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Background: This study evaluated titers and amplitudes of anti-E2 antibodies (anti-E2-Abs) and neutralizing antibodies against hepatitis C virus (HCV; anti-HCV-nAbs) in HIV/HCV-coinfected individuals over five years after successful HCV treatment completion. Methods: We retrospectively analyzed 76 HIV/HCV-coinfected patients achieving sustained virologic response post-HCV treatment. Plasma levels of anti-E2-Abs and anti-HCV-nAbs against five HCV genotypes (Gt1a, Gt1b, Gt2a, Gt3a, and Gt4a) were determined using ELISA and microneutralization assays, respectively. Statistical analyses comparing the three follow-up time points (baseline, one year, and five years post-HCV treatment) were performed using generalized linear mixed models, adjusting p-values with the false discovery rate (q-value). Results: Compared to baseline, anti-E2-Abs titers decreased at one year (1.9- to 2.3-fold, q-value < 0.001) and five years (3.4- to 9.1-fold, q-value < 0.001) post-HCV treatment. Anti-HCV-nAbs decreased 2.9- to 8.4-fold (q-value < 0.002) at one year and 17.8- to 90.4-fold (q-value < 0.001) at five years post-HCV treatment. Anti-HCV-nAbs titers against Gt3a were consistently the lowest. Nonresponse rates for anti-E2-Abs remained low throughout the follow-up, while anti-HCV-nAbs nonresponse rates increased 1.8- to 13.5-fold (q-value < 0.05) at five years post-HCV treatment, with Gt3a showing the highest nonresponse rate. Conclusions: Humoral immune responses against HCV decreased consistently one and five years post-HCV treatment, regardless of HCV genotype and previous HCV therapy or type of treatment (IFN- or DAA-based therapy). This decline was more pronounced for anti-HCV-nAbs, particularly against Gt3. [ABSTRACT FROM AUTHOR]

Previously, we reported a neutralizing monoclonal antibody, A8A11, raised against a novel conserved epitope within the hepatitis C virus (HCV) E2 protein, that could significantly reduce HCV replication. Here, we report the nucleotide sequence of A8A11 and demonstrate the efficacy of a single-chain variable fragment (scFv) protein that mimics the antibody, inhibits the binding of an HCV virus-like particle to hepatocytes, and reduces viral RNA replication in a cell culture system. More importantly, scFv A8A11 was found to effectively restrict the increase of viral RNA levels in the serum of HCV-infected chimeric mice harbouring human hepatocytes. These results suggest a promising approach to neutralizing-antibody-based therapeutic interventions against HCV infection. [ABSTRACT FROM AUTHOR]

Jun Cheng,&ast; Jinjin Pan,&ast; Dongmei Zhao, Xuejiao Ma, Qiulin Sun, Jiabin Li Department of Infectious Disease, The First Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jiabin Li, Tel/Fax +86-551-62922281, Email lijiabin@163.comAbstract: The global prevalence of hepatitis C virus (HCV) infection is approximately 3%, with a post-infection chronicity rate of up to 50%– 85%. HCV reactivation can occur when anti-HCV positive individuals receive antineoplastic therapy. In this study, we report a case of an anti-HCV positive patient with negative HCV RNA after 12 weeks of direct antiviral therapy. Two months later, sorafenib was used to treat hepatocellular carcinoma, and HCV reactivation occurred after 8 months of the treatment. HCV RNA was negative after 12 weeks of antiviral treatment with Sofosbuvir-velpatasvir. We also discussed the mechanism of HCV reactivation caused by sorafenib and the antiviral treatment regimen after HCV reactivation with the relevant literature.Keywords: hepatocellular carcinoma, sorafenib, HCV-RNA, anti-HCV therapy, reactivation

Hepatitis C virus (HCV) infection is a potential risk factor for Sjögren's syndrome (SS). However, it is unclear whether anti-HCV intervention therapy could decrease SS risk. A retrospective cohort analysis from 1997–2012 comprising 17,166 eligible HCV-infected adults was conducted. By 1:2 propensity score matching, a total of 2123 treated patients and 4246 untreated patients were subjected to analysis. The incidence rates and risks of SS and death were evaluated through to the end of 2012. In a total follow-up of 36,906 person-years, 177 (2.8%) patients developed SS, and 522 (8.2%) died during the study period. The incidence rates of SS for the treated and untreated cohorts were 5.3 vs. 4.7/1000 person-years, and those of death for the treated and untreated cohorts were 10.0 vs. 14.8/1000 person-years. A lower risk of death (adjusted hazard ratio, 0.68; 95% CI, 0.53–0.87) was present in HCV-infected patients receiving anti-HCV therapy in multivariable Cox regression, and this remained consistent in multivariable stratified analysis. However, there were no relationships between anti-HCV therapy and its therapeutic duration, and SS risk in multivariable Cox regression. In conclusion, anti-HCV intervention therapy was not associated with lower SS risk in HCV-infected patients, but associated with lower death risk. [ABSTRACT FROM AUTHOR]

Chronic hepatitis C virus (HCV) infection is a significant public health problem, with a worldwide prevalence of approximately 170 million. Current therapy for HCV infection includes the prolonged administration of a combination of ribavirin and PEGylated interferon-α, for over a decade. This regimen is expensive and often associated with a poor antiviral response and unwanted side effects. A highly effective combination treatment is likely required for the future management of HCV infections and entry inhibitors could play an important role. Currently, no entry inhibitor has been licensed for the prophylactic treatment of hepatitis C. Therefore, additional agents that combat HCV infection are urgently needed and must be developed. Many phytochemical constituents have been identified that display considerable inhibition of HCV at some stage of the life cycle. This review will summarise the current state of knowledge on natural products and their possible activities in the context of HCV infection. [ABSTRACT FROM AUTHOR]

Purpose of Review: The US Food and Drug Administration recently issued a black box warning regarding the risk of hepatitis B virus (HBV) reactivation with direct-acting antiviral (DAA) treatment in hepatitis C virus (HCV)-coinfected individuals. The warning included all HBV infection, active and resolved, which, along with the lack of consensus among the gastroenterology and hepatology guidelines, have left clinicians unsure on how to proceed. Recent data have filled some knowledge gaps regarding the true risk of HBV reactivation in HCV treatment. The clinical data pertaining to the risk of reactivation in active and resolved HBV infection are reviewed, and potential prevention and management strategies are proposed, noting there are still some knowledge gaps remaining.Recent Findings: Recent large prospective studies of HBV/HCV-coinfected patients, along with the largest meta-analysis of such patients to date, provide additional insight into the risk of HBV reactivation with HCV antiviral treatment. Subclinical HBV reactivation is not uncommon, occurring in about 25% of patients, but the risk of clinically significant events such as hepatitis remains low in HBsAg-positive individuals, and even lower in isolated HBcAb-positive patients. However, recent case reports have brought to light particular situations, such as concomitant immunosuppression, as potential pitfalls to the previous low risk of reactivation attributed to resolved infection.Summary: Recent prospective data and a large meta-analysis confirm that clinically significant HBV reactivation remains an uncommon event with the use of DAAs in HBsAg-positive patients, and even rarer in isolated HBcAb-positive cases. [ABSTRACT FROM AUTHOR]

Background: There are contradictory data about the influence that hepatitis C virus (HCV) has on immune activation and inflammation in patients coinfected with human immunodeficiency virus (HIV) and HCV.Methods: HIV/HCV-coinfected patients receiving antiretroviral treatment who achieved a sustained virological response with interferon-free regimens were consecutively enrolled in a prospective study. The following factors were assessed before, immediately after the end of, and 1 month after the end of therapy: expression of HLA-DR/CD38, PD-1, and CD57 on CD4+ and CD8+ T-cells; measurement of the total HIV DNA load in peripheral blood mononuclear cells; and determination of plasma levels of soluble CD14 (sCD14), lipopolysaccharide (LPS), 16S ribosomal DNA (rDNA), interleukin 6 (IL-6), D-dimers, and high-sensitivity C-reactive protein (hsCRP).Results: Ninety-seven patients were consecutively included. At the end of therapy and 1 month later, there were significant reductions in the expression of HLA-DR and CD38 in CD4+ and CD8+ T cells, as well as levels of proviral HIV DNA, sCD14, LPS, 16S rDNA, and D-dimer (P < .001). By contrast, the expression of PD-1 and CD57 in CD4+ and CD8+ T cells and levels of IL-6 and hsCRP did not change. The improvement in levels of immune activation markers, proviral HIV DNA, and microbial translocation markers did not translate into an increased CD4+ T-cell count or increased ratio of the CD4+ T-cell count to the CD8+ T-cell count.Conclusions: HCV eradication in HIV/HCV-coinfected patients results in significant decreases in levels of immune activation markers, proviral HIV DNA load, microbial translocation markers, and D-dimers. These findings support the use of HCV treatment for all HIV/HCV-coinfected patients, even those with low-grade fibrosis. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) is both hepatotrophic and lymphotropic virus that causes liver as well extrahepatic manifestations including cryoglobulinemic vasculitis, the most frequent and studied condition, lymphoma, and neurologic, cardiovascular, endocrine-metabolic or renal diseases. HCV-extrahepatic manifestations (HCV-EHMs) may severely affect the overall prognosis, while viral eradication significantly reduces non-liver related deaths. Different clinical manifestations may coexist in the same patient. Due to the variety of HCV clinical manifestations, a multidisciplinary approach along with appropriate therapeutic strategies are required. In the era of interferon-free anti-HCV treatments, international recommendations for the therapeutic management of HCV-EHMs are needed. This implies the need to define the best criteria to use antivirals and/or other therapeutic approaches. The present recommendations, based on qualified expert experience and specific literature, will focus on etiological (antiviral) therapies and/or traditional pathogenetic treatments that still maintain their therapeutic utility. [ABSTRACT FROM AUTHOR]

Patients coinfected with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) are at high risk of liver disease progression. We report a favorable safety profile and SVR12 rates of 96.7% among HIV/HCV coinfected patients participating in an Italian compassionate-use program of ombitasvir/ paritaprevir/ritonavir + dasabuvir (OBV/PTV/r + DSV) ± ribavirin (RBV). [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) infects 200 million people worldwide, and 75% of HCV cases progress into chronic infections, which consequently cause cirrhosis and hepatocellular carcinoma. HCV infection is treated with currently considered standard drugs, including direct anti-viral agents (DAAs), alone or in combination with peginterferon- plus ribavirin. However, sustained viral responses vary in different cohorts, and high costs limit the broad use of DAAs. In this study, the ethanol and water extracts of 12 herbs from Lingnan in China were examined in terms of their inhibitory effect on HCV replication. Among the examined extracts, Spatholobus suberectus ethanol extracts suppressed HCV replication. By comparison, Extracts from Fructus lycii, Radix astragali (root), Rubus chingii Hu (fruit), Flos chrysanthemi Indici (flower), Cassia obtusifolia (seed), Lonicera japonica Thunb (flower), Forsythia suspense Thunb (fruit), Poria cocos (sclerotia), Carthamus tinctorius L. (flower), Crataegus pinnatifida Bge. (fruit), and Leonurus japonicas Houtt. (leaf) extracts failed to show a similar activity. Active S. suberectus fractions containing tannins as the major component also inhibited the in vitro translation of HCV RNA. The combination treatments of single compounds, such as epigallocatechin gallate and epicatechin gallate, were not as potent as crude S. suberectus fractions; therefore, crude S. suberectus extract may be a potential alternative treatment against HCV either alone or in combination with other agents. [ABSTRACT FROM AUTHOR]

Highlights: [•] A scFv from the anti-HCV E1E2 D32.10 mAb was successfully expressed. [•] This scFv consisted of functional monomers as shown by MALLS methodology. [•] The scFv D32.10 mimicked the antibody in binding to patient-derived HCV particles. [•] The scFv D32.10 competed with the parental IgG for binding to antigen. [•] This scFv is the basis of a drug discovery approach for tackling HCV reinfection. [ABSTRACT FROM AUTHOR]

Telaprevir is a direct acting antiviral agent, used with pegylated interferon and ribavirin for the management of chronic hepatitis C virus (HCV) genotype 1 infection, in patients not responding to therapy with pegylated interferon and ribavirin only. Although 75% of patients achieve a sustained virological response after treatment with telaprevir, adverse drug-drug interactions and undesirable events often occur. Therefore, telaprevir monitoring is pivotal to improve the management of HCV infection. Here, the first High-Performance Liquid Chromatography-Ultraviolet (HPLC-UV) method to quantify telaprevir in human plasma of HCV-genotype 1-infected patients is reported. The volume of the plasma sample was 700 μL. This method involved automated solid-phase extraction with Oasis HLB Cartridge 1 cc (divinylbenzene and N-vinylpyrrolidone). The extracted samples were reconstituted with 150 μL of 60/40 water/acetonitrile. Thirty microliters of these samples was injected into a HPLC-UV system, and the analytes were eluted on a X Terra® RP18 column (250 mm × 4.6 mm i.d.) with a particle size of 5 μm. The mobile phase (ammonium acetate buffer, 150 mM, pH 8.0, and methanol:acetonitrile 50:50) was delivered at 1.0 mL/min with linear gradient elution. The total run time for a single analysis was 16 min; telaprevir was detected by UV at 276 and 286 nm. The calibration curve was linear from 312.5 to 20,000 ng/mL ( r2 > 0.996). The absolute recovery of telaprevir ranged between 89 and 93% at concentrations of quality control samples of 800, 4,000, 8,000, and 16,000 ng/mL. Both precision and accuracy were always <15%. The HPLC-UV method reported here: (i) has been validated, (ii) is currently applied to monitor telaprevir in plasma of HCV-infected patients, and (iii) appears useful in a routine laboratory. © 2013 IUBMB Life, 65(9):800-805, 2013 [ABSTRACT FROM AUTHOR]

Hepatitis C virus ( HCV) is mainly hepatotropic; however, several reports document the presence of genomic viral RNA in extrahepatic sites including peripheral blood mononuclear cells ( PBMCs). In this study, the presence of HCV RNA was initially evaluated in the plasma and peripheral blood mononuclear cells ( PBMCs) of 53 HCV-infected patients who were treated per protocol. PBMC-associated HCV RNA was detectable in 79% of patients. Early virological response to combined pegylated interferon-α (Peg IFN) and ribavirin ( RBV) therapy in patients with undetectable levels of PBMCs-associated HCV RNA was 100%, while it was 60% ( P = 0.003) in those who had detectable levels of PBMC-associated HCV RNA. A sustained virological response was observed in 35% of patients with detectable PBMC-associated HCV RNA, but was 70% in patients with undetectable levels of PBMC-associated HCV RNA ( P = 0.07). In a multivariate analysis incorporating parameters such as HCV genotype, viral load, presence of cirrhosis and absence of PBMC-associated HCV RNA, a significant relationship was observed between the detection of PBMC-associated HCV RNA and the sustained virological response ( OR 19.4, 95% CI: 2.1-486.2, P = 0.0061). The association between single nucleotide polymorphism ( SNP) in IL28B, known predictor of antiviral therapy outcome, and the occurrence of HCV RNA in PBMC in 84 chronically infected patients was then evaluated. Results suggest that the presence of a G allele in rs8099917, known to associate to a poor response to Peg IFN/ RBV therapy, also predicts an increased association of HCV RNA with PBMC ( OR: 3.564; 95% CI: 1.114-11.40, P = 0.0437). [ABSTRACT FROM AUTHOR]

Objectives: Recent reports demonstrated in vitro the efficacy of fluvastatin in inhibiting hepatitis C virus (HCV) replication and a synergistic effect in association with interferon-α (IFN-α). In vivo the inhibition of HCV replication by statins has not been demonstrated. We evaluated in this open-label, randomized controlled study the efficacy of fluvastatin as adjuvant to pegylated-(PEG)-IFN and ribavirin in HIV/HCV genotype 1 co-infected patients. Patients and methods: Forty-four HIV/HCV co-infected patients were randomized to receive, in addition to PEGIFN- α 2b and ribavirin, 80 mg of fluvastatin once daily or no medication. Primary and secondary endpoints were the achievement of sustained virological response (SVR) and rapid virological response (RVR), respectively. Results: By intent-to-treat analysis, 25% of the patients achieved an SVR. An SVR was observed in 8/21 patients in the fluvastatin arm and in 3/23 patients in the standard therapy arm (P=0.08). A significantly higher RVR rate was obtained in the fluvastatin arm compared with the standard therapy [7/21 (33%) and 1/23 (4%), respectively; P=0.02]. Baseline alanine aminotransferase (ALT) values and fluvastatin treatment arm were the only predictors of RVR at the univariate analysis; however, no predictors were independently associated with RVR or SVR at the multivariate analysis. Conclusions: Fluvastatin addition to standard therapy did not significantly increase the SVR rate in HIV/HCV genotype 1 co-infected patients; however, it did significantly improve the RVR. Further studies are needed to confirm these promising results and to investigate the mechanisms of action of statins in HCV infection. [ABSTRACT FROM AUTHOR]

Background/Aims: Liver transplantation (LT) in immune-suppressed human immunodeficiency virus (HIV) and hepatitis C virus (HCV) coinfected patients is feasible but raises questions regarding the severity of HCV recurrence on the liver graft and preservation of immune function. We investigated whether LT is deleterious to the immune system. Methods: Fourteen HIV–HCV coinfected patients (HIV viral load [VL] <50copies/ml; median CD4 count of 276/mm3 pretransplantation) were grafted for HCV–cirrhosis and followed over 2years. Nine patients received anti-HCV therapy post-transplantation. HCV and HIV VLs and degree of acute and chronic hepatitis were monitored. Peripheral blood T-cell phenotypes and interferon-γ (IFN-γ) immune responses against opportunistic pathogens, HCV, and HIV-1 p24 were evaluated. Results: Median HCV VLs, CD4 counts, T-cell subsets, and IFN-γ–producing T-cell frequencies against opportunistic pathogens and HIV-1 p24 did not change over time. HCV-specific T cells were observed ex vivo in two patients pretransplantation and in two others post-transplantation. HCV-specific in vitro amplification enabled the detection of HCV-specific IFN-γ-producing responses in three further patients post-transplantation. Anti-HCV responses were observed independently of anti-HCV therapy and were undetectable in patients with severe hepatitis or liver fibrosis. Conclusions: These results demonstrate that LT in HIV–HCV coinfected patients is not deleterious to the immune system and does not alter immune responses directed against HCV, HIV, or opportunistic pathogens. [Copyright &y& Elsevier]

In this pilot study, we evaluated the efficacy of interferon- α (IFN) plus Thymosin- α 1 (TA1) to that of IFN alone in naive patients with chronic hepatitis C. Twenty-two patients were randomized to receive interferon- α2b (3 million units three times a week) plus thymosin- α l (900 μg/m2 body surface area) and 19 received interferon- α2b alone at the same dose. Patients were treated for 6 months and followed up for another 6 months. Biochemical (alanine aminotransferase values) and virological (hepatitis C virus-RNA) responses to treatment were determined. Combination treatment showed significantly higher efficacy than monotherapy in achieving virological end-of-treatment response ( P = 0.03). At 6-month follow up, the sustained biochemical and virological response was not different between the two groups. Our results indicate that the immune modulator TA1 may enhance the end-of-treatment response in naive patients with chronic hepatitis C. Higher doses and/ore more prolonged courses as well as the association with new interferon formulation such as pegylated interferons could improve the sustained response rates to this treatment. [ABSTRACT FROM AUTHOR]

Summary. In this randomized controlled study, we evaluated the efficacy and safety of interferon-α combined with ketoprofen to that of interferon-α alone in naïve patients with chronic hepatitis C. Forty patients were randomized to receive Interferon-α 2a (3 million units three times a week) and ketoprofen (150 mg twice a day) and 40 to receive only interferon-α 2a at the same dose. Patients were treated for 6 months and followed up for 6 months. Response was defined by undetectable HCV-RNA in serum at the end-of-treatment and after 6 months from the completion of therapy (long term response). At the end of treatment the response was similar in the two group. However, combination treatment showed significantly higher efficacy than monotherapy in achieving long term response (10%vs 32.5%; P = 0.014). Overall adverse events were similar in the two groups. ‘Flu-like syndrome was significantly less common in the ketoprofen plus interferon group which experienced a significantly higher incidence of epigastric pain'. Our results indicate that the combination of ketoprofen plus interferon is significantly more effective than interferon alone in the tratment of naïve patients with chronic hepatitis C and is well tolerated. However this combined treatment appears to be less effective than the association of pegylated IFN and ribavirin which represent the current standard treatment. Thus, the role of ketoprofen in the treatment of chronic hepatitis C needs to be further evaluated against such a treatment. [ABSTRACT FROM AUTHOR]

Interactions between human immunodeficiency virus (HIV) and hepatitis C virus (HCV) have been widely studied before the introduction of highly active antiretroviral therapies (HAART). We reviewed the potential impact of HAART on hepatitis C as well as the interactions between HIV and HCV therapies. Physicians should be aware of the potential risk of: (i) symptomatic liver disease in HCV-HIV-coinfected patients at the era of triple antiretroviral therapy; (ii) potential liver deterioration paralleling immune restoration; (iii) lack of impact of triple antiretroviral therapy on HCV load; and (iv) potential drug-related hepatitis which may modify the natural history of HCV-related liver disease. Liver biopsies should be performed regularly in these patients in order to identify patients with severe liver disease who require early initiation of anti-HCV therapy under close monitoring of their immune status. Treatment is, to date, based on the combination of ribavirin and interferon with an expected sustained response rate around 25%. An important unresolved issue is to better delineate the temporal place of anti-HCV and anti-HIV antiviral therapies. At least in coinfected patients with significant liver disease, namely necro-inflammatory activity and/or fibrosis ≥ 2, we believe that anti-HCV therapy is the priority since it lessens the risk of drug-induced hepatitis and of hepatitis due to immune restoration. [ABSTRACT FROM AUTHOR]

Background & Aims: Individuals with chronic hepatitis C virus (HCV) infection and pretreatment anemia are less likely to begin and complete a full course of treatment for HCV. However, among those who are treated for HCV infection, the effect of treatment on mortality is not clear. Methods: We performed a retrospective analysis of 200,139 HCV-infected veterans using data from the Electronically Retrieved Cohort of Hepatitis C–Infected veterans (2001–2008). The effects of treatment and treatment duration on survival were compared based on data from 1820 treated and 27,690 untreated anemic HCV-infected veterans. The association between HCV treatment and mortality was estimated using the Cox proportional hazard models, with adjustments for potential confounders. The main outcome was all-cause mortality. Results: In multivariable analysis, pretreatment anemia was associated significantly with African American race (odds ratio [OR], 2.03; 95% confidence interval [CI], 1.95–2.11), chronic kidney disease (OR, 3.36; 95% CI, 3.23–3.51), and decompensated liver disease (OR, 3.69; 95% CI, 3.53–3.86). All-cause mortality for treated, anemic, HCV-infected veterans was lower (54.2 per 1000 person-years; 95% CI, 49.2–59.7 per 1000 person years) than for untreated, anemic HCV-infected veterans (146.8 per 1000 person-years; 95% CI, 144.2–149.4 per 1000 person-years). The adjusted hazard ratio for treatment of HCV in anemic veterans was 0.45 (95% CI, 0.39–0.51), which was reduced after exclusion of comorbidities (hazard ratio, 0.28; 95% CI, 0.22–0.37). Conclusions: Based on a retrospective analysis of a veterans database, HCV therapy increases survival rates of individuals with pretreatment anemia. Additional studies are needed to determine strategies to increase rates of HCV therapy for this group. [ABSTRACT FROM AUTHOR]