phosphorylation domain of Hepatitis C virus (HCV) E2 envelope glycoprotein is homologous to the host key enzymes in IFN-mediated response. So, if host kinases show no preference on E2 protein phosphorylation over IFN triggering factors, the IFN pathway would be competently inhibited. The aim of this study was to see if the resistance of HCV infected patients to IFN-therapy has something to do with HCV E2 envelope glycoprotein. For this purpose, the partially sequenced HCV E2 proteins obtained from 15 patients that were confirmed to be sustainable, semi-resistant (patients with relapsing infection) and resistant to IFN-therapy. The peptide sequences from 15 patients were analysed as a matter of homology, physicochemical properties and predicted structures using MEGA4 software, ProtParam, PSIPRED and I-TASSER tools, respectively. Then, certain point mutations introduced to sequences that acquired from patients resistant to IFN-therapy. Replacement of Asp 653 with Asn 653 in R1 at C-terminal of the E2 protein changes secondary and tertiary structures of downstream regions of E2 protein. Although the sequence of PKR-eIF2alpha phosphorylation homology domain in E2 protein remains intact during IFN therapy, its structure modifies in patients resistant to IFN-therapy, which then puts its phosphorylation potential in jeopardy. Therefore, structural modification in HCV E2 proteins, acquired form patients resistant to IFN-therapy, suggests a mechanism that shows how HCV gets resistant toward IFN-therapy.

The potential regulatory role of miR16 to the interplay between interferon and transforming growth factor beta pathways through IRF3 and SMAD7 in hepatitis C virus infected patients.

The defensive strategy against hepatitis C virus (HCV) infection depends on two antiviral pathways; interferon (IFN) and transforming growth factor β (TGFβ). We aimed at verifying the relation between TGFβ and IFN antiviral pathways in HCV infection through SMAD7 and IRF3, and whether a possible regulatory role for microRNA-16 (miR16) on the interplay between IFN and TGFβ signaling pathways exists or not. We evaluated miR16, IRF3 and SMAD7 expression by real-time polymerase chain reaction in HCV infected patients and age and gender matched healthy controls. miR16 expression was significantly higher while IRF3 and SMAD7 expression was significantly lower in HCV patients compared with healthy controls. Meanwhile, miR16 was negatively correlated to SMAD7 in HCV patients while IRF3 and SMAD7 were positively correlated. The interplay between IFN and TGFβ pathways through IRF3 and SMAD7 in the context of immunity against HCV infection could be under the control of miR16.

Systematic review: epidemiology and response to direct-acting antiviral therapy in genotype 6 chronic hepatitis C virus infection.

Hepatitis C virus (HCV) genotype 6 (GT6) is predominantly encountered in Southeast Asia and data on GT6 response to direct-acting antiviral (DAA) therapy are relatively limited. To review the epidemiology and virologic outcome of DAA regimens in HCV GT6 patients. Electronic literature search of PubMed, EMBASE, and The Cochrane Library databases were conducted. Hepatitis C virus genotype 6 is the most genetically diverse, has a prevalence of 19.9%-95.6% in HCV infected patients in Southeast Asia and has been associated with a higher risk of HCC in those with cirrhosis. After an extensive literature review, a total of 20 studies were selected to assess study population and treatment outcomes (total of 938 GT6 patients were included); 12 were clinical trials and eight were observational studies. Sustained virologic response at week 12 (SVR 12) following glecaprevir/pibrentasvir (n=4; 108 patients), ledipasvir/sofosbuvir (n=8; 427 patients), sofosbuvir/velpatasvir with or without voxilaprevir (n=5; 171 patients), sofosbuvir/daclatasvir (n=3; 172 patients) and sofosbuvir with ribavirin (n=3; 60 patients) was 98%-100%, 64%-100%, 100%, 88%-94% and 100%, respectively. Failure was mostly in those with cirrhosis and prior treatment experience. DAA therapy was well tolerated and with a serious adverse event rate of <5%. Hepatitis C virus genotype 6 is genetically diverse and is highly prevalent in Asia. While SVR rates have been high, cirrhosis and prior treatment experience marginally compromise response to DAAs. Large scale and exclusive studies in HCV genotype 6 prevalent areas are needed, while the current evidence suggests that DAAs are highly effective and safe.